Caspase inhibitors and use thereof

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I: where A,Y,R and R2 assume values given in the description. The invention also relates to methods of producing compounds of formula I and their intermediate compounds, pharmaceutical compositions and methods of using the compounds and their pharmaceutical compositions for inhibiting caspase.

EFFECT: novel compounds have useful biological properties.

44 cl, 5 tbl, 66 ex

 

The technical field to which the invention relates

The present invention relates to compounds and includes the specified connection compositions which are useful as inhibitors of caspases.

The present invention also relates to methods for obtaining such compounds.

In addition, the present invention relates to pharmaceutical compositions containing these compounds, and use of compounds and related compositions for treating diseases and disorders associated with mediated caspase States.

Background of invention

Caspase represent a family of enzymes cysteine-proteases, which are the main mediators of inflammation. The caspase-1 (ICE) processes pre-IL-1β to induce the active form of IL-1β [WO 99/47545]. ICE is also related to the conversion of pro-IGIF to IGIF and/or production of IFN-γ [Id.]. As IL-1β and IFN-γ are involved in the pathology associated with inflammatory, infectious and autoimmune diseases [see, for example, WO 99/47545;J. Invest. Dermatology, 120(1), pp. 164-167 (2003);Br. J. Dermatology, 141, pp. 739-746 (1999);Science, 282, pp. 490-493 (1998);Schweiz. Med. Wochenschr., 130, pp. 1656-1661 (2000)].

Caspase are also key mediators in signaling pathways during apoptosis and deaggregate cells [N. A. Thornberry,Chem. Biol., 5, pp. R97-R103 (1998)]. These signaling pathways vary depending on cell type and stimulus, but it is proven, that the path of apoptosis are reduced to a common effector path, leading to proteolysis of key proteins. Caspase involved in the effector phase signal path, and all other provisions above (upstream) of initiation. Caspase position upstream involved in the event initiation, become activated and, in turn, activate other caspase, which are involved in the later phases of apoptosis.

The usefulness of caspase inhibitors in the treatment of various diseases of mammals related to increased cellular apoptosis, demonstrated using peptide inhibitors of caspases. For example, in models in rodents shows that caspase inhibitors reduce the size of infarction and prevent apoptosis of cardiomyocytes after myocardial infarction, reduce the amount of damage and neurological disorders resulting from stroke, reduce post-traumatic apoptosis and neurological disorders in traumatic brain injury, are effective in the treatment of fulminant liver damage and increase survival after endotoxic shock [H. Yaoita et al.,Circulation, 97, pp. 276-281 (1998); M. Endres et al.,J. Cerebral Blood Flow and Metabolism, 18, pp. 238-247, (1998); Y. Cheng et al.,J. Clin. Invest., 101, pp. 1992-1999 (1998); A. G. Yakovlev et al.,J. Neurosci., 17, pp. 7415-7424 (1997); I. Rodriquez et al.,J. Exp. Med., 184, pp. 2067-2072 (1996); Grobmyer et al.,Mol. Med., 5, p. 585 (1999)].

However, due to peptide such inhibitors are usually Hara is theresults undesirable pharmacological properties, such as low penetration into cells and cellular activity, low absorption by oral administration, low stability and a fast metabolism [J. J. Plattner and D. W. Norbeck, inDrug Discovery TechnologiesC. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126]. This hindered the development of effective drugs. The above and other studies with peptide caspase inhibitors, it was shown that the aspartic acid residue involved in the main interaction with the enzyme, caspase [K. P. Wilson et al.,Nature, 370, pp. 270-275 (1994); Lazebnik et al.,Nature, 371, p. 346 (1994)].

Therefore, peptidase and not peptidase connection aspartic acid are useful as inhibitors of caspases.

However, there is a need for compounds with the ability to act as inhibitors of caspases, in particular with selectivity against certain caspases.

The invention

The present invention relates to compounds of the formula I:

where the variables take values here.

The present invention also relates to methods for obtaining such compounds, compositions, pharmaceutical compositions and methods of using such compounds and compositions for the inhibition of caspases. These compounds are particularly useful as selective inhib the tori caspase-1/caspase-8.

Detailed description of the invention

The present invention relates to compounds of the formula I:

where:

Y meansor;

R means R3C(O)-, HC(O)R3SO2-, R3OC(O), (R3)2NC(O), (R3)(H)NC(O)R3C(O)C(O)-, R3-, (R3)2NC(O)C(O), (R3)(H)NC(O)C(O) or R3OC(O)C(O)-;

R1the meaning of the substituents: H, aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloalkyl-aliphatic-, cycloalkenyl-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic -, or heteroaryl-aliphatic-, where any hydrogen atom is optionally and independently substituted R8any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl;

the ring A means:

or

where each ring any hydrogen atom is optionally and independently substituted R4any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl;

R3means alternates: aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic-, heterocyclyl-alifaticheskii is - or heteroaryl-aliphatic- ; or two R3groups associated with the same atom, form together with the atom 3-10-membered aromatic or nonaromatic cycle; where any optional cycle is condensed with aryl, heteroaryl, cycloalkyl or heterocyclyl; where up to 3 aliphatic carbon atoms may be substituted by a group selected from the group comprising O, N, NR9, S, SO and SO2where R3has up to 6 substituents independently selected from R8;

R4means halogen, -OR9, -NO2, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9, -SO2N(R9)2, -SO3R9, -C(O)R9, -C(O)C(O)R9, -C(O)C(O)OR9, -C(O)C(O)N(R9)2, -C(O)CH2C(O)R9, -C(S)R9, -C(S)OR9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -OC(O)N(R9)2, -C(S)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)N(R9)COR9, -N(R9)N(R9)C(O)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)SO2R9, -N(R9)SO2N(R9)2, -N(R9)C(O)OR9, -N(R9)C(O)R9, -N(R9)C(S)R9, -N(R9)C(O)N(R9)2, -N(R9)C(S)N(R)2, -N(COR9)COR9, -N(OR9R9, -C(=NH)N(R9)2, -C(O)N(OR9R9, -C(=NOR9R9,-OP(O)(OR 9)2, -P(O)(R9)2, -P(O)(OR9)2or-P(O)(H)(OR9);

R2means-C(R5)(R6)(R7), aryl, heteroaryl or C3-7-cycloalkyl;

R5means H or C1-6- linear or branched alkyl;

R6means H or C1-6- linear or branched alkyl;

R7means-CF3, -C3-7-cycloalkyl, aryl, heteroaryl, heterocycle or C1-6- linear or branched alkyl, where each carbon atom of the alkyl optionally and independently substituted R10;

or R5and R7together with the carbon atom to which the are attached, form a 3-10-membered cycloaliphatic group;

each of R8and R8'independent means halogen, -OR9, -NO2, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9, -SO2N(R9)2, -SO3R9, -C(O)R9, -C(O)C(O)R9, -C(O)C(O)OR9, -C(O)C(O)N(R9)2, -C(O)CH2C(O)R9, -C(S)R9, -C(S)OR9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -OC(O)N(R9)2, -C(S)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)N(R9)COR9, -N(R9)N(R9)C(O)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)SO2R9, -N(R9)SO2N(R9) 2, -N(R9)C(O)OR9, -N(R9)C(O)R9, -N(R9)C(S)R9, -N(R9)C(O)N(R9)2, -N(R9)C(S)N(R9)2, -N(COR9)COR9, -N(OR9R9, -C(=NH)N(R9)2, -C(O)N(OR9R9, -C(=NOR9R9, -OP(O)(OR9)2, -P(O)(R9)2, -P(O)(OR9)2and-P(O)(H)(OR9);

R9the meaning of the substituents: hydrogen, aliphatic, cycloaliphatic, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic -, or heteroaryl-aliphatic-; where any hydrogen atom is optionally and independently substituted R8any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl;

R10means halogen, -OR11, -NO2, -CN, -CF3, -OCF3, -R11or-SR11; where R11means C1-4-aliphatic-.

The present invention also relates to the compounds of formula II:

where:

Y meansor;

R1the meaning of the substituents: H, aliphatic, cycloalkyl (for example, cyclopentyl), cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloalkyl-aliphatic-, cycloalkenyl-aliphatic-, aryl-aliphatic-, heterocyclyl-alifaticheskii is or heteroaryl-aliphatic-, where any hydrogen atom is optionally and independently substituted R8any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl;

the ring A means:

where each ring any hydrogen atom is optionally and independently substituted R4any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl (or, in an alternative embodiment, carbonyl, or (C3-C6)-spirocycles);

R4means halogen, -OR9, -NO2, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9, -SO2N(R9)2, -SO3R9, -C(O)R9, -C(O)C(O)R9, -C(O)C(O)OR9, -C(O)C(O)N(R9)2, -C(O)CH2C(O)R9, -C(S)R9, -C(S)OR9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -OC(O)N(R9)2, -C(S)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)N(R9)COR9, -N(R9)N(R9)C(O)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)SO2R9, -N(R9)SO2N(R9)2, -N(R9)C(O)OR9, -N(R9)C(O)R9, -N(R9)C(S)R9, -N(R9)C(O)N(R9)2, -N(R9)C(S)N(R)2, -N(COR9)COR9, -(OR 9R9, -C(=NH)N(R9)2, -C(O)N(OR9R9, -C(=NOR9R9, -OP(O)(OR9)2, -P(O)(R9)2, -P(O)(OR9)2or-P(O)(H)(OR9);

R2means-C(R5)(R6)(R7), aryl, heteroaryl or C3-7-cycloalkyl;

R5means H or C1-6- linear or branched alkyl;

R6means H or C1-6- linear or branched alkyl;

R7means-CF3, -C3-7-cycloalkyl, aryl, heteroaryl, heterocycle or C1-6- linear or branched alkyl, where each carbon atom of the alkyl optionally and independently substituted R10;

(or, in an alternative embodiment, R5and R7together with the carbon atom to which the are attached, form a 3-10-membered cycloaliphatic group);

R3means phenyl, thiophene or pyridine, where each cycle has optional up to 5 substituents independently selected from the group R8'and where at least one position on the phenyl, thiophene or pyridine, adjacent relationship with x replaced by R12where R12contains no more than 5 atoms in the linear chain;

each of R8and R8'independent means halogen, -OR9, -NO2, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9, -SO2(R 9)2, -SO3R9, -C(O)R9, -C(O)C(O)R9, -C(O)C(O)OR9, -C(O)C(O)N(R9)2, -C(O)CH2C(O)R9, -C(S)R9, -C(S)OR9, -C(O)OR9, -OC(O)R9, -C(O)N(R9)2, -OC(O)N(R9)2, -C(S)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)N(R9)COR9, -N(R9)N(R9)C(O)OR9, -N(R9)N(R9)CON(R9)2, -N(R9)SO2R9, -N(R9)SO2N(R9)2, -N(R9)C(O)OR9, -N(R9)C(O)R9, -N(R9)C(S)R9, -N(R9)C(O)N(R9)2, -N(R9)C(S)N(R9)2, -N(COR9)COR9, -N(OR9R9, -C(=NH)N(R9)2, -C(O)N(OR9R9, -C(=NOR9R9, -OP(O)(OR9)2, -P(O)(R9)2, -P(O)(OR9)2and-P(O)(H)(OR9);

R9the meaning of the substituents: hydrogen, aliphatic, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, cycloaliphatic-aliphatic-, aryl-aliphatic-, heterocyclyl-aliphatic -, or heteroaryl-aliphatic-; (in some embodiments, the exercise of any of a hydrogen atom, R9optionally and independently substituted R8any system of two hydrogen atoms associated with one and the same atom, optionally and independently replaced by carbonyl; provided that if R9substituted R8where R8includes C is the election agent R 9such substituent R9is unsubstituted R8);

R10means halogen, -OR11, -NO2, -CN, -CF3, -OCF3, -R11or-SR11;

R11means C1-4-aliphatic group and

R12means halogen, -OR11, -NO2, -CN, -CF3, -OCF3, -R11, -SR9.

As used in the definition of R12the concept of atoms of the linear chain" refers to the atoms that are linked linearly, regardless of the fact that these atoms can also form branching. According to this definition, ethyl group, triptoreline group contain three atoms in a linear chain and methyl group contains two atoms in a linear chain. In the above embodiment, R12contains no more than 5 atoms in the linear chain. In two other variants of implementation of R12contains no more than 4 atoms in a linear chain and no more than 3 atoms in a linear chain. In other embodiments, implementation of R12contains 2 atoms in a linear chain or 1 atom.

As used here, the position adjacent to x by the relation, means the position following the position of responsible communication x. In aryl cycle this position is often called the "orthopantogram", or, in the case of the phenyl cycle, this regulation may be called "2-position". For example, in the structures shown directly below, R12 associated with cycles of phenyl, thiophene and pyridine, in the position related with communication x".

In one of the embodiments of this invention R means R3C(O)-.

In some embodiments of the invention R3means optionally substituted C6-10-aryl or heteroaryl. In other embodiments of the invention R3means optionally substituted phenyl. In some embodiments of the invention R3means 8-10-membered, optionally substituted heteroaryl (for example, quinoline, isoquinoline or hinzelin). In other embodiments of the invention R3means optionally substituted 5-6-membered heteroaryl (for example, pyridyl, pyrimidyl, pyrazinyl, thiophenyl, furanyl, thiazolyl).

In some embodiments of the invention R3is optionally and independently substituted by 0-5 groups R8'.

In one embodiment of the invention the compound according to this invention is represented by formula II:

where:

a) R3means phenyl, thiophene or pyridine;

b) every cycle has optional up to 5 replacement groups independently selected from R8and

c) at least one position on the phenyl, thiophene or pyridine, adjacent relationship with x replaced by R12where R12contains no more than 5 atoms in the linear chain.

D. the natives variant implementation of the invention relates to compounds, where Y means:

In one of the embodiments of this invention R1has up to 3 alternate groups independently selected from carbonyl and R8.

In another embodiment, R1means alternates: C1-12-aliphatic or C3-10-cycloalkyl, where each R1optionally substituted with 1-3 groups independently selected from R8. In another embodiment, R1means a linear or branched C1-4-alkyl, optionally substituted with 1-3 groups independently selected from R8.

In one embodiment, the implementation of R1means unsubstituted, linear or branched C1-4-alkyl (e.g. ethyl, isopropyl, n-propyl or n-butyl). In another embodiment, R1means ethyl.

In each of these scenarios, R8means halogen, -OR9, -CN, -CF3, -OCF3or-R9. In another embodiment, when R8means R9specified R9means benzyl.

In another embodiment, Y means

In another embodiment, the A ring has up to 3 replacement groups (preferably 1 group)selected independently from carbonyl and R4.

In one embodiment, the implementation of the ring And means:

optionally substituted R4.

In yet another embodiment, ring a represents:

optionally substituted R4.

In another embodiment of this implementation, the ring a represents unsubstituted Proline (i.e. R4means hydrogen).

In yet another embodiment, ring a represents:

oroptional substituted R4.

In one embodiment, the implementation of the ring And meansoptionally substituted R4.

In each of these scenarios, R4means halogen, -OR9, -CF3, -OCF3, -R9or-SR9. In some embodiments, the implementation of R4means H.

In one embodiment, the implementation of R2means3-4branched alkyl group.

In another embodiment, R5means H or-CH3, R6means-CH3and R7means-CH3.

In another embodiment, R12means OCF3, -OCH3, -CF3, -CH3, -CH2CH3, -Cl or-F.

In another embodiment, R12means-CF3, -CH3, -Cl or-F.

In another embodiment, R12means-CH3, -Cl or-F.

In another embodiment, each of R8'the EU is present, independent means halogen, -OR9, -NO2, -CN, -CF3, -OCF3, -R9, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -SR9, -SOR9, -SO2R9, -SO2N(R9)2, -C(O)R9, -C(O)C(O)N(R9)2, -C(O)N(R9)2, -OC(O)N(R9)2, -(CH2)0-2NHC(O)R9, -N(R9)SO2R9, -N(R9)SO2N(R9)2, -N(R9)C(O)OR9, -N(R9)C(O)R9or-N(R9)C(O)N(R9)2.

In another embodiment, R8'means-NH2, -N(R9)2, -N(R9)C(O)R9, -OCF3, -OR9, -CF3, -R9, -SR9or halogen. In this embodiment, the halogen means, preferably Cl or F, and R9means, preferably, linear or branched C1-4-alkyl.

According to one of embodiments the present invention concerns the compounds of formula III:

where the variables have the values listed in any presented here options of implementation.

In one variation of this implementation, the compound has the following stereochemistry:

where the variables have the values listed in any presented here options of implementation.

In another variation of this implementation, the connection has given the military the following stereochemistry:

or;

where the variables have the values listed in any presented here options of implementation.

According to another variant of implementation of the present invention relates to the compounds of formula IV:

where the variables have the values listed in any presented here options of implementation.

In one variation of this implementation, the compound has the following stereochemistry:

where the variables have the values listed in any presented here options of implementation.

To obtain the compounds of the present invention presented here options of implementation can be combined.

According to one of embodiments the present invention relates to compounds selected from the following table 1:

Table 1

According to another variant of implementation of the present invention relates to the compounds of formula II selected from the following table 2:

Table 2

In some embodiments of this invention the values of the variables chosen from the values present in the compounds of table 1 and/or table 2.

As used here, specifically the specified number of atoms includes any integers from the interval. For example, the group consisting of 1-4 atoms, may contain 1, 2, 3 or 4 atoms.

As used here, the aliphatic group include linear and branched groups with a given number of atoms. If the number of atoms is not specified, the aliphatic group may contain from 1 to 12 carbon atoms. Assume that Alchemilla and/or Alchemilla aliphatic group containing at least 2 carbon atoms. Preferred aliphatic groups are alkyl groups (preferably containing from 1 to 6 atoms).

Cycloalkyl and cycloalkenyl groups contain from 3 to 10 carbon atoms and are monocyclic or bicyclic, including linearly condensed, bridged or spirocycles.

As used here, "aromatic group" or "aryl" means a 6-10-membered cyclic system containing at least one aromatic cycle. Examples of aromatic cycles include phenyl and naphthyl.

Ka is used here, "heteroaryl" means a cyclic system containing 5-10 members and 1, 2 or 3 heteroatoms independently selected from N, N(R9), O, S, SO and SO2where at least one cycle is heteroaromatic (e.g., pyridyl, thiophene or thiazole).

As used here, "heterocycle" means a cyclic system containing 3 to 10 members and 1, 2 or 3 heteroatoms independently selected from N, N(R9), O, S, SO and SO2where neither one cycle is aromatic (e.g., piperidine and morpholine).

Further examples of heteroaryl cycles include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (for example, 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuran, benzothiophene, indolyl (e.g., 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazole, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinol, pyrazinyl, 1,3,5-triazinyl, chinoline (for example, 2-chinoline, 3-chinoline, 4-chinoline) and ethenolysis(for example, 1-ethenolysis, 3-ethenolysis or 4-ethenolysis).

Other examples of heterocyclic cycles include 3-1H-benzimidazole-2-it, 3-(1-alkyl)benzimidazole-2-it, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydrofuranyl, 2-morpholino, 3 morpholino, 4-morpholino, 2-thiomorpholine, 3 thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidine, 3-thiazolidine, 4-thiazolidine, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydropyranyl, tetrahydroisoquinoline, benzothiophen, benzodithiol and 1,3-dihydroimidazole-2-it.

Each of the above substituents, aliphatic, aryl, cycloaliphatic, heteroaryl and heterocyclyl may contain appropriate substituents (preferably, up to 5), independently selected from, for example, carbonyl and R8. Preferred substituents are halogen, -OR9, -NO2, -CF3, -OCF3, -R9, oxo, -OR9, -O-benzyl, -O-phenyl, 1,2-methylenedioxy, 1,2-Ethylenedioxy, -N(R9)2, -C(O)R9, -COOR9or-CON(R9)2where R9PR is takes values here (and, preferably, means H, (C1-C6)-alkyl or (C2-C6)-alkenyl and quinil), (C1-C6)-alkyl is preferred). It should be borne in mind that this definition includes perfluorinated alkyl group.

For the person skilled in the art it is obvious that some compounds in this invention can exist in tautomeric forms or hydrated forms, all such forms of the compounds included in the scope of the invention. If not mentioned specifically, it is understood that all patterns depicted here include all stereochemical forms of the structure; i.e., R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixture of the considered compounds are included in the scope of the invention.

If not mentioned specifically, it is understood that all patterns depicted here include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure, except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon on13C - or14C - enriched carbon are included in the scope of the invention.

Compounds according to this invention can be obtained by any method, including General synthetic methods known specialized there in this field, designed for similar compounds (see, for example, WO 99/47545). The following schemes for the synthesis of compounds of the present invention are presented for purposes of illustration.

The following notation:

EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

HOBt is 1-hydroxybenzotriazole

THF means tetrahydrofuran (THF)

TFA means triperoxonane acid

DCM means dichloromethane

DMAP means 4-dimethylaminopyridine

DIPEA means diisopropylethylamine

DMF means dimethylformamide (DMF)

Z means benzyloxycarbonyl

1H NMR means nuclear magnetic resonance (1H-NMR)

TLC means thin layer chromatography (TLC)

Scheme I. General scheme for E and F

Scheme I outlines the General method of preparing compounds E and F, disclosed by the present invention. To bind to the amino group of compounds of type a, can be retrieved easily by restoring the α-carboxyl group of aspartic acid (protected by PG1in the form of ester), with the carboxylic acid group of compounds of the type B (N-protected by PG2), which gives compounds of type C. PG1and PG2are orthogonal protective groups (i.e., protective groups, where the protective group can be selectively removed in the presence of other C the protective group. Ideally, PG1can be removed without removing PG2and Vice versa). Then carry out a sequence of reactions oxidation/catalysate/unprotect/cyclization by aspartate-site molecules, receiving connection type D. the Area of the loop A to D then further functionalitywith, receiving connection type E, forming part of the disclosed invention. Removing the protection Catala network connection type F, which constitute another aspect of the disclosed invention.

In various embodiments, implementation of the present invention PG2represents aminosidine group, including, but not right restrictions, aminosidine groups are described in T. W. Greene &P. G. M Wutz. "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Inc. (1999 and other publications) (the"Greene"). Z-protective group (benzyloxycarbonyl) is a particularly useful N-protective group for use in the present invention. In compounds where PG2used to protect the nitrogen of Proline, PG2preferably means Z. note that the modified Z group (protective group "Z-type"), used in relation to compounds and methods according to this invention, also included in the scope of the present invention. For example, Z may be substituted for CH2group or phenyl group, with R8(preferably halogen or C1-6if anim or branched alkyl), forming a protective group Z-type.

In various embodiments, the implementation of this invention PG1means suitable protective group of carboxylic acid, including, but not right restrictions, acid protective groups described inGreene. In some embodiments, the implementation PG1means C1-6- linear or branched alkyl group. Tert-bucilina group is particularly useful acid protecting group for use in accordance with the present invention.

In scheme I, the compound A is a modified aspartic acid residue. In addition to the compound A can be referred to other modified aspartic acid residues, including the following:

where PG3and PG4refer to the relevant protective group. These modified aspartic acid can also be obtained well-known qualified ways. See, for example, patent application publication US 2002/0042376 (in particular, page 9, paragraph and page 21-22, paragraph [0250] the documents cited in paragraph [0123]) and the US patent 6235899. See, also C. Gros et al. "Stereochemical control in the preparation of a-amino N-methylthiazolidine Masked Aldehydes used for Peptide Aldehyde Synthesis" Tetrahedron, 58, pp. 2673-2680 (2002); K. T. Chapman. "Synthesis of a Potent Reversible Inhibitor of Interleukin-β Converting Enzyme"Bioorg. Med. Chem. Letts., 2, pp. 613-618 (1982); M. D Mullican et al. "The Synthesis and Evaluation of Peptidyl Aspartyl Aldehydes as Inhibitors of ICE'" 4, pp. 2359-2364 (1994); M. H. Chen et al. "An Efficient Stereoselective Synthesis of [3S(1S,9S)]-3-[[[9-(Benzoylamino)octahydro-6,10-Dioxo-6H-pyridazino-(1,2-a)(1,2)-Diazepin-1-yl]-carbonyl]amino]-4-oxobutanoic acid, an interleukin converting enzyme (ICE) Inhibitor" 9, pp. 1587-1592 (1999). Accordingly, the scheme I and scheme III, below) can be adapted to use these other residues aspartic acid.

Scheme II. The formation of compounds of formulas I and II

Reagent and conditions: (a) R3COOH, HOBt, DMAP, EDC, THF; (b) R3CONHCH(R2)COOH, HOBt, DMAP, EDC, THF; (c) 2M HCl, MeCN.

Scheme II describes obtaining compounds of formulas I and II, where the ring a represents unsubstituted Proline. Here form a cyclic acetal compounds of this invention represented by formula I and the aldehyde form is represented by formula II. Compounds containing ring A is other than unsubstituted Proline, can be substituted for the methods described in scheme I.

Scheme II describes the methods used to obtain the compounds of formulas I and II. The compounds I can be obtained from compounds 1 by condensation of the amino group in 1 with appropriately functionalized carboxylic acid (or derivative). This stage contains the standard binding reagents that promote the formation of amide bonds; can also be used other known from the prior art, the conditions for obtaining midnig links.

As you know qualified personnel, carboxylic acid (-C(O)OH) may be associated with the amine under conditions suitable for a combination of amines and carboxylic acids. Alternatively, for such combinations can be used a derivative of carboxylic acid (-C(O)X) instead of the carboxylic acid. Obviously, in the case of a combination of amine and carboxylic acid derivative derived must activate the acid, promoting the combination with the amine. Suitable X groups are essentially leaving groups known and qualified specialists. "March''s Advanced Organic Chemistry", 5th Ed., Ed.: Smith M. B. and J. March, John Wiley & Sons, New York, 2001.

Typical conditions for the combination of amine and acid include the combination of a suitable solvent, carboxylic acids, bases and peptidases reagent. Examples of suitable conditions are described in US 2002/0042376 and WO 01/81330, which are fully incorporated herein by reference. In some embodiments, the implementation used such terms as described in the schemes and examples.

Examples of relevant derivatives include, but are not in the order restrictions, the compounds of formula RX, where X is Cl, F, OC(=O)R" (R" means an aliphatic or aryl), SH, SR, Sar, or SeAr. In some embodiments, the implementation of R is C(=O). Suitable conditions for the application of these respective derivatives known from the prior technical is I.

Scheme III. Getting connection 1

Reagent and conditions: (a) Cbz-Pro-OH, EDC, HOBt, DMAP, DIPEA, THF; (b) Swern; (c) R1OH, 3Å sieves, DCM, TsOH; (d) TFA, DCM; (e) H2Pd(OH)2, EtOAc, DMF, Et3N; (f) EDC, HOBt, Et3N, EtOAc, DMF; (g) (H2Pd/C, citric acid.

Scheme III describes a possible way of obtaining compounds 7 and compounds 1, is shown in scheme I. tie connection 2, is easily obtained by recovering the α-carboxyl group of aspartic acid with N-protected Proline (or other ring, where ring A is different from unsubstituted Proline), which leads to the formation of 3. Here Proline is N-protected with Z (benzyloxycarbonyl-) group. Compound 3 is then oxidised to aldehydes 4, which acetalized in situ, getting acetals 5. Acetals can be obtained in the presence of R1-OH (or a suitable acetal forming reagent), proton acids (for example, TsOH) or Lewis acid and a suitable solvent. Examples of suitable acetal-forming reagents, resulting in compounds, where R1turns into ethyl, can be considered as ethanol equivalents, including, but not right restrictions, triethylorthoformate or diethylacetal, such as (CH3)2C(OCH2CH3)2. Preferably, the solvent is CH2Cl2, toluene or x is orbinson. Suitable protonic acids include, but are not in the order restrictions, TFA, p-TsOH. Suitable Lewis acid include, but are not in the order restrictions, TiCl4, MgBr2and ZnCl2.

In scheme III presents the oxidation of compounds 3 to compounds 4, carried out in conditions Swern'a. Other conditions of oxidation can also be used to obtain compounds according to this invention. The preferred oxidation conditions are those that allow soft or relatively quickly to minimize epimerization on the acid side chain of the modified residue is aspartic acid. In one embodiment, the implementation phase oxidation is a TEMPO-oxidation (see, example I-1, method C, below). Other oxidation conditions include oxidation, Dess-Martin a and oxidation using tetrapropylammonium (TPAP).

Aldehydes 4 can be selected, but preferably, these aldehydes translate directly into 5 without selection. Removing the protective group complex butyl methyl ether (5) is accompanied by spontaneous closure ring with the formation of the loop, which gives a mixture of diastereomers, which divide column chromatography, obtaining enantiomerically pureShin-the ketals of 6 andanti-the ketals (not represented in this diagram). Removing the protection can be done in terms of proton the th acid or Lewis acid in an aprotic solvent. Suitable solvents include, but are not in the order restrictions, toluene, chlorobenzene and DCM. Suitable protonic acids include, but are not in the order restrictions, TFA, p-TsOH. Suitable Lewis acid include, but are not in the order restrictions, TiCl4, MgBr2and ZnCl2. For clarity, the diagram on the following stages are only SYN-ketals, forming compounds 7 and 1, but the same sequence can be used to produce anti-ketals. The connection 6 is subjected to hydrogenolysis and interact obtained compounds 7 with Z-protected amino acids using known from the prior art conditions for obtaining amide bonds, which leads to the formation of compounds 9. Compound 7 can be synthesized and used in situ. In case of separation, it is preferable to use the compound 7 fairly quickly after receipt. Finally, compound (9) is subjected to hydrogenolysis, receiving compound 1, which can be used directly to obtain the compounds I, as shown in scheme II.

Alternatively, compound 7 can be used to obtain compounds I as shown in scheme II. With this obtaining amino acid residue and the desired N-terminal group get on the same stage (see, scheme II, the interaction (b)).

As mentioned with reference to scheme I, the derivatives and paraginomai acid, other than compounds 2, can be used to obtain compounds according to this invention.

Scheme IV. The formation of compounds of formulas III and IV

Reagent and conditions: (a) ROH/HOBt/DMAP/EDC/THF or RCl/Et3N/DCM; (b) RNHCH(R2)COOH, HOBt, DMAP, EDC, THF; (c) 2M HCl, MeCN.

Scheme IV is the formation of compounds of formulas III and IV, where the ring a represents 2-azabicyclo[2.2.1]heptane-3-carboxylic acid. Here a circular form acetal compounds of this invention represented by formula III and the aldehyde form is represented by formula IV. Scheme IV shows the methods used to obtain the compounds of formulas III and IV. Compound III can be obtained from compounds 11 by condensation of the amino group 11, in terms of providing the desired R group, such as the correspondingly functionalized carboxylic acid (or derivative), sulfonic acid (or a derivative), chloroformate or carbamoylated (or isocyanate), for example, when the corresponding condition interaction. This stage has a standard binder reagents used to obtain CO-NH relations; others are known from the prior art conditions of education CO-NH (or alkyl-N, or SO2-N) relations can also be used to obtain the desired compounds containing R-N. Alternatively, the compounds I can be obtained from the of soedinenii 17 by condensation of the amino group in the 17 C, respectively functionalized carboxylic acid (or derivative), sulfonic acid (or a derivative), chloroformate or carbamoylation (or isocyanate). This stage has a standard binder reagents used to obtain CO-NH relations; others are known from the prior art conditions of education CO-NH connections can also be used.

Scheme V. Obtain compound (11)

Reagent and conditions: (a) EDC, HOBt, DMAP, DIPEA, THF; (b) Swern; (c) R1OH, 3Å sieves, DCM, TsOH; (d) TFA, DCM; (e) H2Pd(OH)2, EtOAC, DMF, Et3N; (f) EDC, HOBt, Et3N, EtOAc, DMF; (g) (H2Pd/C,citrate Acid.

Scheme V represents a possible way to obtain compounds 17 and compounds 11, is shown in scheme III. Tie connection 2, is easily obtained by recovering the α-carboxyl group of aspartic acid with N-protected 2-azabicyclo[2.2.1]heptane-3-carboxylic acid 10 (obtained underTetrahedron: Asymmetry13th, 2002, 25-28), which leads to the formation 13. Compound 13 is then oxidised to aldehyde 14, which acetalized in situ, getting acetals 15. Removing the protective group complex butyl ether is accompanied by spontaneous closure ring with the formation of the loop, which gives a mixture of diastereomers, which divide column chromatography, obtaining enantiomericallyShin-the ketals of 16 andanti-the ketals (not represented in this diagram). Alternatives to the s group A rings are either commercially available, described in the literature or can be obtained by known literature methods.

For clarity, the diagram on the following stages are only SYN-ketals, forming connections 17 and 11, but the same sequence can be used to produce anti-ketals. Connection 16 is subjected to hydrogenolysis and interact obtained compounds 17 Z-protected amino acids using known from the prior art conditions for obtaining amide bonds, which leads to the formation of compounds 19.

Alternate, compound 17 can be used to obtain compounds III as shown in scheme IV. Finally, the connection 19 is subjected to hydrogenolysis, receiving connection 11, which can be used directly to obtain the compounds III, as shown in scheme IV.

R3COOH, used according to scheme II are either commercially available, described in the literature or can be obtained by known literature methods. For compound II-30, 2-chloro-3-methoxybenzoic acid is obtained as described inJ. Org. Chem,59, 1994, 2939-2944.

For compound II-32, 2-chloro-3-triftormyetil acid derived from 2-amino-3-cryptomaterial acid (obtained as described inJ. Org. Chem,68, 2003, 4693-4699), using the substitution amino chlorine by Sandmeyer, following the methodology, what about the fact, similar to the method described inJ. Org. Chem,59, 1994, 2939-2944.

Thus, the present invention also relates to a method for obtaining compounds of this invention.

In one of the embodiments describes the method for obtaining compounds of formula I:

where Y means:

and the other variables take any value from these options for implementation;

including the interaction of the compounds of formula 1:

where variables take any value from these options for implementation; and the compounds of formula RX, where X is OH or an appropriate derivative (i.e. a leaving group), in terms of a combination of amine and acid (when X is OH) or amine and the corresponding acid derivative (when X is different from OH (means a leaving group; for example, Cl), resulting in obtaining the compounds of formula I.

Another variant implementation is the method of obtaining the compounds of formula I:

where Y means:

and the other variables take any value from these options for implementation;

including the interaction of the compounds of formula 7:

where variables take any mn the treatment of these options for implementation; and the compounds of formula RNHCH(R2)C(O)X, where X is OH or an appropriate derivative, in terms of a combination of amine and acid (when X is OH) or the corresponding acid derivative (when X is different from OH; for example, X is Cl), resulting in obtaining the compounds of formula I.

Another variant implementation of the present invention is a method of obtaining the compounds of formula IV:

where variables take any value from these options for implementation; including the interaction of the compounds of formula I:

where Y means:

where each of R and R1independently accepts any values of these options for the implementation, under the conditions of hydrolysis, resulting in the formation of compounds of formula II. In some embodiments, the implementation of R means R3C(=O). In other embodiments, implementation, when A denotes Proline, R means R3C(=O). The conditions of hydrolysis for the conversion of I to II is well known qualified personnel (see, for example,Greene). Such conditions include suitable solvent (e.g. acetonitrile) and aqueous acid (e.g., 2M HCl).

Another variant implementation is the method of obtaining the compounds of formula 6-A:

where PGsub> 2means suitable nitrogen-protective group, and R1accepts any value from these options for implementation, including the interaction of the compounds of formula 5-A:

under conditions suitable for closure ring with the formation of the loop, resulting in the formation of compounds of formula 6-A. Conditions suitable for ring closure with the formation of the cycle, include the acid and the appropriate solvent; for example, TFA in DCM.

Another variant implementation is the method of obtaining the compounds of formula 5-A:

including the interaction of the compounds of formula 4-A:

in the presence of R1-OH (or a suitable acetal forming reagent), a proton acid or a Lewis acid (for example, TsOH) and a suitable solvent, resulting in the formation of compounds of formula5-A.

Another variant implementation is the method of obtaining the compounds of formula 4-A:

including the interaction of the compounds of formula 3-A:

in suitable conditions, oxidation (e.g., oxidation Swern'a: A. J. Mancuso, Swern, D. Synthesis, 1981, 165-185), resulting in the formation of compounds of formula 4. the Preferred oxidation conditions include TEMPO-oxidation (see example I-1, method C, below).

<> Another variant implementation is the method of obtaining the compounds of formula 3-A:

including:

the interaction of the compounds of formula 2:

with the compound of the formula 20-A:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is different from OH), resulting in the formation of compounds of formula 3-A.

Another variant implementation is the method of obtaining the compounds of formula 6:

where PG2means suitable nitrogen-protective group, and R1accepts any value from these options for implementation, including the interaction of the compounds of formula 5:

in suitable conditions, cyclization leading to the formation of compounds of formula 6.

Another variant implementation is the method of obtaining the compounds of formula 5:

including the interaction of the compounds of formula 4:

in the presence of R1-OH (or a suitable acetal forming reagent), a proton acid or a Lewis acid (for example, TsOH) and a suitable solvent, resulting in the formation of compounds of formula 5. Before occhialino, the solvent is CH2Cl2, toluene or chlorobenzene.

Another variant implementation is the method of obtaining the compounds of formula 4:

including the interaction of the compounds of formula 3:

in suitable conditions, oxidation (e.g., oxidation Swern'a), resulting in the formation of compounds of formula 4. The preferred oxidation conditions include TEMPO-oxidation (see example I-1, method C, below).

Another variant implementation is the method of obtaining the compounds of formula 3:

including:

the interaction of the compounds of formula 2:

with a compound of formula 20:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is different from OH), resulting in the formation of compounds of formula 3.

Another variant implementation is the method of obtaining the compounds of formula 16:

where PG2means suitable nitrogen-protective group, and R1accepts any value from these options for implementation, including the interaction of the compounds of formula 15:

in suitable conditions, C is klizzie, resulting in the formation of compounds of formula 16.

Another variant implementation is the method of obtaining the compounds of formula 15:

including the interaction of the compounds of formula 14:

in the presence of R1-OH (or a suitable acetal forming reagent), a proton acid or a Lewis acid (for example, TsOH) and a suitable solvent, resulting in the formation of compounds of formula 15.

Another variant implementation is the method of obtaining the compounds of formula 14:

including the interaction of the compounds of formula 13:

in suitable conditions, oxidation (e.g., oxidation Swern'a), resulting in the formation of compounds of formula 14.

Another variant implementation is the method of obtaining the compounds of formula 13:

Including the interaction of the compounds of formula 2 with a compound of formula 21:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is different from OH), resulting in the formation of compounds of formula 13.

Another variant implementation is the method of obtaining the compounds of formula 22:

including the interaction of the compounds of formula 23:

in the presence of R1-OH (or a suitable acetal forming reagent), a proton acid or a Lewis acid (for example, TsOH) and a suitable solvent, resulting in the formation of compounds of formula 22. The acetal-forming equivalents include, but are not in the order restrictions, triethylorthoformate, diethylacetal, such as (CH3)2C(OCH2CH3)2. Preferably, the solvent is CH2Cl2, toluene or chlorobenzene.

Another variant implementation is the method of obtaining the compounds of formula 2:

in suitable conditions, oxidation (e.g., Swern'a), resulting in the formation of compounds of formula 23.

Another variant implementation is the method of obtaining the compounds of formula 5-A:

where PG1means suitable carboxylate protective group PG2means suitable nitrogen-protective group, and R1accepts any of the above values, including:

the interaction of the compounds of formula 20-A:

with a compound of formula 22:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding production is wow carboxylic acid (when X is an appropriate leaving group), resulting in the formation of compounds of formula 5-A.

Another variant implementation is the method of obtaining the compounds of formula 5:

including the interaction of the compounds of formula 20:

with a compound of formula 22:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is different from OH), resulting in the formation of compounds of formula 5.

Another variant implementation is the method of obtaining the compounds of formula 5-A:

including the interaction of the compounds of formula 21:

with a compound of formula 22:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is different from OH), resulting in the formation of compounds of formula 5-A.

According to the present invention methods can be used separately or in combination that leads to the production of compounds according to this invention.

Some specific embodiments of the present invention relate to methods of producing compounds 4 from 3 (in cases when connection 4 videla is t); 5 from 3 (in the cases where connections 4 are not allocated, and continue to be used directly, for example, receive in situ), 5 4 and 6 5 ways described here. In a preferred embodiment, the compound 6 obtained from compounds 5; compound 5 obtained from compounds 4 (no matter allocate or not) and compound 4 is obtained from 3. Preferably, the compound 6 is used for prolinsoderzhashchikh of caspase inhibitors. Such polysterene caspase inhibitors include, but are not in the order limitations consistent with the inhibitors described in WO 95/35308, WO 99/47545, WO 01/81330 and WO 01/90063 (fully incorporated herein by reference). For example, compound IA (and corresponding stereoisomers) WO 01/90063 (fully incorporated herein by reference) can be obtained as described herein (see, for example, page 13). In order to avoid misunderstandings it should be noted that such compounds can be represented by formula I with the exception that the ring represents pyrrolidin(that is a derivative of Proline).

The described methods are preferred for the conversion of compounds 6 in polysterene caspase inhibitors. Preferred is also described herein is a method of obtaining compounds 3. However, other methods known to skilled specialists who Stam can also be used for the conversion of compounds 6 in Proline-containing caspase inhibitors and/or to obtain compound 3.

Other embodiments of this invention relate to compounds of formula 3-6, 3-A - 6-A and 13-16.

One of the embodiments of the present invention relates to compounds of formula 4A:

Another variant implementation of the invention relates to compounds of formula 4:

Another variant implementation of the invention relates to compounds of formula 14:

One of the embodiments of the present invention relates to compounds of formula 5-A:

Another variant implementation of the invention relates to compounds of formula 5:

Another variant implementation of the invention relates to compounds of formula 15:

One of the embodiments of the present invention relates to compounds of the formula 3-A:

Another variant implementation of the invention relates to compounds of formula 3:

Another variant implementation of the invention relates to compounds of formula 13:

<> In all the above variants of the implementation variables take any value from these options. In the preferred form 3 PG2mean Z and PG1means C1-6- linear or branched alkyl group (preferably, tertbutylphenol group or individual, or a combination.

For qualified specialists is obvious that some stage of the method can be performed either in separate stages, or in situ. For example, the removal of protection and the subsequent interaction of the amine can be carried out Paladino (emitting amine) or one way (without allocation Amin).

In some embodiments, the implementation of the above methods implement, as specified here (for example, schemes, examples and the accompanying description).

Compounds such as 3, can be used in the methods of obtaining prolinsoderzhashchikh compounds, such as caspase inhibitors. Polysterene caspase inhibitors include, but are not in the order limitations, inhibitors described in WO 95/35308, WO 99/47545, WO 01/81330 and WO 01/90063 (which are all incorporated herein by reference). For example, compound IA (and corresponding stereoisomers)that are specified in WO 01/90063 (fully incorporated herein by reference), can be obtained as described herein (see, for example, page 13 PCT publication).

The compounds used in the Nasiriyah and methods of the present invention, can also be modified by adding the appropriate functional groups to enhance selective biological properties. Such modifiers known in the art and include modifiers that increase the biological ability of penetration into a given biological system (e.g., blood, lymphatic system, Central nervous system), increase bioavailability when orally administered drug that enhances solubility, allowing for the introduction by injection, alter metabolism and excretion rate.

For example, carboxilate group in the compound according to the invention can be converted, for example, in the ester group. Preferred esters are esters, which include:

C1-6- linear or branched alkyl, alkenyl or quinil, where the alkyl, alkenyl or quinil optionally substituted C6-10-aryl, CF3, Cl, F, OMe, OEt, OCF3CN or NMe2;

C1-6-cycloalkyl, where 1-2 carbon atoms in cycloalkyl optionally replaced by-O - or-NR9-.

Compounds according to the invention, containing a carbonyl group, can be similarly represented in the form of derivatives, such as, for example, acetal, ketal, oxime (=NOR9), hydrazine (=NN(R9)2), thioacetal or thioketal.

Relevant is the following derivatives of amines known from the prior art and are also included in the scope of the present invention.

Some of the above derivatives may include protective group known from qualified professionals (see, for example,Greene). As is obvious to a person skilled in this field, these protective groups can also be used in the methods of the present invention.

Compounds according to this invention can be tested for the ability to inhibit apoptosis, the release of IL-1β or directly the activity of caspases. Test each option activity is known from the prior art. However, as obvious to the person skilled in the art, the connection is a prodrug of the present invention should be active only in trials where forming a prodrug group should be chipped off, as a rule, in the in vivo tests.

Tests for activity against caspase described in WO 99/47545.

According to another variant of implementation considering the invention relates to pharmaceutical compositions containing:

a) the compound according to the invention, as defined herein, or pharmaceutically acceptable salt of such compounds, and

b) a pharmaceutically acceptable carrier, excipient or solvent.

It is understood that the compounds and pharmaceutically acceptable salts of these compounds are included in the scope of the present invention. When these compositions are used pharmaceutical is acceptable salts of the compounds of the present invention, such salts preferably are derived from inorganic or organic acids and bases. Among these acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, citrate, comfort, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, fumarate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate. Basic salts include ammonium salts, alkali metal salts, such as salts of sodium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, salts of N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.

Also, the basic nitrogen-containing groups can be stereoselectivity of such agents as lower alkylhalogenide, such as methyl-, ethyl-, propyl - and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl-, diethyl-, dibutil and dimycolate, long chain halides such as decyl-, lauryl-, myristyl and St is arylhalides, bromides and iodides, aralkylated, such as benzyl and phenetermine and others. So, get water or oil-soluble or dispersible products.

Pharmaceutically acceptable carriers that may be used in these compositions include, but are not in the order restrictions, ion-exchange substances, alumina, aluminum stearate, lecithin, serum proteins, such as serum human albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as preteenslut, intrigejosa, potassium phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, the sodium carboxymethyl cellulose, polyacrylates, waxes, block polymers of polyethylene-polyoxypropylene, polyethylene glycol and wool fat.

According to a preferred variant implementation of the compositions of the present invention formulated for pharmaceutical administration mammal, which, preferably, is the man.

Such pharmaceutical compositions of the present invention can be administered orally, parenterally, by aerosol inhalation, topically, rectal is about, nasal, buccal, vaginally or via an implanted reservoir. The term "parenteral"as used here, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, inside the affected tissue and intracranial ways injection or infusion. Preferably, the composition is administered orally or intravenously.

Sterile form, for injecting the compositions of the present invention can be an aqueous or oil suspension. These suspensions can be formulated according to known prior art methods using suitable dispersing or moisturizers and suspendida funds. A sterile preparation for injection may also be in the form intended for injection of a sterile solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. Among the acceptable environments for drugs and solvents suitable for use include water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are usually used as solvent or suspendida environment. This purpose can be used any tasteless non-volatile oil, including synthetic is practical mono - or diglycerides. Fatty acids such as oleic acid, and the corresponding glyceride derivatives useful for obtaining drugs for injection as, for example, pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylenic forms. These oil solutions or suspensions may also contain long-chain alcohol diluent or dispersing agent, such as carboxymethyl cellulose or similar dispersing substances commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as twins, spiny and other emulsifying agents or amplifiers bioavailability, are commonly applied to industrial production of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of the present invention can be administered orally in any acceptable for oral administration, dosage form, including, but not right restrictions, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration commonly used carriers include lactose and corn starch. Also usually add lubric the options such as magnesium stearate. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When oral administration is required aqueous suspensions of the active ingredient is combined with emulsifying and suspendresume substances. Optionally, can also be added some sweeteners, corrigentov or dyes.

Alternatively, pharmaceutical compositions according to the present invention can be introduced in the form of suppositories for rectal administration. These suppositories can be obtained by mixing the agent with a suitable non-irritating by excipients, which is solid at room temperature, but liquid at rectal temperature and therefore melt in the rectum, releasing the drug. Such substances include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of the present invention can also be injected locally, especially when the object of processing includes the surface or organs readily accessible for topical application, including diseases of the eyes, skin, or the lower area of the intestine. Suitable compositions for topical application can be easily obtained for each of these areas or organs.

Topical application for the lower area of the intestine can be done is by formulating rectal suppositories (see above) or the development of compositions for enemas. Can also be used transdermal patches topical application.

For topical applications, the pharmaceutical compositions can be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not in the order restrictions, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated as a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carrier materials include, but are not in the order restrictions, mineral oil, servicemonitor, Polysorbate 60, wax-based complex of cetyl ether, Cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, sterile salt solution with adjusted pH or, preferably, as solutions in isotonic, Steelmaster salt with adjusted pH, contains or does not contain a preservative, such as Benzylalcohol. Alternatively, for ophthalmic use, the pharmaceutical compositions can be formulated in an ointment such as petrolatum. One of the options for the implementation of the compositions formulated according to, for example, patent US 6645994 and/or patent US 6630473.

The pharmaceutical compositions of the present invention can also be introduced by means of an aerosol for nasal or inhalation. Such compositions have well known from the prior art methods of pharmaceutical formulation, and these compositions can be obtained as solutions in saline, using benzyl alcohol or other suitable preservatives, enhancers suction to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The above compounds and compositions are particularly useful for therapeutic applications in the case of such diseases as mediated by IL-1 disease mediated apoptosis disease, inflammatory disease, autoimmune disease, destructive violation of bone, proliferative violation, infectious disease (e.g., bacterial infection, mainly, eye infections, degenerative diseases is s, a disease caused by cell necrosis, a disease caused by excessive consumption of alcohol-mediated virus disease, disorders of the retina, uveitis, inflammatory peritonitis, osteoarthritis, pancreatitis, asthma, syndrome of respiratory disorders in adults, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, toxic goiter, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, malignant myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, atopic dermatitis, scarring, graft vs. host rejection of the transplant organ, apoptosis body after burn injury, osteoporosis, leukemia and related diseases, myelodysplastic syndrome caused by multiple myeloma damage to bones, acute myeloblastic leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, haemorrhagic shock, sepsis, septic shock, burns, shigellosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, Kennedy disease, diseases caused by prions, cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic heart disease, myocardial infarction,congestive heart failure, atherosclerosis, coronary artery bypass graft, spinal muscular atrophy, amyotrophic lateral sclerosis, multiple sclerosis, caused by HIV encephalitis, aging, alopecia, neurological damage due to stroke, ulcerative colitis, traumatic brain injury, spinal cord injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue fever, Japanese encephalitis, various forms of liver disease, renal disease, polycystic kidney disease associated with H. pylori gastric ulcer and duodenal ulcer, HIV infection, tuberculosis, meningitis, toxic epidermal necrolysis, bladderwort and automorphically disease (sometimes called automorphically febrile syndromes) and related syndromes, such as syndrome Muckle-Wells'a (MWS), familial cold urticaria (FCU), familial Mediterranean fever (FMF), chronic infantile neurological cutaneous and articular syndrome (CINCAS), otherwise known mulitvitamin inflammatory disease of the newborn (NOMID), TNFR1-associated periodic syndrome (TRAPS) and the syndrome of Hyper-IgD intermittent fever (HIDS). Compounds and compositions are also useful for the treatment of complications associated with coronary artery bypass. In addition, the compounds and compositions useful for reducing the production of IGI (also known as IL-18 or IFN-γ. Compounds and compositions are also useful in immunotherapy for the treatment of cancer.

Compounds and compositions can also be used in the methods of preserving cells. These methods are useful for the preservation of organs, in particular intended for transplantation or blood products.

Compounds of the present invention are useful as dual inhibitors, caspase-1 and CAwithgrooves-8. Without going into theory, apparently, R2and R3group of compounds of the present invention are related to this unexpected activity. Bridge group A compounds of the present invention, such asor,also, apparently, for this unexpected activity. As such, the compounds and compositions of the present invention particularly useful for the treatment or prevention of inflammation.

According to another variant implementation of the compositions of the present invention can optionally include other therapeutic agent (namely, one or more additional assets). Such means include, but are not in the order restrictions, thrombolytic agents such as tissue plasminogen activator and streptokinase. When using an additional agent, the additional agent can be introduced in the form of the Department is Noah dosage forms, and as part of a single dosage form containing compounds or compositions of the present invention.

The number of compounds present in the compositions of the present invention, should be sufficient to cause a detectable weakening the severity of the disease or reducing the activity of caspases and/or apoptosis, measured by any known from the prior art method of analysis.

In monotherapy useful dose levels of connection of the active ingredient in the range of about from 0.01 to 50, or about 100 mg/kg of body weight per day, preferably, from 0.5 to about 75 mg/kg of body weight per day and most preferably, from about 1 to 25 or 50 mg/kg of body weight per day.

Typically, the compound or composition according to this invention is administered from about 1 to 5 times per day or alternatively, as a continuous infusion. This introduction can be used as a permanent or acute therapy. The amount of active ingredient that may be combined with the materials of the media to produce a single dosage form varies depending on being treated with the master and a specific way of introduction. A typical preparation contains from about 5% to 95% active compound (m/m). Preferably, such preparations contain AP is sustained fashion from 20% to 80% of the active connection.

When the compositions of this invention comprise a combination of compounds according to this invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at the level of doses in the range of about from 10% to 100% and, more preferably, from 10% to 80% of the dose usually introduced in monotherapy.

While improving the condition of the patient can be entered, if necessary, maintenance dose of a compound, composition or combination according to this invention. Subsequently, the dosage or frequency of administration, or both, may be reduced depending on the symptoms to a level that supports a better condition, when the symptoms are attenuated to the desired level, treatment should be discontinued. Patients, however, may require long-term intermittent treatment in the case of the return of symptoms.

Qualified clear that may require lower or higher doses than those mentioned above. It should be understood that a specific dosage and treatment regimen for a particular patient depends on a number of factors including the activity of the specific compound, the age, body weight, General health, sex, diet, time of administration, rate of excretion, drug combines the Yu, the severity and course of a particular disease, the predisposition of the patient to a treatable disease and the assessment of the attending physician. The number of active ingredients depends on the specific compound and the other therapeutic agent, if present in the composition.

In a preferred embodiment, the invention concerns a method of treatment of the patient, mainly, a person having one of these diseases, including the stage of introduction of a given patient the compound or pharmaceutically acceptable composition mentioned above. In this embodiment, if the patient also introduce another therapeutic agent or an inhibitor of caspases, the delivery of such funds is possible together with the connection according to this invention in one dosage form or in separate dosage forms. With the introduction of a separate dosage forms another caspase inhibitor or the agent may be introduced in advance, at the same time or after the introduction of a pharmaceutically acceptable composition comprising the compound according to this invention.

Compounds according to this invention can also be introduced into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. Thus, the present image is a buy in another aspect, includes a composition for coating an implantable device, containing the compound of the present invention and a carrier suitable for coating of specified implanted device. According to another aspect of the present invention includes an implantable medical device coated with a composition comprising a compound of the present invention and a carrier suitable for coating of specified implanted device.

Another aspect of the invention relates to the suppression of caspase activity in a biological sample, where the method includes contacting a specified biological sample with a compound according to this invention or a composition containing the specified connection. The term "biological sample", as used here, including includes cell culture or relevant extracts; material for biopsy taken from a mammal or extracts of the relevant material and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

Inhibition of caspase activity in a biological sample is useful for a variety of purposes known to the person skilled in the art. Examples of such purposes include, but are not in the order restrictions, blood transfusion, organ transplantation, the Deposit of biological samples and biological tests.

The compounds of this invention are useful in methods for the Ah preservation of cells, may be necessary for the transplantation of organs or preservation of blood products. This application of caspase inhibitors described in [Schierle et al.Nature Medicine,5, 97 (1999)]. The method includes processing cells or tissue intended for canning, the solution containing the inhibitor of caspases. The required amount of inhibitor of caspase dependent upon the effectiveness of the inhibitor with respect to this cell type and period of time that you want to protect cells from apoptotic cell death.

Without going into theory of connections on the basis of the cyclic acetal according to the invention are considered as prodrugs. That is acetaline group is cleaved in vivo, giving the corresponding acid-aldehyde compound. As it is obvious for a skilled specialist, chemical compounds can be subjected to transformations in the process of exchange in vivo, for example, on the site other than the site of cleavage of the prodrug. Any such metabolites are included in the scope of the present invention.

The following preparative examples and examples of the tests are given in order to more fully understand the present invention. These examples are presented solely for the purpose of illustration and in no way can be considered as a limit of the present invention.

Example I-1

[(2R)-etox the-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

The way A

Tributyl ester (S)-3-amino-4-hydroxybutiric acid

A solution of butyl ether (S)-benzyloxycarbonylamino-4-hydroxybutiric acid (obtained as described in Michel et al. Helvetica Chimica Acta, 1999, 1960) (0,94 g) in ethyl acetate (15 ml) hydronaut over palladium hydroxide/carbon (20% m/m, 160 mg). The catalyst was removed by filtration through celite. Concentration of the filtrate in vacuo gives specified in the subtitle compound as a colourless oil (486 mg, 91%);1H NMR (400 MHz, CDCl3) δ to 1.48 (9H, s)1,95 (3H, users), 2,28 (1H, DD), 2,46 (1H, DD), 3,29 (1H, osirm), 3,42 (1H, m), of 3.60 (1H, m).

Method B

Benzyl ether of (1S)-2-((S)-2-tertbutoxycarbonyl-1-hydroxyethylaminomethyl)pyrrolidin-1-carboxylic acid

To a stirred solution of butyl ether (S)-3-amino-4-hydroxybutiric acid (800 mg, of 4.57 mmol) and Z-Pro-OH (1,14 g of 4.57 mmol) in THF (30 ml) is added 2-hydroxybenzotriazole (741 mg, 1.2 EQ.), DMAP (698 mg, 1.25 EQ.), diisopropylethylamine (of 1.03 ml, 1.3 EQ.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, of 1.05 g, 1.2 EQ.). The resulting mixture was stirred at ambient temperature for 18 hours, then diluted with ethyl acetate. The mixture is then washed with water, saturated aqueous sodium bicarbonate and saturated R is the target salt, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified flash chromatography (mixture of 60% ethyl acetate/petroleum ether)to give specified in the subtitle compound as a colourless solid (1,483 g, 90%); MS ES (+) 407,3.

The method C

Benzyl ether of (1S)-2-((S)-2-tertbutoxycarbonyl-1-formalistically)pyrrolidin-1-carboxylic acid

A solution of benzyl ether (1S)-2-((S)-2-tertbutoxycarbonyl-1-hydroxyethylaminomethyl)pyrrolidin-1-carboxylic acid (10 g) in DCM (100 ml) cooled to 0°C in nitrogen atmosphere. Then add 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 38 mg) by adding trichloroisocyanurate acid (6 g)in portions over 30 minutes. The mixture was stirred at ambient temperature for 2 hours, then filtered through celite. The filtrate is washed with water, 1 M sodium thiosulfate solution and water. Dried over magnesium sulfate and concentrated under reduced pressure, obtaining mentioned in the subtitle compound as a pale yellow oil (9,92 g, 99%);1H NMR (400 MHz, d-6 DMSO) δ to 1.38 (9H, d), 1,79 is 1.86 (3H, m), 2,08-of 2.23 (1H, m), 2,36 is 2.51 (1H, 2 × DD), 2,61-of 2.86 (1H, 2 × DD), 3,88-of 3.46 (2H, m), 4,24-4,30 (2H, m), of 5.05 (2H, Quinn.), 7,28-7,37 (5H, m), 8,59-8,64 (1H, 2 × d), of 9.21 (0,57H, C), 9,37 (0,43H, C).

Method D

Benzyl ether of (1S)-2-((S)-1-tertbutoxycarbonyl-2,2-diethoxycarbonyl)pyrrolidin-1-karbonvansty

To a solution of benzyl ether (1S)-2-((S)-2-tertbutoxycarbonyl-1-formalistically)pyrrolidin-1-carboxylic acid (to 4.98 g) in dichloromethane (70 ml) add triethylorthoformate (6.2 ml) and the monohydrate p-toluensulfonate acid (47 mg). The resulting mixture was stirred at ambient temperature until the lack of residual aldehyde by TLC. The mixture was concentrated in vacuo, re-dissolved in dichloromethane (35 ml). Then add saturated aqueous sodium bicarbonate solution (35 ml) and remove the organic phase. Washed with water and saturated salt solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. Get listed in the subtitle compound as a pale yellow oil (4,85 g, 82%);1H NMR (400 MHz, d-6 DMSO) δ 1.04 million-1,11 (6H, m), of 1.35 to 1.37 (9H, m), 1,73-1,89 (3H, m), a 2.01-2.49 USD (3H, m), 3.43 points-to 3.52 (6H, m), 4,05-the 4.29 (3H, m), 4,96-of 5.06 (2H, m), 7,27-7,38 (5H, m), 7,80 (0,5H, d), 7,88 (0,5H, d).

Method E

Benzyl ether of (1S)-2-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.1

Benzyl ether of (1S)-2-((2S,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.2

A solution of benzyl ether (1S)-2-((S)-1-tertbutoxycarbonyl-2,2-diethoxycarbonyl)pyrrolidin-1-carboxylic acid (4,85 g) in dichloromethane (25 ml) ohlajdauche 0°C in nitrogen atmosphere. Then add triperoxonane acid (6 ml) and the mixture was stirred at 0°C for 15 minutes, then heated to ambient temperature and stirring is continued until the completion of engagement by TLC. The mixture is then diluted with dichloromethane (90 ml) and saturated aqueous sodium bicarbonate solution (130 ml) and stirred for 15 minutes. Then the organic phase is removed and washed with a mixture of 1:1 saturated aqueous sodium bicarbonate/saturated salt solution (100 ml), the combined wash water is re-extracted with DCM (100 ml) and the combined organic layers are dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gives specified in the subtitle compound as a mixture of epimeres on katalaveno center (C2). Epimere share on silica gel, elwira a mixture of 30% acetone/petroleum ether.Shin-isomer6.1(white solid);1H NMR (400 MHz, d-6 DMSO) δ 1,08-1,17 (3H, m), 1,78 is 2.01 (3H, m), 2,08-2,12 (1H, m), 2,37-to 2.57 (1H, 2 × DD), 2,61-and 2.79 (1H, 2 × DD), 3,35-3,51 (2H, m), 3,55-3,68 (1H, m), 3,71-3,82 (1H, d), 4,20-4,32 (1H, m), to 4.52-br4.61 (1H, m), 4,98-5,11 (2H, m), of 5.53-to 5.58 (1H, m), 7.24 to 7,42 (5H, m), 8,25-8,31 (1H, m); MS ES + 377,3 (100%), ES - 375,3 (10%); Anti-isomer6.2(colorless oil);1H NMR (400 MHz, d-6 DMSO) δ 1,08-1,19 (3H, m), 1,78-1,89 (3H, m), 2,10-of 2.34 (1H, m), 2,92-of 3.07 (1H, 2 × DD), 3,36-3,51 (3H, m), 3,62-of 3.78 (2H, m), 4,12-is 4.21 (2H, m), equal to 4.97-5,12 (3H, m), 7,28-7,40 (5H, m), 8,51-8,58 (1H, m); MS ES + 377,4 (100%), ES - 375,3 (10%).

Benzyl ether of (1S)-2-((2R,3S)-2-Methoxy-5-oxitetraciclina the n-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.3

Benzyl ether of (1S)-2-((2S,3S)-2-methoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.4

Get a way, similar to those described in methods A-E, using triethylorthoformate at stage D, which gives specified in the subtitle compound as a mixture of epimeres6.3and6.4. Epimere share on silica gel, elwira mixture of 30%-40% 2-butanone/petroleum ether to 70% acetone/petroleum ether.SYN-isomer6.3(viscous colorless oil);1H NMR (400 MHz, d-6 DMSO) δ 1.77 in-1,89 (3H, m), 2,07-2,12 (1H, m), 2,32 is 2.43 (1H, 2 × d), 2,55-2,61 (1H, 2 × d), 2,71-of 2.81 (1H, 2 × d), 3,39-3,62 (4H, m), 4,21-4,30 (1H, m), 4,57 with 4.64 (1H, m), 5,01-5,09 (2H, m), 5,42-vs. 5.47 (1H, m), 7,27-7,42 (5H, m), 8,24-8,31 (1H, m); Anti-isomer6.4(white solid);1H NMR (400 MHz, d-6 DMSO) δ 1,79-1,90 (3H, m), 2,09-of 2.21 (1H, m), 2,23-41 (1H, 2 × d), 2,91 was 3.05 (1H, 2 × DD), 3,35-3,71 (5H, m), 4.09 to is 4.21 (2H, m), 4,98-5,19 (3H, m), 7,28-7,41 (5H, m), 8,51-8,58 (1H, m).

Benzyl ether of (1S)-2-((2R,3S)-2-isopropoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.5

Benzyl ether of (1S)-2-((2S,3S)-2-isopropoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.6

Get a way, similar to those described in methods A-E, using triisopropanolamine at stage D, which gives specified in the subtitle compound as a mixture of epimeres6.5and6.6. Epimere RA is really on silica gel, elwira a mixture of 30%-40% 2-butanone/petroleum ether.SYN-isomer6.5(colorless resin);1H NMR (400 MHz, d-6 DMSO) δ 1,07 is 1.16 (6H, m), 1,81 is 1.86 (2H, m), 2,37-a 2.71 (2H, m), 3,35-of 3.53 (2H, m), 3,86-are 3.90 (1H, m), 4,18-4,24 (1H, m), 4,46-4,55 (1H, m), 4,95-5,10 (2H, m), 5,63 (1H, d), 7,27-7,38 (5H, m), by 8.22-8,30 (1H, m); MS ES + 391,3 (100%); Anti-isomer6.6(white solid);1H NMR (400 MHz, d-6 DMSO) δ 1,07-of 1.15 (6H, m), 1,78-to 1.82 (3H, m), 2,07-to 2.41 (2H, m), 2,87-a 3.01 (1H, m), 3,35-3,50 (2H, m), 3,74-of 3.96 (1H, m), 4,07-4,18 (2H, m), 4,95-5,11 (2H, m), with 5.22 (1H, 2 × s), 7.24 to 7,39 (5H, m), 8,48 are 8.53 (1H, m); MS ES + 391,4 (100%).

Benzyl ether of (1S)-2-((2R,3S)-2-propoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.7

Benzyl ether of (1S)-2-((2S,3S)-2-propoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.8

Get a way, similar to those described in methods A-E, using reproportioned at stage D, which gives specified in the subtitle compound as a mixture of epimeres6.7and6.8. Epimere share on silica gel, elwira a mixture of 30%-40% 2-butanone/petroleum ether.SYN-isomer6.7(colorless resin);1H NMR (400 MHz, d-6 DMSO) δ 0,84 with 0.93 (3H, m)of 1.55 (2H, m), 1,81-1,89 (3H, m), 2,08-2,22 (1H, m), 2,37-2,61 (1H, 2 × DD), 2,71 is 2.80 (1H, 2 × DD), 3,31-of 3.53 (2H, m), 3,60 at 3.69 (1H, m), 4,20-the 4.29 (1H, m), to 4.52-br4.61 (1H, m), 4,95-5,11 (2H, m), of 5.50 (1H, m), 7,27 and 7.36 (5H, m), of 8.27 (1H, m); Anti-isomer6.8(colorless oil);1H NMR (400 MHz, d-6 DMSO) δ 0,82-of 0.90 (3H, m), 1,46-of 1.57 (2H, m), 1.77 in-1,89 (3H, m), 2.06 to to 2.41(1H, m), 2,90 was 3.05 (1H, 2 × DD), 3,33-3,66 (5H, m), 4,11-4,20 (2H, m), 4,94-5,10 (3H, m), 7,28-7,37 (5H, m), 8,51 (1H, m).

Benzyl ether of (1S)-2-((2R,3S)-2-butoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.9

Benzyl ether of (1S)-2-((2S,3S)-2-butoxy-5-oxitetraciclina-3-ylcarbonyl)pyrrolidin-1-carboxylic acid 6.10

Get a way, similar to those described in methods A-E, using tributylammonium at stage D, which gives specified in the subtitle compound as a mixture of epimeres6.9and6.10. Epimere share on silica gel, elwira a mixture of 30%-40% 2-butanone/petroleum ether.SYN-isomer6.9(colorless resin);1H NMR (400 MHz, d-6 DMSO) δ 0,86 to 0.92 (3H, m), of 1.28 to 1.37 (2H, m), 1,45-and 1.54 (2H, m), 1,79-of 1.88 (3H, m), 2,07-of 2.21 (1H, m), 2,35-2,78 (2H, m), 3,31-of 3.54 (2H, m), 3,63-3,70 (1H, m), 4,21-the 4.29 (1H, m), 4,51-br4.61 (1H, m,), 4,95-5,09 (2H, m), of 5.50 (1H, m), 7,27-7,37 (5H, m), of 8.25 (1H, m); Anti-isomer6.10(colorless oil);1H NMR (400 MHz, d-6 DMSO) δ 0,85 with 0.93 (3H, m), 1,26-of 1.36 (2H, m), 1,44-of 1.56 (2H, m), 1.77 in-1,90 (3H, m), 2,08-to 2.40 (1H, m), 2,89 was 3.05 (1H, 2 × DD), 3,34-3,70 (5H, m), 4,08-4,19 (2H, m), 4,95-5,10 (3H, m), 7,28-7,39 (5H, m), 8,53 (1H, m).

Method F

Benzyl ether of {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-pyrrolidin-2-carbonyl]-2,2-dimethylpropyl}-carbamino acid

To a solution of benzyl ether (1S)-2-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-pyrrolidin-1-carbon is Oh acid 6.1(4.68 g) in ethyl acetate (160 ml) and DMF (25 ml), add triethylamine (2.5 g) followed by addition of palladium hydroxide/carbon (20% m/m, 1 g). The mixture is stirred in hydrogen atmosphere, to lack of source materials by TLC. The catalyst was removed by filtration through celite. To the filtrate add (S)-2-benzyloxycarbonylamino-3,3-dimethyloctane acid (4,93 g), hydroxybenzotriazole (2,01 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 2.85 g). The resulting mixture was stirred at ambient temperature overnight. Then add saturated aqueous sodium bicarbonate solution (180 ml) and the organic phase removed. Washed with saturated aqueous ammonium chloride (180 ml), then saturated salt solution (180 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified on silica gel, elwira mixture 40-75% ethyl acetate/petroleum ether. Specified in the subtitle compound obtained as a white foamy substance (as 4.02 g, 66%);1H NMR (400 MHz, CDCl3) δ of 0.97 (9H, s)to 1.14 (3H, t), 1,79-of 1.94 (3H, m), 2,02-2,10 (1H, m)2,44 (1H, DD), a 2.75 (1H, DD), 3,52-3,66 (2H, m), 3,70-with 3.79 (2H, m), 4,22 (1H, d), to 4.38-to 4.41 (1H, m), 4,48-4,58 (1H, m), of 5.03 (2H, square), 5.56mm (1H, d), 7,26 (1H, d), 7,29-7,40 (5H, m), 8,24 (1H, d); MS ES + 490,6 (100%), ES - 488,8 (10%).

Method G

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2)-carboxylic acid

To a solution of benzyl ester {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-pyrrolidin-2-carbonyl]-2,2-dimethylpropyl}carbamino acid (344 mg) in ethyl acetate (20 ml) is added palladium hydroxide/carbon (20% m/m, 74 mg). The mixture is stirred in hydrogen atmosphere, to lack of source materials by TLC. The catalyst was removed by filtration through celite and the filtrate concentrated under reduced pressure, obtaining the amine as a brown foamy substance (260 mg). Some of the listed substances (153 mg) was dissolved in THF and added dropwise 3-methoxy-2-methylbenzoic acid (146 mg), Diisopropylamine (191 μl), hydroxybenzotriazole (77 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 109 mg). The resulting mixture was stirred at ambient temperature for 24 hours, then diluted with saturated aqueous sodium bicarbonate. The organic phase is removed and washed with saturated aqueous ammonium chloride, then with saturated salt solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified on silica gel, elwira with ethyl acetate. This gives specified in the subtitle compound as a white solid (138 mg, 62%); analytical data are summarized in table 3.

Compounds of the formulaI-2-I-58obtained by methods essentially analogion the mi methods, described in exampleI-1.

Example I-2

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-3

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[3-methyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-4

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-hydroxy-2-methylbenzylamino)-3-methyl-butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-5

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1- [(2S)-(3-amino-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-6

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2,6-dichloraniline)-3-methyl-butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-7

(S,S,S,R)-N-{(1S)-[(2S)-((2R)-Ethoxy-5-oxitetraciclina-(3S)-ylcarbonyl)pyrrolidin-1-carbonyl]-2-methylpropyl}-2-nicotine amide

Example I-8

(S,S,S,R)-N-{(1S)-[(2S)-((2R)-Ethoxy-5-oxitetraciclina-(3S)-ylcarbonyl)pyrrolidin-1-carbonyl]-2-methylpropyl}-4-nicotine amide

Example I-9

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-{3-methyl-(2S)-[(3-methylthiophene-2-carbonyl)amino]butyryl}pyrrolidin-(2S)-carboxylic acid

Example I-10

(S,S,S,R)-2,3-Dichloro-N-{(1S)-[(2S)-((2R)-ethoxy-5-oxitetraciclina-(3S)-ylcarbonyl)pyrrolidin-1-carbonyl]-2-methylpropyl}isonicotinamide

Example I-11

(S,S,S,R)for 3,5-Dichloro-N-{(1S)-[(2S)-((2R)-ethoxy-5-oxitetraciclina-(3S)-ylcarbonyl)pyrrolidin-1-carbonyl]-2-methylpropyl}isonicotinamide

Example I-12

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-13

[(2R)-Methoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-14

[(2R)-Isopropoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-15

[5-Oxo-(2R)-propoxy-5-tetrahydrofuran-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-16

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-17

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[3,3-dimethyl-(2S)-(2-methylbenzylamino)butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-18

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[3-methyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-19

[(2R)-Methoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[2(S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-20

[(2R)-Isopropoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[3,3-dimethyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-21

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-22

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[3,3-dimethyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-carboxylic acid

Example I-23

[5-Oxo-(2R)-ProPak tetrahydrofuran-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-24

[(2R)-Butoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-25

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-triphtalocyaninine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-26

[5-Oxo-(2R)-propoxylation-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-27

[5-Oxo-(2S)-propoxylation-(3S)-yl]amide (S,S,S,S)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-28

[(2S)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,S)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-29

[(2R)-Butoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,S)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-30

[(2S)-Butoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,S)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

the example I-31

[(2R)-Isopropoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-32

[(2S)-Isopropoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,S)-1-[(2S)-(2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-33

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-cyclopropylacetylene)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-34

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-methylbenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-35

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide {S,S,S,R)-1-[(2S)-(2-chloro-3-methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-36

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-ethylbenzylamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-37

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-38

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-cyclopropylacetylene)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-39

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-hydroxyethylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-40

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-acetamidobenzoyl)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-41

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-42

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-methyl-3-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-43

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-44

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-fluoro-4-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-45

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-fluoro-4-acetamidobenzoyl)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-46

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-isopropylbenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-47

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-hydroxyethylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-48

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-ethoxymethyleneamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-49

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-isobutylacetophenone)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-50

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-acetamidobenzoyl)-3-cyclohexyl]pyrrolidin-(2S)-carboxylic acid

Example I-51

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-methoxycarbonylaminophenyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-ka is oil acid

Example I-52

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-phenoxybenzamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-53

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-4-thiazolidinedione)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-54

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-amino-2-chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-55

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3-thiazol-4-ylpropionic]pyrrolidin-(2S)-carboxylic acid

Example I-56

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-thiazol-4-ylpropionic]pyrrolidin-(2S)-carboxylic acid

Example I-57

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chloro-3-methoxybenzylamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carboxylic acid

Example I-58

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]piperidine-(2S)-carboxylic what sloty

Example I-59

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(3-methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

METHOD H

Benzyl ether of (1R,3S,4S)-3-((S)-2-tertbutoxycarbonyl-1-hydroxyethylaminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

To a stirred solution of butyl ether (S)-3-amino-4-hydroxybutiric acid (486 mg) and 2-benzyl ester (1R,3S,4S)-2-azabicyclo[2.2.l]heptane-2,3-dicarboxylic acid (obtained as described in Tararov et al.Tett. Asymm. 2002,13, 25-28) (767 mg) in THF (18 ml) is added 2-hydroxybenzotriazole (452 mg), DMAP (426 mg), diisopropylethylamine (631 μl) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 641 mg). The resulting mixture was stirred at ambient temperature for 18 hours, then diluted with ethyl acetate. After which the mixture is washed with water, saturated aqueous sodium bicarbonate and saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified flash chromatography (mixture of 60% ethyl acetate/petroleum ether)to give specified in the subtitle compound as a colourless oil (1.1 g, 91%);1H NMR (400 MHz, d-6 DMSO) δ 1,13-1,25 (1H, m), of 1.30 to 1.48 (9H, what), 1,49-1,88, (6H, m), 2,20-2,52 (2H, m), 3,09-to 3.34 (2H, m)to 3.64 (1H, d), 4,00-4,16 (2H, osirm), 4,80 (1H, m), 4,90-of 5.15 (2H, m), 7,21-7,41 (5H, m), 7,50 to 7.75 (1H, m); MS ES (+) 433,37.

The way I

Benzyl ether of (1R,3S,4S)-3-((S)-2-tertbutoxycarbonyl-1-formalistically)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

A solution of benzyl ester of (1R,3S,4S)-3(S)-2-tertbutoxycarbonyl-1-hydroxyethylaminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid (1.1 g) in DCM (10 ml) cooled to 0°C in nitrogen atmosphere. Then add 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 4 mg) followed by addition of Trichloroisocyanuric acid (621 mg)in portions over 30 minutes. The mixture was stirred at ambient temperature for 1 hour, then filtered through celite. The filtrate is washed with water, 1 M sodium thiosulfate solution and saturated salt solution. Dried over magnesium sulfate and concentrated under reduced pressure, obtaining mentioned in the subtitle compound as a colourless oil (698 mg, 64%);1H NMR (400 MHz, d-6 DMSO) δ 1.16 to-1,89 (16H, m), 2,30 is 2.80 (2H, m), 3,68-3,81 (1H, m), 4,19 (1H, osirm), 4,39, (1H, m), 4,91-5,16 (2H, m), 7,21-the 7.43 (5H, m), 8,45 (0,4H, d), at 8.60 (0,6, d), 9,19 (0,6H, s), 9,37 (0,4H, C).

Method J

Benzyl ether of (1R,3S,4S)-3-((S)-1-tertbutoxycarbonylmethyl-2,2-diethoxycarbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

To a solution of benzyl ester of (1R,3S,4S)-3-((S)-2-t is ebookseller-1-formalistically)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid (698 mg) in dichloromethane (10 ml) add triethylorthoformate (720 mg) and monohydrate p-toluensulfonate acid (6 mg). The resulting mixture was stirred at ambient temperature until the lack of residual aldehyde by TLC. Then add saturated aqueous sodium bicarbonate solution and remove the organic phase. Washed with water and saturated salt solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. Get listed in the subtitle compound as a pale yellow oil (635 mg, 78%);1H NMR (400 MHz, d-6 DMSO) δ 0,96-of 1.15 (6H, m), 1,26-1,84 (16H, m), 2,20-of 2.50 (2H, m), 3,40-3,81 (5H, m), 4,10-to 4.28 (2H, m), 4,37 (1H, m), 4,88-5,14 (2H, m), 7,20-7,40 (5H, m), 7,65 (0,5H, d), 7,80 (0,5H, d).

Method K

Benzyl ether of (1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid

A solution of benzyl ester of (1R,3S,4S)-3-((S)-1-tertbutoxycarbonyl-2,2-diethoxycarbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid (635 mg) in dichloromethane (3 ml) cooled to 0°C in nitrogen atmosphere. Then add triperoxonane acid (0.7 ml) and the mixture was stirred at 0°C for 15 minutes, then heated to ambient temperature and stirring is continued until the completion of engagement by TLC. The mixture is then diluted with dichloromethane (10 ml) and saturated aqueous sodium bicarbonate solution (14 ml). Then the organic phase is removed and washed with a mixture of 1:1 saturated aqueous sodium bicarbonate/acadeny salt solution (8 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. This gives specified in the subtitle compound as a mixture of epimeres on katalaveno center. Epimere share on silica gel, elwira a mixture of 30% 2-butanone/petroleum ether.Shin-isomer (oil) (115 mg, 23%);1H NMR (400 MHz, d-6 DMSO) δ 0,80-1,91 (10H, m), 2,35-and 2.79 (2H, m), of 3.56 (1H, m), 3,66-of 3.80 (2H, m), 4,18 (1H, m), 4,59 (1H, m), 4,94-5,11 (2H, m), of 5.53 (1H, d), 7,20-7,40 (5H, m), 8,18 (0,5H, d), 8,27 (0,5H, d); MS ES + 403,31 (100%), ES -401,37 (15%); Anti-isomer (oil) (103 mg, 20%);1H NMR (400 MHz, d-6 DMSO) δ 0,80-of 1.85 (10H, m), 2,25-2,60 (1H, m), 2,95 (1H, m), 3,42 (1H, m), 3,5-of 3.75 (2H, m), 4,88-of 5.15 (3H, m), 7,21-7,40 (5H, m), and 8.50 (0,4H, d), 8,59 (0,6H, d).

Method L

Benzyl ether of {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-azabicyclo[2.2.1]heptane-2-carbonyl]-2,2-dimethylpropyl}carbamino acid

To a solution of benzyl ester of (1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid (5 g) in ethyl acetate (160 ml) and DMF (25 ml), add triethylamine (2.5 g) followed by addition of palladium hydroxide/carbon (20% m/m, 1 g). The mixture is stirred in hydrogen atmosphere, to lack of source materials by TLC. The catalyst was removed by filtration through celite. To the filtrate add (S)-2-benzyloxycarbonylamino-3,3-dimethyloctane acid (4,93 g), hydroxybenzotriazole (2,01 g) and 1-(3-dimethyl shall aminopropyl)-3-ethylcarbodiimide (EDC, 2.85 g). The resulting mixture was stirred at ambient temperature overnight. Then add saturated aqueous sodium bicarbonate solution (180 ml) and the organic phase removed. Washed with saturated aqueous ammonium chloride (180 ml), then saturated salt solution (180 ml), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified on silica gel, elwira mixture 40-75% ethyl acetate/petroleum ether. Specified in the subtitle compound obtained as a white foamy substance (5,25 g, 81%);1H NMR (400 MHz, d-6 DMSO) δ 0,85-1,03 (10H, m), 1,07 is 1.20 (3H, t), of 1.30 (1H, m)of 1.40 (1H, m), 1,50-1,80 (3H, m)of 1.93 (1H, m), 2.40 a-2,50 (1H, m), 2,78 (1H, m), of 3.60 (1H, m), of 3.78 (1H, m)to 3.89 (1H, s), 4.26 deaths (1H, d)to 4.52 (2H, m), 4,96-5,12 (2H, m)to 5.56 (1H, d), 7,10 (1H, d), 7.24 to yield of 7.40 (5H, m), of 8.27 (1H, d); MS ES + 516,93 (100%), ES - 515,05 (100%).

Method M

((2R,3S)-2-Ethoxy-5-oxitetraciclina-3-yl)amide of (1R,3S,4S)-2-[(S)-2-(3-methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

To a solution of benzyl ester {(S)-1-[(1R,3S,4S)-3-((2R,3S)-2-ethoxy-5-oxitetraciclina-3-ylcarbonyl)-2-azabicyclo[2.2.1]heptane-2-carbonyl]-2,2-dimethylpropyl}carbamino acid (370 mg) in ethyl acetate (20 ml) is added palladium hydroxide/carbon (20% m/m, 74 mg). The mixture is stirred in hydrogen atmosphere, to lack of source materials by TLC. The catalyst was removed by filtration che is ez celite and the filtrate concentrated under reduced pressure, getting amine as a brown foamy substance (272 mg). Some of the listed substances (167 mg) was dissolved in THF and added dropwise 3-methoxy-2-methylbenzoic acid (146 mg), Diisopropylamine (191 μl), hydroxybenzotriazole (77 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, 109 mg). The resulting mixture was stirred at ambient temperature for 24 hours, then diluted with saturated aqueous sodium bicarbonate. The organic phase is removed and washed with saturated aqueous ammonium chloride, then with saturated salt solution, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude product is purified on silica gel, elwira with ethyl acetate. This gives specified in the subtitle compound as a white solid (121 mg, 52%);1H NMR (400 MHz, CDCl3) δ of 1.10 (9H, s)of 1.28 (3H, t), 1,43-of 1.56 (1H, m), 1,79 is 1.86 (3H, m), 1,99 (1H, userd), to 2.29 (3H, s), 2,30-is 2.37 (1H, m), and 2.83 (1H, DD), to 3.02 (1H, users), 3,66-3,74 (1H, m), a 3.87 (3H, s), 3,88-of 3.94 (1H, m), 4,16 (1H, users), of 4.54 (1H, users), 4,66-4,74 (1H, m), equal to 4.97 (1H, d), 5,46 (1H, d), 6,44 (1H, userd), 6,93 (1H, d), of 7.00 (1H, d), 7,22 (1H, t), 7,78 (1H, userd); IR (solid) cm-12960, 1791, 1624, 1505, 1438, 1261, 1115, 975;;MS ES + 530; ES - 528.

Compounds of the formulaI-60-I-73obtained by methods essentially similar to the methods described in exampleI-59.

Example I-60

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-and abicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-61

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(4-acetylamino-2-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-62

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(2-chloro-4-propionylcarnitine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-63

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(2-chloro-3-isobutyleneisoprene)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-64

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(2-fluoro-3-methoxybenzylamine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-65

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(2-fluoro-3-methoxybenzylamine)-3-methylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-66

[(2S)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(3-methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-67

[(2S)-Ethoxy-5-oxitetraciclina(3S)-yl]amide 2-[(2S)-(2-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-68

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(4-acetylamino-3-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-69

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(3-chloro-4-propionylcarnitine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-70

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(isoquinoline-1-ylcarbonyl)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-71

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(4-amino-3-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-72

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]-amide 2-[(2S)-(4-amino-3-chlorobenzylamino)-3-methylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Example I-73

[(2S)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide 2-[(2S)-(isoquinoline-1-ylcarbonyl)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carboxylic acid

Table 3
Identification data of selected compounds of formula I
(connection number)
No.M+1
(the experts.)
1H NMR
I-1490,1(DMSO-d6) 0,94-0,95 (3H, m), 0,98-0,99 (3H, m), 1,13-of 1.16 (3H, m), 1,80-2,0 (4H, m), 2,10 (3H, s), 2,47 is 2.51 (2H, m), 2,73 (1H, m), 3,34-3,61 (2H, m), of 3.73-of 3.77 (2H, m), with 3.79 (3H, s), 3,90 (1H, m), 4,39 (1H, m), 4,55 (1H, m), of 5.55 (1H, d), 6,83 (1H, d), of 6.99 (1H, d), 7,19 (1H, m), of 8.27 (1H, d), a 8.34 (1H, d)
I-2476,0(CDCl3) 1,01-of 1.15 (6H, m)of 1.26 (3H, t), 1,90-to 2.29 (5H, m), 2,55 at 2.59 (1H, m), 2,75-and 2.83 (1H, m), 3,65-3,98 (3H, m), Android 4.04 (3H, s), of 4.44 figure-4.49 (1H, m), 4,62-4,69 (1H, m), 4.75 V-4,80 (1H, m), the ceiling of 5.60 (1H, d), to 7.09 (1H, t), 7,19 (1H, d), 7,52 (1H, t), of 7.97 (1H, d)
I-3530,0(CDCl3) 1,02-of 1.10 (6H, m), of 1.23 to 1.34 (3H, m), 1,88-2,19 (5H, m), 2,32 is 2.44 (2H, m), 2,81-2,89 (1H, m), 3,66-and 3.72 (2H, m), 3,83-3,98 (2H, m), 4,56-to 4.73 (2H, m), 4,84-of 4.90 (1H, m), 5,46 (1H, d), to 7.15 (1H, d), 7,35-7,60 (4H, m), to 7.99 (1H, d)
I-4476,1(CDCl3) of 1.02 (3H, d), of 1.09 (3H, d), of 1.29 (3H, t), 1.93 and-2,19 (4H, m)to 2.29 (3H, s), 2,39 (2H, DD), 2,84 (1H, DD), 3,66-3,71 (2H, m), 3,88-of 3.95 (2H, m), 4,63 (1H, DD), 4,68-4,74 (1H, m), is 4.85 (1H, DD), 5,32 (1H, s), vs. 5.47 (1H, d), 6,44 (1H, d), 6.87 in (1H, d), 6,98-7,00 (1H, m), 7,07 for 7.12 (1H, m), of 7.36 (1H, d)
I-5 475,0(CDCl3) 0,95-1,10 (6H, m)is 1.31 (3H, t), 1,93-of 2.21 (4H, m), of 2.25 (3H, s), 2,34-to 2.41 (2H, m), 2,80-is 2.88 (1H, m), 3,63 of 3.75 (4H, m), a 3.87-3,93 (2H, m), 4,65-of 4.75 (2H, m), 4,82-4,88 (1H, m), vs. 5.47 (1H, d), to 6.43 (1H, d), 6,74 (1H, d), for 6.81 (1H, d),? 7.04 baby mortality (1H, t), 7,40 (1H, d)
I-6514,4(CDCl3) equal to 1.03-1.05 (3H, m), 1,09 is 1.13 (3H, m), 1,22-of 1.30 (3H, m), of 1.95 (1H, m), 2,14-2,17 (2H, m), 2,44 is 2.51 (2H, m), and 2.79 (1H, m), 3,65-3,68 (2H, m), 3,86-are 3.90 (2H, m), of 4.12 (1H, m), 4,60-br4.61 (2H, m), a 4.86 (1H, m), vs. 5.47 (1H, m), 6,4 (1H, 2 × d), 7,29-7,37 (3H, m), 7,54 (1H, m)
I-7461,1(DMSO-d6) 0,95-1,01 (6H, m), 1,13-of 1.16 (3H, m), 1,80-2,10 (4H, m), 2,45 is 2.51 (5H, m), is 2.74 (1H, m), 3.33 and-3,59 (2H, m), 3,68 (1H, m), of 3.95 (1H, m), of 4.38-of 4.44 (2H, m), 4,55 (1H, m), of 5.55 (1H, m), 7,25 (1H, m), a 7.62 (1H, m)of 8.27 (1H, m), 8,48 (1H, m), 8,63 (1H, m)

I-8461,1(CDCl3) of 1.02 (3H, d), a 1.08 (3H, d), of 1.28 (3H, t), of 1.95 to 2.2 (4H, m), of 2.4-2.5 (2H, m)to 2.55 (3H, s), 2,8-2,9 (1H, m), of 3.7-3.8 (2H, m), 3,85-of 3.95 (2H, m), 4,7-4,85 (2H, m), 4,9-of 4.95 (1H, m), of 5.55 (1H, d), 6,6-of 6.65 (1H, m), 7,2-of 7.25 (1H, m), 7,35 to 7.4 (1H, m), and 8.6 (1H, d), and 8.7 (1H, s)
I-9465,6(DMSO-d6) 0,93-of 0.95 (3H, m), 0,99-1,00 (3H, m), 1,13-of 1.16 (3H, m), 1,80-2,10 (4H, m), is 2.40 (3H, s), 2.40 a-2,47 (2H, m), 2,73 (1H, m), 3,59-3,61 (2H, m), of 3.73 of 3.75 (2H, m), 4,37-4,43 (2H, m), 4,55 (1H, m), of 5.53 (1H, d), 6,97 (1H, m), to 7.59 (1H, m), 7,81 (1H, d), of 8.28 (1H, d)
I-10515,0(CDCl3) a 1.01 (3H, d), 1,25 (3H, d), of 1.27 (3H, t), 1,97 is 2.10 (2H, m), 2,14-of 2.26 (1H, m) of 2.38 (2H, DD), 2,84 (1H, DD), 3,67-3,71 (2H, m), 3,81-a 3.87 (1H, m), 3,90-3,98 (1H, m), 4,58-br4.61 (1H, m), 4,65-to 4.73 (1H, m), a 4.86-the 4.90 (1H, DD), vs. 5.47 (1H, d), is 6.78 (1H, d), of 7.23 (1H, d), 7,42 (1H, d), 8,40 (1H, d)
I-11515,0(CDCl3) a 1.01 (3H, d), to 1.14 (3H, d), of 1.28 (3H, t), 1,96-2,12 (2H, m), 2,17-of 2.23 (2H, m), of 2.38 (2H, DD), and 2.83 (1H, DD), 3,66-3,71 (2H, m), 3,82-of 3.95 (2H, m), 4,59-to 4.62 (1H, m), 4,65-4,71 (1H, m), 4,91 (1H, DD), vs. 5.47 (1H, d), is 6.54 (1H, userd), 7,21 (1H, userd), to 8.57 (2H, s)
I-12504,4(DMSO-d6) 0,9-a 1.08 (9H, s)of 1.12 (3H, t), 1,75-2,00 (3H, m), 2.00 in to 2.15 (4H, m), 2,34-of 2.50 (1H, m), 2,80 (1H, m), 3,48-3,91 (7H, m), and 4.40 (1H, m), 4,46-4,70 (2H, m), to 5.58 (1H, d), 7,81 (1H, d), of 7.00 (1H, d), 7,19 (1H, DD), 8,07 (1H, d), of 8.27 (1H, d)
I-13476,0(CDCl3) 0,98 (PI)-1.09 (6H, m), 1,90-of 2.05 (4H, m), 2,35-of 2.56 (2H, m), 2,70-to 2.85 (1H, m), 3,49+3,55 (3H, 2 × s), 3,55-to 3.67 (1H, m), 3,86 (3H, s), EUR 4.00-4.09 to (1H, m), 4,58-of 4.90 (3H, m), 5,34 lower than the 5.37 (1H, m), 6,25+6,40 (1H, 2 × d), 6,90-7,01 (2H, m), 7.18 in-to 7.25 (1H, m), 7,37+7,54 (1H, 2 × d)
I-14504,0(CDCl3) 0,99-1,11 (6H, m), 1,18-of 1.30 (6H, m), 1,86-of 2.15 (4H, m), 1,28+of 1.30 (3H, 2×s), a 2.36-of 2.86 (3H, m), 3,56-3,68 (1H, m), 3,86 (3H, s), a 3.87-of 4.05 (2H, m), 4,50-4,84 (3H, m), 5,55+5,59 (1H, 2 × d), 6,86-7,01 (2H, m,), 7,16-of 7.23 (1H, m), 7,37+7,54 (1H, 2 × d)

I-15504,0(CDCl3) 0,85-1,11 (9H, m), 1,55-of 1.73 (2H, m), 1,89-of 2.20 (4H, m), 2,28+to 2.29 (3H, 2×s), 2,35 is 2.55 (2H, m), 2.71 to 2,87 (1H, m), 3,48 is 3.76 (3H, m), 3,86 (3H, s), 3,98-4,06 (1H, m), to 4.52-a 4.86 (3H, m), 5,44-5,49 (1H, m), 6,24 + 6,35 (1H, 2 × d), 6,88-6,99 (2H, m), 7,14-7,21 (1H, m), 7,41+of 7.55 (1H, 2 × d)
I-16480,5(CDCl3) 1,0-1,15 (6N, m), 1,3-1,4 (3H, m), 1,9-2,2 (4H, m), of 2.4-2.5 (2H, m), 2,8-2,9 (1H, m), of 3.7-3.8 (2H, m), 3,9-4,0 (2H, m), 4,65-of 4.75 (2H, m), 4,88 to 4.92 (1H, m), 5,5-5,52 (1H, m), 6,85-6,9 (1H, m,), 7,4-of 7.55 (1H, m), 7,7-of 7.75 (1H, m)
I-17474,6(DMSO-d6) of 1.05 (9H, s)and 1.15 (3H, t), 1,8-2,1 (4H, m), 2,3 (3H, s), 2,4-2,5 (1H, m), 2,7-2,8 (1H, m), 3,6-3,9 (4H, m), 4,4-of 4.45 (1H, m), 4,5-4,7 (2H, m), 5,55-5,6 (1H, m), 7,2-7,4 (4H, m)and 8.1 (1H, d), to 8.25 (1H, d)
I-18514,5(DMSO-d6) about 0.9-1.0 (6H, m)and 1.15 (3H, t), 1,8-2,1 (4H, m), 2,4-2,5 (1H, m), 2,7-2,8 (1H, m), 3,6-of 3.85 (3H, m), 3,9-of 3.95 (1H, m), 4,4-4,6 (3H, m), 5,55-5,6 (1H, m), 7,4 was 7.45 (1H, m), of 7.6 to 7.8 (3H, m), by 8.22 (1H, d), is 8.75 (1H, d)
I-19480,5(CDC13) 1-13 (9H, s), 1,90-of 2.20 (3H, m), 2,35 is 2.44 (2H, m), of 2.86 (1H, DD), of 3.56 (3H, s), 3.72 points-3,74 (1H, m), 3,90-to 3.99 (1H, m), 4,62 with 4.65 (1H, m), 4,69-4,70 (1H, m), the 4.90 (1H, d), are 5.36 (1H, d), 6,94 (1H, d), 7,28-7,46 (4H, m), 7,71 (1H, DD)
I-20542,5(CDC13) of 1.09(9H, C)of 1.27 (6H, m), 1.93 and with 2.14 (3H, m), 2,34-to 2.42 (2H, m), 2,79-and 2.83 (1H, m), 3,71 (1H, m), 3,90-of 3.94 (1H, m), 4,01-Android 4.04 (1H, m), 4,62-of 4.67 (2H, m), 4,88-4,91 (1H, m)to 5.56 (1H, m), 6,46 (1H, m), 7,40 (1H, m), 7,54 to 7.62 (3H, m), 7,74 (1H, m)
I-21of 494.5(CDCl3) of 1.12 (9H, s)of 1.29 (3H, t), 1,90-of 2.20 (3H, m), 2,36 is 2.43 (2H, m), 2,85 (1H, DD), 3,67-and 3.72 (2H, m), 3,90-of 3.96 (2H, m), 4,62 with 4.65 (2H, m) 4,91 (1H, d), 5,46 (1H, d), to 6.95 (1H, d), 7,34-7,46 (4H, m), 7,71 (1H, DD)
I-22528,4(CDCl3) of 1.10 (9H, s)of 1.29 (3H, t), 1,90-of 2.20(3H, m), 2,35-to 2.42 (2H, m), 2,84 (1H, DD), 3,68-and 3.72 (2H, m), 3,90-of 3.95 (2H, m), 4,62-4,80 (2H, m), 4,89 (1H, d), vs. 5.47 (1H, d), of 6.45 (1H, d), the 7.43 (1H, d), 7,54-to 7.61 (3H, m), 7,73 (1H, DD)

I-23508,5(CDCl3) of 0.95 (3H, t), of 1.12 (9H, s), 1,60-1,70 (2H, m), 1,88-of 2.20 (3H, m), 2,35 at 2.45 (2H, m), 2.77-to 2,85 (1H, m), 3,53-3,61 (1H, m), 3,65 of 3.75 (1H, m), 3,76-a-3.84 (1H, m), 3,88-of 3.96 (1H, m), 4,60-to 4.73 (2H, m), 4,91 (1H, d), 5,44 (1H, d), of 6.96 (1H, d), 7,30 is 7.50 (4H, m), 7,73 (1H, d)
I-24522,5(CDCl3) 0,86 (3H, t), of 1.18 (9H, s), 1,21-of 1.65 (4H, m), 1.85 to 2,17 (3H, m), 2,36 at 2.59 (2H, m), 2,68-2,78 (1H, m), 3,44-of 3.54 (1H, m), 3,56-and 3.72 (2H, m), 3,98-4,10 (1H, m), 4,56-4,85 (3H, m), 5,44 (1H, d), 6,95-7,02 (1H, m), 7,32-7,74 (5H, m)
I-25578,3(DMSO-d6) 0,99-to 1.21 (12H, m), 1.70 to a 2.00 (3H, m), 2,01-2,17 (1H, m), 2.40 a is 2.51 (1H, m) 2,70 is 2.80 (1H, m), 3,50-3,88 (4H, m), and 4.40 (1H, m), 4,55 (1H, m)and 4.65 (1H, m), to 5.58 (1H, d), of 7.36 (1H, m)to 7.50 (1H, m), to 7.61 (1H, m), 8,21 (1H, d), to 8.70 (1H, d)
I-26of 494.5(CDCl3) of 0.95 (3H, t), of 1.05 to 1.15 (6H, m)of 1.55 to 1.8 (3H, m), a 2.0 to 2.25 (4H, m), 2,4-2,5 (1H, m), 2,6-2,9 (2H, m), 3,55 to 3.8 (3H, m), 3,85-of 3.95 (1H, m), 4,05 of 4.1 (1H, m), 4,7-4,85 (2H, m), 5,5-of 5.55 (1H, m), 6,85-of 6.9 (1H, m), 7,4-7,6 (3H, m), 7,7-7, 8 (1H, m)
I-27of 494.5(CDCl3) of 0.95 (3H, t), of 1.05 to 1.15 (6H, m), of 1.5-1.7 (3H, m), of 2.0-2.2 (4H, m), 2,4-2,6 (2H, m), 2,9-3,1 (1H, m), 3,4-3,5 (1H, m), 3,55-3,7 (2H, m), 4,0-4,1 (1H, m), 4,35 to 4.5 (2H, m), 4,6-of 4.75 (1H, m), 4,8-4,9 (0,5H, m), 5,35 is 5.38 (1H, m), 6,85-to 6.95 (1H, m), 7,4-of 7.55 (3H, m), of 7.64-7,8 (1,5H, m)
I-28480,3(CDCl3) 1,02-1,19 (7H, m), 1,22 of 1.28 (2H, m), 1,90-of 2.21 (3H, m), 2,32 of $ 2.53 (2H, m), 2,95 (1H, 2 × DD), 3,44-3,50 (1H, m), 3,59-78 (2H, m), 3,83-to 3.92 (1H, m), as 4.02-4.09 to (1H, m), 4,29-to 4.41 (1H, m), of 5.34 (1H, 2 × s), 6,88 {1H, 2 × userd), 7,31-7,42 (4H, m), EUR 7.57 (1H, 2 × userd), of 7.70 (1H, 2 × DD)
I-29508(CDCl3) of 0.83 to 0.97 (3H, m), of 1.02-1.14 in (6N, m), 1,26-of 1.53 (3H, m), 1,55-of 1.66 (1H, m), 1,91-of 2.20 (4H, m), 2,35-2,61 (2H, m), 2,73-2,90 (1H, m), 3,54-3,74 (3H, m), 3,84-3,90 (0,5H, m), 3,99-4,06 (0,5H, m), br4.61-of 4.75 (2H,, m), 4,77-4,93 (0,5H, m), the 5.45 the 5.51 (1H, m), 6.87 in (1H, userd), 7,34 was 7.45 (4H, m), 7,55 (0,5H, userd), 7,70-7,22 (1H, m)

I-30508 (400 MHz, CDC13) of 0.87 to 0.97 (3H, m), 0,99-of 1.16 (6H, m), 1,27-of 1.40 (2H, m), 1,48-to 1.59 (1H, m), 1.91 a-2,19 (4H, m), 2,30-2,52 (2H, m), 2,90-of 3.07 (1H, m), 3,39-3,45 (0,5H, m), 3,54-3,71 (2H, m), 3,78-3,82 (0,5H, m), 3,86-3,92 (0,5H, m), Android 4.04-4.09 to (0,5H, m), or 4.31 is 4.35 (1H, m), 4,39-4,43 (1H, m), 4,56-4,59 (0,5H, m), 4,66-and 4.68 (1H, m), 4.80 to a 4.86 (0,5H, m), 5,32-5,41 (1H, m), 6.87 in-6,91 (1H, m), 7,31 was 7.45 (4H, m), 7,55-7,76 (2H, m)
I-31494,4(CDCl3) 1,04-1,19 (8H, m), 1.25 or of 1.28 (3H, m), 1,92-to 2.18 (4H, m), 2,32 is 2.43 (1H, m), 2,62-2,87 (2H, m), 3,59-3,71 (1H, m), 3,85-of 3.95 (1H, m), 4,00-of 4.05 (1H, m), 4,60-of 4.67 (3H, m), the ceiling of 5.60 (1H, 2 × d), to 6.88 (1H, userd), was 7.36-to 7.50 (4H, m), 7,52-7,56 (1H, m), 7,76 (1H, 2 × DD)
I-32494,3(CDCl3) 0,87-of 1.24 (10H, m), 1,88-2,07 (3H, m), 2,13-of 2.21 (1H, m), 2,32-of 2.54 (2H, m)to 2.94 (1H, 2 × DD), 3,57-3,68 (1H, m), 3,83-a 3.87 (1H, m), as 4.02-4.09 to (1H, m), 4,27-4,30 (1H, m)to 4.41 (1H, DD), 4,51-4,69 (1H, m), 5,43 (1H, 2 × s), 6,89 (1H, 2 × userid), 7,30 was 7.45 (4H, m), 7,52 (1H, 2 × userid), of 7.70 (1H, 2 × DD)
I-33550,5(DMSO) to 0.70 (2H, m, CH2), 0,89 (2H, m, CH2), 0,95-of 1.20 (12H, m, CH3, tBu), 1,71 and 2.13 (4H, m, CH2), of 2.45 (1H, m, asp CH2), to 2.75 (1H, m, asp CH2), 3,35-to 3.89 (4H, m, CH2, CH), 3,99 (1H, m, CH), 4,37 (1H, m, CH), 4,51 (1H, m, CH)and 4.65 (1H, m, CH), to 5.58 (1H, m, CHO), of 6.90 (1H, m, aryl H), 7,35 (1H, m, aryl H), was 7.45 (1H, m, aryl H), of 8.25 (1H, d, NH), 8,35 (1H, d, NH)
I-34508,5(DMSO) 0,99-to 1.21 (12H, m, CH3, tBu), a 1.75-2,14 (4H, m, CH2), of 2.38 (3H, s, CH3), 2.40 a is 2.51 (1H, m, asp CH2), 2,70-2,82 (1H, m, asp CH2), 3,37-are 3.90 (4H, m, CH2, CH), 4,39 (1H, m, CH, 4,55 (1H, m, CH), of 4.67 (1H, m, CH), to 5.58 (1H, d, CH), to 7.15 (1H, m, aryl H), 7,28 (1H, m, aryl H), 7,38 (1H, m, aryl H), of 8.25 (1H, m, NH), scored 8.38 (1H, m, NH)
I-35510(CDCl3) to 1.00 (3H, d), of 1.10 (3H, d), of 1.27 (3H, t), 1,90-2,19 (4H, m), 2,34 at 2.45 (2H, m), 2,79-2,87 (1H, m), 3,65-3,71 (2H, m), 3,84-is 4.93 (2H, m)to 3.92 (3H, s), 4,56-4,70 (2H, m), 4,82-4,88 (1H, m), of 4.45 (1H, d), 6,69 (1H, d), of 6.99 (1H, d), 7,16 (1H, d), 7,27 (1H, t), 7,37 (1H, d)

I-36522,5(DMSO) 0,95-1,25 (15H, m, tBu, CH3), 1,78 and 2.13 (4H, m, CH2), 2,43 (1H, m, CH2), 2,65 is 2.80 (3H, m, CH2), 3,50-3,88 (4H, m, CH2, CH), 4,42 (1H, m, CH), 4,58 (1H, m, CH), 4,70 (1H, d, CH), to 5.58 (1H, d, CH), to 7.15 (1H, m, aryl H), 7,27 (1H, m, aryl H), 7,38 (1H, m, aryl H), of 8.27 (1H, d, NH), 8,39 (1H, d, NH)
I-37to 510.5(CDCl3) of 1.05 to 1.12 (6H, m), 1,25-1,3 (3H, m), 1,9-2,2 (2H, m), of 2.4-2.5 (2H, m), 2,8-2,9 (1H, m), 3,65 of 3.75 (2H, m), 3,85 (3H, s), 3,9-4,0 (1H, m), 4,65-of 4.75 (2H, m), 4,85 of 4.9 (1H, m), 6,9-6,93 (1H, m), 6,98 (1H, s), 7,05 and 7.1 (1H, m), 7,4 was 7.45 (1H, m), 7,75 one-7.8 (1H, d)
I-38564(CDCl3) 0,38 at 0.42 (2H, m), 0,63-of 0.71 (2H, m), 1,11 (N, C)of 1.23 and 1.35 (4H, m), 1,88-of 2.20 (3H, m), 2,34 at 2.45 (2H, m), was 2.76-2,87 (1H, m), 3,66 of 3.75 (2H, m), a 3.87-of 3.96 (4H, m), 4,62-to 4.73 (2H, m), 4,89 (1H, d), vs. 5.47 (1H, d)to 6.80 (1H, d), of 7.00 (1H, d), 7,19-7,29 (2H, m), of 7.48 (1H, d)
I-39510(DMSO) to 1.11 (9H), of 1.28 (3H, t), 1,83-2,22 (3H, m), 2,36 is 2.43 (2H, m), 2,82-2,87 (1H, m), 3,66 is 3.76 (2H, m), 3,86-of 3.97 (2H, m), 4,62-4,71 (2H, m), 4,88 (1H, d), the 5.45 (1H, d), of 6.31 (1H, s), of 6.73 (1H, d), 7,05-7,20 (3H, m), 7,38 (1H, d)
I-40537,4(CDCl3) of 1.06 (6H, DD), of 1.28 to 1.31 (4H, m), 1,91-of 2.20 (4H, m), of 2.23 (3H, s), 2,39 (1H, DD), 2,84 (1H, DD), 3,65-and 3.72 (2H, m), 3,86-of 3.94 (2H, m), br4.61-to 4.73 (2H, m), to 4.87 (1H, DD), 5,46 (1H, DD), 7,00? 7.04 baby mortality (1H, m), 7,22 (1H, users), 7,38 was 7.45 (2H, m), 7,73 (1H, d), 7,80 (1H, users)
I-41551,5(DMSO) 0,95-of 1.20 (12H, m, tBu, CH3), 2,75-2,15 (7H, m, CH2 COCH3), 2,42 (1H, m, CH2), 2,77 (1H, m, CH2), 3,50-3,88 (4H, m, CH2, CH), 4,37 (1H, m, CH), 4,55 (1H, m, CH), of 4.67 (1H, d, CH), to 5.58 (1H, d, CH), to 7.09 (1H, m, aryl H), 7,32 (1H, m, aryl H), 7,71 (1H, m, aryl H), compared to 8.26 (1H, m, NH), 8,49 (1H, m, NH), 9,58 (1H, m, NH)
I-42531,6(DMSO) 0,95-of 1.20 (12H, m, tBu, CH3), 1,75-2,17 (10H, m, CH3, SON, CH2), of 2.45 (1H, m, CH2), 2,77 (1H, m, CH2), 3,48-3,91 (4H, m, CH2, CH), or 4.31-4,70 (3H, m, CH), of 5.55 (1H, d, CH),? 7.04 baby mortality (1H, m, aryl H), 7,18 (1H, m, aryl H), 7,41 (1H, m, aryl H), to 8.20 (1H, d, NH), of 8.27 (1H, d, NH), 9,39 (1H, users, NH)

I-43551,4DMSO) was 1.04 (9H, s), 1,12-1,17 (3H, m), 1,78-of 1.95 (4H, m)to 2.06 (3H, s), a 2.45 (1H, DD), of 2.72 (1H, DD), 3,52-3,81 (4H, m), 4,36-4,39 (1H, m), 4,47-of 4.54 (1H, m), with 4.64 (1H, d), 5,54 (1H, DD), 7,33-to 7.35 (1H, m), 7,43-7,46 (1H, m), 7,81 (1H, users), 8,21-of 8.25 (2H, m), 10,23 (1H, users)
I-44535,4(DMSO) of 1.02 (9H, s)to 1.14 (3H, t), 1,78-to 1.98 (4H, m), of 2.08 (3H, s), 2,48 (1H, DD), and 2.79 (1H, DD), 3,51-3,82 (4H, m), 4,36-4,39 (1H, m), 4,49-4,58 (1H, m), 4,71 (1H, d), 5,54 (1H, d), 7,31-7,34 (1H, m), 7,65-7,72 (3H, m), 8,49 (1H, d), 10,38 (1H, s)
I-45521,4(DMSO) of 0.95 (6H, DD), 1,12-of 1.16 (4H, m), 1,72-of 1.97 (4H, m)2,07 (3H, s), 2,48 (1H, DD), by 2.73 (1H, DD), 3,51-3,62 (2H, m), 3,71-a 3.83 (2H, m), 4,35-to 4.38 (1H, m), 4,48-4,59 (2H, m), of 5.53 (1H, d), 7,29-7,31 (1H, m), to 7.59-to 7.67 (2H, m), 8,01-with 8.05 (1H, m), of 8.28 (1H, d), 10,35 (1H, s)
I-46538,5(CDCl3) 1,1-of 1.12 (6H, m), 1,3 (3H, m), 1,4 (6H, d), of 2.0-2.2 (2H, m), of 2.4-2.5 (2H, m), 2,8-2,9 (1H, m), 3,7-of 3.75 (2H, m), 3,9-4,0 (1H, m), 4,6-of 4.75 (3H, m), 4,85-of 4.95 (1H, m), 6,85-6,9 (1H, m), to 6.95 (1H, C), 7,05 and 7.1 (1H, m), 7,4 was 7.45 (1H, m), and 7.8 (1H, d)
I-47to 510.5(CDCl3) to 1.15 (9H, m), 1,25 (3H, t), of 2.0-2.2 (4H, m), of 2.4-2.5 (2H, m), 2,8-2,9 (1H, m), 3,7-of 3.85 (2H, m), 3,9-4,0 (1H, m), 4,05 of 4.1 (1H, m), 4,7-4,8 (1H, m), is 4.85 (1H, d), and 5.5 (1H, m), and 6.5 (1H, d), 6,8 (1H, s), 7,2 (1H, d), and 7.4 (1H, d), 7,55 (1H, d)
I-48538,5(CDCl3) of 1.12 (9H, S)of 1.29 (3H, t), 1,90-of 2.20 (3H, m), 2,36 is 2.43 (2H, m), 2,85 (1H, m), 3,42 (3H, s), 3,68-3,74 (2H, m), 3,91-of 3.95 (2H, m), 4,48 (2H, s), 4,62-of 4.75 (2H, m), the 4.90 (1H, m), vs. 5.47 (1H, m), 7,00 (1H, m,), 7,31 (1H, m), 7,43-rate of 7.54 (2H, m), 7,72 (1H, m)
I-49579,5(CDCl 3) 1,12 (N, C)of 1.28 to 1.31 (N, m), 1,90-of 2.20 (3H, m), 2,36 is 2.43 (2H, m), of 2.54 (1H, m), 2,85 (1H, m), 3,68-and 3.72 (2H, m), 3,91-of 3.95 (2H, m), 4,62-4,69 (2H, m), 4,88 (1H, d), vs. 5.47 (1H, m), 7,14 (1H, d), 7,27 (1H, m), 7,41 (1H, m)to 7.50 (1H, d), 7,78 (1H, d), 7,87 (1H, m)
I-50577,3(DMSO) 1,12-1,16 (7H, m), 1,58-of 1.81 (5H, m), 1,83-of 1.92 (5H, m), 2,04-of 2.08 (4H, m), 2,50 (1H, DD), a 2.75 (1H, DD), 3,57-3,66 (2H, m), 3.72 points-of 3.78 (1H, m), 3,82-3,91 (1H, m), 4,33 is 4.36 (1H, m), 4,46 (1H, t), to 4.52-br4.61 (1H, m)5,54 (1H, d), 7,32 (1H, d), the 7.43 (1H, DD), 7,81 (1H, d), of 8.25 (1H, d), of 8.47 (1H, d), 10,22 (1H, s)

I-51567,4(DMSO) 0,98-1,25 (12H, m, tBu, CH3), 1,78 with 2.14 (4H, m, CH2), 2,44 (1H, m, CH2), 2,78 (1H, m, CH2), 3,50-3,88 (7H, m, CH3, CH2, CH), to 4.38 (1H, m, CH), 4,55 (1H, m, CH), of 4.67 (1H, d, CH), to 5.58 (1H, d, CH), 7,30-7,42 (2H, m, aryl H), 7,60 (1H, users, NH), 8,21 (2H, m, aryl H, NH), 9,99 (1H, users, NH)
I-52586,4(DMSO) 0,95-of 1.24 (12H, m, tBu, CH3), 1.70 to a 2.13 (4H, m, CH2), 2,44 (1H, m, CH2), to 2.75 (1H, m, CH2), 3.45 points-are 3.90 (4H, m, CH2, CH), 4,37 (1H, m, CH), 4,55 (1H, m, CH), 4,70 (1H, d, CH), to 5.57 (1H, d, CH), 6,91 (2H, d, aryl H), 7,O6-7,19 (3H, m, aryl H), 7,30 was 7.45 (3H, m, aryl H), to 8.20 (1H, d, NH), 8,55 (1H, d, NH)
I-53578,5(DMSO) about 0.9-1.0 (6H, m)of 1.18 (3H, t), 1,8-of 2.15 (4H, m), 2,4-2,5 (1H, m), 2,7-2,8 (1H, m), 3,6-of 3.85 (4H, m), 4,4-4,6 (3H, m), of 5.55 (1H, d), 7,05 (1H, d), 7,3-to 7.35 (2H, m), 7,98 (1H, s), and 8.3 (1H, d), to 8.45 (1H, d)and 10.7 (1H, s)
I-54495,0(DMSO) of 0.94-0.98 (6H, m), 1,13-of 1.18 (3H, m), 1,80-2,10 (5H, m)of 2.50 (1H, m), 2,73 (1H, m), to 3.58-3,61 (2H, m), 3,74 (1H, m)of 3.9 (1H, m), of 4.38-to 4.41 (2H, m), 4,60 (1H, m), 5,46 (2H, s)5,54 (1H, m), 6.48 in (1H, m)to 6.80 (1H, m),? 7.04 baby mortality (1H, m), of 8.27 (1H, d), 8,40 (1H, d)
I-55535,0(CDCl3) to 1.25 (3H, t), 1,99 for 2.01 (3H, s), 2,30-2,39 (1H, m), 2,68 (1H, DD), and 2.79 (1H, DD), 3,21-of 3.27 (1H, m), 3,39 (1H, DD), 3,47-3,51 (2H, m), 3,65 of 3.75 (1H, m), 3,88-of 3.94 (1H, m), with 4.64-and 4.68 (1H, m), 4,70-4,78 (1H, m), to 5.56 (1H, d), 7,31-to 7.35 (5H, m), 7,63-the 7.65 (1H, m), of 8.00 (1H, d), 8,76 (1H, d)
I-56545,0(CDCl3) to 1.25 (3H, t), 2,01-2,03 (3H, m), of 2.25 (3H, s), 2,30-is 2.37 (1H, m), 2,65 (1H, DD), 2,80 (1H, DD), 3.27 to to 3.41 (2H, m), 3,47 (1H, DD), 3,65-with 3.79 (2H, m), 3,85 (3H, s), 3,86-are 3.90 (1H, m), with 4.64-of 4.67 (1H, m), 4,71-4,80 (1H, m), 5,18 with 5.22 (1H, m)5,54 (1H, d), 6,83 (1H, d), 6.90 to-6,97 (2H, m), 7,19 (1H, t), 7.24 to 7,28 (1H, m), of 7.90 (1H, d), 8,77 (1H, d)
I-57524,0(CDCl3) of 1.12 (9H, s)is 1.31 (3H, t), 1,93-of 2.20 (3H, m), 2,35 is 2.46 (2H, m), 2,79-of 2.86 (1H, m), 3,65-3,74 (2H, m), a 3.87-of 3.96 (2H, m), of 3.95 (3H, s), 4,65-4,74 (2H, m), 4,89 (1H, d), vs. 5.47 (1H, d), 6,76 (1H, d), 7,03 (1H d), 7,30 (1H, t), of 7.48 (1H, d)

I-58530,4(CDCl3) of 1.10 (9H, s)of 1.28 (3H, t), 1,43-of 1.56 (1H, m), 1,79 is 1.86 (3H, m), 1,99 (1H, userd), to 2.29 (3H, s), 2,30-is 2.37 (1H, m), and 2.83 (1H, DD), to 3.02 (1H, users), 3,66-3,74 (1H, m), a 3.87 (3H, what), 3,88-of 3.94 (1H, m), 4,16 (1H, users), of 4.54 (1H, users), 4,66-4,74 (1H, m), equal to 4.97 (1H, d), 5,46 (1H, d), 6,44 (1H, userd), 6,93 (1H, d), of 7.00 (1H, d), 7,22 (1H, t), 7,78 (1H, userd)
I-59520,5(CDCl3) 1,13 (N, C)of 1.29 (3H, t), 1,76-1,90 (3H, m)2,00 (1H, userd), 2,35 (1H, DD), and 2.83 (1H, DD), 3,66-3,74 (1H, m), a 3.87-of 3.94 (1H, m), 4,15 (1H, s), of 4.54 (1H, users), 4,62-4,78 (1H, m), 4,99 (1H, d), 5,46 (1H, d), 6,92 (1H, userd), 7,33-7,46 (3H, m), 7,69 (1H, userd), to 7.77 (1H, userd)
I-60577,5(CDCl3) of 1.12 (9H, s)of 1.26 to 1.31 (3H, m), USD 1.43-of 1.45 (1H, m)and 1.83 (3H, users), 1,99 (1H, userd), to 2.06 (1H, m), of 2.23 (3H, s), 2,34 (1H, userd), and 2.83 (1H, userd), 3,01 (1H, users), 3,66-3,74 (1H, m), a 3.87-of 3.95 (1H, m), 4,12-4,19 (1H, m,), a 4.53 (1H, users), 4,65 was 4.76 (1H, m), to 4.98 (1H, d), the 5.45 vs. 5.47 (1H, m), was 7.08 (1H, userd), 7,30 (1H, m), 7,37 (1H, userd), 7,73 to 7.75 (1H, m), 7,80-of 7.82 (2H, m)
I-61591,5(CDCl3) to 1.14 (9H, s), 1,22-of 1.30 (6H, m), 1,54-of 1.57 (1H, m), 1.77 in-of 1.85 (3H, m)of 1.97 (1H, d), 2,30 at 2.45 (3H, m), 2,75-2,84 (1H, m)3,00 (1H, s), 3,63-and 3.72 (1H, m), 3,84-3,93 (1H, m), 4,10-4,16 (1H, m), 4,51 (1H, s), with 4.64-4,71 (1H, m), 4,96 (1H, d), the 5.45 (1H, d), 7,05 (1H, d), 7,26 (1H, s), of 7.36 (1H, d), 7,73 (1H, d), 7,80 (1H, d), of 7.82 (1H, s)
I-62605,6(CDCl3) to 1.15 (9H, s), 1,3 (3H, t), of 1.35 (6H, d), 1,4-of 1.55 (3H, m), 1,8-of 1.95 (3H, m), 2,0-2,1 (1H, m), 2,3-2,4 (1H, m), 2,65 is 2.75 (1H, m), 2,8-2,9 (1H, m), 3,05 (1H, s), of 3.7-3.8 (1H, m), 3,9-4,0 (1H, m)and 4.2 (1H, s)4,55 (1H, s), 4,7-4,8 (1H, m), 5,0 (1H, d), and 5.5 (1H, is), of 6.6 (1H, d), 7,3 was 7.45 (2H, m), of 7.75 (1H, d), a 7.85 (1H, s), 8,55 (1H, d)
I-63534,4(CDCl3) 1,13 (N, C)is 1.31 (3H, t), of 1.42 to 1.48 (1H, m), and 1.56 (1H, users), 1,77 of-1.83 (3H, m), 1,99 (1H, userd), 2,35 (1H, DD), and 2.83 (1H, DD), 3,01 (1H, users), 3,67 is 3.76 (1H, m), 3,88-3,99 (4H, m), 4,14 (1H, users), to 4.52 (1H, users), the 4.65-to 4.73 (1H, m)5,00 (1H, DD), vs. 5.47 (1H, d), 7,10-7,21 (2H, m), 7,34-7,39 (1H, m), 7,56-to 7.61 (1H, m), 7,89 (1H, d)

I-64520,5(CDCl3) of 1.03 (3H, d), of 1.10 (3H, d), of 1.32 (3H, t)of 1.50 (1H, m)to 1.59 (1H, m), 1,812-of 1.84 (3H, m), 2,0 (1H, m)to 2.15 (1H, m), a 2.36 (1H, m), and 2.83 (1H, m), to 3.02 (1H, users), of 3.69 (1H, m), 3,90-of 3.95 (4H, m), 4,13 (1H, users), and 4.40 (1H, users), of 4.67 (1H, m), equal to 4.97 (1H, m), vs. 5.47 (1H, d), 7,12-7,21 (2H, m), 7,28 (1H, m), to 7.59 (1H, m), 7,80 (1H, m)
I-65530,9(DMSO) 0,91-2,40 (23H, m), 2.95 and is 3.40 (2H, m), 3,51-3,81 (5H, m), 4,00-4,71 (3H, m), from 5.29 (1H, m), to 6.80 (1H, d), of 7.00 (1H, d), 7,19 (1H, t), 7,94 (1H, d), 8,48 (1H, d)
I-66522,8(DMSO) 0,95-of 1.20 (12H, m), 1,24-of 1.40 (2H, m), 1.41 to to 2.40 (6H, m), 3,05 (1H, m), 3,50-of 3.80 (3H, m), is 4.15 (1H, m), 4,60 (1H, m), 4,70 (1H, d), and 5.30 (1H, s), 7,28-to 7.50 (4H, m), 8,35 (1H, d), 8,48 (1H, d)
I-67577,5(CDCl3) 61,10 (9H, s)of 1.26 and 1.33 (3H, m), USD 1.43-of 1.45 (1H, m), 1,74 of-1.83 (2H, m), a 2.01 (1H, userd), to 2.06 (1H, m), is 2.30 (3H, s), is 2.37 (1H, ush the R.D.), to 2.85 (1H, userd), 2,99 (1H, users), 3,69 is 3.76 (1H, m), 3,89-of 3.97 (1H, m), 4,11-or 4.31 (2H, m), a 4.53 (1H, users), 4,65 was 4.76 (1H, m), of 4.95 (1H, d), the 5.45 vs. 5.47 (1H, m), of 6.75 (1H, userd), to 7.67-of 7.69 (2H, m), 7,78 (1H, users), 7,92 (1H, m), 8,55 (1H, userd)
I-68577,5(CDC13) 1,10 (N, C)of 1.26 and 1.33 (3H, m), USD 1.43-of 1.45 (1H, m), 1,74 of-1.83 (2H, m), a 2.01 (1H, userd), to 2.06 (1H, m), is 2.30 (3H, s), is 2.37 (1H, userd), 2,85 (1H, userd), 2,99 (1H, users), 3,69 is 3.76 (1H, m), 3,89-of 3.97 (1H, m), 4,11-or 4.31 (2H, m), a 4.53 (1H, users), 4,65 was 4.76 (1H, m), of 4.95 (1H, d), the 5.45 vs. 5.47 (1H, m), of 6.75 (1H, userd), to 7.67-of 7.69 (2H, m), 7,78 (1H, users), 7,92 (1H, m), 8,55 (1H, userd)
I-69591,5(CDC13) OF 1.10 (9H, s)of 1.26 and 1.33 (6H, m), 1,42 is 1.16 (1H, m), 1,55 of-1.83 (4H, m), a 2.01 (1H, userd), a 2.36 (1H, DD), of 2.53 (2H, q), and 2.83 (1H, DD), 2,99 (1H, users), 3,69 is 3.76 (1H, m), 3,89-of 3.96 (1H, m), 4,11 (1H, s), a 4.53 (1H, users), 4,66-of 4.77 (1H, m), of 4.95 (1H, d), of 5.48 (1H, d), 6,76 (1H, d), to 7.67-7,74 (2H, m), 8,80 (1H, s), of 7.90 (1H, d), 8,58 (1H, d)

I-70537,4(CDC13) OF 1.12 (9H, s), 1,23-of 1.30 (3H, m), 1,36-of 1.41 (1H, m), 1,73-of 1.84 (3H, m), 1,98-2,03 (1H, m), 2,33-to 2.41 (1H, m), 2,75-and 2.83 (1H, m), 2,96 (1H, users), 3,65-to 3.73 (1H, m), 3,84-3,93 (1H, m), 4,11 (1H, users), 4,56 (1H, C)4,63-4,71 (1H, m), 4,96-4,99 (1H, m), 5,43-5,46 (1H, m), of 7.64-7,72 (2H, m), 7,79-7,87 (3H, m), 8,48-charged 8.52 (1H, m), of 8.90 (1H, userd), of 9.51 (1H, d)
I-71535,6(CDCl3) of 1.09 (9H, s)of 1.32 (3H, t), 1.41 to 1,71 (5H, m), 1,6-to 1.87 (3H, m)2,00 (1H, userd), is 2.37 (1H, DD), and 2.83 (1H, DD), 2,98 (1H, users), 3,68-of 3.77 (1H, m), 3,89-of 3.97 (1H, m), 4,11 (1H, s), of 4.54 (1H, users), 4,67-4,74 (1H, m), of 4.95 (1H, d), of 5.48 (1H, d), only 6.64 (1H, userd), is 6.78 (1H, d), rate of 7.54 (1H, DD), 7,71 (1H, userd), 7,78 (1H, d)
I-72521,5(CDCl3) of 1.05 (3H, d)and 1.15 (3H, d), of 1.35 (3H, t), a 1.5-1.6 (1H, m), 1.6 to 1.7 (1H, m), 1,8-1,9 (2H, s), a 2.0 is 2.05 (1H, m), 2,15 was 2.25 (1H, m), 2,35 at 2.45 (1H, m), 2,8-2,9 (1H, m), 2,95 (1H, s), of 3.7-3.8 (1H, m), 3,9-4,0 (1H, m), 4,1 (1H, s), of 4.45 (3H, s), 4,7-4,8 (1H, m), 4,9-of 4.95 (1H, m), of 5.55 (1H, d), 6,7 (1H, d), 6,85 (1H, d), the 7.65 (1H, d), of 7.75 (1H, d), of 7.82 (1H, s)
I-73537,4(CDCl3) to 1.14 (9H, s), 1,25 (3H, t), 1,40-of 1.46 (1H, m), 1.77 in-1,89 (3H, m), 1,98-2,02 (1H, m), 2,34 (1H, DD), 2,99 was 3.05 (1H, m), 3,62 at 3.69 (1H, m), 3,83-3,91 (1H, m), 4,12 (1H, s), 4,29-4,34 (1H, m), 4,59 (1H, s), 4,99 (1H, d), 5,38 (1H, s), to 7.67-7,76 (2H, m), 7,86 (2H, DD), 8,13 (1H, d), 8,56 (1H, d), 8,96 (1H, d), of 9.56 (1H, d)

Example II-1

(S,S,S)-(3S)-[{1-[(2S)-(3-Methoxy-2-methylbenzylamino)-3-methyl-butyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

The way I

[(2R)-Ethoxy-5-oxitetraciclina-(3S)-yl]amide (S,S,S,R)-1-[(2S)-(3-methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carboxylic acid (97,6 mg, 0.20 mmol) dissolved in a mixture of 2M HCl (2 ml) and MeCN (2 ml). The reaction mixture was stirred at room temperature for 2.5 hours. The resulting crude mixture was diluted with EtOAc and washed with water. The aqueous layer was twice EXT Airout EtOAc. The combined organic extracts washed with saturated salt solution, dried over magnesium sulfate, filtered and concentratedin the vacuum. The residue is evaporated together with DCM/petroleum ether, getting mentioned in the title compound as a white solid (81,3 mg, 88% yield).

Compounds of the formulaII-2-II-61obtained by methods essentially similar to the methods described in exampleII-1.

Example II-2

(S,S,S)-(3S)-({1-[(2S)-(2-Chlorobenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-3

(S,S,S)-(3S)-({1-[3-Methyl-(2S)-(2-methylbenzylamino)butyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-4

(S,S,S)-(3S)-({1-[(2S)-(2-Methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-5

(S,S,S)-(3S)-({1-[3-Methyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-6

(S,S,S)-(3S)-({1-[(2S)-(3-Hydroxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-7

(S,S,S)-(3S)-({1-[(2S)-(3-Amino-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-arbonyl}amino)-4-oxomalonate acid

Example II-8

(S,S,S)-(3S)-({1-[(2S)-(2,3-Dichloraniline)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-9

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-triphtalocyaninine)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-10

(S,S,S)-(3S)-({1-[(2S)-(3-Chloro-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-11

(S,S,S)-(3S)-({1-[(2S)-(2,4-Dichloraniline)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-12

(S,S,S)-(3S)-({1-[(2S)-({1-[(2S)-(2,5-Dichloraniline)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-13

(S,S,S)-(3S)-({1-[(2S)-(2,6-Dichloraniline)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-14

(S,S,S)-(3S)-({1-[(2S)-(2,6-Methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-15

(S,S,S)-(3S)-[(1-{3-Methyl-(2S)-[(2-methylpyridin-3-carbonyl)amino]butyryl}pyrrolidin-(2S)-carbonyl)amino]-4-oxomalonate acid

img src="https://img.russianpatents.com/1047/10478392-s.jpg" height="25" width="48" />

Example II-16

(S,S,S)-(3S)-[(1-{3-Methyl-(2S)-[(4-methylpyridin-3-carbonyl)amino]butyryl}pyrrolidin-(2S)-carbonyl)amino]-4-oxomalonate acid

Example II-17

(S,S,S)-(3S)-[(1-{3-Methyl-(2S)-[(3-methylthiophene-2-carbonyl)amino]butyryl}pyrrolidin-(2S)-carbonyl)amino]-4-oxomalonate acid

Example II-18

(S,S,S)-(3S)-[(1-{(2S)-[(2,3-Dichloropyridine-4-carbonyl)amino]-3-methylbutyryl}pyrrolidin-(2S)-carbonyl)amino]-4-oxomalonate acid

Example II-19

(S,S,S)-(3S)-[(1-{(2S)-[(3,5-Dichloropyridine-4-carbonyl)amino]-3-methylbutyryl}pyrrolidin-(2S)-carbonyl)amino]-4-oxomalonate acid

Example II-20

(S,S,S)-(3S)-({1-[(2S)-(3-Methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-21

(S,S,S)-4-Oxo-(3S)-({1-[4,4,4-Cryptor-(2S)-(2-methyl-3-methoxybenzylamine)butyryl]pyrrolidin-(2S)-carbonyl)amino)-butyric acid

Example II-22

(S,S,S)-(3S)-({1-[(2S)-(5-Methoxy-2-methylbenzylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl)amino)-4-oxomalonate acid

Example II-23

(S,S,S)-(3S)-({1-[(2S)-(3-Methoxy-2-methylbenzylamino)-3-thiazol-4-ylpropionic]pyrrolidin-(2S)-carbonyl}amino)-4-kamakana acid

Example II-24

(S,S,S)-(3S)-({1-[(2S)-(2-Chlorobenzylamino)-4,4,4-tripcomputer]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-25

(S,S,S)-(3S)-({1-[(2S)-(2-Chlorobenzylamino)-3-thiazol-4-ylpropionic]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-26

(S,S,S)-(3S)-({1-[3,3-Dimethyl-(2S)-(2-methylbenzylamino)butyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-27

(S,S,S)-(3S)-({1-[3-Methyl-(2S)-(2-triphtalocyaninine)-butyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-28

(S,S,S)-(3S)-({1-[(2S)-(2-Chlorobenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-29

(S,S,S)-(3S)-({1-[3,3-Dimethyl-(2S)-(2-triphtalocyaninine)butyryl]pyrrolidin-(2S)-

carbonyl}amino)-4-oxomalonate acid

Example II-30

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-methoxybenzylamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-31

(S,S,S)-(3S)-({1-[(2S)-(2-Fluoro-3-methoxybenzylamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-exomala the traveler acid

Example II-32

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-triphtalocyaninine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-33

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-cyclopropylacetylene)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-34

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-methylbenzylamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-35

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-36

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-ethylbenzylamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-37

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-methoxybenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-38

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-cyclopropylacetylene)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-39

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-hydroxyethylamino)-3,3-dimethyl the tiril]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-40

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-acetamidobenzoyl)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-41

(S,S,S)-(3S)-(1-[(2S)-(2-Chloro-3-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-42

(S,S,S)-(3S)-({1-[(2S)-(2-Methyl-3-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-43

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-44

(S,S,S)-(3S)-({1-[(2S)-(2-Fluoro-4-acetamidobenzoyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-45

(S,S,S)-(3S)-({1-[(2S)-(2-Fluoro-4-acetamidobenzoyl)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-46

(S,S,S)-(3S)-((1-[(S)-(2-Chloro-4-isopropylbenzylamine)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-47

(S,S,S)-(3S)-({1-[(S)-(2-Chloro-4-hydroxyethylamino)-3,3-dimethylbutyryl]irreligion-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-48

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-ethoxymethyleneamino)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-49

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-isobutylacetophenone)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-50

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-acetamidobenzoyl)-3-cyclohexyl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-51

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-4-methoxycarbonylaminophenyl)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-52

(S,S,S)-(3S)-({1-[(2S)-(2-Chloro-3-phenoxybenzamine)-3,3-dimethylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-53

(S,S,S)-(3S)-((1-[(2S)-(2-Chloro-6-aminobenzoylamino)-3-methylbutyryl]pyrrolidin-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-54

(S,S,S)-(3S)-({1-[(2S)-(2-Chlorobenzylamino)-3,3-dimethylbutyryl]piperidine-(2S)-carbonyl}amino)-4-oxomalonate acid

Example II-55

(3S)-({2-[(2S)-(3-Methoxy-2-methylbenzylamino)-3,3-dimethylbutyryl]-2-(1S,R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-56

(3S)-({2-[(2S)-(2-Chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-57

(3S)-({2-[(2S)-(4-Acetylamino-2-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-58

(3S)-({2-[(2S)-(2-Chloro-4-propionylcarnitine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-59

(3S)-({2-[(2S)-(2-Chloro-3-isobutyleneisoprene)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-60

(3S)-({2-[(2S)-(2-Fluoro-3-methoxybenzylamine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-61

(3S)-({2-[(2S)-(2-Fluoro-3-methoxybenzylamine)-3-methylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-62

(3S)-({2-[(2S)-(4-Acetylamino-3-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-63

(3S)-({2-[(2S)-(3-Chloro-4-propionylcarnitine)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-64

(3S)-({2-[(2S)-(Isoquinoline-1-ylcarbonyl)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-65

(3S)-({2-[(2S)-(4-Amino-3-chlorobenzylamino)-3,3-dimethylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Example II-66

(3S)-({2-[(2S)-(4-Amino-3-chlorobenzylamino)-3-methylbutyryl]-2-(1S,4R)-azabicyclo[2.2.1]heptane-(3S)-carbonyl}amino)-4-oxomalonate acid

Identification data connectionII-1-II-66summarized in the following table 4 and include data for HPLC, LC/MS (experimental) and1H-NMR data.1H-NMR data were obtained at 400 MHz and corresponds to the structure.

Table 4
Identification data of selected compounds of formula II
(connection number)
No.M+1
(the experts.)
1H NMR
II-l462, (DMSO-d6) 0,82-and 0.98 (6H, m), 1,89-2,07 (5H, m), 2,10 (3H, s), and 3.0 (1H, m), 3,63 (1H, m), with 3.79 (3H, s), 3,88 (1H, m)4,00 (1H, m), 4,25 (1H, m), 4,40-of 4.44 (2H, m), the 5.45 (1H, users), 6,83 (1H, d), of 7.00 (1H, d), 7,19 (1H, t), to 7.77 (1H, users), 8,32-of 8.50 (2H, m)
II-2452,0(DMSO-d6) 0,95-0,99 (6H, m), 1,87-2,09 (5H, m)of 3.00 (1H, m)to 3.64 (1H, m), 3,85 (1H, m), Android 4.04 (1H, m), 4,25 (1H, m), and 4.40 (1H, m), 4,47 (1H, m), the 5.45 (1H, m), 7,34-7,49 (4H, m), 7,78 (1H, m), 8,40 (1H, m)8,64 (1H, m)
II-3432,1(DMSO-d6) 0,94 is 0.99 (6H, m), 1,87-2,09 (5H, m), is 2.30 (3H, s), 2,90 (1H, m)to 3.64 (1H, m), 3,88 (1H, m), a 4.03 (1H, m), 4,30,(1H, m), of 4.44 (1H, m), the 5.45 (1H, m), 7,19-7,33 (4H, m), to 7.77 (1H, users), 8,35-to 8.40 (2H, m)
II-4448,0(CD3OD) of 1.05-of 1.18 (6H, m), 2,00-2,30 (5H, m), 2,52 is 2.75 (2H, m), 3,66-a 3.83 (1H, m), 3,92-a 4.03 (1H, m), 4.26 deaths is 4.35 (1H, m), 4,45-4,55 (1H, m), br4.61-4,70 (1H, m), 4,78-is 4.85 (1H, m), 7,13 (1H, t), 7,21 (1H, d), EUR 7.57 (1H t), of 8.00 (1H, d), 8,69 (1H, d)
II-5502,0(CD3OD) 0,98-of 1.15 (6H, m), 1,95-of 2.26 (5H, m), 2,54 was 2.76 (2H, m), of 3.73-a-3.84 (1H, m), 3,99-4,06 (1H, m), 4,21-4,32 (1H, m), 4,45-a 4.53 (1H, m), 4,60-4,70 (2H, m), 7,30-4,47 (2H, m), 7,54-to 7.64 (2H, m)
II-6448,1(DMSO-d6) 0,92-and 0.98 (6H, m), 1.85 to 2,04 (5H, m)2,07 (3H, s)of 3.00 (1H, m), 3,63 (1H, m), a 3.87 (1H, m), a 4.03 (1H, m), 4,25 (1H, m)to 4.41 (1H, m), the 5.45 (1H, m), of 6.68 (1H, m), PC 6.82 (1H, m), 7,01 (1H, m), 7,81 (1H, m), of 8.25 (1H, d), 8,40 (1H, m), and 9.5 (1H, m)
II-7447,0(CD3OD) of 1.02-of 1.18 (6H, m), 1,88-of 2.28 (5H, m), 2,39 (3H, s), 2,50-2,78 (2H, m), 3.75 to a 3.83 (1H, m), 4,00-4,10 (1H, m), 4,21-4,32 (1H, m), 4,45-to 4.52 (1H, m), 4,60 with 4.65 (2H, m), 7,39-rate of 7.54 (3H, m)
II-8446,0(DMSO-d6) 0,94 is 0.99 (6H, m), 1,71-2,12 (4H, m), 2,33 (1H, users), to 2.67 (1H, users), 2,94-of 3.07 (1H, m), 3,61 at 3.69 (1H, m), 3,82-a 3.87 (1H, m), a 4.03-4,10 (1H, m), 4,19-to 4.28 (1H, m), 4,30-4,43 (2H, m), 5,42-vs. 5.47 (1H, m), 7,28-7,30 (1H, m), 7,37-7,40 (1H, m), 7.68 per-of 7.82 (2H, m), 8,77 (1H, d)
II-9519,9(DMSO-d6) 0,94 is 0.99 (6H, m), 1,86-2,09 (5H, m)of 3.00 (1H, m), the 3.65 (1H, m), a-3.84 (1H, m), of 4.05 (1H, m), 4,24 (1H, m), and 4.40 (1H, m), 4,51 (1H, m), the 5.45 (1H, m), EUR 7.57 to 7.62 (2H, m), to 7.77 (1H, d), of 7.90 (1H, m), 8,40 (1H, d), 8,87 (1H, d)
II-10466,0(DMSO-d6) 0,93 is 0.99 (6H, 2 × d), 1,77-2,19 (5H, m)to 2.29 (3H, s), 2,97 (1H, users), 3,62-the 3.65 (1H, m), 3,85-3,88 (1H, m), 4,00-4,32 (2H, osirm), to 4.41-a 4.53 (2H, m), the 5.45 (1H, users), 7,18-7,27 (2H, m), 7,45 is 7.50 (1H, m), a 7.85 (1H, userd), to 8.41 (1H, userd), to 8.57 (1H, d)
II-11485,9(DMSO-d6) 0,82 is 0.86 (3H, m), 0,93-0,98 (3H, m), 1,87-of 2.08 (5H, m)of 3.00 (1H, m)to 3.64 (1H, m), 3,82 (1H, m), 4,10 (1H, m), 4,30 (1H, m), of 4.45 (1H, m), 4,47 (1H, m), 5,44 (1H, d), 7,37 (1H, m), 7,47 (1H, m), 7,65 (1H, m), to 7.77 (1H, m), 8,40 (1H, m), 8,72 (1H, m)/td>
II-12485,9(DMSO-d6) 0,94 is 0.99 (6H, m), 1.91 a-2,09 (5H, m)of 3.00 (1H, m)to 3.64 (1H, m), 3,83 (1H, m), a 4.03 (1H, m), 4,20 (1H, m), and 4.40 (1H, m), 4,47 (1H, m), the 5.45 (1H, m), 7,37 (1H, s), 7,50-7,52 (2H, m), 7,78 (1H, m), 8,44 (1H, m), 8,79 (1H, m)
II-13486,3(DMSO-d6) 0,82 is 0.86 (3H, m), 0,92 is 0.99 (3H, m), 1,80-to 1.87 (2H, m), 1,99-2,02 (4H, m), 2,48 (0.5 H, m), 2.95 points (0.5 H, m), 3,51 (1H, m), 3,80-4,56 (4H, m), 5,00 and 5.47 (1H, 2 × m), 7,37-of 7.48 (3H, m), 7,76-8,32 (1H, m), 8,95-9,39 (1H, 3 × DD)
II-14446,0(DMSO-d6) 0,93 is 0.99 (6H, m), 1,80-2,09 (5H, m), 2,17 (6H, d), 2,95 (1H, users), 3,63-the 3.65 (1H, m), 3.96 points-to 3.99 (1H, m), 4,10 (1H, users), 4,30 (1H, users), of 4.44 (1H, t), of 5.48 (1H, users), of 7.00 (2H, d), 7,14 (1H, t), 7,78 (1H, users), and 8.50 (1H, users), 8,55 (1H, d)
II-15433,1(DMSO-d6) 0,91-of 1.02 (6H, m), 1,80-2,20 (5H, m), 2,66 of 2.68 (3H, s)of 3.00 (1H, m), 3,62-of 3.85 (3H, m, 4,10 (1H, m), 4,24 (1H, m), 4,51 (1H, m), 5,72 (1H, m), 7,73-7,76 (2H, m), 8,19 (1H, m), charged 8.52 (1H, m), is 8.75 (1H, d), of 8.90 (1H, m)
II-16433,1(DMSO-d6) 0,9-1,05 (6H, m), 1.8-to 2.2 (6H, m), 2,3-2,4 (1H, m), 2,7-of 2.75 (1H, m), of 2.9-3.0 (1H, m), 3,65 of 3.75 (1H, m), 3,8-3,9 (1H, m), 4,1-to 4.15 (1H, m), a 4.3 and 4.4 (1H, m), 4,45 with 4.65 (1H, m), 7,8-7,9 (1H, m), of 8.7 to 8.8 (2H, d), 8,9,8,95 (1H, m)
II-17438,0 (DMSO-d6) 0,83 is 0.99 (6H, m), 1,80-2,20 (5H, m), is 2.40 (3H, s)of 3.00 (1H, m), 3,61 (1H, m), 3,81 (1H, m), 4,10 (1H, m), 4,25 (1H, m), 4,42-to 4.46 (2H, m), 5,44 (1H, users), 6,97 (1H, m), 7,34 (1H, m), to 7.59 (1H, m), 7,81 (1H, m), 8,49 (1H, m)
II-18487,0(DMSO-d6) of 0.92 to 1.00 (6H, m), 1,75-of 2.08 (5H, m), 2,30-of 2.34 (1H, m)to 2.99 (1H, DD), 3,62-to 3.67 (1H, m), 3,78-3,82 (1H, m), 3,78-3,82 (1H, m), of 4.05-4.26 deaths (1H, m), of 4.38-of 4.54 (2H, m), 5,44-5,72 (1H, m), 7,37-7,41 (1H, m), to 8.41-8,43 (2H, m), 8,97-9,00 (1H, d)
II-19487,0(DMSO-d6) 0,94-1,00 (6H, m), 1.77 in-of 2.15 (5H, m), to 3.02 (1H, DD), 3,61-3,70 (1H, m), 3,80-are 3.90 (1H, m), a 4.03-4,08 (1H, m), to 4.52-4,56 (1H, m), of 4.95 (2H, users), the 5.45 (1H, s), 8,42 (1H, d), 8,67 (2H, s), 9,17 (1H, d)
II-20476,4(DMSO-d6) 0,91-1,11 (9H, m), 1.70 to 2,14 (7H, m), 2,31 (1H, m), 3,01 (1H, m), 3,50-3,97 (5H, m), 4,00-to 4.62 (3H, m), of 5.50 (1H, m), 6,77 (1H, d), of 7.00 (1H, d), 7,18 (1H, DD), 7,50-of 8.50 (3H, m)
II-21502,1(DMSO-d6) 1,80-2,00 (3H, m), 2,11 (4H, preryvayuscheesya C and m)2,60 is 2.80 (2H, m), 3,64 at 3.69 (1H, m), of 3.80 (3H, s), 4,10 (1H, users), 4,30 (1H, users), 5,00 (1H, m)6,86 (1H, d), 7,03 (1H, d), 7,22 (1H, t), to 8.45 (1H, users), 8,81 (1H, d)
II-22462,4(DMSO-d6) of 0.93 to 1.00 (6H, m), 1.70 to to 2.15 (5H, m), 2,22 (3H, s), 2,33 (1H, d), 2,99 (1H, DD), 3,60-the 3.65 (2H, m), 3,74 (3H, s), 4.04 the-4,08 (1H, m), 4,21-4,27 (1H, m), 4,40-4,58 (2H, m), 5,46 1H, userid), 6,78-for 6.81 (1H, m), 6,85-6,91 (1H, m), 7,09-7,14 (1H, m), of 8.37 (2H, 2 × userid)
II-23517,0(DMSO-d6) 1,77-2,19 (5H, m), 2.95 and of 3.28 (3H, m), 3,60 (1H, userd), 3,71-of 3.78 (4H, m), 4,10-4,42 (6H, m), equal to 4.97 (1H, users), the 5.45 72 (1H, m), 6,74 (1H, d), 6,97 (1H, d), 7,10-7,22 (1H, m), 7,44 (1H, m), of 8.37-8,68 (2H, m), 9,05 (1H, users)
II-24492,0(DMSO-d6) a 1.75-to 1.98 (3H, m), of 2.08 and 2.13 (1H, m), 2,64-2,77 (2H, m), 2,99 (0,5H, DD), 3,63-to 3.73 (2H, m), 4,08 (0,5H, ushort), 4,20 (0,5H, DD), 4,23-4,49 (3 multiplets, 1H total), 5,00-5,10 (1H, m), 5,42 (0,5H, C)of 7.36-7,52 (4H, m), to 7.77 (1H, m), 8.30 to (0,5H, d), which is 9.09 (1H, d)
II-25507,0(DMSO-d6) 1,79 is 1.96 (5H, m), 2,94 of 3.28 (3H, m)to 3.58 (1H, userd), to 3.73 (1H, userd), Android 4.04-4,59 (2H, m), 4,98-5,02 (1H, m), 5,54-5,74 (2H, m), 7,26-7,46 (5H, m), 8,43 (1H, d), 8,82 (1H, d), 9,39 (1H, users)
II-26446,6(DMSO-d6) of 1.05 (9H, s)and 1.15 (3H, t), 1,8-2,1 (4H, m), 2,3 (3H, s), 2,4-2,5 (1H, m), of 2.9-3.0 (1H, m), 3,7-of 3.75 (1H, m), 3,8-of 3.85 (1H, m), 4,1-4,15 (0,5H, m), 4,25 of 4.3 (1H, m), 4.4 to 4.5 (0,5H, m), 4,7-of 4.75 (1H, m), 5,55-5,6 (1H, m), 7,2-7,4 (4H, m), 7,7-of 7.75 (1H, m), 8,1-of 8.15 (1H, m), 8,35 an 8.4 (1H, m)
II-27486,5(DMSO-d6) 0,95-1,05 (6H, m), 1,8-2,1 (4H, m), 2,4-2,5 (1H, m), 3,0-3,1 (1H, m), 3,7-of 3.75 (1H, m), 3,8-of 3.85 (1H, m), 4,1-4,15 (0,5H, m), 4,25 of 4.3 (1H, m), 4.4 to 4.5 (0,5H, m), 5,555,6 (1H, m), 7,4 was 7.45 (1H, m), of 7.6 to 7.8 (3H, m), 8,4-to 8.45 (1H, m), 8,75 was 8.8 (1H, m)
II-28466,1(CDCl3) 1,11-of 1.16 (9H, m), 1,94-2,22 (4H, m), 2,38-of 2.50 (2H, m), 2.77-to 2,87 (1H, m), 3,71-with 3.79 (1H, m), 3.96 points-4,06 (1H, m), 4,56-of 4.67 (2H, m), 4,85-4,91 (1H, m), 6,99-7,02 (1H, m), 7,28 was 7.45 (3H, m), 7,60-to 7.84 (2H, m)
II-29500,2(CDCl3) of 1.07 (9H, s), 1.85 to 2,19 (2H, m), 2,37-to 2.40 (2H, m), 2,81-of 3.07 (1H, m), 3,37 (1H, users), to 4.01 (1H, users), 4,46-of 4.67 (2H, m), to 4.87 (1H, d), 5,73 (1H, users), of 6.68 (1H, users), 7,38-7,74 (5H, m)
II-30496,2(CD3OD) to 1.15 (9H, s), 1.85 to of 2.20 (4H, m), 2,46-of 2.72 (2H, m), 3,74-3,81 (1H, m)to 3.92 (3H, s), 3,93-a 4.03 (1H, m), 4,20-or 4.31 (1H, m), 4,45-to 4.52 (1H, m), 4,60-of 4.75 (1H, m), a 4.83 (1H, s), 7,00 (1H, d), to 7.15 (1H, d), 7,33 (1H, t)
II-31480,5(DMSO-d6) of 1.05 (9H, s), 1,8-2,1 (4H, m), 2,4-2,5 (1H, m), of 3.75 to 3.8 (1H, m), 3,8-of 3.85 (1H, m)of 3.9 (3H, s), 4,1-4,3 (1H, m), 4,7 (1H, d), 5,3-5,5 (0,5H, users), 7,1-7,3 (3H, m), 7,7-7,8 (1H, m), with 8.0 and 8.1 (1H, m), 8,35-to 8.45 (1H, m)
II-32550,3(DMSO-d6) 0,91-of 1.10 (9H, m), 1.70 to to 2.15 (5H, m), 2,60-is 3.08 (1H, m), 3,60-are 3.90 (2H, m), 3,98-4,71 (3H, m), 5.40 to-5,80 (1H, m), 7,30-to $ 7.91 (3H, m), 8.30 to-8,80 (3H, m)
II-33523,3(DMSO) 0,60-0,90 (4H, m, cyclopropyl CH2), of 0.92 to 1.0 (9H, m, tBu), 1,71-of 2.21 (5H, m, CH2), 2,65-3,10 (1H, users, CH2), 3,36-3,50 (1H, m, CH), 3,60-4,75 (6H, m, CH), 6,92 (1H, m, aryl H), of 7.36 (1H, m, aryl H), was 7.45 (1H, m, aryl H), 7,65 at 8.60 (3H, m, NH, OH)
II-34480,3(DMSO) 0,99-of 1.10 (9H, m, tBu), 1.70 to a 2.12 (5H, m, CH2), to 2.35 (3H, s, CH3), 2,60-is 3.08 (1H, m, CH2), to 3.58-a 3.87 (2H, m, CH), 4,00-4,70 (3H, m, CH), 5,38-5,79 (1H, m, CH), 7,12 (1H, m, aryl H), from 7.24 (1H, m, aryl H), 7,38 (1H, m, aryl H), 7,69-8,55 (3H, m, NH, OH)
II-35482(CD3OD) 1,01-of 1.15 (6H, m), 1,95-2,22 (5H, m), 2,48-2,69 (2H, m), of 3.73-of 3.80 (1H, m), 4.92 in (3H, s), 3,99-4,19 (1H, m), 4,20-4,30 (1H, m), 4,58-of 4.67 (2H, m), 7,00 (1H, d), 7,14 (1H, d), 7,31 (1H, t)
II-36494,4(DMSO) 0,94-a 1.08 (9H,s, tBu), to 1.19 (3H, t, CH3), 1.70 to 2,40 (5H, m, CH2), 2,60-is 3.08 (3H, m, CH2), of 3.69 (1H, m, CH), 3,81 (1H, m, CH), 4.04 the-4,71 (3H, m, CH), 5.40 to-5,80 (1H, m, CH), 7,14 (1H, m, aryl H), 7,31 (1H, m,, aryl H), 7,39 (1H, m, aryl H), 7,70-of 8.50 (3H, m, NH, OH)
II-37482,5(DMSO) about 0.9-1.0 (6H, m), 1.85 to-2,3 (4H, m), 3,0-3,1 (1H, m), the 3.65 to 3.7 (1H, m), of 3.78 (3H, s), 3,8-of 3.85 (1H, m), 4,1-4,15 (0,5H, m), 4,25-4,3 (0,5H, m), 4,5-4,55 (1H, m), 5,5-of 5.55 (1H, m), 6,93 (1H, d), 6,98 (1H, s), 7,35 (1H, d), of 7.75 one-7.8 (1H, m), to 8.45 (1H, d)
II-38536(CD3OD) 0,34-0,40 (2H, m), 0.60 and of 0.67 (2H, m), 1,16 (N, C), 1,25-1,32 (1H, m), 1.93 and-2,22 (4H, m), 2,50-of 2.66 (2H, m), 3,74-a-3.84 (1H, m), 3,91-a 4.03 (3H, m), 4,22-4,32 (1H, m), 4,45-of 4.54 (1H, m), br4.61-4,69 (1, m)4,82 (1H, d), of 6.99 (1H, d), 7,12 (1H, d), 7,32 (1H, t), of 8.40 (1H, d)
II-39482(CD3OD) of 1.12 (9H, s), 1,90-2,22 (4H, m), 2,512,70 (2H, m), 3.75 to a 3.83 (1H, m), 3,97-of 4.05 (1H, m), 4,23-4,30 (1H, m), 4,46-of 4.54 (1H, m), 4.63 to-4,70 (1H, m), a 4.83 (1H, d), 6,91 (1H, d), of 6.99 (1H, d), 7,17 (1H,t), at 8.36 (1H, d)
II-40509,3(DMSO) 0,93-0,98 (6H, m) 1,71-2,09 (10H, m), 2,35 at 2.45 (2H, m), 3,61-of 3.64 (1H, m), as 4.02-Android 4.04 (1H, m), 4,06 is 4.35 (2H, m), 4,43-to 4.46 (1H, m), 7,33 (1H, d), 7,43-7,46 (1H, m), 7,80 (1H, userd)8,28-8,49 (2H, m), of 10.25 (1H, users)
II-41523,3(DMSO) 0,95-a 1.08 (9H, s, tBu), 1,70-of 2.38 (8H, m, SON, CH2), 2,58-is 3.08 (1H, m, CH2), of 3.65 (1H, m, CH), 3,82 (1H, m, CHO), 3.95 to 4,69 (3H, m, CH), 5.40 to-ceiling of 5.60 (1H, m, CH), to 7.09 (1H, m, aryl H), 7,31 (1H, m, aryl H), of 7.64-at 8.60 (4H, m, aryl H, NH), of 9.55 (1H, m, CH)
II-42503,4(DMSO) 0,91-a 1.08 (9H, s, tBu), 1.70 to to 2.40 (11H, m, CH3, SON, CH2), 2,60-is 3.08 (1H, m, CH2), 3,66 (1H, m, CH), a 3.87 (1H, m, CH), 4,00 with 4.65 (3H, m, CH), 5.40 to-5,78 (1H, m, CH),? 7.04 baby mortality (1H, m, aryl H), 7,18 (1H, m, aryl H), 7,38 (1H, m, aryl H), 7,65-7,88 (1H, m, NH), 8.07-a to 8.70 (2H, m, NH), 9,34 (1H, m, CH)
II-43523,3(DMSO) of 1.03 (9H, s), 1,71 is 2.00 (3H, m)2,07 (3H, s), 2,55-by 2.73 (1H, m), of 2.97 (1H, DD), 3,60-to 3.67 (1H, m), 3.75 to 3,82 (1H, m), 3,98-Android 4.04 (1H, m), 4,19-4,24 (1H, m), 4,37 is 4.45 (1H, m), 4,63 (1H, d), the 5.45 (1H, d), 7,33-to 7.35 (1H, m), 7,43 was 7.45 (1H, d), 7,76-7,83 (2H, m), 8,25-of 8.28 (1H, m), to 8.41-8,58(1H, m), 10,27 (1H, s)
II-44507,4(DMSO) of 1.01 (9H, 2 × s), 1,72 of 1.99 (4H, m), 2.05 is-is 2.09 (4H, m), 2,35-to 2.57 (2H, m), 2.71 to to 3.00 (1H, userd m), 3,60-the 3.65 (1H, m), 3,71-of 3.80 (1H, m), 4,08-4,37 (2H, userd m), 4,70 (1H, d), 7,32 (1H, DD), 7,65-7,80 (3H, m), 8,33-charged 8.52 (1H, userd m), 10,37 (1H, s)
II-45493,4(DMSO) to 0.94 (6H, DD), 1,72-1,99 (10H, m), a 2.36-2,52 (2H, m), 3,57-3,68 (1H, m), 3,76-3,88 (1H, m), 4,20-4,43 (2H, m), 4,51-4,55 (1H, m), 7,30 (1H, DD), 7,58-to 7.77 (3H, m), 8,00-of 8.04 (1H, m), 10,34 (1H, s)
II-46to 510.5(DMSO) 0,95-1,0 (6H, m), 1,25 (6H, m), 1.85 to about 2.2 (4H, m), 3,0-3,1 (1H, m), 3,9-4,0 (3H, m), 4,2-4,3 (0,5H, m), 4.4 to 4.5 (0,5H, m), 4,7-4,8 (1H, m), 6,9-to 6.95 (1H, d), of 6.99 (1H, s), and 7.3 (1H, d), 8,3 an 8.4 (1H, m)
II-47482,5(DMSO) of 1.05 (9H, m), 1,8-2,1 (4H, m), 2,6-2,7 (1H, m), of 2.9-3.0 (2H, m), 3,6-3,7 (2H, m), 3,8-3,9 (1H, m), 4,0-4,1 (1H, m), 4,2-4,3 (1H, m), 4,6-the 4.65 (1H, m), 5,5-of 5.55 (1H, m), 6.75 in-6,85 (2H, m), to 7.35 (1H, d), of 7.75 (1H, d), with 8.0 and 8.1 (1H, m), 8,35 (1H, m), of 10.25 (1H, s)
II-48to 510.5(DMSO) of 1.03 (9H, s), 1,80-2,10 (4H, m)of 3.00 (1H, users), 3,30 (3H, s), 3,66 (1H, m), 3,81 (1H, m)4,06 (1H, m), 4,25 (1H, m), of 4.44 (2H, s)and 4.65 (1H, d), 5,46 1H, users), 7,29-7,39 (3H, m), to 7.77 (1H, users), 8,43 (1H m)
II-49551,5(DMSO) of 1.03 (9H, s)of 1.09 (3H, m), 1,11 (3H, m), 1,792,15 (4H, m), 2,32 (1H, m), 2,98 (1H, m), 3,51 (1H, m), with 3.79 (1H, m), 4,10 (1H, m)to 4.23 (1H, m), 4,40 with 4.65 (2H, m), the 5.45 5,73 (1H, m), 7,35 (1H, m), 7,49 (1H, m), 7,76-to 7.84 (2H, m), 8,23 at 8.60 (2H, m), 10,11 (1H, )
II-50493,3(DMSO) 0,92-1,19 (4H, m), 1,49-1,90 (9H, m), 1,91 of 1.99 (2H, m)to 2.06 (4H, users), 2,49-2,52 (2H, m), 3,57-3,68 (1H, m), 3,80-are 3.90 (1H, m), 4,01-to 4.28 (2H, m), 4,46 (1H, t), 7,32 (1H, d), the 7.43 (1H, DD), 7,81 (2H, users), 8,31-8,78 (1H, m), 8,46 (1H, d), 10,22 (1H, s)
II-51to 539.3(DMSO) 0,90-of 1.07 (9H, s, tBu), 1.70 to 2,40 (4H, users, CH2), 2,54-of 3.07 (1H, m, CH2), 3,52-3,88 (5H, m, CH3 CH), 4,00 with 4.65 (3H, m, CH), 5.40 to-5,80 (1H, m, CH), 7,30-7,44 (2H, m, aryl H), 7,60 (1H, m, aryl H), to 7.67 (1H, user., NH), 8,10-to 8.70 (2H, m, NH), 10,00 (1H, m, CH)
II-52558,3(DMSO) 0,91-1,11 (9H, s, tBu), 1.70 to to 2.41 (4H, m, CH2), 2,56-to 3.09 (1H, m, CH2), 3,60-are 3.90 (2H, m, CH), 4,14-4,72 (3H, m, CH), 5,38-5,80 (1H, m, CH), 6,98 (2H, m, aryl H), 7,07-7,20 (3H, m, aryl H), 7,31-7,46 (3H, m, aryl H), 7,66-8,67 (3H, m, NH, OH)
II-53467(DMSO) 0,83 was 1.04 (6H, m), 1,81-of 2.08 (5H, m), 3,34-3,63 (1H, m), 3,84-are 3.90 (1H, m), 4,00-4,60 (3H, m), from 5.29-of 5.75 (2H, m), 6,53-6,59 (1H, m), 6,70-of 6.90 (1H, m), 7,20-7,35 (0,5H, m), 7,78 (0,5H, users), 8,43 at 8.60 (2H,m)
II-55502,6(DMSO) to 0.96 (1H, s)of 1.03 (9H, s), 1.30 and 1.39 in (2H, m), 1,68-1,71 (2H, m), 1,79-to 1.82 (1H, m)of 1.97 (1H, userd), 2,11 (3H, s), with 3.79 (3H, s), a-3.84 (1H, users), 4.09 to (1H, users), ,56-4,58 (1H, m), of 4.67 (1H, d), for 6.81 (1H, d), of 7.00 (1H, d), 7,19 (1H, t), 7,79 (0,5H, users), to 7.93 (1H, userd), 8,42 (0,5H, users)
II-56492,5(CDCl3) 1,08-to 1.14 (9H, m), 1.85 to was 2.05 (4H, m), 2,32 at 2.45 (1H, m), 2,79-to 2.85 (1H, m), 3,01-of 3.07 (1H, m), 4,13-4,17 (1H, m), 4.53-in-4,70 (1H, m), to 4.98 (1H, t), 5,70, and of 5.81 (1H total, users and userd), 6,91-7,00 (1H, m), 7,34-7,44 (3H, m), to 7.67 to 7.75 (1H, m)
II-57549,5(DMSO) of 1.03 (9H, s), 1,31-to 1.38 (2H, m), 1,62-of 1.74 (3H, m)to 1.98 (1H, ushort), 2,07 (3H, s), a 2.36 (1H, users), and 2.83 (1H, users), a-3.84 (1H, users), 4,17 (1H, users), 4,54-of 4.57 (1H, m), 4,70 (1H, d), 7,34 (1H, d), 7,42 was 7.45 (1H, m,), 8,16 (1H, t), of 8.37 (1H, users), 10,23 (1H, s)
II-58563,5(CD3OD) of 1.17 (9H, s)to 1.21 (3H, t), 1.41 to 1.55V (2H, m), 1,75-1,90 (3H, m), 2,03-2,19 (1H, m), 2,37-of 2.50 (3H, m), 2,58-2,78 (2H, m), a 3.87-was 4.02 (1H, m), 4,20-4,30 (1H, m), 4,55-4,70 (2H, m), 4,91 (1H, unclear), was 7.45 (1H, d), 7,51 (1H, d), a 7.85 (1H, s), 8,29 (1H, d)
II-59577,5(DMSO) of 1.05 (9H, s)and 1.15 (6H, d), 1,35-1,5 (2H, m), about 1.75 to 1.9 (3H, m), 2,0-2,1 (1H, m), 2,3 at 2.45 (1H, m), 2,7-2,9 (1H, m), 4,05-to 4.15 (1H, m)and 4.65 (1H, s), 4,7-of 4.75 (1H, m), to 7.15 (1H, d), 7,35 (1H, t), and 7.7 (1H, d), and 8.4-8,55 (2H, m), and 9.5 (1H, s)
II-60506,5(DMSO) of 1.03 (9H, s), 1,31-to 1.38 (2H, m), by 1.68 (3H, m), 2,30 is 2.33 (2H, m), 2,67 (0,5H, users), 2,99 (0,5H, users), 3,34 (0,5H, users), 3,76 (3H, s), 4.04 the (0,5H, m), 4,58 (1H, s), 4.2V (1H, d), 7,09 for 7.12 (1H, m), 7,16-7,20 (1H, m), 7,26-7,30 (1H, m), 7,78 (0,5H, users), 8,02 (1H, users), 8,42 (0,5H, users)
II-61492,8(DMSO) of 0.95 (3H, d), 0,10 (3H, d), 1,17 (1H, m), 1,32 (1H, m), 1,64 and 1.80 (3H, m), from 2.00 (1H, m), 2,30 (1H, users), 2,67 (0,5H, users), 2,99 (0,5H, ushers in), 3.75 (0,5H, users), 3,85 (3H, s)4,06 (0,5H, m), 4,50-4,55 (2H, m), 5,42 (1H, users), 7,07 (1H, m), 7,17 (1H, m), 7,26 (1H, m), 7,80 (1H, users), 8,35 (1H, m)
II-62549,5(DMSO) δ was 1.04 (9H, s)of 1.29 to 1.34 (2H, m), 1,59-to 1.67 (3H, m), 1,91-of 1.97 (1H, m)to 2.13 (3H, s), 2,96 (1H, users), of 3.77 (1H, users), 4,10 (1H, users), 4,72 (1H, s), was 4.76 (1H, d), 7,80-7,83 (1H, m), 7,88-to $ 7.91 (1H, m), 8,00-8,02 (1H, m), 8,18-8,24 (12H, m), 8,39 (1H, users), 9,62 (1H, s)
II-63563,5(DMSO) of 1.05 (9H, s)of 1.09 (3H, t), to 1.19 to 1.37 (3H, m), 1,47-to 1.77 (3H, m), 1,91 of 1.99 (1H, m), 2,28 (0,5H, userd), 2,48 (2H, HF), 2,63-to 2.74 (1H, m), 3,01 (0,5H, DD), 3,63 (0,5H, s), 3,78-4,37 (2H total, m), 4,42-4,59 (1H, m), and 4.75 (1H, d), 5,42 (0,5H, d), 7,76 (0,5H, d), 7,80-7,83 (1H, m), 7,87 (1H, d), 8,01 (1H, m), 8,08-of 8.15 (1H, m), at 8.36 (0,5H, d), at 9.53 (1H, s)
II-64509,5(DMSO) of 1.07 (9H, s), of 1.34 to 1.37 (2H, m), 1,64-1,72 (3H, m), 1,95-2,04 (1H, m), 2,31 to 2.35 (1H, m), 2,65-2,70 (1H, m), 3,01-3,03 (1H, m), 3,99 (0,5H, m), 4.26 deaths-4,28 (0,5H, m), and 4.68 (1H, s), 4,82 (1H, d), the 5.45 (0,5H, s), 7,73-7,86 (3H, m), 8,05-8,08 (2H, m), 8,49 (0,5H, d), to 8.57-8,59 (1H, m), 8,69 (0,5H, d), to 9.15 (1H, d)
II-65are 507, 5 (DMSO) of 1.02 (9H, s), of 1.28 to 1.34 (2H, m), 1,57-of 1.64 (3H, m), 1,90 is 1.96 (1H, m), 3.72 points-of 3.80 (1H, m), 4,50 (1H, users), 4,72-4,74 (1H, m), 5,91 (1H, s)6,76 (1H, d), 7,58-to 7.61 (1H, m), 7,81-7,83 (1H, m)
II-66493,5/

EXAMPLE III

BIOLOGICAL METHODS

Compounds according to this invention can be investigated using the techniques described below. Table 5 lists the data on the inhibition of the enzyme caspase-1 and caspase-8 for compounds II-1 to II-25. In the table of compounds with Ki <10 classified as A compound with a Ki 10-20 classified as B and compounds with Ki 21-30 classified as C.

Tests on enzyme inhibition in vitro

The Ki values for test compounds with caspase-1 and caspase-8 obtained by the method of Margolin et al. (J. Biol. Chem., 272 pp. 7223-7228 (1997)). Other caspase can be investigated in a similar way (see, for example, WO 99/47545). Tests carried out in 10 mm Tris (Sigma Corp., St. Louis MO), pH 7.5, 1 mm dithiothreitol (DTT, Organic Research INC., Cleveland, OH) and 0.1% CHAPS (Pierce, Rockford, IL) at 37°C. caspase-3 to analytical buffer add a solution of 8% glycerol to improve the stability of the enzyme. 65 ál aliquot of analytical buffer and 5 ál aliquot of the appropriate dilution of inhibitor in DMSO is applied with a pipette to 96-well plate, treated with 10 μl of the caspase, then diluted analysis is Kim buffer (0.5 to 40 nm active protein titration of active sites). For each definition includes a control containing DMSO, but without a connection. Then the tablets incubated for 15 minutes at 37°C before adding the appropriate substrate (20 μl, final concentration of 1-4 X KM, final analytical volume 100 µl) to initiate interaction. The reaction rate was measured at 37°C or subsequent dependent on the time the increase of absorption at 405 nm (for pNA-substrate) or the corresponding increase in fluorescence (Ex 390, Em 460) (AMC-substrates). Build a dependency graph of the obtained velocity on the concentration of the inhibitor and produce fitting the data to equation strong ties Morrison for competitive inhibitors (Morrison J. F.Biochem. Biophys. Acta, 185 pp. 269-286 (1969)). The substrates used for specific tests, the following:

The caspase-1 Suc-YVAD-pNA (Bachem, King of Prussia, PA) (final concentration in the analysis of 80 μm);

The caspase-8 Ac-DEVD-pNA (Bachem, King of Prussia, PA) (final concentration in the analysis of 80 μm).

II-45
Table 5
Data on the inhibition of caspase-1 (C1) and caspase-8 (C8)
ConnectionKi Cl
(nm)
Ki C8
(nm)
II-1AA
II-2AA
II-3AA
II-4AIn
II-5AIn
II-6AA
II-7AIn
II-8AIn
II-9AIn
II-10AIn
II-11A
II-12AIn
II-13InIn
II-14InAnd
II-15A
II-16 A
II-17AAnd
II-18AIn
II-19InAnd
II-20AAnd
II-21A
II-22A
II-23A
II-24A
II-25A
II-26AAnd
II-27AAnd
II-28AAnd
II-29AAnd
II-30A And
II-31AAnd
II-32AAnd
II-33AndAnd
II-34AndAnd
II-35AndAnd
II-36AndAnd
II-37AndIn
II-38AndAnd
II-39AndAnd
II-40AndIn
II-41AndAnd
II-42AndIn
II-43AndAnd
II-44AndAnd
AndAnd
II-46And
II-47AndAnd
II-48AndAnd
II-49AndAnd
II-50And
II-51AndAnd
II-52AndAnd
II-53And
II-55AndAnd
II-56AndAnd
II-57AndAnd
II-58AndAnd
II-59AndAnd
II-60 AndAnd
II-61AndAnd
II-62AndIn
II-63AndIn
II-64InIn
II-65AndAnd
II-66BAnd

Analysis of PBMC cells

Analysis of IL-1β using a mixed population of mononuclear peripheral blood cells (PBMC) of a person or enriched adhesive mononuclear cells

Processing of pre-IL-1β under the influence of the ICE can be evaluated in cell culture using different sources of cells. PBMC person, from a healthy donor, give a mixed population of subtypes of lymphocytes and mononuclear cells, which produce a range of interleukins and cytokines in response to many classes of physiological stimulants. Adhesion of mononuclear cells from PBMC provide a rich source of normal monocytes for selective studies of the production of cytokines by activated cells.

Ek the pilot method:

Get the original series of dilutions of the test compound in DMSO or ethanol, followed by dilution medium RPMI-10% FBS containing 2 mm L-glutamine, 10 mm HEPES, 50 U and 50 µg/ml penicillin/streptomycin), respectively, giving medication at the 4-final test concentration, containing 0.4% DMSO or 0.4% ethanol. The final concentration of DMSO is 0.1% for all drug dilutions. Concentration titer, allowing you to set the apparent Ki for the test compounds, a specific test for inhibition of ICE, usually used for primary screening of the compounds.

Typically explore 5-6 dilutions of the compounds and cellular component analysis duplicates using duplicate ELISA-definitions for each of the supernatant of the cell culture.

The allocation of PBMC and test for IL-1:

Cells leukocyte film, selected from one pint of human blood (giving a final volume of mixture plasma plus cells 40-45 ml), dilute with medium to 80 ml and in each separation tube LeukoPREP (Becton Dickinson) load 10 ml of cell suspension. After 15 min centrifugation at 1500-1800 × g layer plasma/fluid sucked through the suction pump and then the layer of mononuclear cells are collected using a Pasteur pipette and transferred into a 15 ml conical centrifuge tube (Corning). Add medium to a volume of 15 ml, caution peremeshivayte by inversion of the tube and centrifuged at 300 × g for 15 minutes Sediment PBMC in vitro resuspended in a small volume of medium, to produce a count of the cells and the concentration of these cells was adjusted to 6·106cells/ml

For the analysis of cells with 1.0 ml of cell suspension added to each well of a 24-hole flat-bottomed tablet for tissue cultures (Corning), 0.5 ml of the dilution of the test compound and 0.5 ml LPS (Sigma #L-3012; 20 ng/ml solution prepared in complete RPMI-medium; the final concentration of LPS equal to 5 ng/ml). 0.5 ml of the additives of the test compounds and LPS are usually sufficient for mixing the contents of the wells. Perform three control mixture experiment, the control only with LPS, with a solvent medium and/or an additional medium to bring the final volume of culture to 2.0 ml of the cell Culture is incubated for 16-18 h at 37°C in the presence of 5% CO2.

After the incubation period, cells are harvested and transferred to conical centrifuge tubes 15 ml After centrifugation for 10 min at 200 × g supernatant collected and transferred into a test tube Eppendorf'a 1.5 ml it Should be noted that debris can be used for biochemical evaluation of the content of pre-IL-1β and/or Mature IL-1β in extracts of cytosole by the method of Western blotting or ELISA with specific anticorodal pre-IL-1β.

The selection of adhesive mononuclear cells:

PBMC isolated and prepared as described is use. The holes are initially added to the medium (1.0 ml), after which 0.5 ml suspension of PBMC. After incubation for one hour tablets gently shaken and the non-adhesive cells are sucked off from each well using an aspirator. Then the wells gently washed three times with 1.0 ml of the environment and at the end resuspended in 1.0 ml of medium. Enrichment of adhesive cells usually gives an output of 2.5-3.0×105cells per well. The addition of the tested compounds, LPS, conditions of incubation of the cells and processing supernatants are as described above.

ELISA:

The Quantikine kits (R&D Systems) can be used to determine the Mature IL-1β. Analyses performed according to the manufacturer's instructions. It is established that the levels of Mature IL-1β be about 1-3 ng/ml in PBMC and adhesion of mononuclear positive controls. ELISA assays carried out on a 1:5, 1:10 and 1:20 dilutions of supernatants from LPS-positive controls for optimum breeding for supernatants in the screening test.

Inhibitory efficacy of compounds can be expressed by the value of the IC50corresponding to the concentration of inhibitor at which the supernatant is determined by 50% of Mature IL-1β compared with positive controls.

Qualified it is clear that the values obtained in the tests on cells depends on many factors. Meant is I may not necessarily provide accurate quantitative results.

Selected compounds of this invention were investigated for the inhibition of release of IL-1β from Rumson have the meanings IC50in the range from 300 nm to 4 μm.

Analysis of whole blood on the production of IL-1β

The values of the IC50in the analysis of whole blood for the compounds of this invention can be obtained using the following methods.

Purpose:

Analysis of whole blood is a simple way to estimate the production of IL-1β (or other cytokines) and activity of potential inhibitors. A plurality analyzed this system, with a full set of lymphoid and inflammatory cell types, range of plasma proteins and red blood cells, is an ideal reflection ofin vitrophysiological conditions in a living organism (in vivo).

Materials:

Pyrogen-free syringes (~30 CC)

Pyrogen-free sterile vacuum tubes containing liofilizovannye Na2EDTA (4.5 mg/10 ml vial)

The sample of whole human blood (~30-50 CC)

Tubes Eppendorf'a 1.5 ml

The original solutions of the tested compounds (~ 25 mm in DMSO or other solvent)

Does not contain endotoxin solution of sodium chloride (0.9%) and HBSS

The original solution of lipopolysaccharide (Sigma; catalog. No. L-3012) at 1 mg/ml in HBSS

ELISA-kit for IL-1β (R & D Systems; catalog. No. DLB50)

ELISA-kit for TNF-α (R & D Systems; to talog. No. DTA50)

Water bath or incubator

Experimental methodology the analysis of whole blood:

Set an incubator or water bath at 30°C. an Aliquot of 0.25 ml blood in test tubes Eppendorf'a 1.5 ml.Note: need to turn the tubes with samples of whole blood after every two aliquot. Differences in replicas can occur if the cells are deposited and spiderboy heterogeneous. Using pipettes with adjustable volume also minimizes the differences between the aliquot replicas.

Get drug dilution in sterile pyrogen-free physiological solution by serial dilution. A series of dilutions, allowing you to set the apparent Ki for the test compounds identified by testing for inhibition of ICE, usually used for primary screening of compounds. For highly hydrophobic compounds carry out cultivation compounds of fresh plasma, taken from the same donor blood, or PBS containing 5% DMSO to increase the solubility.

Add 25 ál of dilution of the test compounds or control with solvent and gently mix the sample. Then add in 5.0 μl of the solution of LPS (250 ng/ml source their: 5.0 ng/ml final concentration of LPS) and again stirred. Incubate the tubes at 30°C in a water bath for 16-18 hours, at times peremeci the traveler. Alternatively, tubes may be placed in a rotary machine, set at 4 rpm, the same incubation period. This test should be performed using duplicate or triplicate under the following controls: negative control without LPS; positive control without the test inhibitor; control with solvent, the highest concentration of DMSO or the mixed solvent used in the experiment. The additional amount of saline added to all control tube to normalize the volume, as in the case of both control and test samples for analysis of whole blood.

After the incubation period, samples of whole blood centrifuged 10 minutes at ~2000 rpm in microcentrifuge, the plasma is transferred into a clean microcentrifuge tube and centrifuged at 1000 × g to precipitate residual platelets as needed. Plasma samples can be stored frozen at -70°C prior to the study on the levels of cytokines using ELISA method.

ELISA:

Sets R & D Systems 614 McKinley Place N. E. Minneapolis, MN 55413) Quantikine kits can be used to determine IL-1β and TNF-α. Tests conducted according to the manufacturer's instructions. In a series of individual measurements can be observed levels of IL-1β, is ~1-5 ng/ml Dilution 1:200 plasma for all samples is usually sufficient in the experiment is x, to the results of ELISA fell on the linear plot standard curves ELISA. It may be necessary to optimize the standard dilutions in case there are discrepancies in the analysis of whole blood. Nerad J. L. et al.,J. Leukocyte Biol., 52, pp. 687-692 (1992).

Selected compounds of this invention were investigated for the inhibition of release of IL-1β from whole blood have the meanings IC50in the range from 1 μm to 40 μm.

Tests in vivo

Compounds according to this invention can be studied by in vivo tests, such as described in WO 99/47545.

WO 99/47545 and all other cited documents are incorporated herein by reference.

Although applicants described a number of embodiments of the present invention, it is obvious that these basic examples may be altered, which will lead to other options implementation using compounds and methods according to this invention. In addition, it should be considered that the scope of the present invention are determined by the applications and not the specific implementation options presented above as an example.

1. The compound of the formula I

where
or;
Y means
R1the meaning of the substituents: H, C1-12-alkyl or phenyl, where any hydrogen atom neobyazatel and independently substituted R 8;
ring And means
,,
when the ring And means:
R means R3C(O)-, and R3the meaning of the substituents: phenyl or ethanolic;
when the ring And means:
or
R means R3C(O)-, as shown in formula II

and R3means phenyl, thiophene or pyridine, where each cycle has optional up to 5 substituents independently selected from the group R8'and where at least one position on the phenyl, thiophene or pyridine, adjacent relationship with x replaced by R12where
R12contains no more than 5 atoms in the linear chain;
R2means-C(R5) (R6) (R7);
R5means N or C1-6- linear or branched alkyl;
R6means N or C1-6- linear or branched alkyl;
R7means-CF3- 3-7-cycloalkyl, thiazolyl or C1-6-linear or branched alkyl, where each carbon atom of the alkyl optionally and independently substituted R10;
or R5and R7together with the carbon atom to which the are attached, form a 3-10-membered cycloaliphatic group;
each of R8and R8'independent means halogen, -OR9 , -CF3, -OCF3, -R9, -N(R9)2,
-N(R9)C(O)OR9, -N(R9)C(O)R9;
R9the meaning of the substituents: hydrogen, C1-12-alkyl, C3-10-cycloalkyl, phenyl, thiazolyl, (C3-10-cycloalkyl) - (C1-12-alkyl)-;
where any hydrogen atom is optionally and independently substituted OR9where R9means C1-12-alkyl;
R10means halogen;
R11means1-4-alkyl-; and
R12means halogen, -OR11, -CF3, -OCF3, -R11.

2. The compound according to claim 1, where R means R3C(O) - and R3means phenyl or ethanolic.

3. The compound of formula II:

where
Y meansor;
R1the meaning of the substituents: H, C1-12-alkyl, or phenyl, where any hydrogen atom is optionally and independently substituted R8;
ring And means:
or
R3means phenyl, thiophene or pyridine, where each cycle has optional up to 5 substituents independently selected from the group R8'and where at least one position on the phenyl, thiophene or pyridine, adjacent relationship with x replaced by R12where R12contains no more than 5 atoms in the linear chain;
R2means-C(R5) (R6) (R7);
R5 is N or C 1-6- linear or branched alkyl;
R6means N or C1-6- linear or branched alkyl;
R7means-CF3- 3-7-cycloalkyl, thiazolyl or C1-6-linear or branched alkyl, where each carbon atom of the alkyl optionally and independently substituted R10;
or R5and R7together with the carbon atom to which the are attached, form a 3-10-membered cycloaliphatic group;
each of R8and R8'independent means halogen, -OR9, -CF3, -OCF3, -R9, -N(R9)2,
-N(R9)C(O)OR9, -N(R9)C(O)R9;
R9the meaning of the substituents: hydrogen, C1-12-alkyl, C3-10-cycloalkyl, phenyl, thiazolyl, (C3-10-cycloalkyl) - (C1-12-alkyl)-;
where any hydrogen atom is optionally and independently substituted OR9where R9means C1-12-alkyl;
R10means halogen;
R11means1-4-alkyl-; and
R12means halogen, -OR11, -CF3, -OCF3, -R11.

4. The compound according to any one of claims 1 to 3, where Y means

5. The compound according to claim 4, where R1means1-12-alkyl, optionally substituted with 1-3 groups independently selected from R8.

6. The compound according to claim 5, where R1means a linear or branched C1-4-alkyl, neo is Astelin substituted by 1-3 groups independently selected from R8.

7. The connection according to claim 6, where R1means unsubstituted linear or branched
C1-4-alkyl.

8. The connection according to claim 7, where R1means ethyl, isopropyl, n-propyl or n-butyl.

9. The connection of claim 8, where R1means ethyl.

10. The compound according to claim 4, where R8means halogen, -OR9, -CF3, -OCF3or-R9.

11. The compound according to any one of claims 1 to 3, where Y means

12. The compound according to claim 1, where the ring And means

13. The compound according to claim 3 in which the ring And means:

14. The connection section 12 or 13, where R2means3-4branched alkyl group.

15. The connection 14, where R5means H or-CH3, R6means-CH3and R7means-CH3.

16. The connection indicated in paragraph 13, where R12contains no more than 4 atoms in the linear chain.

17. Connection P16, where R12contains no more than 3 atoms in a linear chain.

18. The connection 17, where R12means OCF3, -Och3, -CF3, -CH3, -CH3CH3, -Cl or-F.

19. Connection p, where R12means-CF3, -CH3, -Cl or-F.

20. The connection according to claim 19, where R12means-CH3, -Cl or-F.

21. The connection section 12 or 13, where each of R8'n is dependent means halogen,
-OR9, -CF3, -OCF3, -R9, -N(R9)2or N(R9)C(O)R9.

22. Connection item 21, where each of R8'independent means-NH2, -N(R9)2, -N(R9)C(O)R9, -OCF3, -OR9, -R9or halogen.

23. Compound selected from the group including

24. Pharmaceutical composition having inhibitory activity against caspase containing:
a) the compound according to claim 1 and
b) a pharmaceutically acceptable carrier or solvent.

25. The method of treatment of a patient, where the disease is a pancreatitis, osteoarthritis, rheumatoid arthritis, syndrome of respiratory disorders in adults, systemic lupus erythematosus, scleroderma, diabetes, chronic active hepatitis, hepatitis-B, hepatitis-C, hepatitis-G, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, graft vs. host rejection of an organ transplant, osteoporosis, sepsis, septic shock, Alzheimer's disease, Huntington's disease, cerebral ischemia, epilepsy, myocardial ischemia, myocardial infarction, atherosclerosis, coronary artery W is sterowanie, amyotrophic lateral sclerosis, multiple sclerosis, neurological damage caused by stroke, traumatic brain damage, kidney disease, syndrome Muckle-Wells'a family of cold urticaria, familial Mediterranean fever, chronic infantile neurological cutaneous and articular syndrome, a Multisystem inflammatory disease of the newborn, TNFR1-associated periodic syndrome or the syndrome of Hyper-IgD intermittent fever, including the stage of introduction of a given patient connection according to claim 1 or a pharmaceutical composition according to paragraph 24.

26. The method of inhibition mediated by caspase function in a patient, comprising the stage of introduction of a given patient connection according to claim 1 or a pharmaceutical composition according to paragraph 24.

27. The way to reduce production IGIF or IFN-γ in the body of the patient, including the introduction of a specified patient connection according to claim 1 or a pharmaceutical composition according to paragraph 24.

28. Method of preserving cells, including the stage of contacting cells in a liquid medium with a composition of the compound according to claim 1 or a corresponding pharmaceutically acceptable derivative.

29. The method according to p, where these cells are located in:
a) the body intended for transplantation, or
b) the product of blood.

30. The method of obtaining the compounds of formula I:
;
where Y means:
,
and the other variables take the values specified in claim 1;
including the interaction of the compounds of formula 1:

where the variables take the values specified in claim 1, and the compounds of formula RX, where X means IT, or a corresponding derivative, or a leaving group, in terms of a combination of amine and acid (when X is OH) or the corresponding acid derivative (when X is an appropriate leaving group), resulting in obtaining the compounds of formula I.

31. The method of obtaining the compounds of formula I:
;
where Y means:
;
and the other variables take the values specified in claim 1;
including the interaction of the compounds of formula 7-a:

where the variables take the values specified in claim 1; and compounds of formula RNHCH (R2) C (O) X, where X means IT, or a corresponding derivative, or a leaving group, in terms of a combination of amine and acid (when X is OH) or the corresponding acid derivative (when X is different from IT), resulting in obtaining the compounds of formula I.

32. The method of obtaining the compounds of formula IV:

where the variables take the values specified in claim 1, including the interaction of the compound f is rmula I:
,
where Y means:
;
where R1takes the values specified in claim 1, in conditions
hydrolysis leading to the compounds of formula IV.

33. The method of obtaining the compounds of formula 3-a:
,
where PG1means tert-butyl; PG2means benzyloxycarbonyl; and the ring And takes values according to claim 1; including:
the interaction of the compounds of formula 2-A:

and the compounds of formula 20 is:

where X means HE or appropriate leaving group, in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is an appropriate leaving group), resulting in obtaining the compounds of formula 3-A.

34. The method of obtaining the compounds of formula 3:

where PG1means tert-butyl and PG2means benzyloxycarbonyl, including: the interaction of compounds of formula 2-A:

with a compound of formula 20:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is an appropriate leaving group), which receive the compounds of formula 3.

35. The method of obtaining the compounds of formula 13:

where PG1means tert-butyl; and PG2means benzyloxycarbonyl; including: the interaction of compounds of formula 2:

with a compound of formula 21:

in terms of a combination of amine and carboxylic acid (when X is OH) or amine and the corresponding carboxylic acid derivative (when X is an appropriate leaving group), resulting in obtaining the compounds of formula 13.

36. The compound of formula 5-a:

where PG1means tert-butyl, PG2means
benzyloxycarbonyl; and R1means1-12-alkyl.

37. The compound of formula 5:
,
where Z denotes benzyloxycarbonyl, PG1means tert-butyl and R1means C1-12-alkyl.

38. The compound of formula 15:

where PG1means tert-butyl, PG2means benzyloxycarbonyl and R1means C1-12-alkyl.

39. The compound of formula 3-a:
,
where PG1means tert-butyl, PG2means benzyloxycarbonyl and R1means1-12-alkyl.

40. The compound of formula 3:
,
where Z denotes benzyloxycarbonyl and PG1 represents tert-butyl.

41. The compound of formula 13:
,
where PG1means tert-butyl and PG2means benzyloxycarbonyl.

42. The compound of formula 4A:
,
where PG1means tert-butyl and PG2means benzyloxycarbonyl.

43. The compound of formula 4:
,
where Z denotes benzyloxycarbonyl and PG1means tert-butyl.

44. The compound of formula 14:
,
where PG1means tert-butyl and PG2means benzyloxycarbonyl.



 

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SUBSTANCE: crystalline monohydrate has X-ray powder pattern which includes four or more values 2θ, selected from a group consisting of: 18.0 ± 0.2, 18.4 ± 0.2, 19.2 ± 0.2, 19.6 ± 0.2, 21.2 ± 0.2, 24.5 ± 0.2, 25.9 ± 0.2 and 28.0 ± 0.2. The invention also relates to a method of producing crystalline monohydrate, to a pharmaceutical composition for treating disorders caused by protein tyrosine kinase containing crystalline monohydrate, to a crystalline butanol solvate of formula and to a crystalline ethanol solvate compound of formula (IV).

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10 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to 2-cycloalkylamino-5-thienyl-1,2,3-thiadiazines hydrobromides with antiaggregant activity , where R=H; CH3; Br, = morpholino-; thiomorpholino-; pyrrolidino-; 2,6-dimethylmorpholino-; hexamethylenimino-.

EFFECT: obtaining novel compounds which can be used in medicine for treating and preventing such diseases as myocardial infarcation, stroke, rejection of transplanted organs and tissue, and can also prevent embolism and thrombosis formation.

1 cl, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I or formula II, to their pharmaceutically acceptable salts, enantiomers and diastereoisomers as metalloprotease inhibitors, and also to a pharmaceutical composition based thereon and to versions of application thereof. Said compounds can find application in treatment of the diseases mediated by activity of metalloproteases, Her-2 SHEDDASE, ADAM-10 and ADAM-17, such as arthritis, cancer, cardiovascular disorders, skin diseases, inflammatory and allergic conditions, etc. In general formula I or II: A represents CWNHOH; B represents CH2; G represents CH2; D represents oxygen; X represents CH2NRb; Y represents CH2; M represents C; U is absent or represents NRb; V is absent or represents phenyl, or 4-10-members heterocyclyl containing 1-2 heteroatoms chosen from N and S, substituted with 0-5 groups Re; U' is absent or represents C1-10alkylene, O or combinations thereof; V' represents H, C1-8alkyl, NRbRc, C6-10carbocyclyl substituted with 0-3 groups Re, or 5-14-members heterocyclyl containing 1-3 heteroatoms chosen from N, O and C substituted with 0-4 groups Re; Ra and Re, independently represents H, T, C1-8alkylene-T, C(O)NRa'(CRb'Rc')r-T, (CRb'Rc')r-O-(CRb'Rc')r-T, OH, Cl, F, CN, NO2, NRIRII, COORIV, ORIV, CONRIRII, C1-8halogenalkyl, C3-13carbocyclyl; Rb and Rc independently represents H, T, C1-6alkylene-T, C(O)O(CRb'Rc')r-T, C(O)(CRb'Rc')r-T, S(O)p(CRb'Rc')r-T; T represents H, C1-10alkyl substituted with 0-1 groups Rb'; C3-6carbocyclyl, 5-6-members heterocyclyl containing one oxygen atom; Ra' Rb' and Rc' independently represents H, ORIV or phenyl; R1 represents hydrogen; R2 represents hydrogen; R3 represents: (i) C1-10alkyl; (ii) 4-14-members heterocyclyl containing 1-3 nitrogen atoms optionally substituted with one or two substitutes chosen from C1-6alkyl, OR13, 5-10-members heterocyclyl containing 1-3 heteroatoms chosen from N O and C, or phenyl; (iii) NR16R17; R4 represents H; R4' represents H; R5' represents H; W represents oxygen; R13 represents C1-C6alkyl; R16 and R17 independently represents C1-C10alkyl or phenyl where each is optionally substituted with one C1-4alkyl; RI and RIIindependently represents H or C1-6alkyl; RIV represents C1-6alkyl; i is equal to 0; p is equal to 1 or 2 and r is equal to 0, 1 or 2; provided that a) a spiro ring represents a stable chemical base unit and b) NR8 and NRb do not contain neither N-N, nor N-O bonds.

EFFECT: higher efficiency of the composition and method of treatment.

54 cl, 1 tbl, 9 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing new 3,4-dithienyl-substituted maleic anhydrides or maleimides of general formula I: , where X=O, or NR1; R1 and R2=alkyl C1-C4; R3=alkyl C1-C4, or nitrogen- and/or sulphur-containing heterocyclic substitute. The method involves reacting the corresponding 2,5-disubstituted 3-thienyl-acetic acid with the corresponding 2,5-disubstituted 3-halogen acetythiophenes while heating in the presence of a base in a medium of inert organic solvent in atmospheric oxygen with subsequent separation of the end product of general formula I, where X=O, or, if necessary, the latter is converted to a compound of general formula I, where X=NR1, where R1 assumes values given above, by treating it with the corresponding amine. These compounds can be used as photochromes, which are widely used as optical switches in high-capacity data carriers used for recording, processing and storing data.

EFFECT: versatility of the method, ie possibility of obtaining compounds with and without equivalent heterocyclic substitutes using readily available thienyl-acetic acid and halogen ketones of the thiophene family, which considerably widens the assortment of organic photochromic dithienylethenes.

4 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3-diiminoisoindoline, and more specifically to N1,N3-bis(5-amino-3-pentyl-1,3,4-thiadiazol-2-ylidene)-2H-isoindole-1,3-diamine. This compound is soluble in organic solvents and can be used for colouring hydrocarbons, synthetic fibre, fats, wax, alcohols, polymers of plastics, rubber.

EFFECT: wider assortment of fat-soluble light tone dyes.

1 cl, 2 dwg, 1 dwg

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where Qa is phenyl or heteroaryl, and Qa can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; R1 and R2 are each independently selected from hydrogen and (1-6C)alkyl; Qb is phenyl or heteroaryl, and Qb can possibly carry 1 or 2 substitutes selected from hydroxy, halogen, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkoxycarbonyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, (1-6C)alkylthio, (1-6C)alkylsulfinyl and (1-6C)alkylsulfonyl; where any of the substitutes Qa and Qb defined above, containing a CH2 group which is bonded to 2 carbon atoms, or a CH3 group bonded to a carbon atom, can possibly carry on each of the said CH2 or CH3 group one or more substitutes selected from hydroxy, amino, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; where heteroaryl is an aromatic 5- or 6-member monocyclic ring which can contain up to three heteroatoms selected from oxygen, nitrogen and sulphur, and can be condensed with a benzene ring or a five-member nitrogen-containing ring containing 2 nitrogen atoms; as well as pharmaceutically acceptable salts thereof. The invention also relates to a method of producing formula I compounds, a pharmaceutical composition and use of these compounds for treating conditions mediated by effect of TNF cytokines.

EFFECT: more effective treatment.

13 cl, 3 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazole derivatives with general formula (I) and their pharmaceutically acceptable acid addition salts, optically pure enantiomers, racemates and diastereomer mixtures as adenosine receptor ligands and to a pharmaceutical preparation based on said compounds. In general formula (I), R1 represents C3-7cycloalkyl substituted with a OR group, or 2-(7-oxa-bicyclo[2.2.1]hept-1-yl)-ethyl; R represents hydrogen or C(O)-lower alkyl; X represents -CHR'-; and R' represents hydrogen or lower alkyl.

EFFECT: compounds can be used for treating or preventing diseases mediated by adenosine A2A receptors, for example Alzheimer's disease, certain depressive conditions, toxicomania and Parkinson's disease.

8 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of diaryl compounds with formulae given below ,

.

, in which M is S(O)2, Rx represents alkyl, R1, R2, R3 and R4 are each independently selected from OH and -NR7S(O)2R8, R5 and R7 each independently represents hydrogen or alkyl, R8 is alkyl; and their pharmaceutically acceptable derivatives, as well as to pharmaceutical compositions containing said compounds and their use in making a medicinal agent with inhibitory activity on Aβ, IAPP amyloid fibrils or synuclein fibrils.

EFFECT: substituted n-arylbenzamide and related compounds for treating amyloid diseases and synucleinopathy are disclosed.

11 cl, 19 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidine-3,4-dicarboxamide derivatives of formula (I): , where: X is N or C-R6; R1 is C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluoro-C1-7alkyl, hydroxy-C1-7alkyl, CN-C1-7alkyl, R10C(O), R10OC(O)-, N(R11,R12)C(O)-; R10OC(O)C1-7alkyl, N(R11,R12)C(O)-C1-7alkyl, R10SO2, R10-SO2-C1-7alkyl, N(R11, R12)-SO2, N(R11,R12)-SO2-C1-7alkyl, aryl-C1-7alkyl, 5-member monocyclic heteroaryl containing a nitrogen atom, where the ring carbon atom can be substituted with a carbonyl group, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents an aromatic -member monocyclic ring with 1 S atom or a 6-member monocyclic ring with 1 N atom, C1-7alkoxy-C1-7alkyl, C1-7alkoxycarbonyl-C3-10cycloalkyl-C1-7alkyl or halogen substituted 4-member heterocyclyl-C1-7alkyl with one O atom; R2 is H, C1-7alkyl; R3 is aryl, aryl-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 1 S atom, a 6-member monocyclic ring with 1 or 2 N atoms, 9-, 10-member bicyclic system with 1 or 2 N atoms in one ring; R4 is H, C1-7alkyl, OH; R5, R6, R7, R8 are independently selected from a group consisting of H, halogen, C1-7alkyl, C1-7alkoxy, flouro-C1-7alkyl, fluoro-C1-7alkyloxy; R9 is aryl, heterocyclyl, heteroaryl, heterocyclyl-C(O)-; R10 is H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7alkyl, fluro-C1-7alkyl, heteroaryl, heteroaryl-C1-7alkyl, where the term "heteroaryl" represents a 5-member monocyclic ring with 4 N atoms, a 5-member heterocyclyl with 1 N atom; R11, R12 are independently selected from a group consisting of H, C1-7alkyl, C3-10cycloalkyl, C3-10cycloalkyl-C1-7 alkyl; and pharmaceutically acceptable salts thereof; where the term "aryl" represents a phenyl group which can be optionally substituted with 1 to 5 substitutes which are independently selected from a group consisting of the following: halogen, CF3, NH2, C1-7alkylsulphonyl, C1-7alkoxy, fluoro-C1-7alkyl, fluoro-C1-7 alkoxy; the term "heterocyclyl" represents a nonaromatic monocyclic 5-, 6-member heterocyclic group with 1, 2 N atoms, or with 1 N atom and 1 O atom, where the heterocyclyl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heterocyclyl group can be substituted with a carbonyl group; the term "heteraryl" represents an aromatic 5- or 6-member monocyclic ring system which can have 1, 2, 3 N atoms, or 1 N atom and 1 S atom, where the heteroaryl group can be substituted as indicated with respect to the term "aryl", and one carbon atom of the ring system of the heteroaryl group can be substituted with a carbonyl group. Formula I compounds have inhibitory activity towards coagulation factor Xa.

EFFECT: possibility of using said compounds in a pharmaceutical composition and for preparing a medicinal agent.

27 cl, 90 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: pharmacology.

SUBSTANCE: invention refers to compounds of formula (I) as inhibitor of phosphotyrosinphosphotase 1B, and to application thereof for making a based medical product. In general formula (I) X represents C-R2; Y represents O, R1 represents phenyl, 5-merous heterocycle with one sulphur atom with phenyl residue, and heterocyclic residue being mono-, twice- or trisubstituted with halogen, CN, -OH, -CF3, -(C1-C6)alkyl, -COOH, -(CH2)-COOH, phenyl, -O-phenyl with phenyl ring being substituted with halogen; R2, R3, R4, R5, R6, R7 and R8 represent H.

EFFECT: compounds can find application in treating adipose and carbohydrate metabolic disorders, including for controlling blood glucose.

3 cl, 2 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

FIELD: chemistry.

SUBSTANCE: novel compound is N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or its pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with CFTR activity modulation properties.

2 cl, 485 ex, 3 tbl

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