N-hydroxyformamide compounds as metalloproteinase inhibitors

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

 

The present invention relates to certain N-hydroxyvitamin derivatives, useful for the inhibition of metalloproteinases, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

The compounds of this invention are inhibitors of one or more than one enzyme, metalloproteinase. Metalloproteinases are a superfamily of proteases (enzymes), a known number of which in recent years has increased significantly. Based on structural and functional analysis of these enzymes are classified into families and subfamilies, as described in N.M. Hooper (1994) FEBS Letters 354:1-6. Examples of metalloproteinases include the matrix metalloproteinases (MMP)such as collagenase (MMR, MR, MMR), gelatinase (MMR, MMR), stromelysin (MMRS, MMR, MMR), matrilysin (MMR), metalloelastase (MMR), enamelin (MMR), MT-MMP (MMR, MR, MMR, MMR); radiolysis or adamisin, or family MDC, which includes secretase and sheddase, such as TNF-converting enzyme (ADAM10 and TACE); ostalnoe family, which includes such enzymes as protease catalyzing the processing of procollagen (procollagen processing proteinase, PCP); and other metalloproteinases such as aggrecanases, the family of endothelin-converting enzyme and family of the angiotensin converting enzyme.

I Think that metalloproteinases are important in plethora in painful physiological processes are involved in remodeling of tissues, such as embryonic development, bone formation and uterine remodeling during menstruation. This is substantiated by the ability of metalloproteinases cleave a wide range of matrix substrates, such as collagen, proteoglycan and fibronectin. Also metalloproteinases are considered to be important for processing, or secretion of biologically important cellular mediators, such as tumor necrosis factor (TNF), and post-translational proteolytic processing, or shedding, biologically important membrane proteins, such as IgE receptor CD23 with low affinity (a more complete list, see N.M. Hooper et al., (1997) Biochem j 321:265-279).

Metalloproteinases are associated with many painful conditions. The inhibition activity of one or more than one metalloproteinases can be very useful for these painful conditions, such as when various inflammatory and allergic diseases such as inflammation of the joints (in particular, rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (in particular psoria is, eczema, dermatitis); metastases or invasion of tumors; when the disease is associated with uncontrolled destruction of the extracellular matrix, such as osteoarthritis; when disease characterized by bone resorption (such as osteoporosis or Paget's disease); diseases associated with aberrant angiogenesis; with increased collagen remodeling associated with diabetes, periodontal disease (such as gingivitis), ulceration of the cornea, the formation of skin ulcers, post-operative conditions (such as colonic anastomosis) and the healing of skin wounds; demyelinating diseases of the Central and peripheral nervous systems such as multiple sclerosis); Alzheimer's disease; the remodeling of the extracellular matrix observed in cardiovascular diseases such as restenosis and atherosclerosis, and chronic obstructive lung disease, COPD (involving MMR).

The number of known inhibitors of metalloproteinases; different classes of compounds may have different degrees of effectiveness and selectivity in relation to the inhibition of various metalloproteinases. The authors of the present invention have discovered a new class of compounds, which are inhibitors of metalloproteinases, in particular, are of special interest in relation to Engibarov is of collagenase 3 (also known as MMP-13). Compounds according to this invention have a favorable impact and/or pharmacokinetic properties.

Originally collagenase 3 (MMR) was cloned from a cDNA library derived from breast tumors [J. M. P. Freije et al. (1994) Journal of Biological Chemistry 269(24):16766-16773]. PCR RNA analysis RNA wide variety of tissues showed that the expression of collagenase 3 (MMR) was limited to carcinomas of the breast, as it was not detected in fibroadenoma of the breast, normal or resting mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or cell lines of breast cancer (T47-D, MCF-7 and ZR75-1). After that collagenase 3 (MMR) was detected in transformed epidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ. 8(2):242-250], squamous cell carcinomas [N. Johansson et al., (1997) Am. J. Pathol. 151 (2):499-508] and epidermal tumors [K. Airola et al., (1997) J. Invest. Dermatol. 109(2):225-231]. These results confirm that collagenase 3 (MMR) secreted transformed epithelial cells and may be involved in degradation of extracellular matrix and interaction cell-matrix associated with metastasis, especially as it is observed in invasive foci of breast cancer and malignant epithelial tumor with skin carcinomas.

In a recently published data implies that the collagenases is 3 (MMR) plays a role in updating other connective tissues. For example, in accordance with the substrate specificity of collagenase 3 (MMR) and preference for the collapse of collagen type II [.G.Mitchell et al., (1996) J.Clin. Invest. 97(3):761-768; V.Knauper et al., (1996) The Biochemical Journal 271:1544-1550], collagenase 3 (MMR), as was expected, plays a role during primary ossification and remodeling of the skeleton [.Stahle-Backdahl et al., (1997) Lab. Invest. 76(5):717-728; N.Johansson et al., (1997) Dev. Dyn. 208(3): 387-397], in destructive joint diseases, such as rheumatoid and osteoarthritis [D.Wernicke et al., (1996) J.Rheumatol. 23:590-595; P.G.Mitchell et al., (1996) J. Clin. Invest. 97(3):761-768: O.Lindy et al., (1997) Arthritis Rheum 40(8):1391-1399] and during aseptic loosening of hip arthroplasty [S.Imai et al., (1998) J.Bone Joint Surg. Br. 80(4):701-7101. Collagenase 3 (MMR) are also involved in chronic periodontitis in adults, as it is localized in the epithelium chronically inflamed mucosa gingival tissue [V.J.Uitto et al., (1998) Am. J.Pathol 152(6): 1489-1499] and when the remodeling of the collagen matrix in chronic wounds [.Vaalamo et al., (1997) J.Invest. Dermatoi. 109(1):96-101].

Compounds that inhibit the action of metalloproteinases, in particular collagenase 3 (MMR), described in WO 00/12478, WO 00/75108 and WO 01/62742. Among these inhibitors, reported included aryl/heteroarylenevinylenes N-hydroxyproline compounds, in which the aryl ring is substituted by next possible substitutes, including cf is di other things alkoxy, aryloxy. Nowhere disclosed that the alkoxy - or aryloxyalkyl in such compounds itself optionally can be substituted.

Substituted alkoxy - or aryloxy-aryl/heteroarylenevinylenes N-hydroxyproline compounds as inhibitors of matrix metalloproteinases are described in General in the description of WO 99/38843. Among the many listed possible substitutes for alkoxygroup is halogen. However, such alkoxy-substituted compound is not disclosed, and really, the only specifically disclosed N-hydroxyvitamin compound is N-{1S-[4-(4-chlorophenyl)piperazine-1-sulfanilyl]-2-methylpropyl}-N-hydroxyvitamin.

The authors of the present invention have found that substituted aryl - or heteroaryl-piperazineethanesulfonic N-hydroxyproline compounds, in which the Deputy is alkoxygroup, which is itself substituted by one or more than one group of fluorescent, are particularly useful inhibitors of metalloproteinases, in particular collagenase 3 (MMR), and possess the desired activity.

In the first aspect of the present invention proposed a compound of formula (I)

or its pharmaceutically acceptable salt, prodrug or MES,

where the ring is a monocyclic aryl ring having above the th ring atoms, or monocyclic heteroaryl ring having up to six ring atoms and containing one or more than one ring heteroatom, where each said heteroatom is a nitrogen;

R2 represents a group selected from C1-alkyl or aryl, where the group is substituted by one or more than one group of fluorescent;

n is 1, 2 or 3 and

R1 represents a possibly substituted group selected from C1-alkyl, C5-cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, C1-alkyl-aryl, C1-alkyl-heteroaryl, C1-alkyl-cycloalkyl or C1-alkyl-geterotsiklicheskie.

The term "aryl", as used here, means an aromatic carbocyclic moiety with one or two rings having up to ten ring atoms, such as phenyl or naphthyl. In cases where refers to an aromatic carbocyclic radical with one ring, it is designated as "monocyclic aryl ring. In those cases where it is alleged that the aryl ring having six ring atoms, specifically indicated.

"Heteroaryl" refers to aromatic ring systems having up to ten atoms, in particular up to six ring atoms and containing one or more ring heteroatoms, which may be the same or different, selected from N, O and S. Examples included the Ute pyrrolyl, furanyl, thiophenyl, imidazolyl, thiazolyl, pyridinyl, pyrimidinyl and pyrazinyl. Heteroatoms of nitrogen will be replaced as needed; they can also be in the form of N-oxides. Sulfur atoms may be in the form of S, S(O) or S(O)2. In those cases where it is alleged heteroaromatic system with one ring, it is denoted as "monocyclic heteroaryl ring, and in those cases where it is alleged that the maximum number of ring atoms of the heteroaryl ring is less than ten, this point specifically. In those cases where it is alleged that ring heteroatom is one of N, S or O, in particular, or that the heteroaryl ring contains more than one heteroatom, in a certain combination, for example, where the heteroatoms are identical, this point specifically.

The term "halogen" includes fluorine, chlorine, bromine and iodine, in particular fluorine.

Unless otherwise noted, the term "C1-alkyl", when used separately or in combination, refers to an alkyl group with unbranched or branched chain, having from one to six carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. Accordingly, under the "C1-alnilam" shall mean the designation alkyl group with unbranched or branched chain, having from one is about four carbon atoms.

The term "cycloalkyl" refers to a saturated alicyclic group having five, six or seven carbon atoms, and includes, for example, cyclopentyl and cyclohexyl. Geteroseksualnoe ring refers to a saturated five-, six - or semilunar ring containing one or more ring heteroatoms, which may be the same or different, selected from N, O and S, and includes, for example, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl.

The term "possibly substituted" is used here to indicate possible replacement by a group or groups provided in any suitable available position.

Accordingly, the ring is a monocyclic aryl ring having six ring atoms, such as phenyl, or monocyclic heteroaryl ring having up to six ring atoms and containing from one to four ring nitrogen atoms, such as pyridinyl or pyrimidinyl, triazinyl or tetrazini.

In those cases, when ring b is a heteroaryl ring, is preferred six-membered ring containing from one to four ring nitrogen atoms, more preferably six-membered ring containing one or two ring nitrogen atom, such as pyridinyl or pyrimidinyl.

In one preferred the embodiments of the ring is a phenyl ring.

In another preferred embodiment the ring is a six-membered heteroaryl ring containing one or two ring nitrogen atom. One of the preferred values for the ring is pyridinyl, in particular 2-pyridinyl. A particularly preferred value for rings is pyrimidinyl, in particular 2-pyrimidinyl.

R2 may represent an aryl group having up to ten ring atoms, in particular monocyclic aryl group having six ring atoms (such as phenyl), substituted by one or more than one group of fluorescent, but preferably represents C1-alkiline, in particular C1-alkiline, group (such as methyl and especially ethyl), substituted by one or more than one group of fluorescent.

Preferably R2 is substituted groups, fluorescent in number from one to five, in particular three or four groups with fluorescent.

In one of the preferred embodiments R2 is a C1-alkyl, in particular C1-alkyl, substituted with three or four groups with fluorescent.

One of the preferred values for R2 is CF2CHF2.

In another particularly preferred embodiment R2 represents CH2CF3.

The appropriate value of n is 1 or 2 and preferably 1. Preferably Deputy R2O - ring is in the para-position relative to the designated connec the deposits to the ring.

R1 represents a suitable possibly substituted group selected from C1-4-alkyl (such as methyl or ethyl), aryl having six ring atoms (such as phenyl), 5-6-membered geteroseksualbnogo ring containing one or two ring heteroatoms, which may be the same or different, selected from N, O and S, such as piperidinyl or tetrahydropyranyl), or C1-alkyl-heteroaryl where heteroaryl has up to six ring atoms and contains one or two ring heteroatoms selected from N, O and S (such as alkylpyridine or alkylpyridine).

Preferably R1 represents a possibly substituted 5-6-membered geteroseksualnoe ring containing one or two ring heteroatoms, which may be the same or different, selected from N, O and S, or C1-alkyl-heteroaryl group having up to six ring atoms and containing one or more heteroatoms, which may be the same or different, selected from N, O and S, possibly substituted on the heteroaryl ring.

In one of the preferred embodiments R1 is unsubstituted.

In one of the preferred embodiments R1 is tetrahydropyranyloxy group, in particular 4-tetrahydropyranyl.

In another preferred embodiment R1 represents a C2-alkyl-pyrimidinyl group is, possibly substituted by pyrimidinedione ring.

One of the preferred values for R1 is 2-pyrimidinyl-SNSN-. Other particularly preferred value for R1 is 2-pyrimidinyl-SNSDS-.

Suitable possible substituents for R1 include one or more than one group independently selected from NO2, CF3, CN, halogen, C1-alkyl, carboxy(C1-4)alkyl, cycloalkyl, -OR4, -SR4, C1-alkyl, substituted by-OR4, SR4 (and its oxidized analogues), NR4, N-Y-R4, or C1-alkyl-Y-NR4 where R4 represents hydrogen, C1-alkyl, aryl, heteroaryl or C1-alkyl-aryl, each of which independently possibly substituted with halogen, NO2, CN, CF3, C1-alnilam, -S-C1-alkyl, -SO-C1-alkyl, -SO2-C1-alkyl or C1-alkoxy, and Y is selected from-SO2 - and-CO-.

When R1 in the compounds of formula (I) is substituted, preferably it is substituted by one or two substituents, which may be identical or different, chosen from C1-alkyl, halogen, CF3 and CN. The preferred Deputy is halogen, in particular fluorine. Preferably, when R1 is substituted, it is monosubstituted. One of the preferred values for R1 in the compounds of formula (I), where R1 is substituted, is 5-F-2-pyrimidinyl-SNSN-.

It should be understood that the number and nature of substituents on the ring formed by R1 and/or R2 in the compounds according to the invention are selected so that and in order to escape steric undesirable combinations.

In one preferred group of compounds according to the invention R2 represents a C1-alkyl, substituted groups, fluorescent in number from one to five; n is 1; ring b is a phenyl, pyridinyl or pyrimidinyl and R1 represents a possibly substituted 5-6-membered geteroseksualnoe ring containing one or two ring heteroatoms, which may be the same or different, selected from N, O and S, or C1-alkyl-heteroaryl group having up to six ring atoms and containing one or more heteroatoms, which may be the same or different, selected from N, O and S, possibly substituted on the heteroaryl ring.

Particularly preferred compounds according to the invention in this group are compounds in which R1 is not substituted or substituted with halogen, in particular fluorine.

Specific compounds include

In those cases where the compounds according to the invention contain one or more than one asimmetricheskii substituted carbon atom, the invention includes all stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures. Also includes tautomers and mixtures thereof.

The racemates can be separated into individual enantiomers using known techniques (see Advanced Organic Chemistry: 3rdEdition: author J March, p.104-107). A suitable method involves the formation of diastereomeric derivatives by reacting racemic substances with a chiral auxiliary substance with subsequent separation of diastereoisomers, for example, by chromatography, and then the removal of these auxiliary substances.

Not wanting to be limited to the original definitions, I believe that in this case, the active enantiomer has S-stereochemistry. This is based on comparison with related compounds have been confirmed by this absolute configuration. Accordingly, the S-structure is indicated in the following formulas in the examples. However, it should be understood that the racemate of any of the compounds according to the invention can be separated into individual enantiomers by the way, the presentation is mentioned above, and the more active enantiomer can then be identified by a suitable method of analysis without the need for determination of absolute configurations.

Compounds according to the invention can be offered in the form of pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include basic salts such as alkali metal salt, e.g. sodium salt, alkaline earth metal, e.g. calcium or magnesium salt of an organic amine, such as triethylamine, research, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylamine, or amino acids, for example lysine. In another aspect, when the connection is fairly basic, suitable salts include salts of joining acids such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate and salts formed with phosphoric and sulphuric acid.

Suitable prodrugs of the compounds of formula (I) are compounds that are hydrolyzed in vivo to form compounds of formula (I). They can be obtained by traditional methods.

In the present invention is also a method for obtaining compounds of formula (I)as defined above, or its pharmaceutically acceptable salts, prodrugs or solvate comprising transforming a suitable gidrauxilirovania formula (V)

where R2, n, ring b and R1 are as defined in formula (I), the compound of formula (I) by formirovaniya with a suitable mixed anhydride and then, if necessary, the conversion of the compounds obtained into another compound of the invention and/or the formation of pharmaceutically acceptable salts, prodrugs or MES this connection.

The process of formirovaniya can appropriately carry out by reacting the compounds of formula (IV) with the mixed anhydride obtained by the interaction of formic acid and acetic anhydride. Interaction is easily carried out in the presence of organic acids, such as formic acid. The interaction is preferably carried out in a suitable inert solvent or diluent, such as dichloromethane (DHM) or tetrahydrofuran, and at a temperature in the range of, for example, from 0 to 50°C.

The compounds of formula (IV) can be obtained from the corresponding alkene of formula (III)

where R2, n, and R1 are as defined in formula (I), which itself can be obtained from the corresponding compounds of formula (II)

where R2, n and ring b are as defined in formula (I), by reacting with a suitable compound of formula R1CHO (where R1 are the two which is the same as defined for formula (I)or by reacting with a suitable complex ether with the formation of the ketone, followed by reduction to the corresponding alcohol and dehydration. It should be understood that the compound of formula (III) may be in the form of E - or Z-isomer, or mixtures thereof. The structure presented in formula (III), does not imply limitation to any specific geometric isomerism around the double bond.

Compounds of formulas (III) and (IV) can be obtained using known methods by methods similar to the methods described in the aforementioned WO 00/12478, WO 00/75108 and WO 01/62742. Examples of ways of getting some of these compounds are given below in the examples.

The compounds of formula (II), (III) and (IV) are new and form a further aspect of the invention. Specific compounds of formula (II) include the

Examples of methods for obtaining these compounds are given below in the examples.

The compounds of formula (I) can be converted into other compounds of formula (I) using standard techniques common in the art.

It should be understood that the formation of compounds of formula (I) may include, at various stages of the accession and the removal of one or more than od is Oh protective group. The introduction of protective groups and unprotect functional groups described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, by T.W. Greene and P.G.M. Wuts, Wiley-lnterscience (1991).

Compounds according to the invention are inhibitors of metalloproteinases, in particular, they are inhibitors of collagenase 3 (MMR) and therefore indicated for the treatment of diseases or conditions mediated by metalloproteinase enzymes, including arthritis (such as osteoarthritis), atherosclerosis and chronic obstructive pulmonary disease (COPD), as discussed above. In particular, the compounds according to the invention is shown in the treatment of diseases or conditions mediated by collagenase 3 (MMR). A particular advantage of inhibitors of collagenase 3 according to the invention is that they exhibit improved selectivity compared with other metalloproteinases.

Thus, in an additional aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, prodrug or MES, as defined above, for use in therapy of the human or animal.

Also in the invention it is proposed to use the compounds of formula (I) or its pharmaceutically acceptable salt, prodrug or MES, as defined above, in the production of drugs for use in therapy.

When edue to understand what "therapy" also includes "prevention", unless otherwise specified. The terms "therapeutic" and "therapeutically" should be understood accordingly.

In yet another additional aspect of the present invention, a method of treatment of a pathological state mediated metalloproteinases, including the introduction of a warm-blooded animal a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, prodrug or MES.

It should be understood that the insertion dosage will vary depending on the compound, the route of administration, the desired treatment and the disorder. Usually take a daily dose of from 0.5 to 75 mg/kg of body weight (and preferably from 0.5 to 30 mg/kg body weight). This daily dose can be given in divided doses, if necessary, with the exact number of accepted connections and route of administration depend on the weight, age and sex of the patient treated, and the specific painful conditions, which are treated in accordance with principles known in this field.

The compounds of formula (I) and their pharmaceutically acceptable salts, prodrug and the solvate can be used by themselves, but usually they will enter in the form of a pharmaceutical composition together with a pharmaceutically acceptable adjuvant, R is zbavitel or the media.

Thus, the present invention also proposed a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt, prodrug or MES together with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions according to the invention can be activated by a method generally accepted for a painful condition, which is required to treat, for example oral, local, parenteral, buccal, nazalnam, vaginal or rectal insertion or by inhalation. For these purposes the compounds according to this invention can be prepared using known in this field means in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely ground powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) in the form of a sterile aqueous or oily solutions or suspensions or sterile emulsions.

In addition to the compounds of the present invention the pharmaceutical composition according to the invention may also contain one or more than one pharmacological agent, is indicated for the treatment of one or more than one painful condition that is specified to enter the, or it can be put together with so(s) agent(s) (simultaneously or sequentially). Usually the standard dosage forms will contain from about 1 to 500 mg of the compounds according to the invention.

The activity and selectivity of the compounds according to the invention can be determined using the appropriate test on the inhibition of the enzyme as described in WO 00/12478, WO 00/75108 and WO 01/62742. Inhibitory activity against collagenase 3 (MMR) can be estimated, for example, using methods described below.

Recombinant human proMMP13 can be expressed and purified as described Knauper et al. [V. Knauper et al., (1996) The Biochemical Journal 271:1544-1550 (1996)]. The purified enzyme can be used to control the activity of inhibitors as follows: purified proMMP13 activate using 1 mm aminophenylarsonic acid (amino phenyl mercuric acid, ARMA), for 20 hours at 21°C; activated MMR (11,25 ng per assay) are incubated for 4-5 hours at 35°C in the buffer for testing (0.1 M Tris-HCl, pH 7.5, containing 0.1 M NaCl, 20 mm CaCl2, 0.02 mm ZnCl and 0.05% (wt./about.) Brij 35 using the synthetic substrate 7-methoxycoumarin-4-yl)acetyl. Pro. Leu.Giy.Leu. N-3-(2,4-dinitrophenyl)-L-2,3-.Ala.Arg.NH2in the presence or in the absence of inhibitors. The activity is determined by measuring fluorescently when λ 328 nm and λem 393 nm. ISM is losing activity in the concentration range can be obtained curve, from which can be determined IC50 represents the inhibitor concentration at which the enzyme activity is reduced by 50%.

It should be understood that the pharmacological properties of the compounds according to the invention will vary depending on their structure, but, in General, as determined by the analysis described above, the compounds according to the invention show inhibitory activity against collagenase 3 with IC50 concentrations in the range from 0.01 to 1000 nm. The following table shows the IC50 values for representative samples of the compounds according to the invention that were tested in the above assay.

Compound of example No.IC50 (nm)
2B0,24
2nd13,0
53,6
7a0,12
7b0,19
7th2,8
8b1,5
G4,0

The compound of the formula I can apply the combination with other drugs and therapies, used in the treatment of painful conditions in which it is useful in the inhibition of metalloproteinases, in particular collagenase 3 (MMR). For example, the compound of the formula I can be used in combination with other drugs and therapies used in the treatment of rheumatoid arthritis, asthma, inflammatory bowel disease, multiple sclerosis, AIDS, septic shock, congestive heart failure, ischemic heart disease, psoriasis and other painful conditions mentioned above in this description.

For example, due to its ability to inhibit metalloproteinases compound of formula I useful in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with nonsteroidal anti-inflammatory drug (NSAID), inhibiting cyclooxygenase, such as indomethacin, Ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of compounds of formula 1 according to the present invention with an NSAID may cause a reduction in the number of the last agent required to achieve a therapeutic effect. In this regard, decreases the likelihood of adverse side effects from NSAlD, such as effects on the gastrointestinal tract. Thus, in accordance with an additional aspect of the image is to be placed the proposed pharmaceutical composition, which includes a compound of formula I or its pharmaceutically acceptable salt in combination or mixture with non-steroidal anti-inflammatory agent, inhibiting cyclooxygenase, and a pharmaceutically acceptable diluent or carrier.

The compound of the formula I can also be used with anti-inflammatory agents, such as inhibitors of the enzyme 5-lipoxygenase.

The compound of the formula I can also be used in the treatment of conditions such as rheumatoid arthritis, in combination with anti-arthritis agents, such as gold, methotrexate, steroids and penicillinases, and conditions such as osteoarthritis, in combination with steroids.

The compound of formula I also can be used to degradative diseases, such as osteoarthritis, chondroprotective, antidegradation and/or reparative agents such as Diacerhein, hyaluronic acid, such as hyalgan, rumalon, arteparon and glucosamine salts such as antril.

The compound of the formula I can be used in the treatment of asthma in combination with anti-asthmatic agents, such as steroids, bronchodilators, and leukotriene antagonists.

In particular, for the treatment of inflammatory diseases, rheumatoid arthritis, osteoarthritis, psoriasis, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma and the lergicheskie rhinitis compound of the present invention can be combined with such agents, as inhibitors of TNF-α, such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D.sub2.E.sub7.) and TNF receptor immunoglobulin molecules (such as Enbrel.reg.), non-selective inhibitors of cyclooxygenase-1 (MOR-1)/cyclooxygenase-2 (SOH-2) (such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as mefenamovaya acid, indomethacin, sulindac, Amazon, pyrazolones such as phenylbutazone, salicylates such as aspirin), inhibitors MOR-2 (such as meloxicam, celecoxib, rofecoksib, valdecoxib or etoricoxib), methotrexate in low doses, lefunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with a leukotriene biosynthesis inhibitor, inhibitor of 5-lipoxygenase (5-LO) or an antagonist of a protein that activates 5-lipoxygenase (FLAP), such as zileuton; ABT-761; Finlayson; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophene-2-alkylsulfonamides; 2,6-di-tert-butylbenzothiazole; methoxyethylamine, such as Zeneca ZD-2138; the compound SB-210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739010; 2-cyanohydrine compounds such as L-746530; indole and quinoline is e connection such as MK-591, MK-886, and BAY x 1005.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with leukotriene receptor antagonists LTB4, LTC4, LTD4and LTF4selected from the group consisting of phenothiazines-3-ones such as L-651392; amidinopropane, such as CGS-s; benzoxazepine, such as ontazolast; benzoperoxide, such as BIIL 284/260, and of compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-254913, iralukast (CGP A), and BAY × 7195.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with a PDE4 inhibitor including an inhibitor of the isoform PDE4D.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with antagonists antihistaminic receptors H1such as cetirizine, loratadine, desloratadine, Fexofenadine, astemizole, azelastine and chlorpheniramine.

In addition, the present invention additionally relates to the combination of the compounds of formula 1 together with gastroprotective receptor antagonist N2.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with agonist α1and α2-adrenoceptors sympathomimetic agent such as profile sedrin, phenylephrine, phenylpropanolamine, pseudoephedrine hydrochloride nafazolina, Oxymetazoline hydrochloride, the hydrochloride of tetrahydrozoline, hydrochloride Xylometazoline and hydrochloride Ethylmorphine.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with anticholinergic agents such as ipratropium bromide; Tiotropium bromide; oxytrope bromide; pirenzepine, telenzepine.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with agonists β14-adrenergic receptors, such as metaproterenol, isoproterenol, izoprenalin, albuterol, salbutamol, formoterol, salmeterol, terbutaline, oxydianiline, mesilate of bitolterol and pirbuterol, or methylxanthine, including theophylline and aminophylline; kromoglikatom sodium, or an antagonist of muscarinic receptors (M1, M2 and M3).

In addition, the present invention additionally relates to the combination of the compounds of formula I together with mimetic insulin-like growth factor type I (IGF-I).

In addition, the present invention additionally relates to the combination of the compounds of formula I together with inhaled by glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beckom is Casona dipropionate, budesonide, fluticasone propionate and mometasone furoate.

In addition, the present invention additionally relates to the combination of the compounds of formula I, together with other modulators of the function of chemokine receptors such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR3, CXR4 and CXCR5 (for the C-X-C family) and CX3CR1 for C-X3-From the collection.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with antiviral agents such as Viracept, AZT, acyclovir, and famciclovir, and antiseptic compounds, such as Valant.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with cardiovascular agents such as calcium channel blockers, agents for reducing lipid levels, such as statins, fibrates, beta-blockers, inhibitors of angiotensin-converting enzyme (ACE inhibitors, receptor antagonists angiotensin-2 and platelet aggregation inhibitors.

In addition, the present invention additionally relates to the combination of the compounds of formula I together with agents for the Central nervous system, such as antidepressants (such as sertraline), anti-Parkinson drugs (such as deprenyl, L-DOPA, Requip, Mirapex inhibitors IAIA, such as selgin and rasag the Lin, the comP inhibitors such as Tasmar inhibitors a-2, inhibitors of reuptake of dopamine, NMDA inhibitors, agonists nicotine, dopamine agonists and inhibitors of neuronal synthase nitric oxide) and drugs for treatment of Alzheimer's disease, such as donepezil, taken inhibitors SOH-2, propentofylline or metrifonate.

In addition, the present invention additionally relates to the combination of the compounds of formula I, together with (1) tryptase inhibitors; (2) antagonists of platelet activating factor (PAF); (3) inhibitors of interleukin converting enzyme (ICE); (4) IMPDH inhibitors; (5) inhibitors of adhesion molecules, including antagonists of VLA-4; (6) cathepsins; (7) inhibitors MAR-kinase; (8) inhibitors of glucose-6-phosphate-dehydrogenase; (9) receptor antagonists kinin-In1and-B2; (10) anti-gout, such as Kalinina; (11) inhibitors of xanthine oxidase, for example allopurinol; (12) the means for facilitating the excretion of uric acid, for example probenecid, sulfinpirazonom and benzbromarone; (13) a stimulant of growth hormone secretion; (14) transforming growth factor (TGFβ); (15) platelet-derived growth factor (PDGF); (16) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (17) granulocyte-macrophagecolony colony-stimulating factor (GM-CSF); (18) capsaicin is the first cream; (19) receptor antagonists tachykinin NK1and NK3selected from the group consisting of NKP-608C, SB-233412 (talnetant) and D-4418; (20) elastase inhibitors selected from the group consisting of UT-77 and ZD-0892; (21) inhibitors TNF converting enzyme (TACE); (22) inhibitors of the inducible synthase nitric oxide (iNOS inhibitors) or (23) receptor-homologous molecule for chemoattractant located on T-cells (CRTH2 antagonists).

The compound of the formula I can also be used in combination with anti-osteoporosis agents, such as raloxifen, droloxifene, lasofoxifene or fosomax, and immunosuppressive agents such as FK-506, rapamycin, cyclosporine, azathioprine and methotrexate.

The compound of the formula I can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's)such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, Ketoprofen and ibuprofen, fenamate, such as mefenamovaya acid, indomethacin, sulindac, Amazon, pyrazolones such as phenylbutazone, salicylates such as aspirin, inhibitors SOH-2 such as celecoxib, valdecoxib, rofecoksib or etoricoxib, analgesics and intra-articular therapeu the practical agents, such as corticosteroids and hyaluronic acids such as hyalgan and synvisc, and receptor antagonists RH.

The compound of the formula I can also be used in combination with existing therapeutic agents for the treatment of cancer. Suitable agents are used in combination, include:

(1) antiproliferative/antineoplastic drugs and combinations thereof, used in medical Oncology, such as alkylating agents (for example CIS-Platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoanatabine); antimetabolites (for example antifolates such as ftorpirimidinu like 5-fluorouracil and tegafur, raltitrexed, methotrexate, citizenoriented, hydroxyurea, gemcitabine and paclitaxel (Taxol®); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsina, mitomycin-C, dactinomycin and mithramycin); antimitoticescoe agents (for example, vinylchloride, such vincristine, vinblastine, vindesine and vinorelbine, and taxaide like Taxol and Taxotere) and topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(2) cytostatic agents such as antiestrogens (for example tamoxifen, t is Reifen, raloxifene, droloxifene and idoxifene), negative regulators of estrogen receptors (for example fulvestrant), antiandrogens (for example, bikalutamid, flutamide, nilutamide and acetate cyproterone), LHRH antagonists or LHRH agonists (for example goserelin, leiprorelina and buserelin), POCs (for example, megestrol acetate), aromatase inhibitors (e.g. anastrozole, letrozole, varsol and exemestane) and inhibitors of 5α-reductase such as finasteride;

(3) agents which inhibit the invasion of cancer cells (for example, inhibitors of metalloproteinases, such marimastat, and inhibitors function urokinase receptor plasminogen activators);

(4) inhibitors of the function of growth factor such inhibitors include antibodies, growth factor, antibodies to the receptor of the growth factor (e.g., anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibody cetuximab [S]), inhibitors farnesyltransferase, tyrosine kinase inhibitors and inhibitors of serine/trionychinae, for example, inhibitors of the family of growth factor epidermis (for example inhibitors of protein tyrosine kinase EGFR, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)hinzelin-4-amine (CI 1033)), for example ing bitory family of platelet-derived growth factors, and, for example, inhibitors of the family of growth factors hepatocyte;

(5) antiangiogenic agents, such as agents that inhibit the effects of vascular endothelial growth factor (for example, an antibody against vascular endothelial growth factor bevacizumab [Avastin™], compounds such as the compounds disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)and compounds with other mechanisms (for example, linomide, inhibitors of the function of αvβ3 integrin and angiostatin);

(6) sosudorasshiryayuschee agents, such as Combretastatin A4 and compounds disclosed in international patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(7) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, antisense anti-ras;

(8) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme proletarienne therapy), such as approaches that use citizendiumissue, timedancing or bacterial enzyme nitroreductase, and approaches to increase the tolerance of the patient to chemotherapy or radiotherapy such as gene therapy multidrug resistance, and

(9) immunotherapeutical approaches, including, for example the EP, ex vivo and in vivo approaches to increase the immunogenicity of tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophagecolony colony stimulating factor, approaches to decrease the anergy of T cells, approaches using transfetsirovannyh immune cells such as cytokine-transfetsirovannyh dendritic cells, approaches using cytokine-transfetsirovannyh tumor cell lines and approaches using anti-idiotypical antibodies.

If a pharmaceutical product is presented in the form of a fixed dose, such combination products employ the compound of formula I in the dosage range described in this document, and other pharmaceutically-active agent in the relevant dose range. Consistent application provided for in cases where a combined pharmaceutical preparation is unsuitable.

Although the compound of formula I is mainly useful as a therapeutic agent for use in warm-blooded animals (including humans), also it is always useful when you want inhibition effects metalloproteinases. Thus, the compound is useful as pharmacological standards for use in the development of new biological tests is when the search for new pharmacological agents.

Further, the invention is illustrated in the following non-limiting examples.

Suitable source materials are commercially available or they can be obtained by any suitable method described in the literature or known to the specialist-chemist, or described in the examples given in this description. In addition, the following table presents detailed information about the intermediate compounds and their corresponding registration numbers in Chemical Abstracts.

Registration
rooms at Chemical
Abstracts
5-Iodine-2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine497915-65-8
Ethyl-4-pyrimidine-2-ibotnet459818-75-8
4-Pyrimidine-2-albuterol260441-10-9
Ethyl-3-pyrimidine-2-ispropanol459818-76-9

The spectra of nuclear magnetic resonance (NMR spectra)specified in the examples were measured at room temperature on a spectrometer BRUKER DPX at field strength of 400 MHz, unless otherwise specified. SPECT is s contain a link to an internal deuterium standard. Mass spectra (MS) were measured on a Micromass spectrometer MZD (elektrorazpredelenie).

Used the following abbreviations:

DHM - dichloromethane

THF - tetrahydrofuran

LiHMDS - hexamethyldisilazide lithium

DMSO-dimethyl sulfoxide

TFU - triperoxonane acid

EXAMPLE 1

Hydroxy{(1S)-4-pyrimidine-2-yl-1-[({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)methyl]butyl}formamide

To formic acid (114 ml, 3.03 mol) at 0°C was added acetic anhydride (28,6 ml, 0,303 mol) and the mixture was stirred at room temperature (RT) for 10 minutes. Then the reaction mixture was again cooled to 0°C and added to a solution of 2-(4-{[2-(hydroxyamino)-5-pyrimidine-2-alpental]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine (30,6 g of 60.5 mmol) and formic acid (114 ml, 3.03 mol) in THF (600 ml). The reaction mixture was brought to room temperature and was stirred for one hour. Then the vacuum was removed volatiles and the residue was subjected to azeotropic distillation with toluene (2×300 ml). Then the residue was dissolved in methanol (300 ml) and was heated to 40°C for one hour. Then the solution was cooled to room temperature and concentrated in vacuum. Then the residue was purified flash chromatography (silica gel, 10% Meon in EtOAc) with the formation of the racemic compounds as pale orangevalley (22,94 g, 43 mmol, 71%).

The racemic mixture was separated chiral HPLC using the following conditions:

Column 20 μm Chiralpak AD, Merck 100 mm

Eluent MeCN/Meon 90/10 (7 min, isocratic elution),

MeCN/MeOH 90/10 (speed), MeCN/Meon 85/15 (10 min, isocratic), MeCN/Meon 85/15 (gradient, 1 min), MeCN/EtOH 85/15 (isocratic, 37 min).

The flow rate 120 ml/min

Individual enantiomers may be obtained in crystalline form by using the following methods.

40 g specified in the title compound was stirred with ethanol (50 ml) at room temperature for 30 minutes. The solvent was removed in vacuum. The resulting solid was stirred in acetone (20 ml) at room temperature for 24 hours. The solvent was removed in a stream of argon, and then in vacuum.

1H NMR (DMSO-D6, C): 9.39 (br s, 1H), 8.67 (d, 2H), 8.32 (s, 2H), 8.15 (br s, 1H),7.28(t, 1H), 4.70 (q, 2H), 4.39 (br s,1H), 3.79 (m, 4H), 3.47 (dd, 1H), 3.29 (m, 4H), 3.17 (dd, 1H), 2.91 (m, 2H), 1.75 (m, 4H).

MS (ESI): 534,01 (MH+).

TPL 129-133°C.

Starting material was prepared as follows.

To a stirred suspension of 5-iodine-2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine (25,0 g, with 67.9 mmol), benzyl alcohol (125 ml), 1,10-phenanthroline (2,45 g, 20 mol.%) and cesium carbonate was added copper iodide(I) (12.9 g, with 67.9 mmol) and the reaction mixture was heated to 110°C for 90 minutes and then cooled to room temperaturesare added DHM (250 ml) and the insoluble substance was filtered through a gasket from celite. The precipitate was washed DHM (250 ml) and DHM the filtrate washed with water. Then the aqueous phase was subjected to back extraction with additional DHM (500 ml), the combined DHM extracts were washed with brine (500 ml), dried (MgSO4), filtered and concentrated in vacuum to obtain a dark brown thick sludge. This thick residue is then purified flash chromatography (silica gel, 50% EtOAc/hexane)to give 5-(benzyloxy)-2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine in the form of a whitish solid (14.2 g, up 40.7 mmol, 60%).

1H NMR (CDCl3): 8.20 (s, 2H), 7.49 (m, 5H), 5.05 (s, 2H), 3.88 (m, 4H), 3.30 (m, 4H), 2.79 (s, 3H).

MS (ESI): 349,08 (MH+).

5-(Benzyloxy)-2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine (57,9 g to 0.17 mol) was dissolved in TFU (600 ml) and the reaction mixture is boiled under reflux with stirring for 7 hours, then cooled to room temperature. Then the vacuum was removed TFU and the residue was subjected to azeotropic distillation with toluene (2×300 ml). The resulting solid is triturated with DHM, was filtered, washed with ether, and dried, obtaining 2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine-5-ol as a pale yellow solid (54,4 g, 0.15 mol, 88%, salt TFU).

1H NMR (DMSO-D6): 8.02 (s, 2H), 3.68 (m, 4H), 3.12 (m, 4H), 2.86 (s, 3H).

To a stirred suspension of 2-[4-(methylsulphonyl)piperazine-1-yl]pyrimidine-5-ol (53,5 g, 0,145 mol), K2 CO3(100,1 g, 0,725 mol) in acetone (1 l) was added 2,2,2-triptorelin-nonattributable (78 g, 0,203 mol) and the reaction mixture was heated to 60°C for 6 hours and then cooled to room temperature. Then the reaction mixture was filtered and the filtrate was evaporated until dry. The residue was distributed between DHM (500 ml) and water (500 ml), was extracted DHM (500 ml), the combined organic extracts were washed with brine (500 ml), dried (MgSO4), filtered and concentrated in vacuum, obtaining 2-[4-(methylsulphonyl)piperazine-1-yl]-5-(2,2,2-triptoreline)pyrimidine in the form of a whitish solid (45,3 g, 0.133 mol, 92%).

1H NMR (CDCl3): 8.15 (s, 2H), 4.32 (m, 2H), 3.90 (m, 4H), 3.30 (m, 4H), 2.78 (s, 3H).

MS (ESI): 341,08 (MN+).

Method 1

To a stirred suspension of 2-[4-(methylsulphonyl)piperazine-1-yl]-5-(2,2,2-triptoreline)pyrimidine (8,05 g, 23.6 mmol) in THF (175 ml) dropwise at -78°C. was added LHMDS (47,2 ml, to 47.2 mmol) and the reaction mixture was stirred for 15 minutes. Then at -78°C was added a solution of ethyl-4-pyrimidine-2-albuminate (5.5 g, 28.3 mmol) in THF (50 ml)was heated to -20°C and was stirred for 2 hours. Then the reaction was suppressed by addition of a saturated solution of NH4Cl (250 ml), and was twice extracted with EtOAc (2×250 ml), the combined organic extracts were washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuum to about the education yellow solid. This substance was then purified flash chromatography (silica gel, 50% EtOAc/hexane), receiving 5-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)pentane-2-it is in the form of a whitish solid (for 9.47 g of 19.4 mmol, 82%).

1H NMR (CDCl3): 8.66 (d, 2H), 8.16 (s, 2H), 7.12 (t, 1H), 4.30 (m, 2H), 4.00 (s, 2H), 3.82 (m, 4H), 3.34 (m, 4H), 2.98 (t, 2H), 2.85 (t, 2H), 2.16 (m, 2H).

MS (ESI): 489,02 (MN+).

To a stirred solution of 5-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)pentane-2-she (for 9.47 g of 19.4 mmol) in a mixture DHM/Meon (100 ml/100 ml) portions was added NaBH4(807 mg, of 21.3 mmol) and the reaction mixture was stirred at room temperature. Then the reaction was suppressed by addition of a saturated solution of NH4Cl (250 ml) and the organic matter was removed in vacuum. The aqueous residue was then extracted with EtOAc (2×250 ml), the combined organic extracts were washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuum, obtaining 5-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)pentane-2-ol as a white solid (9,10 g of 18.6 mmol, 96%).

MS (ESI): 491,13(MH+).

To a stirred solution of 5-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)pentane-2-ol (9,10 g of 18.6 mmol), triethylamine (13 ml, 93,0 mmol) in DHM (200 ml) at 0°C was added methanesulfonamide (2,16 ml, 7.9 mmol). The reaction mixture was stirred at 0°C for 15 minutes, heated to room temperature and was stirred for 16 hours. Then the reaction mixture was washed with water (200 ml) and the aqueous portion was subjected to back extraction DHM (200 ml). United DHM extracts were washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuum, obtaining 2-(4-{[(1E)-5-pyrimidine-2-ipent-1-EN-1-yl]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine as an orange solid (8,79 g of 18.6 mmol, 100%).

MS (ESl): 472,49 (MN+).

To a stirred solution of 2-(4-{[(1E)-5-pyrimidine-2-ipent-1-EN-1-yl]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine (8,79 g of 18.6 mmol) in THF (90 ml) was added 50%aqueous solution of hydroxylamine (18 ml) and the reaction mixture was stirred at room temperature for 2 hours. Then was added a saturated solution of NH4Cl (200 ml)and then twice was extracted with EtOAc (2×250 ml), the combined organic extracts were washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuum, obtaining 2-(4-{[2-(hydroxyamino)-5-pyrimidine-2-alpental]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine as a pale yellow solid (8,96 g of 17.7 mmol, 95%).

MS (ESl): 506,05 (MH+).

Method 2

To a stirred suspension of 2-[4-(methylsulphonyl)piperazine-1-yl]-5-(2,2,2-cryptgetuserkey (850 mg, of 2.50 mmol) in THF (25 ml) dropwise at -78°C. was added LHMDS (5.5 ml, 5.5 mmol) and the reaction mixture was stirred for 15 minutes. Then add diethylphosphate (0.4 ml, a 2.75 mmol) and was stirred for 15 minutes. Then this solution was treated with a solution of 4-pyrimidine-2-ivatans (413 mg, of 2.75 mmol) in THF (5 ml) dropwise, was left to warm to -20°C and was stirred for 1 hour. Then the reaction was suppressed by addition of a saturated solution of NH4Cl (100 ml), and was twice extracted with EtOAc (2×100 ml), the combined organic extracts were washed with brine (100 ml), dried (MgSO4), filtered and concentrated in vacuum with the formation of a yellow oil. This oil was then purified flash chromatography (silica gel, 50% EtOAc/hexane)to give 2-(4-{[(1E)-5-pyrimidine-2-ipent-1-EN-1-yl]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine as a yellow solid (1.13 g, 2,39 mmol, 96%).

MS (ESl): 472,49 (MH+).

Then this substance was converted into 2-(4-{[2-(hydroxyamino)-5-pyrimidine-2-alpental]sulfonyl}piperazine-1-yl)-5-(2,2,2-triptoreline)pyrimidine and then in hydroxy{(1S)-4-pyrimidine-2-yl-1 -[({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfonyl)methyl]butyl}formamide by the same methods as described in method 1.

EXAMPLE 2

Also, there were obtained the following compounds.

No.XR1M+NWas obtained using method 1 or method 2
and2-Pyrimidinylidene532,982
b2-Pyrimidinyl-5-ferns537,102
in4-Tetrahydropyranyl497,021
gN2-Pyrimidinyl519,882
dN2-Pyrimidinyl-5-ferns537,892
eN4-Tetrahydropyranyl498,091

EXAMPLE 3

Hydroxy{(1S)-3-pyrimidine-2-yl-1-[({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)methyl]propyl}formamide

To formic acid (54 ml, 1.4 mol) at 8°C was added acetic anhydride (11 ml, 100 mmol) and the mixture was stirred at RT for 10 minutes. Then the mixed anhydride was again cooled to 8°C and added to pre-cooled to 0°C. a solution of 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)butyl]pyrimidine (16,32 g, 33.3 mmol) in DHM (170 ml) and formic acid (65 ml, 1.7 mol). The reaction mixture was brought to room temperature and was stirred for one hour. Then the vacuum was removed volatiles and the residue was subjected to azeotropic distillation with toluene (2×50 ml). Then the residue was dissolved in a mixture of Meon/GHM (1:1, 250 ml) and was stirred over night at room temperature. Then the solution was concentrated in vacuum and distributed between DHM (250 ml) and saturated NaHCO3(250 ml). After that DHM layer was filtered through silica gel (20 g), washing with a mixture of 5% Meon/DHM, and volatiles were removed in vacuum, obtaining specified in the racemic title compound as a pale yellow foam (15,68 g, 302 mmol, 91%).

Racemic mixture (86,5 g) was separated into the enantiomers by chiral HPLC using the following conditions:

Column 20 μm Chiralpak AD, Merck 100 mm

Eluent MeCN/MeOH 90/10 (17 min, isocratic elution), MeCN/MeOH 90/10 (speed), MeCN/EtOH 90/10 (8 min, isocratic), MeCN/EtOH 90/10 (the gradient is, 1 min), MeCN/EtOH 85/15 (isocratic, 39 min).

The flow rate 120 ml/min

Concentrated in vacuo to a foam. Was subjected to crystallization from hot ethanol (430 ml), was filtered and washed with ethanol and ether. Dried, obtaining mentioned in the title compound as a white crystalline solid (28 g, 54 mmol).

1H NMR (DMSO, C): 9.41 (s, 1H), 8.66 (d, 2H), 8.07 (s, 1H), 7.99 (d, 1H), 7.38 (dd, 1H), 7.26 (t, 1H), 6.83 (d, 1H), 4.61 (q, 2H), 4.45 (B, 1H), 3.51 (t, 4H), 3.47 (d, 1H), 3.27 (t, 4H), 3.24 (d, 1H), 2.91 (t, 2H), 2.17 (m, 2H).

MS (ESI): 519(MH+);

TPL 149-151°C.

Starting material was prepared as follows.

Intensively stirred suspension of 1-(5-bromopyridin-2-yl)piperazine (CAS number 73406-97-0, 116 g, 479 mmol), 1,10-phenanthroline (17.3 g, 96 mol), cesium carbonate (312 g, 960 mmol) and copper iodide(I) (91 g, 480 mmol) in benzyl alcohol (960 ml) was stirred at 120°C in an atmosphere of inert gas within 24 hours, adding every hour additional aliquots of copper iodide(I) (5×91 g).

Was cooled to 40°C. and diluted DHM (1 l)while stirring at room temperature for 30 minutes. Filtered through celite, rinsing well DHM (500 ml). Fractions were washed with NaOH (2 M, 300 ml)were combined and extracted with HCl (2 M, 5×1 l). The combined acid extracts were washed DHM (500 ml), cooled to 0°C. and was extracted with DHM (1 l), slowly Podlachia NaOH (~46%by weight) to pH 10. The aqueous layer was additionally extraheavy and DHM (2×500 ml) and the volatiles were removed in vacuum, getting 1-[5-(benzyloxy)pyridin-2-yl]piperazine in the form of a black liquid (104 g, 278 mmol @ 72 wt.%, 58%).

1H NMR (CDCl3): 8.0 (d, 1H), 7.2 (dd, 1H), 6.3 (d, 1H), 5.0 (s, 2H), 3.50 (s, 8H), 1.48 (s, 9H), 3.4 (IN, 5H), 3.0 (IN, 4H);.

MS (ESI): 270 (MH+)

Mix a solution of 1-[5-(benzyloxy)pyridin-2-yl]piperazine (104 g, 278 mmol) in CH2Cl2(1.1 l) at 0°C was sequentially treated with triethylamine (94 ml, 672 mmol) and methanesulfonamide (31 ml, 400 mmol). The reaction mixture was brought to room temperature and was stirred for 3 hours. Then the reaction mixture was diluted DHM (3 l) and washed with water (1 l), HCl (0.5 M, 2×800 ml) and saturated NaHCO3(800 ml), exposing the reverse extraction DHM (500 ml). Then the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuum, obtaining 1 -[5-(benzyloxy)pyridin-2-yl]-4-(methylsulphonyl)piperazine as a dark liquid (120 g, 278 mmol @ 81 wt.%, 100%).

1H NMR (CDCl3): 8.0 (d, 1H), 7.35 (m, 5H), 7.2 (dd, 1H), 6.65 (d, 1H), 5.05 (s, 2H), 3.55 (t, 4H), 3.3 (t, 4H), 2.8 (s, 3H).

MS (ESl): 348 (MN+).

1-[5-(Benzyloxy)pyridin-2-yl]-4-(methylsulphonyl)piperazine (120 g, 278 mmol) was dissolved in TFU (1.3 l) and the reaction mixture is boiled under reflux with stirring for 3 hours, then cooled to room temperature. Then TFU was removed in vacuum and the residue was subjected to azeotropic distillation with toluene (2×300 ml). About azovavto liquid was diluted DHM (100 ml) and slowly neutralized with saturated NaHCO 3(700 ml) to pH 8. The suspension was filtered, washed with water, a minimum number DHM and ether and dried, obtaining 6-[4-(methylsulphonyl)piperazine-1-yl]pyridine-3-ol as a beige solid (69 g, 270 mol, 97%).

1H NMR (DMSO-D6): 7.7 (d, 1H), 7.1 (dd, 1H), 6.75 (d, 1H), 3.45 (t, 4H), 3.2 (t, 4H), 2.85 (s, 3H).

MS (ESl): 257 (MH+).

To a stirred suspension of 6-[4-(methylsulphonyl)piperazine-1-yl]pyridine-3-ol (69 g, 270 mmol), K2CO3(112 g, 810 mmol) in acetone (1.8 l) was added 2,2,2-triptorelin-nonattributable and/or 2,2,2-triptorelin-triftorbyenzola (total 324 mmol) and the reaction mixture was stirred for 18 hours at room temperature. Then the reaction mixture was filtered and the filtrate was evaporated until dry. The residue was distributed DHM (2.5 l 500 ml) and water (1.5 l, 300 ml), was extracted DHM (500 ml), dried (MgSO4) and filtered. Concentrated in vacuo, diluted EtOH to a small volume, filtered and dried, obtaining 1-(methylsulphonyl)-4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine in the form of a whitish solid (62 g, 183 mmol, 68%).

1H NMR (CDCl3): 8.0 (d, 1H), 7.25 (dd, 1H), 6.65 (d, 1H), 4.3 (q, 2H), 3.6 (t, 4H), 3.35 (t, 4H), 2.8 (s, 3H).

MS (ESI): 340 (MN+).

To a stirred suspension of 1-(methylsulphonyl)-4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine (13.3 g, is 39.2 mmol) in THF (200 ml) dropwise at -70°C. was added LHMDS (75 ml, 75 mmol) and the reaction mixture was stirred for 20 minutes. Then at -70°C was added a solution of ethyl-3-pyrimidine-2-ImproveNet (9,2 g, 51 mmol) in THF (55 ml)was heated to -20°C and was stirred for 2 hours. Then the reaction was suppressed by addition of a saturated solution of NH4CI (250 ml), and was twice extracted with EtOAc (3×250 ml), the combined organic extracts were washed with brine (250 ml), dried (MgSO4), filtered and concentrated in vacuum with the formation of a yellow solid. This solid was stirred for 20 minutes in a mixture of 20% isohexane/ether (100 ml), filtered, washed with isohexane and dried, obtaining 4-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfanyl)butane-2-it is in the form of a whitish solid (15.2 g, to 32.2 mmol, 82%).

1H NMR (CDCl3): 8.6 (d, 2H), 7.95 (d, 1H), 7.2 (dd, 1H), 7.1 (t, 1H), 6.6 (d, 1H), 4.30 (q, 2H), 4.15 (s, 2H), 3.55 (t, 4H), 3.4 (t, 4H), 3.35 (t, 2H), 3,3 (t, 2H).

MS (ESl): 472 (MN+).

To a stirred solution of 4-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfanyl)butane-2-it (15 g, of 31.6 mmol) in a mixture of 10% Meon/DHM (300 ml) portions was added NaBH4(0.52 g, 15.8 mmol) and the reaction mixture was stirred at room temperature for 45 minutes. Then the reaction was suppressed by addition of a saturated solution of NH4Cl (100 ml), diluted with water (150 ml) and was extracted with DHM (3×200 ml), the combined organic extracts were dried (brine, MgSO4), filtered and which has koncentrirebuli in vacuum. Triturated with ether, filtered and dried, obtaining 4-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyrimidine-2-yl]piperazine-1-yl}sulfanyl)butane-2-ol in the form of a cream solid (13.8 g, 29,0 mmol, 92%).

MS (ESl): 476 (MN+).

To a stirred solution of 4-pyrimidine-2-yl-1-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfanyl)butane-2-ol (13,7 g, 28.8 mmol) in DHM (250 ml) at 0°C was added methanesulfonamide (2,68 ml, 34.6 mmol). The reaction mixture was stirred at 0°C for 20 minutes, then dropwise added triethylamine (18,1 ml, 129 mmol). Was heated to room temperature and was stirred for 16 hours. Then the reaction mixture was diluted DHM (1 l), washed with water (150 ml) and dried (brine, MgSO4), filtered and concentrated in vacuum. Then the residue was purified flash chromatography (silica, 0-5% Meon in DHM)to give 2-[(3E)-4-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)but-3-EN-1-yl]pyrimidine as a yellow solid (11.9 g, to 18.6 mmol, 90%).

MS (ESl): 458 (MN+).

To a stirred solution of 2-[(3E)-4-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)but-3-EN-1-yl]pyrimidine (10,9 g, with 23.7 mmol) in THF (200 ml) was added 50%aqueous solution of hydroxylamine (11 ml) and the reaction mixture was stirred at room temperature for 2 hours. Then added water (100 ml), then EtOAc (3×100 ml) and dried (brine, MgSO4), filtered and concentrated in vacuum, obtaining 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)butyl]pyrimidine as a pale yellow solid (11.1 g, and 22.6 mmol, 96%).

MS (ESl): 491 (MH+).

Alternative starting material was prepared as follows.

To a stirred suspension of 1-(methylsulphonyl)-4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine (23 g, 67.8 mmol, obtained as described above) in THF (450 ml) dropwise at -65°C. was added a solution of LiHMDS in THF (149 ml, 1.0 M solution, 149 mmol). Was stirred for 30 minutes. Added diethylphosphate (11.3 ml, 78 mmol) and was stirred for 1 hour. The solution was treated dropwise with a solution of 3-(2-pyridinyl)propionic aldehyde (12 g, at 88.1 mmol) in THF (290 ml), then left to warm to 0°C for 3 hours, and then extinguished with a solution of hydroxylamine (41 ml, 50%aqueous solution, 680 mmol). The reaction mixture was stirred for 16 hours at RT. The reaction mixture was washed with saturated NH4Cl (250 ml), exposing the back extraction with ethyl acetate (250 ml). Then the combined organic extracts were dried (brine and MgSO4), filtered and concentrated in vacuum. Then the residue triturated with ether for 1 hour, filtered and dried, obtaining 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-triptoreline)pyridine-2-yl]piperazine-1-yl}sulfonyl)b is Teal]pyrimidine (31,5 g, and 64.3 mmol, 95%).

1H NMR (CDCl3): 8.65 (d, 2H), 8.0 (d, 1H), 7.25 (dd, 1H), 7.15 (t, 1H), 6.65 (d, 1H), 4.3 (q, 2H), 3.55 (m, 6H), 3.4 (t, 4H), 3.2 (t, 2H), 2.9 (d, 1H), 2.25 (m, 1H), 2.1 (m,1H);

MS (ESl): 491 (MH+).

Example 4

Hydroxy[(1S)-2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)ethyl]formamide

It chilled in ice to a solution of 1-{[(2S)-2-(hydroxyamino)-2-(tetrahydro-2H-Piran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (52,9 g, 0.1 mol) in a mixed solvent system THF/formic acid (1 l /20 ml) was added a previously prepared mixture of formic acid (19 ml) and acetic anhydride (65 ml). The mixture was stirred at room temperature overnight. Then the solvents evaporated to small volume and the residue was distributed between dichloromethane (500 ml) and a saturated solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated to oil. Then it was stirred in methanol (500 ml) overnight, and then concentrated, receiving nonformulary product as a white solid. This solid contained small amounts of impurities, so it was stirred in diethyl ether for 4 hours, then was filtered and dried, obtaining hydroxy[(1S)-2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]peep the Razin-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)ethyl]formamide (51,41 g, 92%).

Hydroxy[(1S)-2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)ethyl]formamide (51,4 g) was dissolved in hot methanol (80 ml) and then left to cool slowly to room temperature over night. The white crystalline substance was filtered and dried. Then, this solid was stirred in isopropyl alcohol (190 ml) for 24 hours, then was filtered and dried at 50°C during the night. The crystalline substance was washed with diethyl ether and again dried for 2 days.

1H NMR (DMSO-D6): 9.95 and 9.60 (1H, s), 8.30 a.m. and 8.00 (1H, s), 7.15 (2H, d), 7.05 (2H, d), 6.75 (1H, tt), 4.45 and 3.85 (1H, t), 3.85 (2H, m), 3.40 (2H, m), 3.25 (10H, m), 1.75 (2H, m), 1.50 (1H, m), 1.25 (2H, m).

MS (ES): 514 (MH+).

TPL 175-176°C.

Starting material was prepared as follows.

1-Bromo-4-tetrabromodibenzo (number in CAS 68835-05-9, 12 g, 0.044 M) was dissolved in toluene (250 ml) in an argon atmosphere. Was added N-boc-piperazine (CAS number 57260-71-6, 9,79 g, 0,053 M), tert-butyl sodium (5,93 g 0,062 M), BINAP (96 mg) and diallydimethylammonium (96 mg). Was stirred at 80°C for 4 hours, cooled and filtered, the insoluble substance (rinsing with toluene). The filtrate was evaporated until dry, receiving the crude tert-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-carboxylate. Output 15,36 g (92%).

1H NMR (CDCl3): δ 7.10 (D, 2H), 6.90 (D, 2H), 5.90 (TT, 1H), .60 (M, 4H), 3.15 (M, 4H), 1.50 (S,9H).

MS (ES): 323,0 (MN-tert-butyl).

The crude tert-butyl 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-carboxylate (15,30 g, 0.04 M) was dissolved in DHM (150 ml) was added TFU (30 ml). The mixture was stirred at room temperature overnight, evaporated to the dry state and subjected to azeotropic distillation with toluene. The residue was distributed between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was collected, dried over MgSO4, filtered and evaporated to the dry state, receiving 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a solid (10,97 g, 98%).

1H NMR (CDCl3): δ 7.15 (d, 2H), 6.90 (d, 2H), 5.90 (t, 1H), 3.35 (m, 8H).

MS (ES): 279,0.

1-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]piperazine (10,95 g, 0.04 M) was dissolved in DHM (500 ml) was added triethylamine (18.5 ml, 0.13 mmol). The mixture was cooled to 0°C was added methanesulfonamide (7,4 ml, 0,048 mol). Left to reach ambient temperature and was stirred overnight. The reaction mixture was washed with water and the organic phase was collected, dried over MgSO4, was filtered and was evaporated until dry. The remaining solid was subjected to crystallization from ethanol, obtaining 1-(methylsulphonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a white solid. Yield 12.3 g (78.5 per cent).

1H NMR (CDCl3): δ 7.15 (d, 2H), 6.95 (d, 2H), 5.9 (tt, 1H), 3.35 (m, H), 3.3 (m, 4H), 2.8 (s, 3H).

MS (ES): 357,26 (MH+).

1-(Methylsulphonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (2.85 g, be 0.008 mol) was dissolved in anhydrous THF (200 ml) and cooled to -10°C in argon atmosphere. Upon cooling to -30°C was added 1.0 M solution of bis(trimethylsilyl)amide lithium in THF (17.6 ml, 0,0176 mol) and to the mixture was added a solution of methyltetrahydro-2H-Piran-4-carboxylate (CAS number 110238-91-0) in THF (2 ml). The mixture was left to reach room temperature and was stirred for 2 hours. The reaction was suppressed with saturated solution of NH4Cl and the mixture was diluted with H2O and ethyl acetate. The organic phase was collected, dried over MgSO4, filtered and evaporated to the dry state, receiving the crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)alanon (of 3.64 g, 97%).

1H NMR (CDCl3): δ 7.15 (d, 2H), 6.95 (d, 2H), 5.90 (tt, 1H), 4.05 (s, 2H), 4.00 (m, 2H), 3.50 (m, 6H), 3.25 (m, 4H), 2.95 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H).

MS (ES): 469,08 (MN+).

The crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)alanon (of 3.60 g, 0,008 M) was dissolved in DHM (120 ml) and methanol (40 ml) at ambient temperature was added borohydride sodium (334 mg, 0,0088 mol). Was stirred for 2 hours, added an H2O (250 ml) and was extracted with DHM. The organic phase was collected, dried over MgSO4, was filtered and was evaporated to a dry status the status, getting 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)ethanol (3.6 g, 95%).

1H NMR (CDCl3): δ 7.15 (d, 2H), 6.90 (d, 2H), 5.90 (tt, 1H), 4.00 (m, 2H), 4.00 (m, 1H), 3.45 (m, 4H), 3.40 (m, 2H), 3.25 (m, 4H), 3.10 (m, 2H), 3.05 (m, 1H), 1.75 (m,2H), 1.50 (m,3H).

MS (ES): 471,08 (MH+).

2-({4-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)-1-(tetrahydro-2H-Piran-4-yl)ethanol (3.6 g, 0,008 M) was dissolved in DHM (100 ml) was added triethylamine (5,58 ml, 0.04 mol). The mixture was cooled to 0°C and overnight at room temperature and stirring was added methanesulfonamide (0,94 ml of a 0.012 M). Added water and the organic phase was separated, dried over MgSO4, filtered and evaporated to the dry state, receiving 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-Piran-4-yl)vinyl]sulfonyl}piperazine. The output of 3.15 g (86,6%).

1H NMR (CDCl3): δ 7.1 (d, 2H), 6.9 (d, 2H), 6.75 (dd, 1H), 6.1 (d, 1H), 5.85 (tt, 1H), 4.0 (m, 2H), 3.4 (m, 2H), 3.25 (m, 8H), 2.5 (m, 1H), 1.7 (m, 2H), 1.55 (m, 2H).

MS (ES): 452,88 (MH+).

1 -[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-Piran-4-yl)vinyl]sulfonyl}piperazine (3.13 g, to 0.007 mol) was dissolved in THF (50 ml) was added 50%hydroxylamine in N2O (12 ml). Was stirred at ambient temperature over night, extinguished a saturated solution of NH4Cl and extracted with ethyl acetate. The organic phase was dried over MgSO4, was filtered and was evaporated until dry, the floor is tea racemic 1-{[2-(hydroxyamino)-2-(tetrahydro-2H-Piran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine. It was separated into enantiomers using a Chiralpak AD chiral preparative HPLC column and elwira a mixture of 20% methanol/acetonitrile. The second compound isolated from the column consisted of a desired enantiomer, 1-{[(2S)-2-(hydroxyamino)-2-(tetrahydro-2H-Piran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine.

1H NMR (CDCl3): δ 7.2 (d, 2H), 6.9 (d, 2H), 5.9 (tt, 1H), 3.85 (m, 2H), 3.5-3.1 (m, 11H), 3.05 (m, 2H), 1.951.8 (dd, 2H), 1.6 (d, 2H), 1.35 (m, 2H).

MS (ES): 485,92 (MH+).

EXAMPLE 5

Hydroxy[1-phenyl-2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)ethyl]formamide

This compound was obtained using the method described in example 4.

1H NMR (CDCl3): 8.45 and 8.2 (d, 1H), 7.4 (m, 5H), 7.15 (d, 2H), 6.85 (d, 2H), 5.9 (tt, 1H), 5.5 (d, 1H), 3.4 (br s, 4H), 3.3 (s, 2H), 3.15 (br, 4H).

Intermediate 1-[(-2-phenylphenyl)sulfonyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine was obtained as described below.

1-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]piperazine (1.39 g, of 0.005 mol) was dissolved in DHM (250 ml) was added triethylamine (2.1 ml, 0.015 mol). The mixture was cooled to 0°C was added storycontinued (number in CAS 52147-97-4, 1,11 g, 0,0055 mol). Left to reach ambient temperature and was stirred overnight. Washed N2Oh, and separated the organic phase. Dried over MgSO4, filtered and evaporated to the dry state in obtaining oil, is AutoRAE was purified flash column chromatography (Merck 9385 silica), elwira a mixture of 80% ISO-hexane/ethyl acetate and receiving 1-[(2-phenylphenyl)sulfonyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a yellow solid. Yield 650 mg (25%).

1H NMR (CDCl3): δ 7.5 (m, 3H), 7.4 (m, 3H), 7.15 (d, 2H), 6.9 (d, 2H), 6.7 (d, 1H), 5.85 (tt, 1H), 3.4 (m, 4H), 3.25 (m, 4H).

MS (ES): 445,27 (MH+).

EXAMPLE 6

Hydroxy{4-pyrimidine-2-yl-1 -[({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)methyl]butyl}formamide

This compound was obtained using the method described in example 4.

MS (ES): 550,03 (MH+).

The intermediate 2-[5-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)Penta-4-EN-1-yl]pyrimidine was obtained as described below.

1-(Methylsulphonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (356 mg, 0.001 mol) was dissolved in anhydrous THF (100 ml) and cooled to -10°C in argon atmosphere. Added a 1.0 M solution of bis(trimethylsilyl)amide lithium in THF (2.2 ml, 0,0022 mol) and was stirred at -10°C for 30 minutes and then for another 30 minutes under stirring at -10°C was added diethylphosphate (0.15 ml, 0.001 mol). Solution was added 2-pyrimidinyl-4-butyric aldehyde in anhydrous THF (5 ml), the mixture was stirred at -10°C for 60 minutes or until the mixture remained cold, extinguished the reaction of a saturated solution of NH4Cl. Then was diluted with H2Oh and ethyl acetate, the organic phase was collected, dried the over MgSO 4, filtered and evaporated to the dry state with the formation oil. Clean flash column chromatography (Merck 9385 silica) with elution by ethyl acetate gave 2-[5-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine-1-yl}sulfonyl)Penta-4-EN-1-yl]pyrimidine. Yield 230 mg (47%).

1H NMR (CDCl3): 8.8 (d, 2H), 7.2 (s, 1H), 7.1 (d, 2H), 6.85 (d, 2H), 6.2 (d, 2H), 5.8 (tt, 1H), 4.05 (br, 1H), 3.25 (br, 8H), 3.05 (m, 2H), 2.3 (m, 1H), 2.05 (m, 2H), 1.4 (m, 2H).

MS (ESI): 489 (MH+).

EXAMPLE 7

Also, there were synthesized the following compounds.

No.RThe racemate or S-enantiomerMN+Was obtained using the method described in example
and2-PyrimidinylideneS-Enantiomer550,006/
b5-F-2-PyrimidinylThe racemate554,176
in5-F-2-PyrimidinylS-Enantiomer553,946//
g2-PyrimidinylThe racemate535,986
d2-PyrimidinylS-Enantiomer535,986//
eEthylThe racemate457,956
WMethylThe racemate443,976
/ enantiomer was isolated using OJ chiral preparative HPLC column, elwira methanol,
// synthomer was isolated using a chiralpak AD preparative HPLC column, elwira a mixture of 20% methanol/acetonitrile.

EXAMPLE 8

The following compounds were obtained as described in the previous examples.

No.RMH+Was obtained using the method described in example
andThe racemate 2-Pyrimidinyl517,996
bS-Enantiomer2-Pyrimidinyl518,126/
inThe racemate5-F-2-Pyrimidinyl535,886
gS-Enantiomer5-F-2-Pyrimidinyl536,006//
dThe racemate2-Pyrimidinylidene531,886
eS-Enantiomer2-Pyrimidinylidene532,046/
WS-Enantiomer4-Tetrahydropyran496,104///
/ allocated on a Chiralpak AD column, elwira mixture: 10% Meon, MeCN,
// allocated on a Chiralpak AD column, elwira mixture: 15% Meon, MeCN,
/// allocated on the stage of the hydroxyl is on Chiralpak AD column, elwira mixture: 20% Meon, MeCN.

Starting material for this synthesis was prepared as follows.

1-(Methylsulphonyl)-4-[4-(2,2,2-triptoreline)phenyl]piperazine

To a solution of 4-bromophenol (to 9.57 g, 55 mmol) in acetone (200 ml) was added potassium carbonate (22,89 g, 166 mmol) and 2,2,2-triptorelin-triftorbyenzola (16.0 g, 69 mmol). The reaction mixture was stirred at room temperature overnight, then filtered and concentrated under 300 mbar (30 kPa) and 30°C to remove acetone. Received 1-bromo-4-(2,2,2-triptoreline)benzene in the form of a waxy solid (yield >100%, because there are some acetone).

1H NMR (DMSO-D6), δ: 7.50 (2H, d), 7.05 (2H, d), 4.75 (2H, q).

1-Bromo-4-(2,2,2-triptoreline)benzene (14.5 g, 57 mmol) was dissolved in toluene (250 ml) in an argon atmosphere. Added tert-butylpiperazine-1-carboxylate (12.7 g, 68 mmol), tert-butyl sodium (7.6 g, 79.5 mmol), RAC-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (200 mg, 0.32 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.2 mmol) and the reaction mixture was heated up to 80°C for 4 hours. The mixture is then cooled and filtered through celite, receiving the crude tert-butyl 4-[4-(2,2,2-triptoreline)phenyl]piperazine-1-carboxylate (32,47 g).

1H NMR (400 MHz, CDCl3): δ 6.90 (4H, s), 4.30 (2H, q), 3.60 (4H, m), 3.05 (4H,m), 1.45(9H,s).

m/z (ES) 305 (MH+-t Bu).

The crude tert-butyl 4-[4-(2,2,2-triptoreline)phenyl]piperazine-1-carboxylate (32,47 g, approximately 57 mmol) was dissolved in DHM (300 ml) and was added TFU (69 ml). The reaction mixture was stirred at room temperature overnight, then evaporated until dry, exposing azeotropic distillation with toluene. The residue was distributed between DHM and saturated sodium bicarbonate solution. The organic phase was separated, dried (MgSO4), filtered and concentrated, obtaining 1-[4-(2,2,2-triptoreline)phenyl]piperazine as a solid (13,48 g, 91%).

1H NMR (400 MHz, CDCl3): δ 6.90 (4H, s), 4.30 (2H, q), 3.30 (8H, m).

MS (ES) 261 MH+.

1-[4-(2,2,2-Triptoreline)phenyl]piperazine (13,48 g, 50 mmol) was dissolved in DHM (500 ml) and cooled to 0°C. was Added triethylamine (29 ml, 0.2 mol), and then dropwise methanesulfonanilide (4,2 ml, 55 mmol). Then the reaction mixture was left to warm to room temperature and was stirred overnight, then was suppressed by the addition of water. The layers were separated and the organic phase was dried (MgSO4), filtered and concentrated. The residue was recrystallized from hot ethanol, getting pure 1-(methylsulphonyl)-4-[4-(2,2,2-triptoreline)phenyl]piperazine (3.3 g, 18%).

1H NMR (CDCl3): δ 6.90 (4H, s), 4.30 (2H, q), 3.40 (4H, m), 3.20 (4H, m), 2.85 (3H, s).

m/z (ES) 339 MN+.

1. N-Hydroxytyramine connection is ormula (I)

or its pharmaceutically acceptable salt,
where ring b is a phenyl, pyridinyl or pyrimidinyl;
R2represents a group selected from C1-6of alkyl, phenyl or naphthyl, where the group is substituted by one or more than one group of fluorescent;
n is 1, 2 or 3 and
R1is tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-2-pyrimidinyl-CH2CH2CH2-, 5F-2-pyrimidinyl-CH2CH2-With1-6alkyl or phenyl.

2. The compound according to claim 1, where R2represents a C1-6alkyl group substituted by the groups of fluorescent in number from one to five.

3. The compound according to claim 1, where R2replaced three or four groups with fluorescent.

4. The compound according to claim 3, where R2represents the group-CF2CHCF2.

5. The compound according to claim 3, where R2represents a group-CH2CF3.

6. The compound according to any one of claims 1 to 5, where n is equal to 1.



 

Same patents:

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: object of the present invention are compounds: N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidine-4-yl]methoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]-propoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, 2-{3-[(7-{3-[cycloamyl(2-hydroxyethyl)-amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}-N-(2,3-difluorophenyl)acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)-pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide and others named in formula of invention.

EFFECT: compounds are intermediate for synthesis of phosphonooxyquinazoline derivatives with properties of aurora-kinase-A and/or aurora-kinase-B inhibitor.

3 cl, 5 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: description is given of diazepane derivatives with formula I where R1 stands for C1-C4alkyl, R2 stands for unsubstituted C1-C4alkyl or C1-C4alkyl, substituted with quinolinyl, benzo[1,3]dioxolyl, phenyl, phenyl, substituted with 1-3 substitutes, chosen from a group, comprising halogen, halogen(C1-C4)alkyl, C1-C4alkoxy, cyano, amino, dimethylamino, carboxy(C1-C2)alkylcarbonylamino, amino(C1-C2)alkylcarbonylamino, C2-C4alkylenecarbonylamino, heterocyclylcarbonyl(C1-C2)alkylcarbonylamino, where heterocyclyl contains 6 atoms in the ring and 2 heteroatoms, chosen from N or N and O, R3 stands for phenyl, substituted with one or two substitutes, chosen from a group, comprising halogen, halogen(C1-C6)alkyl, halogen(C1-C6)alkoxy, cyano, phenyl or aromatic heterocyclyl, containing 6 atoms in a ring and two nitrogen heteroatoms.

EFFECT: obtaining compounds with inhibiting effect on LFA-1/ICAM-1.

6 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new derivatives of benzodiazine of the formula (1), which possess properties of inhibiting proliferative action and can be used during treatment of hyper-proliferative diseases like cancer. In formula (I) G1 and G2 each independently representing a halogen; X1 -R1 selected C1-C6-alkoxy, X2 represents a simple bond; Q1 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, where Q1 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different , selected from cyano, carbamoyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkylthio, C1-C6-alkyl-sulfinyl C1-C6-alkyl-sulfonyl, N-C1-C6-alkyl-carbamoyl N,N-di-[C1-C6-alkyl]carbamoyl, C1-C6-alkanoyl, sulfamoyl, N-C1-C6-alkyl-sulfamoyl, N,N-di-[C1-C6-alkyl-]sulfamoyl, carbamoyl C1-C6-alkyl, N-C1-C6-alkyl-carbamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]carbamoylC1-C6-alkyl, sulfamoylC1-C6-alkyl, N-C1-C6-alkyl-sulfamoylC1-C6-alkyl, N,N-di-[C1-C6-alkyl]sulfamoylC1-C6-alkyl, C1-C6-alkanoylC1-C6-alkyl, or from the group with the formula: Q2 -X3-, where X3 represents CO and Q2 represents a non-aromatic saturated 3-7-member monocyclic heterocyclic ring with 1 circular nitrogen heteroatom and not necessarily 1 or 2 heteroatoms, selected from nitrogen and sulphur, and where. Q2 does not necessarily have 1, 2 or 3 substitute groups, which can be similar or different, selected from halogens, C1-C4-alkyl, and where any C1-C6-alkyl and C2-C6-alkaloid groups within the limits of Q1 does not necessarily have one or more substitute groups, which can be similar or different, selected from hydroxy and C1-C6-alkyl and/or not necessarily a substitute selected from cyano, C1-C6-alkoxy, C2-C6-alkanoxy and NRaRb, where Ra represents hydrogen or C1-C4-alkyl and Rb represents hydrogen or C1-C4-alkyl, or Ra and Rb together with a nitrogen atom, to which they are attached, they form a 4-, 5- or 6- member non-aromatic saturated monocyclic heterocyclic ring with 1 circular heteroatom of nitrogen and not necessarily 1 or 2 heteroatoms, selected from nitrogen, oxygen and sulphur, which not necessarily have 1 or 2 substitutes, which can be similar or different, on the available carbon atom, and selected from halogens and C1-C3-alkilenedioxy.

EFFECT: obtaining new derivatives benzodiazine, which possess properties of inhibiting proliferative action and can be used during the treatment of hyper-proliferative diseases such as cancer

27 cl, 73 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , in which Ra is H, CH3 or isopropyl, Rb is H, halogen, C1-6alkoxygroup or C1-6alkyl, and or I. R is radical of formula (b) , R4 is 1-pyperasinyl, substituted with CH3 in positions 3 and/or 4, Ra is not H or CH3, when R4 is 4-methyl-1-pyperazinyl; or III. R is remaining part of formula (c) , in which R14 is 1-pyperazinyl, optionally substituted with CH3 in position 3; or 4,7-diase-spiro[2,5]oct-7-yl, R15 is halogen, CF3 or CH3, R15 is not CH3, when R16 stands for CH3, Ra is H or CH3, Rb is H, and R14 is 4-methyl-1-pyperazinyl, and R16 is H, CH3 or CF3, R16 is not H, when R15 is Cl, Ra is H or CH3, Rb is H, and R14 is 4-methyl-1-pyperazinyl, or IV. R is radical of formula (d) , in which R8 is 1-pyperazinyl, 3- methyl-1-pyperazin-l-yl or 4-benzyl-pyperazin-1-yl, or V. R is radical of formula (e) , in which R9 is 4,7-diase-spiro[2,5]oct-7-yl or pyperazin-1-yl, substituted in position 3 with ethyl, or its salt, method of their production, based on them pharmaceutical composition and application for obtaining medication for treatment or prevention of T-lymphocyte and-or "ПКС"-mediated diseases or disorders.

EFFECT: increase of composition and treatment method efficiency.

12 cl, 5 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted indoles of general formula , where: X stands for -S(O)n-, -C(O)-; A stands for C1-C6alkyl, -(CH2)p-NRaRb; R1, R2, R3 and R4 each is independently selected from group including H, halogen, halogen(C1-C6)alkyl, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, NO2, -NRaRb, phenyl, benzyl and benzyloxy, said phenyl cycles are optionally substituted with substituent, selected from group including C1-C6alkyl, halogen, NO2, halogen(C1-C6)alkyl, C1-C6alkoxy; R5 stands for H, C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxy C1-C6alkyl, C1-C6alkylthio, C1-C6alkylsulfinyl, C1-C6alkylsulfonyl, hydroxyl-(C1-C6)alkyl, hydroxy(C1-C6)alkylamino, halogen, halogen(C1-C6)alkyl-NRaRb, -NRc-( C1-C6)alkylene-NRaRb, or R5 and A together form radical C2-C3alkylene; R6 stands for H, C1-C6alkyl; R' and R" each independently stand for H, C1-C6alkyl; Ra, Rb and Rc each is independently chosen from group including H, C1-C6alkyl, hydroxy(C1-C6)alkyl, C2-C6alkenyl, C3-C6cycloalkyl-(C1-C6)alkyl, or Ra and Rb together with nitrogen atom, to which they are attached, form 5-7 member non-aromatic heterocyclic cycle, optionally containing in cycle O as additional heteroatom; m is equal 1 or 2; n is equal 0, 1 or 2 under condition that, if n is equal 0, R5 does not stand for NRaRb, and p is equal 0, 1 or 2; or their pharmaceutically acceptable salts.

EFFECT: obtaining compounds possessing agonistic activity which allows using them in pharmaceutical composition.

24 cl, 2 tbl, 22 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to method for production of indolo-pyrrolo-carbazole derivative according to formula (I) , or its pharmaceutically acceptable salt, that have antitumour activity. Invention also relates to method for production of indole compound according to formula (XII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, distinguished by conducting interreaction between compound with formula (XIII) , or its pharmaceutically acceptable salt, where R1 is definitely above, Ra and Rb are either separately C1-C7-alkyl, or together form C3-C6-alkylene group, and hydrogen gas at 1 to 5 atmospheres, in presence of hydrogenation catalyst (applied as novel catalyst as well), which consist of rhodium compound, metal compound, and optionally amine, in inert solvent at room temperature; the rhodium compound being 1 to 10% rhodium on carbon, aluminium oxide, calcium carbonate, or barium sulphate, and metal compound being nickel (II), iron (II), iron (III), cobalt (II), or cobalt (III). Method is also submitted for production of bis-indole compound by formula (VIII) , or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, Y is hydrogen, C1-C7-alkyl, phenyl, benzyloxymethyl, or C7-C12-aralkyl, consisting in reaction of indole compound by formula (XII), or its pharmaceutically acceptable salt, where R1 is protective hydroxy-group, with ethylmagnesium chloride, or butylmagnesium chloride, or magnesium compound by formula (X) RdMgRd, where Rd is butyl, in inert solvent, followed by conducting interreaction between product obtained and maleimide compound by formula (IX) , where X is halogen, and Y as above, in inert solvent.

EFFECT: improved method for indolo-pyrrolo-carbazole production.

15 cl, 68 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns polymorphs of 1-pyrrol-substituted 2-indolinone compound (2-pyrrolidine-1-ylethyl)amide 5-(5-fluor-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-carboxylic acid, namely polymorphic form of the formula I: in the form of polymorphic form II mainly free of polymorph I characterised by PXRD powder radiogram with characteristic peaks expressed in degrees (±0.1) of double angle 7.1, 13.9, 16.0, 20.9 and 24.7, obtained with the use of CuKα1 radiation (wavelength = 1.5406 A), and polymorphic compound form of the formula I in the form of polymorphic form I mainly free of polymorph II characterised by PXRD powder radiogram with characteristic peaks expressed in degrees (±0.1) of double angle 5.0, 16.7, 18.9, 24.8 and 27.3 obtained with the use of CuKα1 radiation (wavelength = 1.5406 A). The invention also concerns pharmaceutical composition capable of catalytic proteinkynase activity and based on these forms, method of catalytic proteinkynase activity modeling and treatment method for patients with proteinkynase-induced diseases.

EFFECT: improved efficiency of preparations.

26 cl, 3 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: chemistry; pharmacology.

SUBSTANCE: object of the present invention are compounds: N-(2,3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl)piperidine-4-yl]methoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxy-1,1-dimethylpropyl)amino]-propoxy}quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)(butyl)amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, 2-{3-[(7-{3-[cycloamyl(2-hydroxyethyl)-amino]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}-N-(2,3-difluorophenyl)acetamide, N-(2,3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide, N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl)-pyrrolidine-1-yl]propoxy}-quinazoline-4-yl)amino]-1H-pyrazole-5-yl}acetamide and others named in formula of invention.

EFFECT: compounds are intermediate for synthesis of phosphonooxyquinazoline derivatives with properties of aurora-kinase-A and/or aurora-kinase-B inhibitor.

3 cl, 5 tbl, 50 ex

FIELD: medicine.

SUBSTANCE: in the formula I or it pharmaceutically comprehensible salt: m it is peer 3; n it is peer from 0 to 2; all R1 independently mean H; R2 means aryl, unessentially replaced 1-2 assistants chosen from group, including halogen, and C1-C12alcoxy; R3 means H, C1-C12alkyl; p it is peer 2 or 3; R5, R6, R7 and R8 independently mean H, C1-C12alkyl, or one of R5 and R6 together with one of R7 and R8 and the atoms located between them can form a 4-7-termed heterocyclic ring, or R7 and R8 together with atom of nitrogen to which they are attached, can form a 5-7-termed heterocyclic ring; or one of R5 and R6 together with R3 and the atoms located between them can form a 5-7-termed heterocyclic ring. Bonds I possess selective opposing activity in the relation of 5-NT6 receptor.

EFFECT: possibility to use bond in a pharmaceutical composition for treatment of CNS and gastroenteric tract.

16 cl, 8 dwg, 2 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula I: , where L represents radical , in which R1 represents H, C1-4alkyl; n represents 0 or 1; or L represents radical , in which R1 represents H, C1-4alkyl; m equals 1; R represents H, halogen, C1-C4alkyl or C1-C4-alkoxy; Z represents a bond, -C(O)NH-, O or S; p is an integer from 1 to 5; Q represents a bond with the condition that, Z is not a bond, when p equals 1; or represents O, S or -C(O)NR6-, where R6 represents H, C1-4alkyl or C3-6cycloalkyl; or W and R6 together with a nitrogen atom, to which they are bonded, form or or Q represents -NR6-, or in the condition that, p is not equal to 1; W represents , , , , ,

, , ,

, , ,

, , , ,

, , , ,

, , , ,

, , , , ,

, , , , , and

.

EFFECT: obtaining compounds with agonistic activity towards PPAR receptors, which enables them to be used in pharmaceutical compositions and methods of treating conditions, mediated by these receptors.

12 cl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to application of indazole derivatives of general formula (I) , in which: R stands for O; R3 stands for radical (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkinyl, said radicals being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R4, R5, R6 and R7, independently on each other are selected from following radicals; hydrogen atom, halogen, CN, NO2, NH2, NHSO2R9, trifluoromethyl, trifluoromethoxygroup, (C1-C6)-alkyl, phenyl, phenyl-(C1-C6)-alkyl, pyridyl, possibly substituted with amino or hydroxygroup, thienyl, furanyl, morpholino, phenyl being unsubstituted or substituted with one or several substitutes, given in item 1 of the formula; R8, R9, R10, R11, independently on each other, stand for hydrogen atom, (C1-C6)-alkyl, phenyl possibly substituted with halogen; their racemates, enantiomers, diastereoisomers and their mixtures, their tautomers and their pharmaceutically acceptable salts for obtaining medication, inhibiting phosphorylation of Tau-protein. Invention also relates to novel compounds of formula (I), particular indazole derivatives, their racemates, enantiomers, tautomers and pharmaceutically acceptable salts, pharmaceutical composition and based on them medication which inhibits Tau-protein phosphorylation, as well as to method of obtaining compounds of formula (I).

EFFECT: obtaining medication based on indazole derivatives, inhibiting Tau-protein phosphorylation.

9 cl, 118 ex, 3 ex

FIELD: chemistry.

SUBSTANCE: in general formula (I) , R1 represents similar or different 2 groups, each of which is selected from group consisting of C1-3alkyl, or when R1 are two adjacent groups, two groups R1, taken together, can form saturated or unsaturated 5- or 6-member cyclic group, which can have 1 or 2 oxygens as heteroatom; X represents oxygen or sulphur; values of other radicals are given in invention formula.

EFFECT: increase of composition efficiency.

16 cl, 11 tbl, 31 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry.

SUBSTANCE: described are novel compounds of series 2-propen-1-on of general formula or their tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, where Q stands for heteroaryl cycle, containing up to 2 nitrogen atoms. Compounds I induce HSP-70 and are useful in treatment of diseases accompanying pathologic process in organisms of mammals, including humans.

EFFECT: novel compounds possess useful biological properties.

26 cl, 7 tbl, 179 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

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