Cathepsin-cysteine protease inhibitors

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

 

PREREQUISITES TO the CREATION of INVENTIONS

A number of disorders in humans and other mammals is abnormal bone resorption or associated with it. Such violations include, but not limited to, osteoporosis, osteoporosis, inductively glucocorticoids, Paget's disease (deforming fibrosa), abnormally increased bone metabolism, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthrit, oculoplasty of survivorship, defect osteogenesis, metastatic bone disease, hypercalcemia malignant tumors and multiple myeloma. One of the most common violations is osteoporosis, the highest frequency of appearance which occurs in women after menopause. Osteoporosis is a systemic skeletal disease characterized by low bone mass and destruction of microarchitectural bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality of the elderly population. At least 50% of women and one third men often osteoporotic fracture. The large proportion of the older population already have low bone density and higher risk of fractures. There is a high demand both in prevention and in the treatment of osteo is orosa and other conditions, associated with bone resorption. Since osteoporosis, and other disorders associated with bone destruction, are mostly chronic conditions, it is believed that proper treatment would require a permanent treatment.

Osteoporosis is characterized by progressive destruction of the bone architecture and mineralization, which leads to loss of bone strength and increase the percentage of fractures. The skeleton is constantly reconstructed by establishing a balance between osteoblasts, which lay down new bone, and osteoclasts, which destroy, or resorbent, bone. Certain medical conditions and in old age the balance between bone formation and resorption violated; bone liquidated with greater speed. This long-term imbalance of the prevalence of resorption over formation leads to weaker bone structure and increased risk of fractures.

Bone resorption is originally performed by osteoclasts, which are multinuclear giant cells. Osteoclasts resorbent bone, forming the initial cell attachment to bone tissue, followed by the formation of extracellular compartment or gaps. These gaps are kept at low pH using proton ATP pump. The acidic environment in the gap initiates the demineralization to the STI with the subsequent degradation of bone proteins or collagen under the action of proteases, such as cysteinate. Cm. Delaisse, J. M. et al., 1980, Biochem J192:365-368; Delaisse, J. et al., 1984, Biochem Biophys Res Commun:441-447; Delaisse, J. M. et al.,1987, Bone 8:305-313, which is incorporated herein by reference in its full. Collagen makes up 95% of the organic matrix of bone. Therefore, the protease involved in the degradation of collagen, are essential components of bone metabolism and, as a consequence, the development and progression of osteoporosis.

Cathepsins belong to papaikonomou the superfamily of cysteinate. These proteases function in normal physiological and pathological degradation of connective tissue. Cathepsins play an important role in the destruction of intracellular proteins and their updating and remodeling. At the present time has been identified and sequenced a number of cathepsins from various sources. These cathepsins are usually found in various tissues. For example, was cloned cathepsin B, F, H, L, K, S, W and z Cathepsin K (which is also known under the abbreviation cat) also known as cathepsin About and cathepsin O2. Cm. The PCT application WO 96/13523, Khepri Pharmaceuticals, Inc., published may 9, 1996, which is incorporated herein by reference in its full. Cathepsin L involved in normal lysosomal proteolysis, and also in some painful conditions, including, but not limited to, metastasis chalk is rated Cathepsin S implicated in Alzheimer's disease and certain autoimmune disorders, including, but not limited to, juvenile diabetes, diffuse sclerosis, a common disease, disease Gravis, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto Hashimoto; allergic disorders, including, but not limited to, asthma, and allogeneic immune responses, including, but not only, to the exclusion of organtransplantation or tissue transplants. In tumors detected elevated levels of Cathepsin b and redistribution of this enzyme, which confirms role in tumor invasion and metastasis. In addition, aberrant activity of Cathepsin involved In such painful conditions like rheumatoid arthritis, osteoarthritis, pneumocystiis carinii, acute pancreatitis, inflammatory airway disease and bone and joint disorders.

It is known that inhibitors cysteinate, such as E-64 (TRANS-epoxyamine-L-leucinamide-(4-guanidino)butane) is effective in the inhibition of researcii bones. Cm. Delaisse, J. M. et al., 1987, Bone8:305-313, incorporated herein by reference in its full. Was recently cloned catepsin To, and found specific expression in osteoclasts. Cm. Tezuka, K. et al., 1994, J Biol Chem269:1106-1109; Shi, G. P. et al., 1995, FEBS Lett357:129-134; Bromme, D., and Okamoto, K., 1995, Biol Chem Hoppe Seyler376:379-384; Bromme, D. et al., 1996. J Biol Chem271:2126-2132; Drake, F. H. et al., 1996, J Biol Chem271:12511-12516, incorporated herein as references in full. Simultaneously with the cloning of an autosomal recessive violation, pycnogenols characterized by the phenotype of congenital systemic osteoporosis low bone resorption, was mapped on the mutation present in the gene for cathepsin K. In the present time, it became known that all mutations identified in the gene for cathepsin K, result in inactivation of the protein. Cm. Gelb, B. D. et al., 1996, Science273:1236-1238; Johnson, M. R. et al, 1996, Genome Res6:1050-1055, included here as a reference in their entirety. Thus, we can assume that cathepsin involved in mediated osteoclastic bone resorption.

Catepsin To synthesize in the form of a 37 KDa precursor proferment localized in lysosomal Department, where he presumably someactivity in the Mature enzyme 27 kDa at low pH. Cm. McQueney, M. S. et al., 1997, J Biol Chem272:13955-13960; Littlewood-Evans, A. et al., 1997, Bone20:81-86, included here as a reference in their entirety. Catepsin To the closest cathepsin S with 56% sequence identical to the amino acid levels. S2P2the substrate specificity of cathepsin K is similar to that of cathepsin S with a preference in positions P1 and P2 of positively charged residues, such as arginine, and GI is rotovnik residues, such as phenylalanine or leucine, respectively. See, Bromme, D. et al., 1996, J Biol Chem271:2126-2132; Bossard, M. J. et al., 1996, J Biol Chem271:12517-12524 included here as a reference in their entirety. Cathepsin active in a wide pH range and substantially active at pH 4-8, which, therefore, enables you to appear a good catalytic activity in the resorption lacunae of osteoclasts, where pH is about 4-5.

Collagen is human type I, the main collagen in bones, is a good substrate for cathepsin K. Cm. Kafienah, W., et al., 1998, Biochem J331:727-732, incorporated herein by reference in its entirety. In vitro experiments using antisense oligonucleotides for cathepsin K showed reduced bone resorption in vitro, possibly due to the decrease of the mRNA cathepsin K. Cm. Inui, T. et al., 1997, J Biol Chem272:8109-8112, incorporated herein by reference in its entirety. Was established crystal structure of cathepsin K. Cm. McGrath, M. E. et al., 1997, Nat Struct Biol4:105-109; Zhao, B. et al., 1997, Nat Struct Biol4: 109-11, which are included here as a reference in their entirety. Were also developed selective inhibitors of cathepsin K, based on the peptides. Cm. Bromme, D. et al., 1996, Biochem J315:85-89; Thompson, S. K. et al., 1997, Proc Natl Acad Sci USA94:14249-14254, which are included here as a reference in their entirety. Thus, inhibitors of cathepsin K m is able to reduce bone resorption.

Such inhibitors would be useful in the treatment of disorders involving bone resorption, such as osteoporosis.

SUMMARY of the INVENTION

The present invention relates to compounds that can be used for the treatment and/or prevention of cathepsin-dependent conditions or diseases of mammals, in need. One variant of implementation of the present invention is illustrated by a compound of Formula I and its pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives

DETAILED description of the INVENTION

The present invention relates to compounds of the following chemical formula:

where R1is a hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and alkeneamine groups optionally substituted from one to six halogen atoms, With3-6cycloalkyl, -SR9, -SR12-SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -OR9, -N(R12)2, aryl, heteroaryl or heterocyclyl where these aryl, heteroaryl and heterocyclic group is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydrox is, alkoxy or keto;

R2is a hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and alkeneamine groups optionally substituted from one to six halogen atoms, With3-6cycloalkyl, -SR9, -SR12-SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -OR9, -N(R12)2, aryl, heteroaryl or heterocyclyl where these aryl, heteroaryl and heterocyclic group is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto

or R1and R2can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl or heterocyclic ring, where this ring system is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, hydroxyalkyl, halogenoalkane or halogen;

R3represents hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and Alchemilla group optionally substituted C3-6cycloalkyl or from one to six halogen atoms;

R4represents hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and alkenyl the Aya group optionally substituted C 3-6cycloalkyl or from one to six halogen atoms

or R3and R4can be taken together with the carbon atom to which they are attached with the formation of C3-8cycloalkyl ring, With5-8cycloalkenyl ring, or five to seven membered heterocyclic radical, where these cycloalkyl, cycloalkenyl and heterocyclic group optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R5selected from hydrogen or C1-6of alkyl, substituted by 1-6 halogen atoms;

R6represents aryl, heteroaryl, C1-6halogenated, arylalkyl or heteroaromatic where these aryl, heteroaryl, arylalkyl and heteroallyl group optionally substituted by one, two or three substituents, independently selected from halogen, C1-6of alkyl, C1-6halogenoalkane,3-6cycloalkyl, halogenoalkane, -SR9, -SR12-SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -N(R10)(R11), cyano, or aryl, optionally substituted-SO2R12;

each D independently represents a C1-3alkyl, C2-3alkenyl; C2-3quinil, aryl, heteroaryl,3-8 cycloalkyl or heterocyclyl, where each specified aryl, heteroaryl, cycloalkyl and heterocyclyl group which can be monocyclic or bicyclic, optionally substituted or carbon atom or heteroatom with one to five substituents, independently selected from C1-6of alkyl, halogenoalkane, halogen, keto, alkoxy, -SR9, -SR12, -OR9, -OR12N(R12)2, -SO2R9or-SO2R10;

R7represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil, C1-6alkyloxy, halogen, nitro, cyano, aryl, heteroaryl, C3-8cycloalkyl, heterocyclyl, -C(O)OR10, -C(O)OSi[CH(CH3)2]3, -OR9, -OR10, -C(O)R10, -R10C(O)R9, -C(O)R9, -C(O)N(Ra)(Rb), -C(O)N(R12)(R12), -C(O)N(R10)(R11), -C(R10)(R11)OH, -SR12, -SR9, -R10SR9, -R9, -C(R9)3, -C(R10)(R11)N(R9)2, -NR10C(O)NR10S(O)2R9, -SO2R12, -SO(R12), -SO2R9, -SOmN(Rc)(Rd), -SOmCH(R10)(R11), -SO2N(R10)C(O)(R12), -SO2(R10)C(O)N(R12)2, -OSO2R10, -N(R10)(R11), -N(R10)C(O)N(R10)(R9), -N(R10)C(O)R9, -N(R10)C(O)R10,-N(R 10)C(O)OR10, -N(R10)SO2(R10), -C(R10)(R11)NR10C(R10)(R11R9, -C(R10)(R11)N(R10R9, -C(R10)(R11)N(R10)(R11), -C(R10)(R11)SC(R10)(R11)(R9), R10S-, -C(Ra)(Rb)NRaC(Ra)(Rb)(R9), -C(Ra)(Rb)N(Ra)(Rb), -C(Ra)(Rb)C(Ra)(Rb)N(Ra)(Rb), -C(O)C(Ra)(Rb)N(Ra)(Rb), -C(Ra)(Rb)N(Ra)C(O)R9, -C(O)C(Ra)(Rb)S(Ra), C(Ra)(Rb)C(O)N(Ra)(Rb), -B(OH)2, -OCH2O - or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, where the aforementioned groups are optionally substituted or carbon atom or heteroatom with one to five substituents, independently selected from C1-6of alkyl, halogen, keto, cyano, halogenoalkane, hydroxyalkyl, -OR9, -NO2, -NH2, -NHS(O)2R8, -R9SO2R12, -SO2R12, -SO(R12), -SR12, -SR9, -SOmN(Rwith)(Rd), -SOmN(R10)C(O)(R12), -C(R10)(R11)N(R10)(R11), -C(R10)(R11)OH, -COOH, -C(Ra)(Rb)C(O)N(Ra)(Rb), -C(O)(Ra)(Rb), -N(R10)C(R10)(R11)(R9), -N(R10)CO(R9), -NH(CH2)2OH, -NHC(O)OR10, -Si(CH3)3heterocy is Lila, aryl or heteroaryl;

R8represents hydrogen or C1-6alkyl

or R4and R8or can be taken together with any of the atoms to which they can be attached or are between them, with the formation of 4-10-membered heterocyclic ring system, where this ring system, which may be monocyclic or bicyclic, optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR10, -SR10or-N(R10)2;

R9selected from the group consisting of hydrogen, aryl, aryl(C1-4)alkyl, heteroaryl, heteroaryl(C1-4)alkyl, C3-8cycloalkyl, C3-8cycloalkyl(C1-4)alkyl and heterocyclyl(C1-4)alkyl, where these groups may be optionally substituted by one, two or three substituents, independently selected from halogen, alkoxy or-SO2R12;

R10represents hydrogen or C1-6alkyl;

R11represents hydrogen or C1-6alkyl;

R12represents hydrogen, C1-6alkyl, which is optionally substituted one, two or three substituents, independently selected from halogen, alkoxy, cyano, -NR10or-SR10;

Rarepresents hydrogen, C16 alkyl, (C1-6alkyl)aryl, (C1-6alkyl)hydroxyl, -O(C1-6alkyl), hydroxyl, halogen, aryl, heteroaryl,3-8cycloalkyl, heterocyclyl, where specified, the alkyl, aryl, heteroaryl,3-8cycloalkyl and heterocyclyl may be optionally substituted or carbon atom or heteroatom with one, two or three substituents, independently selected from C1-6the alkyl or halogen;

Rbrepresents hydrogen, C1-6alkyl, (C1-6alkyl)aryl, (C1-6alkyl)hydroxyl, alkoxyl, hydroxyl, halogen, aryl, heteroaryl,3-8cycloalkyl, heterocyclyl, where specified, the alkyl, aryl, heteroaryl,3-8cycloalkyl and heterocyclyl may be optionally substituted or carbon atom or heteroatom with one, two or three substituents, independently selected from C1-6the alkyl or halogen

or Raand Rbcan be taken together with the atom ugleroda to which they are attached or are between them to form with3-8cycloalkene rings or3-8heterocyclic ring, where the specified 3-8-membered ring system may be optionally substituted by one or two substituents, independently selected from C1-6of alkyl and halogen;

Rcrepresents hydrogen or C1-6alkyl, which is not necessarily Sames the n one, two or three substituents, which option is selected from halogen or-OR9;

Rdrepresents hydrogen or C1-6alkyl, which is optionally substituted one, two or three substituents, which option is selected from halogen or-OR9

or Rcand Rdcan be taken together with the nitrogen atom to which they are attached or are between them with the formation of C3-8heterocyclic ring, which is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogennitroalkane, hydroxy, alkoxy or keto;

n is independently selected from an integer from zero to three;

each m is independently selected from an integer from zero to two;

and their pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives.

Preferably the present invention relates to compounds of the following chemical formula:

where R1is a hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and Alchemilla groups optionally substituted from one to six halogen atoms, With3-6cycloalkyl, -SR9, -SR12-SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -OR9, -N(R12)2, aryl, heteroaryl lieterally, where these aryl, heteroaryl and heterocyclyl group optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R2is a hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and Alchemilla groups optionally substituted from one to six halogen atoms, With3-6cycloalkyl, -SR9, -SR12, -SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -OR9, -N(R12)2, aryl, heteroaryl or heterocyclyl where these aryl, heteroaryl and heterocyclyl group optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto

or R1and R2can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl or heterocyclic ring, where this ring system is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, hydroxyalkyl, halogenoalkane or halogen;

R3represents hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and Alchemilla group neo is Astelin substituted C 3-6cycloalkyl or from one to six halogen atoms;

R4represents hydrogen, C1-6alkyl or C2-6alkenyl, where these alkyl and Alchemilla group optionally substituted C3-6cycloalkyl or from one to six halogen atoms

or R3and R4can be taken together with the carbon atom to which they are attached, with the formation of C3-8cycloalkyl ring, With5-8cycloalkenyl ring or five-semichasnoho heterocyclic radical, where these cycloalkyl, cycloalkenyl and heterocyclyl group optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto;

R5selected from hydrogen or C1-6of alkyl, substituted by 1-6 halogen atoms;

R6represents aryl, heteroaryl, C1-6halogenated, arylalkyl or heteroaromatic where these aryl, heteroaryl, arylalkyl and heteroallyl group optionally substituted by one, two or three substituents, independently selected from halogen, C1-6of alkyl, C1-6halogenoalkane,3-6cycloalkyl, halogenoalkane, -SR9, -SR12-SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR 12, -N(R10)(R11), cyano or aryl, optionally substituted-SO2R12;

each D independently represents a C1-3alkyl, C2-3alkenyl, C2-3quinil, aryl, heteroaryl,3-8cycloalkyl or heterocyclyl, where each specified aryl, heteroaryl, cycloalkyl and heterocyclyl group which can be monocyclic or bicyclic, optionally substituted or carbon atom or heteroatom with one to five substituents, independently selected from C1-6of alkyl, halogenoalkane, halogen, keto, alkoxy, -SR9, -SR12, -OR9, -OR12N(R12)2, -SO2R9or-SO2R10;

R7represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6quinil, C1-6alkyloxy, halogen, nitro, cyano, aryl, heteroaryl, C3-8cycloalkyl, heterocyclyl, -C(O)OR10, -C(O)OSi[CH(CH3)2]3, -OR9, -OR10, -C(O)R10, -R10C(O)R9, -C(O)R9, -C(O)N(Ra)(Rb), -C(O)N(R12)(R12), -C(O)N(R10)(R11), -C(R10)(R11)OH, -SR12, -SR9, -R10SR9, -R9, -C(R9)3, -C(R10)(R11)N(R9)2, -NR10C(O)NR10S(O)2R9, -SO2R12, -SO(R12), -SO2R9, -SOmN(Rc)(Rd), -SOm CH(R10)(R11), -SO2N(R10)C(O)(R12), -SO2(R10)C(O)N(R12)2, -OSO2R10, -N(R10)(R11), -N(R10)C(O)N(R10)(R9), -N(R10)C(O)R9, -N(R10)C(O)R10, -N(R10)C(O)OR10, -N(R10)SO2(R10), -C(R10)(R11)NR10C(R10)(R11R9, -C(R10)(R11)N(R10R9, -C(R10)(R11)N(R10)(R11), -C(R10)(R11)SC(R10)(R11)(R9), R10S-, -C(Ra)(Rb)NRaC(Ra)(Rb)(R9), -C(Ra)(Rb)N(Ra)(Rb), -C(Ra)(Rb)C(Ra)(Rb)N(Ra)(Rb), -C(O)C(Ra)(Rb)N(Ra)(Rb), -C(Ra)(Rb)N(Ra)C(O)R9, -C(O)C(Ra)(Rb)S(Ra), C(Ra)(Rb)C(O)N(Ra)(Rb), -B(OH)2, -OCH2O - or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, where the aforementioned groups are optionally substituted or carbon atom or heteroatom with one to five substituents, independently selected from C1-6of alkyl, halogen, keto, cyano, halogenoalkane, hydroxyalkyl, -OR9, -NO2, -NH2, -NHS(O)2R8, -R9SO2R12, -SO2R12, -SO(R12), -SR12, -SR9, -SOmN(Rwith)(Rd), -SOmN(R10)C(O)(R12), -C(R10)(R11)N(R10)(R11), -C(R1 )(R11)OH, -COOH, -C(Ra)(Rb)C(O)N(Ra)(Rb), -C(O)(Ra)(Rb), -N(R10)C(R10)(R11)(R9), -N(R10)CO(R9), -NH(CH2)2OH, -NHC(O)OR10, -Si(CH3)3, heterocyclyl, aryl or heteroaryl;

R8represents hydrogen or C1-6alkyl;

or R4and R8or can be taken together with any of the atoms to which they can be attached or are between them with education, 4-10-membered heterocyclic ring system, where this ring system, which may be monocyclic or bicyclic, optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, keto, -OR10, -SR10or-N(R10)2;

R9selected from the group consisting of hydrogen, aryl, aryl(C1-4) alkyl, heteroaryl, heteroaryl(C1-4)alkyl, C3-8cycloalkyl, C3-8cycloalkyl(C1-4)alkyl and heterocyclyl(C1-4)alkyl, where these groups may be optionally substituted by one, two or three substituents, independently selected from halogen, alkoxy or-SO2R12;

R10represents hydrogen or C1-6alkyl;

R11represents hydrogen or C1-6alkyl;

R12is own the th hydrogen or C 1-6alkyl, which is optionally substituted one, two or three substituents, independently selected from halogen, alkoxy, cyano, -NR10or-SR10;

Rarepresents hydrogen, C1-6alkyl, (C1-6alkyl)aryl, (C1-6alkyl)hydroxyl, -O(C1-6alkyl), hydroxyl, halogen, aryl, heteroaryl,3-8cycloalkyl, heterocyclyl, where specified, the alkyl, aryl, heteroaryl,3-8cycloalkyl and heterocyclyl may be substituted or carbon atom or heteroatom with one, two or three substituents, independently selected from C1-6the alkyl or halogen;

Rbrepresents hydrogen, C1-6alkyl, (C1-6alkyl)aryl, (C1-6alkyl)hydroxyl, alkoxyl, hydroxyl, halogen, aryl, heteroaryl,3-8cycloalkyl, heterocyclyl, where specified, the alkyl, aryl, heteroaryl,3-8cycloalkyl and heterocyclyl may be optionally substituted or carbon atom or heteroatom with one, two or three substituents, independently selected from C1-6the alkyl or halogen;

or Raand Rbcan be taken together with the carbon atom to which they are attached or are between them to form with3-8cycloalkene rings or3-8heterocyclic ring, where the specified 3-8-membered ring system may be neoba is consequently substituted by one or two substituents, independently selected from C1-6of alkyl and halogen;

Rcrepresents hydrogen or C1-6alkyl, which is optionally substituted one, two or three substituents, which option is selected from halogen or-OR9;

Rdrepresents hydrogen or C1-6alkyl, which is optionally substituted one, two or three substituents, which option is selected from halogen or-OR9;

or Rcand Rdcan be taken together with the nitrogen atom to which they are attached or are between them with the formation of C3-8heterocyclic ring, which is optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen of hydroxyalkyl, hydroxy, alkoxy or keto;

n is independently selected from an integer from zero to three;

each m is independently selected from an integer from zero to two,

and their pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives.

In one embodiment of this invention R1and R2each represent hydrogen. In another embodiment of this invention R1and R2in case of finding the same carbon atom can be taken together with the carbon atom to which they are attached, with the formation of a 3-8-membered cycloalkyl ring system is neither, where this ring system optionally substituted C1-6the alkyl, hydroxyalkyl and halogen. Examples of ring systems, which can be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In the preferred embodiment, is formed cyclopropyl.

In another embodiment of this invention R1and R2taken together with the carbon atom to which they are attached, with the formation of a 3-8-membered heterocyclic ring system, where specified ring system optionally substituted C1-6the alkyl, hydroxyalkyl or halogenation. Examples of such ring systems, which can be formed include piperidinyl, pyrrolidinyl or tetrahydropyranyl.

In one embodiment of this invention R3and R4each, independently, represent a C1-4alkyl or H. In the following embodiment of this invention R3represents isobutyl or n-propyl and R4represents H, more preferably R3represents n-propyl.

In the following embodiment of this invention R3represents a C1-6alkyl, where the specified alkyl substituted With3-6cycloalkyl or halogen. Preferably R3is a 2-f the PR-2-methylpropyl, 2-cryptomaterial, 3-fluoro-2-(2-permitil)propyl, 2,2-dottorati, 2,2-direcror, 3,3,3-cryptochromes or 2,2-dichloroethyl and R4represents hydrogen. More preferably R3represents 2-fluoro-2-methylpropyl.

In another embodiment of this invention R3and R4taken together with the carbon atom to which they are attached, form a C3-8cycloalkyl ring, C5-8cycloalkenyl ring or five - semicolony heterocyclic radical, where the specified cycloalkyl, cycloalkenyl and heterocyclic group optionally substituted C1-6by alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, but not limited to, the following, given that the heterocycle optionally substituted by one or more substituents as described above: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In one category of carrying out the invention is formed cyclohexyl.

In one embodiment of this invention R5represents a C1-6alkyl, substituted by 1-6 halogen atoms, and R6represents a C1-6alkyl, substituted by 1-6 halogen atoms. In another embodiment of the invention R5represents hydrogen and R6not only is em a C 1-5alkyl, substituted by 1-6 halogen atoms. In the following embodiment, R5represents hydrogen and R6represents a C1-6alkyl, substituted by 1-6 fluorine atoms. In the following embodiment, R5represents hydrogen and R6represents a C1-3alkyl, substituted 3 fluorine atoms. In another embodiment, R5represents hydrogen and R6represents trifluoromethyl or 3,3,3,2,2-pentaverate, more preferably R6represents trifluoromethyl.

In another embodiment of this invention R5represents hydrogen and R6represents aryl or heteroaryl where these aryl and heteroaryl optionally substituted with halogen or-SO2R12.

In another embodiment of this invention R1and R2taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl; R3represents n-propyl, isobutyl, 2-fluoro-2-methylpropyl, 2-cryptomaterial, 3-fluoro-2-(2-permitil)propyl, 2,2-dottorati, 2,2-direcror, 3,3,3-cryptochromes or 2,2-dichloroethyl; R4and R5represent hydrogen and R6represents a C1-6alkyl, substituted the first 1-6 halogen atoms; preferably R6represents a C1-3alkyl, substituted 3 fluorine atoms, more preferably R6represents trifluoromethyl or 3,3,3,2,2-pentaverate, most preferably trifluoromethyl. Within this option, the implementation of the particularly preferred embodiment is the case where n is 1. Another particularly preferred embodiment is the case where n is 2. Another particularly preferred embodiment is the case where n is 3. Preferably n is 1 when D is heteroaryl, which is optionally substituted with halogen or phenyl, substituted by hydroxyalkyl, -COR10(where R10represents a C1-6alkyl), or-SO2R12or D represents phenyl, which is optionally substituted with halogen, -CONRandRb(where Randrepresents hydrogen or C1-6alkyl, and Rbrepresents hydrogen, C1-6alkyl, cycloalkyl or C1-6alkoxy, or Raand Rbtogether with the nitrogen atom to which they are attached, form heterocyclyl where specified heterocyclyl optionally substituted by alkyl, hydroxyalkyl, or halogenation), -SO2R12(where R12represents a C1-6alkyl), -COOR10, quinil, long is Ino substituted hydroxy or cycloalkyl, alkenyl, substituted hydroxy, alkyl, optionally substituted hydroxy, -OR9(where R9represents aryl), -OR10, -CR10R11SC10R11R9(where R9represents aryl), -CH2S(aryl), cyano, -COR9or heteroaryl.

Preferably n is 2 and each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring (phenyl attached to the carbon atom bearing the group R5and R6and additionally each phenyl optionally substituted by one or two substituents independently selected from C1-6of alkyl, halogen, hydroxy, alkoxy, halogenoalkane, halogenoalkane or-SO2R12(where R12represents a C1-6alkyl), and the second phenyl optionally substituted by the radical R7. More preferably, each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring and the second phenyl optionally substituted by the radical R7, which is located in position 4 of the phenyl ring and represents-SO2R12(where R12represents a C1-6alkyl, optionally substituted hydroxyl group or halogen), -SO2NRcRd(where Rwithand Rdindependently represent hydrogen or C1-6alkyl, or Rcand Rd together with the nitrogen atom to which they are attached, form a heterocyclic ring), -SR12(where R12represents a C1-6alkyl), -SOR12(where R12represents a C1-6alkyl), -NHCOR10(where R10represents a C1-6alkyl), -NR10R11(where R10and R11represents a C1-6alkyl), -SO2NHCOR10heteroaryl, halogen, -COOR10(where R10represents hydrogen or C1-6alkyl), -OR9(where R9represents hydrogen or aryl), -OR10(where R10represents a C1-6alkyl), aryl, substituted-SO2R12(where R12represents a C1-6alkyl), cyano, halogenated, -C(R10)(R11)OH, C1-6alkyl, optionally substituted-OR10and halogen, COR9(where R9represents aryl), -COR10or-NHSO2R10(where R10represents a C1-6alkyl), and optionally the second phenyl ring optionally substituted by another Deputy, selected from C1-6of alkyl, -CHO, -COOR10, -COR10, -NHCOR10, halogen, halogenoalkane, -OR10(where R10represents hydrogen or C1-6alkyl, where the specified alkyl optionally substituted with halogen), -SO2NH2, -NHCOR10(where R10represents a C1-6alkyl), or-SO R12(where R12represents a C1-6alkyl). More preferably the second phenyl substituted by a radical R7in position 4, where R7represents-SOR12, -SO2R12where R12represents a C1-6alkyl (preferably methyl) or-SOmNRwithRdwhere Rwithand Rdindependently represent hydrogen or alkyl or Rwithand Rdtogether form heterocyclyl, and m is an integer from zero to two. Preferably R7represents methylsulphonyl, N-methylaminomethyl, aminosulfonyl or morpholine-4-ylsulphonyl.

Preferably n is 2, in the case where the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is heterocyclyl (preferably morpholine-4-yl, piperazine-1-yl or piperidine-4-yl), optionally substituted by cycloalkyl, heteroaryl, C1-6the alkyl or hydroxyalkyl, more preferably by cyclopropyl, stands, ethyl or hydroxyethyl, and this heterocyclic ring is attached in position 4 of the phenyl ring.

Preferably n is 2, in the case where the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is heteroaryl, replaced by the ne or two substituents, independently selected from hydroxyalkyl, -SO2R12(where R12represents a C1-6alkyl), C1-6of alkyl, halogen, halogenoalkane, amino or10.

Preferably n is 3, where the first and second D are phenyl, and the third D is heterocyclyl and optionally substituted as defined above. More preferably the first and second D represents phenyl, where the second phenyl attached in position 4 of the first phenyl, and heterocyclyl represents morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl or piperazine-1-yl, substituted by the radical R7. Preferably R7represents hydrogen, alkyl, hydroxyalkyl, halogenated, cycloalkyl, COOR10or-SO2R12(where R12represents a C1-6alkyl).

In another embodiment of this invention R1and R2taken together with the carbon atom to which they are attached, to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably of cyclopropyl; R3and R4taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl ring, C5-8cycloalkenyl ring or five - semichasnoho heterocyclic radical, where these cycloalkyl, cyclo is canilla and heterocyclyl group optionally substituted C 1-6by alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or keto. Examples of ring systems that may be formed include, but not limited to, the following, given that the heterocycle optionally substituted by one or more substituents as described above: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-4-yl, piperidine-4-yl. Preferably R3and R4taken together with the carbon atom to which they are attached, form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The preferred embodiment of the invention is, when R3and R4taken together with the carbon atom to which they are attached, form a cyclohexyl. In this embodiment, particularly preferred is a variant, where the radicals R5represent hydrogen, and R6represents a C1-6alkyl, substituted by 1-6 halogen atoms, preferably R6represents a C1-3alkyl, substituted 3 fluorine atoms, more preferably R6represents trifluoromethyl or 3,3,3,2,2-pentaverate, most preferably trifluoromethyl. In this embodiment, particularly preferred is the case where n is 1. Another particularly preferred variant of the two is the n option, where n is 2. Another particularly preferred embodiment is the case where n is 3. Preferably n is 1 in the case when D is heteroaryl, optionally substituted with halogen or phenyl, substituted by hydroxyalkyl, -COR10(where R10represents a C1-6alkyl), or-SO2R12or D represents a phenyl, optionally substituted with halogen, -CONRandRb(where Rarepresents hydrogen or C1-6alkyl, and R5represents hydrogen, C1-6alkyl, cycloalkyl or C1-6alkoxy, or Randand Rbtogether with the nitrogen atom to which they are attached, form a heterocyclic radical, where the specified heterocyclyl optionally substituted by alkyl or halogenation), -SO2R12(where R12represents a C1-6alkyl), -COOR10, quinil, substituted hydroxy, alkenyl, substituted hydroxy, alkyl, optionally substituted hydroxy, -OR10, -CR10R11SC10R11R9(where R9represents aryl), -CH2S(aryl)-COR9or heteroaryl.

Preferably n is 2 and each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring (phenyl attached to the carbon atom bearing the group R5and R6and, more is positive, where each phenyl optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxy, alkoxy, halogenoalkane, halogenoalkane, and the second phenyl optionally substituted by the radical R7. More preferably, each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring, the second phenyl optionally substituted by the radical R7, which is located in position 4 of the phenyl ring and represents-SO2R12(where R12represents a C1-6alkyl, optionally substituted with halogen), -SO2NRwithRd(where Rwithand Rdindependently represent hydrogen or C1-6alkyl, or Rwithand Rdtogether with the nitrogen atom to which they are attached, form a heterocyclic ring), -SR12(where R12represents a C1-6alkyl), -NHCOR9(where R9represents a C1-6alkyl), -NR10R11(where R10and R11represent1-6alkyl), heteroaryl, halogen, -COOR10(where R10represents hydrogen or C1-6alkyl), -OR9(where R9represents hydrogen or aryl), aryl, substituted-SO2R12(where R12represents a C1-6alkyl), cyano, halogenated, -CHO, -C(R10)(R11)OH, C1-6/sub> alkyl, optionally substituted by a radical OR10and halogen, -COR10or-NHSO2R10(where R10represents a C1-6alkyl), and optionally, the second phenyl ring optionally substituted by another Deputy, selected from halogen, halogenoalkane, -OR10(where R10represents hydrogen or C1-6alkyl, where the specified alkyl optionally substituted with halogen or-SO2R12(where R12represents a C1-6alkyl). More preferably the second phenyl substituted by a radical R7in position 4, where R7represents-SO2R12where R12represents a C1-6alkyl (preferably methyl) or-SOmNRwithRdwhere Rwithand Rdindependently represent hydrogen or alkyl or Rwithand Rdtogether form heterocyclyl, and m is an integer from zero to two. Preferably R7represents methylsulphonyl, N-methylaminomethyl, aminosulfonyl, or morpholine-4-ylsulphonyl.

Preferably n is 2 in the case when the first D (D, attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is a heterocyclic radical (preferably piperazine-1-yl or piperidine-4-yl), substituted by cycloalkyl, C1-6what Kilom or hydroxyalkyl, more preferably cyclopropyl, stands, ethyl or hydroxyethyl, and this heterocyclic ring is attached in position 4 of the phenyl ring.

Preferably n is 2 in cases where the first D (D, attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is heteroaryl substituted by one or two substituents, independently selected from hydroxyalkyl, -SO2R12(where R12represents a C1-6alkyl), C1-6alkyl, halogen, or-OR10.

Preferably n is 3, where the first and second D are phenyl, and the third D is a heterocyclic radical and optionally substituted as defined above. More preferably the first and second D represents phenyl, where the second phenyl attached in position 4 of the first phenyl and heterocyclic radical is a morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl or piperazine-1-yl, substituted by the radical R7. Preferably R7represents hydrogen, alkyl, hydroxyalkyl, halogenated or cycloalkyl.

In another embodiment of this invention R5represents hydrogen and R6represents aryl, optionally substituted one, two or three substituents, n is dependent selected from halogen, C1-6of alkyl, C1-6halogenoalkane, C3-6cycloalkyl, halogenoalkane, -SR9, -SR12, -SOR9, -SOR12, -SO2R9, -SO2R12, -SO2CH(R12)(R11), -OR12, -N(R10)(R11), cyano, or aryl, which is optionally substituted-SO2R12. More preferably phenyl substituted C1-6by alkyl, halogen, halogenation or halogenoalkane. In this embodiment, another preferred is when R1and R2each represents hydrogen. In this embodiment, another preferred is when R1and R2taken together with the carbon atom to which they are attached to form a 3-8-membered cycloalkyl or heterocyclic ring system, where this ring system optionally substituted C1-6the alkyl, hydroxyalkyl and halogen. Preferred ring systems, which can be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl. In these preferred and more preferred embodiments, the implementation of an even more preferred embodiment is the case where R3represents a C1-4alkyl, and R4represents H. Predpochtitel is but R 3represents n-propyl or isobutyl and R4represents H. In these preferred and more preferred embodiments, the implementation of other, even more preferred embodiment, it is the option where R3represents 2-fluoro-2-methylpropyl, 2-cryptomaterial, 3-fluoro-2-(2-permitil)propyl, 2,2-dottorati, 2,2-direcror, 3,3,3-cryptochromes or 2,2-dichloroethyl and R4represents hydrogen. In these preferred and more preferred embodiments, the implementation of other, even more preferred embodiment, it is the option where R3and R4can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl ring, With5-8cycloalkenyl ring or five - semichasnoho heterocyclic radical, where these cycloalkyl, cycloalkenyl and heterocyclyl group optionally substituted C1-6by alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or ketone. Examples of ring systems that may be formed include, but not limited to, the following, given that this heterocycle optionally substituted by one or more substituents as described above: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The preferred implementation,when there is cyclohexyl.

In this embodiment of the invention particularly preferred variant, where n is 1. Another preferred variant, when n is 2. Another preferred variant, when n equals 3. Preferably n is 1 in the case when D is heteroaryl, which is optionally substituted by halogen, or phenyl, substituted by hydroxyalkyl, -COR10(where R10represents a C1-6alkyl), or SO2R12or D represents a phenyl, optionally substituted with halogen, -CONRandRb(where Rarepresents hydrogen or C1-6alkyl, and Rbrepresents hydrogen, C1-6alkyl, cycloalkyl or C1-6alkoxy, or Raand Rbtogether with the nitrogen atom to which they are attached, form a heterocyclic radical, where the specified heterocyclyl optionally substituted by alkyl or halogenation), -SO2R12(where R12represents a C1-6alkyl), -COOR10, quinil, substituted hydroxy, alkenyl, substituted hydroxy, alkyl, optionally substituted hydroxy, -OR10, -CR10R11SC10R11R9(where R9represents aryl), -CH2S(aryl) -COR9or heteroaryl.

Preferably n is 2 and each D represents phenyl, where the second phenyl attached in position 4 of the phenyl first to LCA (phenyl attached to the carbon atom, carrying the group R5and R6and, optionally, where each phenyl optionally substituted by one or two substituents, independently selected from C1-6of alkyl, halogen, hydroxy, alkoxy, halogenoalkane, halogenoalkane, and the second phenyl optionally substituted by the radical R7. More preferably, each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring, and the second phenyl optionally substituted by the radical R7, which is located in position 4 of the phenyl ring and represents-SO2R12(where R12represents a C1-6alkyl, optionally substituted with halogen), SO2NRcRd(where Rcand Rdindependently represent hydrogen or C1-6alkyl, or Rcand Rdtogether with the nitrogen atom to which they are attached, form a heterocyclic ring), -SR12(where R12represents a C1-6alkyl), -NHCOR9(where R9represents a C1-6alkyl), -NR10R11(where R10and R11represents a C1-6alkyl), heteroaryl, halogen, -COOR10(where R10represents hydrogen or C1-6alkyl), -OR9(where R9represents hydrogen or aryl), aryl, substituted radical-SO2R12(where R12represents a C 1-6alkyl), cyano, halogenated, -CHO, -C(R10)(R11)OH, C1-6alkyl, optionally substituted by a group-OR10and halogen, -COR10or-NHSO2R10(where R10represents a C1-6alkyl), and optionally the second phenyl ring optionally substituted by another Deputy, selected from halogen, halogenoalkane, -OR10(where R10represents hydrogen or C1-6alkyl, where the specified alkyl optionally substituted with halogen or-SO2R12(where R12represents a C1-6alkyl). More preferably the second phenyl substituted by a radical R7in position 4, where R7represents-SO2R12where R12represents a C1-6alkyl (preferably methyl) or-SOmNRcRdwhere Rwithand Rdindependently represent hydrogen or alkyl or Rwithand Rdtogether form heterocyclyl and m is an integer from zero to two. Preferably R7represents methylsulphonyl, N-methylaminomethyl, aminosulfonyl or morpholine-4-ylsulphonyl.

Preferably n is 2, in the case where the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is a heterocyclic radical (preferably piperaz the n-1-yl or piperidine-4-yl), replaced by cycloalkyl, C1-6the alkyl or hydroxyalkyl, more preferably by cyclopropyl, stands, ethyl or hydroxyethyl, and this heterocyclic ring is attached in position 4 of the phenyl ring.

Preferably n is 2, in the case where the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is heteroaryl substituted by one or two substituents, independently selected from hydroxyalkyl, -SO2R12(where R12represents a C1-6alkyl), C1-6of alkyl, halogen or-OR10.

Preferably n is 3, when the first and second D represents a phenyl, and a third D represent a heterocyclic radical and optionally substituted as defined above. More preferably the first and second D represents phenyl, where the second phenyl attached in position 4 of the first phenyl, and heterocyclic radical is a morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl or piperazine-1-yl, optionally substituted by a group R7. Preferably R7represents hydrogen, alkyl, hydroxyalkyl, halogenated or cycloalkyl.

In one embodiment of this invention R5represents hydrogen, and R6isone heteroaryl, optionally substituted C1-6by alkyl, halogen, halogenation or halogenoalkane. Preferably R6represents thiazolyl, pyridinyl, tetrazolyl, thienyl or furanyl, optionally substituted C1-4by alkyl or halogen. In this embodiment, the preferred embodiment is a variant, where R1and R2each represents hydrogen. In this embodiment, another preferred option is the option where R1and R2taken together with the carbon atom to which they are attached, form a 3-8-membered cycloalkyl or heterocyclic ring system, where this ring system optionally substituted C1-6the alkyl, hydroxyalkyl and halogen. Preferred ring systems, which can be formed include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, more preferably cyclopropyl. In these preferred and more preferred embodiments, the implementation of even more preferable is the case where R3represents a C1-4alkyl, and R4are H. Preferably, R3represents n-propyl or isobutyl and R4represents H. In these preferred and more preferred embodiments, Khujand the exercise of another, more preferred option is option where R3represents 2-fluoro-2-methylpropyl, 2-cryptomaterial, 3-fluoro-2-(2-permitil)propyl, 2,2-dottorati, 2,2-direcror, 3,3,3-cryptochromes or 2,2-dichloroethyl and R4represents hydrogen. In these preferred and more preferred embodiments, the implementation of other more preferred option is the option where R3and R4can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl ring, With5-8cycloalkenyl ring or five - semichasnoho heterocyclic radical, where these cycloalkyl, cycloalkenyl and heterocyclic group optionally substituted C1-6by alkyl, halogen, hydroxyalkyl, hydroxy, alkoxy or ketone. Examples of ring systems that may be formed include, but not limited to, the following, given that the heterocycle optionally substituted by one or more substituents as described above: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The preferred option when there is cyclohexyl.

In this embodiment, particularly preferred is the case where n is 1. Another, particularly preferred embodiment, it is an option, where n is equal to 2. Another particularly preferred variants of the MD implementation is an option where n is 3. Preferably n is 1 in the case when D is heteroaryl, optionally substituted with halogen or phenyl, substituted by hydroxyalkyl, -COR10(where R10represents a C1-6alkyl), or-SO2R12or D represents a phenyl, optionally substituted with halogen, -CONRandRb(where Randrepresents hydrogen or C1-6alkyl, and Rbrepresents hydrogen, C1-6alkyl, cycloalkyl or C1-6alkoxy, or Randand Rbtogether with the nitrogen atom to which they are attached, form a heterocyclic radical, where the specified heterocyclyl optionally substituted by alkyl or halogenation), -SO2R12(where R12represents a C1-6alkyl), -COOR10, quinil, substituted hydroxy, alkenyl, substituted hydroxy, alkyl, optionally substituted hydroxy, -OR10, -CR10R11SC10R11R9(where R9represents aryl), -CH2S(aryl)-COR9or heteroaryl.

Preferably n is 2 and each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring (phenyl attached to the carbon atom bearing the group R5and R6and, optionally, where each phenyl optionally substituted by one or two substituents, together with the IMO selected from C 1-6of alkyl, halogen, hydroxy, alkoxy, halogenoalkane, halogenoalkane, and the second phenyl optionally substituted by a group R7. More preferably, each D represents phenyl, where the second phenyl attached in position 4 of the first phenyl ring and the second phenyl optionally substituted by a group R7, which is located in position 4 of the phenyl ring and represents-SO2R12(where R12represents a C1-6alkyl, optionally substituted with halogen), -SO2NRwithRd(where Rcand Rdindependently represent hydrogen or C1-6alkyl, or Rcand Rdtogether with the nitrogen atom to which they are attached, form a heterocyclic ring), -SR12(where R12represents a C1-6alkyl), -NHCOR9(where R9represents a C1-6alkyl), -NR10R11(where R10and R11represents a C1-6alkyl), heteroaryl, halogen, -COOR10(where R10represents hydrogen or C1-6alkyl), -OR9(where R9represents hydrogen or aryl), aryl, substituted by a group-SO2R12(where R12represents a C1-6alkyl), cyano, halogenated, -CHO, -C(R10)(R11)OH, C1-6alkyl, optionally substituted by a group-OR10and halogen, -COR10or-NHSO2R (where R10represents a C1-6alkyl), and optionally, the second phenyl ring optionally substituted by another Deputy, selected from halogen, halogenoalkane, -OR10(where R10represents hydrogen or C1-6alkyl, where the specified alkyl optionally substituted with halogen or-SO2R12(where R12represents a C1-6alkyl). More preferably, the second phenyl substituted by a group R7in position 4, where R7represents-SO2R12where R12represents a C1-6alkyl (preferably methyl) or-SOmNRwithRdwhere Rwithand Rdindependently represent hydrogen or alkyl, or Rcand Rdtogether form a heterocyclic radical, and m is an integer from zero to two. Preferably R7represents methylsulphonyl, N-methylaminomethyl, aminosulfonyl or morpholine-4-ylsulphonyl.

Preferably n is 2 in the case when the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is a heterocyclic radical (preferably piperazine-1-yl or piperidine-4-yl), substituted by cycloalkyl, C1-6the alkyl or hydroxyalkyl, more preferably by cyclopropyl, stands, ethyl or HYDR what czitrom, and this heterocyclic ring is attached in position 4 of the phenyl ring.

Preferably n is 2 in the case when the first D (D is attached to the carbon atom bearing the group R5and R6represents phenyl, and the second D is heteroaryl, optionally substituted by one or two substituents, independently selected from hydroxyalkyl, -SO2R12(where R12represents a C1-6alkyl), C1-6of alkyl, halogen or-OR10.

Preferably n is 3, where the first and second D are phenyl, and the third D is a heterocyclic radical, optionally substituted as described above. More preferably the first and second D represents phenyl, where the second phenyl attached in position 4 of the first phenyl, and heterocyclic radical is a morpholine-4-yl, pyrrolidin-1-yl, piperidine-1-yl, piperidine-4-yl or piperazine-1-yl, substituted by a group R7. Preferably R7represents hydrogen, alkyl, hydroxyalkyl, halogenated or cycloalkyl.

In one embodiment of this invention R4and R8or can be taken together with any of the atoms to which they can be attached or are between them with education, 4-10-membered heterocyclic ring system, where is the th ring system, which may be monocyclic or bicyclic, optionally substituted C1-6by alkyl, halogen, hydroxyalkyl, hydroxy, geography, -OR10, -SR10or-N(R10)2. In the following embodiment of this invention R4and R8defined in such a way that they can be taken together with the nitrogen atom to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen atom, 1 or 2 additional heteroatoms selected from N, O and S, said heterocycle optionally substituted by one or more substituents selected from C1-6of alkyl, halogen, hydroxyalkyl, hydroxy, geograpy, -OR10, -SR10or-N(R10)2. In the following example, R4and R8defined in such a way that they can be taken together with the nitrogen atom to which they are attached to form a 5 - or 6-membered heterocyclic ring system. Examples of such heterocycles that can thus be formed include, but not limited to, five - or six-membered ring containing at least one nitrogen atom, optionally substituted by one or more substituents as described above. The preferred implementation, when formed of neobythites is but substituted pyrrolidinyl.

In one embodiment of this invention Raand Rbdefined in such a way that they can be taken with the carbon atom or the nitrogen to which they are attached to form a monocyclic or bicyclic carbocycle or heterocycle with 5-7 members in each ring. This heterocycle may optionally contain, in addition to the nitrogen atom, 1 or 2 additional heteroatoms selected from N, O and S. the Specified carbocycle and heterocycle may be optionally substituted by one or more substituents selected from C1-6of alkyl and halogen.

Reference to the foregoing preferred embodiments of means to include all combinations of particular and preferred groups are, unless otherwise stated.

Another variant of implementation of the present invention covers a method of producing compounds of the present invention, including:

(i) the interaction of the compounds of formula (a):

(a)

where R1-R6and D defined above, n1is an integer from 1-3, and X is a halogen,

with the compound of the formula (b):

R7(D)n2-Y

(b)

where R7defined above, n2is an integer from 0 to 2, provided that n1and n2together is an integer from to 3, and Y represents Bronevoy acid or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl; or

(ii) vzaimodeistvie the compounds of formula (c):

where R3-R7n and D are defined above, and Z represents hydroxy, halogen or ester of succinimide,

with the compound of the formula (d):

(d)

or its salt, where R1and R2defined above;

(iii) optionally, modifying any of the groups R1-R7and D;

(iv) optionally, processing the compounds of formula (I)obtained in the above stage (i)-(iii), acid to obtain the corresponding acid salt additive;

(v) optionally, processing the compounds of formula (I)obtained in the above stage (i)-(iii), a base to obtain the corresponding free base and

(vi) optionally separating a mixture of stereoisomers of the compounds of formula (I)obtained above in stage (i), (ii), (iii), (iv) or (v)obtaining the individual stereoisomer.

The present invention relates to methods for treating disorders associated with abnormal bone resorption. Such violations include, but not limited to, osteoporosis, osteoporosis induced by glucocorticoids, Paget's disease (deforming fibrosa), abnormally increased bone metabolism, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoart is it allopatry osteolysis, failure of osteogenesis, bone disease associated with metastasis, hypercalcemia malignant tumors and multiple myeloma. The preferred implementation includes methods of treatment of osteoporosis and bone diseases associated with metastasis. More preferred implementation includes the treatment of osteoporosis.

Typical compounds of the present invention are presented in Tables I-IV below.

The compound of formula I, where R1R2, R4, R5and R8represent hydrogen, shown in Table I, below.

(I)

Table I

2-methylpropyl 3'-aminosulfonyl-4'-banditen-4-yl
The stereochemistry at*C**C)R3R6(D)n-R7
RS,S2-methylpropylCF3phenyl
RS,S2-methylpropylCF34'-(4-tert-butoxycarbonylmethyl-1-yl)defen-4-yl
RS,S2-methylpropylCF34'-(piperazine-1-yl)defen-4-yl
RS,S2-methylpropylCF34'-[4-(2-hydroxyethyl)Pieper is Zin-1-yl]defen-4-yl
RS,S2-methylpropylCF34'-[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]defen-4-yl
RS,R2-methylpropylCF34-bromophenyl
RS,R2-methylpropylCF34'-methylsulfonylmethane-4-yl
RS,R2-methylpropylCF34'-morpholine-4-ylsulphonyl-4-yl
RS,R2-methylpropylCF34'-N-methylaminoacetaldehyde-4-yl
R,S2-methylpropylCF34-pyridin-4-ylphenyl
RS.S2-methylpropylCF34-N,N-dimethylaminocarbonylmethyl
R,S2-methylpropylCF34-(pyridin-4-yl-1-N-oxide)phenyl
RS,S2-methylpropylCF34-[6-(1-hydroxy-1-methylethyl)pyridine-3-yl-1-N-oxide]phenyl
RS,S2-methylpropylCF34-(6-methylsulfonylmethyl-3-yl)phenyl
RS,S2-methylpropylCF34'-(methylsulphonyl)defen-4-yl
RS,S2-methylpropylCF34-morpholine-4-ylphenyl
RS,S2-methylpropylCF34-piperazine-1-ylphenyl
RS,S2-methylpropyl2,4,6-tryptophanyl4-bromophenyl
RS,S2-methylpropylCF34-cyclopropanecarbonitrile
RS,S2-methylpropylCF34'-methylthiophene-4-yl
RS,S2-methylpropylCF34-(2-methylinosine-7-yl)phenyl
RS,S2-methylpropylCF34-(1H-indol-5-yl)phenyl
RS,S2-methylpropylCF34-carboxyphenyl
RS,S2-methylpropylCF33'-acetaminophen-4-yl
RS,S2-methylpropylCF34-piperidine-4-ylphenyl
RS,S2-methylpropylCF34-(4-pyridine-2-reparation-1-yl)phenyl
RS,S2-methylpropyl2,4,6-tryptophanyl4-pyridin-4-ylphenyl
RS,S2-methylpropylCF34-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl
RS,S2-methylpropylCF34-(4-ethylpiperazin-1-yl)phenyl
RS,S2-methylpropylCF34'-(4-(2-foradil)piperazine-1-yl)defen-4-yl
RS,S2-methylpropylCF34-(4-methylpiperazin-1-ylcarbonyl)phenyl
RS,S2-methylpropylCF34'-dimethylaminomethyl-4-yl
RS,S2-methylpropylCF34-(piperazine-1-ylcarbonyl)phenyl
RS,S2-methylpropylCF34-[4-(2-hydroxyethyl)piperazine-1-ylcarbonyl]phenyl
R,S2-methylpropylCF34-[4-(2-foradil)piperazine-1-yl-carbonyl]phenyl
RS,S2-methylpropylCF34-[4-(2-hydroxy-2-methylpropyl " piperazine-1-ylcarbonyl]phenyl
R,S2-methylpropylCF34-cyanomethaemoglobin
RS,RScyclopropylmethylCF3 4-bromophenyl
RS,RScyclopropylmethylCF34-pyridin-4-ylphenyl
S,S2-methylpropylCF34-morpholine-4-ylcarbonyl
RS,S2-methylpropylCF34'-(pyridine-4-yl)defen-4-yl
S,S2-methylpropylCF34-(2-methylpyridin-5-yl)phenyl
RS,S2-methylpropylCF35-penalties-2-yl
RS,S2-methylpropylCF34-quinoline-8-ylphenyl
RS,S2-methylpropylCF3defen-4-yl
S,S2-methylpropylCF34-pyridine-2-ylphenyl
S,S2-methylpropylCF34-[3-(3-triptoreline)

oxidiazol-5-yl]phenyl
RS,S2-methylpropylCF34'-(aminosulfonyl)defen-4-yl
S,S2-methylpropylCF34'-(N-methyl-N-methoxyaminomethyl)phenyl
RS,S2-methylpropylCF3 4-(3-hydroxy-3-methylbut-1-inyl)phenyl
S,S2-methylpropylCF34-(TRANS-3-hydroxy-3-methylbut-1-enyl)phenyl
R,S2-methylpropylCF34-(3-hydroxy-3-methylbutyl)phenyl
S,S2-methylpropylCF2CF34-bromophenyl
S,S2-methylpropylCF2CF34-pyridin-4-ylphenyl
S,S2-methylpropylCF34-(2-methyl-1,3-thiazol-4-yl)phenyl
RS2-methylpropylCF34-(3-tert-butyl-1,2,4-triazine-5-yl)phenyl
S,S2-methylpropylCF34'-forgiven-4-yl
S,S2-methylpropylCF34-ethoxycarbonylphenyl
S,S2-methylpropylCF34-(E-2-quinoline-2-retinyl)phenyl
RS,S2-methylpropylCF33'-methylsulfonylmethane-4-yl
RS,S2-methylpropylCF34'-carboxylate-4-yl
S,SCF2CF34'-methylthiophene-4-yl
R,S2-methylpropylCF31,3-thiazol-2-yl
S,S2-methylpropylCF34'-methoxydiphenyl-4-yl
RS,S2-methylpropylCF34'-(N-methyl-N-methoxyamino)defen-4-yl
S,S2-methylpropylCF34-methoxyphenyl
S,S2-methylpropylCF2CF34'-methylsulfonylmethane-4-yl
RS,S2-methylpropylCF34-[2-(3-methylsulfinylphenyl)-1,3-thiazol-4-yl]phenyl
S,S2-methylpropylCF34-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl
S,S2-methylpropylCF34-(4-methylsulfonylbenzoyl)phenyl
S,S2-methylpropylCF34-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl
S,S2-methylpropylCF34-(3-chloropyridin-6-yl)phenyl
S,S2-methylpropylCF3
S,S2-methylpropylCF33'-methylsulphonyl-4'-banditen-4-yl
S,S2-methylpropylCF34-phenoxyphenyl
S,S2-methylpropylCF34-[3-(5-bromopyridin-3-yl)[1,2,4]oxadiazol-5-yl]phenyl
S,S2-methylpropylCF34-(phenylthiomethyl)phenyl
S,S2-methylpropylCF34-(benzoyl)phenyl
S,S2-methylpropylCF34'-banditen-4-yl
RS,S2-methylpropylCF34'-[4-methylsulfonylmethane-1-yl]defen-4-yl
S,S2-methylpropylCF34-(4-chloropyridin-3-yl)phenyl
S,S2-methylpropylCF34'-acetylamino-2'-merdiven-4-yl
S,S2-methylpropylCF34'-triftormetilfullerenov-4-yl
S,S2-methylpropylCF34-(4-tormentilline)phenyl
SS 2-methylpropylCF34-(Tien-2-ylcarbonyl)phenyl
S,S2-methylpropylCF34-methylsulfinylphenyl
S,S2-methylpropylCF34-(1,3-thiazol-2-ylcarbonyl)phenyl
S,S2-methylpropylCF34-(6-methoxypyridine-3-yl)phenyl
S,S2-methylpropylCF34-(6-methoxypyridine-2-yl)phenyl
S,S2-methylpropylCF34-ethylsulfonyl-4-yl
S,S2-methylpropylCF34-(3-(2-chloro-6-forfinal)-5-methylisoxazol-4-ylcarbonylglycine)phenyl
S,S2-methylpropylCF34-(CIS-2-(4-methylsulfinylphenyl)ethynyl)phenyl
S,S2-methylpropylCF34-(9-chloro-3-methyl-4-oxitocina[4,3-c]quinoline-5(H)ylmethyl)phenyl
S,S2-methylpropylCF34'-methoxy-3'-methylsulfonylmethane-4-yl
RS,S2-methylpropylCF33-bromophenyl
S,S2-methylpropylCF34'-(4-methylsulfinylphenyl)defen-4-yl
S,S2-methylpropylCF34'-(4-isopropylphenyl)

defen-4-yl
S,S2-methylpropylCF34'-methylsulphonyl-2'-(4-chlorophenyl)defen-4-yl
S,S2-methylpropylCF34'-methylsulphonyl-2'-methoxydiphenyl-4-yl
S,S2-methylpropylCF34-(4-bromo-1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF32'-chloro-4'-methylsulfonylmethane-4-yl
S,S1-methylcyclopropyl-methylCF34-bromophenyl
S,S1-methylcyclopropyl-methylCF34'-methylsulfonylmethane-4-yl
RS,S2-methylpropylCF32-Bratan-5-yl
S,S2-methylpropylCF34-Tien-3-ylphenyl
S,S2-methylpropylCF34-pyridine-2-ylphenyl
S,S2-methylpropyl CF34-(4-methylpyridin-2-yl)phenyl
S,S2-methylpropylCF32'-forgiven-4-yl
S,S2-methylpropylCF34-(3,5-dimethylisoxazol-4-yl)phenyl
S,S2-methylpropylCF34'-hydroxyethylidene-4-yl
S,S2-methylpropylCF34'-cyanotype-4-yl
S,S2-methylpropylCF33',4'-giftgift-4-yl
S,S2-methylpropylCF32'-methoxycarbonylmethyl-4-yl
S,S2-methylpropylCF33'-methoxycarbonylmethyl-4-yl
S,S2-methylpropylCF33',4'-dimethoxyethan-4-yl
S,S2-methylpropylCF32'-triptorelin-4-yl
S,S2-methylpropylCF33',4'-dichlorophen-4-yl
S,S2-methylpropylCF33'-formaldives-4-yl
S,S2-methylpropylCF3/sub> 4-(2-oxo-2,3-dihydrobenzofuran-6-yl)phenyl
S,S2-methylpropylCF34-(5-bromopyridin-3-yl)phenyl
S,S2-methylpropylCF34'-cryptomaterial-4-yl
S,S2-methylpropylCF34-(1H-indol-4-yl)phenyl
S,S2-methylpropylCF34-(pyrimidine-5-yl)phenyl
S,S2-methylpropylCF34-(quinoline-3-yl)phenyl
S,S2-methylpropylCF34-(1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34'-methoxycarbonylmethyl-4-yl
S,S2-methylpropylCF34-(pyrimidine-2-yl)phenyl
S,S2-methylpropylCF34-(3-methylpyridin-2-yl)phenyl
S,S2-methylpropylCF34-(furan-3-yl)phenyl
S,S2-methylpropylCF34-(pyridin-3-yl)phenyl
S,S2-methylpropylCF 4'-(morpholine-4-ylsulphonyl)defen-4-yl
S,S2-methylpropylCF34-(TRANS-2-methylsulfinylphenyl)phenyl
S,S2-methylpropylCF3defen-4-yl
R,S2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF34-banditen-4-yl
S,S2-methylpropylCF34-pyridin-4-ylphenyl
S,S2-methylpropylCF34'-(pyridine-4-yl)defen-4-yl
S,S2-methylpropylCF34'-methylthiophene-4-yl
S,S2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF34-(3-hydroxy-3-methylbutyl)phenyl
S,S2-methylpropylCF34-(3-hydroxy-3-methylbutyl)phenyl
S,S2-methylpropylCF34'-aminosulfonyl-4-yl
RS,S2 methylp the filing CF34'-piperazine-1-indepen-4-yl
R,S2-methylpropylCF34-cyanomethaemoglobin
RS,S2-methylpropylCF34-(4-(2-foradil)piperazine-1-yl-carbonyl)phenyl
RS,S2-methylpropylCF34-(4-methylpiperazin-1-ylcarbonyl)phenyl
S,S2-methylpropylCF34-(pyridin-3-yl-N-oxide)phenyl
RS,S2-methylpropylCF34'-(piperazine-1-yl)defen-4-yl
S,S2-methylpropylTien-2-yl4-bromophenyl
R,S2-methylpropyl4-trifloromethyl4-bromophenyl
S,S2-methylpropyl4-trifloromethyl4'-methylsulfonylmethane-4-yl
S,S2-methylpropylTien-2-yl4'-methylsulfonylmethane-4-yl
S,S2-methylpropylTien-2-yl4'-(tert-butoxycarbonylmethyl-1-yl)defen-4-yl
S,S2-methylpropylTien-2-yl 4'-piperazine-1-indepen-4-yl
S,S2-methylpropyl4-forfinal4'-methylsulfonylmethane-4-yl
S,S2-methylpropylfuran-2-yl4-bromophenyl
S,S2-methylpropylfuran-2-yl4'-methylsulfonylmethane-4-yl
RS,Sn-propylCF34-bromophenyl
RS,Sn-propylCF34'-methylsulfonylmethane-4-yl
R,S2-methylpropyl4-CF3-phenyl4-bromophenyl
S,S2-methylpropyl4-CF3-phenyl4'-methylsulfonylmethane-4-yl
S,Sn-propylCF34'-methylsulfonylmethane-4-yl
RS,Sn-propylCF34'-(4-cyclopropylmethyl-1-yl)defen-4-yl
R,S2-methylpropyl4-chlorophenyl4-bromophenyl
S,S2-methylpropyl4-chlorophenyl4'-methylsulfonylmethane-4-yl
S,S2-methylpropyl3-methyltin-2-yl4-Romper
S,S2-methylpropylTien-3-yl4-bromophenyl
RS,RS2-methylpropyl2,4-differenl4-bromophenyl
S,S2-methylpropyl2,4-differenl4'-methylsulfonylmethane-4-yl
S,S2-methylpropylTien-3-yl4'-methylsulfonylmethane-4-yl
S,S2-methylpropyl3-methyltin-2-yl4'-methylsulfonylmethane-4-yl
S,S2-methylpropyl3-methyltin-2-yl4'-(4-cyclopropylmethyl-1-yl)defen-4-yl
S,S2-methylpropylTien-3-yl4'-(4-cyclopropylmethyl-1-yl)defen-4-yl
RS,S3,3,3-cryptochromesCF34-bromophenyl
S,S3,3,3-cryptochromesCF34'-methylsulfonylmethane-4-yl
S,S2-methylpropylFuran-3-yl4'-methylsulfonylmethane-4-yl
S,S2-methylpropyl4-Bratan-2-yl4-bromophenyl
S,S2-methylpropyl4-(4-matilal phenylphenyl)-Tien-2-yl 4'-methylsulfonylmethane-4-yl
S,S2-methylpropylTien-3-yl4'-aminosulfonyl-4-yl
S,Sn-propylCF34'-methylsulfonylmethane-4-yl
RS,SN-propylpyridine-4-yl4-bromophenyl
RS,Sn-propylthe thiazole-2-yl4-bromophenyl
S,S2-methylpropylthe thiazole-2-yl4-bromophenyl
S,S2-methylpropylthe thiazole-2-yl4'-methylsulfonylmethane-4-yl
RS,S2-methylpropyl1H-tetrazol-5-yl4-bromophenyl
S,S2-fluoro-2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S2S-triptime-ylpropylCF34'-methylsulfonylmethane-4-yl
S,S2S-triptime-ylpropylCF34'-methylthiophene-4-yl
S,S2-methylpropylCF2CF34-(6-methylpyridin-3-yl)phenyl
S,S2-methylpropylCF3/td> 4'-(1-hydroxyethyl)defen-4-yl
S,S2-methylpropylCF34'-(2,2,2-Cryptor-1-hydroxyethyl)defen-4-yl
S,S2R-triptime-ylpropylCF34'-(methylsulphonyl)defen-4-yl
S,S2-methylpropylCF2CF34-(1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34-(5-methyl-1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34-(4-methyl-1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34-(4,5-dimethyl-1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF2CF34-(2-hydroxy-2-methylpropylsulfonic)defen-4-yl

The compounds of formula I, where R1and R2together with the carbon atom to which they are attached, form cyclopropyl, R4, R5and R8represent hydrogen, shown in table II, below.

Table II

The stereochemistry at (*,**)R3R6(D) -R7
RS,S2-methylpropylCF34-bromophenyl
S,S2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S2-methylpropyl3-methyltin-2-yl4-bromophenyl
S,S2-methylpropyl3-methyltin-2-yl4'-methylsulfonylmethane-4-yl
S,Sn-propylCF34'-methylsulfonylmethane-4-yl
S,Sn-propylCF34-bromophenyl
S,S2-methylpropylTien-3-yl4-bromophenyl
S,S2-methylpropylTien-3-yl4'-methylsulfonylmethane-4-yl
S,Sn-propylCF34'-aminosulfonyl-4-yl
S,S2-methylpropylTien-3-yl4'-aminosulfonyl-4-yl
S,Sn-propylCF34'-methoxy-3'-methylsulfonylmethane-4-yl
S,Sn-propylCF34-(2-methylpyridin-4-yl)phenyl
S,S3,3,3-cryptochromesCF34'-methylsulfonylmethane-4-yl
S,Sn-propylCF34-(1H-pyrazole-3-yl)phenyl
S,Sn-propylCF34'-(1-hydroxy-1-methylethyl)defen-4-yl
S,Sn-propylCF34-(5-methylpyridin-2-yl)phenyl
S,Sn-propylCF34'-azetidin-4-yl
S,Sn-propylCF32',4'-giftgift-4-yl
S,Sn-propylCF33',4'-giftgift-4-yl
S,Sn-propylCF33'-chloro-4'-forgiven-4-yl
S,Sn-propylCF34'-methylsulfonylamino-4-yl
S,Sn-propylCF34'-klonipin-4-yl
S,Sn-propylCF34'-chloro-3'-merdiven-4-yl
S,Sn-propylCF34'-chloro-2'-merdiven-4-yl
S,Sn-propylCF3 4'-indol-5-ylphenyl
S,Sn-propylCF33'-methylsulfonylamino-4-yl
S,Sn-propylCF34'-forgiven-4-yl
S,Sn-propylCF34'-fluoro-3'-merdiven-4-yl
S,Sn-propylCF33'-fluoro-4'-merdiven-4-yl
S,Sn-propylCF34'-cryptomaterial-4-yl
S,Sn-propylCF34'-merdiven-4-yl
S,Sn-propylCF34'-cyanotype-4-yl
S,Sn-propylCF34'-methoxydiphenyl-4-yl
S,Sn-propylCF34-(3,4-methylenedioxyphenyl)phenyl
S,Sn-propylCF34'-methoxycarbonylmethyl-4-yl
S,S2-methylpropylthe thiazole-2-yl4-bromophenyl
S,Sn-propylCF34'-triptorelin-4-yl
S,Sn-Roper CF32'-triptorelin-4-yl
RS,S2-methylpropylthe thiazole-2-yl2',4'-giftgift-4-yl
RS,S2-methylpropylthe thiazole-2-yl4'-methylsulfonylmethane-4-yl
S,S2-methylpropyl4-Bratan-2-yl4-bromophenyl
S,S2-methylpropylCF34-were
S,S2-methylpropylCF34-(1H-pyrazole-3-yl)phenyl
S,S2-methylpropylCF34-(2-methyl-1,3-oxazol-4-yl)phenyl
S,S2-methylpropylCF34-(2-methylpyridin-4-yl)phenyl
S,S2-methylpropylCF34-(4-methylpyridin-3-yl)phenyl
S,S2-methylpropylCF33'-azetidin-4-yl
S,S2-methylpropylCF35-[4-(1-hydroxy-1-methylethyl)phenyl]pyridine-2-yl
S,S2-methylpropylCF34'-methoxy-3'-methylsulfonylmethane-4-yl
S,S 2-methylpropylCF33'-aminosulfonyl-4'-methoxydiphenyl-4-yl
S,S2-methylpropylCF34-(6-methoxypyridine-3-yl)phenyl
S,S2-methylpropylCF2CF34-(5-methylpyridin-2-yl)phenyl
S,S2-methylpropylCF34-(5-methylsulfinylphenyl-2-yl)phenyl
S,S2-methylpropylCF34-(5-methylpyridin-2-yl)phenyl
S,S2-fluoro-2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S2-fluoro-2-methylpropylCF32'-methyl-4'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF35-(quinoline-6-yl)pyridin-2-yl
S,S2-methylpropylCHF24'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF2CF34'-azetidin-4-yl
S,S2-methylpropylCF36-chloropyridin-3-yl
S,S2-methylpropylCF3 5-(4-acetylphenyl)pyridine-2-yl
S,S2-methylpropylCF36-(4-acetylphenyl)pyridine-3-yl
S,S2-methylpropylCF35-(3-acetylphenyl)pyridine-2-yl
S,S2-methylpropylCF35-[4-(1-hydroxyethyl)vinylpyridin-2-yl
S,S2-methylpropylCF34-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl
S,S2-methylpropylCF34-(2-methyl-1,3-thiazol-4-yl)phenyl
S,S2-methylpropylCF34-(2-methylpyridin-4-yl)phenyl
S,S2-methylpropylCF34-(2-methylpyridin-3-yl)phenyl
S,S2-fluoro-2-methylpropylCF33'-azetidin-4-yl
S,S2-fluoro-2-methylpropylCF34-(1H-pyrazole-3-yl)phenyl
S,S2-methylpropylCF35-(4-methylsulfinylphenyl)pyridine-2-yl
S,S2-methylpropylCF34'-(1-hydroxy-1-methylethyl)defen-4-yl
S,S2S-cryptomaterialCF34'-methylsulfonylmethane-4-yl
S,S2S-cryptomaterialCF34'-methylthiophene-4-yl
S,S2-methylpropylCF2CF34-(6-methylpyridin-3-yl)phenyl
S,S2-methylpropylCF34-(6-methylpyridin-3-yl)phenyl
S,S2-methylpropylCF2CF34-(1-hydroxy-1-methylethyl)defen-4-yl
S,S2-methylpropylCF2F34'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF2F34-(6-methoxypyridine-2-yl)phenyl
S,S2R-cryptomaterialCF34'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF34-(1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34-(5-methyl-1,3-thiazol-2-yl)phenyl
S,S2-methylpropylCF34-(4-methyl-1,3-thiazol-2-yl)phenyl
S 2-fluoro-2-methylpropylCF34'-ethylsulfonyl-4-yl
S,S2-fluoro-2-methylpropylCF34-pyridin-3-ylphenyl
S,S2-fluoro-2-methylpropylCF34'-methoxy-3'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF34'-(2-hydroxy-2-methylpropylsulfonic)defen-4-yl
S,S2-methylpropylCF32'-methyl-4'-methylsulfonylmethane-4-yl
S,S2-methylpropylCF34'-ethylsulfonyl-4-yl
S,S2-fluoro-2-methylpropylCF34'-aminosulfonyl-4-yl

The compounds of formula I, where R3and R4together with the carbon atom to which they are attached, form a cyclohexyl, R1, R5and R8represent hydrogen, shown in table III, below.

Table III

The stereochemistry at (*C)R2R6(D)n-R7
RSHCF3 phenyl
RSHCF34-bromophenyl
RSHCF34'-piperazine-1-yl)defen-4-yl

The compounds of formula I, where R1, R4, R5and R8represent hydrogen, shown in table IV, below.

Table IV

The stereochemistry at*C**C***C)R2R3R6(D)n-R7
S,S,Smethyl2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S,S2-methylthioethyl2-methylpropylCF34'-methylsulfonylmethane-4-yl
S,S,S2-methylsulfonylmethyl2-methylpropylCF34'-methylsulfonylmethane-4-yl

Specific embodiments of the present invention include, but not limited to, the following connections:

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-phenylethyl)-L-l is sciname;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-fluoro-3-were)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(lR)-2,2,2-Cryptor-1-(4-{[4-(2-foradil)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-foradil)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N2-[1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbut-1-inyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbutyl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4-pyridin-4-ylphenyl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}ethyl)-L-is alname;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxipiridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(morpholine-4-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[methoxy(methyl)amino]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-Tien-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(hydroxymethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-cyano-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(3',4'-debtor-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

methyl ester of 4'-{1-[1-(cyanomethylene the oil)-3-methylbutylamine]-2,2,2-triptorelin)diphenyl-2-carboxylic acid;

methyl ester of 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-3-carboxylic acid;

N1(cyanomethyl)-N2-[(1S)-1-(3',4'-dimethoxy-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-(trifluoromethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(3',4'-dichloro-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-formyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)phenyl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4-(5-bromopyridin-3-yl)phenyl]-2,2,2-triptorelin}-Nl(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(triptoreline)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-indol-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

methyl ester of 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

N1(cyanomethyl)-N2-[(1S)2,2,2-Cryptor-1-(4-(pyrimidine-2-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-furyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[3-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[4-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4'-(acetylamino)-3'-fluoro-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methyltin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4-(5-acetylthio-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-(trifluoromethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(5'-f the PR-2'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(3',5'-debtor-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2',3',5'-Cryptor-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

3-(4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-3-yl)acrylic acid;

N2-{(1S)-1-[4-(9-antrel)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4'-benzoyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(3'-acetyl-4'-hydroxy-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[2'-(cyanomethyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-(morpholine-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(5-penalties-2-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-(quinoline-8-ylphenyl)ethyl]-L-lazy the amide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-2-ylphenyl)ethyl]-L-leucinamide;

N2-{1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(morpholine-4-ylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(isopropylphenyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-((1S)-1-{4'-[(acetylamino)sulfonyl]-1,1'-diphenyl-4-yl}-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[1-(5-Bratan-2-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N2-[1-(4-shall Ravenel)-2,2,2-triptorelin]-N 1(cyanomethyl)-L-leucinamide;

tert-butyl ester 4-(4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-yl)piperazine-1-carboxylic acid;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-hydroxyethyl)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(1-{4-[(dimethylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-(1-{4-[(cyclopropylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamide;

4-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acid;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-foradil)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucine is the Ministry;

N2-{1-[4-(3-tert-butyl-1,2,4-triazine-5-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{2-[3-(methylsulphonyl)phenyl]-1,3-thiazol-4-yl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(methylsulphonyl)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-3-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(3-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-3-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-3-yl]ethyl}-L-leucinamide;

N-(cyanomethyl)-1-[(2,2,2-Cryptor-1-phenylethyl)amino]cyclohexanecarboxylic;

1-{[1-(4-bromophenyl)-2,2,2-triptorelin]amino}-N-(cyanomethyl)cyclohexanecarboxylic;

N-(cyanomethyl)-1-{[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]amino}cyclohexanecarboxylic;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperidine-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-pyridine-2-reparation-1-yl)F. the Nile]ethyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-cyclopropylalanine;

N1(cyanomethyl)-3-cyclopropyl-N2-[2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]alaninate;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-pyridin-4-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(1,3-thiazol-2-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-methoxyphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-pyridin-4-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-phenoxyphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4'-bromo-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4-(4-chloropyridin-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4'-(acetylamino)-2'-methyl]-1,1'-diphenyl-4-yl}-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamide;

N1-cyanomethyl)-N 2-{(1S)-2,2,2-Cryptor-1-[4"-(methylsulphonyl)-1,1':4',1"-terphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-(1-methylcyclopropyl)-L-alaninate;

N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(hydroxymethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-D-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-D-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(morpholine-4-ylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-D-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[(methylamino)sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-D-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(cinemati the)-N 2-(2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-1-oxipiridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperazine-1-ylphenyl)ethyl]-L-leucinamide;

N2-{1-[3'-(acetylamino)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-propylpiperazine-1-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(piperazine-1-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-hydroxyethyl)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}phenyl)ethyl]-L-leucinamide;

methyl ester of 4-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acid;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(E)-2-quinoline-2-retinyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl}-L-leucinamide;

N2 -((1S)-1-{4-[3-(5-bromopyridin-3-yl)-1,2,4-oxadiazol-5-yl]phenyl}-2,2,2-triptorelin)-N1-cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4-benzoylphenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(Tien-2-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{(Z)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{(E)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isobutylphenyl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4-(4-bromo-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-cyanophenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-Lac named;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{1-[4'-(dimethylamino)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

methoxyethylamine 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-({[4-(methylsulphonyl)benzyl]thio}methyl)phenyl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[3'-(aminosulfonyl)-4'-bromo-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4'-bromo-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-{5-chloro-3-[4-(methylsulphonyl)phenyl]pyridine-2-yl}phenyl)-2,22-triptorelin]-N 1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(phenylthio)methyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(trifluoromethyl)sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[(4-perbenzoic)amino]methyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(methylsulphonyl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N2-((1S)-1-{4-[({[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-yl]carbonyl}amino)methyl]phenyl}-2,2,2-triptorelin)-Nl(cyanomethyl)-L-leucinamide;

N2-((1S)-1-{4-[(9-chloro-3-methyl-4-oxitocina[4,3-c]quinoline-5(4H)-yl)methyl]phenyl}-2,2,2-triptorelin)-Nl(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4"-chloro-4'-(methylsulphonyl)-1,1':2',1"-terphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methoxy-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[2'-chloro-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]-,2,2-triptorelin}-N 1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxyethyl)thio]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-fluoro-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxyethyl)sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-({2-[methoxy(methyl)amino]-2-oxoethyl}sulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(4-bromophenyl)(2,4,6-tryptophanyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(4-pyridin-4-ylphenyl)(2,4,6-tryptophanyl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[[4-(4-terbisil)phenyl](phenyl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-{phenyl[4-(pyridine-3-ylmethyl)phenyl]methyl}-L-leucinamide;

N2-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{[4-(methylsulphonyl)is enyl][4'-(methylthio)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-{[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(methylsulphonyl)phenyl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-trichloro-1-(4-picolomini)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2-fluoro-1-(permitil)-1-phenylethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(pyrrolidin-1-ylacetic)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(piperazine-1-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-3-(1-methylcyclopropyl)-N2-(2,2,2-Cryptor-1-{4-[1-(2-hydroxyethyl)prolyl]phenyl}ethyl)-L-alaninate;

N2-[[4-(4-tert-butylpiperazine-1-yl)phenyl](pentafluorophenyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N-(cyanomethyl)-1-{1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}piperidine-2-carboxamide;

N2-[[4-(4-tert-butylpiperazine-1-yl)phenyl](pyridin-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N2-{[4-(4-tert-butylpiperazine-1-yl)phenyl][5-(trifluoromethyl)pyridin-2-yl]methyl}-N1(cyanomethyl)-L-leucinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[(1R)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N-(cyanomethyl)-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-cast new the amide;

N-(cyanomethyl)-1-[(1R)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N-(cyanomethyl)-4,4-debtor-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-were)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-oxazol-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrazin-2-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-fluoro-4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(1-hydroxy-1-methylethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(1-hydroxy-1-methylethyl)-1,1-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4'-methyl-1,1'-diphenyl-4-yl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-3-yl)phenyl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(2'-fluoro-1,1'-diphenyl-4-yl)propyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[3'-(aminosulfonyl)-4'-methoxy-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(5-methylpyridin-2-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(methylsulphonyl)pyridine-2-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-is alname;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(1H-pyrazole-3-yl)pyridine-2-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-5-espiridion-2-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-6-espiridion-2-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1-ethoxyphenyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N2-[(1S)-1-(4-acetylphenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isopropylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-phenylethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-methylcyclopropyl)phenyl]ethyl}-L-leucinamide;

N 1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(2',4',6'-trimethyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[5-(4-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[6-(4-acetylphenyl)pyridine-3-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[5-(3-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(1-hydroxyethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N'-(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-(1-benzyl-2,2,2-triptorelin)-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(4-tert-butylphenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4-methyl-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-methyl-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-trip the EOS-1-{4-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyanoethyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyano-3-(methylthio)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-2-yl)phenyl]propyl}-L-leucinamide;

N2-[(1S)-1-(5-bromopyridin-2-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N1-(-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(6'-methyl-3,3'-piperidin-6-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-1,6-dihydropyridines-2-yl)phenyl]ethyl}-L-leucinamide;

(4S)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-5,5,5-Cryptor-L-leucinamide;

(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-L-leucinamide;

N2-{(1S)-1-[4-(6-aminopyridine-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1(cyanomethyl)-N2

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methylpyridin-3-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(2,2,2-Cryptor-1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-2-yl)phenyl]propyl}-L-leucinamide;

(4R)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

(4R)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4'-methyl-1,1'-diphenyl-4-yl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(1,3-thiazol-2-yl)phenyl]prop is l}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,3,3,3-pentafluoropropyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,3,3,3-pentafluoropropyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(4,5-dimethyl-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methyls Lionel)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-alaninate;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,3,3,3-pendaftar-1-{4'-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}propyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(isopropylphenyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyano-1-methylethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(triptoreline)phenyl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-2-the l)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-(4'-piperazine-4-FMD-1-yl-1,1'-diphenyl-4-yl)(Tien-2-yl)methyl]-L-leucinamide methansulfonate;

N1(cyanomethyl)-N2-{(S)-(4-forfinal)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(trifluoromethyl)phenyl]methyl}-L-leucinamide;

N2-{(S)-(4-chlorophenyl)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(Tien-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl](Tien-2-yl)methyl]-L-leucinamide;

N2-{(R)-(4-bromophenyl)[4-(triptoreline)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][4-(triptoreline)phenyl]methyl}-L-leucinamide;

N2-[(S)-(4-bromophenyl)(2-furyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-2-furyl[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-Norvaline;

N2-{(R)-(4-bromophenyl)[4-(trifluoromethyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide,

N1-(C is animetal)-N 2-{1-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-Norvaline;

N2-[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-(2,4-differenl)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-5,5,5-Cryptor-L-Norvaline;

N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2 -[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-3-furyl[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide;

Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-Norvaline;

N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-((S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]{4-[4-(methylsulphonyl)phenyl]Tien-2-yl}methyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-Norvaline;

N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(S)-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(S)-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

p> N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-Norvaline;

2-{[(4-bromophenyl)pyridine-4-ylmethyl]amine}pentanol acid cyanomethylene;

2-{[(4-bromophenyl)thiazol-2-ylmethyl]amino}pentanol acid cyanomethylene;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(4'-acetylbiphenyl-4-yl)-2,2,2-triptorelin]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(2',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(3',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(3'-chloro-4'-forgivenes-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acids;

cyanomethylene (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-3'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-2'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethylamine}pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(3'-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acids;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-fluoro-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-fluoro-3'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-fluoro-4'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-triptoreline-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-methylbiphenyl-4-yl)ethylamine]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(4'-cyanobiphenyl-4-yl)-2,2,2-triptorelin]pentanol acids;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(be the AOR[1,3]dioxol-5-yl)phenyl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methoxycarbonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

cyanomethylene (2S)-2-{(S)-[(4'-methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amine}-4-methylpentanoic acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-triptorelin-4-yl)ethylamino]pentanol acids;

(cyanocobalamin)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(2'-triptorelin-4-yl)ethylamine]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(2',4'-giftgiver-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4'-methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxido-2,3-dihydro-1-benzothieno-5-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-2,3-dihydro-1-benzothieno-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxide-is-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

(2S)-N-(cyanomethyl)-4,4-debtor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-N-(1-cyanocyclohexyl)-4,4-debtor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-N-(1-cyanocyclohexyl)-4,4-debtor-2-({(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-N-(cyanomethyl)-4,4-debtor-2-({(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(cyanomethyl)-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulfone is)-1,1'-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-4,4-dichloro-N-(1-cyanocyclohexyl)-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(1-cyanocyclohexyl)-2-({(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(cyanomethyl)-2-({(1S)-2,2,2-trichloro-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)butanamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-[(1S)-1-(2'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-the l]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

Nl-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{6-[4-(methylsulphonyl)phenyl]pyridine-3-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-{6-[(methylsulphonyl)amino]pyridine-3-yl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-{6-[(methylsulphonyl)amino]pyridine-3-yl}phenyl)ethyl]-L-leucinamide;

Nl-(1-cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-2-cyclopropylethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-2-pyridin-3-retil)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-3-hydroxy-3-methylbutyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,3-diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dimethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-diethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(1,1-dimethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(1,1-diethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(3,3-diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-2,5-dihydrofuran-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(2,2-diethyl-5-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-oxo-2,5-dihydrofuran-3-yl)phenyl]ethyl}-L-leucinamide;

Nl-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(5,5-diethyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-4-oxaspiro[2.4]hept-6-EN-7-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-5-oxaspiro[3.4]Oct-7-EN-8-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-4-oxaspiro[2.4]hept-6-ene-6-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-5-oxaspiro[3.4]Oct-7-EN-7-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)the Tyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N 1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-5-methylpyridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4,4-debtor-L-what is named;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(1S)-1-hydroxyethyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(1R)-1-hydroxyethyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-TRIFLUOROACETYL)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(2-naphthyl)pyridin-2-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N2-[(4-bromophenyl)(phenyl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-[4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

<> N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(methylsulphonyl)amino]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano shall ecoprofile)-N 2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-5-methylpyridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-latinae is;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(1S)-1-hydroxyethyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(1R)-1-hydroxyethyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(TRIFLUOROACETYL)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(2-naphthyl)pyridin-2-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N2-[(4-bromophenyl)(phenyl)methyl]-N1-(1-cyanocyclohexyl)-L-l is sciname;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4'-[(methylsulphonyl)amino]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide

and their pharmaceutically acceptable salts, Stere the isomers and N-oxide derivatives.

In the scope of the present invention also includes a pharmaceutical composition comprising a compound of formula I, as described above, and a pharmaceutically acceptable carrier. The invention also includes obtaining a pharmaceutical composition comprising pharmaceutically acceptable carrier and any of the compounds specifically described in the present invention. These and other aspects of the present invention will be apparent from the information contained herein.

Utility

Compounds of the present invention are inhibitors of cathepsins and, therefore, are useful for the treatment or prevention of cathepsin-dependent diseases or conditions mammals, preferably humans. In particular, the compounds of the present invention are inhibitors of Cathepsin K, and therefore useful for the treatment or prevention of diseases or conditions that are dependent on Cathepsin K, in mammals, preferably in humans.

"Cathepsin-dependent disease or condition" refers to pathological States, which depend on the activity of one or more of the cathepsins. "The disease or condition dependent on Cathepsin K" refers to pathological States, which depend on the activity of Cathepsin K. Diseases associated with Cathepsin K, include osteoporo is, osteoporosis induced by glucocorticoids, Paget's disease, abnormally increased bone metabolism, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, oculoplasty osteolysis, impaired osteogenesis, metastatic bone disease, hypercalcemia of malignant tumors and multiple myeloma. In the treatment of such conditions stated in this connection the required therapeutic amount will vary in accordance with a specific disease, and it can be easily determined by the person skilled in the art. Although the treatment and prevention are considered in the scope of the present invention, the preferred application is the treatment of these conditions.

The embodiment of the present invention is a method of inhibiting the activity of cathepsin at a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.

One group accomplishments is the way in which the activity of cathepsin represents the activity of cathepsin K.

Another embodiment of the present invention is a method of treatment or prevention of cathepsin-dependent conditions in a mammal, ordaudio, includes introduction to the specified mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above.

Group of this implementation is the way in which the activity of cathepsin represents the activity of cathepsin K.

Another embodiment of the present invention is a method of inhibiting bone destruction in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. Another embodiment of the present invention is a method of reducing bone destruction in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of farmacevticheskih compositions described above. The usefulness of inhibitors of cathepsin K by suppression of bone resorption, are known from the literature, see Stroup, G.B., Lark, M.W., Veber, DF., Bhattacharrya, A., Blake, S., Dare, L.C., Erhard, K-F., Hoffman, S.J., James, I.E., Marquis, R.W., Ru, Y., Vasko-Moser, J.A., Smith, B.R., Tomaszek, T. and Gowen, M. Strong and selective inhibition of cathepsin K man leads to the suppression of bone resorption in vivo in nonhuman primates. J. Bone Miner. Res., 16:1739-1746; 2001; Votta, B.J., Levy, M.A., Badger, A., Dodds, R. A., James, I.E., Tompson, S., Bossard, M.J., Carr, T., Connor, J.R., Tomaszek, T.A., Szewczuk, L., Drake, F.H., Veber, D. and Gowen, M. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption in vivo and in vitro. J. Bone Miner. Res. 12:1396-1406; 1997.

Another option of the present invention is a method of treating or preventing osteoporosis in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of soedinenii or any of the above pharmaceutical compositions described above. The usefulness of inhibitors of cathepsin K in the treatment or prevention of osteoporosis is known from the literature, see Saftig, P., Hunziker, E., with their neck occurring, O., Jones, S., Boyde, A., Rommerskirch, W., Moritz, J.D., Schu, P. and Vonfigura, K. Weakened bone resorption by osteoclasts leads to osteoporosis in mice deficient for cathepsin K. Proc. Natl. Acad. Sci. USA 95:13453-13458; 1998.

Another embodiment of the present invention is a method of treatment or prevention of rheumatoid arthritis in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. From the literature it is known that the progressive destruction of individual bones is the main cause of joint dysfunction and disability in patients with rheumatoid arthritis (RA), see Goldring SR, "Pathogenesis of bne erosions in rheumatoid arthritis". Curr. Opin. Rheumatol. 2002; 14: 406-10. Analysis of joint tissue of patients with RA presented evidence that cathepsin To positive osteoclasts are cells that mediate focal bone resorption associated with rheumatoid synovial damage, see Hou, W-S, Li, W, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring, SR, Bromme D, "Comparision of Cathepsin K and S expression within the Rheumatoid and Osteoarthritic Synovium", Arthritis Rheumatism 2002; 46: 663-74. In addition, generalized bone destruction is a major cause of morbidity associated with severe RA. The frequency of fractures of the hip and spine significantly increased in patients with chronic RA, see Gould A, Sambrook P, Devlin J, and others, "Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis". J. Rheumatol 1998; 25: 1282-9. The usefulness of inhibitors of cathepsin K in the treatment or prevention of resorption in subarticular bones and generalized bone destruction is a rational approach to pharmacological intervention in the development of rheumatoid arthritis.

Another embodiment of the present invention is a method of treating or preventing the development of osteoarthritis in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. From the letter is as URS known that osteoarthritis (OA) is accompanied by distinct changes in the joints, including the erosion of the surface of articular cartilage, periarticular nutrigrain stiffening/osteophytosis and subchondral bone sclerosis and cyst formation, see Oettmeier R, Abendroth K, "Osteoarthritis and bone: osteologic types of osteoarthritis of the hip". Skeletal Radiol. 1989; 18: 165-74. Lately suggested the possible contribution subkhankulova sclerosis of the bone in the emergence and development of OA. Hardened subchondral bone, as a reaction of the joint to repetitive pulsed load, less able to cushion and distribute the efforts of the joint, exposing it more significant mechanical pressure onto the surface of articular cartilage. This, in turn, accelerates the wear of the cartilage and fibrillation, see Radin, EL and Rose RM, "Role of subchondral bone in the initiation and progression of cartilage damage", Clin. Orthop. 1986; 213: 34-40. Suppression of excessive subarticular bone resorption action antiresorptive agent such as an inhibitor of cathepsin K, will lead to the suppression subkhankulova bone metabolism, therefore, may have a beneficial effect in the progression of OA. In addition to the above hypothesis, the expression of cathepsin K was recently identified in synovial fibroblasts, microfactory cells and chondrocytes and synovial layer and in the samples of the articular is Rama, obtained from patients with OA, see Hou, W-S, Li, W, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring, SR, Bromme D, "Comparison of Cathepsin K and S expression within the Rheumatoid and Osteoarthritic Synovium", Arthritis Rheumatism 2002; 46: 663-74; Dodd, RA, Connor, JR, Drake, FH, Gowen, M, "Expression of Cathepsin K messenger RNA in giant cells and their precursors in human osteoarthritic synovial tissues". Arthritis Rheumatism 1999; 42: 1588-93; Konttinen, YT, Mandelin J, Li, T-F, Salo, J, Lassus, J and others, "Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis", Arthritis Rheumatism 2002; 46: 953-60. These recent studies, therefore, implied the role of cathepsin K in the decomposition of collagen type II in articular cartilage associated with osteoarthritis. The usefulness of inhibitors of cathepsin K in the treatment or prevention of osteoarthritis, as described in this invention, therefore, involves two different mechanisms: the first is the inhibition managed by osteoclasts subkhankulova bone metabolism and the second is a direct suppression of degeneration of collagen type II in the synovial layer and cartilage in patients with OA.

Another embodiment of the present invention is a method of treating cancer in a mammal, in need thereof, comprising the introduction of a given mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described above. From literature it is known that cathepsin It is expressed in carcinomas of the breast of man, see Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA, "The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma". Cancer Res 1997 Dec 1;57(23):5386-90.

Confirmation of this invention for example is the use of any of the compounds described above in the preparation of a medicinal product for treating and/or preventing osteoporosis in a mammal, in need thereof. Further confirmation of this invention for example is the use of any of the compounds described above in the preparation of medicines for the treatment and/or prevention of bone destruction, bone resorption, bone fractures, metastatic bone disease and/or disorders associated with the operation of cathepsin.

Compounds according to this invention it is possible to enter a mammal, preferably humans, either alone or preferably in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as aluminum, in the pharmaceutical composition, according to standard pharmaceutical practice. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and local routes of administration.

In the case of tablets for oral administration are typically used media is clucalc the lactose and corn starch, and usually add lubricating agents such as magnesium stearate. For oral administration in the form of a capsule used diluents include lactose and dried corn starch. For oral therapeutic use of the compound according to this invention, the selected compound may be introduced, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. For oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, calcium diphosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, in the case where it is desirable or necessary, the mixture may also be included suitable binder, lubricant, dezintegriruetsja agents and coloring agents. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic is LaCie substances, such as the Arabian gum, tragacanth gum or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like. In those cases, when for oral administration required aqueous suspensions of the active ingredient combined with emulsifying and suspenders agents. If desired, can be added to certain sweeteners and/or flavoring agents. For intramuscular, intraperitoneal, subcutaneous and intravenous administration is usually prepared sterile solutions of the active component, and the pH of the solutions should be stable set and buffered. For intravenous use should control the total concentration of dissolved substances to provide drug isotonicity.

Compounds of the present invention can also be entered in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine and the and phosphatidylcholine.

Compounds of the present invention can also be delivered using monoclonal antibodies as individual carriers to which the binding molecules of the connection. Compounds of the present invention can also be associated with soluble polymers as induced carriers of drugs. Such polymers can include polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted residues of Palmitoyl. In addition, the compounds of the present invention can be connected to a class of biodegradable polymers used to achieve a controlled release of drug funds, for example, polylactic acid, polyglycolic acid, copolymers of polyacrylic and polyglycolic acid, poly-Epsilon-caprolactone, polyhydroxyalkanoic acid, polyarteritis, polyacetylene, policyidreference, polycyanoacrylates and cross stitched or amphipathicity blocked copolymers of hydrogels.

These compounds are also applicable in combination with known agents used for the treatment or prevention of osteoporosis, osteoporosis induced by glucocorticoids, Paget's disease, abnormal high metabol the PCA bone, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, coloproctol of osteolysis, defect osteogenesis, metastatic bone disease, hypercalcemia of malignant tumors and multiple myeloma. The combination of compounds disclosed in the present moment with other agents used in the treatment or prevention of osteoporosis or other bone disorders are within the scope of this invention. An ordinary person skilled in the art can understand which combinations of agents would be useful, on the basis of specific characteristics of drugs and caused disease. Such agents include: organic biphosphonate; modulator of estrogen receptors; modulators of the androgen receptor; inhibitors of the proton ATPase osteoclasts; an inhibitor of HMG-CoA reductase inhibitors; antagonist integranova receptor; anabolic agent osteoblasts, such as PTH (PTH), and their pharmaceutically acceptable salts and mixtures. The preferred combination is a compound of the present invention and the organic biphosphonate. Another preferred combination is a compound of the present invention and a modulator of estrogen receptors. Another preferred combination is a combination of truly izaberete the Oia and modulators of the androgen receptor. Another preferred combination is a compound of the present invention and anabolic agent osteoblasts.

"Organic biphosphonate" includes, but not limited to, compounds of chemical formula

where n is an integer from 0 to 7 and where a and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30of alkyl, C3-C30branched or cyclic alkyl, bicyclic ring structure containing two or three N, C1-C30substituted alkyl, C1-C10of alkyl, substituted NH2C3-C10branched or cyclic alkyl, substituted NH2C1-C10the dialkyl substituted NH2C1-C10alkoxy, C1-C10of alkyl, substituted thio, thiophenyl, halogenfrei, C1-C10of alkyl, substituted phenyl, pyridium, TuranAlem, pyrrolidinium, imidazolium, imidazopyridine and benzyl, so that both A and X are not selected from H or OH when n is 0, or A and X, taken together with the carbon atom to which they are attached, form a C3-C10ring.

In the above chemical formula, the alkyl groups can be straight, branched or cyclic, provided that for a given chemical formula pick up is enough atoms. C1-C30substituted alkyl may include a wide range of substituents, non-limiting examples of which include substituents selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, NH2C1-C10the alkyl or dialkyl substituted NH2, OH, SH, and C1-C10alkoxy.

The above chemical formula also encompasses complex carbocyclic, aromatic and heteroatom patterns for a and/or X substituents, non-limiting examples of which include naphthyl, hinely, ethanolic, substituted and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives bifosfonatami also used here. Non-limiting examples of salts include salts selected from the group consisting of alkali metal, ammonium and mono-, di-, tri - or Tetra-C1-C30-alkyl-substituted ammonium. Preferred salts are salts selected from the group consisting of salts of sodium, potassium, calcium, magnesium and ammonium. More preferred are the salts of sodium. Unlimited examples of the derivatives include derivatives selected from the group consisting of esters, hydrates and amides.

It should be noted that the terms "biphosphonate" and "bisphosphonates", as used here, therapeutic agents of the present from which retene, also intended to cover diphosphonates, biphosphonate acids and diphosphonic acids and salts, and derivatives of these substances. The use of specific items in relation to biphosphonate or bifosfonatami not intended to limit the scope of the present invention, unless otherwise specified. Through the use of currently conventional specialists in this area of the mixed nomenclature reference to the proportion or percentage composition biphosphonates compounds in the present invention is based on the mass of active acid, if not specifically mentioned here. For example, the phrase "about 5 mg biphosphonate, inhibiting bone resorption, selected from the group consisting of alendronate, its pharmaceutically acceptable salt, based on the weight of active alendronova acid" means that the number of selected biphosphonates connection count based on 5 mg alendronova acid.

Non-limiting examples of bifosfonatami used here include the following:

Alendronate acid, 4-amino-1-hydroxybutylidene-1,1-biphosphonate acid.

Alendronate (also known as alendronate sodium or alendronate monosodium trihydrate), 4-amino-1-hydroxybutylidene-1,1-biphosphonate acid monolatry trihydrate.

Alendronat acid and alendronate described in U.S. patent 492007, Kieczykowski, and others, published may 1, 1990; 5019651, Kieczykowski, etc. published on may 28, 1991; 5510517, Dauer and others, published April 23, 1996; 5648491, Dauer and others, published July 15, 1997, each of which is incorporated herein by reference in its full scope.

Cycloheptylmethyl-1,1-bebopalula acid, YM 175, Yamanouchi (encadrant, formerly known as comadronas), described in U.S. patent 4970335, Isomura and others, opublikowano November 13, 1990, incorporated herein by reference in its full scope.

1,1-dihlormetilen-1,1-diphosphonic acid (cladonema acid), disodium salt (clodronate, Procter and Gamble) is described in Belgium patent 672205 (1966) and J. Org. Chem 32, 4111 (1967), included here in by reference in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)propylidene-1,1-bebopalula acid (EB-1053).

1-hydroxyethane-1,1-diphosphonic acid (heteronomy acid).

1-hydroxy-3-(N-methyl-N-pentylamine)propylidene-1,1-bebopalula acid, also known as BM-210955, Boehringer-Mannheim (ibandronate), described in U.S. patent 4927814, published on may 22, 1990, incorporated herein by reference in its full scope.

1-hydroxy-2-imidazo-(1,2-a)pyridine-3-iletiler (minodronate).

6-amino-1-hydroxybenzylidene-1,1-bebopalula acid (meridional).

3-(dimethylamino)-1-hydroxypropylamino-1,1-bebopalula acid (olpadronate).

3-amino-1-hydroxypropylamino-1,1-bebopalula acid (pamer the NAT).

[2-(2-pyridinyl)ethylidene]-1,1-bebopalula acid (Piedmont) described in U.S. patent 4761406 included as references in its full scope.

1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bebopalula acid (risedronate).

(4-chlorophenyl)Tibetan-1,1-dispositiona acid (tiludronate), described in U.S. patent 4876248, Breliere, etc., October 24, 1989, which is incorporated herein by reference in its full scope.

1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bebopalula acid (zoledronate).

Non-limiting examples of bifosfonatami include alendronate, Cimatron, clodronate, etidronate, ibandronate, encadrant, minodronate, meridional, olpadronate, pamidronate, Piedmont, risedronate, tiludronate and zolendronate and their pharmaceutically acceptable salts and esters. Especially preferred biphosphonates is alendronate, especially sodium, potassium, calcium, magnesium or ammonium salt of alendronova acid. Illustrating an example of a preferred biphosphonate is the sodium salt alendronova acid, especially hydrated sodium salt alendronova acid. This salt can be gidratirovana integer number of moles of water or not is a whole number of moles of water. Additional illustrating an example of a preferred biphosphonate is hydrated sodium salt alendronova acid, mainly when the hydrated salt is a alendronate mononitride.

Obviously, that can be used in mixture of two or more biphosphonate active substances.

The exact dosage of organic biphosphonate will change depending on the schedule of dosages, specifically selected biphosphonate, age, size, sex and condition of the mammal or human, the nature and severity of the disease being treated, and other relevant medical and physical factors. Therefore, accurate pharmaceutically effective amount cannot be specified in advance and can easily be determined by the Trustee or by the Clinician. Appropriate amounts can be determined in the usual experiment in animal models and clinical studies in humans. In General, a suitable amount of biphosphonate choose to obtain inhibitory effect on bone resorption, i.e. enter the number of biphosphonate inhibiting bone resorption. For people effective dose biphosphonate for oral administration is generally from about 1.5 to about 6000 mg/kg body weight and preferably about 10 to 2000 μg/kg of body weight. For alendronate of monastritiritis common input dose for humans are typically in the range from about 2 mg/day to 40 mg/day, preferably from about 5 mg/day to 40 mg/day. In the United States tested in the present dose for al is dronate of monastritiritis be 5 mg/day for the prevention of osteoporosis, 10 mg/day for the treatment of osteoporosis and 40 mg/day for the treatment of Paget's disease.

In alternative modes dosage biphosphonate you can enter in the intervals other than daily, such as dosage times per week, dosage twice a week, two-week dosing and dosage twice a month. When the dosage is once a week alendronate mononitride you can enter at a dose of 35 mg/day or 70 mg/week.

"Selective modulators of estrogen receptor" refers to compounds that prevent or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of modulators of estrogen receptors include, but not limited to, estrogen, progestogen, estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone and SH646.

A "modulator of beta-estrogen receptor is a compound that selectively acts as an agonist or antagonist of beta-estrogen receptor (ERβ). Agonizing ERβ increases transcription of the gene tryptophan hydroxylase (TPH, a key enzyme in the synthesis of serotonin) through ERβ-mediated event. Examples of agonists of beta-receptor astrogeology to be found in a publication of the international application PCT WO 01/82923, published November 08, 2001, and WO 02/41835, published may 20, 2002, both incorporated herein by reference in their entirety.

"The modulator of androgen receptor" refers to compounds that prevent or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of modulators of estrogen receptors include finasteride and other 5 inhibitorsα-reductase, nilutamide, flutamide, bikalutamid, liarozole and abiraterone acetate.

"An inhibitor of the proton ATPase osteoclasts" refers to an inhibitor of the proton ATPase, which is located on the apical membrane of osteoclast and was informed that plays an important role in the process of bone resorption. This proton pump is an attractive target for development of inhibitors of bone resorption, which are potentially useful for the treatment and prevention of osteoporosis and related metabolic diseases. Cm. C. Farina and others, "Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents," DDT, 4: 163-172 (1999)), incorporated herein by reference in its full scope.

"Inhibitors of HMG-CoA reductase" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds with inhibitorbased action against HMG-CoA reductase, can be easily identified using analysis, well known in this field. For example, see anal is SHL, described or cited in U.S. patent 4231938 in No. 6, and WO 84/02131 on pages 30-33. The term "HMG-CoA reductase inhibitor" and "inhibitor of HMG-CoA reductase" when used here have the same value.

Examples of inhibitors of HMG-CoA reductase, which can be used include, but not limited to, lovastatin (MEVACOR®; see U.S. patent 4231938, 4294926 and 4319039), simvastatin (ZOCOR®see U.S. patent 4444784, 4820850 and 4916239), pravastatin (PRAVACHOL®; see U.S. patent 4346227, 4537859, 4410629, 5030447 and 5180589), fluvastatin (LESCOL®; see U.S. patent 5354772, 4911165, 4929437, 5189164, 5118853, 5290946 and 5356896), atorvastatin (LIPITOR®; see U.S. patent 5273995, 4681893, 5489691 and 5342952) and tseriwastatina (also known as mevastatin and BAYCHOL®; see U.S. patent 5177080). Structural formulas of these and additional inhibitors of HMG-CoA reductase, which can be used in these ways, described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry &Industry, pp. 85-89 (5 February 1996), and in U.S. patent 4782084 and 4885314. Used herein, the term "inhibitor of HMG-CoA reductase inhibitor" includes all pharmaceutically acceptable forms of lactones and outdoor acids (i.e., where the lactone ring opened to form the free acid)as well as the form of salts and esters of compounds with inhibitory effect on HMG-CoA reductase, and therefore, the use of such salts, esters, forms of lactones and open sour is included in the scope of this invention. The image of the lactone ring part and the corresponding shape of the open acid is shown below as structures I and II

The inhibitors of HMG-CoA reductase, where there may be a form of open-acid forms salts and esters preferably can be formed from an open-acids, and all such forms are included in the value used here, the term "inhibitor of HMG-CoA reductase". Preferably the inhibitor of HMG-CoA reductase inhibitor selected from lovastatin and simvastatin, most preferably simvastatin. Here, the term "pharmaceutically acceptable salt" in relation to an inhibitor of HMG-CoA reductase shall mean non-toxic salts of the compounds used in this invention, which are mainly produced by interaction of the free acid with an organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and Tetramethylammonium, as well as those salts which are formed from amines such as ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, 1-p-Chlorobenzyl-2-pyrrolidin-1'-iletilerimde, diethylamine, piperazine and Tris(hydroxymethyl)aminomethane. The following examples of the salt is Orme inhibitors of HMG-CoA can include, but not limited to, acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, edetate calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesilate, methyl sulfate, mukat, napsylate, nitrate, oleate, oxalate, pamat, palmitate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannat, tartrate, teoclate, tosylate, triethiodide and valerate.

Ester derivatives of the above compounds are inhibitors of HMG-CoA reductase can act as precursors of drugs, which, upon absorption into the bloodstream of a warm-blooded animal, can be broken down thus to release dosage form, and give the drug a chance to provide improved therapeutic efficacy.

As used above, "antagonists integranova receptor" refers to compounds which selectively exert an antagonistic effect, inhibit or counteract binding of a physiological ligand to αvβ3 integrin, to compounds which have an antag the Communist action inhibit or counteract binding of a physiological ligand to αvβ5 integrin, to compounds which have an antagonistic effect, inhibit or counteract binding of a physiological ligand and αvβ3 integrin and αvβ5 integrin, and to compounds which have an antagonistic effect, inhibit or counteract the activity of individual integrin(s)expressed on endothelial cells of capillaries. This term also refers to antagonists αvβ6, αvβ8, α1β1,α2β1that α5β1that α6β1and α6β4, integrins. This term also refers to antagonists of any combination of αvβ3,αvβ5,αvβ6,αvβ8,α1β1,α2β1that α5β1that α6β1and α6β4integrins. H.N. Lode al. in PNAS USA 96: 1591-1596 (1999) observed synergistic effects between antagonist antiangiogenic αvintegrin and opukholespetsificheskaya antibody-cytokine (interleukin-2) fused protein in the elimination of spontaneous tumor metastases. Their results suggest that h is about this combination has the potential to treat cancer, and metastatic tumor growth. Antagonists of receptor αvβ3integrin inhibits bone resorption through a new mechanism different from the mechanism of all currently available drugs. Integrins are heterodimeric transmembrane adhesion receptors, which mediate the interaction between cell-cell and cell-matrix. α and β subunit of integrins interact ecovalence and bind ligands of intracellular matrix dependent on divalent cations. The most abundant integrin on osteoclasts is αvβ3(>107/osteoclast), which apparently plays a rate-limiting role in the organization of the cytoskeleton, important for cell migration and polarization. Antagonistic action αvβ3selected from inhibition of bone resorption, inhibition of restenosis, delays degeneration stains, inhibition of arthritis and suppress the growth of cancer cells and metastasis.

"Anabolic agent osteoblasts" refers to agents that build bone, such as PTH. It was shown that the abrupt introduction parathyroid hormone (PTH) or aminobenzene fragments and analogues prevents, delays, partly draws the destruction of the bones and stimulates bone formation in animals and humans. For discussion refer to DW. Dempster and others, "Anabolic actions of parathyroid hormone on bone", Endocr Rev 14: 690-709 (1993). The study demonstrated the clinical benefit of parathyroid hormone stimulation of bone formation and, thus, increase bone mass and strength. The results were reported Neer RM, etc., New Eng J Med 344 1434-1441 (2001).

In addition, fragments of the protein, parathyroid related hormone or analogues, such as PTHrP-(1-36) demonstrated strong antikaliuretic effects [see M.A. Syed and others, "Parathyroid hormone-related protein-(l-36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy", JCEM 86: 1525-1531 (2001)] and may also have potential as an anabolic agent for the treatment of osteoporosis.

As part of a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) in its prescribed dosage range. Compounds of the present invention can be used with alternative well-known pharmaceutically acceptable agent (agents), in the case where the drawing up of the combination is inappropriate.

The term "introduction" and its variants (e.g., the destination of the connection in the connection according to this invention means the introduction of this compound or precursor drugs this link is to the system of the animal, in need of treatment. In the case where the connection according to this invention or a prodrug is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), under "introduction" and its variants under each mean parallel and sequential introduction of this compound or its prodrug, or other agents. The present invention includes within its scope prodrugs of the compounds according to this invention. Typically, such prodrugs will be functional derivatives of the compounds according to this invention, which are easily converted in vivo to the desired connection. Therefore, in the treatment methods of the present invention, the term "assignment" shall encompass the treatment of various conditions, described, disclosed separately or with the connection, which may not be disclosed separately, but which turns into a certain compound in vivo after administration to the patient. Conventional methods of selection and preparation of suitable derivatives of prodrugs are described, for example, in "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985, incorporated herein by reference in its entirety. Metabolites of these compounds include active species produced in the introduction of compounds according to this invention in a biological environment.

Used herein, the term "compositions the Oia" is intended to encompass a product containing certain components in certain amounts, as well as any product which results, directly or indirectly, from the combination of certain components in certain amounts.

The term "therapeutically effective amount", as used here, means the amount of active compound or pharmaceutical agent that causes the biological or medical response in a tissue, system, animal or person sought by a researcher, veterinarian, medical doctor or other Clinician.

The terms "treating" or "treatment" of the disease, as used here, include the prevention of disease, i.e. it is not allowed to develop clinical symptoms of a disease in a mammal that may be exposed to this disease or be predisposed to it, but still do not have or does not exhibit symptoms of the disease; the delay of the disease, i.e. stopping or reducing the development of the disease or its clinical symptoms, or mitigation of disease, i.e. the call regression of the disease or its clinical symptoms.

Used the term "bone resorption" refers to the process by which osteoclasts destroy bone.

The present invention also covers a pharmaceutical composition suitable for treatment of osteopo the oz or other bone disorders involving the introduction of a therapeutically effective amount of the compounds according to this invention with pharmaceutically acceptable carriers or diluents, or without them. Suitable compositions of this invention include aqueous solutions containing the compounds of this invention and pharmaceutically acceptable carriers, such as saline solution with uroven pH, for example, to 7.4. Such solutions can be injected into the bloodstream of the patient by local bolus injection.

In the case where the connection according to this invention is administered to human, the daily dosage will normally be determined by the prescribing physician with changes mainly in accordance with age, weight and response of the particular patient as well as severity of symptoms of the patient.

In one typical application of the appropriate amount of compound administered to the mammal, whose treatment of cathepsin-dependent state. Oral dosages of the present invention, when used to obtain these effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably from 0.01 to 10 mn/kg/day and most preferably from 0.1 to 5.0 mg/kg/day. For oral administration, the composition preferably supply is in the form of tablets, containing 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage of the patient receiving treatment. The drug typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of the active component. Intravenously, the most preferred doses will be in the range of from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Mainly compounds of the present invention can be introduced in a single daily dose or the total daily dose can be administered separated by a dose of two, three or four times a day. Furthermore, preferred compounds for the present invention can be introduced in intranasal form via topical application suitable intranasal carriers or transdermal routes, using those forms of transdermal skin pieces of plaster, well-known specialists in this field. With the introduction in the form of a transdermal delivery system, enter the dosage will be continuous rather than intermittent throughout the dosage regimen.

Compounds of the present invention can be used in combination with other agents used to treat cathepsin-mediated conditions. In ividually components of such combinations can be entered separately at different times during the course of treatment or concurrently in divided or single combination forms. It is clear that the present invention, therefore, includes all such regimes of simultaneous or alternative treatment and the term "purpose" interpreterpath respectively. It will be understood that the scope of combinations of the compounds of this invention with other agents used to treat cathepsin-mediated conditions includes in principle any combination with any pharmaceutical composition used for treating disorders associated with the activity of estrogen.

The volume of this invention therefore encompasses the use claimed in the present compounds in combination with another agent selected from organic biphosphonate; modulator of estrogen receptor; modulators of androgen receptor; inhibitors of the proton ATPase of osteoclasts and an inhibitor of HMG-CoA reductase inhibitor; an antagonist of integrin receptor; anabolic agent of osteoblasts, such as PTH (PTH), and their pharmaceutically acceptable salts and mixtures.

These and other aspects of the present invention will be seen from the information contained herein.

Definitions

Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, mixtures of racemates and in the form and the individual of diastereoisomers, with all possible isomers and mixtures thereof, including optical isomers are included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are included within the scope of the present invention, even if depicted only one tautomeric structure. For example, it is clear that any claim in connection And, below, includes the tautomeric structure and Vice versa, and also mixtures thereof.

In the case when any variable (for example, R1, R2, Randand so on) occurs more than one time in any constituent, its definition in each case is independent in every other case. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. A line drawn inside the ring systems from substituents indicates that the link can be attached to any replaceable carbon atoms of the ring. If the ring system is polycyclic, it means that the link attached to any replaceable carbon atoms only at the proximal ring.

It is clear that substituents and substitution patterns in the compounds of the present invention can be selected ordinary person skilled in the art to obtain with the joining, which are chemically stable and that can be readily synthesized using techniques known in this field, as well as by the methods described below, from readily available starting materials. If the Deputy is itself substituted by more than one group, it is clear that these various groups can be on the same carbon atom or on different carbon atoms, while the result is a stable structure. The phrase "optionally substituted with one or more substituents" should take the equivalent of the phrase "optionally substituted with at least one Deputy, and in such cases the preferred option implementation will have from zero to three substituents.

Used herein, "alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups having from one to ten carbon atoms, unless otherwise stated. For example, With1-C10as in "C1-C10alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear, branched or cyclic arrangement. For example, "C1-C10alkyl, in particular, includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

"Alkoxy" or "alkyloxy" represents an alkyl group, to the to defined above, unless otherwise stated, where this alkyl group attached through an oxygen bridge.

The term "cycloalkyl" or "carbocycle" shall mean cyclic rings of alkanes with the total number of carbon atoms from three to eight, if not specifically mentioned, or any number in this interval (i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

If the number of carbon atoms is not specified, the term "alkenyl" refers to non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon-carbon double bond. Preferably there is 1 carbon-carbon double bond and may be present up to 4 non-aromatic carbon-carbon double bonds. Thus, "C2-C6alkenyl" means alkanniny radical having from 2 to 6 carbon atoms. Alkeneamine groups include ethynyl, propenyl, butenyl and cyclohexenyl. As described above in relation to the alkyl, straight, branched or cyclic part alkenylphenol group may contain double bonds and may be substituted, if substituted Alchemilla group.

The term "cycloalkenyl" shall mean cyclic rings, content from 3 to 10 carbon atoms, unless otherwise noted, containing at least 1 angle is od-carbon double bond (i.e. cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctyl).

The term "quinil" refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms, unless otherwise noted, containing at least 1 carbon-carbon triple bond. May contain up to 3 carbon-carbon triple bonds. Therefore, "C2-C6quinil" means alkynylaryl radical having from 2 to 6 carbon atoms. Alkyline group include ethinyl, PROPYNYL and butynyl. As described above in relation to the alkyl, straight, branched or cyclic part alkenylphenol group may contain a triple bond and may be substituted, if substituted Alchemilla group.

In some cases, the substituents may be specified carbon range includes zero, for example (C0-C6)alkylaryl. If taken aryl represents phenyl, this definition would include the phenyl, and-CH2Ph, -CH2CH2Ph, CH(CH3)CH2CH(CH3)Ph, etc.

Used herein, "aryl" shall mean any stable monocyclic or bicyclic carbon ring that contains up to 12 atoms in each ring, where at least one ring is aromatic. Examples of such aryl elements include all the I phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, tenantry, antrel or acenaphthyl. In cases where the aryl Deputy is bicyclic and one ring is non-aromatic, it is clear that accession takes place through the aromatic ring.

The term "heteroaryl", used herein, represents a stable monocyclic, bicyclic or tricyclic ring containing up to 10 atoms in each ring, where at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include, but not limited to, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzotriazolyl, benzothiophene, benzoxazole, carbazolyl, carbolines, cinnoline, furanyl, indolinyl, indolyl, indolizinyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyrimidines, pyridyl, pyrimidinyl, pyrrolyl, hintline, hinely, honokalani, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroisoxazole, dihydroindole, dihydroquinoline, methylenedioxybenzene, be satyasai, sensational, chinoline, ethenolysis, oxazolyl and tetrahydroquinolin. When the heteroaryl Deputy is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is clear that the connection is through an aromatic ring or through the ring containing the heteroatom, respectively. If heteroaryl contains nitrogen atoms, it is clear that their corresponding N-oxides are also covered by this definition.

Specialists in this field it is clear that the "halogen atom" or "halogen"as used here includes chlorine, fluorine, bromine and iodine. The term "keto" refers to the carbonyl (C=O). The term "alkoxy", as used here, means an alkyl portion where alkyl is defined above, connected to the remainder of the molecule via an oxygen atom. Examples of alkoxy include methoxy, ethoxy and the like.

The term "halogenated" means an alkyl radical, as defined above, unless otherwise stated, which is substituted one to five, preferably one to three halogen atoms. Typical examples include, but not limited to, trifluoromethyl, dichloroethyl and the like.

The term "halogenoalkane" represents a radical-OR where R is an alkyl as defined above which is substituted one to five, preferably one to three halogen atoms. Typical examples include, n is not only cryptometrics, declarations and the like.

The term "arylalkyl" includes alkyl portion where alkyl is defined above, and includes aryl part, where aryl is defined above. Examples of arylalkyl include, but not limited to, benzyl, tormentil, Chlorobenzyl, phenylethyl, phenylpropyl, florfenicol and chlorophenolates. Examples of alkylaryl include, but not limited to, toluyl, ethylphenyl and propylphenyl.

Used herein, the term "heteroaromatic" will refer to a system that includes heteroaryl part where heteroaryl defined above and contains the alkyl part. Examples of heteroaromatic include, but not limited to, thienylmethyl, titilate, tamiltamil, pyridylmethyl, pyridylethyl and imidazolyl.

The term "cycloalkenyl" includes alkyl portion where alkyl is defined above, and also includes cycloalkyl the part where cycloalkyl defined above. Examples of cycloalkenyl include, but not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, and the like.

The term "hydroxyalkyl" means a linear monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, substituted by one or two hydroxy groups is mi, provided that in the presence of two hydroxy groups they are not on the same carbon atom. Typical examples include, but not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl and the like.

The term "heterocycle" or "heterocyclyl"used here means a 5-10 membered non-aromatic ring, unless otherwise noted, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO2, and includes bicyclic groups. "Heterocyclyl"thus includes, but not limited to, the following: piperazinil, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholine, tetrahydropyranyl, dihydropyridines, tetrahydrothiophene and the like. If the heterocycle contains nitrogen, it is clear that its corresponding N-oxides are also covered by this definition.

The present invention also includes N-oxide derivatives and protected derivatives of compounds of Formula I. for Example, in the case where the compounds of formula I contain an oxidizable nitrogen atom, the nitrogen atom may be converted to N-oxide by methods well known in the field. Also, in the case where the compounds of formula I contain groups such as hydroxy, carboxy, thiol or any group containing the atom(s) of nitrogen, these groups may be protected with suitable protecting groups which mi. A complete list of suitable protecting groups can be found in T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc. 1981, the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of compounds of formula I can be obtained by methods well known in the field.

When the term "alkyl" or "aryl" or either of them ahead of roots appear in a name of a substituent (e.g., aryl (C0-8alkyl) should be interpreted including those limitations given above for "alkyl" and "aryl". The indicated number of carbon atoms (for example, C1-10) will refer independently to the number of carbon atoms in the alkyl or cyclic alkyl part of the molecule or to the alkyl portion of a larger substituent in which alkyl appears as its preceding root.

Pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds according to this invention, formed of inorganic or organic acids. For example, conventional non-toxic salts include salts that are derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts derived from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova, triperoxonane and the like. Getting pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts are more fully described in Berg et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977:66:1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds according to this invention can be sinisiraan of the compounds according to this invention, which contain the basic and the acid part of the molecule, traditional chemical methods. Typically, the salts of the basic compounds are prepared either ionoobmennoi chromatography, or by the interaction of the free base with stoichiometric amounts or with an excess of the desired salebrosa inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.

For the purposes of this description indicated the values of the following abbreviations:

Asón = acetic acid

BF = boron TRIFLUORIDE

BOC = tert-butyloxycarbonyl

Vos2About = di-tert-BUTYLCARBAMATE

BuLi = utility

CCl4= carbon tetrachloride

CH2Cl2= methylene chloride

CH3CN = acetonitrile

CHCl3= chloroform

Cs2CO3= cesium carbonate

CuI = copper iodide

DAST = TRIFLUORIDE diethylaminoethyl

DIPEA = diisopropylethylamine

DMA = N,N-dimethylacetamide

DMAP = 4-(dimethylamino)pyridine

DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide

DPPA = diphenylphosphoryl

EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

Et2O = diethyl ether

Et3N = triethylamine

EtOAc = ethyl acetate

EtOH = ethanol

HATU = o-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine

HOAc = acetic acid

K2CO3= potassium carbonate

KHMDS = hexamethyldisilazane potassium

KOBut= tert-piperonyl potassium

LDA = diisopropylamide lithium

LiOH = lithium hydroxide

mCPBA = meta-chloroperbenzoic acid

MeOH = methanol

MeSO3H = methansulfonate

MgSO4= magnesium sulfate

Ms = methanesulfonyl = mesyl

MsCl = methanesulfonanilide

NaBH4= borohydride sodium

NaH = sodium hydride

Nal = sodium iodide

NaCNBH3= cyanoborohydride sodium

Na2CO3= sodium carbonate

NaHCO3= hydrogencarbon is at sodium

NaOH = sodium hydroxide

Na2SO4= sodium sulfate

NBS = N-bromosuccinimide

NH3= ammonia

NH4Cl = chloride ammonium

Pd/C = palladium on coal

PdCl2= dichloropalladium(II)

PdCl2(dppf) = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd2(dba)3= Tris(dibenzylideneacetone)tiplady(0)

PG = protecting group

PPh3= triphenylphosphine

(PhO)3PMeI = iodide methyltrimethoxysilane

PPTS = pyridine-p-toluensulfonate

iPr2Nli = lithium diisopropylamide

PyBOP = benzotriazol-1-yloxytris(pyrrolidino)phosphonium-hexaphosphate

K.T. = room temperature

The feast upon. = saturated aqueous solution

TFA = triperoxonane acid

THF = tetrahydrofuran

TiCl4= chloride titanium(IV)

tlc = thin layer chromatography

TMSCl = chlorotrimethylsilane

Me = methyl

Et = ethyl

n-Pr = normal propyl

i-Pr = isopropyl

n-Bu = normal butyl

i-Bu = isobutyl

s-Bu = secondary butyl

t-Bu = tertiary butyl

The new compounds of the present invention can be obtained in accordance with the following standard methods using appropriate substances, and additionally illustrates some examples. The compounds illustrated in the examples, however, not be interpreted as forming the only genus that is considered is t as this invention. The following additional examples illustrate the details of receiving data of the compounds of the present invention. The person skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to obtain these compounds. All temperatures are given in degrees Celsius, unless separately.

SCHEMA

Compounds of the present invention can be obtained in accordance with Scheme 1 below. Thus, for halogenoalkane can be added complicated α-aminoether to obtain amines, which can be dehydration in Imin in the presence of a dehydrating agent, such as TiCl4, MgSO4or isopropyl trifenatate. Recovery imine regenerating agent, such as cyanoborohydride sodium or borohydride sodium, gives Amin. The hydrolysis of ester and amide formation respectively replaced by aminoacetonitrile gives compounds of the present invention. If the Deputy on the D system is a halogen catalyzed by palladium linking by Suzuki method (Suzuki) with the corresponding Bronevoy acid provides additional compounds of the present invention.

SCHEME 1

Compounds of the present invention can also be obtained in accordance with the tvii with Scheme 2, below. The ketone or aldehyde may be condensed with aminosterol obtaining cyclic amines. Treatment with 3 equivalents of Grignard reagent or organolithium reagent gives the corresponding alkilirovanny amerosport. Oxidation of alcohol chrome system, such as oxidation by Jones (Jones), or by using H5IO6/CrO3or alternatively by two-stage oxidation (for example, oxalicacid/DMSO/Et3N, then NaClO) will give the corresponding carboxylic acid. Peptide interaction and the Suzuki reaction described in Scheme 1, will give the compounds of the present invention.

SCHEME 2

Compounds of the present invention can also be obtained in accordance with Scheme 3, below. The ketone or aldehyde may be condensed with aminosterol obtaining cyclic amines. Processing a large number of equivalents of the Grignard reagent or organolithium reagent gives the corresponding alkilirovanny amerosport. This alcohol can be converted to the compound of the present invention by the method described in Scheme 2.

SCHEME 3

Compounds of the present invention can also be obtained in accordance with Scheme 4. Acetate, substituted appropriately, can be prohibited is sirawan a suitable base (including but not only, LDA, KHMDS, NaH or n-BuLi) and treated with paraformaldehyde with the formation of the diol. This diol can be converted to dittoed using a fluorinating reagent such as DAST. Hydrolysis of ester with posleduushie then regrouping Curtis (Curtius) then gives Amin. This amine may be substituted respectively substituted complex alpha barometer, providing complex alpha aminoether. It can be converted into compounds of the present invention by the method described in Scheme 1.

SCHEME 4

Compounds of the present invention can also be obtained in accordance with scheme 5, below. Hemiacetal may be condensed with aminosterol, in which the alcohol portion of the molecule is protected with a suitable protecting group. Processing of the resulting imine with Grignard reagent or organolithium reagent gives the corresponding alkilirovanny amerosport. Alcohol protective group can then be removed and the alcohol can be converted into compounds of the present invention or by the method described in Scheme 2, or the first conducting the Suzuki reaction with subsequent oxidation of the alcohol the influence of H5IO6/CrO3and then the peptide binding.

SCHEME 5

Compounds of the present invention can also be obtained in accordance with scheme 6, below. Peptide compound alpha-amino acids described in schemes 1, 2, or 5, with an alpha aminoamides with subsequent dehydration of the resulting primary amide (Voegel, J. J.; Benner, S. A. Helv. Chem. Acta 1996, 79, 1863) gives compounds of the present invention.

Synthesis of some aminoalcohols used as initial products for schemes 2, 3 and 5, are presented on figures 7-11. For example, the synthesis of (2S)-2-amino-4-fluoro-4-methylpentan-1-ol, where R=Me, presented in figure 7 below. Starting with a suitable diamesinae aspartic acid, the carboxyl group can be restored in alcohol using standard literature methods (for example, the formation of a mixed anhydride, followed by reduction NaBH4). Protected option 2-amino-4-methylpentane-1,4-diol (R=Me) can then be formed using the respective impact of the Grignard reagent or orginality. Finally, the hydroxyl portion of the molecule can be converted to the desired Porosimeter using a fluorinating agent such as DAST. Secured or unsecured option of this amerosport can then be converted into compounds of the present invention according to schemes 1, 2, 3, and 5.

SCHEME 7

4-Ferracina can also be synthesized according to scheme 8. 4,5-Dihydralazine converted to (4S)-4-(2-methylprop-2-enyl)-1,3-oxazolidin-2-it, as shown in the diagram below. This intermediate compound is then treated hydroperiods reagent, such as HF-pyridine, to obtain the (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-it. The base hydrolysis (i.e. Ba(OH)2or NaOH) then gives (2S)-2-amino-4-fluoro-4-methylpentan-1-ol.

Synthesis of 4,4-debtor-L-Norvaline, where R=Me, presented in figure 9 below. On the basis of respectively desasosiego serine iodination can be carried out using a reagent such as (PhO)3P+MeI-. The introduction of zinc in the resulting iodide can be carried out using Zn-Cu couple and TMSCl. The resulting Zinnat then subjected to the combination makes reactions catalyzed by palladium, alcantarillado to obtain a ketone. In the end, this ketone portion of the molecule can be converted into the desired debtorprovidian using a fluorinating agent such as DAST. Secured or unsecured option of this amino acid or amerosport can then be converted into compounds of the present invention according to schemes 1, 2, 3, and 5.

SCHEME 9

The aminoalcohols used in the present invention can also be synthesized in accordance with scheme 10. Protective restore amino acid regenerating agent such as NaBH4,in the presence or in the absence of LiCl, in a solvent such as EtOH, or mixed solvents such as EtOH and THF. Aminosidine group then remove the appropriate method in accordance with the nature of the protecting group.

SCHEME 10

Synthesis of (2S,4S)-2-amino-5,5,5-Cryptor-4-methylpentan-1-ol used in the present invention, will find in Scheme 11. N-Benzoyl-5,5,5-triptorelin (Ojiima et. al. J. Org. Chem., 1989, 54, 4511 - 4522) may be hydrolyzed with aqueous acid solution, such as 6M HCl at reflux. The intermediate compound HCl salt of the amino acids, then converted into N-acetyl-5,5,5-triptorelin and the amino group of a chiral center decompose enzymatic method (Synthetic Communications, 1996, 26, 1109 - 1115). Selected 5,5,5-Cryptor-L-leucine then protect by using a protective group, such as benzylcarbamoyl, and atrificial group of carboxylic acid. Two diastereoisomer in position 4 then divide thin-layer column chromatography. One of the enantiomers (2S,4S) protective amino acid, and then converted into amerosport, as presented to nashama 10.

SCHEME 11

Compounds of the present invention, where R5represents hydrogen and R6represents aryl or heteroaryl, can also be obtained according to scheme 12, as shown below. The condensation of the aryl or heteroaryl aldehyde with aminosterol, in which the alcohol portion of the molecule is protected with a suitable protecting group, followed by treatment of the resulting imine with Grignard reagent or organolithium reagent of the formula halogen-(D)n-Li or halogen-(D)n-MgX (where D is defined in the section "Summary of the invention"), with the subsequent removal kislorodozaschitny group, gives alkilirovanny amerosport. This alkilirovanny amerosport then converted into compounds of the present invention or by using the method presented in scheme 2 or by carrying out the Suzuki reaction with bronovil complex ester of the formula R7-B(OH)2then oxidation of the alcohol with a suitable oxidizing agent such as H5IO6/CrO3pick acids and, in the end, the treatment of this acid aminoacetonitrile in the conditions of peptide binding, as described earlier.

Compounds of the present invention can also be obtained in accordance with scheme is th 13, shown below. Interaction sootvetstvuyuschim way N-protected amino acid derivative with axeanosilas in the presence of sodium iodide in a suitable organic solvent, such as dimethylformamide, gives the corresponding ester oxetane that when processed by DIBORANE gives complex orthoepy. Remove aminosidine group gives Amin, which by condensation with an aldehyde of the formula R6CHO (where R6represents aryl or heteroaryl) or hemiacetal formula R6C(OH)(OR) (where R represents an alkyl group) in the reaction conditions described above, gives Imin. The processing of this imine Grignard reagent or organolithium reagent under the reaction conditions described above gives N-alkilirovanie derived. Remove orthoevra gives the corresponding carboxylic acid, which is then converted into the compounds of the present invention by condensation with aminoacetonitrile in the conditions of peptide binding and subsequent Suzuki reaction as described above.

The following examples describe the synthesis of selected compounds of the present invention.

EXAMPLE 1

Synthesis of N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-phenylethyl)-L-leucinamide

To a solution of methyl ester hydrochloride, L-leucine (mg, 5.37 mmol) in dichloromethane (30 ml) was added 2,2,2-trifurcation (0.75 ml, of 5.34 mmol)was added dropwise diisopropylethylamine (3.5 ml, 20 mmol), TiCl4(with 0.55 ml, 5.0 mmol) in 0.45 ml of dichloromethane and the mixture was stirred over night. Then another was added TiCl4(0.4 ml, 3.6 mmol) and the mixture was stirred 3 hours the solution was Added NaCNBH3(1050 mg, and 16.7 mmol) in MeOH (20 ml) and the mixture was stirred 2 hours was Poured into 1N NaOH and extracted with ethyl acetate (2x). The organic phase is washed with 1N NaOH and saturated saline, then was dried over MgSO4and evaporated. Purification via ISCO column chromatography (gradient from 30% to 90% ethyl acetate/hexane) gave methyl-N-(2,2,2-Cryptor-1-phenylethyl)-L-Latinate.

At room temperature to a solution of methyl-N-(2,2,2-Cryptor-1-phenylethyl)-L-Latinate (150 mg, 0.50 mmol) in 2:1 THF/MeOH was added 1M LiOH. The mixture was stirred overnight and concentrated. The residue was distributed between ethyl acetate and phosphate buffer with a pH of 3.5. The organic phase was washed with saturated saline solution, dried over MgSO4and concentrated to obtain N-(2,2,2-Cryptor-1-phenylethyl)-L-leucine.

A mixture of N-(2,2,2-Cryptor-1-phenylethyl)-L-leucine (149 mg, 0.50 mmol), aminoacetonitrile hydrochloride (102 mg, 1.1 mmol) and PyBOP (260 mg, 0.50 mmol) was dissolved in DMF (5 ml). Was added triethylamine (0.3 ml, 2.1 mmol) and the mixture was stirred overnight, then poured in FOSFA the hydrated buffer with a pH of 3 and was extracted with 3:1 ether/ethyl acetate. The organic phase is then washed with saturated aqueous NaHCO3and saturated saline solution, dried over MgSO4and evaporated. Purification via ISCO column chromatography (gradient from 20% to 50% ethyl acetate/hexane) gave N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-phenylethyl)-L-leucinamide in a 1:1 mixture of diastereoisomers.

MS (+APCI): 313,9 [M+1].

EXAMPLE 2

Synthesis of N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide

Using the method of Example 1 was obtained N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide.

MS (-ESI): 403,9, 405,9 [M-1]-.

EXAMPLE 3

Synthesis of N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide

To N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide (242 mg, of 0.60 mmol) and 4-[4-(tert-butoxycarbonyl)-1-piperazinil]phenylboronic acid (220 mg, to 0.72 mmol) in DME (3 ml) in a stream of dry nitrogen was added 2M aqueous sodium carbonate (0.9 ml, 1.8 mmol) and then the catalyst PdCl2(dppf) (63 mg, 0,077 mmol). Reational the mixture was heated to 85°C for 18 hours. Added water and the product was extracted with EtOAc, the organic layer was dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography using the receiving EtOAc in hexane to obtain tert-butyl(4'-{1-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amino]-2,2,2-triptorelin}-1,1'-diphenyl-4-yl)-1-piperidinecarboxylate.

To tert-butyl(4'-{1-[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)amine]-2,2,2-triptorelin}-1,1'-diphenyl-4-yl)-1-piperidinecarboxylate (275 mg, 0.47 mmol) in dry THF (1 ml) in a dry nitrogen was added dropwise MeSO3H (125 μl, 1.9 mmol) for 15 min and the reaction was allowed to proceed for 18 hours. The reaction mixture was distributed between EtOAc and water + saturated NaHCO3to establish a pH of 7.5. The organic layer was dried over Na2SO4and concentrated in vacuum. The crude product was purified by chromatography using silica gel, suirable NH4OH conc./MeOH/CH2Cl2, (1/10/89) to obtain the N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide in the form of a light yellow foam.

MS (+ESI): 488,3 [M+1]+.

EXAMPLE 4

Synthesis of N1(cyanomethyl)-N2-{[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(methylsulphonyl)phenyl]methyl}-L-leucinamide

Stage 1: methyl-N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methylene}-L-Latinate

A solution of (4-bromophenyl)[4-(methylsulphonyl)phenyl]methanone (202 mg, 0.59 mmol), hydrochloride of the methyl ester of L-leucine (328 mg, 2.0 mmol) and camphorsulfonic acid (52 mg, 0.22 mmol) in toluene was heated under reflux for 18 hours and using nozzles Dean-stark. The solvent was removed in vacuum obtained in the region is the result of the residue was purified using chromatography using EtOAc and hexane as eluent, to obtain the 1:1 mixture specified in the connection header and source (4-bromophenyl)[4-(methylsulphonyl)phenyl]methanone.

Stage 2:methyl-N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-L-Latinate

To a solution of 1:1 mixture of methyl-N-{(bromophenyl)[4-(methylsulphonyl)phenyl]methylene} Latinate and (4-bromophenyl)[4-(methylsulphonyl)phenyl]methanone with stage 1 (185 mg, ˜0.2 mmol) in acetic acid/methanol (1:3, 4 ml) was added borohydride sodium (˜400 mg) in portions every 30 min for 2 days (at night, adding continued) using a funnel for the addition of solid particles. The reaction mixture was distributed between EtOAc and water, the organic layer was dried over Na2SO4and concentrated. The resulting mixture was purified by chromatography using EtOAc and hexane as eluent. Methyl-N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl]}-L-Latinate was obtained as a colourless resin (4-bromophenyl)[4-(methylsulphonyl)phenyl]methanol was obtained as a white solid.

Stage 3: N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-L-leucine

To a solution of methyl-N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-L-Latinate from stage 2 (81 mg, 0,17 mmol) in THF (1 ml) and MeOH (0.5 ml) was added 1N LiOH (0.3 ml, 0.3 mmol). The resulting mixture was stirred at room temperature for 1 hours, and then was distributed between EtOAc and water + 1N HCl (0.5 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to obtain specified in the title compounds as a colourless resin.

Stage 4:N2-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide

To a solution of N-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-L-leucine with stage 3 (76 mg, 0,17 mmol), HATU (146 mg, 0.38 mmol), aminoacetonitrile (52 mg, 0,56 mmol) in DMF (1.1 ml), cooled to -10°C, was added N,N-diisopropylethylamine made (0.13 ml, 0.75 mmol). The reaction was left to proceed at room temperature for 18 h and was distributed between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by chromatography using EtOAc and hexane as eluent to obtain specified in the title compounds as a colourless resin.

Stage 5:N1(cyanomethyl)-N2-{[4-(methylsulphonyl)phenyl][4'-(methylthio)-1,1-diphenyl-4-yl]methyl}-L-leucinamide

A heterogeneous mixture of N2-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide with stage 4 (72 mg, 0.15 mmol), 4-(methylthio)phenylboronic acid (37 mg, 0.22 mmol) in dimethyl ether of ethylene glycol (1 ml) and 2M aqueous sodium carbonate was degirolami the vacuum and purged with nitrogen. To this mixture was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (19 mg, is 0.023 mmol) followed by degassing and by blowing with nitrogen. Reational the mixture was heated at 85°C for 16 hours with efficient stirring. The reaction mixture was distributed between EtOAc and aqueous NH4OAc (25% wt./vol.). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by chromatography using EtOAc and hexane as eluent to obtain specified in the title compounds as a colourless resin.

Step 6:N1(cyanomethyl)-N2-{[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(methylsulphonyl)phenyl]methyl}-L-leucinamide

To a solution of N1(cyanomethyl)-N2-{[4-(methylsulphonyl)phenyl][4'-(methylthio)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide (63 mg, 0.12 mmol), sodium tungstate dihydrate (2 mg, 0,006 mmol), tetrabutylammonium hydrosulfate (4 mg, 0.01 mmol) was added a solution of 30% (wt./about.) aqueous hydrogen peroxide (100 μl, 0.9 mmol) and the resulting mixture was stirred at room temperature for 10 minutes the Reaction mixture was distributed between EtOAc and water + 1M NaHSO3(˜3:1). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by chromatography using is the use of EtOAc and hexane as eluent to obtain specified in the title compounds as a colourless resin.

MS (+ESI): 568,2 [M+1]+.

EXAMPLE 5

Synthesis of N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-3-yl]ethyl}-L-leucinamide

Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide specified in the title compound was obtained as a colourless resin.

MS (+ESI): RUB 482.2 [M+1]+.

EXAMPLE 6

Synthesis of N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(3-pyridin-4-ylphenyl)ethyl]-L-leucinamide

Using the procedure described for example 8, where N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide specified in the title compound was obtained as a colourless resin.

MS (+ESI): 405,1 [M+1]+.

EXAMPLE 7

Synthesis of N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-3-yl)ethyl]-L-leucinamide

Using the procedure described for example 3, where N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide was substituted for N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide received is shown in the title compound as a colourless resin.

MS (+ESI): 488,3 [M+1]+.

EXAMPLE 8

Synthesis of N1(cyanomethyl)-N2{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

Stage 1:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine

At room temperature to a solution of L-leucinol (6.0 g) in dichloromethane (100 ml) was added triethylamine (11 ml), DMAP (0.1 g) and tert-butyldimethylsilyl (8.5 g). This mixture was stirred at room temperature for 2 hours and then added water. The organic layer was separated, and additional water was extracted with dichloromethane. The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a precipitate indicated in the title compound, which was used as such in the next reaction.

1H NMR (CD3COCD3) δ of 3.48 (m, 2H), 3,32 (m, 1H), was 2.76 (m, 1H), 1,78 (m, 1H), 1,22-1,02 (m, 2H), 0.88 to (m, 15 NM), 0,06 (C, 6N).

Stage 2:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-triptoreline]pentane-2-amine

A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine from step 1 (50 g) in toluene (300 ml) and triptorelin methyl hemiacetal (35 ml) was heated to boiling under reflux for 16 hours, during which time water was collected with POM is using nozzles Dean-stark. The solvent is evaporated in vacuum and the residue was purified on SiO2using hexane and ethyl acetate (9:1) as eluent to obtain specified in the connection header.

1H NMR (CD3COCD3) δ 7,88 (m, 1H), 3,76 is-3.45 (m, 3H), 1.60-to 1,25 (m, 3H), 0.88 to (m, 15H), is 0.06 (s, 3H), of 0.04 (s, 3H).

Stage 3:obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}methylpentan-1-ol.

n-BuLi (2.5 M in hexane, 42 ml) was added at -70°C to THF-GE (400 ml) solution of 1,4-dibromobenzene with (25,8 g) and the mixture was stirred for 25 minutes. Then was added dropwise THF-tion (30 ml) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2,2-triptoreline]pentane-2-amine (31 g) and the mixture was stirred for 1.5 hours. Then slowly poured into a mixture of ethyl acetate (500 ml), water (2 l), ice (300 g) and ammonium chloride (100 g) under vigorous stirring. The organic layer was separated and water was additionally extracted with ethyl acetate (2x500 stretch-forming press ml). The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was used as such. The above residue was dissolved in THF (250 ml) and the solution was cooled to 0°C. was Added dropwise 1M THF th solution of fluoride tert-butylamine (110 ml), the mixture was worked for 4 hours. The mixture was poured into ethyl acetate (300 ml), water (2 l) and chloride and mania (100 g) under vigorous stirring. The organic layer was separated and water was additionally extracted with ethyl acetate (CH ml). The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using a gradient of ethyl acetate and hexane (from 1:5 to 1:4) as eluent to obtain specified in the connection header.

1H NMR (CD3COCD3) δ and 7.6 (2H, d), was 7.45 (2H, d), 4,55 (1H, m), the 3.65 to 3.7 (1H, m), 3,5-3,55 (1H, m), of 3.25 to 3.35 (1H, m), 2,6-2,7 (1H, m), of 2.25 to 2.35 (1H, m)of 1.65 and 1.75 (1H, m), to 1.3-1.4 (1H, m), 1,2-1,3 (1H, m), 0.75 to 0,9 (6H, DD).

Stage 4:obtain (2S)-4-methyl-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}amino)pentane-1-ol

Through the suspension obtained from the bromide from step 3 (27.7 g), 4-(methylthio)phenylboronic acid (15.7 g), 2M Na2CO3(100 ml) and n-propanol (500 ml)was passed a stream of nitrogen for 15 minutes. Then was added a 1:3 mixture (3.5 g) Pd(OAc)2and PPh3the reaction mixture was heated to 70 °C and stirred under nitrogen atmosphere for 8 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (500 ml) and poured into water (2 l) and ice (500 g). The ethyl acetate layer was separated and the aqueous layer was additionally extracted with ethyl acetate (200 ml). Obyedinennye an ethyl acetate extracts were washed 0,5N NaOH (g ml), aqueous NH4Cl, saturated salt solution and silicongate magnesium. After removal of the solvent left a residue that was purified by chromatography on SiO2using a gradient of ethyl acetate and hexane (from 1:4 to 1:3), and again with acetone and toluene (1:10). The residue was dissolved in hot hexane (200 ml) and the solution was allowed to cool to 0°C under stirring. The obtained solid was filtered and dried to obtain specified in the connection header.

1H NMR (CD3COCD3) δ and 7.7 (2H, d), the 7.65 (2H, d), and 7.6 (2H, d), 7,35 (2H, d), 4,5-4,6 (1H, m), and 3.7 (1H(OH), m), 3,5-3,6 (1H, m), 3,3-3,4 (1H, m), 2,7 (1H, m), 2,5 (3H, s), 2,3-2,4 (1H(NH), m)of 1.65 and 1.75 (1H, m), 1,2-1,4 (3H, m), 0,8-0,9 (6H, DD).

Stage 5:obtain (2S)-4-methyl-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentane-1-ol

When 0°C to a solution of sulfide (19 g) from step 4 in toluene (400 ml) was added Na2WO4·2H2O (0.16 g) and Bu4NHSO4(0,81 g). Then slowly added 30%hydrogen peroxide (12,2 ml), the mixture was stirred at room temperature for 4.5 hours. The mixture was slowly poured into a mixture of ice and dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated and water was additionally extracted with ethyl acetate (CH ml). The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using e is racette and hexane (1:1) as eluent to obtain the product.

1H NMR (CD3COCD3) δ with 8.05 (2H, d), and 8.0 (2H, d), a 7.85 (2H, d), and 7.7 (2H, d), 4,6-4,7 (1H, m in), 3.75 (1H, m), and 3.6 (1H, m), 3,35 is-3.45 (1H, m), and 3.2 (3H, s), 2,7-2,8 (1H, m), 2,35 at 2.45 (1H, m), a 1.7-1.8 (1H, m), 1,2-1,5 (2H, m), 0,8-0,95 (6H, DD).

Step 6:obtain N-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucine

A suspension of N5IO6/CrO3(529 ml of 0.44 M in CH3CN; see note below) was cooled to 0°C was added dropwise a solution of alcohol from step 5 (20 g) in CH3CN (230 ml). The mixture was stirred at 0-5°C for 3.5 hours. The mixture was poured in Na2HPO4whenpH 4 (1.5 l) under vigorous stirring and the mixture was extracted with diethyl ether (3x250 ml). Combined ether extracts were washed with water and saturated salt solution (1:1), dilute aqueous NaHSO3and saturated salt solution. The organic extract was dried with sodium sulfate, filtered and the solvents evaporated to dryness to obtain a residue, which was divided into two parts for further treatment.

The above crude acid (10 g) was dissolved in izopropilazette (250 ml) and was extracted with cold 0.1 n NaOH (3x250 ml). The combined extracts washed with diethyl ether (250 ml), and then slowly acidified using 6N HCl to pH 4. Carboxylic acid were extracted with isopropylacetate (2x250 ml), a layer of isopropylacetate was dried and concentrated to obtain a product of high degree who Yeni cleaning, used as such in the next stage.

Note: oxidizing reagent (H5IO6/CrO3) was prepared as described in Tetrahedron Letters 39 (1998), 5323-5326, but with the use of CH3CN purity HPLC (contains 0.5% water); water was added.

1H NMR (CD3COCD3) δ with 8.05 (2H, d), of 7.95 (2H, d), 7,8 (2H, d), the 7.65 (2H, d), 4,45-4,55 (1H, m), 3,55-3,6 (1H, m), and 3.2 (3H, s), 2.8 to 3.0 (SIRM, NH/OH), 1,95-2,05 (1H, m), 1,55-1,6 (2H, m), 0.9 to 1.0 (6H, m).

Step 7:obtaining N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

To DMF-GE (200 ml) solution of the acid from step 7 (9 g) was added benzotriazol-1-yloxytris(dimethylamine)phosphodiesterase (11.6 g), hydrochloride aminoacetonitrile (3.94 g) and the mixture was cooled to 0°C. Triethylamine (9,9 ml) was added dropwise, the mixture was heated to room temperature and was stirred for 16 hours. The mixture is poured into ice and saturated aqueous sodium bicarbonate and was extracted with diethyl ether (CH ml). The combined extracts were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum. The residue was purified by chromatography on SiO2using ethyl acetate and hexane (1:1). Specified in the header of the connection is then stirred in diethyl ether for 16 hours, filtered and dried (TPL to 140.5 °C).

1H NMR (CD3COCD3) δ 8,0 (2H, d), of 7.95 (2H, d), 7,8 (2H, d), the 7.65 (2H, d), 4,35-5 of 4.45 (1H, m), 4,1-4,2 (2H, m), 3,45-3,55 (1H, m)and 3.15 (3H, s), 2,65-2,7 (1H, m), 1.85 to 1,95 (1H, m), 1,4-1,6 (2H, m), 0,85-0,95 (6H, m).

EXAMPLE 9

Synthesis of N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide

Stage 1:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide

A suspension of N5IO6/CrO3(1925 ml 0,44M in CH3CN; see note on stage 6, example 8) was cooled to 0°C was added dropwise a solution of (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}-4-methylpentan-1-ol from step 4 of example 8 (60 g) in CH3CN (1500 ml). The mixture was stirred at 0-5°C for 3.5 hours. The mixture was poured in Na2HPO4pH 4 (2.5 l) under vigorous stirring and was extracted with diethyl ether (CH ml). The combined ether extracts were washed with water and saturated salt solution (1:1), dilute aqueous NaHSO3and saturated salt solution. The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo to obtain N-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-L-leucine used as such in the subsequent connection aminoacetonitrile.

To DMF-GE (1500 ml) solution of the crude acid (46 g) was added benzotriazol-1-yloxytris(dimethylamine)phosphonium hexaflurophosphate (71,5 g), hydrochl the reed aminoacetonitrile (25.4 g) and the mixture was cooled to 0° C. Triethylamine (of 60.8 ml) was added dropwise and the mixture was heated to room temperature and was stirred for 16 hours. The mixture is poured into ice and saturated aqueous sodium bicarbonate and was extracted with diethyl ether (CH ml). The combined extracts were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum. The residue was purified by chromatography on SiO2using a gradient of ethyl acetate and hexane (1:3 to 1:2) to obtain specified in the title compound, sufficiently pure for use in the next stage.

1H NMR (CD3COCD3) δ 7,95-8,05 (CL, NH), and 7.6 (2H, d), was 7.45 (2H, d), and 4.4 (1H, m), 4.1 to 4.2 (2H, m), 3,4-3,5 (1H, m), 2,6-2,7 (1H, m), 1,8-of 1.95 (1H, m), 1,4-1,6 (2H, m), 0,85-0,95 (6H, m).

Stage 2:obtaining N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-L-leucinamide

The stream of nitrogen was passed through the DMF-s (700 ml) suspension of N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide with stage 1 (28.5 g), bis(pinacolato)diboron (23 g) and potassium acetate (24 g) for 15 minutes followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex (1:1) with dichloromethane (2.9 g). The mixture was heated to 65°C and stirred under nitrogen atmosphere for 2.5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and hexa is ω (1:1, 300 ml) and poured into water (2 l) and ice (500 g). The organic layer was separated and the aqueous layer was additionally extracted with ethyl acetate and hexane (1:1, h ml). The combined extracts were washed with saturated saline and dried with magnesium sulfate. After removal of the solvent left a residue that was purified by chromatography on SiO2using ethyl acetate and hexane (1:2) to obtain boronate.

1H NMR (CD3COCD3) δ 7,95-8,05 (CL, NH), 7,7-7,8 (2H, d), 7,45-of 7.55 (2H, d), a 4.3 and 4.4 (1H, m), 4,05-to 4.15 (2H, m), 3,4-3,5 (1H, m), 2,55-to 2.65 (1H, m), 1.85 to 1,95 (1H, m), 1,45-1,55 (2H, m), of 1.15 to 1.4 (12H, m; as impurities also present some the number of pinacol), 0,85-0,95 (6H, m).

Stage 3: obtaining N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide

The stream of nitrogen was passed through the suspension obtained from boronate from stage 2 (4 g), 4-bromobenzaldehyde (3.3 grams), 2M Na2CO3(20 ml) and n-propanol (100 ml) for 15 minutes. Then was added a 1:3 mixture (0.25 g) Pd(OAc)2and PPh3the reaction mixture was heated to 85°C and stirred under nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and poured into water (500 ml) and ice (100 g). Separating the layer of ethyl acetate and the aqueous layer was additionally extracted with ethyl acetate (100 ml). United an ethyl acetate extracts industry is Ali dilute aqueous NaHCO 3saturated saline and dried with magnesium sulfate. After removal of the solvent left a residue that was purified by chromatography on SiO2using a gradient of ethyl acetate, hexane and dichloromethane (2:3:0.1 to 1:1:0,1). The product was then stirred in diethyl ether for 16 hours, filtered and dried to obtain specified in the connection header.

1H NMR (CD3COCD3) δ 8-8,1 (3H, m), and 7.9 (2H, d), 7,8 (2H, d), the 7.65 (2H, d), and 6.6 and 6.7 (2H, m), 4,4 (1H, m), 4,1-4,2 (2H, m), 3,5 (1H, m), 2,6-2,7 (1H, m), and 1.9 (1H, m), 1,45-1,6 (2H, m), is 1.4-1.6 (4H, m), about 0.9-1.0 (6H, m).

EXAMPLE 10

Synthesis of N1-(1-cyanocyclohexyl)-N2-{(1S)2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

To a mixture of N-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucine from Example 8 (0,83 g), O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethyluronium of hexaflurophosphate (0,78 g), cyclopropylamine hydrochloride (0,466 g) in DMF (18 ml) at 0°C was added triethylamine (0.9 ml). The mixture was stirred at room temperature for 48 hours and then poured into dilute aqueous ammonium chloride and diethyl ether. Separated ether layer, and additional water was extracted with diethyl ether. The combined ether extracts were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum. The residue was purified in SiO 2using ethyl acetate and hexane (1:1) as eluent, followed by dilution in tietelbaum live with obtaining specified in the connection header.

1H NMR (CD3COCD3) δ 8,15 (1H, CL), with 8.05 (2H, d), and 8.0 (2H, d), 7,8 (2H, d), the 7.65 (2H, d), 4,35 is 4.45 (1H, m), 3,35 is-3.45 (1H, m), and 3.2 (3H, s), 2,65-2,7 (1H, m), 1.85 to 1,95 (1H, m), 1.3 to 1.6 (5H, m), 1,05-1,15 (1H, m), 0,85-0,95 (6H, m).

EXAMPLE 11

Synthesis of N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4-pyridin-4-ylphenyl)propyl]-L-leucinamide

Stage 1:receipt of(4S)-4-isobutyl-2-(pentafluoroethyl)-1,3-oxazolidine

Pentafluoropropyl methyl hemiacetal (14.9 g, of 82.8 mmol) and L-leucinol (9.7 g, of 82.8 mmol) was dissolved in 100 ml of benzene and heated under reflux overnight in a flask equipped with a nozzle Dean-stark. The resulting solution was cooled and concentrated to obtain specified in the connection header in the form of oil, which was used directly in the next stage.

Stage 2:obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]amine}-4-methylpentan-1-ol

To -78°C the solution dibromobenzene with (9,85 g of 41.8 mmol) in 100 ml THF was added BuLi with 16.5 ml of a 2.5m solution of hexane, 41.2 mmol)to give a thick suspension. After stirring for 10 min was added to a solution of (4S)-4-isobutyl-2-(pentafluoroethyl)-1,3-oxazolidine (3.3 g, 13 mmol) in 3 ml THF, getting a dark brown Rast is op. The solution was allowed to warm to room temperature, then poured into saturated aqueous ammonium chloride and was extracted with ether. Purification via chromatography on silica gel (10% to 40% ethyl acetate/hexane gradient) gave the titled compound as a single diastereoisomer.

Stage 3:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide

Total sample (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]amine}-4-methylpentan-1-ol (1.6 g, 4.0 mmol) were converted into listed in the title compound using the method of example 8, stages 6 and 7. Purification via chromatography on silica gel (15% to 80% ethyl acetate/hexane gradient) gave the titled compound in the form of solids.

1H NMR (CD3COCD3, 500 MHz) δ 7,8 (1H, W), at 7.55 (2H, m), 7,40 (2H, m), 4,4-4,5 (1H, m), of 3.95 (2H, m)to 3.33 (1H, m)of 2.75 (1H, m), equal to 1.82 (1H, m), and 1.5 (1H, m), 1,38 20 (1H, m)to 0.88 (6H, DD).

Stage 4:obtaining N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4-pyridin-4-ylphenyl)propyl]-L-leucinamide

To a solution of N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide (82 mg, 0.18 mmol), 4-pyridylamino acid (30 mg, 0.24 mmol) and PdCl2(dppf) (14 mg, 0.02 mmol) in 2.5 ml DMF was added 2M Na2CO3(0.25 ml). The mixture was heated to 95°C for 2.5 h, then was cooled and distributed between water Na2CO3 and ether. The aqueous phase was washed with saturated saline and was dried over MgSO4. Purification by chromatography on silica gel (65% to 95% ethyl acetate/hexane gradient) gave the titled compound.

1H NMR (CD3COCD3, 500 MHz) δ 8,66 (2H, m), a 7.85 (1H, W), 7,81 (2H, m), of 7.70 (2H, m), a 7.62 (2H, m), 4,5-4,6 (1H, m), of 3.95 (2H, m), 3,4 (1H, m), of 2.81 (1H, m), a 1.88 (1H, m)of 1.55 (1H, m)of 1.42 (1H, m)to 0.92 (6H, DD).

EXAMPLE 12

Synthesis of N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

Stage 1:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine

Obtained as in stage 1 of Example 8.

Stage 2:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-[(1E)-2,2-defloration]-4-methylpentan-2-amine

A mixture of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (8.5 g, to 36.8 mmol) and divorcecollege of ethylenically (5.0 g, and 39.7 mmol) in benzene was heated under reflux with a nozzle Dean-stark during the night. The solvent was removed in vacuum. The residue was passed through a short column with silica gel and was suirable hexane:EtOAc (10:1) to obtain specified in the title compounds as a pale yellow oil.

1H NMR (CD3COCD3) δ 7,72 (m, 1H), 6,12 (dt, 1H), 3,70 (DD, 1H), 3,54 (DD, 1H), 3,36 (m, 1H), 1,48 (m, 2H), 1,32 (m, 1H), 0,95 - 0,78 (m, 15H), is 0.06 (s, 3H), of 0.02 (s, 3H).

Stage 3:the floor is giving (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2-dottorati]amine}-4-methylpentan-1-ol

n-BuLi (2.5 M in hexane, 1,43 ml) was added to -70°C THF (8.5 ml) solution of 1,4-dibromobenzene with (884 mg) and the mixture was stirred for 15 minutes. Then added on Kaplan THF (8.5 ml) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-N-[(1E)-2,2-defloration]pentane-2-amine (1.0 g) and the mixture was stirred for 1.5 hours. This mixture was then slowly poured into ice-cold saturated aqueous solution of ammonium chloride under vigorous stirring and was extracted with 3 portions of ethyl acetate. The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using a gradient of hexane and ethyl acetate (90:10 to 75:25) as eluent to obtain (2S)-N-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine. (2S)-N-[(1S)-1-(4-Bromophenyl)-2,2-dottorati]-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine (200 mg) was dissolved in CH3CN (4 ml) and the solution was cooled to 0°C. was Added dropwise HF-pyridine (40 μl) and the mixture is worked for 16 hours. The mixture was poured into saturated sodium bicarbonate solution were added ethyl acetate and the resulting mixture was intensively shaken. The organic layer was separated and water was additionally extracted with ethyl acetate (CH ml). The combined organic layers washed is whether saturated salt solution, was dried with magnesium sulfate, the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using a gradient of hexane and ethyl acetate (80:20 to 60:40) as eluent, to obtain specified in the connection header.

1H NMR (CD3COCD3) δ and 7.6 (2H, d), was 7.45 (2H, d), and 6.0 (1H, dt), 4,25 (1H, m), the 3.65 (1H, t), 3,5-3,55 (1H, m), 3,3-to 3.35 (1H, m), 2,55-to 2.65 (1H, m), 2,15 was 2.25 (1H, m), 1.6 to 1.7 (1H, m), to 1.3-1.4 (1H, m), 1,2-1,3 (1H, m), and 0.9 (3H, d), and 0.8 (3H, d).

Stage 4: obtaining N-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-L-leucine

A suspension of N5IO6/CrO3(5.5 ml 0,40M in CH3CN; see note below) was cooled to 0°C was added dropwise a solution of alcohol from step 3 (250 mg) in CH3CN (3,7 ml). The mixture was stirred at 0-5°C for 3.5 hours. After this period, was added 2.0 ml of the developer. After 1.5 hours the mixture was poured in Na2HPO4buffer (0.4 g in 10 ml) under vigorous stirring and the mixture was extracted with diethyl ether (3h20 ml). The combined ether layers were washed with water and saturated salt solution (1:1), dilute aqueous NaHSO3and saturated salt solution. The organic extract was dried with magnesium sulfate, filtered and the solvent evaporated to dryness to obtain specified in the title compound, which was used without further purification.

Note: oxidizing reagent (N5IO6/CrO3) was prepared as described is Tetrahedron Letters 39 (1998), 5323-5326, but using CH3CN purity HPLC (contains 0.5% water); water was added.

1H NMR (CD3COCD3) δ at 7.55 (2H, d), and 7.4 (2H, d), equal to 6.05 (1H, dt), 3,95-of 4.05 (1H, m), of 3.45 (1H, t), 2,7-3,0 (BL, NH/OH), 1.85 to 1,95 (1H, m), 1,5 (2H, t), of 0.95 (3H, d), 0,9 10 (3H, d).

Stage 5:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide

To a DMF (2 ml) solution of the acid from step 4 (258 mg) was added O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (337 mg) and 1-aminocyclopropane hydrochloride (175 mg). After stirring for 1 min was added dropwise diisopropylethylamine (0.45 ml) and the mixture was stirred for 16 hours. The resulting mixture was poured into saturated aqueous sodium bicarbonate and was extracted with ethyl acetate (CH ml). The combined extracts were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum. The residue was purified by chromatography on SiO2using hexane and ethyl acetate(80:20 - 50:50), getting a named connection.

1H NMR (CD3COCD3) δ with 8.05 (1H, m), 7,55 (2H, d), and 7.4 (2H, d), equal to 6.05 (1H, dt), 3,95-of 4.05 (1H, m), 3.25 to a 3.3 (1H, m), 2,4-of 2.45 (1H, m), as 1.8-1.9 (1H, m), 1,4-of 1.55 (2H, m), 0,95-1,1 (2H, m)of 0.95 (6H, t).

Step 6:obtaining N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

A stream of nitrogen was passed through the suspension aryl is of romida with stage 5 (65 mg), 4-(methylthio)phenylboronic acid (40 mg), 2M Na2CO3(0,22 ml) and DMF (1.0 ml) for 5 minutes. Then was added PdCl2(dppf), the reaction mixture was heated to 80°C and stirred under nitrogen atmosphere for 4 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml) and poured into saturated sodium bicarbonate solution. An ethyl acetate layer was separated and water was additionally extracted with ethyl acetate (CH ml). United an ethyl acetate extracts were washed with saturated saline and dried with magnesium sulfate. Removal of the solvent left a residue that was purified by chromatography on SiO2using a gradient of hexane and ethyl acetate(90:10 - 50:50), getting a named connection.

1H NMR (CD3COCD3) δ 8,1 (1H, m), 7,6-the 7.65 (4H, m), 7,45 (2H, d), 7,35 (2H, d), equal to 6.05 (1H, dt), 3,9-4,0 (1H, m), 3,2 and 3.3 (1H, m), 2,5 (3H, s), 2,35-2,4 (1H, m), as 1.8-1.9 (1H, m), of 1.3-1.5 (4H, m), 0,85-1,0 (8H, m).

Step 7:obtaining N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

To a solution of sulfide (50 mg) from step 6 in toluene (1.0 ml) and ethyl acetate (0.1 ml) was added Na2WO4·2H2About (1 mg) and Bu4NHSO4(2 mg). Then slowly added 30% hydrogen peroxide (30 μl) and the mixture was stirred at room temperature for 1.5 hours. The mixture was poured into diluted aqueous solution of t is sulfate sodium and ethyl acetate. The organic layer was separated and water was additionally extracted with ethyl acetate (2x10 ml). The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using hexane and ethyl acetate(50:50 - 0:100), then dichloromethane and diethyl ether (90:10) as eluent to obtain specified in the connection header.

1H NMR (CD3COCD3) δ 8,15 (1H, m), and 8.0 (2H, d), of 7.95 (2H, d), of 7.75 (2H, d), at 7.55 (2H, d)and 6.1 (1H, dt), 4,0-4,1 (1H, m), of 3.25 to 3.35 (1H, m)and 3.15 (3H, s), 2,4-2,5 (1H, m), as 1.8-1.9 (1H, m), 1,4-of 1.55 (4H, m), 0,85-of 1.05 (8H, m).

EXAMPLE 13

Synthesis of N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide

Stage 1:obtain (2S)-2-{[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]amine}-4-methylpentan-1-ol

To a solution of 5-bromo-2-chloropyridine (2.5 g, 13 mmol) in ether (30 ml) at -78°C was added n-utility (13 mmol, 2.5m in hexane). The mixture was stirred at -78°C for 1 h was Added (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methyl-M-[(1E)-2,2,2-triptoreline]pentane-2-amine (of 3.64 g, 11.7 mmol, see step 2 of Example 8). The mixture was stirred at -78°C for 2 hours To the reaction mixture were added saturated aqueous NH4Cl and the mixture was twice extracted with EtOAc. The combined organic extracts were washed n is sasenum salt solution, was dried over anhydrous MgSO4and concentrated to an oil (5.3g). Crude oil (2.0 g) was then treated with (Bu)4NF (6 ml, 1M in THF). The mixture was stirred at room temperature for 1 h, was added saturated aqueous NH4Cl and the mixture was twice extracted with EtOAc. The combined organic extracts were washed with saturated saline, dried over anhydrous MgSO4and concentrated to oil. Chromatography (20% EtOAc/hexane) gave specified in the header of the connection.

Stage 2:obtaining N-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]-L-leucine.

Prepared matrix solution of N5IO6/CrO3the dissolution of H5IO6(68,4 g, 0.3 mol) and CrO3(138 mg, 1.2 mol%) in CH3CN (684 ml) to obtain 0,44M solution. To a solution of N5IO6/CrO3(16 mmol, 36 ml, 0,44M in THF) at -5°C (ice-salt bath) solution was added (2S)-2-{[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-tiptoety]amine}-4-methylpentan-1-ol (1 g) in 3 ml THF dropwise. Monitored internal temperature and the reaction temperature was not allowed to rise above 0°C. the Reaction was controlled by TLC until completion of the reaction (3-4 hours). To the reaction mixture was added Na2HPO4(80 ml), then was extracted with EtOAc. The organic extract was washed with saturated saline solution, NaHSO3(120 ml) and again with saturated sollevamento, was dried over anhydrous MgSO4and concentrated to oil. The oil was re-dissolved in EtOAc and filtered through a thin layer of silica gel, was suirable EtOAc and the filtrate was concentrated to obtain specified in the connection header.

Stage 3:obtaining N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide

To a solution of the crude acid (0.73 g, 2.25 mmol) from step 2 in DMF (12 ml) was added 1-aminocyclopropane hydrochloride (0.4 g, 3,37 mmol) and HATU (0,86 g, 2.25 mmol). Added diisopropylethylamine (1,96 ml, 11,24 mmol), the mixture was stirred at room temperature for 20 hours was Added EtOAc and water. The mixture was separated after mixing, the organic extract was washed with water and saturated saline and dried over anhydrous MgSO4. Concentration of the organic extract with subsequent chromatography (30-50% EtOAc/hexane) gave specified in the header of the connection.

MS (+ESI): 389,3 [M+1]+.

1H NMR (CD3COCD3, 500 MHz): δ to 0.92 (d, 3H, J = 6.6 Hz), of 0.93 (d, 3H, J = 6.6 Hz), 1.00 m ( m, 1H), 1,09 (m, 1H), 1,45 (m, 4H), 1,90 (m, 1H), 2,81 (m, 1H), 3.43 points (m, 1H), 4,47 (m, 1H), 7,54 (d, 1H, J = 8,3 Hz), 7,98 (d, 1H J = 6.2 Hz)and 8.1 (s, 1H), 8,5 (s, 1H).

EXAMPLE 14

Synthesis of N2-{(1S)-1-[6-(4-acetylphenyl)pyridine-3-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide

To a solution of N2-[(1S)-1-(6-x is herperidin-3-yl)-2,2,2-triptorelin]-N 1-(1-cyanocyclohexyl)-L-leucinamide (100 mg, 0.26 mmol) in toluene (1.5 ml) and n-propanol (0.4 ml) was added in a stream of nitrogen of 4-(acetyl)phenylboronic acid (55 mg, 0.33 mmol), Pd(PPh3)4(15 mg, of 0.013 mmol) and Na2CO3(2M, 0.5 ml). The mixture was degirolami rapid stream of nitrogen, barbotine through the mixture, and the mixture was heated to 150°C in a microwave reactor Smith Creator (Personal Chemistry AB, Uppsala, Sweden) for 800 seconds. The mixture was cooled, diluted with EtOAc and washed with water. Chromatography (50% EtOAc/hexane) gave specified in the header of the connection.

MS (+ESI): 473,2 [M+1]+.

1H NMR (500 MHz, CD3COCD3): δ of 0.93 (d, 3H, J = 6.6 Hz), were 0.94 (d, 3H, J = 6.6 Hz), with 1.07 ( m, 1H), 1,40 (m, 2H), 1,49 (m, 1H), 1.55V (m, 1H), 1,92 (m, 1H), 2,66 (s, 3H), and 2.83 (m, 2H), 3.45 points (m, 1H), 4,50 (m, 1H), 8,15 (m, 5H), 8,30 (d, 2H, J = 8.5 Hz), 8,79 (s, 1H).

EXAMPLE 15

Synthesis of N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

Stage 1:obtain benzyl(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutanoic

N-(tert-Butoxycarbonyl)-L-asparaginases acid 4-benzyl ester (30 g) was dissolved in dimethoxyethane (90 ml) and the solution was cooled to -5°C. was Added N-methylmorpholine (10,32 ml) followed by slow addition of isobutylphthalate (12,66 ml) so that the reaction temperature was kept below -10°C. the Mixture was stirred during the course the e 0.5 hours. The solids were rapidly filtered and washed with dimethoxyethane (90 ml). The filtrate was cooled to -50°C, was slowly added a solution of sodium borohydride (4.4 g) in water (45 ml) so that the reaction temperature was maintained between -30 and -15°C. Then was added water (500 ml) so that the temperature of the reaction mixture was kept below -15°C. the Suspension was filtered, the solid washed with water (400 ml) and dried to obtain benzyl(3S)-3-[(tert-butoxycarbonyl)amine]-4-hydroxybutanoic.

1H NMR (CD3COCD3) δ 7,3 was 7.45 (5H, m), 5,85-5,95 (1H, NH), of 5.15 (2H, s), 3.95 to a 4.1 (2H, m), of 3.5-3.7 (2H, m), 2,55 is 2.75 (2H, m), and 1.4 (9H, s).

Stage 2: obtain benzyl[(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate

To a solution of alcohol (95,7 g) from step 1 in dichloroethane (925 ml) was added pyridine (625 ml) and the mixture was cooled to 0-5°C. was Added anhydrous n-toluensulfonyl anhydride (105,7 g) and the mixture was heated to room temperature and was stirred for 1 hour and then was heated to 90°C for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 ml) and washed with 1N HCl (g ml). The organic layer was washed with saturated saline solution, dried with sodium sulfate and the solvent was removed in vacuum. The residue was purified by chromatography on SiO2using ethyl acetate and hexane in a ratio of 1:1, then ethyl acetate to obtain benzyl[(4S)-2-oxo-1,3-oxazolidin-4-yl]acetate.

1/sup> H NMR (CD3SOCD3) δ 7,8 (1H, NH), 7,3 was 7.45 (5H, m), of 5.05-of 5.15 (2H, m), 4,4-4,5 (1H, m), 4,1-4,2 (1H, m), 4,0-of 4.05 (1H, m), 3,6-3,8 (2H, m).

Stage 3:receipt of (4S)-4-(2-hydroxy-2-methylpropyl)-1,3-oxazolidin-2-it

Bromide Metalmania (227 ml of 3M solution in diethyl ether) was added to a mixture of toluene (340 ml) and THF (340 ml) at -20°C. Then was added dropwise warm THF th solution (170 ml) of the ester from step 2 (40 g), keeping the temperature below -10°C. the Mixture was stirred for 2 hours, and then was slowly added to a mixture of water (1000 ml) and acetic acid (200 ml) and the resulting mixture was stirred for 2 hours at room temperature. Separated water layer, and the organic layer was extracted with water (I ml). The product was extracted from the combined aqueous layers using dichloromethane and extraction apparatus of continuous operation. The dichloromethane extract was evaporated to dryness using heptane as a co-solvent for azeotropic distillation of acetic acid. The residue was purified by chromatography on SiO2using ethanol and dichloromethane (1:30), with (4S)-4-(2-hydroxy-2-methylpropyl)or 11.3-oxazolidin-2-it.

1H NMR (CD3COCD3) δ 6,1-a 6.4 (1H, NH), 4,45-4,55 (1H, m), 4,1-4,2 (1H, m), 3.95 to of 4.05 (1H, m), and 3.7 (1H, s), 1,65-of 1.85 (2H, m), 1,25 (6H, m).

Stage 4: receive (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-it

Dichloromethane solution (100 ml) alcohol (47,8 g) with the stage 3 was added to the solution TRIFLUORIDE(diethylamino)sulfur (48,8 g) in dichloromethane (500 ml) at -70° C. the Mixture was heated to room temperature and was stirred for 1 hour. Then the mixture was carefully added to the mixture at 0°C saturated aqueous NaHCO3(800 ml). The organic layer was separated and washed with saturated aqueous NaHCO3. The aqueous layer was additionally extracted with dichloromethane (100 ml) and the combined dichloromethane layers were dried and concentrated. The residue was purified by chromatography on SiO2using ethyl acetate and hexane (1:5), then with ethyl acetate to obtain (4S)-4-(2-fluoro-2-methylpropyl)-1,3-oxazolidin-2-it.

1H NMR (CD3SOCD3) δ and 7.6 (1H, NH), 4,4-4,5 (1H, m), 3.95 to of 4.05 (1H, m), 3,9-of 3.95 (1H, m), 1,8-of 1.95 (2H, m), 1,25-1,4 (6H, 2s).

Stage 5: obtain (2S)-2-amino-4-fluoro-4-methylpentan-1-ol

To a solution of porpoising (21,0 g) from step 4 in 90% aqueous ethanol (216 ml) was added potassium hydroxide (21,9 g). The mixture was heated under reflux for 4 hours and cooled to room temperature. The mixture is then concentrated and co evaporated with toluene (g ml). The residue was dissolved in dichloromethane (500 ml) and was stirred for 0.5 hour. The suspension was filtered through celite and the celite was washed with dichloromethane (I ml). The filtrate was concentrated to dryness to obtain (2S)-2-amino-4-fluoro-4-methylpentan-1-ol.

1H NMR (CD3OD) δ 3,4-3,5 (1H, m), 3,2 and 3.3 (1H, m), 3,0-3,1 (1H, m), 1,5-1,7 (2H, m)of 1.35 (3H, s), 1,3 (3H, s).

Step 6:the floor is giving (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine

Amerosport (21,0 g) from step 5 was dissolved in dichloromethane (300 ml) and the solution was cooled to 0°C. was Added 4-(dimethylamine)pyridine (0,051 g) and chloride tert-butyldimethylsilyl (21 g), then triethylamine (25 ml). The mixture was stirred at room temperature overnight. The reaction mixture was slowly poured into a 0°C saturated aqueous ammonium chloride and was extracted with dichloromethane (I ml). The organic layer was washed with saturated saline solution, dried with sodium sulfate, and the solvent was removed in vacuum to obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine.

1H NMR (CD3OD) δ 3,6-the 3.65 (1H, m), 3,4-3,5 (1H, m), 3,1-3,2 (1H, m), 1,6-1,8 (2H, m), 1,35-1,45 (6H, m)of 0.93 (9H, s), 0,1 (6H, s).

Step 7:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methyl-N-[(1E)-2,2,2-triptoreline]pentane-2-amine

To a solution of amine (31,5 g) from step 6 in benzene (126 ml) was added triptorelin of methylgalactose (21,6 ml). The solution was heated under reflux overnight using a nozzle Dean-stark water collection. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was purified on SiO2using 4% ethyl acetate in hexane to obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-fluoro-4-methylpentan-2-amine.

1H NMR (CD3COCD3) δ 7,9-of 7.95 (1H, m), 3.75 to of 3.85 (1H, m), 3,7-of 3.75 (1H, m), 3,53-3,6 (1H, m), 1,9-,0 (2H, m), 1,3-1,4 (6H, m), and 0.9 (9H, s), 0,1 (3H, s), 0,05 (3H, s).

Step 8:obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amine}-4-fluoro-4-methylpentan-1-ol

To -75°C to a solution of 1,4-dibromobenzene with (0.26 g) in THF (4 ml) was added n-BuLi (0,42 ml of a 2.5m solution of hexane) and the mixture was stirred for 20 minutes. Added Imin (0,329 g) from step 7 in THF (2 ml) and the mixture was stirred for 2 hours. Then the mixture was added to a mixture of water (50 ml), NH4Cl (1 g) and crushed ice. The mixture was extracted with ethyl acetate (CH ml) and the combined an ethyl acetate layers were dried and evaporated to dryness.

The same procedure was repeated on a larger scale, using 1,4-dibromobenzyl (1.2 g), n-BuLi (1,84 ml) and Imin (1,38 g)and the reaction mixture was treated as described above. United remains of two preparations was dissolved in THF (10 ml) and cooled to 0°C. was Added fluoride n-tetrabutylammonium (6 ml of 1M THF solution), the mixture was stirred at +5°C for 16 hours the Mixture was poured into a mixture of water (50 ml), ammonium chloride (1 g) and crushed ice and the separated organic layer. The aqueous layer was additionally extracted with ethyl acetate (CH ml), the combined organic layers were dried and concentrated. The residue was purified on SiO2using ethyl acetate and hexane (1:5), to obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amine}-4-fluoro-4-methylpentan-1-ol.

1H NMR (CD3COCD3) δ the 7.65 (2H, m), and 7.5 (2H, m), 4,5-4,6 (1H, m), and 3.8 (1H, m),3,6 (1H, m), 3,3-3,4 (1H, m), 2,85-2,0 (1H, m)to 2.55 (1H, m), 1,7-1,9 (2H, s), 1,3-1,4 (6H, m).

Step 9:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide

A suspension of N5IO6/CrO3(66 ml 0,44M in CH3CN; see note) was cooled to 0°C was added dropwise a solution of alcohol from step 8 (1.55 g) in CH3CN (5 ml). The mixture was stirred at 0-5°C for 3.5 hours. The mixture was poured in Na2HPO4pH 4 (200 ml) with vigorous stirring and the mixture was extracted with diethyl ether (CH ml). The combined ether extracts were washed with water and saturated salt solution (1:1), then diluted aqueous NaHSO3and saturated salt solution. The mixture was dried with sodium sulfate, filtered and the solvents evaporated to dryness to obtain N-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-4-fluoro-L-leucine, which is used as such in the next stage.

Note: oxidizing reagent (N5IO6/CrO3) was prepared as described in Tetrahedron Letters 39 (1998), 5323-5326, but using CH3CN purity HPLC (contains 0.5% water); water was added.

Diisopropylethylamine (4,2 ml) was added to a 0° (C) suspension of the acid (1.5 g), above, 1-amino-1-cyclopropanecarbonitrile hydrochloride (1.18 g), O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea of hexaflurophosphate (1,94 g) and dimethylformamide (5 ml), the mixture vzaimodeistvov the La at room temperature for 48 hours The mixture is then poured into ice and diluted with aqueous ammonium chloride. The mixture was extracted with ethyl acetate and ether (1:1) and the combined organic layers were washed with diluted Na2HPO4, pH 3, and saturated salt solution. The solvents are evaporated to dryness and the residue was purified by chromatography on SiO2using ethyl acetate and hexane (1:2), with N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide sufficient purity for the next stage.

1H NMR (CD3COCD3) δ 8,15 (1H, NH), and 7.6 (2H, m), 7,45 (2H, m), 4,35 is 4.45 (1H, m), 3,45-3,55 (1H, m), 1,9-2,1 (2H, m), 1,75-of 1.85 (1H, NH),1,35-of 1.55 (8H, m), 1,1-of 1.15 (1H,m), 0,95-1,05 (1H, m).

Step 10:obtaining N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

A stream of nitrogen was passed through a suspension of the bromide from step 9 (0,338 g), 4-(methylthio)phenylboronic acid (0,252 g), 2M aqueous Na2CO3(0.8 ml) and DMF (4 ml) for 15 minutes. Then was added PdCl2dppf (0.3 g) and the reaction mixture was heated to 85°C and stirred under nitrogen atmosphere for 5 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 ml) and poured into water (50 ml) and ice. Separating the layer of ethyl acetate, and water was additionally extracted with ethyl acetate. United an ethyl acetate extracts were dried and dissolve and was removed in vacuum. The residue was purified by chromatography on SiO2using ethyl acetate and hexane (1:2), with N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide.

1H NMR (CD3COCD3) δ 8,15 (1H, NH), 7,1-7,2 (4H, m),7.5 to at 7.55 (2H, m), 7,35 to 7.4 (2H, m), a 4.3 and 4.4 (1H, m), 3,45-3,55 (1H, m), 2,75-2,8 (1H, NH), 2,5 (3H, s), 1,9-of 2.05 (2H, m), 1.3 to 1.5 (8H, m), to 1.0-1.1 (1H, m), 0,85-0,95 (1H, m).

Stage 11:obtaining N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

0°With the solution of the sulfide (0,265 g) from stage 10 in toluene (5 ml) and dichloromethane (5 ml) was added Na2WO4·2H2O (0.002 g) and n-Bu4NHSO4(0.01 g). Then slowly added 30% hydrogen peroxide (0,137 ml) and the mixture was stirred at room temperature for 3 hours. The mixture was slowly poured into a mixture of ice and dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated and water was additionally extracted with ethyl acetate. The combined organic layers were washed with saturated salt solution, dried by magnesium sulfate and the solvent was removed in vacuum to obtain a residue, which was purified on SiO2using ethyl acetate, hexane and dichloromethane (1:1:0,1) as eluent. The residue was ground into powder in diethyl ether to obtain N1-(1-cyanocyclohexyl)-4-fluoro-N -{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide.

1H NMR (CD3COCD3) δ or 8.2 (1H, NH), 8,05 and 8.1 (2H, m), 7.95 is to 8.0 (2H, m), 7,8 (2H, m), the 7.65 (2H, m), 4,35 is 4.45 (1H, m), 3,5-3,6 (1H, m), and 3.2 (3H, s), 2,8-2,9 (1H, NH), 1,9-2,1 (2H, m), 1.3 to 1.5 (8H, m), 1,05-1,15 (1H, m), 0.9 to 1.0 (1H, m).

EXAMPLE 16

Synthesis of (4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

Stage 1: paluchemie salt 5,5,5-triptorelin hydrochloride

Racemic diastereomer a mixture of ethyl-N-benzoyl-5,5,5-triptoreline (10.0 g, to 31.5 mmol), obtained in accordance with the methodology Ojima et al. (J. Org. Chem., 1989, 54, 4511-4522), was heated under reflux in 6M aqueous HCl (100 ml) for 16 hours After cooling, the mixture was washed Et2O and concentrated in vacuum to obtain racemic diastereomeric mixture of 5,5,5-triptorelin HCl salt.

1H NMR (methanol-d4) δ 4,10 (m, 1H), 2,65 (m, 1H), 2,35 and 1.80 (m, 2H), 1,25 (m, 3H).

Stage 2:methyl(4S)-N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-Latinate and methyl(4R)-N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-Latinate

To a cold (0° (C) the salt solution 5,5,5-triptorelin·HCl (from step 1 above) in H2O (30 ml) was added 1M aqueous NaOH (60 ml, 60 mmol)and then acetic anhydride (3.5 ml, to 36.7 mmol). The mixture was stirred at room temperature for 30 min - 1 hour After podci is of 6M aqueous HCl (6 ml) the mixture was extracted with EtOAc (6x). The combined EtOAc extracts were washed with saturated salt solution, dried (MgSO4) and concentrated. The residue was diluted with hexane:Et2O (1:1) to obtain N-acetyl-5,5,5-triptorelin in the form of a white solid.

To a suspension of N-acetyl-5,5,5-triptorelin (4,2 g, 18.5 mmol) in H2O (35 ml) was added 1M aqueous NaOH (18.5 ml, 18.5 mmol), the mixture was stirred for 15 to 30 minutes to obtain a homogeneous solution. Added acylase I (EC 3.5.1.14, from Sigma, Cat. # A 3010; 55 mg), the mixture was stirred at room temperature overnight. NMR small aliquots (evaporated in vacuum) of the crude substances showed a ratio of 53:47 for the educt and product. The mixture is then acidified 6M aqueous HCl (˜3.5 ml) and was extracted with EtOAc (4x, every EtOAc extract was washed with a small amount of H2About). The combined EtOAc extracts were washed with saturated salt solution, dried (MgSO4) and concentrated to obtain crude N-acetyl-5,5,5-Cryptor-D-leucine in the form of a pale yellow solid, [α]D= + 27,6° (1.5, EtOH). The aqueous layer was concentrated in vacuum and dried in vacuum overnight to obtain 5,5,5-Cryptor-L-leucine, possibly contaminated with NaCl and HCl salts, [α]D= -4,1° (c 0,77, H2O).

To a stirred solution of 5,5,5-Cryptor-L-leucine (12 g) in H2O (150 ml) at 0°C was added benzylchloride (4,8 is l, 34 mol), followed by adding dropwise 1M aqueous NaOH (120 ml, 120 mmol). Additionally added benzylchloride (4.8 ml, 34 mmol). The mixture was additionally stirred at 0°C and the pH of the mixture became ˜7. The mixture was washed Et2O (2x) and acidified aqueous HCl. The aqueous layer was extracted with EtOAc (3x), dried (Na2SO4) and concentrated in vacuo to obtain N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-leucine. The crude acid was dissolved in Et2O, treated with a solution of diazomethane in Et2O. Chromatography over silica gel and elution with hexane:Et2O (7:3) gave methyl(4S)-N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-Latinate in the less polar fractions.

1H NMR (acetone-d6) δ 7,45 - 7,25 (m, 5H), 6,86 (d, 1H), 5,10 (m, 2H), to 4.38 (m, 1H), 3,70 (s, 3H), of 2.45 (m, 1H), 2.05 is (m, 1H), of 1.85 (m, 1H), of 1.16 (d, 3H).

Further elution gave (4R)-N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-Latinate as the more polar fraction contaminated with a small amount of benzyl alcohol.

1H NMR (acetone-d6) δ 7,40 - 7,25 (m, 5H), 6,86 (d, 1H), to 5.08 (s, 2H), 4,35 (m, 1H), 3,70 (s, 3H), of 2.54 (m, 1H), measuring 2.20 (m, 1H), 1,75 (m, 1H), of 1.16 (d, 3H).

Stage 3:(2S,4S)-2-amino-5,5,5-triflora-4-methylpentan-1-ol

To a solution of methyl(4S)-N-[(benzyloxy)carbonyl]-5,5,5-Cryptor-L-Latinate (5,4 g, 16.2 mmol) in EtOH (150 ml) at room temperature was added LiCl (2.8 g, 66 mol) and the mixture was stirred for 10 - 15 min, followed the m by addition of NaBH 4(2.5 g, 66 mmol). The mixture was stirred at room temperature for 6 hours After dilution H2O (60 ml) and the mixture was suppressed 6M aqueous HCl (18 ml). Added additional number of H2O and the mixture was extracted with EtOAc (2x). The combined EtOAc extracts were washed with saturated salt solution, dried (Na2SO4) and concentrated to obtain the crude benzyl(1S,3S)-4,4,4-Cryptor-1-(hydroxymethyl)-3-methylbutylamine.

The above alcohol was dissolved in EtOH (150 ml) was added 10% Pd/C (˜500 mg). The mixture was stirred in an atmosphere of H2(balloon) overnight. The catalyst was filtered through celite and the filtrate was concentrated to obtain specified in the title compounds as colorless oils.

1H NMR (methanol-d4) δ of 3.48 (DD, 1H), 3,38 (DD, 1H), 2,85 (m, 1H), 2,50 (m, 1H), 25 1,62 - of 1.40 (m, 2H), 1,12 (d, 3H).

Stage 4:(2S,4S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-Cryptor-4-methyl-N-[(1E)-2,2,2-triptoreline]pentane-2-amine

(2S,4S)-2-Amin-5,5,5-Cryptor-4-methylpentan-1-ol (2.6 g, of 15.2 mmol) were converted into listed in the title compound, as described in stages 1 and 2 of example 8.

1H NMR (acetone-d6) δ 7,98 (m, 1H), 3,80 (m, 1H), 3,60 (m, 2H), 2,18 (m, 1H), up to 1.98 (m, 1H), 1,65 (m, 1H), 1,12 (d, 3H), from 0.88 (s, 9H), 0.06 to (s, 3H), of 0.02 (s, 3H).

Stage 5:(2S,4S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}-5,5,5-Cryptor-4-methylpentan-1-ol

To a cold (-78° (C) to a solution of 1,4-di is romensya (7.0 g, 29.7 mmol) in Et2O (75 ml) was added dropwise a solution of 2.5 M n-BuLi in hexane (7.0 ml, 17.5 mmol) and the mixture was stirred for 2 h at -78°C. was Added a solution of (2S,4S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-Cryptor-4-methyl-N-[(1E)-2,2,2-triptoreline]pentane-2-amine (3.7 g, 10.1 mmol) in a small amount of Et2O and the mixture was additionally stirred at -78°C for additional 1 h the mixture is Then extinguished H2O, was extracted with EtOAc, dried (MgSO4) and concentrated.

The above crude product was dissolved in THF (20 ml) was added HOAc (0.3 ml). After adding a solution of 1M tetrabutylammonium fluoride in THF (20 ml, 20 mmol), the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the residue was diluted with H2O and was extracted with EtOAc. The EtOAc extract was washed with saturated saline solution, dried (MgSO4) and concentrated. Chromatography over silica gel and elution with hexane:EtOAc (4:1) gave specified in the title compound as a pale yellow oil.

1H NMR (acetone-d6) δ of 7.60 (d, 2H), of 7.48 (d, 2H), 4,58 (m, 1H), 3,80 (t, 1H), 3.45 was 20 (m, 2H), 2,90 (m, 1H), 2,70 (m, 1H, in), 2.25 (m, 1H), 1,75 (m, 1H), 1,45 (m, 1H), 1.14 in (d, 3H).

Step 6:(4S)-N-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-5,5,5-Cryptor-L-leucine

Specified in the title compound was obtained as described in stage 9 of Example 15 from (2S,4S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amine}-5,5,5-three of the top-4-methylpentan-1-ol.

1H NMR (acetone-d6) δ 7,58 (d, 2H), 7,46 (d, 2H), 4,46 (m, 1H), to 3.58 (DD, 1H), 2,80 (m, 1H), 1,92 (m, 1H), 1,72 (m, 1H), 1,20 (d, 3H).

Step 7:(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-L-leucinamide

Specified in the title compound was obtained as described in stage 9 of Example 15 from (4S)-N-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-5,5,5-Cryptor-L-leucine.

1H NMR (acetone-d6) δ 8,20 (Sirs, 1H), to 7.59 (d, 2H), 7,43 (d, 2H), 4,34 (m, 1H), 3,48 (m, 1H), 2,78 (m, 1H), of 1.85 (m, 1H), 1.55V (m, 1H), 1.39 in (m, 2H), 1.14 in (d, 3H), 1,15 - of 0.90 (m, 2H).

MS (+ESI): 486,488 [M+1]+.

Step 8:(4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide

The named compound was obtained as described for Stages 10 and 11 of Example 15 from (4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-L-leucinamide.

[α]D= +66° (c 0.5, acetone).

1H NMR (acetone-d6) δ 8,20 (Sirs, 1H), 8,03 (d, 2H), 7,94 (d, 2H), 7,78 (d, 2H), a 7.62 (d, 2H), to 4.41 (m, 1H), 3,52 (m, 1H), 3,17 (s, 3H), 2,88 (m, 1H), up to 1.98 (m, 1H), 1,58 (m, 1H), 1,35 (m, 2H), of 1.16 (d, 3H), 1,15 - 0,85 (m, 2H).

MS (+ESI): 562 [M+1]+.

EXAMPLE 17

Synthesis of N-benzyl-1-(benzyloxy)-4-fluoro-4-methylpentan-2-amine

Stage 1:obtaining N-(tert-butoxycarbonyl)-4-methylindoline

To a solution of degidro-L-leucine (2.00 g, 15,48 mmol) and di-tert-BUTYLCARBAMATE (10,14 g of 46.4 mmol) in THF OK. 100 ml) and water (about 50 ml) was added triethylamine (12,94 ml of 92.8 mmol). The reaction mixture was stirred at ambient temperature overnight. Added citric acid (about 100 ml of 1M aqueous solution) and the product was extracted with approximately 400 ml of methylene chloride. The organic phase was dried with sodium sulfate, filtered and concentrated by rotary evaporation. Purification by chromatography on silica gel using 0-10% methanol in dichloromethane as eluent gave specified in the header of the connection.

Stage 2:obtain tert-butyl-1-(hydroxymethyl)-3-Metalbud-3-talkabout

To a solution of Boc-degidro-L-leucine (2,84 g, 12.4 mmol) and 4-methylmorpholine (1,36 ml, 12.4 mmol) in dry THF (40 ml), the solid, down to -10°C, was added dropwise isobutylparaben (1,61 ml, 12.4 mmol). The reaction mixture was allowed to mix for 30 minutes and the precipitate was removed by filtration. The filtrate was balanced at 0°C and with stirring was added dropwise a solution of sodium borohydride (0,938 g of 24.8 mmol) in about 10 ml of water. The reaction mixture was allowed to return to ambient temperature and was stirred for an additional hour. The reaction extinguished saturated aqueous sodium bicarbonate and the product was extracted into ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated using a rotary evaporator with Poluchenie specified in the connection header.

MS (+ESI): 216,1 [M-boc-+1]+ .

Stage 3:obtain tert-butylbenzyl{1-[(benzyloxy)methyl]-3-methylbut-3-enyl}carbamate

To a solution of Boc-degidro-L-leucinol (2,56 g, 11,91 mmol) and benzylbromide (3,54 ml, to 29.8 mmol) in DMF (50 ml) was added sodium hydride (1.19 g of 60% dispersion in mineral oil, to 29.8 mmol) and the reaction was left to mix for 3 hours. Added more benzylbromide (3,54 ml) and dispersion of sodium hydride (1.19 g) and the reaction mixture was left to mix for an additional 16 hours. Was added water (about 100 ml) and the product was extracted twice in dichloromethane (100 ml). The organic phases were combined and washed twice about 100 ml of water. The organic phase was dried with magnesium sulfate, filtered and concentrated using a rotary evaporator. Purification via chromatography on silica gel using a gradient of 0-5% ethyl acetate in hexane gave specified in the header of the connection.

Stage 4:obtain N-benzyl-1-(benzyloxy)-4-fluoro-4-methylpentan-2-amine

A solution of 70% hydrohloride in pyridine (3.75 ml) was balanced to 0°C in polypropylene tank. Solution was added benzyl ester N-benzyl-boc-(L)-leucinol (1.52 g, of 3.85 mmol) and the reaction mixture was left to mix for 6 hours. The reaction vessel was then balanced in an ice bath and left for the flow is eacli for 5 days. The reaction was suppressed by the addition of ice water and the product was extracted into methylene chloride. Purification by chromatography on silica gel using a gradient of 0-10% methanol in dichloromethane gave specified in the header of the connection.

MS (+ESI): 316,0 [M+1]+.

EXAMPLE 18

Synthesis of cyanoethylated (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentanol acid

Stage 1:obtaining methyl ester 2-benzyloxycarbonylamino-5,5,5-Cryptor-Penta-2-enoeou acid

Timetravel ether N-(benzyloxycarbonyl)-α-phosphoglycan and DBU were dissolved in dry methylene chloride (50 ml) and the reaction mixture was cooled to -30°C. 3,3,3-Tryptophanol (1 EQ.) was added dropwise to a cooled and stirred solution and the reaction mixture was left to mix for an additional hour at -30°C, and then overnight at ambient temperature. Added methylene chloride (about 100 ml) and the organic phase is washed with 1N HCl (about 100 ml), then saturated saline solution (about 100 ml). The organic phase was dried over MgSO4, was filtered and was concentrated using a rotary evaporator. This crude product was purified by chromatography on silica gel with a gradient of 10-30% ethyl acetate in hexane to obtain methyl ester 2-benzyloxycarbonylamino-5,5,5-thrift cent-2-enoeou acid as a white crystalline solid.

MS (+ESI): 318,0 [M+1]+.

Stage 2:obtaining methyl ester (S)-2-benzyloxycarbonylamino-5,5,5-cryptocentrus acid

Methyl ester 2-benzyloxycarbonylamino-5,5,5-triterpen-2-enoeou acid (shed 15.37 g of 48.5 mmol) was dissolved in absolute ethanol (100 ml) in a hydrogenation vessel Parra. The solution was barbotirovany stream of nitrogen, and then was added (+)Duphos (350 mg). The reaction mixture was placed in a hydrogenation apparatus Parra and pumped the air from the space above the mixture, and then created a pressure of 50 pounds per square inch of hydrogen. This process was repeated seven times, and the vessel is then subjected to a pressure of 50 psi of hydrogen and stirred in a Parr apparatus overnight. The reaction mixture was then concentrated by rotary evaporation, dissolved in 1:1 ethyl acetate:hexane and filtered through a layer of silica to remove the catalyst. The filtrate was concentrated using rotary evaporator to obtain the crude methyl ester (S)-2-benzyloxycarbonylamino-5,5,5-cryptocentrus acid, which transferred without additional purification.

Stage 3:getting benzyl ester (S)-(4,4,4-Cryptor-1-hydroxymethyluracil)carbamino acid

Methyl ester (2S)-2-benzyloxycarbonylamino-5,5,5-cryptocentrus acid from step 2 was dissolved in dry THF (400 ml). A solution of LiBH4/sub> (2,11 g in 100 ml dry THF) was added dropwise with stirring and the solution was left to mix at ambient temperature over night. The reaction mixture was concentrated using a rotary evaporator and was added 400 ml of water. Then brought the pH to 2 by addition of concentrated HCl, and then the product was extracted into ethyl acetate. The organic phase is washed twice with water, dried with MgSO4, filtered and concentrated using rotary evaporator to obtain the crude benzyl ether (S)-(4,4,4-Cryptor-1-hydroxymethyluracil)carbamino acid.

MS (-ESI): 290,2 [M-1]+.

Stage 4:getting benzyl ester [1-(tert-butyldimethylsilyloxy)-4,4,4-tripcomputer]carbamino acid

To a solution of benzyl ether (S)-(4,4,4-Cryptor-1-hydroxymethyluracil)carbamino acid (13,89 g of 47.7 mmol) and triethylamine (7,32 ml of 52.5 mmol) in DMF (60 ml) was added dropwise, with stirring, a solution of tert-butyldimethylsilyloxy (to $ 7.91 g in 40 ml DMF) at ambient temperature. The solution was left to mix overnight at ambient temperature. The reaction mixture was then concentrated by rotary evaporation and was added ethyl acetate. The organic phase is twice washed with water, dried using MgSO4, filtered and concentrated using rotary is spartia. The crude product was purified by chromatography on silica gel using 10% ethyl acetate in hexane as the eluent, to obtain the benzyl ester [1-(tert-butyldimethylsilyloxy)-4,4,4-Cryptor-butyl]carbamino acid as a white crystalline solid.

MS (+ESI): 406,2 [M+1]+.

Stage 5:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-triterpene-2-amine

Benzyl ether [1-(tert-butyldimethylsilyloxy)-4,4,4-tripcomputer]carbamino acid was dissolved in absolute ethanol (100 ml) in a hydrogenation vessel Parra and the solution was barbotirovany nitrogen. Was added 10% Pd on coal (1.8 g) and the vessel was placed in a hydrogenation apparatus Parra. Pumped air from the free space of the vessel, and then created a pressure of 50 pounds per square inch of hydrogen. This process was repeated seven times, and then the vessel of podurgiel pressure 50 psi of hydrogen and stirred in a Parr apparatus overnight. The catalyst was removed by filtration through Celite®and then the reaction mixture was concentrated by rotary evaporation to obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-triterpene-2-amine.

MS (+ESI): 272,1 [M+1]+.

Step 6:obtain (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-Cryptor-N-[(1E)-2,2,2-triptoreline]pentane-2-amine

A solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5-triterpene-2-amine (3.00 g, 11,06 mmol) and triptoreline of ethylenically (1.6 g, 11.1 mmol) in benzene (20 ml) was heated under reflux for 2 hours, during which time water was collected in the nozzle Dean-stark. The solvent was removed in vacuo to obtain crude (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-Cryptor-N-[(1E)-2,2,2-triptoreline]pentane-2-amine.

MS (+ESI): 352,2 [M+1]+.

Step 7:obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}-5,5,5-triterpene-1-ol

n-BuLi (2.5 M in hexane, to 21.4 ml) was added dropwise to a stirred solution of 1,4-dibromobenzene with (12,6 g) in dry diethyl ether (80 ml) at -30°C and the reaction mixture was stirred for 30 minutes. Then was added dropwise a solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-5,5,5-Cryptor-N-[(1E)-2,2,2-triptoreline]pentane-2-amine (3.75 g, is 10.7 mmol) in dry diethyl ether (30 ml) and the reaction mixture was left to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was then extinguished with 100 ml of water. The organic phase was washed with saturated saline solution, dried by magnesium sulfate and filtered. The filtrate was concentrated by rotary evaporation to obtain crude product, which was purified by chromatography on silica gel using 1% ethyl acetate in hexane as eluent to obtain (S)-[1-(4-brave who yl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)-4,4,4-tripcomputer]amine (1.8 g). (S)-[1-(4-Bromophenyl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)-4,4,4-tripcomputer]amine was dissolved in THF (50 ml) and cooled to 0°C and added dropwise fluoride tert-butylamine a (10.6 ml, 1M THF th solution). The reaction mixture was left to warm to ambient temperature and was stirred for 4 hours. The reaction mixture was extinguished saturated aqueous ammonium chloride, and then added ethyl acetate and the mixture was intensively shaken. The organic layer was separated and washed twice with saturated saline solution, dried by magnesium sulfate and filtered. The solvent was removed by rotary evaporation to obtain a residue, which was purified on SiO2using a gradient of 20-25% ethyl acetate in hexane as eluent to obtain (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}-5,5,5-triterpene-1-ol.

MS (+ESI): 393,9, 395,8 [M+1]+.

Step 8:obtain (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentane-1-ol

A stream of nitrogen was passed through a suspension of (2S)-2-{[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]amino}-5,5,5-triterpene-1-ol (0.55 g), 2-(4-methanesulfonyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0,59 g), 2,5M K2CO3(2,75 ml) and DMF (0,91 ml) for 20 minutes. Then chloride was added [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) (1:1 complex with dichloromethane, 34 mg)was ecoterminal and the reaction mixture was heated to 85° C and stirred under nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 ml) and water (50 ml) and was intensively shaken. Separating the layer of ethyl acetate and washed 3 times with water, dried with magnesium sulfate and filtered. Removal of the solvent left a residue that was purified by chromatography on SiO2using a gradient of 10-30% ethyl acetate in hexane. Rotary evaporation of the appropriate fractions gave (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentane-1-ol.

Step 9:obtain (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1-diphenyl-4-yl]ethyl}amino)pentanol acid

Matrix suspension of oxidizing agent was obtained by mixing period acid (2.28 g) and chromium trioxide (4.6 mg) in wet acetonitrile (0.75 percent water to form a suspension with a total volume of 22.8 ml Suspension of oxidant (4,22 ml) was then added dropwise to a stirred solution of (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentane-1-ol (0.35 g, of 0.74 mmol) in wet acetonitrile (3,7 ml), keeping the temperature between 0-5°C. the Reaction mixture was left to warm to ambient temperature over one hour, and then was stirred for additional 4 hours. The reaction was extinguished by the water phosphate sodium (6 g/100 ml), add recipients is whether toluene and the mixture was intensively shaken. The organic phase is washed with 1:1 brine:water, then aqueous sodium bisulfite (2.2 g/50 ml), then saturated saline solution. The organic layer was then dried with sodium sulfate, filtered and concentrated by rotary evaporation. The crude product was purified by chromatography on silica gel using 5-10% methanol in methylene chloride as eluent to obtain (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentanol acid.

MS (-ESI): 482,0 [M-1]-.

Step 10:getting cyanoethylated (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentanol acid

(2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentane acid (0.55 g, 0,114 mmol), aminoacetonitrile hydrochloride (21 mg, 0,228 mmol) and HATU (43 mg, 0,114 mmol) was dissolved in DMF (2 ml) and the reaction mixture was cooled to -20°C. was Added diisopropylethylamine (0.10 ml, or 0.57 mmol) and the reaction mixture was stirred at -20 °C for three hours and then at ambient temperature for 16 hours. Added ethyl acetate (OC ml) and water (OC ml) and the mixture was intensively shaken. The organic layer was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated by rotary evaporation and the residue was purified using the chromatograph and on silica gel, using 30% ethyl acetate in hexane as the eluent, to obtain cyanoethylated (2S)-5,5,5-Cryptor-2-({(1S)-2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}amino)pentanol acid as a white solid.

MS (+ESI): 522,3 [M+1]+.

1H NMR (CDCl3) δ 8,0-8,053 (2H, d), 7,74 for 7.78 (2H, d), 7,63-7,66 (2H, d), of 7.48-7,51 (2H, d), 6,94-7,00 (1H, bt, NH), 4,06-4,22 (3H, m), 3,36-of 3.43 (1H, m), 2.21 are is 2.37 (3H, m), 1,88-2,03 (2H, m).19F NMR (CDCl3) δ -66,74 - -66,83 (3F, t), -74,14 - -74,17 (3F, d).

EXAMPLE 19

Synthesis of N1(cyanomethyl)-N2-{(S)-(4-forfinal)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide

Stage 1:obtain (S)-2-[(4-formanilide)amino]-4-methylpentan-1-ol

A mixture of (L)-leucinol (1.13 g, 9,67 mmol) and 4-forventelige (1.20 g, 9,67 mmol) was dissolved in benzene (30 ml) and was heated under reflux for 1 hour, using the unit Dean-stark removal of water. (S)-2-[(4-Formanilide)amino]-4-methylpentan-1-ol were isolated by concentration in vacuo and immediately used without further purification.

Stage 2:obtain (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentan-1-ol

To a solution of 1,4-dibromobenzene with (11.4 g, 48,35 mmol) in ether (120 ml) at -30°C was added n-utility (and 24.2 ml, 2,0M cyclohexane solution) for 10 minutes. The reaction mixture was stirred for 45 minutes, after which was added by ka the NML solution (S)2-[(4-formanilide)amino]-4-methylpentan-1-ol (maximum of 2.16 g, 9,67 mmol previous stage) in ether (30 ml). After 2 hours, during which time the reaction mixture was left to warm to 0°C, was added water (200 ml). The product was extracted with ethyl acetate (150 ml), washed with saturated saline (100 ml), dried over MgSO4was filtered , concentrated in vacuo and purified by thin layer silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentan-1-ol.

MS (+APCI): 380, 382 [M+1}+.

1H NMR (CDCl3) δ of 0.91 (d, 6H), 1,22 (m, 1H), USD 1.43 (m, 1H), 1,61 (m, 1H), 2,62 (m, 1H), or 3.28 (m, 1H), 3,63 (m, 1H), 4.95 points (s, 1H); 7,00 (m, 2H), 7,22 (d, 2H), 7,2 (m, 2H), 7,44 (d, 2H).

Stage 3:obtain (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic acid

To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentan-1-ol (3.28 g, 8,65 mmol) in acetonitrile (50 ml)containing water (0,375 ml), at 0-5°C was added, over 20 minutes, a solution of periodic acid and chromium oxide (VI) in acetonitrile (50 ml, prepared by dissolving 11.4 g H5IO6and 23 mg CrO3in 100 ml of CH3CN and stirring for 2 hours at room temperature according to the method described in Tetrahedron Letters, 1998, vol. 39, p. 5323-5326). The reaction mixture was stirred overnight, warming to room temperature. Added donatia phosphate (1.8 g/100 ml water). The reaction mixture was extracted with toluene (150 m is), washed with 1:1 saturated brine/water (50 ml), a freshly prepared solution of sodium bisulfite (2 g/50 ml water), saturated brine (50 ml), dried over MgSO4was filtered , concentrated in vacuo and purified by thin layer silica gel (30% ethyl acetate/hexane elution to remove non-polar impurities, then 50% ethyl acetate/dichloromethane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic acid.

Stage 4:getting cyanoethylated (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic acid

To a solution of (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic acid (1,17 g of 2.86 mmol) in THF (20 ml) at -10°C was added 4-methylmorpholine (0,315 ml of 2.86 mmol) and isobutylparaben (0,371 ml of 2.86 mmol). The reaction mixture was stirred for 10 minutes, then added aminoacetonitrile hydrochloride (0,318 g of 3.43 mmol), then 4-methylmorpholine (0,315 ml of 2.86 mmol). The solution was stirred for 90 minutes. Added ethyl acetate (30 ml) and water dontreboot (30 ml). The organic phase was separated, washed with saturated saline solution, dried over MgSO4and evaporated to dryness. The product was purified by thin layer silica gel (10-50% ethyl acetate/hexane gradient elution) to produce cyanoethylated (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic to the slots.

Stage 5:obtaining N1(cyanomethyl)-N2-{(S)-(4-forfinal)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide

A mixture of cyanoethylated (2S)-2-{(R)-[(4-bromophenyl)-(4-forfinal)methyl]amino}-4-methylpentanoic acid (0.27 g, 0,636 mmol), 2-(4-methanesulfonyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0,177 g, 0,626 mmol) and potassium carbonate (0,703 ml of 2.0 M solution) in DMF (5 ml) was degirolami. Was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (27 mg, of 0.038 mmol). The reaction mixture was heated in a sealed tube at 80 to 85 °C for 3 hours and cooled to room temperature. Added ethyl acetate (15 ml). The reaction mixture was washed with saturated saline (10 ml), saturated aqueous NaHCO3(10 ml), saturated brine (10 ml), filtered through a layer of MgSO4/DARCO activated carbon/silica gel, concentrated in vacuo and was purified preparative thin-layer chromatography (TLC) (Chromatotron®using 5% ethyl acetate/dichloromethane for the elution, to obtain the N1(cyanomethyl)-N2-{(S)-(4-forfinal)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide.

1H NMR (CDCl3): δ of 0.77 (d, 3H), and 0.9 (d, 3H); to 1.38 (m, 1H), 1.57 in (m, 1H), 1,71 (m, 1H), 2,01 (Sirs, 1H), to 3.09 (s, 3H), to 3.09 (m, 1H), 4,07 (m, 2H), 4,89 (1H, s), 7,03 (m, 2H), 7,21 (m, 1H), 7,33 (m, 2H), 7,42 (d, 2H), 7,53 (m, 2H), 7,68 (d, 2H), of 7.97 (d, 2H).

EXAMPLE 20

Synthesis of cyanoethylated (2S)-2-(S)-[(2,4-differenl)-(4'-methysulfonylmethane-4-yl)methyl]amino}-4-methylpentanoic acid

Stage 1:obtain (2S)-2-[(2,4-differenziale)amino]-4-methylpentan-1-ol

A solution of (S)-(+)-leucinol (2,47 g, 21 mmol) and 2,4-diferentialglea (3 g, 21 mmol) in benzene (50 ml) was heated under reflux for 4 hours, during which time water was collected in the nozzle Dean-stark. The solvent is evaporated in vacuum to obtain (2S)-2-[(2,4-differenziale)amino]-4-methylpentan-1-ol.

1H NMR (CD3SOCD3) δ 8,18 (s, 1H), 7,51 (d, 1H), for 6.81 (d, 2H), 4,6 (Shir. s, 1H), 3,8-3,2 (m, 3H), 1,6-1,2 (m, 3H), 0,9-0,8 (m, 6H).

Stage 2:obtain (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentan-1-ol

To a solution of 1,4-dibromobenzene with (24.5 g, 100 mmol, 5 EQ.) in dry ether (200 ml) in a nitrogen atmosphere at -30°C was added n-BuLi (64,75 ml of 1.6 M solution in hexane, 5 EQ.) and the reaction mixture was stirred for 1 h was Slowly added a solution of 2-[(2,4-differenziale)amino]-4-methylpentan-1-ol (5 g, 20 mmol) in dry ether at -30°C. After stirring for 4 h the reaction was extinguished by the water. The ether layer was washed with saturated solution of NaCl and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was subjected to flash chromatography on 500 cm3silica gel using 8:2 hexane:EtOAc as eluent to obtain (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentan-1-ol./p>

1H NMR (CD3SOCD3) δ 7,31 (DD, 2H), 7,05 (d, 1H), 6,94, (DD, 2H), 6,63 (d, 1H), is 6.54 (d, 1H), 5,02 (s,1H), 4,45 (t, 1H), 3,5-3,3 (m, 2H), 2,3 (s, 1H), 2,15 (s, 1H), of 1.85 (m, 1H), 1,18-1,4 (m, 2H), 0,9-0,8 (m, 6H).

Stage 3:obtain (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanoic acid

Using the methodology described in stage 3 of Example 19, oxidized 2-{[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentan-1-ol to obtain (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanoic acid in the form of a cream solid color.

Stage 4:getting cyanoethylated (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanoicacid

Using the methodology described in stage 4 of Example 19 (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanol acid was combined with aminoacetonitrile with getting cyanoethylated (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanoic acid as a white solid.

1H NMR (CD3SOCD3) δ 7,31 (DD, 2H), 7,05 (d, 1H), 6,94 (DD, 2H), 6,63 (d, 1H), is 6.54 (d, 1H), 4.92 in (s, 1H), 4,14 (t, 2H), 3,32 (m, 1H), 3,19 (m, 1H), 2,98 ( m, 1H), of 1.85 (m, 1H), 1,46 (m, 1H), 0,9-0,8 (m, 6H).

Stage 5:getting cyanoethylated (2S)-2-{(S)-[(2,4-differenl)-(4'-methysulfonylmethane-4-yl)methyl]amino}-4-methylpentanoic acid

Using the technique shown in stage 5 of Example 19 was performed interaction is Suzuki (Suzuki) cyanomethylation (2S)-2-{(S)-[(4-bromophenyl)-(2,4-differenl)methyl]amino}-4-methylpentanoic acid with getting cyanoethylated ((2S)-2-{(S)-[(2,4-differenl)-(4'-methysulfonylmethane-4-yl)methyl]amino}-4-methylpentanoic acid in the form of a white solid.

1H NMR (CD3SOCD3) δ 8,01 (DD, 2H), and 7.8 (DD, 2H), 7,35 (DD, 2H), 7,11 (DD, 2H), 7,03 (d, 1H), 6,93 (d, 2H), 6,62 (d, 1H), 6,55 (d, 1H), 5,0 (s, 1H), 4,13 (t, 2H), 3,35 (m, 1H), 3.0 a (m, 1H), 2,99 ( m, 1H), 2,85 (s, 3H), of 1.84 (m, 1H), 1,45 (m, 1H), 0,9-0,8 (m, 6H).

EXAMPLE 21

Synthesis of N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl-L-nonvalidated

Stage 1:obtain (S)-[1-(tert-butyldimethylsilyloxy)butyl]-(2,2,2-triptoreline)Amin

A mixture of (S)-1-(tert-butyldimethylsilyloxy)butylamine (27 g, 126 mmol) and triptoreline of methylgalactose (17,2 g, 132 mmol) in benzene (250 ml) was heated under reflux, using a nozzle Dean-stark removal of water. After 2 hours, more water is not collected. The reaction mixture was cooled and concentrated to obtain (S)-[1-(tert-butyldimethylsilyloxy)butyl]-(2,2,2-triptoreline)amine, which was used in the next stage without additional purification or continued drying because of its volatility.

Stage 2:obtain (2S)-(S)-[1-(4-bromophenyl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)butyl]amine

To a solution of dibromobenzene with (63.7 g, 270 mmol) in ether (600 ml) at -30°C was added n-BuLi (108 ml of 2.5 M hexane solution) for 15 minutes via addition funnel. The solution was allowed to warm to -10°C for 35 minutes is again cooled to -30° C. was Added (S)-[1-(tert-butyldimethylsilyloxy)butyl]-(2,2,2-triptoreline)Amin (35,12 g, 108 mmol) in ether (200 ml) for 20 minutes. The reaction mixture was stirred for 1 hour, heating to 0°C. was Added water (200 ml). The organic phase was separated, washed with saturated saline (200 ml), dried over MgSO4, filtered and evaporated to dryness to obtain (2S)-(S)-[1-(4-bromophenyl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)butyl]amine, which was used directly in the next stage without additional purification.

Stage 3:obtain (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol

To a solution of (2S)-(S)-[1-(4-bromophenyl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)butyl]amine (49,58 g, 109 mmol) in THF (200 ml) was added tetrabutylammonium fluoride (110 ml of 1.0 M solution). The reaction mixture was stirred over night at room temperature. After concentration of the reaction mixture was added ether (300 ml). The reaction mixture was washed with water (2x100 ml), saturated brine (100 ml), evaporated to dryness, and then purified using flash chromatography (3% ethyl acetate/hexane elution of strongly non-polar substances, then 40% ethyl acetate/hexane for elution of the product). The fractions containing the product were combined, concentrated to a volume of 300 ml, washed with 0.25 M citric acid (200 ml), saturated salt RA is TAROM (100 ml), dried over MgSO4, filtered and evaporated to obtain (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol. This substance is used posredstvenno in the next stage without additional purification. TLC (30% ethyl acetate/hexane) Rf = 0.28 in.

Stage 4:obtain (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentanol acid

To a solution of crude (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol (37,1 g, 109 mmol in dry acetonitrile (500 ml) at -78°C was added a solution of periodic acid (71.7 g) and chromium trioxide (144 mg) in dry acetonitrile (630 ml) for 1 hour. The reaction mixture was left to warm to room temperature with stirring overnight. The reaction mixture was concentrated under reduced pressure to a total volume of approximately 500 ml) was Added a solution of citric acid (22 g in 250 ml of H2O) and the mixture was extracted with ethyl acetate (800 ml). The solution was washed with freshly prepared NaHSO3(2 x 200 ml, 25 g of solids dissolved to 200 ml water), saturated brine (300 ml), dried over MgSO4, filtered and evaporated to obtain a pale orange solid, which was poroshkovo 5% ethyl acetate/hexane to obtain (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentanol acid. An additional amount of acid was obtained by concentration of the mother liquor is in, distribution of the residue between ether and aqueous NaHCO3, acidification of the aqueous layer citric acid, extraction with ethyl acetate, drying over MgSO4filtration and evaporation of the solvent.

Stage 5:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-nonvalidated

A mixture of (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentanol acid (19,0 g, 53.6 mmol), 1-aminocyclopropane hydrochloride (12,71 g, 107 mmol, synthesized according to O'donnell, M.J. et al. Synthesis, 1984, 127-128) and HATU (are 22.42 g of 59.0 mmol) was dissolved in DMF (200 ml) and cooled to -78°C. was Added diisopropylethylamine (37,35 ml, 214 mmol) and after stirring for 1 hour the cooling bath was removed. The reaction mixture was left to mix for an additional 1 hour, after which was added a saturated NaHCO3(300 ml). The product was extracted with ethyl acetate (500 ml), washed with saturated saline (100 ml), 0.25 M citric acid (200 ml), saturated NaHCO3(200 ml), saturated brine (200 ml), dried over MgSO4/DARCO, filtered through silica and evaporated to dryness. After elution of the residue through another thin layer of silicon dioxide 10% ethyl acetate/dichloromethane as mobile phase product was concentrated and recrystallized from ether/hexane to obtain N2-[(1S)-1-(4-pompini is)-2,2,2-triptorelin]-N 1-(1-cyanocyclohexyl)-L-nonvalidated.

MS (-ESI): 416, 418 [M-1]-.

1H NMR (CDCl3): δ to 0.97 (3H, t), and 0.98 (m, 1H), 1,07 (m, 1H), 1,41 (m, 2H), 1,49 (m, 2H), 1,62 (m, 1H), 1,72 (m, 1H), with 3.27 (1H, m), 1.04 million (m, 1H), 7,1 (Sirs, 1H), 1,24 (l, 25 2H), of 7.75 (d, 2H).

EXAMPLE 22

Synthesis of N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

A mixture of N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-nonvalidated (6,46 g, 15,44 mmol), 4-methanesulfonylaminoethyl acid (3,40 g, 16,98 mmol), and 2M K2CO3(19.3 ml) was dissolved in DMF (75 ml) in a thick-walled flask. The reaction mixture was degirolami and was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (0,678 g, 0,926 mmol). The flask was sealed, heated at 80-85°C for 3 hours, cooled and diluted with ethyl acetate (300 ml). The solution was washed with 1:1 water/saturated saline (200 ml), saturated brine (200 ml), filtered through a three-layer tube of silicon dioxide (bottom) DARCO and MgSO4(top), concentrated in vacuo and purified on a layer of silica gel (50-70% ethyl acetate/hexane elution). The product is then further purified through recrystallization from ethyl acetate/hexane to obtain specified in the connection header. MS (+ESI): 494 [M+1]+.

1H NMR (CDCl 3): δ to 0.97 (t, 3H), and 0.98 (m, 1H), 1,1 (m, 1H), 1,42 (m, 2H), 1,29 (m, 2H), and 1.63 (m, 1H), 1.77 in (m, 1H), 3,13 (s, 3H), of 3.28 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs, 1H), 7,47 (d, 2H), 7,63 (d, 2H), 7,78 (d, 2H), 8,02 (d, 2H).

EXAMPLE 23

Synthesis of N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-nonvalidated

N2-[1-(4-Bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-Norvaline was obtained in a similar manner with the N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-normalization using aminoacetonitrile at the stage of interaction with (2S)-2-[(S)-1-(4-bromophenyl)-2,2,2-triptoreline]pentanol acid.

MS (+ESI): 392, 394 [M+1]+.

EXAMPLE 24

Synthesis of N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

N1(Cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline received shodim way with N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-normalization using the N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-Norvaline described above, in collaboration with Suzuki 4-methanesulfonylaminoethyl acid or pinacolborane. Alternatively, this compound could be obtained in swazilan what I Suzuki between (2S)-(S)-[1-(4-bromophenyl)-2,2,2-triptorelin]-[1-(tert-butyldimethylsilyloxy)butyl]amine and 4-methanesulfonylaminoethyl acid in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex in accordance with metoday described above, with subsequent cleavage salelologa ether with tetrabutylammonium fluoride, oxidation using H5IO6/CrO3(see above) to obtain (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-methysulfonylmethane-4-yl)ethylamino]pentanol acid and the compound of this substance with aminoacetonitrile in the presence of HATU/diisopropylethylamine/DMF, getting a named connection.

MS (+ESI): 468 [M+1]+.

EXAMPLE 25

Synthesis of N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

Stage 1: receive (4S)-4-propyl-2-triftormetilfullerenov

(L)-Norvaline hydrochloride (5,25 g, 37,60 mmol) and triptorelin mergemaster (5 ml, of 37.6 mmol) was heated in benzene (100 ml) in the presence of triethylamine (5,26 ml of 37.6 mmol) under reflux, using the unit Dean-stark water collection. After 3 hours the reaction mixture was cooled, diluted with ether (100 ml), filtered and evaporated to dryness, obtaining (4S)-4-propyl-2-triftormetilfosfinov, which was used without further purification.

Stage 2:obtain (2S)-2-[1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol

Utility (41 ml of 2.0 M cyclohexane solution) was added at -30°C to a solution of 1,4-disrobes the La (19.3 g, 81,89 mmol) in ether (250 ml) for 10 minutes. After 1 hour a solution of (4S)-4-propyl-2-triftormetilfullerenov (3.00 g, 16,38 mmol) was added in ether (50 ml) over 30 minutes via addition funnel. After stirring for 90 minutes was added water (100 ml). The organic phase was washed with saturated saline (100 ml), dried over MgSO4, filtered and evaporated to dryness. The residue was purified on a layer of silica gel (10-30% ethyl acetate/hexane elution). Approximately 2:1 mixture of diatomea (2S)-2-[1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol in and 0.98 ppm (1H NMR) at the end of CF3based on the triplet of normalisatie observed approximately 2:1 mixture of diatomea (2S)-2-[1-(4-bromophenyl)-2,2,2-triptoreline]pentane-1-ol.

Stage 3:obtaining N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated and N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

Synthesis of (2S)-2-[1-(4-bromophenyl)-2,2,2-triptoreline]pentanol acid and conversion to aminoacetonitrile product fitting was performed by the way, is identical to that described above for N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-nonvalidated. Interaction Suzuki this product in a manner identical to that described for N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulfone the l)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated with obtaining a 2:1 mixture of N l(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1-diphenyl-4-yl]ethyl}-L-nonvalidated and N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1-diphenyl-4-yl]ethyl}-L-nonvalidated which gave way preparative TLC (Chromatotron®).

MS (+ESI): 468 [M+1]+.

EXAMPLE 26

Synthesis of N1(cyanomethyl)-N2-{1-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-nonvalidated

Specified in the title compound was obtained cross-linking according to the method of Suzuki 4-cyclopropanemethylamine with cyanomethylation (2S)-2-{2,2,2-Cryptor-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]ethylamino}pentanol acid in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex, as described above, followed by purification using preparative TLC (Chromatotron®).

MS (+ESI): 514 [M+1]+.

EXAMPLE 27

Synthesis of N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-nonvalidated

Specified in the title compound was obtained by way similar to that described for N1(cyanocobalamin)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated (Example 24).

MS (+ESI): 495 [M+1]+.

1H NMR (CDCl3): δ to 0.97 (3H, t), and 0.98 (m*, 1H); 1,08 (m, 1H), 1,42 (m, 2H), 1,44 (m, 2H), 1,57 of 1.8 (m, 4H), of 3.28 (m, 1H), 4.16 the (q, 1H), 4,9 (Sirs*, 1H), 7,2 (s, 1H), 7,43 (d, 2H), and 7.6 (d, 2H), 7,72 (d, 2H), to 7.99 (d, 2H).

EXAMPLE 28

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-[(1S)-1-(4'-acetylbiphenyl-4-yl)-2,2,2-triptoreline]pentanol acid

Specified in the title compound was obtained by way similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated by cross-linking method between Suzuki 4-acetylphenylalanine acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (+ESI): 458 [M+1]+, 480 [M+1+Na]+.

1H NMR (CDCl3): δ to 0.97 (t, 3H), and 0.98 (m, 1H), 1,07 (m, 1H), 1,42 (m, 2H), 1.57 in (s, 2H), and 1.63 (m, 1H), 1,78 (m, 1H), 2,33 (s, 3H), of 3.33 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs, 1H), 7,43 (d, 2H), 7,65-7,69 (HD, 4H), 8,03 (d, 2H).

EXAMPLE 29

Obtain (1-cyanocyclohexyl)amide (2S)-2-[(1S)-1-(2',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acid

Specified in the title compound was synthesized manner similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated through on Aracinovo binding according to the method of Suzuki between 2.4 to diftorhinolonom acid and N 2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (+ESI): 452 [M+1]+, 474 [M+1+Na]+.

1H NMR (CDCl3): δ of 0.90 (m, 1H), 0,97 (t, 3H), 1.04 million (m, 1H), 1.41 to 1,5 (m, 4H), of 1.62 (m, 1H), 1,78 (m, 1H), 2,19 (Sirs, 1H), 3,32 (DD, 1H), 4,13 (DD, 1H), 6,95 (m, 2H), 7,19 (Sirs, 1H), 7,41 (m, 3H), 7,53 (d, 2H).

EXAMPLE 30

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-[(1S)-1-(3',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acid

Specified in the title compound was obtained by way similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated by cross-linking method between Suzuki 3,4-diftorhinolonom acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (+ESI): 452 [M+1]+, 474 [M+1+Na]+.

1H NMR (CDCl3): δ to 0.97 (t, 3H), and 0.98 (m, 1H), 1,07 (m, 1H), 1,42 (m, 2H), 1,5 (m, 2H), 1,62 (m, 1H), 1.77 in (m, 1H), 2,18 (Sirs, 1H), 3,29 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs, 1H), 7,13-to 7.3 (m, 2H), 7,38 (m, 1H), 7,42 (d, 2H), EUR 7.57 (d, 2H).

EXAMPLE 31

Obtain (1-cyanocyclohexyl)amide (2S)-2-[(1S)-1-(3'-chloro-4'-forgivenes-4-yl)-2,2,2-triptoreline what about]pentanol acid

Specified in the title compound was obtained by way similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated by cross-linking method between Suzuki 3-chloro-4-ftorhinolonovy acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (+ESI): 468 [M+1]+.

1H NMR (CDCl3): δ 0,99 (t, 3H), 1.00 m (m, 1H), 1,08 (m, 1H), 1,42 (m, 2H)and 1.51 (m, 2H), 1,62 (m, 1H), 1,79 (m, 1H), 2,19 (Shir. s, 1H), 3,33 (DD, 1H), 4,17 (kV, 1H), 7,21 (m, 2H), 7,42 (m, 3H), EUR 7.57 (d, 2H), 7.62mm (m, 1H).

EXAMPLE 32

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-[(1S)-2,2,2-Cryptor-1-(4'-methylbiphenyl-4-yl)ethylamino]pentanol acid

Specified in the title compound was synthesized manner similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated by cross-linking according to the method of Suzuki between p-tolylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (ESI): 430 [M+1] +.

1H NMR (CDCl3): δ of 0.90 (m, 1H), and 0.98 (t, 3H), of 1.02 (m, 1H) 1,4-1,5 (m, 4H), of 1.62 (m, 1H), 1.69 in (m, 1H), 2,19 (Sirs, 1H), 2,41 (s, 3H), at 3.35 (DD, 1H), 4,1 (kV, 1H), 7,21 (s, 1H) 7,24 (d, 2H), 7,38 (d, 2H), 7,46 (d, 2H), 7,60 (d, 2H).

EXAMPLE 33

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-[(1S)-1-(4'-cyanobiphenyl-4-yl)-2,2,2-triptoreline]pentanol acid

Specified in the title compound was synthesized manner similar to that described for N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated by cross-linking method between Suzuki 4-cyanophenylacetic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-normalization in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (+ESI): 441 [M+1]+.

EXAMPLE 34

Synthesis of cyanoethylated (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

Stage 1:obtaining 3-methyl-3-(toluensulfonate)oxetane

p-Toluensulfonate (57,2 g, 300 mmol) was dissolved in dry pyridine (400 ml) under nitrogen atmosphere. Was slowly added 3-methyl-3-(hydroxymethyl)oxetan (20.4 g, 200 mmol) and the solution was stirred for 1.5 h and Then was added to crushed ice (400 g) to intensively peremeshannoy mixture, which is Oh was allowed to mix for an additional 0.5 hours Then the white precipitate was collected on filter paper Whatman #1 and washed with cold water. The product was dried under high vacuum to obtain 3-methyl-3-(toluensulfonate)oxetane (oceanliteracy) in the form of a white powder oceanliteracy.

1H NMR (CDCl3): δ 7,81 (d, 2H), 7,37 (d, 2H), 4,37 (m, 4H), 4,11 (s, 2H), 2,46 (s,3H), of 1.31 (s, 3H).

Stage 2:obtaining 3-methyloxiran-3-Eletropaulo ester (2S)-2-benzyloxycarbonylamino-4-methylpentanoic acid

Cbz-L-leucine (2 g, 7.5 mmol) and Cs2CO3(1,46 g, 4.5 mmol, 0.6 EQ.) was dissolved in water (20 ml). Then the water was removed in vacuum and the resulting oil liofilizirovanny for 12 hours to obtain a white solid. This solid matter was added 3-methyl-3-(toluensulfonate)oxetan (oxetanone) (1.8 g, 4.5 mmol) and NaI (224 mg, 1.5 mmol, 0.2 equiv.) taken in DMF (35 ml), and left to mix in a nitrogen atmosphere for 48 hours and Then DMF was removed in vacuo, the resulting solid was dissolved in EtOAc (60 ml) and washed with 10% NaHCO3(20 ml) and saturated NaCl (10 ml) and dried over MgSO4. The solvent was removed under reduced pressure to obtain a yellow oil, which was subjected to column flash chromatography on 200 cm3silica gel, using 3:1 hexane:EtOAc as eluent to obtain 3-methyloxiran-3-Eletropaulo ester (2S)-2-benzyloxy is Beniamino-4-methylpentanoic acid (ester Cbz-Leu of oxetane) as a thick yellow oil.

1H NMR (CD3SOCD3) of 7.75 (d, 1H), 7,26-7,38 (m, 5H), of 5.05 (s, 2H), of 4.0-4.4 (m, 8H), of 1.45 to 1.7 (m, 3H), 1,25 (s, 3H), 0,85-0,9 (m, 6H).

Stage 3:getting benzyl ester [3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]carbamino acid

(2S)-2-Benzyloxycarbonylamino-4-methylpentanoic acid 3-methyloxiran-3-ymetray ether (ester Cbz-Leu of oxetane) (2 g, 5.7 mmol) was dissolved in dry CH2Cl2(10 ml) under nitrogen atmosphere. BF3.Et2(40 μl, 0.3 mmol, 0,054 EQ.) was diluted in dry CH2Cl2(1 ml) and was added into the reaction vessel. The reaction mixture was allowed to warm to room temperature and was stirred for 12 hours was Added triethylamine (335 μl, 3.3 mmol, 0,58 EQ.) and the reaction mixture was stirred for additional 30 min before concentration in thick oil. The crude product was re-dissolved in EtOAc (15 ml), washed with 3% NH4Cl (10 ml), and saturated NaCl (10 ml), dried (MgSO4) and evaporated to dryness. The reaction gave a colorless thick oil, which crystallized upon standing, giving benzyl ester [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]Oct-1-yl)butyl]carbamino acid (ester Cbz-Leu-OBO).

1H NMR (CD3SOCD3) 7,25-7,35 (Shir. m, 5H), to 6.88 (d, 1H), of 5.05 (s, 2H), 3,80 (s, 6H), and 3.7 (m, 1H) of 1.2-1.6 (m, 3H), 0,75-0,85 (m, 6H), 0.70 and (s, 3H).

Stage 4:obtaining 3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butylamine

To benzyl ether [3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]carbamino acid (3.2 g, 9.2 mmol) in absolute EtOH (30 ml) was added 10% Pd on activated carbon (320 mg, 10 %) in nitrogen atmosphere. The reaction mixture was hydrogenosomal at 50 psi for 6 hours the Reaction was controlled by TLC and the reaction mixture was filtered through Celite. The solvent was removed to obtain 3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butylamine in the form of a white solid.

1H NMR (CD3SOCD3) of 3.80 (s, 6H), 3,2-3,4 (Sirs, 3H), of 1.75 (m, 1H), 1,0-1,4 (m, 2H), 0.75 to about 0.90 (m, 6H), 0.75 in (s, 3H).

Stage 5:obtain [3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]thiazole-2-ylmethylamino

A solution of 3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butylamine (1.9 grams, 8,8 mmol) and thiazole-2-carboxaldehyde (998 mg, 8,8 mmol) in benzene was heated under reflux for 3 h, using a nozzle Dean-stark during this time water was collected and the remaining residue is evaporated under reduced pressure to obtain [3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]thiazole-2-ylmethylamino in a solid orange color.

1H NMR (CD3SOCD3) a 8.4 (s, 1H), of 7.97 (d, 1H), to 7.84 (d, 1H), 3,82 (s, 6H), 3,4 (m, 1H), 1,7 (m, 1H), 1,5 (m, 1H), 1,3 (m, 1H), and 0.9 (m, 6H), 0.75 in (s, 3H).

Step 6:getting [(4-bromophenyl)thiazol-2-ylmethyl]-[3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]amine

To a solution of dibromobenzene with (760 mg, 3.2 mmol) in dry ether was added 2.5 M R is the target n-BuLi in hexane (1.3 ml, 3.2 mmol) at -30°C. After stirring for 1 h was slowly added a solution of [3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]thiazole-2-ylmethylamino (500 mg, 1.6 mmol) in 5 ml dry ether. The reaction mixture was left to be mixed at the same temperature for 2 h and then the reaction was extinguished with water and was extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4. The solvent is evaporated in vacuum. The crude product was subjected to column flash chromatography using 2:1 hexane:EtOAc as eluent to obtain [(4-bromophenyl)thiazol-2-ylmethyl]-[3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butyl]amine as a pale yellow solid.

1H NMR (CD3SOCD3) to 7.64 (d, 1H), to 7.59 (d, 1H), 7.5 (d, 2H), 7,28 (d, 2H), of 5.68 (s, 1H), 3,82 (s, 6H), 3,3 (m, 1H), 2,65 (m, 1H), 1,95 (m, 1H), 1,4 (m, 1H), 1,2 (m, 1H), and 0.9 (d, 3H), 0.75 in (s, 3H), and 0.7 (d, 3H).

Step 7:obtain (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

To a solution of [(4-bromophenyl)thiazol-2-ylmethyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]Oct-1-yl)butyl]amine (500 mg, 1.06 mmol) in THF (20 ml) and water (18 ml), was added 1N HCl (3.5 ml). The reaction mixture was stirred for 2 hours After mapping TLC for the disappearance of the original substance was added Li(OH)·H2O (280,2 mg, 6.3 EQ.) and stirred at room temperature for 2 hours Then was added 1N HCl DL is establishing a pH of 4-6 and the product was extracted with EtOAC, the organic layer was dried over MgSO4. The solvent is evaporated to obtain (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid as a yellow solid.

Step 8:getting cyanoethylated (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

In the presence of HATU (1 EQ.) and diisopropylethylamine (4 equiv.) connected (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanol acid with aminoacetonitrile (2 EQ., 1 EQ. the excess) to produce cyanoethylated (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid in the form of a cream solid color.

1H NMR (CD3SOCD3) 8,73 (t, 1H), 7,66 (d, 1H), to 7.64 (d, 1H), and 7.5 (DD, 2H), 7,25 (DD, 10 2H) to 4.92 (d, 1H), 4,14 (t, 2H), 3,32 (s, 1H), 3,19 (m, 1H), 2,98 (m, 1H), of 1.85 (m, 1H), 1,46 (m, 1H), from 0.9 to 0.85 (m, 6H).

EXAMPLE 35

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

Specified in the title compound was obtained compound (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-ylmethyl]amino}-4-methylpentanoic acid with 1-aminocyclopropane in the presence of HATU and Diisopropylamine a manner similar to that described for obtaining of Example 34. Synthesis of (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid was performed by adding brompheniramine (obrazovannogo situ from 1,4-dibromobenzene with and n-utility) to the product kinoway condensation between the thiazole-2-carboxaldehyde and 3-methyl-1-(4-methyl-2,6,7-dioxabicyclo[2.2.2]Oct-1-yl)butylamine (ester L-leucine OBO, received in accordance with the method described for Example 34), followed artaphernes deprotecting.

1H NMR (CDCl3): δ of 0.82 (d, 3H), of 0.95 (d, 3H), 1.04 million (m, 2H), 1,46-of 1.62 (m, 4H), of 1.80 (m, 1H), 3,12 (DD, 1H), 4.95 points (s, 1H), 7,22 (s, 1H), 7.23 percent-of 7.25 (d, 2H), 7,31 (m, 2H), 7,47 (d, 2H), 7,74 (m, 1H).

EXAMPLE 36

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(2',4'-giftgiver-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

Specified in the title compound was obtained by cross-linking according to the method of Suzuki (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid with 2,4-differentviews acid, in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (-ESI): 479 [M-1]-.

1H NMR (CDCl3): δ 0,84 (d, 3H), of 0.97 (d, 3H), of 1.03 (m, 2H), 1,47 (m, 2H), 1,57-of 1.62 (m, 4H), of 1.95 (m, 1H), 3.27 to (DD, 1H), 5,02 (s, 1H), 6,93 (m, 2H), 7,32 (m, 1H), 7,39 (m, 1H), 7,42 (m, 3H), of 7.48 (d, 2H), to 7.77 (d, 1H).

EXAMPLE 37

Synthesis of (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4'-methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid

Specified in the title compound was obtained by way similar to the one described for (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(2',4'-giftgiver-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid by cross-linking on m is todo Suzuki (1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid 4-methanesulfonylaminoethyl acid in the presence of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex.

MS (-ESI): 521 [M-1]-.

EXAMPLE 38

Synthesis of N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

Stage 1: obtaining methyl-N-((benzyloxy)carbonyl)-3-iodide-L-alaninate

To a solution of carbobenzoxy-L-serine (25 g, 104 mmol) in ethyl acetate (200 ml) solution was added diazomethane in the air to save a pale yellow color. The solvent is evaporated in vacuum. To the residue was added N,N-dimethylformamide (400 ml) and iodide methyltrimethoxysilane (50 g, 110 mmol). The mixture was stirred for 15 minutes, then was added methanol (15 ml), the mixture was then poured into 20% sodium thiosulfate and extracted with a mixture of 1:1 ethyl acetate:hexane (2 l). The organic layer was washed with water, saturated salt solution (3x), dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The residue was purified by chromatography on silica gel using ethyl acetate and hexane. The compound obtained was poroshkovo in diethyl ether/hexane, filtered and air-dried to obtain methyl-N-((benzyloxy)carbonyl)-3-iodide-L-alaninate.

Stage 2:obtaining methyl-N-((benzyloxy)carbonyl)-4-oxo-L-Norvaline

A mixture of methyl-N-((benzyloxy)carbonyl)-3-iodide-L-alaninate (10 g, 27.5 mmol) from stage 1, zinc-copper PA is s (3.3 grams) in benzene (110 ml) and N,N-dimethylacetamide (7,4 ml) was subjected to the action of ultrasound in an ultrasonic bath for 2 hours. During this period, was added 3 servings 1,2-dibromethane (0,24 ml) and chlorotrimethylsilane (0.17 ml). To this mixture was then added chloride bis(triphenylphosphine)palladium (0,958 g, 1.4 mmol) and acetylchloride (2.5 ml, of 35.2 mmol) and the mixture was heated at 70°C for 2 hours. After cooling to room temperature the mixture was filtered on celite with ethyl acetate, then the organic layer was washed with a saturated solution of ammonium chloride, saturated brine (2x), dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The residue was purified by chromatography on silica gel using ethyl acetate and hexane, to obtain methyl-N-((benzyloxy)carbonyl)-4-oxo-L-Norvaline.

Stage 3:obtaining methyl-N-((benzyloxy)carbonyl)-4,4-debtor-L-Norvaline

To a solution of methyl-N-((benzyloxy)carbonyl)-4-oxo-L-Norvaline (1.3 g and 4.65 mmol) in dichloromethane (20 ml) and methanol (0,019 ml) at 0°C was slowly added DAST (2,46 ml). The ice bath was removed and replaced the bath with hot water (57°C). Bath with hot water was changed 3 times, then the mixture was stirred over night at room temperature. The mixture was slowly poured into cold saturated NaHCO3was extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The residue was purified by means of which cromatografia on silica gel, using ethyl acetate and hexane, to obtain methyl-N-((benzyloxy)carbonyl)-4,4-debtor-L-Norvaline.

Stage 4:obtain benzyl(1S)-3,3-debtor-1-(hydroxymethyl)BUTYLCARBAMATE

To a solution of methyl-N-((benzyloxy)carbonyl)-4,4-debtor-L-Norvaline (1,59 g of 5.29 mmol) in ethanol (50 ml) was added lithium chloride (919 mg) and the mixture was stirred for 10 minutes. Was slowly added borohydride sodium (820 mg), the mixture was stirred for 2 hours. Then added another portion of sodium borohydride (100 mg) and stirring was continued for 30 minutes. The mixture was diluted with water (20 ml) and slowly neutralized with 1N HCl followed by the addition of another aliquot of water. The mixture was extracted with ethyl acetate (2x), washed with saturated saline, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum to obtain benzyl(1S)-3,3-debtor-1-(hydroxymethyl)BUTYLCARBAMATE.

Stage 5:obtain (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-diferente-2-amine

To a solution of benzyl(1S)-3,3-debtor-1-(hydroxymethyl)BUTYLCARBAMATE (stage 4) in ethanol (25 ml) was added palladium on coal (10%, 150 mg) and the mixture was stirred in an atmosphere of H2(balloon) for 2 hours was Added dichloromethane and the mixture was filtered on celite. The solvent is evaporated in vacuum. The residue was dissolved in dichloromethane (15 ml) was added triethylamine (1 ml), N,N-is metiletilpiridin (10 mg) and chloro-tert-butyldimethylsilyl (844 mg). The mixture was stirred overnight, then added water and salt solution. The mixture was extracted with ethyl acetate (2x), washed with saturated saline, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum to obtain (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-diferente-2-amine.

Step 6:obtain (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-debtor-N-((1E)-2,2,2-triptoreline)pentane-2-amine

A solution of (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-diferente-2-amine from step 5 and triptorelin of methylgalactose (80 %, 0.9 ml) in benzene (20 ml) was heated under reflux during the night, using the unit Dean-stark. The solvent is evaporated in vacuum and the residue was purified by chromatography on silica gel using ethyl acetate and hexane, to obtain (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-debtor-N-((1E)-2,2,2-triptoreline)pentane-2-amine.

Step 7:obtain (2S)-2-(((1S)-1-(4-bromophenyl)-2,2,2-triptorelin)amino)-4,4-diferente-1-ol

To -78°C to a solution of 1,4-dibromobenzene with (330 mg) in THF (5.2 ml) was added 2.5m n-BuLi in hexane (0,52 ml) and the solution was kept for 30 minutes. Then solution was added (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-debtor-N-((1E)-2,2,2-triptoreline)pentane-2-amine (333 mg) in THF (5.2 ml). The mixture was stirred at -78°C for 45 minutes, then poured into cold saturated chlorine is d ammonium, were extracted with ethyl acetate (2x), washed with saturated saline, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum. The residue was dissolved in THF (10 ml), cooled in a bath of ice/water, was added fluoride, n-tetrabutylammonium (1M in THF, 1.5 ml). The mixture was stirred at 0°C for 1 h, then poured into cold water, extracted with ethyl acetate (2x), washed with saturated saline, dried over magnesium sulfate, filtered and the solvent evaporated in vacuum to obtain (2S)-2-(((1S)-1-(4-bromophenyl)-2,2,2-triptorelin)amino)-4,4-diferente-1-ol.

Step 8:obtaining N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-nonvalidated

(2S)-2-(((1S)-1-(4-Bromophenyl)-2,2,2-triptorelin)amino)-4,4-diferente-1-ol was converted to the specified in the title compound using the method described in stage 9 of Example 15.

Step 9:obtaining N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-nonvalidated

N2-[(1S)-1-(4-Bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline turned specified in the title compound using the method described in stage 10 of Example 15.

Step 10:obtaining N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-given the l-4-yl]ethyl}-L-nonvalidated

N1-(1-Cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-Norvaline turned specified in the title compound using the method described in stage 11 of Example 15.

Using experimental techniques, similar to those listed above, were synthesized following the connection.

td align="left"> N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2',3',5'-Cryptor-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide
NameDescription
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-phenylethyl)-L-leucinamideMS (+ESI): 328,3 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-fluoro-3-were)ethyl]-L-leucinamideMS (+ESI): 360,2 [M+1]+
N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 405,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 405,1 [M+1]+
N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 405,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 405,1 [M+1]+
N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-{[4-(2-foradil)Pieper is Zin-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide MS (+ESI): 486,3 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-foradil)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamideMS (+ESI): 486,2 [M+1]+
N2-[1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 404,2 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbut-1-inyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 410,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbutyl)phenyl]ethyl}-L-leucinamideMS (+ESI):436,2 [M+Na]+that level of 414.2 [M+1]+
N2-[(lS)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 458,1, 456,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4-pyridin-4-ylphenyl)propyl]-L-leucinamideMS (+ESI): to 455.2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 422,2 [M+l]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}ethyl)-L-leucinamideMS (+ESI): of 434.1 [M+Na]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]propyl}-L-LEU is inamed MS (+ESI): 500,1 [M+Na]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+ESI): 532,1 [M+Na]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxipiridin-3-yl)phenyl]ethyl}-L-leucinamideMS(+ESI): UAH 421,2 [M+Na]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(morpholine-4-ylcarbonyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 441,3 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[methoxy(methyl)amino]carbonyl}phenyl)

ethyl]-L-leucinamide
MS (+ESI): 415,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-Tien-3-ylphenyl)ethyl]-L-leucinamideMS (-ESI): 388,3 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamideMS (-ESI): 397,2 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamideMS (-ESI): 397,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-L-leucinamideMS (-ESI): 401,4 [M-21]-
N2-[(1S)-1-(4'-cyano-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucine is ID MS (-ESI): 407,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-1-(3',4'-debtor-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamideMS (-ESI): 418,4 [M-21]-
Methyl ester of 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin)diphenyl-2-carboxylic acidMS (-ES1): 440,5 [M-21]-
Methyl ester of 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-3-carboxylic acidMS (-ESI): 440,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-1-(3',4'-dimethoxy-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamideMS (-ES1): 442,5 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-(trifluoromethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (-ESI): 450,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-1-(3',4'-dichloro-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamideMS (-ESI): 450,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-formyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (-ESI): 410,2 [M-21]-
N2-{(1S)-1-[4-(5-bromopyridin-3-yl)phenyl]-2,2,2-triptorelin}-Nl(cyanomethyl)-L-leucinamideMS (-ESI): 461,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(triptoreline)-1,1'-diphenyl-4-ileti}-L-leucinamide MS (-ESI): 466,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-indol-4-yl)phenyl]ethyl}-L-leucinamideMS (-ESI): 421,5 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamideMS (-ESI): 384,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-3-ylphenyl)ethyl]-L-leucinamideMS (-ESI): 433,5 [M-21]-
Methyl ester of 4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acidMS (-ESI): 440,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-(pyrimidine-2-ylphenyl)ethyl]-L-leucinamideMS (-ESI): 384,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-furyl)phenyl]ethyl}-L-leucinamideMS (-ESI): 372,4 [M-21]-
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[3-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamideMS (-ESI): 451,4 [M-21]-
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[4-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamideMS (-ESI): 451,4 [M-21]-
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamideMS (ESI): 451,4 [M-21] -
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (-ESI): 412,4 [M-21]-
N2-{(1S)-1-[4'-(acetylamino)-3'-fluoro-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (-ESI): 457,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methyltin-2-yl)phenyl]ethyl}-L-leucinamideMS (-ESI): 402,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (-ESI): 400,4 [M-21]-
N2-{(1S)-1-[4-(5-acetylthio-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (-ESI): 430,4 [M-21]-
N2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (-ESI): 424,4 [M-21]-
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-(trifluoromethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (-ESI): 450,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(5'-fluoro-2'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (-ESI): 430,4 [M-21]-
N1(cyanomethyl)-N2-[(1S)-1-(3',5'-debtor-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamideMS (-ESI): 418,4 [M-21]-
MS (-ESI): 436,4 [M-21]-
3-(4'-{1-[1-(Cyanomethyl-carbarnoyl)-3-methyl-butylamino]-2,2,2-triptorelin}dipel-3-yl)acrylic acidMS (-ESI): 452,5 [M-21]-
N2-{(1S)-1-[4-(9-antrel)phenyl]-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamideMS (-ESI): 482,5 [M-21]-
N2-[(1S)-1-(4'-benzoyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (-ESI): 486,5 [M-21]-
N2-[(1S)-1-(3'-acetyl-4'-hydroxy-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (-ESI): 440,5 [M-21]-
N1(cyanomethyl)-N2-{(1S)-1-[2'-(cyanomethyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamideMS (-ESI): 421,4 [M-21]-
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): RUB 482.2 [M+l]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APGI): 466,1 [M+l]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-(morpholine-4-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 413,2 [M+1]+
N1-(cyano shall ethyl)-N 2-{(1R)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 419,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 419,0 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(5-penalties-2-yl)ethyl]-L-leucinamideMS (+ESI): 409,4 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-(quinoline-8-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 419,0 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-2-ylphenyl)ethyl]-L-leucinamideMS (+ESI): to 455.2 [M+1]+
N2-{1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 483,2 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 483,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 482,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 450,2 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(zenome who yl)-L-leucinamide MS (+ESI): 407,2/408,2 [M+l]+/[M+2]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(morpholine-4-ylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 553,2 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(isopropylphenyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 510,3 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 483,2 [M+1]+
N2-((1S)-1-{4'-[(acetylamino)sulfonyl]-1,1'-diphenyl-4-yl}-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamideMS (+APCI): 525,4 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 496,2 [M+1]+
N2-[1-(5-Bratan-2-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 413,2 [M+1]+
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (-ESI): 403,9, 405,9 [M+1]-
tert-Butyl ester 4-(4'-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-yl)piperazine-1-carboxylic acidMS (+ESI): 588,2 [M+1]+
N1(cyanomethyl)-N2-[,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide MS (+ESI): 488,3 [M+1]+
Nl(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-hydroxyethyl)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 532,3 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 559,9 [M+1]+
N1(cyanomethyl)-N2-(1-{4-[(dimethylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamideMS (+ESI): 399,2 [M+1]+
N1(cyanomethyl)-N2-(1-{4-[(cyclopropylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamideMS (+ESI): 411,2 [M+1]+
4-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acidMS (-ESI): 370,2 [M-1]-
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(2-foradil)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+ESI): 534,3 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethyl)-L-leucinamideMS (+ESI): of 454.3 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamideMS (+ESI): 512,3 [M+1]+
N1-(zenome who yl)-N 2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 425,1 [M+1]+
N2-{1-[4-(3-tert-butyl-1,2,4-triazine-5-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 463,2 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{2-[3-(methylsulphonyl)phenyl]-1,3-thiazol-4-yl}phenyl)ethyl]-L-leucinamideMS (+ESI): 565,1 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamideMS (+ESI): 477,1 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4'-[4-(methylsulphonyl)piperazine-1-yl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+ESI): 566,3 [M+1]+
N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 406,0, 408,1 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-3-yl]ethyl}-L-leucinamideMS (+ESI): of 450.1 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(3-pyridin-4-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 405,1 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-3-yl)ethyl]-L-leucinamideMS (+ESI): 488,3 [M+1]+
N1-(zenome who yl)-N 2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-3-yl]ethyl}-L-leucinamideMS (+ESI): RUB 482.2 [M+1]+
N-(cyanomethyl)-1-[(2,2,2-Cryptor-1-phenylethyl)amino]cyclohexanecarboxylicMS (-ESI): 337[M-1]'
1-{[1-(4-bromophenyl)-2,2,2-triptorelin]amino)-N-(cyanomethyl)cyclohexanecarboxylicMS (+ESI): 418, 420 [M+1]+
N-(cyanomethyl)-1-{[2,2,2-Cryptor-1-(4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]amino}cyclohexanecarboxylicMS (+ESI): 500 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperidine-4-ylphenyl)ethyl]-L-leucinamideMS(+ESI):411[M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-pyridine-2-reparation-1-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 489 [M+1]+
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-cyclopropylalanineMS (+ESI): 404, 406 [M+1]+
N1(cyanomethyl)-3-cyclopropyl-N2-[2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]alaninateMS (+ESI): 403 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4'-pyridin-4-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS(+ESI):481 [M+1]+
N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(1,3-thiazol-2-yl)ethyl]-L-leucinamideMS (+ESI) 335 [M+1] +
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-methoxy-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 434 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-methoxyphenyl)ethyl]-L-leucinamideMS (+ESI): 358 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-pyridin-4-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 481 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-phenoxyphenyl)ethyl]-L-leucinamideMS (+ESI): 420 [M+1]+
N2-[(1S)-1-(4'-bromo-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 482, 484 [M+1]+
N2-{(1S)-1-[4-(4-chloropyridin-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 439 [M+1]+
N2-{(1S)-1-[4'-(acetylamino)-2'-methyl-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 475 [M+1]+
N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 404 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 435 [M+1]+
N1(cyanomethyl)-N2-{(1S)2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamide MS (+ESI): 435 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4"-(methylsulphonyl)-1,1':4',1"-terphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 558 [M+1]+
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-(1-methylcyclopropyl)-L-alaninateMS(+ESI):418,420 [M+1]+
N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-alaninateMS (+ESI): 494 [M+1]+
N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-alaninateMS (+ESI): 462 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS(+ESI):418 [M+1]+
N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 446 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(hydroxymethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS(+ESI):434 [M+1]+
N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 421,4 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)Fe is Il]ethyl}-L-leucinamide MS (+ESI): 421,4 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-1-oxipiridin-3-yl]phenyl}ethyl)-L-leucinamideMS (+ESI): 479,3 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamideMS (+ESI): 483,2 [M+1]+
N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamideMS (+ESI): 509,2 [M+1]+
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 434,2 [M+1]+MS (+ESI): 432,0 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperazine-1-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 412,2 [M+1]+
N2-{1-[3'-(acetylamino)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 461,2 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-propylpiperazine-1-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): of 454.3 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(piperazine-1-ylcarbonyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 440,2 [M+1]+
N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-hydroxyethyl)PIP the Razin-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide MS (+ESI): 484,3 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}phenyl)ethyl]-L-leucinamideMS (+ESI): 540,1 [M+1]+
Methyl ester of 4-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acidMS (+ESI): 386,2 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(E)-2-quinoline-2-retinyl]phenyl}ethyl)-L-leucinamideMS (+ESI): 481,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 553,3 [M+1]+
N2-((1S)-1-{4-[3-(5-bromopyridin-3-yl)-1,2,4-oxadiazol-5-yl]phenyl}-2,2,2-triptorelin)-N1-cyanomethyl)-L-leucinamideMS (+ESI): 553,3 [M+1]+MS (+ESI): 551,1 [M+1]+
N2-[(1S)-1-(4-benzoylphenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 432,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(Tien-2-ylcarbonyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 438,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-ylcarbonyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 439,2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4{(Z)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)

ethyl]-L-leucinamide
MS (+ESI): 508,2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{(E)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)

ethyl]-L-leucinamide
MS (+ESI): 508,2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isobutylphenyl)ethyl]-L-leucinamideMS (+ESI): 398,2 [M+1]+
N2-{(1S)-1-[4-(4-bromo-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 491,1 [M+1]+MS (+ESI): 489,0 [M+1]+
N1(cyanomethyl)-N2-[(1S)-1-(4-cyanophenyl)-2,2,2-triptorelin]-L-leucinamideMS (+ESI): 353,2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,2-triptorelin]-L-leucinamideMS (+ESI): 352,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2'-fluoro-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 422,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 411,1 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 450,2 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-leucinamide MS (+ESI): 469,2 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethyl}-L-leucinamideMS (+ESI) : 443,2 [M+1]+
N1(cyanomethyl)-N2-{1-[4'-(dimethylamino)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin]-L-leucinamideMS (+ESI): 447,2 [M+1]+
N1(cyanomethyl)-N2-[(1S)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamideMS (+APCI): 410,2 [M+1]+
N1(cyanomethyl)-N2-[(1R)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamideMS (+APCI) : 410,2 [M+1]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 482,1 [M+1]+
4'-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acidMS (+APCI): 448,0 [M+1]+
Methoxyethylamine 4'-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acidMS (+APCI) : 491,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-({[4-(methylsulphonyl)benzyl]thio}methyl)phenyl]ethyl)-L-leucinamideMS (+APCI): USD 542.3 [M+1]+
N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1(Sanomat the l)-L-leucinamide MS (+APCI): 439,1 [M+1]+
N2-{(1S)-1-[3'-(aminosulfonyl)-4'-bromo-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+APCI): 561,1 and 563,1 [M+1]+
N2-{(1S)-1-[4'-bromo-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+APCI): 560,1 and 562,1 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamideMS (+ESD): 497,2 [M+1]+
N2-[(1S)-1-(4-{5-chloro-3-[4-(methylsulphonyl)phenyl]pyridine-2-yl}phenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 593,2 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(phenylthio)methyl]phenyl}ethyl)-L-leucinamideMS (+APCI): 450,0 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(trifluoromethyl)sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 536,1 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[(4-perbenzoic)amino]methyl}phenyl)ethyl]-L-leucinamideMS (+APCI): 479,1 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(methylsulphonyl)phenyl]ethyl}-L-leucinamideMS (+APCI): 406,1 [M+1]+
N1-(1-tzia is cyclopropyl)-N 2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 508,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamideMS (+APCI): 496,1 [M+1]+
N2-((1S)-1-{4-[({[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-yl]carbonyl}amino)methyl]phenyl}-2,2,2-triptorelin)-Nl(cyanomethyl)-L-leucinamideMS (+APCI): 594,4 [M+1]+
N2-((1S)-1-{4-[(9-chloro-3-methyl-4-oxitocina[4,3-c]quinoline-5(4H)-yl)methyl]phenyl}-2,2,2-triptorelin)-Nl(cyanomethyl)-L-leucinamideMS (+APCI) : 574,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 512,2 [M+1]+
N2-{(1S)-1-[4"-chloro-4'-(methylsulphonyl)-1,1':2',1"-terphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+APCI): 592,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methoxy-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 512,2 [M+1]+
N2-{(1S)-1-[2'-chloro-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamideMS (+APCI): 516,3 and 518,2 [M+1]+
N1(cyanomethyl)-N 2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxyethyl)thio]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (-ESI): 478,1 [M-1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-fluoro-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 500,1 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxyethyl)sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 512,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 482,1 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-({2-[methoxy(methyl)amino]-2-oxoethyl}sulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 569,3 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 540,2 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamideMS (+APCI): 506,2 [M+1]+
N2-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamideMS (+ESI): 492,0, 494,0 [M+1]+
N1(cyanomethyl)-N2-{[4-(methylsulphonyl)phenyl][4'-(Matilde is)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide MS (-ESI): 534,2 [M-1]"
N1(cyanomethyl)-N2-{[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(methylsulphonyl)phenyl]methyl}-L-leucinamideMS (+ESI): 568,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-were)ethyl]-L-leucinamideMS (+ESI): 368,4 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 420,1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-oxazol-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 435,4 [M+1]+
N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrazin-2-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 406,2 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 419,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 419,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-4-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 420,1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamideN2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 472,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(3'-fluoro-4'-methyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 462,1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(1-hydroxy-1-methylethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamideMS (+ESI): 489,6 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+ESI): 512,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4'-methyl-1,1'-diphenyl-4-yl)propyl]-L-leucinamideMS (+ES1): 494,1 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-3-yl)phenyl]propyl}-L-leucinamideMS (+ESI): 485,2 [M+1]+
Nl(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(2'-fluoro-1,1'-diphenyl-4-yl)propyl]-L-leucinamideMS (+ESI): 472,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 538,1 [M+1]+
N2-{(1S)-1-[3'-(amino Lionel)-4'-methoxy-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N 1-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 539,1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 461,3 [M+1]+
N1(cyanomethyl)-N2{(1S)-2,2,3,3,3,-pendaftar-1-[4-(5-methylpyridin-2-yl)phenyl]propyl}-L-leucinamideMS (+ESI): 469,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(methylsulphonyl)pyridine-2-yl]phenyl}ethyl)-L-leucinamideMS (+APCI): 509,2 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamideMS (+APCI): 446,1 [M+1]+
N1(cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 500,1 [M+1]+
N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 526,1 [M+1]+
Nl-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 540,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(1H-pyrazole-3-yl)pyridine-2-yl]ethyl}-L-leucinamideMS (+APCI): 421,0 [M+1] +
N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-5-espiridion-2-yl)ethyl]-L-leucinamideMS (+APCI): 482,3 [M+1]+
N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-6-espiridion-2-yl)ethyl]-L-leucinamideMS (+APCI): 482,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide1H NMR (CD3COCD3) δ 8,15 (1H, m), and 8.0 (2H, d), of 7.95 (2H, d), of 7.75 (2H, d), at 7.55 (2H, d)and 6.1 (1H, dt), 4,0-4,1 (1H, m), of 3.25 to 3.35 (1H, m)and 3.15 (3H, s), 2,4-2,5 (1H, m), as 1.8-1.9 (1H, m), 1,4-of 1.55 (4H, m), 0,85-of 1.05 (8H,m)
N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 522,3 [M+1]+
N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 430,2 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (-ESI): 557,2 [M-1]-
N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1-ethoxyphenyl)phenyl]-2,2,2-triptorelin}-L-leucinamideMS (-ESI): 422,2 [M-1]-
N2-[(1S)-1-(4-acetylphenyl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-L-leucinamide MS (+ESI): 396,0 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isopropylphenyl)ethyl]-L-leucinamideMS (+ESI): 396,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-phenylethyl]-L-leucinamideMS (+ESI): 354,0 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-L-leucinamideMS (+ESI): 434,3 [M+Na]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-methylcyclopropyl)phenyl]ethyl)-L-leucinamideMS (+ESI): 408,2 [M+l]+
N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(2',4',6'-trimethyl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamideMS (+ESI): 472,2 [M+l]+
N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 389,3 [M+l]+
N2-{(1S)-1-[5-(4-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 473,2 [M+l]+
N2-{(1S)-1-[6-(4-acetylphenyl)pyridine-3-yl]-2,2,2-triptorelin}-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 473,2 [M+l]+
N2-{(1S)-1-[5-(3-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-Nl-(1-cyanocyclohexyl)-L-leucine is ID MS (+ESI): 473,4 [M+l]+
N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(1-hydroxyethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamideMS (+ESI): 475,5 [M+l]+
N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N'-(cyanomethyl)-L-leucinamideMS (-ESI): 452,2 [M-1]-
N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-Nl(cyanomethyl)-L-leucinamideMS (+ESI): 495,83 [M+1]+
N2-[(1S)-1-(1,1'-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 479,8 [M+1]+
N2-(1-benzyl-2,2,2-triptorelin)-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (-APCI): 366,1 [M-1]-
N2-[(1S)-1-(4-tert-butylphenyl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-L-leucinamideMS (+APCI): 410,2 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4-methyl-L-leucinamideMS (+APCI): 420,2 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-methyl-L-leucinamideMS (+APCI): 446,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamideMS (+PCI): 503,2 [M+1] +
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 451,2 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 445,2 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 445,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 445,2 [M+1]+
N2-[(1S)-1-(3'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamideMS (+ESI): 490,3 [M+1]+
N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 438,3 [M+1]+
N1-[(1S)-1-cyanoethyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 496,3 [M+1]+
N1-[(1S)-1-cyano-3-(methylthio)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 556,3 [M+1]+
Nl-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl)-L-leucinamide MS (+ESI): 588,2 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 482, 484 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-2-yl)phenyl]propyl}-L-leucinamideMS (+ESI): 485 [M+1]+
N2-[(1S)-1-(5-bromopyridin-2-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamideMS (+ESI): 407, 409 [M+1]+
N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamideMS(+ESI):483 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS(+ESI):488 [M+1]+
Nl(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(6'-methyl-3,3'-piperidin-6-yl)ethyl]-L-leucinamideMS (+ESI): 420 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 461 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-1,6-dihydropyridines-2-yl)phenyl]ethyl}-L-leucinamideMS(+ESI):421 [M+1]+
(4S)-Nl(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(matilal the Nile)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide MS (+ESI): 536 [M+1]+
(4S)-Nl-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 562 [M+1]+
(4S)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 504 [M+1]+
(4S)-NI-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 530 [M+1]+
(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-Nl(cyanomethyl)-5,5,5-Cryptor-L-leucinamideMS (+ESI): 460, 462 [M+1]+
(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-5,5,5-Cryptor-L-leucinamideMS (+ESI): 486, 488 [M+1]+
N2-{(1S)-1-[4-(6-aminopyridine-3-yl)phenyl]-2,2,2-triptorelin}-Nl(cyanomethyl)-L-leucinamideMS (+ESI): 420 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamideMS (+ESI): 450, 452 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methylpyridin-3-yl)phenyl]propyl}-L-leucinamideMS (+ESI): 468,8 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{1S)-2,2,3,3,3-pendaftar-1-[4-(6-methylpyridin-3-yl)phenyl]propyl}-L-leucinamide MS (+ESI): 494,8 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 445,0 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESD: 447,8 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(2,2,2-Cryptor-1-hydroxyethyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 501,8 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+ESI): 526,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+ESI): 538,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+ESI): 558,2 [M+1]+
(4R)-Nl(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS(+ESI): 536,1 [M+1]+
(4R)-Nl-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 562,1 [M+] +
N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4'-methyl-1,1'-diphenyl-4-yl)propyl]-L-leucinamideMS (+ESI): 468,2 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(1,3-thiazol-2-yl)phenyl]propyl}-L-leucinamideMS (+ESI): 461,0 [M+1]+
N1-(1-cyanocyclohexyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,3,3,3-pentafluoropropyl]-L-leucinamideMS (+ESI): 428,1 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamideMS (+ESI): 392,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamideMS (+ESI): 418,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 425,3 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 437,1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 451,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,3,3,3-pentafluoropropyl}-L-leucinamide MS (+ESI): 468,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 451,2 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamideMS (+ESI): 425,3 [M+1]+
N1(cyanomethyl)-N2-{(1S)-1-[4-(4,5-dimethyl-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-L-leucinamideMS (+ESI): RUR 439,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamideMS (+ESI): 540,1 [M+1]+
N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 449,2 [M+1]+
Nl-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+ESI): 556,3 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-alaninateMS (+APCI): 363,8, 365,8 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-N1(cyanomethyl)-L-leucinamideMS (+APCI): 533,2 [M+1]+
Nl(cyanomethyl)-N2-((1S)-2,2,3,3,3-pendaftar-1-{4-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}propyl)-L-leucinamide MS (+APCI): 590,4 [M+1]+
N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-alaninateMS (+APCI): 440,1 [M+1]+
Nl(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4'-(isopropylphenyl)-1,1'-diphenyl-4-yl]propyl}-L-leucinamideMS (+APCI): 560,2 [M+1]+
N1-(1-cyano-1-methylethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 510,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4'-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1'-diphenyl-4-yl}ethyl)-L-leucinamideMS (+APCI): 566,4 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[2'-methyl-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamideMS (+APCI): 522,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-1-[4'-(ethylsulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamideMS (+APCI): 522,3 [M+1]+
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamideMS (+APCI): 527,3 [M+1]+
Nl(cyanomethyl)-N2-{(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(triptoreline)phenyl]methyl}-L-leucinamideMS(-ESI): 572,2 [M-1] -and 573,3
Nl(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-2-yl)methyl]-L-leucinamide1H NMR (d6-DMSO): δ to 8.7 (m, 2H), 7,52 (d, 2H), 7,50 (d, 2H), 7,39 (d, 2H), 7,38 (m, 1H), 7,03 (2H, d), 6,98 (d, 1H), 6,92 (DD, 1H), 4,90 (1H, s)to 4.15 (m, 2H), 3,30 (8H, m), 3,23 (1H, m), 2,65 (1H, d), 1,80 (1H, m)of 1.45 (1H, m), 1,25 (1H, m)0,86 (3H, d), 0,81 (3H, d). LC/MS M+1: 502,4
Nl(cyanomethyl)-N2-[(S)-(4'-piperazine-4-FMD-1-yl-1,1'-diphenyl-4-yl)(Tien-2-yl)methyl]-L-leucinamide methansulfonate1H NMR (d6-DMSO): δ to 8.7 (m, 2H), 7,52 (d, 2H), 7,50 (d, 2H), 7,39 (d, 2H), 7,38 (m, 1H), 7,03 (2H, d), 6,98 (d, 1H), 6,92 (DD, 1H), 4,90 (1H, s)to 4.15 (m, 2H), 3,30 (8H, m), 3,23 (1H, m), 2,65 (1H, d), 1,80 (1H, m)of 1.45 (1H, m), 1,25 (1H, m)0,86 (3H, d), 0,81 (3H, d). LC/MS M+1: 502,4
Nl(cyanomethyl)-N2-{(S)-(4-forfinal)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamide1H NMR H NMR δ (CDC13): of 0.77 (d, 3H), and 0.9 (d, 3H); to 1.38 (m, 1H), 1.57 in (m, 1H), 1,71 (m, 1H), 2,01 (Sirs, 1H), to 3.09 (s, 3H), to 3.09 (m, 1H), 4,07 (m, 2H), 4,89 (1H, s), 7,03 (m, 2H), 7,21 (m, 1H), 7,33 (m, 2H), 7,42 (d, 2H), 7,53 (m, 2H), 7,68 (d, 2H), of 7.97 (d, 2H)
Nl(cyanomethyl)-N2-{(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl][4-(trifluoromethyl)phenyl]methyl}-L-leucinamideMS (+APCI): 556,5 and 558,5 [M+1]+
N2-{(S)-(4-chlorophenyl)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-Nl(cyanomethyl)-L-leucinamideMS (+APCI): 524,3 and 525,5 [M+1]+
N1 (cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 468 [M+1]+
N2-[(S)-(4-bromophenyl)(Tien-2-yl)methyl]-Nl(cyanomethyl)-L-leucinamide1H NMR (d6-DMSO): δ 8,64 (1H, t), of 7.48 (2H, d), 7,39 (DD, 1H), 7,31 (2H, d), of 6.96 (1H, m)6,91 (1H, DD), of 4.90 (1H, s), 4,13 (2H, m)and 3.15 (1H, m), 2,70 (1H, m), of 1.85 (1H, m)of 1.40 (1H, m), 1,25 (1H, m), 0,85 (3H, d), to 0.80 (3H, d). LC/MS, M-1: 3,81
N1(cyanomethyl)-N2-[(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl](Tien-2-yl)methyl]-L-leucinamideLC/MS,M-1:466,1
N2-{(R)-(4-bromophenyl)[4-(triptoreline)phenyl]methyl}-Nl(cyanomethyl)-L-leucinamideMS (-ESI): 496,1 [M-1]-
N1(cyanomethyl)-N2-{(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][4-(triptoreline)phenyl]methyl)-L-leucinamideMS (+APCI): 545,2 and 546,3 [M+l]+
N2-[(S)-(4-bromophenyl)(2-furyl)methyl]-Nl(cyanomethyl)-L-leucinamideMS (+APCI): 404,1 and 405,3 [M+l]+
Nl(cyanomethyl)-N2-{(S)-2-furyl[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamideMS (+APCI): 479,2 [M+1]+
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-Nl(cyanomethyl)-L-NorvalineMS (+ESI): 392, 394 [M+1]+
N2-{(R)-(4-pompini who)[4-(trifluoromethyl)phenyl]methyl}-N l(cyanomethyl)-L-leucinamideMS (+APCI): 482,1 and 481,2 [M+1]+
Nl(cyanomethyl)-N2-{1-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-L-NorvalineMS(+ESI): 514 [M+1]+
N2-[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]-Nl(cyanomethyl)-L-leucinamideMS (+APCI): 482,1 and 481,2 [M+l]+
N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 468 [M+1]+
N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-N1(cyanomethyl)-L-leucinamideLC/MS,M-1: 432,0
N2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-Nl(cyanomethyl)-L-leucinamideLC/MS,M-1: 418,2
Nl(cyanomethyl)-N2-{(S)-(2,4-differenl)[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamideMS (+APCI) 525,3, 524,3 [M-1]-and to 526.4 [M+l]+.1H NMR (CD3SOCD3) δ 8,01 (DD, 2H), and 7.8(DD, 2H), 7,35 (DD, 2H), 7,11(DD, 2H), 7,03 (d, 1H), 6,93(d, 2H), 6,62(d, 1H), 6,55(d, 1H), 5,0(s, 1H), 4,13(t, 2H), 3,35(m, 1H), 3.0 a(m, 1H), 2,99(m, 1H), 2,85(s,3H), of 1.84(m, 1H), 1,45(m, 1H), 0,9-0,8(m, 6H),
N1(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide1H NMR (d6-DMSO): δ to 8.62 (1H, t), of 7.95 (2H, d), a 7.85 (2H, m), the 7.65 (2H, d), 7,49 (2H, d), 7,47 (2H, m), 7,10 (1H, DD),4,80 (1H, d), of 4.13 (2H, m), 3,24 (3H, s), 3,05 (1H, m), 2,65 (1H, m), 1.8 m (1H, m)of 1.45 (1H, m)of 1.30 (1H, m), is 0.84 (3H, d), from 0.76 (3H,d).LC/MS,M-l: 493,5
N1(cyanomethyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamideLC/MS, M-1: are 507, 5
Nl(cyanomethyl)-N2-[(S)-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamideLC/MS M+1: 556,1, M-1: 554,0
Nl(cyanomethyl)-N2-[(S)-[4'-(4-cyclopropylmethyl-1-yl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamideLC/MS, M-1: 540,1
N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-Nl(cyanomethyl)-5,5,5-Cryptor-L-NorvalineMS (+ESI): 446,1, 448,1 [M+1]+
Nl(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 522,3 [M+1]+
N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-Nl-(1-cyanocyclohexyl)-L-leucinamideLC/MS, M-1: 460,1,
Nl-(1-cyanocyclohexyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide1H NMR (d6-DMSO): δ 8,96 (1H, s), of 7.96 (2H, d), 7,87 (2H, d), of 7.69 (2H, d), was 7.45 (2H, d), 7,31 (1H, d), 7,76 (1H, d), to 4.98 (1H, s), 3,24 (3H, s), 3,10 (1H, m), 2,5 (1H, d), is 2.09 (3H, s), of 1.85 (1H, m), 1,50 (2H, m)of 1.40 (1H, m), 1,25 (1H, m), 1,10 (2H, m)0,86 (3H, d), or 0.83 (3H, d). LC/MS, M: 534,2
N1(cyanomethyl)-N2-{(S)-3-furyl[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]methyl}-L-leucinamideMS (+APCI): 479,2 and 478,3 [M-1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 494 [M+1]+,1H NMR (CDC13): δ to 0.97 (t, 3H), and 0.98 (m, 1H), 1,1 (m, 1H), 1,42 (m, 2H), 1,29 (m, 2H), and 1.63 (m, 1H), 1.77 in (m, 1H), 3,13 (s, 3H), of 3.28 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs, 1H), 7,47 (d, 2H), 7,63 (d 2H), 7,78 (d, 2H), 8,02 (d, 2H)
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-Nl-(1-cyanocyclohexyl)-L-NorvalineMS(-ESI):416,418[M-1]-1H NMR (CDC13): δ to 0.97 (3H, t), and 0.98 (m, 1H), 1,07 (m, 1H), 1,41 (m, 2H), 1,49 (m, 2H), 1,62 (m, 1H), 1,72 (m,lH), with 3.27 (1H, m), 1.04 million (m, 1H), 7,1 (Sirs, 1H), 1,24 (d, 2H), of 7.75 (d, 2H),
N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-Nl(cyanomethyl)-L-leucinamide1H NMR (d6-DMSO): δ 8,69 (1H, t), 7,52 (1H, m), 7,49 (2H, d), 7,31 (2H, d), of 7.00 (1H, d), 4,91 (1H, s), 4,14 (2H, m)and 3.15 (1H, m), of 2.81 (1H, DD), of 1.85 (1H, m)of 1.45 (1H, m)of 1.30 (1H, m)0,86 (3H, d) 0,82 (3H, d)
N2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-Nl-(1-cyanocyclohexyl)-L-leucinamideLC/MS, M-1: 443,8
N1(cyanomethyl)-N2-((S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]{4-[4-(methylsulphonyl)phenyl]Tien-2-yl}methyl)-L-leucinamide1H NMR (d6-DMSO): δ is 8.75 (1H, t), of 7.90(9H, m), of 7.70 (2H, d), EUR 7.57 (3H, m), is 5.06 (1H, s), 4,18 (2H, m), 3,23 (3H, s), up 3.22 (1H, m), 3,19 (3H, s), 2,85 (1H, d), 1,90 (1H, m), 1,50 (1H, m)of 1.35 (1H, m)to 0.89 (3H, d), of 0.85 (3H, d). LC/MS, M-l: 648,1
N1-(1-cyanocyclohexyl)-N2-[(S)-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamideLC/MS M+1: 522,3, M-1: 521,4
N2-{(1S)-1-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl]-2,2,2-triptorelin}-Nl-(1-cyanocyclohexyl)-L-NorvalineMS (+ESI): 495 [M+1]+.1H NMR (CDC13): δ to 0.97 (3H, t), and 0.98 (m*, 1H); 1,08 (m, 1H), 1,42 (m, 2H), 1,44 (m, 2H), 1,57 of 1.8 (m, 4H), of 3.28 (m, 1H), 4,16 (kV, 1H), 4,9 (Sirs*, 1H), 7,2 (s, 1H), 7,43 (d, 2H), and 7.6 (d, 2H), 7,72 (d, 2H), to 7.99 (d, 2H)
N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-Nl-(1-cyanocyclohexyl)-L-leucinamideLC/MS, M-1: 526,2
N2-[(S)-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamideLC/MS, M-1: 521,4
N2-[(S)-[4'-(aminosulfonyl)-1,1'-diphenyl-4-yl](Tien-3-yl)methyl]-Nl(cyanomethyl)-L-leucinamide1H NMR (d6-DMSO): δ 8,63 (1H, t), to 7.84 (2H, d), 7,79 (2H, d), 7,63 (2H, d), 7,47 (2H, d), 7,40 (2H, m), to 7.09 (1H, DD), to 4.81 (1H, d), of 4.13 (2H, m), 3,05 (1H, m), 2,65 (1H, DD), of 1.80 (1H, m)of 1.45 (1H, m), 0,85 (3H, d), from 0.76 (3H, d). LC/MS, M-1: 495,4
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-3'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 524,2 M+1] +
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-NorvalineMS (+ESI): 431,0 [M+1]+
N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 548,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-NorvalineMS (+ESI): 406,3 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(1-hydroxy-1-methylethyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 474,2 [M+1]+(100%).1H NMR (400 MHz, DMSO-d6): δ to 7.6 (m, 8H) to 7.4 (m, 1H) to 7.25 (s, 1H) 5,2 (s, 1H) 4,1 (m, 2H) 3,3 (m, 1H) 2,05 (s, 1H) a 1.75 (m, 1H) and 1.6 (s, 6H) 1,4 (m, 2H) 1,25 (t, 2H) 1,0 (m, 4H)
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-Norvaline1H NMR (d6-DMSO): δ 8,72 (1H, s), 8,48 (1H, m), 8,02 (2H, d), to 7.84 (1H, d), to 7.67 (1H, DD), 7,46 (2H, d), 4,30 (1H, m), of 3.13 (1H, m), 2,85 (1H, DD), of 2.33 (3H, s)of 1.46 (2H, m), 1,32 (4H, m)to 0.88 (1H, m), 0,86 (3H, t)to 0.73 (1H, m). LC/MS M+1: 431,2
2-{[(4-Bromophenyl)pyridine-4-ylmethyl]amine}pentanol acid cyanomethyleneMS (+APCI): 400,9 and 401,2 [M+1]+
2-{[(4-Bromophenyl)thiazol-2-ylmethyl]amino+}pentanol acid cyanomethyleneM (+APCI): 407,1 and 406 [M+1] +
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-1-(4'-acetylbiphenyl-4-yl)-2,2,2-triptorelin]pentanol acidMS (+ESI): 458 [M+l]+, 480 [M+1+Na]+.1H NMR (CDC13): δ to 0.97 (t, 3H), and 0.98 (m, 1H), 1,-7 (m, 1H), 1,42 (m, 2H), 1.57 in (s, 2H), and 1.63 (m, 1H), 1,78 (m, 1H), 2,33 (s, 3H), of 3.33 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs, 1H), 7,43 (d, 2H), 7,65-7,69 (HD, 4H), 8,03 (d, 2H)
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-1-(2',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acidMS (+ESI): 452 [M+1]+, 474 [M+1+Na]+,1H NMR (CDC13): δ of 0.90 (m, 1H), 0,97 (t, 3H), 1.04 million (m, 1H), 1.41 to 1,5 (m,4H), of 1.62 (m, 1H), 1,78 (m, 1H), 2,19 (Sirs, 1H), 3,32 (DD, 1H), 4,13 (DD, 1H), 6,95 (m, 2H), 7,19 (Sirs, 1H), 7,41 (m, 3H), 7,53 (d, 2H),
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-1-(3',4'-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acidMS (+ESI): 452 [M+1]+, 474 [M+1+Na]+.

1H NMR (CDC13): δ to 0.97 (t, 3H), and 0.98 (m,

1H), 1,07 (m, 1H), 1,42 (m, 2H), 1,5 (m,

2H), 1,62 (m, 1H), 1.77 in (m, 1H), 2,18 (Sirs,

1H), 3,29 (DD, 1H), 4,17 (kV, 1H), 7,21 (Sirs,

1H), 7,13-to 7.3 (m, 2H), 7,38 (m, 1H), 7,42 (d, 2H), EUR 7.57 (d, 2H)
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-1-(3'-chloro-4'-forgivenes-4-yl)-2,2,2-triptoreline]pentanol acidMS (+ESI): 468 [M+1]+.1H NMR (CDC13): δ 0,99 (t, 3H), 1.00 m (m, 1H), 1,08 (m, 1H), 1,42 (m, 2H)and 1.51 (m, 2H), 1,62

(m, 1H), 1,79 (m, 1H), 2,19 (Sirs, 1H), 3.33 and

(DD, 1H), 4,17 (kV, 1H), 7,21 (m, 2H), 7,42 (m, 3H), EUR 7.57 (d, 2H), 7.62mm (m, 1H)
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acidMS (-ESI): 507,0 [M-1]-
(2S)-2-{(S)-[(4-Bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid cyanomethyleneMS (+APCI): 479,2 and 478,3 [M-1]-
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): of 450.1 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-3'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 464,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-chloro-2'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): rub464.3 [M+1]+
(1-Cyanocyclohexyl)amide (2S)-2-((S)-2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethylamine}pentanol acidMS (+ESI): 455,1 [M+1]+
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(3'-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acidMS (+ESI): 509,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-fluoro-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 434,4 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-fluoro-3'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-norvale the amide MS (+ESI): USD 448,2 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[3'-fluoro-4'-methyl-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 448,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-triptoreline-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 500,1 [M+1]+
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4'-methylbiphenyl-4-yl)ethylamine]pentanol acidMS (+ESI): 430 [M+1]+.1H NMR (CDC13): δ of 0.90 (m, 1H), and 0.98 (t, 3H), of 1.02 (m, 1H) 1,4-1,5 (m, 4H), of 1.62 (m, 1H), 1.69 in (m, 1H), 2,19 (Sirs, 1H), 2,41 (s, 3H), at 3.35 (DD, 1H), 4,1 (kV, 1H), 7,21 (s, 1H) 7,24 (d, 2H), 7,38 (d, 2H), 7,46 (d, 2H), 7,60 (d, 2H)
(1-Cyanocyclohexyl)amide (2S)-2-[(S)-1-(4'-cyanobiphenyl-4-yl)-2,2,2-triptorelin]pentanol acidMS (+ESI): 441 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-methoxy-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 446,3 [M+1]+
Nl-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(benzo[1,3]dioxol-5-yl)phenyl]ethyl)-L-NorvalineMS (+ESI): 460,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methoxycarbonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 474,3 [M+1]+
(1-Cyanocyclohexyl)amide (2S)-2-{(S)-[(bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid MS(-ESI): 445, 447 [M-l]-.1H NMR (CDC13): δ of 0.82 (d, 3H), of 0.95 (d, 3H), 1.04 million (m, 2H), 1,46-of 1.62 (m, 4H), of 1.80 (m, 1H), 3,12 (DD, 1H), 4.95 points (s, 1H), 7,22 (s, 1H), 7.23 percent-of 7.25 (d, 2H), 7,31 (m, 2H), 7,47 (d, 2H), 7,74 (m, 1H),
(2S)-2-{(S)-[(4'-Methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amine}-4-methylpentanoic acid cyanomethyleneMS (+APCI): 418,9,420,9 [M-1]+
(2S)-2-[(S)-2,2,2-Cryptor-1-(4'-triptorelin-4-yl)ethylamino]pentanol acid (1-cyanocyclohexyl)amideMS (+APCI): 483,3 [M+1]+
(2S)-2-[(S)-2,2,2-Cryptor-1-(2'-triptorelin-4-yl)ethylamine]pentanol acid (1-cyanocyclohexyl)amideMS (+APCI): 483,3 [M+1]+
(2S)-2-{(S)-[(2',4'-giftgiver-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid (1-cyanocyclohexyl)amideMS (-ESI): 479 [M-1]-.1H NMR (CDC13): δ 0,84 (d, 3H), of 0.97 (d, 3H), of 1.03 (m, 2H), 1,47 (m, 2H), 1,57-of 1.62 (m, 4H), of 1.95 (m, 1H), 3.27 to (DD, 1H), 5,02 (s, 1H), 6,93 (m, 2H), 7,32 (m, 1H), 7,39 (m, 1H), 7,42 (m, 3H), of 7.48 (d, 2H), to 7.77 (d, 1H)
(2S)-2-{(S)-[(4'-Methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acid (1-cyanocyclohexyl)amideMS (-ESI): 521 [M-1]-
N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamideMS (+APCI): 499,4 [M+1]+
N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4'(methylsulfonyl)-1,1'-diphenyl-4-yl]ethyl}-L-leucinamide MS (+APCI): 510,1 [M+1]+
N2-[(1S)-1-(4'-acetyl-1,1'-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamideMS (+ESI): 472,1 [M+1]+
N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamideMS (+ESI): 482 [M+1]+
N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-NorvalineMS (+ESI): 454,1, 456,2 [M+1]+
N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylthio)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): 498,3 [M+1]+
N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4'-(methylsulphonyl)-1,1'-diphenyl-4-yl]ethyl}-L-NorvalineMS (+ESI): us $ 530, 3 [M+1]+

The pharmaceutical composition

As a separate variant of this invention, 100 mg of N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-[4'-piperazine-1-yl-1,1'-diphenyl-4-yl)ethyl]-L-leucinamide formulated with sufficient finely powdered lactose to provide the total number of from 580 to 590 mg to fill hard gelatin capsules 0 size.

Compounds disclosed in the present invention are active in the following tests. In addition, the compounds disclosed in the present who eat the invention possess advanced pharmacological profile with respect to the previously disclosed compounds.

Cathepsin K research

Serial dilution (1/3) of 500 μm up to 0,0085 μm of the test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μl of DMSO from each dilution was added to 50 µl sample buffer (MES, 50 mm (pH 5.5); EDTA, 2.5 mm; and DTT, 2.5 mm and 10% DMSO) and 25 μl of cathepsin K man (0.4 nm) in the solution of the buffer. The analyzed solution was stirred for 5-10 seconds on a vibrating plate, and incubated for 15 minutes at room temperature. Z-Leu-Arg-AMC (8 mm) in a 25 µl sample buffer was added to the sample solutions. Hydrolysis kumaranatunga group (AMC) was accompanied by spectrofluorimetry (Exλ =355 nm; Emλ = 460 nm) for 10 minutes. The percentage of inhibition was calculated by conversion of the experimental values to the standard mathematical model for the curve dose-response.

Cathepsin L research

Serial dilution (1/3) of 500 μm up to 0,0085 μm of the test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μl of DMSO from each dilution was added to 50 µl sample buffer (MES, 50 mm (pH 5.5); EDTA, 2.5 mm; and DTT, 2.5 mm and 10% DMSO) and 25 μl of cathepsin L person (0.5 nm) in the studied buffer solution. The analyzed solution was stirred for 5-10 seconds on a vibrating plate, and incubated for 15 minutes at room temperature. Z-Leu-Arg-AMC (8 mm) in a 25 µl sample buffer DOB is ulali to the investigated solutions. Hydrolysis kumaranatunga group (AMC) was accompanied by spectrofluorimetry (Exλ =355 nm; Emλ = 460 nm) for 10 minutes. The percentage of inhibition was calculated by conversion of the experimental values to the standard mathematical model for the curve dose-response.

Cathepsin B study

Serial dilution (1/3) 500 µm up to 0,0085 μm of the test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μl of DMSO from each dilution was added to 50 µl sample buffer (MES, 50 mm (pH 5.5); EDTA, 2.5 mm; and DTT, 2.5 mm and 10% DMSO) and 25 μl of cathepsin B person (4.0 nm) in the studied buffer solution. The analyzed solution was stirred for 5-10 seconds on a vibrating plate, and incubated for 15 minutes at room temperature. Z-Leu-Arg-AMC (8 mm) in a 25 µl sample buffer was added to the sample solutions. Hydrolysis kumaranatunga group (AMC) was accompanied by spectrofluorimetry (Exλ =355 nm; Emλ = 460 nm) for 10 minutes. The percentage of inhibition was calculated by conversion of the experimental values to the standard mathematical model for the curve dose-response.

Cathepsin S research

Serial dilution (1/3) 500 µm up to 0,0085 μm of the test compounds were prepared in dimethyl sulfoxide (DMSO). Then 2 μl of DMSO from each dilution was added to 50 µl sample buffer (MES, 50 mm (pH 5.5); EDTA, 2.5 mm; and DTT, 2.5 mm and 10% DMSO) and 25 μl of human cathepsin S (20 nm) in the studied buffer solution. The analyzed solution was stirred for 5-10 seconds on a vibrating plate, and incubated for 15 minutes at room temperature. Z-Leu-Arg-AMC (8 mm) in a 25 µl sample buffer was added to the sample solutions. Hydrolysis kumaranatunga group (AMC) was accompanied by spectrofluorimetry (Exλ =355 nm; Emλ = 460 nm) for 10 minutes. The percentage of inhibition was calculated by conversion of the experimental values to the standard mathematical model for the curve dose-response.

1. Compounds represented by the following formula:

where R1represents hydrogen or C1-6alkyl, where the optionally substituted from one to six halogen atoms, -SR12, -SO2R12;

R2represents hydrogen or C1-6alkyl, where the optionally substituted from one to six halogen atoms, -SR12, -SOR12;

or R1and R2can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl ring;

R3represents hydrogen or C1-6alkyl, where the optionally substituted C3-6cycloalkyl or from one to six halogen atoms;

R4represents hydrogen or C1-6/sub> alkyl, where the optionally substituted C3-6cycloalkyl or from one to six halogen atoms;

or R3and R4can be taken together with the carbon atom to which they are attached to form with3-8cycloalkyl ring, which optionally may be substituted by one or two substituents, independently selected from C1-6the alkyl or halogen;

R5selected from hydrogen or C1-6of alkyl, substituted by 1-6 halogen atoms;

R6represents phenyl, heteroaryl, which represents a 5-6-membered monocyclic ring containing 1-4 atoms N, O and/or S, C1-6halogenated, where mentioned phenyl and heteroaryl optionally substituted one, two or three substituents, independently selected from halogen, C1-6of alkyl, C1-6halogenoalkane, -SR12, -SOR12, -SO2CH(R12)(R11), phenyl, -OR12or aryl, optionally substituted-SO2R12;

each D independently represents a C1-3alkyl, C2-4alkenyl,2-4quinil, phenyl, heteroaryl representing a 5-10-membered monocyclic ring containing 1-3 atoms N, O or S, heterocyclyl, where each specified aryl, heteroaryl and heterocyclic group, optionally substituted or carbon atom or CGU is Euroatom one to five substituents, independently selected from C1-6of alkyl, halogen, keto, C1-6alkoxy, -SR9, -SR12N(R12)2or-SO2R10;

R7represents hydrogen, C1-6alkyl, C2-6alkenyl,2-6quinil, C1-6alkyloxy, halogen, cyano, aryl, a 5 - or 6-membered mono - or bicyclic hydrocarbon ring, heteroaryl, which represents a 5 - or 6-membered mono - or bicyclic hydrocarbon ring containing 1-2 atoms N, O or S, With3-8cycloalkyl, heterocyclyl, which represents a 5 - or 6-membered monocyclic hydrocarbon ring containing 1-2 N atom or Oh, -C(O)OR10, -OR9, -OR10, -C(O)R10, -C(O)N(Ra)(Rb), -C(O)N(R12)(R12), -C(O)N(R10)(R11), -SR12, -SR9, -SO2R12, -SO(R12), -SOmN(Rc)(Rd), -SOmCH(R10)(R11), -SO2N(R10)C(O)(R12), -N(R10)C(O)R9, -N(R10)C(O)R10, R10S-, -C(O)C(Ra)(Rb)S(Raor 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl,

where these groups optionally substituted or carbon atom or heteroatom with one to five substituents, independently selected from C1-6of alkyl, halogen, keto, cyano, halogen, C1-6of alkyl, hydroxy, C1-6of alkyl, -OR9, -NH2, -R9SO2R12 , -SO2R12, -SR12, -SOmN(Rc)(Rd), -COOH, -C(O)(Ra)(Rb), -N(R10)C(R10)(R11)(R9), heterocyclyl, which represents a 5 - or 6-membered mono - or bicyclic hydrocarbon ring containing 1-2 N atom;

R8represents hydrogen;

R9selected from the group consisting of hydrogen, phenyl, phenyl(C1-4)alkyl, heteroaryl, which represents a 5-membered monocyclic hydrocarbon ring containing 1-2 atoms of N or O heteroaryl(C1-4)alkyl, represents a 5 - membered monocyclic hydrocarbon ring containing 1-2 N atom or, where these groups may be optionally substituted by one, two or three substituents, independently selected from halogen;

R10represents hydrogen or C1-6alkyl;

R11represents hydrogen or C1-6alkyl;

R12represents hydrogen, C1-6alkyl, which is optionally substituted one, two or three substituents, independently selected from halogen or C1-6alkoxy;

Rarepresents hydrogen, C1-6alkyl, hydroxyl or3-8cycloalkyl;

Rbrepresents hydrogen, C1-6alkyl, hydroxyl or3-8cycloalkyl;

Rcperformance is possessing a hydrogen or C 1-6alkyl;

Rdrepresents hydrogen or C1-6alkyl;

n is independently selected from an integer from zero to three;

each m is independently selected from an integer from zero to two;

and their pharmaceutically acceptable salts, stereoisomers.

2. The compound according to claim 1, where R1represents hydrogen and R2represents hydrogen, or R1and R2can be taken together with the carbon atom to which they are attached, to form with3-8cycloalkyl ring, where this ring system is optionally substituted by one or two substituents selected from C1-6the alkyl or halogen, and pharmaceutically acceptable salts, stereoisomers.

3. The compound according to claim 2, where R3represents a C1-6alkyl, which is optionally substituted from one to six halogen atoms, and R4represents hydrogen, and their pharmaceutically acceptable salts, stereoisomers.

4. The compound according to claim 3, where R3represents n-propyl, isobutyl, 2-fluoro-2-methylpropyl, 2-cryptomaterial, 3-fluoro-2-(2-permitil)propyl, 2,2-dottorati, 2,2-direcror, 3,3,3-cryptochromes, or 2,2-dichloroethyl and R4represents hydrogen, and their pharmaceutically acceptable salts, stereoisomers.

5. The compound according to claim 3, where R5represents hydrogen, and R6 represents phenyl, heteroaryl, which represents a 5-6-membered monocyclic ring containing 1-4 atoms N, O and/or S, where mentioned phenyl and heteroaryl optionally substituted one, two or three substituents selected from halogen or-SOR12and their pharmaceutically acceptable salts, stereoisomers.

6. The compound according to claim 3, where R5represents hydrogen and R6represents a C1-6halogenated, and their pharmaceutically acceptable salts, stereoisomers.

7. The connection according to claim 6, where R5represents hydrogen and R6represents trifluoromethyl or 3,3,3,2,2-pentafluoroethyl, and their pharmaceutically acceptable salts, stereoisomers.

8. The connection according to claim 6, where n is equal to two, each D independently represents phenyl or heteroaryl and R7represents-SOmCH(R10)(R11or-SOm(Rc)(Rd), Rcand Rdeach independently represent hydrogen or C1-6alkyl, and their pharmaceutically acceptable salts, stereoisomers.

9. The compound according to claim 1, selected from the group including

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-phenylethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-rifter-1-(4-fluoro-3-were)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2[(1S)-2,2,2-Cryptor-1-(4-pyridine-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(4-{[4-(2-foradil)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-foradil)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N2-[1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbut-1-inyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-hydroxy-3-methylbutyl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4-pyridin-4-ylphenyl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(1E)-3-hydroxy-3-methylbut-1-enyl]phenyl}this is l)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxipiridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(morpholine-4-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[methoxy(methyl)amino]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-Tien-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(hydroxymethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-cyano-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1-(manometer)-N 2-[(1S)-1-(3′,4′-debtor-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

Methyl ester of 4′-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin)diphenyl-2-carboxylic acid;

Methyl ester of 4′-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-3-carboxylic acid;

N1(cyanomethyl)-N2-[(1S)-1(3′,4′-dimethoxy-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2′-(trifluoromethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(3′,4′-dichloro-1,1-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3′-formyl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)phenyl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4-(5-bromopyridin-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′ (triptoreline)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-indol-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-(pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N1/sup> (cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-3-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

Methyl ester of 4′-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-(pyrimidine-2-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-3-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-furyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[3-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[4-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3′-methoxy-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3′-methoxy-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4′-(acetylamino)-3′-fluoro-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4(3-methyltin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(3′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4-(5-acetylthio-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(3′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3′-(trifluoromethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(5′-fluoro-2′-methoxy-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(3′,5′-debtor-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2′,3′,5′-Cryptor-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

3-(4′-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-3-yl)acrylic acid;

N2-{(1S)-1-[4-(9-antrel)phenyl]-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4′-benzoyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(3′-acetyl-4′-hydroxy-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[2′-(cyanomethyl)-1,1′-diphenyl-4-yl]-2,2,2-triffterer the l}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylsulfonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-(morpholine-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(5-penalties-2-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-quinoline-8-ylphenyl]-ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridine-2-ylphenyl)ethyl]-L-leucinamide;

N2-{1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-Nsup> 1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(morpholine-4-ylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(isopropylphenyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-((1S)-1-{4′-[(acetylamino)sulfonyl]-1,1′-diphenyl-4-yl}-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2′-methyl-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[1-(5-Bratan-2-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

tert-butyl ester 4-(4′-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-yl)piperazine-1-carboxylic acid;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4′-piperazine-1-yl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4′-[4-(2-hydroxyethyl)piperazine-1-yl]-1,1′-diphenyl-4-yl}ethyl)-L-Le is cynamid;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4′-[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(1-{4-[(dimethylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4′-piperazine-1-yl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-(1-{4-[(cyclopropylamino)carbonyl]phenyl}-2,2,2-triptorelin)-L-leucinamide;

4-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acid;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4′-[4-(2-foradil)piperazine-1-yl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4{[4-(2-hydroxy-2-methylpropyl " piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucinamide;

N2-{1-[4-(3-tert-butyl-1,2,4-triazine-5-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{2-[3-(methylsulphonyl)phenyl]-1,3-thiazol-4-yl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[2-(spirutal-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4′-[4-(methylsulphonyl)piperazine-1-yl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[1-(3-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-3-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-l-(3-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4′-piperazine-1-yl-1,1′-diphenyl-3-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-3-yl]ethyl}-L-leucinamide;

N-(cyanomethyl)-1-[(2,2,2-Cryptor-1-phenylethyl)amino]cyclohexanecarboxylic;

1-{[1-(4-bromophenyl)-2,2,2-triptorelin]amino)-N-(cyanomethyl)cyclohexanecarboxylic;

N-(cyanomethyl)-1-{[2,2,2-Cryptor-1-(4′-piperazine-1-yl-1,1′-diphenyl-4-yl)ethyl]amino}cyclohexanecarboxylic;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperidine-4-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-pyridine-2-reparation-1-yl)phenyl]ethyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-cyclopropylalanine;

N1(cyanomethyl)-3-cyclopropyl-N2-[2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]laminated;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4′-pyridin-4-yl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-2,2,2-Cryptor-1-(1,3-thiazol-2-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4′-methoxy-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-methoxyphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4′-pyridin-4-yl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-phenoxyphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4′-bromo-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4-(4-chloropyridin-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4′-(acetylamino)-2′-methyl]-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4″ (methylsulfone is)-1,1′ :4′,1″-terphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-3-(1-methylcyclopropyl)-L-alaninate;

N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-3-(1-methylcyclopropyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4′-methyl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(hydroxymethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-D-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-D-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(morpholine-4-ylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-D-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4′-[(methylamino)sulfonyl]-1,1′-diphenyl-4-yl}ethyl)-D-leucinamide;

N1(cyanomethyl)-N2-{(1R)-2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1/sup> (cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1-oxipiridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-1-oxipiridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-piperazine-1-ylphenyl)ethyl]-L-leucinamide;

N2-{1-[3′-(acetylamino)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(4-propylpiperazine-1-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(piperazine-1-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-Cryptor-1-(4-{[4-(2-hydroxyethyl)piperazine-1-yl]carbonyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}phenyl)ethyl]-L-leucinamide;

Methyl ester of 4-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}benzoic acid;

N1-(zenome who yl)-N 2-((1S)-2,2,2-Cryptor-1-{4-[(E)-2-quinoline-2-retinyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]ethyl}-L-leucinamide;

N2-((1S)-1-{4-[3-(5-bromopyridin-3-yl)-1,2,4-oxadiazol-5-yl]phenyl}-2,2,2-triptorelin)-N1-cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4-benzoylphenyl)-2,2,2-triptorelin]-N1-cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(Tien-2-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{(Z)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-Cryptor-1-(4-{(E)-2-[4-(methylsulphonyl)phenyl]ethynyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isobutylphenyl)ethyl]-L-leucinamide;

N2-{(1S)-1-[4-(4-bromo-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-cyanophenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(2′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethyl}-L-leucinamide;

N-(cyanomethyl)-N2-{1-[4′-(dimethylamino)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-[(1R)-1-(4-{[(cyanomethyl)amino]carbonyl}phenyl)-2,2,2-triptorelin]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[3′-(methylsulphonyl)-1,1-diphenyl-4-yl]ethyl}-L-leucinamide;

4′-{1-[1-(Cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

methoxyethylamine 4′-{1-[1-(cyanomethylene)-3-methylbutylamine]-2,2,2-triptorelin}diphenyl-4-carboxylic acid;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-({[4-(methylsulphonyl)benzyl]thio}methyl)phenyl]ethyl)-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[3′ (aminosweet the Il)-4′ -bromo-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-{(1S)-1-[4′-bromo-3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-{5-chloro-3-[4-(methylsulphonyl)phenyl]pyridine-2-yl}phenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[(phenylthio)methyl]phenyl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4′-[(trifluoromethyl)sulfonyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-{[(4-perbenzoic)amino]methyl}phenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(methylsulphonyl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4′-(ethylsulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N2-((1S)-1-{4-[({[3-(2-chloro-6-forfinal)-5-methylisoxazol-4-yl]carbonyl}amino)methyl]phenyl}-2,2,2-triptorelin)-N1(cyanomethyl)-L-leucinamide;

N2-((1S)-1-{4-[(9-chloro-3-methyl--oxitocina[4,3-c]quinoline-5(4H)-yl)methyl]phenyl}-2,2,2-triptorelin)-N 1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-methoxy-3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[4″-chloro-4′-(methylsulphonyl)-1,1′:2′,1″-terphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[2′-methoxy-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[2′-chloro-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4′-[(2-hydroxyethyl)thio]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3′-fluoro-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4′-[(2-hydroxyethyl)sulfonyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-({2-[methoxy(methyl)amino]-2-oxoethyl}sulfonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{4′-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1′WPPT, the Il-4-yl}ethyl)-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(4-bromophenyl)(2,4,6-tryptophanyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(4-pyridin-4-ylphenyl)(2,4,6-tryptophanyl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[[4-(4-terbisil)phenyl](phenyl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-{phenyl[4-(pyridine-3-ylmethyl)phenyl]methyl}-L-leucinamide;

N2-{(4-bromophenyl)[4-(methylsulphonyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{[4-(methylsulphonyl)phenyl][4′-(methylthio)-1,1′-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-{[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl][4-(methylsulphonyl)phenyl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[2,2,2-trichloro-1-(4-picolomini)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-[2-fluoro-1-(permitil)-1-phenylethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(pyrrolidin-1-ylacetic)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4-(piperazine-1-ylcarbonyl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-(2,2,2-Cryptor-1-{4-[2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl]Fe is Il}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-3-(1-methylcyclopropyl)-N2-(2,2,2-Cryptor-1-{4-[1-(2-hydroxyethyl)prolyl]phenyl}ethyl)-L-alaninate;

N2-[[4-(4-tert-butylpiperazine-1-yl)phenyl](pentafluorophenyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N-(cyanomethyl)-1-{1-[4-(4-methylpiperazin-1-yl)phenyl]ethyl}piperidine-2-carboxamide;

N2-[[4-(4-tert-butylpiperazine-1-yl)phenyl](pyridin-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N2-{[4-(4-tert-butylpiperazine-1-yl)phenyl][5-(trifluoromethyl)pyridin-2-yl]methyl}-N1(cyanomethyl)-L-leucinamide;

(4S)-N-(cyanomethyl)-4-methyl-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

(4S)-N(cyanomethyl)-4-methyl-1-[(1R)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N-(cyanomethyl)-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N-(cyanomethyl)-1-[(1R)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N-(cyanomethyl)-4,4-debtor-1-[(1S)-1-(4-piperazine-1-ylphenyl)ethyl]-L-prolinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-were)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-oxazol-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pirati the-2-ylphenyl)ethyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(3′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(3′-fluoro-4′-methyl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(1-hydroxy-1-methylethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4′-methyl-1,1′-diphenyl-4-yl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-3-yl)phenyl]propyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(2′-fluoro-1,1′-diphenyl-4-yl)propyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-tripto the-1-[4′ -methoxy-3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-{(1S)-1-[3′-(aminosulfonyl)-4′-methoxy-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2{(1S)-2,2,3,3,3,-pendaftar-1-[4-5-methylpyridin-2-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[5-(methylsulphonyl)pyridine-2-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2′-methyl-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(1H-pyrazole-3-yl)pyridine-2-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-5-espiridion-2-yl)ethyl]-L-leucinamide;

N1-(1-cyanocycline the)-N 2-[(1S)-2,2,2-Cryptor-1-(5-quinoline-6-espiridion-2-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1-ethoxyphenyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N2-[(1S)-1-(4-acetylphenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-isopropylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-phenylethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-methylcyclopropyl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(2′,4′,6′-trimethyl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(6-CHL is pyridin-3-yl)-2,2,2-triptorelin]-N 1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[5-(4-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[6-(4-acetylphenyl)pyridine-3-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-{(1S)-1-[5-(3-acetylphenyl)pyridine-2-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{5-4-(1-hydroxyethyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-(1-benzyl-2,2,2-triptorelin)-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(4-tert-butylphenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4-methyl-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-methyl-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4-[2-(1H-pyrazole-4-yl)-1,3-thiazol-4-yl]phenyl}ethyl)-L-Latinum is d;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methyl-1,3-thiazol-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-2-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(3′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyanoethyl]-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyano-3-(methylthio)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,3,3,3-pentafluoropropyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-2-yl)phenyl]propyl}-L-leucinamide;

N2[(1S-1-(5-brokered the h-2-yl)-2,2,2-triptorelin]-N 1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,2-Cryptor-1-(6′-methyl-3,3′-piperidin-6-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methoxypyridine-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-1,6-dihydropyridines-2-yl)phenyl]ethyl}-L-leucinamide;

(4S)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-5,5,5-Cryptor-L-leucinamide;

(4S)-N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanotic is propyl)-5,5,5-Cryptor-L-leucinamide;

N2-{(1S)-1-[4-(6-aminopyridine-3-yl)phenyl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N2-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methylpyridin-3-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methylpyridin-3-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(2,2,2-Cryptor-1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(6-methoxypyridine-2-yl)phenyl]propyl}-L-leucinamide;

(4R)-N1 (cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

(4R)-N1-(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(1S)-2,2,3,3,3-pendaftar-1-(4′-methyl-1,1′-diphenyl-4-yl)propyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4-(1,3-thiazol-2-yl)phenyl]propyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-1-(4-ethynylphenyl)-2,2,3,3,3-pentafluoropropyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(cyclopropylmethyl)phenyl]-2,2,3,3,3-pentafluoropropyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]those who}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-1-[4-(4,5-dimethyl-1,3-thiazol-2-yl)phenyl]-2,2,2-triptorelin}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(ethylsulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-pyridin-3-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-methoxy-3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-alaninate;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,3,3,3-pentafluoropropyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-((1S)-2,2,3,3,3-pendaftar-1-{4′-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1′-diphenyl-4-yl}propyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-alaninate;

N1(cyanomethyl)-N2-{(1S)-2,2,3,3,3-pendaftar-1-[4′-(isopropylphenyl)-1,1′-diphenyl-4-yl]propyl}-L-leucinamide;

N1-(1-cyano-1-methylethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-lazy the amide;

N1-(1-cyanocyclohexyl)-N2-((1S)-2,2,2-Cryptor-1-{4′-[(2-hydroxy-2-methylpropyl " sulfonyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[2′-methyl-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(ethylsulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl][4-(triptoreline)phenyl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl](Tien-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-(4′-piperazine-4-FMD-1-yl-1,1′-diphenyl-4-yl)(Tien-2-yl)methyl]-L-leucinamide methansulfonate;

N1(cyanomethyl)-N2-{(S)-(4-forfinal)[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl][4-(trifluoromethyl)phenyl]methyl}-L-leucinamide;

N2-{S-(4-chlorophenyl)[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2 -{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(Tien-2-yl)methyl]-N-(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl](Tien-2-yl)methyl]-L-leucinamide;

N2-{(R)-(4-bromophenyl)[4-(triptoreline)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][4-(triptoreline)phenyl]methyl)-L-leucinamide;

N2-[(S)-(4-bromophenyl)(2-furyl)methyl]-N-(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-2-furyl[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]methyl}-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-L-Norvaline;

N2-{(R)-(4-bromophenyl)[4-(trifluoromethyl)phenyl]methyl}-N1(cyanomethyl)-L-leucinamide,

N1(cyanomethyl)-N2-{1-[4′-(4-cyclopropylmethyl-1-yl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-L-Norvaline;

N2-[(R)-(4-bromophenyl)(4-chlorophenyl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N 2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-(2,4-differenl)[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]methyl}-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4′-(4-cyclopropylmethyl-1-yl)-1,1′-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-[(S)-[4′-(4-cyclopropylmethyl-1-yl)-1,1′-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N2-[1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-5,5,5-Cryptor-L-Norvaline;

N1(cyanomethyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(S)-(4-bromophenyl)(3-methyltin-2-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(S)-[4′-methylsulphonyl)-1,1′-diphenyl-4-yl](3-methyltin-2-yl)methyl]-L-leucinamide;

N1(cyanomethyl)-N2-{(S)-3-furyl[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]methyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-three of the top-1-[4′ -(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-Norvaline N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-N1(cyanomethyl)-L-leucinamide;

N2-[(S)-(4-bromophenyl)(Tien-3-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1(cyanomethyl)-N2-((S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]{4-[4-(methylsulphonyl)phenyl]Tien-2-yl}methyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(S)-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl](Tien-3-yl)methyl]-L-leucinamide;

N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-L-Norvaline;

N2-[(S)-(4-bromophenyl)(4-Bratan-2-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(S)-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl](Tien-3-yl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N2-[(S)-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl](Tien-3-yl)methyl]-N-(cyanomethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-methoxy-3′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylpyridin-4-yl)phenyl]ethyl}-L-Norvaline;

N1 -(1-cyanocyclohexyl)-5,5,5-Cryptor-N2-{(1S)-2,2,2-Cryptor-1-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(1H-pyrazole-3-yl)phenyl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methylpyridin-2-yl)phenyl]ethyl}-L-Norvaline;

cyanomethylene 2-{[(4-bromophenyl)pyridine-4-yl-methyl]amine}pentanol acids;

cyanomethylene 2- {[(4-Bromophenyl)thiazol-2-ylmethyl]amino}pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(4′-acetylbiphenyl-4-yl)-2,2,2-triptorelin]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(2′,4′-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(3′,4′-giftgiver-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(3′-chloro-4′-forgivenes-4-yl)-2,2,2-triptoreline]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4′-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acids;

cyanomethylene (2S)-2-{(S)-[(4-Bromophenyl)thiazol-2-yl-methyl]amino}-4-methylpentanoic sour is you;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-chloro-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-chloro-3′-methyl-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-chloro-2′-methyl-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-((S)-2,2,2-Cryptor-1-[4-(1H-indol-5-yl)phenyl]ethylamine}pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(3′-methanesulfonylaminoethyl-4-yl)ethylamine]pentanol acids;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-fluoro-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-fluoro-3′-methyl-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[3′-fluoro-4′-methyl-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-triptoreline-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4′-methylbiphenyl-4-yl)ethylamine]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-1-(4′-cyanobiphenyl-4-yl)-2,2,2-triptorelin]pentanol acids;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-methoxy-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4-(benzo[1,3]dioxol-5-yl)phenyl]ethyl)-L-Norvaline;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methoxycarbonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4-bromophenyl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

cyanomethylene (2S)-2-{(S)-[(4′-methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amine}-4-methylpentanoic acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(4′-triptorelin-4-yl)ethylamino]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-[(S)-2,2,2-Cryptor-1-(2′-triptorelin-4-yl)ethylamine]pentanol acids;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(2′,4′-giftgiver-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

(1-cyanocyclohexyl)amide (2S)-2-{(S)-[(4′-methysulfonylmethane-4-yl)thiazol-2-ylmethyl]amino}-4-methylpentanoic acids;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxido-2,3-dihydro-1-benzothieno-5-yl)phenyl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-2,3-dihydro-1-benzothieno-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-Latinum is d;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulfonyl)-1,1′-diphenyl-4-ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-define the-4-yl]ethyl}-L-Norvaline;

(2S)-N-(cyanomethyl)-4,4-debtor-2-({(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-N-(1-cyanocyclohexyl)-4,4-debtor-2-({(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-ethyl}amino)butanamide;

(2S)-N-(1-cyanocyclohexyl)-4,4-debtor-2-({(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-N-(cyanomethyl)-4,4-debtor-2-({(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(cyanomethyl)-2-({(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amine)butanamide;

(2S)-4,4-dichloro-N-(1-cyanocyclohexyl)-2-({(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(1-cyanocyclohexyl)-2-({(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amino)butanamide;

(2S)-4,4-dichloro-N-(cyanomethyl)-2-({(1S)-2,2,2-trichloro-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}amino)butanamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4′-methyl-1,1′-diphenyl-4-yl)et the l]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-[(1S)-1-(2′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[2′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{5-[4-(methylsulphonyl)phenyl]pyridine-2-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{6-[4-(methylsulphonyl)phenyl]pyridine-3-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-{6-[(methylsulphonyl)amino]pyridine-3-yl}phenyl)ethyl]-L-leucinamide;

N 1(cyanomethyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-{6-[(methylsulphonyl)amino]pyridine-3-yl}phenyl)ethyl]-L-leucinamide;

N1-(1-cyanomethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-2-cyclopropylethyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-2-pyridin-3-retil)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyano-3-hydroxy-3-methylbutyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,3-diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dimethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-the top-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-diethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′(3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(1,1-dimethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(1,1-diethyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′(1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(3,3-dimethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4′-(3,3-diethyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-2,5-dihydrofuran-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(2,2-dimethyl-5-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-Le is cynamid;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(2,2-diethyl-5-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-oxo-2,5-dihydrofuran-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(5,5-diethyl-2-oxo-2,5-dihydrofuran-3-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-4-oxaspiro[2.4]hept-6-EN-7-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-5-oxaspiro[3.4]Oct-7-EN-8-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-oxo-4-oxaspiro[2.4]hept-6-ene-6-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-oxo-5-oxaspiro[3.4]Oct-7-EN-7-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulfonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′ -diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-[(1S)-1-cyano-3-(methylsulphonyl)propyl]-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulfonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-[(1S)-1-(4-bromophenyl)-2,2,2-thrift retil]-N 1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N4-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-5-methylpyridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-methyl-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-Metelkin the in-7-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(1S)-1-hydroxyethyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(1R)-1-hydroxyethyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-TRIFLUOROACETYL)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(2-naphthyl)pyridin-2-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N2-[(4-bromophenyl)(phenyl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-[4′-methyl-1,1′-diphenyl-4-yl)ethyl]-L-latinae is;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(methylsulphonyl)amino]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2-debtor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N1-[(1S)-1-cyano-3-(metals hanil)propyl]-N 2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulfonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-[(1S)-2,2,2-Cryptor-1-(4-quinoline-6-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[5-methyl-6-(methylsulphonyl)pyridine-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4-[6-(1-hydroxy-1-methylethyl)-5-methylpyridin-3-yl]phenyl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4′-fluoro-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-methyl-4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(6-methylpyridin-3-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(1-hydroxy-1-methylethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(2-methylinosine-7-yl)phenyl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2,2-triptorelin]-N1(cyanomethyl)-4,4-debtor-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(1S)-1-hydroxyethyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(1R)-1-hydroxyethyl]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(TRIFLUOROACETYL)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-2,2,2-Cryptor-1-[5-(2-naphthyl)Piri is in-2-yl]ethyl}-L-leucinamide;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1(cyanomethyl)-4,4-debtor-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-Norvaline;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4-(5-methyl-1,3-thiazol-2-yl)phenyl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(1,1-dioxido-3-oxo-2,3-dihydro-1,2-benzisothiazol-5-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

N2-[(4-bromophenyl)(phenyl)methyl]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4′-methyl-1,1′-diphenyl-4-yl)ethyl]-L-leucinamide;

N2-[(1S)-1-(1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N2-{(1S)-1-[4-(5-chloropyridin-2-yl)phenyl]-2,2,2-triptorelin}-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyridin-4-ylphenyl)ethyl]-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-((1S)-2,2,2-Cryptor-1-{4′-[(methylsulphonyl)amino]-1,1′-diphenyl-4-yl}ethyl)-L-leucinamide;

N2-[(1S)-1-(4-bromophenyl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1 cyanotic propyl)-N 2-{(1S)-2,2-debtor-1-[4′-(methylthio)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-[(1S)-2,2,2-Cryptor-1-(4-pyrimidine-5-ylphenyl)ethyl]-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2,2-triptorelin]-N1-(1-cyanocyclohexyl)-4-fluoro-L-leucinamide;

N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[3′-(1-hydroxyethyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide;

N2-[(1S)-1-(4′-acetyl-1,1′-diphenyl-4-yl)-2,2-dottorati]-N1-(1-cyanocyclohexyl)-L-leucinamide;

N1-(1-cyanocyclohexyl)-N2-{(1S)-1-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2,2,2-triptorelin}-4-fluoro-L-leucinamide;

and their pharmaceutically acceptable salts, stereoisomers.

10. The connection according to claim 9, representing the N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide or its pharmaceutically acceptable salt.

11. The connection according to claim 9, representing the N1-(1-cyanocyclohexyl)-4-fluoro-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide or its pharmaceutically acceptable salt.

12. The connection according to claim 9, representing the N1(cyanomethyl)-N2-{(1S)-2,2,2-Cryptor-1-[4′-(methylsulphonyl)-1,1′-diphenyl-4-yl]ethyl}-L-leucinamide or f is rmaceuticals acceptable salt.

13. The connection according to claim 9, representing the N2-{(1S)-1-[4′-(aminosulfonyl)-1,1′-diphenyl-4-yl]-2,2,2-triptorelin}-N1(cyanomethyl)-L-leucinamide or its pharmaceutically acceptable salt.

14. Pharmaceutical composition having inhibitory activity against cathepsin containing an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to 14 obtained by combining the compound according to claim 1 and a pharmaceutically acceptable carrier.

16. A method of obtaining a pharmaceutical composition, comprising combining the compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A method of inhibiting the activity of cathepsin we need in a mammal, comprising an introduction to the specified mammal a therapeutically effective amount of a compound according to claim 1.

18. The method according to 17, where the activity of cathepsin represents the activity of Cathepsin K.

19. The use of compounds according to claim 1 for the manufacture of drugs having inhibitory activity against cathepsin.

20. The application of claim 19, where the drug is used in the treatment and prevention of diseases mediated by cathepsin where a disease selected from osteoporosis, osteoporosis induced by glucocorticoids, disease PED the ETA, abnormally increased bone metabolism, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, coloproctol of osteolysis, defect osteogenesis, metastatic bone disease, hypercalcemia of malignant tumors or multiple myeloma in need of this mammal.

21. The application of claim 20, where the disease is a osteoporosis.

22. Method of inhibiting bone resorption using compounds according to claim 1.

23. A method of increasing bone mineral density using compounds according to claim 1.

24. The way to reduce the risk of fractures using compounds according to claim 1.

Priority items:

05.03.2002 according to claims 1-7, 9-21;

06.09.2002 according to claims 1, 9;

28.02.2003 according to claims 1, 9, 22-24.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to using compounds of the general formula (I): and their pharmaceutically acceptable acid-additive salts. Compounds are used for preparing medicinal agents used in treatment diseases and state associated with system of adenosine receptors A2A, such as Alzheimer's disease, Parkinson's diseases, Huntington's syndrome, schizophrenia, anxiety state, pain, depression, narcomania to such substances as amphetamine, cocaine, opioides, ethyl alcohol, nicotine, cannabinoids, or in treatment of hypoxia, ischemia, epileptic attack. Also, proposed compounds exert neuroprotective effect and can be used as sedative, antipsychotic or anti-epileptic agents.

EFFECT: valuable medicinal properties of compounds.

18 cl, 1 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means lower alkyl, -(CH2)n-O-lower alkyl, -(C3-C6)-cycloalkyl or -(CH2)n-NR'2 wherein R' means hydrogen atom, lower alkyl or -(CH2)n-O-lower alkyl independently of one another for R'2; or R'2 in common with nitrogen atom can form pyrrolidine ring, and wherein n = 1, 2 or 3. Also, invention relates to a pharmaceutical composition possessing antagonistic activity with respect to A2 receptors and containing one or some compounds of the general formula (I) and its pharmaceutically acceptable excipients. Invention provides synthesis of compound of the general formula (I) possessing antagonistic activity with respect to A2 receptors.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

11 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazoles of the general formula (I): , wherein R1 represents hydrogen atom (H), direct or branched (C1-C4)-alkyl or COO-(C1-C4)-alkyl or phenyl optionally substituted with one or some substitutes chosen from halogen atom; R2 represents H, direct or branched (C1-C4)-alkyl, COO-(C1-C4)-alkyl. Method for synthesis involves addition to aqueous solution of 4-R1-5-R2-1-hydrazino-1,3-thiazole hydrochloride of the formula (II): , wherein R1 and R2 have above given values of N-cyanoguanidine of the formula (III): in the mole ratio (II) : (III) = (1.10-1.20):100. Prepared mixture is heated at temperature 80-95°C followed by its neutralization, filtering off and recrystallization. Method provides preparing 2-(3',5'-diamino-1',2',4'-triazol-1'-yl)-4-R1-5-R2-1,3-thiazole from inexpensive and available raw and without using complex technological procedures. Synthesized compounds can be used in synthesis of medicinal and biologically active substances.

EFFECT: improved method of synthesis.

10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative compound of carboxylic acid represented by the formula (I): , wherein each X and Y represents independently (C1-C4)-alkylene; Z means -O-; each R1, R2, R3 and R4 means independently hydrogen atom or (C1-C8)-alkyl; R5 means (C2-C8)-alkenyl; A means -O- or -S-; D means D1, D2, D3, D4 or D5 wherein D1 means (C1-C8)-alkyl; D2 means compound of the formula: wherein ring 1 represents saturated 6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom chosen from oxygen, sulfur and nitrogen atoms; D3 means compound of the formula: wherein ring 2 represents (1) completely saturated (C3-C10)-monocarboxylic aryl, or (2) optionally saturated 5-membered monoheteroaryl comprising 3 atoms chosen from nitrogen and sulfur atoms, or completely saturated 6-membered monoheteroaryl comprising 1 heteroatom representing oxygen atom; D4 means compound of the formula: ; D5 means compound of the formula: ; R6 represents (1) hydrogen atom, (2) (C1-C8)-alkyl, (3) -NR7R8 wherein R7 or R8 represent hydrogen atom or (C1-C8)-alkyl, or R7 and R8 taken in common with nitrogen atom to which they are added form saturated 5-6-membered monoheteroaryl comprising one nitrogen atom and, optionally, another one heteroatom representing oxygen atom; E means -CH or nitrogen atom; m means a whole number 1-3, or its nontoxic salt. Invention relates to a regulator activated by peroxisome proliferator receptor, agent used in prophylaxis and/or treatment of diseases associated with metabolism disorders, such as diabetes mellitus, obesity, syndrome X, hypercholesterolemia or hyperlipoproteinemia, hyperlipidemia, atherosclerosis, hypertension, diseases coursing with circulation disorder, overeating or heart ischemic disease, and to an agent that increases cholesterol level associated with HDL, reduces cholesterol level associated with LDL and/or VLDL, eliminates risk factor in development of diabetes mellitus and/or syndrome X and comprising a compound represented by the formula (I) or its nontoxic salt as an active component and a carrier, excipient or solvent optionally. Invention proposes derivative compounds of carboxylic acid possessing the modulating activity with respect to peroxisome proliferator receptor (PPAR).

EFFECT: valuable medicinal properties of compounds.

15 cl, 5 tbl, 48 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

18 cl, 138 tbl, 527 ex

Benzothiazoles // 2293736

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3- or 4-yl, cyclohex-1-enyl, cyclohexyl, or it represents 1,2,3,6-tetrahydropyridin-4-yl or piperidin-4-yl that are optionally substituted with -C(O)CH3 or -C(O)OCH3 in position 1 at nitrogen atom (N); R2 represents lower alkyl, piperidin-1-yl substituted with hydroxy-group optionally, or it represents phenyl optionally substituted with -(CH2)n-N(R')-C(O)-(CH2)n-NR'2, -(CH2)n-halogen, lower alkyl or -(CH2)n-N(R')-(CH2)n-O-lower alkyl, or it represents morpholinyl or pyridinyl that is substituted optionally with halogen atom, -N(R')-(CH2)n-O-lower alkyl, lower alkyl, lower alkoxy-group, morpholinyl or -(CH)n-pyrrolidinyl; n = 0, 1 or 2; R' represents hydrogen atom or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicament possessing affinity to adenosine A2A-receptors and containing one or some compounds of the general formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of compounds.

17 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel derivatives if 1,3,5-triazine of the general formula (1): wherein R1 means halogen atom, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, N-(di)-(C1-C3)-alkyl, NH-(C2-C3)-alkynyl, N,N-(C1-C3)-alkyl, (C2-C3)-alkynyl or 1-pyrrolidinyl, 1-piperidinyl or 1-morpholinyl group; R2 means hydrogen atom (H), (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy- or phenoxy-group; R3 means H, -CF3, (C1-C3)-alkyl possibly substituted with hydroxy-, (C1-C3)-alkoxy-, phenoxy-group or 1-morpholinyl group; or R2 and R3 in common with phenyl group to which they are bound form benzodioxolane or naphthalene cyclic system; R4 means H, -CF3 or (C1-C3)-alkoxy-group; X means -NH, N-(C1-C3)-alkyl, -CH2, oxygen atom (O) or a bond carbon-carbon; Y means group of the general formula (A) , (B) or (C) wherein R5 means -OH or -CH2OH; R6 means H or phenyl; n = 0 or 1; R7 means (C1-C3)-alkyl; R8 means H, -OH or (C1-C3)-alkoxy-group; R9 means H or (C1-C3)-alkoxy-group; R10 and R11 mean independently H or (C1-C3)-alkyl; Z means -NOH or O, or their pharmacologically acceptable salts, pharmaceutical composition possessing (ant)agonistic activity to adenosine-A3 receptors and using novel compounds in treatment of such diseases as chronic pains, arthritis, cerebrospinal sclerosis, asthma, psoriasis and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 4 tbl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a compound of the formula (I): , wherein carbon atom designated as * is in (R)- or (S)-configuration; R1 represents (C1-C6)-alkyl; R2 represents hydrogen atom (H), (C1-C6)-alkyl or (C1-C6)-halogenalkyl; R3 represents H or halogen atom; R4 represents phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl wherein R4 group is substituted optionally with 1-4 R14-substitutes; each among R5, R6 and R7 is chosen independently from the following group: H, halogen atom, -OR11, -CN, (C1-C4)-halogenalkyl or (C1-C6)-alkyl; or R5 and R6 taken in common can represent -O-C-(R12)2-O-; R8 represents H; R11 represents H or (C1-C4)-alkyl; R12 represents (C1-C4)-alkyl; R12 is chosen independently in each case from a substitute chosen from the following group: halogen atom, -OR11, -NR11R12, morpholinyl, (C1-C6)-alkyl and (C1-C4)-halogenalkyl, or its pharmaceutically acceptable salt or solvate. Also, invention describes a pharmaceutical composition used in blocking in reuptake of norepinephrine, dopamine and serotonin based on compounds of the formula (I). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties, improved method of treatment.

39 cl, 2 tbl, 49 ex

FIELD: organic chemistry.

SUBSTANCE: described is 3-phenylsulfonyl-8-piperazin-1-yl-quinoline of formula I or pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or C1-C6-alkyl, or R1 and R2 together form group (CH2)2, (CH2)3 or (CH2)4; R3, R4 and R5 are hydrogen, halogen or C1-C6-alkyl; m = 1-4; n = 1-3; A is -Ar1, Ar1 is optionally substituted with 1 or more substituents. Disclosed are four methods for production of abovementioned compounds.

EFFECT: new compounds with affinity to 5-HT6 receptor.

23 cl, 5 tbl, 52 ex, 6 dwg

FIELD: organic chemistry, medicine, neurology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a group of novel compounds of the formula (1): wherein S1 represents, hydrogen, halogen atom; S3 represents halogen atom; X represents nitrogen or carbon atom; Y represents nitrogen or oxygen atom when X represents nitrogen atom, or Y represents nitrogen atom when X represents carbon atom; R5 represents hydrogen atom or (C1-C6)-alkyl; R6 represents hydrogen atom or (C1-C3)-alkyl; R7 represents hydrogen atom or (C1-C3)-alkyl; Z1, Z2 and Z3 represent carbon atom, or Z1 represents nitrogen atom, and Z2 and Z3 represent carbon atom; or Z1 and Z3 represent carbon atom; Z2 represents nitrogen atom; or Z1 and Z2 represent carbon atom, and Z3 represents nitrogen atom; A represents (poly)cycloalkyl system consisting of (4-10)-membered rings that can be substituted with alkyl or -CN, and its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition and using compounds based on the formula (1) possessing inhibitory activity with respect to enzymes that cleave a neuropeptide neurotensin. Invention provides synthesis of novel biologically active compounds and pharmaceutical composition based on thereof that possess inhibitory activity with respect to enzymes destructing a neuropeptide neurotensin.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

4 cl, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions possessing inhibitory effect with respect to MC2R-receptors, for preparing medicinal preparations as tablets, granules, capsules, suspensions, solutions or injections placed into pharmaceutically acceptable package. As active substance the composition comprises azaheterocyclic compound of general formulas (1.1.1) , (1.2.1) or (1.3.1) , wherein R1 in the general formula (1.1.1) represents substituted alkyl, aryl, heteroaryl, heterocyclyl, or R1 in the general formula (1.2.1) represents a substitute of amino-group chosen from hydrogen atom or possibly substituted lower alkyl or lower acyl; each R2, R3 and R4 represents independently of one another a substitute of cyclic system chosen from hydrogen atom, azaheterocyclyl, possibly substituted lower alkyl, possibly substituted hydroxy-group, carboxy-group, cycloalkyl; or R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle, or R1 in common with nitrogen atom to which it is bound, and R3 and R4 in common with carbon atoms to which they are bound form azaheterocycle through R1, R3 and R4; R18 and R19 represent independently of one another substitutes of amino-group chosen from hydrogen atom or lower alkyl substituted with azaheterocycle as their racemates, optically active isomers or their pharmaceutically acceptable salts and/or hydrates; R20 and R21 in common with nitrogen atom to which they are bound form possibly substituted azaheterocycle. Also, invention relates to a method for preparing a pharmaceutical composition and using compounds and compositions for preparing medicinal preparations and for treatment or prophylaxis of diseases associated with enhanced activation of adrenocorticotropic hormone for compounds of general formulas (1.1.1), (1.2.1) and (1.3.1), and for using compounds for experimental investigations of indicated processes in vitro or in vivo also.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions, improved preparing method.

15 cl, 1 dwg, 4 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA) or (IB) given in the invention description wherein R1 means hydrogen atom, (C1-C7)-alkyl, -(CH2)n-OH, -(CH2)n-N(R6)2; R2 means (C1-C7)-alkyl, -(CH2)n-N(R6)2, -NR6C(O)C(O)O-(C1-C7)-alkyl, -NR6-(CH2)n-OH, -NR6C(O)-(C1-C7)-alkyl, -NH-benzyl; R3 means hydrogen atom or amine; or R2 and R3 in common with carbon atoms to which they are bound mean the group -N(R6)-CH2-O-CH2-; R4 means hydrogen atom or (C1-C7)-alkyl; R5 means hydrogen atom; R6 means independently of one another hydrogen atom or (C1-C7)-alkyl; R' means hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3. Also, invention relates to a medicinal agent possessing the selective blocking activity with respect of subspecies of NMDA-receptors and containing one or more compounds of the formula (IA) or (IB) or their pharmaceutically acceptable acid-additive salt or inert carrier. Invention provides preparing novel compounds possessing the high affinity to NMDA-receptors that can be used as components of a medicinal agent for treatment of diseases mediated by these receptors.

EFFECT: valuable medicinal properties of compounds and drug.

13 cl, 35 ex

FIELD: organic synthesis.

SUBSTANCE: 1-oxo-3-(1H-indol-3-yl)-1,2,3,4-tetrahydroisoquinolines (including their cis- and trans-isomers) are depicted by following general formulae: (1) and (2), in which R1, R2, and R4 independently represent cyclic system substituents selected from hydrogen atom and alkyl; R3 is amino group selected from alkyl, cycloalkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, alkoxy, amino, alkylamino, and dialkylamino; R5 and R6 independently represent amino group substituents selected from hydrogen, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkyl, and alkyl optionally substituted by aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkoxy, amino, alkylamino, dialkylamino, or arylalkylamino; or R5 and R6, together with nitrogen atom to which they are linked, form optionally substituted aza-heterocycle. Method of preparing compounds 1 consists in reaction of corresponding indol-3-ylmethylamines with homophthalic anhydrides in an organic solvent. Compounds 2 are prepared by treating compounds 1 with thionyl chloride or 1,1'-carbonyldiimidazole to form corresponding derivatives, which are reacted with corresponding amines in an organic solvent. Compounds of invention exhibit proteinkinase inhibiting activities. Combinatory and focused libraries are also provided to reveal leading compounds.

EFFECT: expanded synthetic possibilities in quinoline series and increased choice of proteinkinase inhibitors.

3 cl, 3 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinoline that can be used as ligands of neuropeptide Y (NPY) receptors and being first of all as neuropeptide Y (NPY) antagonists. Invention describes compounds of the formula (I): wherein R1 means -O-R4 or -NR5R6; R2 means hydrogen atom, alkyl, alkoxy-group or halogen atom; R3 means alkyl or halogen atom; R means hydrogen atom, alkyl, phenyl, phenyl substituted with 1-3 substitutes chosen independently of one another from group comprising alkyl, cyano-group, trifluoromethyl, alkoxy-group, halogen atom, pyrrolidinylcarbonyl and nitro-group, alkoxyalkyl or heterocyclyl that means saturated or aromatic 4-10-membered heterocycle comprising one heteroatom chosen from nitrogen, oxygen atoms; R5 and R6 are chosen independently of one another from group comprising hydrogen atom, alkyl or phenyl; or R5 and R6 in common with nitrogen atom (N) to which they are added form 5-10-membered heterocyclic ring comprising nitrogen atom optionally; A1 means 5-7-membered saturated heterocyclic ring comprising nitrogen atom added to quinoline ring and the second nitrogen atom optionally and wherein ring is substituted optionally with 1-3 substitutes chosen independently of one another from group comprising alkyl, alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, tetrahydropyranyloxyalkyl and cycloalkylalkoxy-group; A2 means -CH2- or -C(O)- wherein alkyl individually or in combination means alkyl group with a direct chain that comprises 1-8 carbon atoms; and their pharmaceutically acceptable salts and alkyl esters. Also, invention describes methods for synthesis of compounds of the formula (I) and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 117 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula: or their pharmaceutically acceptable salts wherein Ra - R8a mean phenyl; R8b means pyridyl, or R8 means naphthyl; R1 means hydrogen atom; R2 - R9, R10, R11 mean substituted phenyl; R9, R10, R11 mean substituted pyridyl or pyrimidyl; R9, R10, R11 mean substituted pyridyl-N-oxide or pyrimidyl-N-oxide; R12, R13 mean substituted oxazolyl, naphthyl, fluorenyl, compounds of formulae , or ; R3 means hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C6)-alkyl; R8 means phenyl; R8 means phenyl-(C1-C6)-alkyl, or R8 means thienyl-(C1-C6)-alkyl; R4, R5, R7 and R13 mean independently hydrogen atom or (C1-C6)-alkyl; R6 means hydrogen atom or (C1-C6)-alkyl; R8 means 1-3 substitutes that mean independently hydrogen atom, halogen atom, (C1-C6)-alkoxyl or -CF3; R8a means 1-3 substitutes that mean independently hydrogen atom, halogen atom, -CF3, -CF3O, -CN; R14 means phenyl, -NHCOCF3 and imidazolyl; R8b means 1-3 substitutes that mean independently hydrogen atom or halogen atom; R9 and R10 mean independently (C1-C6)-alkyl, halogen atom, -NR17R18, -OH, -CF3 and -OCH3; R11 means R9, hydrogen atom, phenyl, -NO2, -CN, -CH2F, -CHF2, -CHO, -CN=NOR17, pyridyl, pyridyl-N-oxide, pyrimidinyl, pyrazinyl, -N(R17)CONR18R19, -NHCONH-(chloro-(C1-C6)-alkyl), -NHCONH-((C3-C10)-cycloalkyl-(C1-C6)-alkyl), -NHCO-(C1-C6)-alkyl, -NHCOCF3, -NHSO2N-((C1-C6)-alkyl)2, -NHSO2-(C1-C6)-alkyl, -N(SO2CF3)2, -NHCO2-(C1-C6)-alkyl, (C3-C10)-cycloalkyl, -SR20, -OSO2-(C1-C6)-alkyl, -SO2CF3, hydroxy-(C1-C6)-alkyl, -CONR17R18, -CON(CH2CH2-O-CH3)2, -OCONH-(C1-C6)-alkyl, -Si(CH3)3 or -B(OC(CH3)2)2; R12 means (C1-C)-alkyl or R14-phenyl; R14 means 1-3 substitutes that mean independently hydrogen, (C1-C6)-alkyl, -CF3, -CO2R17, -CN, (C1-C6)-alkoxyl and halogen atom; R15 and R16 mean independently hydrogen atom and (C1-C6)-alkyl, or R15 and R16 mean in common (C2-C5)-alkylene group and in common with carbon atom to which they are bound form (C3-C6)-spiran ring; R17, R18 and R19 mean independently hydrogen atom or (C1-C6)-alkyl; R20 means (C1-C6)-alkyl. Also, invention describes pharmaceutical compositions containing these compounds and using novel compounds as CCR5 antagonists in treatment of HIV infection, arthritis, asthma, cerebrospinal sclerosis and other diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

29 cl, 30 tbl, 31 ex

FIELD: organic chemistry, antibacterial agents.

SUBSTANCE: invention relates to an agent used against acid-resistant microorganisms containing derivative of pyridone carboxylic acid as an active component, its pharmaceutically acceptable salt or its hydrate that elicits high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms. Invention describes agent used against acid-resistant microorganisms containing compound represented by the following formula (I) its salt or its hydrate as an active component wherein R1 represents cyclic alkyl group comprising 3-6 carbon atoms that can comprise substitute(s) chosen from halogen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; A1 represents incomplete structure represented by the formula (2): wherein X2 represents halogen atom, alkyl group comprising 1-6 carbon atoms or alkoxy-group comprising 1-6 carbon atoms; A1, A2 and A3 form incomplete structure of the formula: in common with carbon atoms combined with them; X1 represents halogen atom; Y represents hydrogen atom; Z represents phenylpiperazine substitute. Invention provides synthesis of pyridone carboxylic acid eliciting high antibacterial activity against Mycobacterium tuberculosis and atypical acid-resistant microorganisms in combination with good pharmacokinetics indices and safety.

EFFECT: valuable biological property of agent.

10 cl, 9 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

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