Bicyclic heteroaromatic compounds, pharmaceutical composition based on thereof and using

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

 

The invention relates to compounds with agonistic or antagonistic activity against glycoprotein hormone, in particular to the compounds with agonistic activity against luteinizing hormone (LH). In addition, the invention relates to bicyclic heteroaromatic derivatives containing their pharmaceutical compositions and to the use of these compounds in medical therapy, particularly for use for regulation of fertility.

The gonadotropins play a significant role in many body functions, including metabolism, temperature regulation and reproductive process. Pituitary gonadotropin FSH, for example, plays a major role in stimulating the development and maturation of the follicle, whereas LH induces ovulation (Sharp R. Clin. Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, Recent Prog.Horm.Res. 35:301-342, 1979). Now LH is used clinically in combination with FSH to stimulate the ovaries, for example, ovarian hyperstimulation for in vitro fertilization (IVF) and induction of ovulation in infertile popularmusic women (Insler V., Int.J.Fertility 33:85-97, 1988, Navot and Rosenwaks, J.Vitro Fert. Embryo Transfer 5:3-13, 1988), as well as the underdevelopment of the reproductive system in men and male infertility.

The gonadotropins act on specific gonadal cell types to initiate ovarian and testicular the modification and steroidogeneza. These mucous membranes and placental hormones mediated by specific plasma membrane receptors that belong to the large family of G-protein-coupled receptors. They consist of a single polypeptide with seven transmembrane domains and are able to interact with the Gs protein, leading to activation of adenylcyclase.

The gonadotropins, intended for therapeutic purposes, can be isolated from human urine as a source and have a low purity (Morse et al., Amer.J.Reproduct. Immunol. And Microbiology 17:143, 1988). Alternatively, they can be obtained as a recombinant gonadotropins.

As in the case of other therapeutic proteins, gonadotropins, you must enter either subcutaneously or intramuscularly. However, it would be preferable to activate the receptor by small molecules that could be introduced, for example, oral or dermal routes.

The present invention describes the obtaining of such low molecular weight analogues of hormones that selectively activate one of gonadotropinum receptors, which is one of the main advantages of the present invention.

Thus, the invention relates to bicyclic heteroaromatic derivatives of General formula I or their pharmaceutically acceptable salts

the de

R1represents a C3-C8cycloalkyl,2-C7heteroseksualci,6-C14aryl or4-C13heteroaryl; preferably R1represents a C6-C14aryl or4-C13heteroaryl;

R2represents a C1-C4alkyl, C2-C4alkenyl,2-C4quinil,6-C14aryl or4-C13heteroaryl;

R3represents a C1-C8alkyl, C3-C8cycloalkyl,2-C7heteroseksualci,6-C14aryl or4-C13heteroaryl;

Y represents CH or N;

Z represents NH2or HE;

And represents S, N(H), N(R4), O or a bond;

R4can be selected from the groups described for R2and In is an N(H), or link.

Ring system in R1optionally can be substituted by one or more substituents selected from R5,N(R4R5, Other5, OR5and/or SR5in which R5represents a C6-C14aryl, C4-C13heteroaryl,6-C14arylcarbamoyl,2-C7heteroseksualci,3-C8cycloalkyl,6-C14arylsulfonyl,6-C14allumination,6- 14aryloxyalkyl,6-C14arylamination,6-C14aryloxyalkyl,2-C8alkenyl,2-C8quinil,2-C7geterotsiklicheskikh,2-C8alkanesulfonyl,2-C8ascenoccary or1-C8alkyl, C1-C8alkylsulphonyl,1-C8alkylsulfonyl, C1-C8(di)alkylaminocarbonyl,1-C8alkoxycarbonyl,1-C8(di)alkylaminocarbonyl or1-C8alkoxycarbonyl, an alkyl group in which optionally may be substituted by one or more substituents selected from hydroxyl, C1-C8alkoxy, C2-C7heteroseksualci(C1-C8)alkoxy, C3-C8cycloalkyl(C1-C8)alkoxy, C6-C14aryl(C1-C8)alkoxy, C4-C13heteroaryl1-C8alkoxy, C2-C7geterotsiklicheskie,3-C8cycloalkyl,6-C14aryl, C4-C13heteroaryl,1-C8alkoxycarbonyl,6-C14aryloxyalkyl,1-With8alkylcarboxylic,6-C14arylcarboxylic,1-C8alkylcarboxylic,6-C14arylcarbamoyl, Amin, C1-C8alkylaminocarbonyl,6-the 14arylenecarborane,1-C8alkylcarboxylic,6-C14arylcarboxamide,6-With14(di)arylamino, (di)[P1-C3alkoxy(C1-C3)alkyl]amino and/or C1-C8(di)alkylamino. Preferably the substituents in R1choose from other5or or5. R5in any of the substituents at R1preferably represents C2-C7geterotsiklicheskikh,6-C14arylcarbamoyl or1-C8alkyl, C1-C8alkylsulphonyl or1-C8(di)alkylaminocarbonyl, an alkyl group in which optionally may be substituted With2-C7heterocyclization,4-C13heteroaryl,1-C8alkoxycarbonyl,1-C8alkylaminocarbonyl,1-C8alkylcarboxylic,6-C14arylcarboxamide, an amine, and/or C1-C8(di)alkylamino. The most preferred substituents in the alkyl group are a2-C7heteroseksualci,1-C8(di)alkylamino, Amin and1-C8(di)alkylaminocarbonyl.

The most preferred R1is phenyl, optionally substituted one of the above substituents, preferably the substitution is implemented in the meta-position.

In the compounds and is gaining X1-x2 represents C=C, C(O)-NH, NH-C(O), C(O)-O, O-C(O), C=N or N=C If R5represents a C1-C8alkylsulfonyl, C6-C14arylsulfonyl,1-C8(di)alkylaminocarbonyl,6-C14allumination,1-C8alkoxycarbonyl,6-C14aryloxyalkyl,1-C8(di)alkylaminocarbonyl,6-C14arylamination,1-C8alkoxycarbonyl,2-C7geterotsiklicheskikh,2-C8alkanesulfonyl,2-C8ascenoccary or6-C14aryloxyalkyl, then X1-x2 may additionally represent S or O.

Preferred compounds according to the invention are compounds of General formula I, where In is an N(H) or communications, and/or Z represents NH2. Among these preferred compounds, especially preferred are those in which In is an N(H) or a bond, and Z represents NH2. More preferred are compounds, in which preferably, in addition to the above noted definitions, and Z, R1defined as6-C14aryl or4-C13heteroaryl, optionally substituted by one or more substituents selected from N(R4R5, Other5, R5, OR5and/or SR5, prefer the Ino other 5or or5.

Preferably, all of the above compounds, Y is N, preferred is N(H) or link. If a is a bond, R3preferably represents C2-C7heteroseksualci.

In addition, all the above compounds X1-x2 preferably represents C=C, C=N or N=C, most preferably C=C.

If R5represents a C1-C8alkylsulfonyl, C6-C14arylsulfonyl,1-C8(di)alkylaminocarbonyl,6-C14allumination,1-C8alkoxycarbonyl,6-C14aryloxyalkyl,1-C8(di)alkylaminocarbonyl,6-C14arylamination,1-C8alkoxycarbonyl, C2-C7geterotsiklicheskikh,2-C8alkanesulfonyl,2-C8ascenoccary or6-C14aryloxyalkyl, then preferred to X1-x2, in addition to the above groups, is S.

Most preferred are compounds selected from the group comprising tert-butyl 5-amino-2-methylthio-4-(3-((N,N-diethylamino)carbonyloxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(methoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-AMI is o-2-methylthio-4-(3(allyloxycarbonyl-amino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(ethoxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(morpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(1,2,3,6-tetrahydropyridine-carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-phenyl-4-(3-((N,N-dimethylamino)carbonyloxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide.

Such compounds as ethyl 5-hydroxy-2-methyl-4-(piperidine-1-yl)-pyrido[2,3-d]pyrimidine-6-carboxylate, ethyl 5-hydroxy-2-methyl-4-(morpholine-4-yl)-pyrido[2,3-d]pyrimidine-6-carboxylate or ethyl 5-hydroxy-2-methyl-4-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidine-6-carboxylate is excluded from the scope of the present invention.

The exception relates to the disclosure of these compounds Chem. Pharm. Bull., 18(7), 1385-1393 (1970).

The term1-C8alkyl, as it is used in the definition of formula I means a branched or unbranched alkyl group having 1-8 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl and octyl. C1-C6Alkyl groups are preferred, C1-C3alkyl groups are preferred.

The term2-C8alkenyl means a branched or unbranched alkenylphenol group having 2-8 carbon atoms, such as at the Nile, 2-butenyl etc. C1-C6Alkeneamine group are preferred, C1-C3alkeneamine group are most preferable.

The term2-C8quinil means a branched or unbranched alkylamino group having 2-8 carbon atoms, such as ethinyl and PROPYNYL. Most preferred are C2-C4alkyline group.

The term6-C14aryl means an aromatic hydrocarbon group having 6-14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, antracol, which may not necessarily be substituted by one or more substituents, such as, but not limited to, hydroxy, halogen, nitro, trifluoromethyl, cyano, C1-C8alkylcarboxylic,1-C8alkylaminocarbonyl or1-C8(di)alkylamino, alkyl fragments have the same meaning as defined previously. More preferred are6-C10aryl group. The most preferred aromatic hydrocarbon group is phenyl.

The term3-C8cycloalkyl means cycloalkyl group containing 3-8 carbon atoms, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term C2-C7heteroseksualci oz is achet geterotsyklicescoe group, having 2-7 carbon atoms, preferably 2-5 carbon atoms, and at least including one heteroatom selected from N, O or S. Preferred heteroatoms are N or O. the Nitrogen-containing heteroseksualnymi groups can be linked through a carbon atom or nitrogen. The most preferred heteroseksualnymi groups include piperidine, morpholine and pyrrolidine.

The term C2-C7geterotsiklicheskikh means geterotsyklicescoe group having 2-7 carbon atoms, as defined previously, is connected to the carbonyl group.

The term1-C8alkoxy means CNS group having 1-8 carbon atoms, alkyl fragment has the values defined previously. C1-C6CNS group are preferred, C1-C3CNS group are most preferable.

The term1-C8alkoxycarbonyl means alkoxycarbonyl group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. C1-C6Alkoxycarbonyl group are preferred, C1-C3alkoxycarbonyl group are most preferable.

The term1-C8ascenoccary means allenxlenalee group, Alchemilla group in which the gain of 2-8 carbon atoms and has a value certain previously. With2-C6Allenxlenalee groups are preferred, With2-C3allenxlenalee group are most preferable.

The term1-C8alkoxycarbonyl means alkoxycarbonyl group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. C1-C6Alkoxycarbonyl group are preferred, C1-C3alkoxycarbonyl group are most preferable.

The term1-C8(di)alkylamino means (di)alkylamino having 1-8 carbon atoms, alkyl fragment which has the meaning given previously. More preferred are C1-C6(di)alkylamino group.

The term di[C1-C3alkoxyl1-C3alkyl]amino means (di[alkoxyalkyl]amino group, in which alkyl and CNS fragments have 1-3 carbon atoms and the values defined previously.

The term6-C14(di)arylamino means (di)killingray having 6-14 carbon atoms, aryl fragment has the meaning given previously. More preferred are6-C10(di)arylamino group. The most preferred (di)arylamino group is (di)phenylamino.

The term1- 8alkylthio means alkylthio group having 1-8 carbon atoms, alkyl fragment has the meaning given previously. Most preferred are1-C4alkylthio group.

The term6-C14aryloxyalkyl means aryloxyalkyl group, aryl group which contains from 5 to 14 carbon atoms, more preferably 6 to 10 carbon atoms and has a value defined previously. Most preferred are phenoxycarbonyl group.

The term6-C14aryloxyalkyl means aryloxyalkyl group, aryl group which contains 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms and has a value defined previously. Most preferred are phenoxycarbonyl group.

The term6-C14arils1-C8alkyl means arylalkyl group having 7-22 carbon atoms, where the alkyl group is a C1-C8alkyl group, and aryl group represents a C6-C14aryl group, as defined previously. More preferred are6-C10arils1-C4alkyl groups. Panels1-C4alkyl groups such as benzyl, are the most preferred Uralkalij groups.

The term4-C13g is tetraaryl means a substituted or unsubstituted aromatic group, having 4-13 carbon atoms, preferably 4 to 9, and comprising at least one heteroatom selected from N, O and/or S, such as imidazolyl, thienyl, Bastiani, hinely, tetrahydropyranyl, ethanolic, tetrahydroisoquinoline, indolyl, acridinae, furyl or pyridyl. Deputy heteroaryl group may be selected from the group of substituents listed above for aryl groups. Preferred heteroaryl groups are thienyl, furyl, pyridyl and pyrimidyl. Nitrogen-containing heteroaryl group can be linked via a carbon atom or nitrogen.

The term halogen means fluorine, chlorine, bromine or iodine.

The term C2-C7heterocyclics1-C8alkoxy means geterotsyklicescoe group containing 2 to 7 carbon atoms as previously defined, attached to C1-C8CNS group, CNS fragment has the meaning given previously. More preferred are C2-C5heterocyclics1-C4CNS group.

The term3-C8cycloalkyl1-C8alkoxy means cycloalkyl group containing 3-8 carbon atoms as previously defined, attached to C1-C8CNS group, CNS fragment has the meaning given previously. More preferred are C3 6cycloalkyl1-C4CNS group.

The term6-C14arils1-C8alkoxy means an aryl group containing 6-14 carbon atoms as previously defined, attached to C1-C8CNS group, CNS fragment has the meaning given previously. More preferred are C6-C10arils1-C4CNS group, panels1-C4CNS group are most preferred. C4-C13Heteroaryl1-C8CNS group are similar With6-C14arils1-C8CNS groups comprising at least one heteroatom selected from N, O and S in the heteroaryl ring. More preferred are4-C9heteroaryl1-C4CNS group.

The term1-C8alkylsulphonyl means alkylcarboxylic group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. More preferred are C1-C6acylcarnitine group, C1-C4acylcarnitine group are most preferable.

The term6-C14arylcarbamoyl means arylcarbamoyl group, aryl group which contains 6 to 14 carbon atoms and has a value of ODA is defined previously. More preferred are C6-C10arylcarbamoyl group, phenylcarbonylamino group are most preferable.

The term1-C8alkylsulfonyl means alkylsulfonyl group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. More preferred are C1-C6alkylsulfonyl group, C1-C4alkylsulfonyl group are most preferable.

The term2-C8alkanesulfonyl means alkanesulfonyl group, Alchemilla group contains 2-8 carbon atoms and has a value defined previously. More preferred are C2-C6alkanesulfonyl group, C2-C4alkanesulfonyl group are most preferable.

The term6-C14arylsulfonyl means arylsulfonyl group, aryl group which contains 6 to 14 carbon atoms and has a value defined previously. More preferred are C6-C10arylsulfonyl group, phenylsulfonyl group are most preferable.

The term1-C8alkylcarboxylic means alkylcarboxylic group, an alkyl group which contains from 1 to 8 carbon atoms and has a value, determine the Noah earlier. More preferred are C1-C6alkylcarboxylic group. More preferred are C1-C4alkylcarboxylic group.

The term6-C14arylcarboxylic means arylcarboxylic group, aryl group which contains 6 to 14 carbon atoms and has a value defined previously. More preferred are C6-C10arylcarboxylic group, phenylcarbamoyloxy group are most preferable.

The term1-C8(di)alkylaminocarbonyl means (di)alkylaminocarbonyl group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. More preferred are C1-C6(di)alkylaminocarbonyl group, C1-C4(di)alkylaminocarbonyl group are most preferable.

The term6-C14(di)arellanobond means (di)arylaminomethylene group, aryl group which contains 6 to 14 carbon atoms and has a value defined previously. More preferred are C6-C10(di)arylaminomethylene group, (di)phenylenecarbonyl group are most preferable.

The term1-C8(di)alkylaminocarbonyl means (di)alkylaminocarbonyl group, an alkyl group to the second contains 1-8 carbon atoms and has a value certain previously. More preferred are C1-C6(di)alkyl-aminosulfonyl group, C1-C4(di)alkylaminocarbonyl group are most preferable.

The term6-C14(di)arylamination means (di)arylaminomethylene group, aryl group which contains 6 to 14 carbon atoms and has a value defined previously. More preferred are C6-C10(di)arylaminomethylene group, (di)phenylenesulfonyl group are most preferable.

The term1-C8alkylcarboxylic means alkylcarboxylic group, an alkyl group which contains from 1 to 8 carbon atoms and has a value defined previously. More preferred are C1-C6alkylcarboxylic group, C1-C4alkylcarboxylic group are most preferable.

The term6-C14arylcarboxamide means arylcarboxamide group, aryl group which contains 6 to 14 carbon atoms and has a value defined previously. More preferred are C6-C10arylcarboxamide group, phenylcarbonylamino group are most preferable.

The term C2-C7heterocyclizations means geterotsyklicescoe group that contains asuu 2-7 carbon atoms, as previously defined, attached to the oxygen atom. Most preferred are C2-C5heterocyclizations group.

The term3-C8cycloalkane means cycloalkyl group containing 3-8 carbon atoms as previously defined, attached to the oxygen atom.

The term6-C14aryloxy means an aryl group containing 6-14 carbon atoms as previously defined, attached to the oxygen atom. More preferred are C6-C10aryloxy group, fenoxaprop are the most preferred. With4-C13Heteroaromatic groups are similar With6-C14aryloxy groups containing at least one heteroatom selected from N, O and S in the heteroaryl ring. More preferred are4-C9heteroaromatic group.

It was shown that the compounds of the above formula I are able to contact LH receptor and exhibit agonistic activity against LH.

The invention additionally relates to pharmaceutical compositions comprising a bicyclic heteroaromatic derivative or its salt having the General formula I.

Thus, the compounds according to the invention can be used in therapy. An additional aspect of the invention relates to the use of bizi the symbolic heteroaromatic compounds having the General formula I to obtain drugs for regulating fertility. Preferably these compounds are used for activation of the LH receptor.

Bicyclic heteroaromatic derivatives according to this invention can have one or more chiral carbon atoms. Therefore, the compound can be obtained in the form of chiral pure compounds or as mixtures of diastereoisomers and/or enantiomers. Methods of obtaining pure chiral compounds is well known in this field, for example, crystallization or chromatography.

For therapeutic use of salts of compounds of formula I are salts where the counterion is pharmaceutically acceptable. However, it can also find application, for example, upon receipt or purification of pharmaceutically acceptable compounds, acid additive salts of the bases of the compounds of formula I. All salts that are pharmaceutically acceptable, or are not, included in the scope of the present invention.

Examples of the acid additive salts include salts derived from mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid, preferably obtained from hydrochloric acid, and organic acids such as citric acid, tartaric acid, acetic acid, lactic to the slot, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid and the like.

Suitable routes of administration of compounds of the formula I or their pharmaceutically acceptable salts, also referred to in the present description as the active ingredient, are intramuscular injection, subcutaneous injection, intravenous injection or intraperitoneal injection, oral or vnutripuzarnoe introduction. Preferably, the compounds can be administered orally. The exact dose and mode of administration of the active ingredient or pharmaceutical composition in a certain way will depend on the desired therapeutic effect (treatment of infertility, contraception) and can vary depending on the particular compound, the route of administration, the age and condition of the individual subject, which is injected the drug.

In General, parenteral require lower doses than for other routes of administration, which are largely dependent on adsorption. However, the dosage for men is preferably of 0.0001 to 25 mg per kg of body weight. The desired dose may be presented as a single dose or as multiple divided doses, administered with suitable intervals during the day, or, in the case of a recipient female, in the form of a dose for injection with a suitable the day intervals during the menstrual cycle. Dose and mode of administration can vary for the recipient, male and female.

In the case of in vitro or ex vivo applications, such as IVF applications, the compounds according to the invention should be used in the incubation medium at a concentration of about 0.01 to 5 mg/ml

Thus, the present invention also relates to pharmaceutical compositions comprising a bicyclic heteroaromatic compound of the formula (I) in a mixture with a pharmaceutically acceptable auxiliary additives and, optionally, other therapeutic agents. Adjuvants must be "acceptable" in the sense of compatibility with other ingredients of the composition and non-toxic to recipients.

Pharmaceutical compositions include those that are suitable for oral, rectal, nasal, local (including dermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The composition can be obtained by any method well known in the pharmaceutical field, for example, using methods described in Gennaro et al., Remington''s Pharmaceutical Science (18thed., Mark Publishing company, 1990, see especially part 8: Pharmaceutical Preparations and Their Manufacture (Pharmaceuticals and their receipt).

Such methods include studieprivate contact of the active ingredient with any auxiliary agent. Auxiliary agent(s), also referred to as incremental ingredient includes conventional in the art (Gennaro, above), such as fillers, binders, diluents, loosening agents, lubricants, colorants, flavoring agents and wetting agents.

Pharmaceutical compositions suitable for oral administration may be presented as separate standard preparative forms, such as pills, tablets or capsules, or in the form of powders or granules, or in the form of a solution or suspension. The active ingredient may also be presented as a bolus or paste. The composition optionally can be recycled in suppositories or enemas for rectal administration.

For parenteral doing the suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in the form of a container with a single dose or multiple doses, for example, sealed tubes or vials and may be stored in dried by freezing condition requiring only the addition of sterile liquid carrier, for example water, before use.

Compositions or formulations suitable for administration by nasal inhalation include fine dusty or mists that may be generated using aerosols, sprays and apparatus for injection.

Bicyclic heteroaromatic derivatives according to the invention can also be administered in the form of implantable pharmaceutical devices, consisting of a core of active substance enclosed in a membrane that controls the rate of release. Such implants can be used subcutaneously, or topically, and they will release the active ingredient with approximately constant speed over a relatively large period of time, for example, from weeks to years. Methods of obtaining implantable pharmaceutical devices, per se, known in the field, for example, described in European patent 0303306 (AKZO N.V.).

Thus, the compounds according to the present invention can be used in the same clinical purposes as natural LH, with the advantage that they have modified the properties of stability and can be entered differently.

Compounds of the present invention, where a=NH, represented by formula (I-a) can usually be obtained in accordance with known in this area by condensation of the acids of formula (II) with the amine of formula (III).

The above reaction is carried out at room temperature in a suitable solvent, for example, in an aprotic solvent such as N,N-dimethylformamide (DMF) or dichloromethane using a condensing reage is the such as tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea (TBTU) or hexaphosphate postreproductive (PyBrOP) and the base is a tertiary amine, e.g. N,N-diisopropylethylamine (DiPEA).

Also the compounds of formula (I), where=O, represented by formula (I-b)can be obtained in the same manner as described above for compounds of formula (I-a), on the basis of the acids of the General structure (II) and alcohols of the formula (IV).

The compounds of formula (I), where is a link represented by formula (I-c)can be obtained by the interaction of a suitable ORGANOMETALLIC reagent derivative of the formula (V) in an aprotic solvent such as THF. Related substitution reactions can be found in the literature: S.V.Frye, M.C.Johnson, N.L.Valvano, J.Org.Chem. 56:3750, 1991. Amides Weinrebe (Weinreb) of the formula (V) can be synthesized from the acid of formula (II) and N-methoxy-N-methylamine using the conditions described for obtaining the amides of the formula (I-a).

Suitable means for receiving the intermediate acid (II) is known in this field saponification in the main environment ethyl esters of the General structure (VI). Saponification occurs in the presence of a base such as lithium hydroxide. The potassium hydroxide or sodium hydroxide in aqueous dioxane at elevated temperature (40° the boiling point), followed by treatment with acid.

Bicyclic lactams of the formula (VII) are useful starting materials for the production of the respective Eminov (VIII). In a typical experiment, the lactam is transformed into the corresponding Chloramin using phosphorylchloride at elevated temperature (60° the boiling point) in a suitable solvent such as 1,4-dioxane. When processing a reducing agent such as hydrogen in the presence of a suitable catalyst in ethanol, can be allocated target Imin General formula (VIII). Related recovery has been described in the literature, see, for example: E.Bisagni, C.Landras, S.Thirot and C.Huel, Tetrahedron 52: 10427, 1996.

Bicyclic lactams of the General structure (VII) can be obtained by condensation of the acids of type (IX) with Diethylaminoethanol under the action of the condensing agent, such as TBTU/DiPEA and cyclization of the intermediate amides in ethanol in the basic environment. Aromatization with concomitant diethoxycarbonyl then gives Bicycle type (VII). In an alternative method, the ethyl ester of glycine can be used instead of diethylaminobenzoate. See, for example, M.Blanco, M.G.Lorenzo, I.Perillo, C.B.Schapira, J.Heterocycl.Chem., 33:361, 1996. Cyclization of the intermediate amides can also be carried out under the action of chloride of tin is(IV). On the application of tin chloride(IV) to effect the ring closure cycle in related systems reported: A.C.Veronese, R.Callegari, C.F.Morelli, Tetrahedron 51:12277, 1995.

Treatment of the acid of formula (IX) ethylbromoacetate in an aprotic solvent under the action of a non-nucleophilic base, such as potassium carbonate or tert-piperonyl potassium can give aromatic lactone of the General structure (X). Related patterns have been described in the literature: C.Bhakta, Indian J.Chem.Sect.B. 25:180, 1986.

Processing of the vinyl derivative of formula (XI) diethylmalonate in basic terms enables a paired connection. Intermediate adduct can cilitates in Bicycle formula (XII) by reaction under the action of chloride of tin (IV) and subsequent processing.

Alternative tert-butylethylamine can be used in this way instead of diethylmalonate.

When processing a suitable oxidant such as DDQ or palladium catalyst at elevated temperature in a suitable solvent, such as xylene, aromatization derivatives of the formula (XII) leads to hinazolinam or quinoline General formula (XIII). See also: K.Kobayashi, T.Uneda, K.Takada, T.Kitamura, O.Morikawa, H.Konishi, J.Org.Chem.62:664, 1997.

In another approach, methyl is IRI(mi)Dina General formula (XIV) deprotonated by a methyl group under the action of a strong base, such as hexamethyldisilazane lithium (LiHMDS) or diisopropylamide lithium (LDA)in a suitable aprotic solvent such as THF at low temperature (-78°). Anion then reacts with ethyl 3-ethoxyacrylate. After conjugated addition cyclization occurs in the quinoline or hintline General formula (XIII)as described K.Kobayashi, K.Takada, H.Tanaka, T.Uneda, T.Kitamura, Chem.Lett.:25, 1996; K.Kobayashi, T.Uneda, K.Takada, H.Tanaka, T.Kitamura, O.Morikawa, H.Konishi, J.Org.Chem.62:664, 1997.

Handling chlorides of General formula (XV) ethyl ester (N-alkyl)-beta-alanine (XVI) in basic conditions gives Bicycle General formula (XVII). Related transformations have been described: P.Y.Boamah, N.Haider, G.Heinisch, Arch.Pharm. (Weinheim) 323:207, 1990.

The compounds of formula (XVII), where R6=H can be oxidized to the derivatives of formula (XVIII) using palladium on charcoal at an elevated temperature. See, for example, M.Onda, K.Kawakami, Chem.Pharm.Bull. 20:1484, 1972. The compounds of formula (XVII), where R6=H or alkyl, can be converted into imini formula (XVIII) using DDQ as described: H.Ishii, Chem.Pharm.Bull. 26:864, 1978; J.I.DeGraw, P.H.Christie, W.T.Colwell, F.M.Sirotnak, J.Med.Chem., 35:320, 1992.

Alternatively, imini formula (XVIII) can be obtained from the corresponding lactams of the formula (XIX) in a similar way (see above) as their registereditor the situations analogues of the formula (VIII), for example, the transformation in Chloramin using POCl3and then dihalogenoalkane using hydrogen and a suitable catalyst.

The lactam of formula (XIX) can be obtained by acylation amidopirin(mi)Dean of the formula (XX) florecimiento in the presence of a suitable base. Subsequent ring closure in an intermediate acyclic malonamide under the action of bases (ethoxide sodium in ethanol) or chloride tin(IV) then leads to the bicyclic lactam type (XIX). Similar transformations have been described in the literature. See, for example, A.C.Veronese, R.Callegari, C.F.Morelli, Tetrahedron 51:12277, 1995; W.Stadlbauer, S.Prattes, W.Fiala, J.Heterocycl.Chem.35:627, 1998.

Depending on system replacement amidopirin(mi)of dinov formula (XX), the lactam of formula (XIX) can be obtained by condensation of diethylmalonate under the action of chloride of tin (IV) followed by cyclization at a high temperature in a suitable solvent (for example, 240°in diphenyl ether).

Similarly, the lactones of type (XXII) can be obtained by O-acylation of lactams of the formula (XXI) florecimiento and subsequent cyclization.

Propery(mi)Dina General formula (XXIII) are obtained by selective O-alkylation of lactams type (XXI) using potassium carbonate in ACE the region and the subsequent closure of the loop under the action of ethoxide sodium in ethanol.

Tenopir(mi)Dina General formula (XXIV) is obtained by processing chlorides (XVI) ethylmercaptan under the action of strong bases. In a typical experiment, one equivalent of chloride (XV) is subjected to interaction with 1.5 equivalents of ethylmercaptan and 2 equivalents of tert-butoxide potassium in THF. Under such conditions acyclic sulfide undergoes spontaneous cyclization with the formation of tenopir(mi)Dean of General formula (XXIV). If R1represents a (hetero)aryl, substituted by an electronegative group such as the nitro-group, the above-mentioned cyclization is carried out in two stages, including the allocation of intermediate tiefer followed by treatment of the tertiary base, such as DIPEA in toluene/EtOH at boiling point for the implementation of the education of the rings.

Piri(mi)dicarboxylate General formula (IX) is obtained by saponification alkoxycarbonyl(mi)of dinov formula (XXV) using a strong base such as lithium hydroxide or potassium hydroxide in a mixture of water and organic co-solvent, such as 1,4-dioxane or methanol at elevated temperature (40°C to the boiling temperature) followed by treatment with an acid. If W=CO2alkyl, R7preferably represents benzyl, to give the te selective hydrogenation of benzyl ester functions thus to Deputy W remained unaffected.

The compounds of formula (XXV) can be obtained by palladium-catalyzed alkoxycarbonylmethyl chloride (XV) in the presence of carbon monoxide and a suitable alcohol (R7OH, XXVI). Such transformations are described in the literature, see, for example: Y.Bessard, R.Crettaz, Heterocycles 51:2589, 1999.

Palladium-catalyzed reactions of chlorides (XV) with vinyltrimethylsilane or terminalova give vinylene(mi)Dina General structure (XI). This type of transformation is widely described in the literature, see, for example: L.L.Gundersen, A.K.Bakkestuen, A.J.Aasen, H.Oeveras, F.Rise, Tetrahedron 50:9743, 1994; F.Guillier, F.Nivoliers, A.Godard, F.Marsais, G.Queguiner, J.Heterocycl.Chem., 36:1157, 1999.

Depending on the structure of the substitution of the chlorides of General formula (XV) vinylene(mi)Dina General formula (XI) can also be obtained by substitution of chloride by methyltriphenylphosphonium with subsequent interaction with the (pair)formaldehyde.

Similarly, the processing of the chlorides of General formula (XV) with trimethylaluminum in the presence of palladium catalyst in an aprotic solvent such as THF, gives metylene(mi)Dina General formula (XIV). Related syntheses were published in: Q.Lu, I.Mangalagiu, T.Benneche and K.Undheim, Acta Chem.Sc. 51:302, 1997.

The compounds of formula (XXI), where Y=N, the pre is raised by the formula (XXI-a), can be obtained using several methods, based on literature data.

For example, derivatives of the formula (XXI-a), where R1=C6-C14aryl or4-C13heteroaryl, can be synthesized by the condensation of ethyl esters (XXVII), where W is as previously defined, with aldehydes (XXVIII) and compounds (XXIX), which can be estimatedin (XXIX-a), smokeview (XXIX-b), monosubstituted guanidine (XXIX-c), disubstituted guanidine (XXIX-d) or amidine (XXIX-e).

In a typical experiment components (XXVII), (XXVIII) and (XXIXa-e) are suspended in a suitable solvent, e.g. ethanol, methanol, N,N-dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran or pyridine and add a base such as potassium carbonate, sodium acetate, sodium methoxide or ethoxide sodium. The interaction occurs at elevated temperatures (from 70°C to the boiling point). See, for example: S.Kambe, K.Saito and H.Kishi, Synthesis: 287, 1979; A.M.Abd-Elfattah, S.M.Hussain and A.M.El-Reedy, Tetrahedron 39: 3197, 1983; S.M.Hussain, A.A.El-Barbary and S.A.Mansour, J.Heterocycl.Chem., 22:169, 1985. In the case of W=C(O)OEt, aromatization occurs when adding an oxidant such as DDQ or oxygen. The genus is the result of the cyclization can also be carried out on a solid substrate, such as Merrifield resin (Merrifield) using a suitable linker, see, for example, A.L.Mrzinzik and E.R.Felder, J.Org.Chem. 63:723, 1998; T.Masquelin, D.Sprenger, R.Baer, F.Gerber and Y.Mercadal, Helv.Chim.Acta 81:646, 1998.

Compounds of General formula (XX), where Y=N, is represented by the formula (XX-a) can be obtained in the same by condensation using malonitrile.

Alternatively, compounds of General formula (XX) is obtained by ammonolysis of the chlorides of the formula (XV) using aqueous ammonia or a suitable organic co-solvent, such as 1,4-dioxane. This transformation can also be performed using ammonium chloride and the base is a tertiary amine, such as DiPEA, in an aprotic solvent such as DMF.

Chlorides of General formula (XV) can be synthesized by known in this field by the reaction of lactams (XXI) with POCl3in a suitable solvent such as 1,4-dioxane, at elevated temperature (60°C to the boiling point).

Derivatives of the formula (XV), where Y=N and R1isn't C6-C14the aryl or4-C13heteroaryl can be obtained by monozameschennaya Cl derivatives of the formula (XXX) with various nucleophiles. Related substitution reactions can be found in the literature, for example, S.Kohra, Y.Tominaga and A.Hosomi, J.Heterocycl.Chem. 25:959,1988; A.A.Santilli, D.H.Kim and S.V.Wanser, J.Heterocycl Chem.8:445, 1971; J.Clark, M.S.Shannet, D.Korakas and G.Varvounis, J.Heterocycl. Chem. 30:1065, 1993; S.Tumkevicius, Liebigs Ann.Org.Bioorg.Chem. 9:1703, 1995.

Pyridine General formula (XXI), where Y=CH, A=S and W=CN, represented by formula (XXI-b), receive consecutive alkylation α,β-unsaturated dinitriles General structure (XXXI) with carbon disulfide and idestam the alkyl R2-I, with the formation of compounds of General formula (XXXII), as described P.Milart, Tetrahedron 54:15643-15656, 1998. Cyclization of compounds of formula (XXXII) in acidic conditions, as described K.Peseke, Z.Chem. 29:442-443 (1989), gives pyridine General formula (XXI-b).

Compounds of General formula (XXI), where a represents a bond, Y=CH and W is as defined previously, is represented by the formula (XXI-c) can be obtained by interaction α,β-unsaturated ketones of General formula (XXXIII) with inorganic salts of General formula (XXXIV), where W is as previously defined, using a strong base such as tert-piperonyl potassium, in the presence of oxygen in a suitable solvent, such as dimethylsulfoxide. Related cyclization described in R.Jain, F.Roschangar, M.A.Ciufolini, Tetrahedron Lett. 36:3307, 1995.

Methods of determination of receptor binding and in vitro and in vivo assays to determine biological activity of gonadotropins horo is known about. In General, the downregulation of the receptor is brought into contact with a test compound and measuring the binding, or stimulation or inhibition of a functional response.

To measure the functional response selected DNA encoding the LH receptor gene, preferably the receptor is human, Express in appropriate cell hosts. Such a cell can be a cell of the ovary of the Chinese hamster, but other cells are also suitable. Preferably the cells are derived from mammals (Jia et al., Mol.Endocrin., 5:759-776, 1991).

How to create recombinant LH expressing cell lines are well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor laboratory Press, Cold Spring Harbor, latest edition). Ekspressirovali receptor achieve using the expression of the DNA encoding the desired protein. Methods site-directed mutagenesis, ligation of additional sequences, PCR and construction of suitable expression systems are all, by now, well known in this field. Part or all of the DNA encoding the desired protein can be constructed synthetically using standard solid-phase methods, it is preferable to include restriction sites for ease of ligation. Suitable control elements for transcription and the translation is AI enabled the coding sequence can be provided for the DNA coding sequences. As is well known, are currently available expression systems that are compatible with a large variety of hosts, including prokaryotic hosts, such as bacteria, and eukaryotic hosts such as yeast, plant cells, insect cells, mammalian cells, bird cages and the like.

Cells expressing the receptor, and then enter into contact with a test compound to observe binding, or stimulation or inhibition of a functional response.

Alternatively, to link connection you can use a dedicated cell membrane containing the expressed receptor.

To measure binding, you can use radioactively or fluorescently labeled compounds. As reference compounds can be used recombinant LH man. Alternatively, can also be performed analyses of competitive binding.

Other analysis includes the selection of compounds for agonist of LH receptor by determining the stimulation of receptor-mediated camp-accumulation. Thus, this method involves receptor expression on the cell surface of the host cell and the effect on the cell of the investigated compounds. Then measure the amount of camp. The level of camp will decrease or increase, depending on ingibirujut the th or stimulating effect of the compounds on the binding with the receptor.

In addition to the direct measurement, such as camp levels in the affected cell, you can also use a cell line that is in addition to the transfection of DNA that encodes a receptor, also transfection second DNA that encodes a reporter gene, expression of which responds to the level of camp. Such reporter genes may be cyclic amp-induced or can be designed in such a way that they are associated with the new camp-conforming elements. Typically, the reporter gene expression can be controlled by any of the responding element, reacting to changes in camp levels. Suitable reporter genes include LacZ, alkaline phosphatase, Firefly luciferase and green fluorescent protein. Principles such transactivity assays well known in this field and are described, for example, Stratowa Ch., Himmler A. And Czernilofsky A.P. (1995) Curr.Opin.Biotechnol. 6:574.

To select the active compounds tested at 10-5M should lead to activity in more than 20%, when LH is used as a comparative compound. Another criterion may be the value of the EU50that should be <10-5M, preferably <10-7M.

A qualified specialist will be obvious that the required values of the EU50depend on the studied compounds. For example, connect the tion with the EU 50that is less than 10-5M is usually considered as a candidate to obtain drugs. Preferably this value is lower than 10-7M, more preferably 10-8M. However, the connection that has higher values EU50but is selective for a particular receptor, may even be a good candidate.

Screening of compounds for agonist of LH receptor can also be performed using the bioanalysis of mouse Leydig cells (Van Damme M., Robertsen D. And Diczfalusy, E. (1974). Acta Endocrinol. 77:655-671; Mannaerts B., Kloosterboer H and Schuurs, A. (1987). Neuroendocrinology of reproduction (Neuroendocrinology of reproduction. R. Rolland et al. Eds., Elsevier Science Publishers B.V., 49-58). In this analysis, mediated by stimulation of LH receptor production of testosterone can be measured in Leydig cells isolated from male mice.

To measure the in vivo activity of the compounds agonist of LH receptor can be examined induction of ovulation in young mice. In this analysis, young female mice can enter FSH urine and approximately 48 hours to process LH-agonistic connection. Animals are killed after processing LH agonist and the number of ova in the fallopian tube can be estimated using a microscope.

Compounds of the present invention can be applied clinically in those modes, as this is the first time use LH or hCG. They include LH replacement in subjects with hypogonadism underdevelopment of the reproductive system either in men or in women, the introduction in the middle of the cycle to induce ovulation (OI) or controlled ovarian hyperstimulation (SLEEP) or stimulation of the yellow body.

The following examples are illustrative in this invention, and should not be interpreted as limiting the scope of invention.

Examples

Example 1

Tert-butyl 5-amino-2-methylthio-4-(3-methoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

(a). 5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-hydroxypyrimidine

A mixture of sulfate S-methylisothiazoline (139 mg), 3-methoxybenzaldehyde (243 μl), ethyl cyanoacetate (112 μl) and potassium carbonate (145 mg) in absolute ethanol (2 ml) was stirred at 60°C for 5 hours. The reaction mixture was cooled to 0°C in an ice bath, filtered and the residue was heated in water (H2O) to obtain a clear solution. The solution was acidified with 2 n aq. HCl to pH 2 and was cooled to 0°C in an ice bath. The obtained crystals were collected by filtration and dried in vacuum.

Yield: 186 mg

MS-ESI: [M+H]+=274,2

TLC: Rf=0,50, silica gel, dichloromethane (CH2Cl2)/methanol (CH3HE)=9/1 (V/V)

(b). 6-Chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthiopyrimidin

The phosphorus oxychloride (0.75 ml) was added to a stirred solution of 5-cyano-4-3-methoxyphenyl)-2-methylthio-6-hydroxypyrimidine (example 1a, 305 mg) in dry 1,4-dioxane (1 ml). Was added a drop of N,N-dimethylaniline. After 3 hours at 80°C, the mixture was cooled to 0°C in an ice bath and slowly added to crushed ice. After the termination of the exothermic reaction was added N2O (3 ml). The solids were collected by filtration and dried in vacuum.

Output: 244 mg

MS-ESI: [M+H]+=292,2

TLC: Rf=0,86, silica gel, CH2Cl2

(c). Ethyl 5-amino-4-(3-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate

Tert-piperonyl potassium (150 mg) was added to a stirred solution of ethyl 2-mercaptoacetate (92 μl) and 6-chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthiopyrimidine (example 1b, 244 mg) in dry tetrahydrofuran (THF) (4 ml). After 1 hour the mixture was cooled to 0°C in an ice bath, diluted with H2O (10 ml). The solids were collected by filtration and dried in vacuum.

Yield: 260 mg

MS-ESI: [M+H]+=376,2

TLC: Rf=0,44, silica gel, CH2Cl2

(d). 5-Amino-4-(3-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid

Ethyl 5-amino-4-(3-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate (example 1c, 9,27 g) was dissolved in a mixture of 1,4-dioxane (270 ml) and H2O (30 ml). Was added lithium hydroxide (10 g) and the mixture was stirred at 80°C for 48 hours. 1,4-Dioxane was removed from the mixture by evaporation and the residue was placed in H2O. the Remaining solution was acidified d is pH 2 by addition of 3 N. aq. HCl. The precipitate was filtered and washed with H2O. Traces of water in the sediment was removed by joint evaporation with 1,4-dioxane and then with diethyl ether and dried in vacuum at 50°C during the night.

Output: 8,45 g

MS-ESI: [M+H]+=348,0

TLC: Rf=0,2, silica gel, CH2Cl2/CH3OH=9/1 (V/V)

(e). Tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide

5-Amino-4-(3-methoxyphenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1d, 7.0 g) was dissolved in dry CH2Cl2(100 ml). Added tetrafluoroborate benzotriazol-1-yl-N,N,N,N'-tetramethylurea (TBTU) (8.0 g), N,N-diisopropylethylamine (DIPEA) (6,6 ml) and tert-butylamine (4,0 ml) and the mixture was stirred at room temperature for 5 hours. The reaction mixture is washed with 5% aq. NaHCO3(2×100 ml) and 1 M aq. HCl (2×100 ml). The organic layer was dried (MgSO4) and concentrated in vacuum. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane (hept/ethyl acetate (EtOAc)=1/0 to 3/2 (V/V) as eluent.

Yield: 6.5 g

MS-ESI: [M+H]+=403,0

HPLC: Rt=33,56 min, column 3 μm Luna C-18(2) 100×2.0 mm, a flow of 0.25 ml/min, oven temperature 40°C, detection 210 nm + 254 nm, eluent H2O/acetonitrile (CH3CN)/CH3OH=70/28,5/1,5 to 0/95/5 (V/V) for 50 minutes.

(f). Tert-BU is Il 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 1e, 1.8 g) was dissolved in dry CH2Cl2(30 ml) and the resulting solution was cooled to 0°C. was Added dropwise a solution of tribromide boron (1,28 ml) in dry CH2Cl2(30 ml) and the mixture was stirred over night at room temperature. To the reaction mixture was added dropwise a saturated aq. NaHCO3before termination of the exothermic reaction. Then CH2Cl2was removed from the mixture by evaporation and added a large number of EtOAc. The organic layer was washed with saturated aq. NaHCO3, dried (MgSO4) and concentrated in vacuum.

Yield: 1.3 g

MS-ESI: [M+H]+=389,2

HPLC: Rt=17,44 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN/CH3OH = 90/9,5/0,5 to 0/95/5 (V/V) for 50 minutes.

(g). Tert-butyl 5-amino-2-methylthio-4-(3-(methoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f (100 mg) was dissolved in dry CH2Cl2(5 ml). Added DBPEA (500 μl) and methyl chloroformate (199 μl) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. the Organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title is information compound was purified by HPLC using a column Luna C-18 using the following gradient: CH 3CN/H2O=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 93 mg

MS-ESI: [M+H]+=447,4

HPLC: Rt=17,56 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 25 minutes.

Example 2

Tert-butyl 5-amino-2-methylthio-4-(3-(allyloxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f (100 mg) with allylchloroformate (274 μl) was carried out in accordance with the procedures described in example 1g. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/H2O=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 102 mg

MS-ESI: [M+H]+=473,4

HPLC: Rt=received 19.82 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 25 minutes

Example 3

Tert-butyl 5-amino-2-methylthio-4-(3-(antioxygenic)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f (100 mg) with benzylchloride (368 μl) was performed according the methods, described in example 1g. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/H2O=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 112 mg

MS-ESI: [M+H]+=523,2

HPLC: Rt=22,22 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 25 minutes

Example 4

Tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-benzyloxycarbonyloxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f (100 mg) with p-nitrobenzenesulfonate (554 mg) was carried out in accordance with the procedures described in example 1g. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/H2O=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 47 mg

MS-ESI: [M+H]+=568,4

HPLC: Rt=21,45 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN = 40/60 to 0/100 (V/V) for 25 minutes.

Example 5

Tert-butyl 5-amino-2-methylthio-4-(3-(phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Interaction tre the-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 100 mg) with phenylcarbamate (324 μl) was carried out in accordance with the procedures described in example 1g. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/H2O=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 89 mg

MS-ESI: [M+H]+=509,4

HPLC: Rt=21,12 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 25 minutes.

Example 6

Tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 400 mg) with p-nitrophenylphosphate (207 mg) was carried out in accordance with the procedures described in example 1g. Evaporation of the solvent under reduced pressure gave the crude specified in the header of the connection.

Output: 569 mg

MS-ESI: [M+H]+=554,6

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V)

Example 7

Tert-butyl 5-amino-2-methylthio-4-(3-((N,N-diethylamino)carbonyloxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 1f (100 mg) was dissolved in dry CH2Cl2(5 ml) and added several who are drops of N,N-dimethylformamide (DMF). Added diethylcarbamoyl (68 mg) and DIPEA (217 μl) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. the Organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/N2About=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 75 mg

MS-ESI: [M+H]+=488,4

TLC: Rfor =0.6, silica gel, heptane/EtOAc=1/1 (V/V)

Example 8

Tert-butyl 5-amino-2-methylthio-4-(3-(1,2,3,6-tetrahydropyranyloxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 6, 142 mg) was dissolved in CH2Cl2. Added 1,2,3,6-tetrahydropyridine (117 μl) and DIPEA (224 μl) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2and washed with N2O. the Organic layer was concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/H2O=20/80 to 100/00 (V/V) for 45 minutes. Specified in the header is connected to the e then liofilizovane of a mixture of 1,4-dioxane and H 2O.

Yield: 76 mg

MS-ESI: [M+H]+=498,2

HPLC: Rt=13,90 min, column (5 μm Luna C-18(2) 150×4,60 mm, flow 1 ml/min, detection 210 nm, eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 15 minutes.

Example 9

Tert-butyl 5-amino-2-methylthio-4-(3-(p-toluensulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

(a). 5-Cyano-4-(3-nitrophenyl)-2-methylthio-6-hydroxypyrimidine

A mixture of sulfate S-methylisothiazoline (69,0 g), 3-nitrobenzaldehyde (75,0 g), ethylcyanoacrylate (56,0 ml) and potassium carbonate (72.5 g) in .EtOH (1500 ml) was stirred at 60°C for 16 hours. The reaction mixture was cooled to 0°C in an ice bath. The precipitate was filtered off, washed with .EtOH and dissolved in hot water (100°C). The solution was cooled to room temperature, acidified 2 N. HCl to pH 2 and was cooled to 0°C in an ice bath. The precipitate was filtered and washed with ice water. The remaining water in the sediment was removed by joint evaporation with 1,4-dioxane.

Output: 54,0 mg.

MS-ESI: [M+H]+=289,0

TLC: Rf=0,3, silica gel, DHM/MeOH=9/1 (V/V).

(b). 6-Chloro-5-cyano-4-(3-nitrophenyl)-2-methylthiopyrimidin

POCl3(100 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-hydroxypyrimidine (example 9(a)of 25.0 g) in dry 1,4-dioxane (300 ml). After 3 hours at 90°C, the mixture was cooled to room temperature and concentrated the Ali under reduced pressure. The residue was dissolved in 1,4-dioxane (100 ml) and the resulting solution was cooled to 0°C. was Carefully added to ice water. The precipitate was filtered and washed with water. The remaining water in the sediment was removed by joint evaporation with 1,4-dioxane.

Output: 26,0,

MS-ESI: [M+H]+=307,0

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V).

(c). Ethyl 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-(ethoxycarbonylmethyl)pyrimidine

DIPEA (15.7 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (9,3 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthiopyrimidine (example 9(b), 26,0 g) in a mixture of EtOH (250 ml) and DHM (250 ml). After 1 hour at room temperature, was added to a mixture of 0.1 n aq. HCl (500 ml), which was then extracted DHM (3×500 ml), dried (MgSO4) and concentrated under reduced pressure.

Output: 28,0 g

MS-ESI: [M+H]+=RUR 390.4

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V).

(d). Ethyl 5-amino-4-(3-nitrophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylate

A mixture of ethyl 5-cyano-4-(3-nitrophenyl)-2-methylthio-6-(ethoxycarbonylmethyl)pyrimidine (example 9(c)of 28.0 g) and DIPEA (30 ml) in a mixture of toluene (150 ml) and EtOH (150 ml) was stirred while boiling under reflux (100°C) for 16 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. Residual DIPEA were joint removed by evaporation with tolua the om.

Output: 28,0 g

MS-ESI: [M+H]+=391,2

TLC: Rfor =0.6, silica gel, heptane/EtOAc=3/2 (V/V).

(e). Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide

Ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)thieno[2,3-d]pyrimidine-6-carboxylate (example 9d, 780 mg) was dissolved in 1,4-dioxane (10 ml). Was added ethanol (10 ml) and tin chloride (II) (1.1 g) and the reaction mixture was stirred overnight at 90°C. After concentrating the reaction mixture in vacuo, the residue was re-dissolved in EtOAc (50 ml) and washed with 4 M aq. NaOH (10 ml), dried (MgSO4) and concentrated under reduced pressure. Ester ethyl group derived ethyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxylate (558 mg) omilami to the corresponding acid (430 mg)using the method described in example 1d and subsequently subjected to interaction with tert-butylamine (200 μl) to form the corresponding tert-butylamide (according to example 1e). Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/1 (V/V) as eluent.

Output: 391 mg

MS-ESI: [M+H]+=388,0

TLC: Rf=0,43, silica gel, heptane/EtOAc=3/2 (V/V)

(f). Tert-butyl 5-amino-2-methylthio-4-(3-(p-toluensulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)t is prohibited[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) was dissolved in dry pyridine (5 ml). Added p-toluensulfonate (70 mg) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2and washed with 0.1 M aq. HCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent.

Yield: 63 mg

MS-ESI: [M+H]+=542,4

HPLC: Rt=23,46 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN/CH3HE=10/72/17/1 to 10/18/68/4 (V/V) for 50 minutes.

Example 10

Tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 2.5 g) was dissolved in a mixture of CH2Cl2(25 ml) and pyridine (25 ml). 2-Bromo-acanaloniidae received, as described in Bull. Chem. Soc. Jpn. 39,1937-1941 (1966). Was added dropwise a solution of 2-bromo-acanaloniidae (2 g) in CH2Cl2(5 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2and washed with saturated aq. NaHCO3. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in sagola the ke compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent.

Yield: 1.4 g

MS-ESI: [M+H]+=478,6

TLC: Rf=0,80, silica gel, heptane/EtOAc=3/2 (V/V)

Example 11

Tert-butyl 5-amino-2-methylthio-4-(3-(2-piperazineethanesulfonic)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was dissolved in dry THF (5 ml). Added piperidine (181 μl) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2and washed with saturated aq. NaHCO3. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was initially purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent and then by HPLC using a column Luna C-18 and the following gradient: CH3CN/0.1% aq. triperoxonane acid (TFUC)=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and 0.1% aq. TFUCK.

Yield: 89 mg (TFUC salt)

MS-ESI: [M+H]+=563,4

HPLC: Rt=18,4 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=60/40 to 0/100 (V/V) for 25 minutes.

Example 12

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(thiomorpholine-4-yl)-acanaloniidae)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Interaction thiomorpholine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was carried out in accordance with the procedure described in example 11. Specified in the title compound was initially purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent and then by HPLC using a column Luna C-18 and the following gradient: CH3CN/0.1% aq. TFOC=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and 0.1% aq. TFUCK.

Yield: 120 mg (TFUC salt)

MS-ESI: [M+H]+=581,2

HPLC: Rt=17,2 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=60/40 to 0/100 (V/V) for 25 minutes.

Example 13

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(bis-(2-methoxyethyl)amino)acanaloniidae)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of bis-(2-methoxyethyl)amine (244 mg) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was carried out in accordance with the method described in example 11. Specified in the title compound was initially purified by chromatography on silica gel using heptane/EtOAc=3/2 (V/V) as eluent and then by HPLC using a column Luna C-18 and following the th gradient: CH 3CN/0.1% aq. TFOC=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and 0.1% aq. TFUCK.

Yield: 60 mg (TFUC salt)

MS-ESI: [M+H]+=611,4

HPLC: Rt=17,9 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=60/40 to 0/100 (V/V) for 25 minutes

Example 14

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(N-methylpiperazine)-acanaloniidae)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Interaction of N-methylpiperazine (184 μl) with tert-butyl 5-amino-2-methylthio-4-(3-(vinylsulfonate)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 10, 87 mg) was carried out in accordance with the procedure described in example 11. Specified in the title compound was initially purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent and then by HPLC using column Luna C-18 and the following gradient: CH3CN/0.1% aq. TFOC=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and 0.1% aq. TFUCK.

Yield: 85 mg (TFUC salt)

MS-ESI: [M+H]+=578,4

HPLC: Rt=16,1 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=60/40 to 0/100 (V/V) for 25 minutes.

Example 15

Tert-butyl 5-amino-2-methylthio-4-(3-(methoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tr is t-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) was dissolved in dry CH2Cl2(5 ml). Added methylchloroform (199 μl) and DIPEA (500 μl) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with H2O. the Organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 80 mg

MS-ESI: [M+H]+=446,2

HPLC: Rt=20,44 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/72/18 to 10/18/72 (V/V) for 20 minutes.

Example 16

Tert-butyl 5-amino-2-methylthio-4-(3-(allyloxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with allylchloroformate (274 μl) was performed using methods described in example 15. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2 O.

Yield: 66 mg

MS-ESI: [M+H]+=472,2

HPLC: Rt=22,37 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/72/18 to 10/18/72 (V/V) for 20 minutes.

Example 17

Tert-butyl 5-amino-2-methylthio-4-(3-(benzyloxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with benzylchloride (368 μl) was carried out in accordance with the methods described in example 15. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 112 mg

MS-ESI: [M+H]+=522,4

HPLC: Rt=24,10 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/72/18 to 10/18/72 (V/V) for 20 minutes.

Example 18

Tert-butyl 5-amino-2-methylthio-4-(3-(ethoxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with etelcharge.com (247 μl) was performed using methods described in example 15. Specified in the title compound was purified with what omashu HPLC using a column Luna C-18 and the following gradient: CH 3CN/10% aq. CH3CN=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 74 mg

MS-ESI: [M+H]+=460,4

HPLC: Rt=to 21.77 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/72/18 to 10/18/72 (V/V) for 20 minutes.

Example 19

Tert-butyl 5-amino-2-methylthio-4-(3-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The interaction of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) with phenylcarbamate (324 μl) was performed using methods described in example 15. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: CH3CN/10% aq. CH3CN=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 47 mg

MS-ESI: [M+H]+=508,4

HPLC: Rt=23,25 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/72/18 to 10/18/72 (V/V) for 20 minutes.

Example 20

Tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 1 g) was dissolved is in dry CH 2Cl2(10 ml). Next, was added dropwise a solution of p-nitro-phenylcarbamate (520 mg) in dry CH2Cl2(10 ml) and the reaction mixture was stirred at room temperature. After 1 hour the reaction mixture was washed with H2O. the Organic layer was dried (MgSO4) and concentrated under reduced pressure.

Yield: 1.42 g

MS-ESI: [M+H]+=553,6

TLC: Rf=0,7, silica gel, heptane/EtOAc=3/2 (V/V)

Example 21

Tert-butyl 5-amino-2-methylthio-4-(3-(morpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 20, 142 mg) was dissolved in dry CH2Cl2(5 ml). Added morpholine (112 μl) and DIPEA (225 μl) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with CH2Cl2and washed with H2O. the Organic layer was concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 22 mg

MS-ESI: [M+H]+=501,2

HPLC: Rt=8,62 min, column Luna C-18 (see example 8), eluent H2O/CH3CN=40/60 to 0/100 (sum) for 15 minutes.

Example 22

Tert-butyl 5-amino-2-methylthio-4-(3-(o-antigingermoomin)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Linking c using urea tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-5-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 20, 142 mg) with ortho-anisidine (159 mg) was carried out in accordance with the methods described in example 21. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 18 mg

MS-ESI: [M+H]+=537,2

HPLC: Rt=12,94 min, column Luna C-18 (see example 8), eluent H2O/CH3CN = 40/60 to 0/100 (V/V) for 15 minutes.

Example 23

Tert-butyl 5-amino-2-methylthio-4-(3-(1,2,3,6-tetrahydro-pyridinecarboxamide)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Linking with urea tert-butyl 5-amino-2-methylthio-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 20, 142 mg) 1,2,3,6-tetrahydropyridine (118 μl) was carried out in accordance with the methods described in example 21. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 Minotaure in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H 2O.

Yield: 18 mg

MS-ESI: [M+H]+=497,2

HPLC: Rt=11,19 min, column Luna C-18 (see example 8), eluent H2O/CH3CN=40/60 to 0/100 (V/V) for 15 minutes.

Example 24

Tert-butyl 5-hydroxy-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxamide

(a). Ethyl 2-methylthio-4-(3-methoxyphenyl)-6-methyl-1,4-dihydropyrimidin-5-carboxylate

A mixture of sulfate S-methylisothiazoline (13,9 g), 3-methoxybenzaldehyde (7.5 g), ethylacetoacetate (6.5 g) and sodium hydrogen carbonate (21 g) in DMF (200 ml) was stirred at 70°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed with H2O and saturated aq. NaCl. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent.

Output: 7,3 g

MS-ESI: [M+H]+=321,0

TLC: Rf=0,2, silica gel, heptane/EtOAc=3/1 (V/V)

(b). Ethyl 2-methylthio-4-(3-methoxyphenyl)-6-methylpyrimidin-5-carboxylate

Ethyl-2-methylthio-4-(3-methoxyphenyl)-6-methyl-1,4-dihydropyrimidin-5-carboxylate (example 24a, 7,65 g) was dissolved in a mixture of toluene (200 ml) and CH2Cl2(100 ml). Added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (of 5.45 g) and the reaction mixture was stirred at room temperature for 15 minutes. Was added to 0.2 M aq. NaOH (250 ml). The organic layer was separated, washed with H2O (2×250 ml) and NASA the n aq. NaCl (2×250 ml), dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=4/1 (V/V) as eluent.

Yield: 4.0 g

MS-ESI: [M+H]+=spreads for about 319.2

TLC: Rf=0,4, silica gel, heptane/EtOAc=3/1 (V/V)

(c) Ethyl 5-hydroxy-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylate

A solution of ethyl 2-methylthio-4-(3-methoxyphenyl)-6-methylpyrimidin-5-carboxylate (example 24b, 318 mg) in dry THF (2 ml) was added to their solution of LDA in dry THF (1 ml), cooled to -78°C. the Mixture was stirred at -78°C for 30 minutes and was added 3-ethoxyacrylate (217 μl). The mixture then was stirred for 3 hours, raising the temperature from -78°C to room temperature. Was added 0.1 M aq. HCl (20 ml) to the reaction mixture, which then was extracted with EtOAc (25 ml). The organic layer was washed with water (25 ml) and saturated aq. NaCl (25 ml), dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/1 (V/V) as eluent and recrystallized from CH3HE.

Yield: 38 mg

MS-ESI: [M+H]+=371,2

TLC: Rfor =0.6, silica gel, heptane/EtOAc=2/3 (V/V)

(d). Tert-butyl 5-hydroxy-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carbox the amide

Ethyl-5-hydroxy-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylate (example 24c, 38 mg) was dissolved in a mixture of 1,4-dioxane (4 ml) and 1 M aq. KOH (0.5 ml). The mixture was boiled under reflux for 48 hours, then cooled to room temperature and acidified by the addition of 0.1 M aq. HCl (15 ml). The mixture was extracted with CH2Cl2(15 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure, obtaining 5-hydroxy-4-(3-methoxyphenyl)-2-methylthiazole-6-carboxylic acid. The latter was dissolved in DMF (2 ml). Added tert-butylamine (53 μl) and TBTU (96 mg) and the mixture was stirred at room temperature for 3 hours. Added EtOAc (15 ml) and the organic layer was washed with saturated aq. NaHCO3(15 ml) and saturated aqueous NaCl (15 ml), dried (MgSO4) and evaporated under reduced pressure. Specified in the title compound was initially purified by chromatography on silica gel using a mixture of heptane/EtOAc=7/3 (V/V) as eluent. Then it was purified by HPLC using the following gradient: 10% aq. CH3CN/CH3CN/0.1% aq. TFOC = 57/40/3 to 7/90/3 (V/V) for 30 minutes. Specified in the title compound was liofilizovane from a mixture of water and 1,4-dioxane.

Yield: 25 mg

MS-ESI: [M+H]+=398,2

HPLC: Rt=9,75 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN/CH 3OH=5/35/57/3 to 5/10/81/4 (V/V) for 15 minutes.

Example 25

Tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxamide

(a). 5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-vinylpyridin

6-Chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthio-pyrimidine (example 1b, 1,46 g) suspended in 1,4-dioxane (10 ml). Added tetrakis(triphenylphosphine)palladium(0) (350 mg) and the mixture was placed in a nitrogen atmosphere. Added terminillo (1,26 ml) and the mixture is boiled under reflux for 5 hours. The reaction mixture was then poured into a mixture of EtOAc (100 ml) and N2O (100 ml). The organic layer was washed with saturated aq. NaCl, dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/CH2Cl2=Up to 1/3 1/0 (on/about).

Output: 1,05 g

MS-ESI: [M+H]+=284,2

TLC: Rf=0,4, silica gel, heptane/CH2Cl2=1/2 (V/V)

(b). 5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-(1,1-bis-(etoxycarbonyl)prop-3-yl)pyrimidine

5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-vinyl-pyrimidine (example 25a) was dissolved in ethanol (2 ml) and toluene (2 ml). Was added potassium carbonate (690 mg) and diethylmalonate (272 μl) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was then poured into a mixture of 0,5M aq. HCl (25 ml) and EtOAc (50 ml). The organic layer was washed the H 2O (50 ml) and saturated aq. NaCl (50 ml), dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of toluene/EtOAc=100/0 to 95/5 (V/V) as eluent

Output: 344 mg

MS-ESI: [M+H]+=444,2

TLC: Rf=0,3, silica gel, toluene/EtOAc=95/5 (V/V)

(c). Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-7,8-dihydroquinazolin-6-carboxylate

5-Cyano-4-(3-methoxyphenyl)-2-methylthio-6-(1,1-bis(etoxycarbonyl)prop-3-yl)pyrimidine (example 25b, 81 mg) was dissolved in dry CH2Cl2(1 ml). Was added dropwise 1M solution of tin chloride(IV) in CH2Cl2(1 ml) and the mixture was stirred at room temperature for 1 hour. Then to the reaction mixture were added N2O (10 ml) and EtOAc (10 ml). The organic layer was washed N2O (10 ml) and saturated aq. NaCl (10 ml), dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=1/0 to 3/2 (V/V) as eluent.

Yield: 24 mg

MS-ESI: [M+H]+=372,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/1 (V/V)

(d). Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylate

Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-7,8-dihydroquinazolin-6-carboxylate (example 25c, 22 mg) was dissolved in CH2Cl2(1 ml. Added 0,06M solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in CH2Cl2(1.2 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of toluene/EtOAc=95/5 (V/V) as eluent.

Yield: 20 mg

MS-ESI: [M+H]+=370,0

TLC: Rf=0,3, silica gel, heptane/EtOAc=1/3 (V/V)

(e). 5-Amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylic acid

Ethyl 5-amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylate (example 25d, 490 mg) was dissolved in 15 ml of 1,4-dioxane was added 2 M aqueous solution of KOH (3 ml). The mixture was boiled under reflux for 5 hours and at 70°C for 76 hours. The mixture was cooled to room temperature and was added a 0.5 M solution of HCl in water. The mixture was extracted with CH2Cl2(2×50 ml), the combined organic layers were dried (MgSO4) and concentrated under reduced pressure, obtaining the crude specified in the header of the connection.

Output: 406 mg (crude)

MS-ESI: [M+H]+=342,2

TLC: Rf=0,0, silica gel, heptane/EtOAc=2/3 (V/V)

(f). Tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)-hinzelin-6-carboxamide

To 1,8M solution of 5-amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxylic acid in DMF (1.8 ml) was added TBTU (173 is g) and tert-butylamine (95 μl). The reaction mixture was stirred for 2 hours and then poured into a mixture of EtOAc (25 ml) and saturated aqueous NaHCO3(50 ml). The organic phase was separated and washed with 0.5 M aqueous HCl (50 ml) and saturated salt solution (50 ml), followed by drying (MgSO4) and concentration under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=1/0 to 2/3 (V/V) as eluent. Specified in the title compound was liofilizovane from a mixture of dioxane and water containing 1.5 equivalents of HCl.

Yield: 44 mg

MS-ESI: [M+H]+=397,2

HPLC:Rt=21,52 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/70/20 to 10/10/80 (V/V) for 20 minutes.

Example 26

Tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)hinzelin-6-carboxamide

(a). Tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-hinzelin-6-carboxamide

A solution of tert-butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)hinzelin-6-carboxamide (example 25f, 1.5 g) in dry CH2Cl2was cooled to 0°C. was Added dropwise a solution of BBr3(1.1 ml) in CH2Cl2(25 ml) and after completion of addition, the mixture was stirred for 3 hours at room temperature. The mixture was diluted with CH2Cl2and carefully added a saturated aqueous solution of NaHCO3 (200 ml). The mixture was intensively stirred for 1.5 hours to dissolve all solids. The aqueous layer was extracted twice, CH2Cl2. The first organic layer is washed with saturated aq. NaHCO3and a saturated solution of salt. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=1/0 to 1/1 (V/V) as eluent.

Output: 930 mg

MS-ESI: [M+H]+=383,4

TLC: Rf=0,3, silica gel, heptane/EtOAc=2/3 (V/V)

(b). Tert-butyl 5-amino-2-methylthio-4-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)hinzelin-6-carboxamide

Mixture To2CO3(1.0 g), the hydrochloride of 1-(2-chloroethyl)pyrrolidine (66 mg) and tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)hinzelin-6-carboxamide (example 26a, 121 mg) in acetone over night and boil under reflux. The mixture was cooled to room temperature, solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was placed in EtOAc and washed with water and saturated salt solution. The organic phase was dried (MgSO4) and concentrated in vacuum. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: 10% aq. CH3CN/CH3CN/0.1% aq. TFOC=7225/3 to 27/70/3 (about/about/about) for 30 minutes. Specified in the title compound was liofilizovane from a mixture of water, TFUK and CH3CN.

Yield: 42 mg (TFUC salt)

MS-ESI: [M+H]+=480,4

HPLC: Rt=12,93 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/70/20 to 10/10/80 (V/V) for 20 minutes.

Example 27

Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxamide

(a). 5-Cyano-2-methylthio-4-(3-nitrophenyl)-6-[(triphenylphosphonio)methyl]pyrimidine

To a suspension of anhydrous bromide methyltriphenylphosphonium (29.5 g) in dimethoxyethane (400 ml) at -78°C was added a 1.6 M solution of n-utility in hexano. The mixture was stirred at -78°C for 1 hour and the solution was added 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9b, the 10.1 g) in dimethoxyethane (100 ml) and the cooling bath was removed. After 1 hour the reaction was completed and added water (15 ml). Removing solids by filtration, followed by concentration of the reaction mixture gave a dark residue which was stirred with ethyl acetate, obtaining a suspension. Concentration in vacuo was carried out after filtration, washing of the residue with water and saturated salt solution and drying of the organic layer MgSO4. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=4/1 to 1/1 (V/V) as eluent.

Output:? 7.04 baby mortality g

MS-ESI: [M+H]+299,2

TLC: Rf=0,4, silica gel, heptane/EtOAc=3/2 (V/V)

(b) 5-Cyano-2-methylthio-4-(3-nitrophenyl)-6-vinylpyridin

A solution of 5-cyano-2-methylthio-4-(3-nitrophenyl)-6-[(triphenylphosphonio)methyl]pyrimidine (example 27a,? 7.04 baby mortality g) in THF (64 ml) was treated with aqueous formaldehyde (37 wt.%, 3.55 ml) at 60°C for 1 hour. After cooling the mixture to room temperature, it was diluted with EtOAc (100 ml) and washed with water (2×50 ml), dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=9/1 to 3/2 (V/V) as eluent.

Yield: 1.42 g

MS-ESI: [M+H]+=547,2

TLC: Rfor =0.6, silica gel, heptane/EtOAc=3/2 (V/V)

(c). Tert-butyl ethyl (2-(5-cyano-2-methylthio-4-(3-nitrophenyl)pyrimidine-6-yl)ethyl)malonate

Potassium carbonate (1.88 g) and tert-butylacrylate suspended in EtOH (82 ml) and was slowly added (about 1.5 hours) solution of 5-cyano-2-methylthio-4-(3-nitrophenyl)-6-vinylpyridine (example 27b, 2,71 g) in a mixture of toluene/CH2Cl2(33 ml). After completion of addition, the mixture was stirred additionally for 40 minutes. The mixture was diluted with EtOAc and washed with water (2x) and saturated salt solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel with IP is the use of a mixture of heptane/CH 2Cl2=1/1 (V/V) as eluent.

Yield: 1.42 g

MS-ESI: [M+H]+=487,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V)

(d). Ethyl 5-amino-2-methylthio-4-(3-nitro-phenyl)-7,8-dihydroquinazolin-6-carboxylate

A solution of tert-butyl ethyl {2-[5-cyano-2-methylthio-4-(3-nitro-phenyl)pyrimidine-6-yl]ethyl}malonate (example 27c, 1.40 g) in CH2Cl2(15 ml) was cooled to 0°C. was Added dropwise a solution of SnCl4(1 M in CH2Cl2, 11.5 ml), the ice bath was removed and the solution was stirred additionally for 30 minutes at room temperature. Was added water (64 ml) and EtOAc (64 ml) and the mixture was intensively stirred to dissolve all solids. The organic phase is washed with water and saturated salt solution, dried (MgSO4) and concentrated under reduced pressure, obtaining mentioned in the title compound as crude product.

Yield: 1.19 g (crude)

MS-ESI: [M+H]+=387,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V)

(e). Ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)hinzelin-6-carboxylate

A solution of the crude ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)-7,8-dihydroquinazolin-6-carboxylate (example 27d, 1.19 g) in CH2Cl2(31 ml) was cooled to 0°C. was Added dropwise a solution of DDQ (1,14 g) in toluene (31 ml), the ice bath was removed and the solution was stirred additionally for 30 minutes at room temperature the re. The mixture was diluted with CH2Cl2(about 100 ml) and washed with saturated aqueous NaHCO3(3×100 ml) and saturated salt solution (2×50 ml). The combined aqueous layers are re-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=9/1 to 3/2 (V/V) as eluent.

Output: 735 mg

MS-ESI: [M+H]+=385,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V)

(f). Ethyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxylate

To a mixture of ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)hinzelin-6-carboxylate (example 27e, 1.54 g) and SnCl2-2H20 (4.52 g) in 1,4-dioxane (35 ml) was added EtOH (35 ml) and concentrated aqueous HCl (690 μl). The reaction mixture was stirred at 90°C for 5 hours. After cooling to room temperature and concentration under reduced pressure, the residue suspended in EtOAc (35 ml). The mixture was brought to pH 10 by addition of 2 M NaOH was added THF and saturated salt solution. The resulting mixture was stirred for 40 minutes, after which the organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. Specified in the title compound was purified by chromatography on silica gel using the mixture of heptane/EtOAc=9/1 to 3/2 (V/V) as eluent.

Output: 818 mg

MS-ESI: [M+H]+=355,2

TLC: Rf=0,3, silica gel, heptane/EtOAc=3/2 (V/V)

(g). 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxylic acid

A solution of 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxylate (example 27f, 658 mg) in 1,4-dioxane was treated with aqueous solution of KOH (2 M, 4,2 ml) at 70°C for 18 hours. After cooling the reaction mixture to room temperature, it was acidified to pH 1 using 4 N. HCl. The mixture was extracted with CH2Cl2(3x). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure, obtaining the crude specified in the header of the connection.

Yield: 215 mg

MS-ESI: [M+H]+=327,2

TLC: Rf=0,3, silica gel, heptane/EtOAc=3/2 (V/V)

(h) Tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxamide

Conversion of 5-amino-2-methylthio-(3-AMINOPHENYL)hinzelin-6-carboxylic acid (example 27g, 192 mg) in the corresponding tert-butylamide carried out in accordance with the method described in example 1e. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=9/1 to 3/2 (V/V) as eluent.

Output: 243 mg

MS-ESI: [M+H]+=382,2

HPLC: Rt=6,57 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=45/55 to 0/100 (V/V) for 20 minutes

Example 28

Tert-butyl 5-and the Ino-2-methylthio-4-(3-(2-(morpholine-4-yl)acetamido)phenyl)hinzelin-6-carboxamide

(a). Tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamide)phenyl)hinzelin-6-carboxamide

To a suspension of tert-butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)hinzelin-6-carboxamide (example 27h, 791 mg) in CH2Cl2(60 ml) was added DIPEA (1.08 ml), followed by slow addition of bromoacetanilide (242 μl) in CH2Cl2(20 ml). After 40 minutes at room temperature, the reaction mixture was washed with a saturated aqueous solution NHCO3(3x), then dried (MgSO4) and concentrated under reduced pressure. Untreated specified in the title compound, used without further purification in the next stage.

Yield: 1.20 g (crude)

MS-ESI: [M+H]+=504,2

TLC: Rf=0,4, silica gel, heptane/EtOAc=3/2 (V/V)

(b). Tert-butyl 5-amino-2-methylthio-4-(3-(2-(morpholine-4-yl)acetamido)phenyl)hinzelin-6-carboxamide.

To a solution of tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamide)phenyl)hinzelin-6-carboxamide (example 28a, 88 mg) in acetonitrile was added morpholine (148 l) and the mixture was stirred for 18 hours. By the end of this time added CH2Cl2(15 ml) and the mixture washed with saturated aqueous NaHCO3. The organic layer was dried (MgSO4) and concentrated in vacuum. Specified in the title compound was purified by chromatography on silica gel using a mixture of CH2Cl2/Meon=1/0 to 9/1 (sum) as eluent. Specified in the title compound was liofilizovane from a mixture of acetonitrile and water containing 1.5 equivalents of HCl.

Yield: 82 mg (HCl salt)

MS-ESI: [M+H]+=509,2

HPLC: Rt=13,00 min, column Luna C-18 (see example 1e), eluent H2O/CH3CN=75/25 to 0/100 (V/V) for 20 minutes.

Example 29

Tert-butyl 5-amino-2-methylthio-4-(3-((N-(tert-butyl)glycinyl)amino)phenyl)hinzelin-6-carboxamide

The interaction of tert-butylamine (275 ml) with tert-butyl 5-amino-2-methylthio-4-(3-(2-bromoacetamide)phenyl)hinzelin-6-carboxamide (example 28a, 130 mg) was performed according to the method described in example 28b. Specified in the title compound was initially purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent and then by HPLC using a column Luna C-18 and the following gradient: CH3CN/0.1% aq. TFOC=10/90 to 90/10 (V/V) for 30 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and aq. HCl.

Yield: 28 mg (HCl salt)

MS-ESI: [M+H]+=495,4

HPLC: Rt=12,93 min, column Luna C-18 (see example 1e), eluent phosphate buffer 50 mm pH 2,1/H2O/CH3CN=10/70/20 to 10/10/80 (V/V) for 20 minutes.

Example 30

Ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)-7-hydroxy-pyrido[2,3-d]pyrimidine-6-carboxylate

(a). 6-Amino-5-cyano-2-methylthio-4-(3-nitrophenyl)pyrimidine

A solution of 6-chloro-cyano-4-(3-nitrophenyl)-2-methylthiopyrimidine (example 9b, 10.0 g) was treated with ammonium hydroxide (28% NH3in water, 15 ml) and the mixture was stirred over night. The resulting crystals were collected by filtration and washed with water. The product was dried at 50°C in vacuum, obtaining specified in the header of the connection.

Output: 8,9 g

MS-ESI: [M+H]+=288,2

TLC: Rf=0,3, silica gel, heptane/EtOAc=3/2 (V/V)

(b). Diethyl 2-(amino-[6-amino-2-methylthio-4-(3-nitrophenyl)pyrimidine-5-yl]methylene)malonate

To a suspension of 6-amino-5-cyano-2-methylthio-4-(3-nitrophenyl)pyrimidine (example 30a, grade of 5.74 g) in 1,2-dichloropropane (200 ml) was added diethylmalonate (9.1 ml). The mixture was cooled to 0°C was added dropwise a solution of SnCl4(14 ml) in 1,2-dichloropropane (50 ml). After completion of the addition, the suspension is boiled under reflux for 18 hours. The mixture was cooled to room temperature and after deposition of solids 1,2-dichloropropan careful decantation. The obtained solid was stirred with EtOAc (300 ml) and water (300 ml) until complete dissolution. The organic layer was washed with water (500 ml) and saturated salt solution (500 ml), dried (MgSO4) and concentrated in vacuum. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=1/0 to 3/2 (V/V) as eluent.

Output: 3,78

MS-ESI: [M+H]+=448,4

TLC: Rf=0,2, silica gel, heptane/EtOAc=3/2 (V/V)

(c). Ethyl 5-amino-2-methylthio-4-(3-nitrophenyl)-7-hydroxy-pyrido[2,3-d]pyrimidine-6-carboxylate

A suspension of diethyl 2-(amino-[6-amino-2-methylthio-4-(3-nitrophenyl)pyrimidine-5-yl]methylene)malonate (example 30b, to 1.34 g) in diphenyl ether (30 ml) was heated in a stream of nitrogen at 240°C for 2 hours. After cooling the mixture to room temperature, was added heptane (200 ml) and the solids were collected by filtration. Specified in the title compound was purified by chromatography on silica gel using a mixture of CH2Cl2/acetone=1/0 to 4/1 (V/V) as eluent.

Yield: 590 mg

MS-ESI: [M+H]+=402,4

TLC: Rf=0,3, silica gel, CH2Cl2/acetone=9/1 (V/V)

Example 31

Tert-butyl 5-amino-2-phenyl-4-(3-((thiomorpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

(a). 5-Cyano-4-(3-nitrophenyl)-2-phenyl-6-hydroxypyrimidine

A mixture of the hydrochloride of benzamidine (16.4 g), 3-nitrobenzaldehyde (15.1 g), ethyl cyanoacetate (11.2 ml) and potassium carbonate (16.6 g) in abs. EtOH (250 ml) was stirred at 60°C for 8 hours. The reaction mixture was cooled to 0°C in an ice bath. The precipitate was filtered off, washed with abs. EtOH and heated in water (100° (C) to obtain a clear solution. The solution was cooled to 50°C, acidified to pH 2 by addition of 2 n aq. HCl and cooled to 0°C in an ice bath. The precipitate was filtered, is washed with ice water. The remaining water was removed by joint evaporation with 1,4-dioxane.

Output: 15,0,

MS-ESI: [M+H]+=spreads for about 319.2

TLC: Rf=0,3, silica gel, DHM/MeOH=9/1 (V/V).

(b). 6-Chloro-5-cyano-4-(3-nitrophenyl)-2-phenyl-pyrimidine

POCl3(50 ml) was added to a stirred solution of 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-hydroxypyrimidine (example 31(a), 15.0 g) and dimethylaniline (0.5 ml) in dry 1,4-dioxane reagent grade. (200 ml). After 3 hours at 90°C warm mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane was added ice-cold water. The precipitate was filtered and washed with water. The remaining water was removed by joint evaporation with 1,4-dioxane.

Output: 15,8 g

MS-ESI: [M+H]+=337,4

TLC: Rf=0.8, silica gel, heptane/EtOAc=3/2 (V/V).

(c). Ethyl 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-(ethoxycarbonylmethyl)pyrimidine

DIPEA (8,71 ml) was added to a stirred solution of ethyl 2-mercaptoacetate (5,15 ml) and 6-chloro-5-cyano-4-(3-nitrophenyl)-2-phenylpyrimidine (example 31(b), to 15.8 g) in a mixture of EtOH (125 ml) and DHM (125 ml) under nitrogen atmosphere. After 2 hours at room temperature, the mixture was diluted DHM until dissolved, washed with 0.5 N. .HCl, dried (MgSO4) and concentrated under reduced pressure.

Yield: 19.7 g

MS-ESI: [M+H]+=UAH 421,2,

TLC: Rf=0,7, silica gel, heptane/EtOAc=3/2 (V/V).

(d) Ethyl 5-amino-4-(3-nitrophe who yl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate.

DIPEA (20,0 ml) was added to a stirred solution of ethyl 5-cyano-4-(3-nitrophenyl)-2-phenyl-6-(ethoxycarbonylmethyl)-pyrimidine (example 31(c)of 19.7 g). in a mixture of abs. EtOH (100 ml) and reagent grade toluene.(pure for analysis) (100 ml). After 48 hours at 100°C, the mixture was cooled to 0°C. the precipitate was filtered off, washed with chilled EtOH and dried in vacuum at 40°C.

Yield: 17.0 g

MS-ESI: [M+H]=UAH 421,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V).

(e) Ethyl 5-amino-4-(3-AMINOPHENYL)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate

A solution of tin chloride(II) (23,0 g) in abs. EtOH (250 ml) was added to a solution of ethyl 5-amino-4-(3-nitrophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (example 31(d), 16.6 g) in 1,4-dioxane reagent grade. (250 ml). Added 37% aq. HCl (6.9 ml) and the mixture was heated under reflux (90°C) for 16 hours. The mixture was left to cool to room temperature and concentrated under reduced pressure. The residue is suspended in EtOAc (500 ml). To achieve pH 10-11) was added 4 n aq. NaOH. The mixture was diluted by addition of saturated aq. NaCl. The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure.

Yield: 17.0 g

MS-ESI: [M+H]+=UAH 421,2

TLC: Rf=0,5, silica gel, heptane/EtOAc=3/2 (V/V).

(f). 5-Amino-4-(3-AMINOPHENYL)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid

Potassium hydroxide (20,0 g) was added to a solution of e is Il 5-amino-4-(3-AMINOPHENYL)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (example 31(e), 17.0 g) in a mixture of 1,4-dioxane (210 ml) and water (80 ml). After 16 hours at 90°C, the mixture was cooled to 0°C. the precipitate was filtered, suspended in water (300 ml) and cooled to 0°C. the Mixture was acidified to pH 3 by addition of 2 n aq. citric acid and stirred, raising the temperature from 0°C to room temperature for 2 hours. The precipitate was filtered off, washed with water and dried in vacuum at 40°C.

Output: 13.3 g

MS-ESI: [M+H]+=363,0

TLC: Rf=0,2, silica gel, DHM/MeOH=95/5 (V/V).

(g). Tert-butyl 5-amino-4-(3-AMINOPHENYL)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxamide

DIPEA (15.3 ml), tert-butylamine (9,3 ml) and TBTU (14.1 g) was added to a mixture of 5-amino-4-(3-AMINOPHENYL)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 31(f), 13.3 g) in a mixture DHM (250 ml) and DMF (50 ml) under nitrogen atmosphere. After 3 hours at room temperature the mixture was diluted DHM and washed with saturated aq. NaHCO3, 0.1 N. aq. HCl and saturated aq. NaCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, using a mixture of heptane/EtOAc=3/7 to 1/1 (V/V) as eluent.

Output: 14,7 g

MS-ESI: [M+H]+=418,4

TLC: Rf=0,4, silica gel, heptane/EtOAc=3/2 (V/V).

(h) Tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxy-carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

p> Tert-butyl 5-amino-2-phenyl-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 31(g), 2.0 g) was dissolved in dry CH2Cl2(20 ml). Subsequently was added dropwise a solution of p-nitro-phenylcarbamate (520 mg) in dry CH2Cl2(10 ml) and the reaction mixture was stirred at room temperature. After 3 hours the reaction mixture was washed with H2O. the Organic layer was dried (MgSO4) and concentrated under reduced pressure.

Yield: 2.9 g

MS-ESI: [M+H]+=583,2

TLC: Rfor =0.6, silica gel, heptane/EtOAc=1/1 (V/V).

(i). Tert-butyl 5-amino-2-phenyl-4-(3-((thiomorpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Thiomorpholine (300 μl) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with CH2Cl2and washed with H2O. the Organic layer was concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and N2O.

Yield: 89 mg

MS-ESI: [M+H] +=547,2

HPLC: Rt=11,71 min, column Luna C-18(2), 3 ám, 100 x 2.0 mm, UV detection=210 nm, oven temperature = 40°C, flow = 0.25 ml/min, eluent phosphate buffer 50 mm pH 2,1/water/ACN=10/30/60 to 10/5/85 (about/about/about), runtime = 20 minutes.

Example 32

Tert-butyl 5-amino-2-phenyl-(3-((N,N-dimethylamino)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

The dimethylamine hydrochloride (150 mg) was added to a solution of N,N-diisopropylethylamine (DIPEA, and 0.50 ml) and tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 250 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Next, the reaction mixture was diluted with CH2Cl2and washed with H2O. the Organic layer was concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 75 mg

MS-ESI: [M+H]+=489,2

HPLC: Rt=19,58 min, column Luna C-18(2), 3 μm, 100×2.0 mm, UV detection = 210 nm, oven temperature = 40°C, flow = 0.25 ml/min, eluent phosphate buffer 50 mm pH 2,1/water/ACN=10/60/30 to 10/5/85 (about/about/about), runtime = 20 minutes.

Example 33

Tert-Buti is 5-amino-2-phenyl-4-(3-(morpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Morpholine (250 mg) was added to a solution of tert-butyl 5-amino-2-phenyl-4-(3-(p-nitro-phenoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (example 31(h), 150 mg) in dichloromethane (5 ml) and the reaction mixture was stirred at room temperature overnight. Next, the reaction mixture was diluted with CH2Cl2and washed with H2O. the Organic layer was concentrated under reduced pressure. Specified in the title compound was purified by HPLC using a column Luna C-18 and the following gradient: H2O/CH3CN=80/20 to 0/100 (V/V) for 45 minutes. Specified in the title compound was then liofilizovane of a mixture of 1,4-dioxane and H2O.

Yield: 63 mg

MS-ESI: [M+H]+=489,2

HPLC: Rt=19,39 min, column Luna C-18(2), 3 μm, 100×2.0 mm, UV detection = 210 nm, oven temperature = 40°C, flow = 0.25 ml/min, eluent phosphate buffer 50 mm pH 2,1/water/ACN=10/60/30 to 10/5/85 (about/about/about), runtime = 20 minutes.

Example 34

CHO-LH and CHO-FSH bioactivity in vitro

LH agonistic activity of the compounds was studied on cells of the Chinese hamster ovary (CHO) stably transfection human LH receptor and co-transfection camp responsible element (CRE)/promoter directing the expression of a luciferase reporter gene Firefly. The binding of ligand to Gs-associated LH receptor will lead to an increase in the AMP, that, in turn, will induce increased transactivation luciferase reporter construct. Luciferase signal was evaluated quantitatively using a luminescence counter. For the studied compounds were calculated EU50(concentration of test compound that causes half-maximal (50%) stimulation). With this purpose used the software GraphPad PRISM version 3.0 (GraphPad Software Inc., San Diego). The results showed that the value of the EU50for the compounds of examples 9, 11, 12, 13, 14, 25 and 27 were in the range between 10-6and 10-7M. Connection examples 1, 2, 3, 4, 5, 17, 22, 26, 28, 29, 31 and 33 showed values EC50in the range between 10-7and 10-8M, whereas the values EC50for the compounds of examples 7, 15, 16, 18, 21, 23 and 32 were below 10-8M.

1. Bicyclic heteroaromatic compound of General formula I or its pharmaceutically acceptable salt

where R1represents phenyl, optionally substituted with other5or or5;

R2represents a C1-C4alkyl or phenyl;

R3represents a C1-C8alkyl;

R5is phenylcarbinol,4-C6heteroseksualci-carbonyl, C2-C8alkanesulfonyl, the 2-C8ascenoccary, phenylsulfonyl, phenylenecarbonyl, vinyloxycarbonyl,1-C8alkyl, C1-C8alkylsulphonyl,1-C8alkylsulfonyl, C1-C8(di)alkylaminocarbonyl,1-C8alkoxycarbonyl, an alkyl group in which optionally can be substituted by the Deputy, is selected from C4-C6geterotsiklicheskie, phenyl, C1-C8alkoxycarbonyl, (di) [P1-C3alkoxyl1-C3alkyl]amino or C1-C8(di) alkylamino;

Y represents N;

Z represents NH2or HE;

And is a S or a bond;

In represents the N(H) or;

X1-x2 represents C=C NH-C(O), C=N, N=C or optionally S, if R5represents a C1-C8alkylsulfonyl, phenylsulfonyl, C1-C8(di)alkylaminocarbonyl, phenylenecarbonyl, C1-C8alkoxycarbonyl, phenoxycarbonyl,4-C6heteroseksualci-carbonyl, C2-C8alkanesulfonyl or2-C8ascenoccary.

2. The compound according to claim 1, where In is an N(H).

3. The compound according to claim 1 or 2, where Z represents NH2.

4. The compound according to claims 1-3, where R5is phenylcarbinol,4-C6geterotsiklicheskikh the Il or 1-C8alkyl, C1-C8alkylsulphonyl, C1-C8(di)alkylaminocarbonyl, an alkyl group in which optionally may be substituted With4-C6heterocyclization, phenyl, C1-C8alkoxycarbonyl and/or C1-C8(di) alkylamino.

5. The compound according to claims 1-4, where R1substituted in metaprogram.

6. The compound according to claims 1-5, where X1-x2 represents C=C, C=N, S, or N=C.

7. The connection according to claim 6, where X1-x2 is a C=C or S.

8. A compound selected from the group comprising tert-butyl 5-amino-2-methylthio-4-(3-((N,N-diethylamino)carbonyloxy)phenyl)thieno [2,3-d] pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(methoxycarbonylamino)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(allyloxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(ethoxycarbonyl)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(morpholine-4-yl)carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide, tert-butyl 5-amino-2-methylthio-4-(3-(1,2,3,6-tetrahydropyridine-carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide or tert-butyl 5-amino-2-phenyl-4-(3-((N,N-dimethylamino)-carbylamine)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide.

9. Pharmaceutical composition having agonistic activity against LH R is Ceptor, containing bicyclic heteroaromatic compound according to claims 1-8, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable auxiliary additive.

10. The use of bicyclic heteroaromatic derivatives according to claims 1-8, or their pharmaceutically acceptable salts, pharmaceutical composition having agonistic activity against LH receptor.



 

Same patents:

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to 2-aminomethylthieno[2,3-d]pyrimidines of the general formula (I): wherein R1 and R2 in common with C-atoms with which they are bound form 5-7-membered monounsubstituted cycloalkenyl ring; R3 and R4 are similar or different and represent independently of one another (C1-C8)-alkoxy-group or halogen atom; R5 and R6 can be similar or different and represent independently of one another hydrogen atom, linear or branched (C1-C8)-alkyl group that can be substituted with one or more hydroxyl, (C1-C8)-alkoxy-group, amine, mono-(C1-C8-alkyl)-amine or di-(C1-C8-alkyl)-amine groups, or in common with nitrogen atom to which they are bound form a heterocyclic ring that comprises optionally one or more additional nitrogen atoms and substituted with one or more hydroxyl, (C1-C8)-alkoxy- or (C1-C8)-alkylol groups. Compounds elicit the inhibitory effect with respect to activity of phosphodiesterase V and can be used in treatment of cardiovascular system states and in disturbance in the potency injury. Also, invention describes a medicinal preparation based on compounds said, a method for its preparing and a method for preparing compounds.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.

6 cl, 1 tbl, 16 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (1)

wherein A represents bicyclic or tricyclic azepine derivative; V1 and V2 both represent hydrogen atom (H) or one among V1 and V2 represents hydrogen atom (H), OMe, OBn, OPh, O-acyl, Br, Cl, F, N3, NH2, NHBn and another represents hydrogen atom (H); or V1 and V2 represent in common =O or -O(CH2)pO-; W1 represents oxygen (O) or sulfur (S) atom; X1 and X2 both represent hydrogen atom (H) or in common represent =O or =S; Y represents OR5 or NR6R7; R1 means hydrogen atom (H), lower alkyl, F, Cl and Br; R2 means lower alkoxy-group or values given for R1; R3 and R5 are taken independently among hydrogen atom (H) and lower alkyl; R4 means hydrogen atom (H); R6 and R7 are taken independently among hydrogen atom (H) and lower alkyl, or they in common mean -(CH2)n-; n = 3, 4, 5 or 6; p = 2 or 3. These compounds are agonists of vasopressin V2 receptors and useful as antidiuretic and procoagulants, and also to pharmaceutical compositions comprising these vasopressin agonists. These compositions are useful especially in treatment of diabetes insipidus of the central origin and night enuresis.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

26 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of piperazine of the general formula (I): wherein Y represents lower alkylene; R1 represents phenyl substituted with one or two similar or different substitutes taken among a group including lower alkoxy-group, mono- (or di-, or tri-)-halogen-lower)-alkyl, nitro-, amino-, lower alkylamino-, di-(lower)-alkylamino-, lower alkylthio-group,alkylsulfonyl, lower alkylaminosulfonyl, di-(lower)-alkylaminosulfonyl, and pyrrolyl; R2 means phenyl substituted with hydroxy-group at position 3 and with lower alkyl and halogen atom additionally; R3 means hydrogen atom; R4 represents (2,6-dimethylmorpholino)-(lower)-alkyl, (2-methoxymethylmorpholino)-(lower)-alkyl, (3-methoxymethylmorpholino)-(lower)-alkyl. Also, invention relates to their pharmaceutically acceptable salts, to method for their preparing, pharmaceutical composition and a method for vomiting inhibition. Proposed compounds are antagonists of tachykinin and can be used for vomiting inhibition.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 47 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new oxathiepino[6,5-b]dihydropyridines of the formula (I):

wherein: (a) R1, R2, R3, R4 and R5 are taken independently among group consisting of hydrogen atom (H), halogen atom, nitro-group (NO2); (b) R6 is taken among group consisting of unbranched or branched (C1-C5)-alkyl wherein indicated alkyl can be substituted with phenylacetyloxy-, hydroxy- carboalkoxy-group or group NR'R'' wherein R' and R'' are taken independently among group consisting of hydrogen atom (H), unbranched or branched (C1-C8)-alkyl, benzyl; (c) R7 is taken among group consisting of hydrogen atom (H), alkyl; (d) R9 represents oxygen atom; (e) n is a whole number from 1 to 2, or its pharmaceutically acceptable salt. Compounds are useful as antagonists of calcium channels and elicit cardiovascular, anti-asthmatic and anti-bronchoconstricting activity. Also, invention describes the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

28 cl, 2 tbl, 3 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of β-carboline of the general formula (I)

showing properties of phosphodiesterase V inhibitor (PDE V). In the general formula (I) R1 means hydrogen atom; n = 0; X is taken among the group consisting of oxygen (O), sulfur (S) atoms and NRD; R2 is taken among the following group: phenyl (that can be optionally substituted with 1-3 RB), 6-membered nitrogen-containing heteroaryl and 5-6-membered heterocycloalkyl comprising 1-2 oxygen atoms and condensed with benzene ring (optionally substituted with 1-3 RB); R4 is taken among the group consisting of hydrogen atom, carboxy-group. (C1-C6)-alkylcarbonyl, di-[C1-C8)-alkyl]-aminoalkoxycarbonyl, di-[(C1-C8)-alkyl]-amino-(C1-C8)-alkylaminocarbonyl; a = a whole number from 0 to 1; Y is taken among the group consisting of -CH2, -C(O); Z is taken among the group consisting of -CH2, -CHOH, and -C(O) under condition that when Z represents -CHOH or -C(O) then X represents -NH; is taken among the group consisting of naphthyl, 5-6-membered heteroaryl comprising 1-3 heteroatoms taken among nitrogen, oxygen and/or sulfur atoms possibly condensed with benzene ring; m = a whole number from 0 to 2; R3 is taken independently among the group consisting of halogen atom, nitro-group, (C1-C8)-alkyl, (C1-C8)-alkoxy-group, trifluorophenyl, phenyl (optionally substituted with 1-3 RB), phenylsulfonyl, naphthyl, (C1-C8)-aralkyl, 5-6-membered heteroaryl comprising 1-3 nitrogen atoms in the ring (optionally substituted with 1-3 RB). Also, invention relates to a pharmaceutical composition, a method for its preparing and methods for inhibition of phosphodiesterase V activity (PDE V), and for increase of the cGMP concentration.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

14 cl, 11 sch, 7 tbl, 13 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of pyridopyrimidines of the formula (I): or (II): wherein Z means nitrogen atom (N) or -CH; W means -NR2; X1 means oxygen atom (O), -NR4 (wherein R4 means hydrogen atom or alkyl), sulfur atom (S) or -CR5R6 (wherein R5 and R6 mean hydrogen atom); X2 means oxygen atom (O); Ar1 means unsubstituted or substituted phenyl; R2 means hydrogen atom, alkyl or acyl; R1 means hydrogen atom, alkyl, halide alkyl and others; R3 means alkyl; cycloalkyl and others; R8 and R9 mean hydrogen atom, alkylsulfonyl and others, and to their pharmaceutically acceptable salts, and to intermediate compounds that are used for preparing compounds of the formula (I) and (II). Indicated compounds show inhibitory activity with respect to activity of p38 kinase and can be used in preparing a medicine agent for treatment of p38-mediated disturbances.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

38 cl, 3 tbl, 116 ex

FIELD: biochemistry, medicine, in particular new bioactive compounds having peptide hormone vasopressin agonistic activity.

SUBSTANCE: disclosed are compounds of general formula 1 or 2 or tautomers, or pharmaceutically acceptable salts thereof, wherein W represents N or C-R4; R1-R4 are independently H, F, Cl, Br, alkyl, O-alkyl, NH2, NH-alkyl, N(alkyl)2, NO2 or R2 and R3 together may form -CH=CH-CH=CH-; G1 represents bicyclic or tricyclic condensed azepine derivatives selected from general formulae 3-8 wherein A1, A4, A7, and A10 are independently CH3, O, and NR5; A2, A3, A9, A11, A12, A14, and A15 are independently CH and N; or A5 represents covalent bond and A6 represents S; or A5 represents N=CN and A6 represents covalent bond; A8 and A12 are independently NH, N-CH3 and S; A16 and A17 both represent CH2 or one of A16 and A17 represents CH2 and the other represents CH(OH), CF2, O, SOa, and NR5; R5 represents H, alkyl, CO-alkyl, and (CH2)bR6; R6 represents phenyl, pyridyl, OH, CO2H; a = 0-2; b = 1-4; Y represents CH or N; Z represents CH=CH or S; and G2 represents group selected from groups of formulae 9-11 wherein Ar represents phenyl, pyridyl, naphthyl, and mono- or polysubstituted phenyl, pyridyl, wherein substituents are selected from F, Cl, Br, alkyl, NO2; D represents covalent bond or NH; E1 and E2 both are H, OMe, F, or one of E1 and E2 represents OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N2, NH2, NHBn or NHAc and the other represents H; or E1 and E2 together form =O, -O(CH2)gO- or -S(CN2)gS-; F1 and F2 both represent H or together form =O or =R; L represents OH, O-alkyl, NH2, NH-alkyl, and NR9R10; R7 represents COR8; R8 represents OH, O-alkyl, NH2, NH-alkyl, N(alkyl)2, pyrolidinyl, and piperidinyl; R9 and R10 both are alkyl or together form -(CH2)h-; V represents O, N-CN or S; c = 0 or 1; d = 0 or 1, e = 0 or 1; f = 0-4; g = 2 or 3; h = 3-5, with the proviso, that both d and e are not 0. Also disclosed are pharmaceutical composition having agonistic activity in relate to V2 receptor, method for treatment one or more diseases (e.g., enuresis, nycturia, diabetes insipidus, hemorrhage disorders, urinary incontinence.

EFFECT: new compounds with value biological characteristics.

41 cl, 19 tbl, 193 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes bicyclic N-acylated imidazo-3-amines or imidazo-5-amines salts of the general formula (I): wherein R1 means tert.-butyl, 1,1,3,3-tetramethylbutyl, (C4-C8)-cycloalkyl, phenyl disubstituted with (C1-C4)-alkyl, -CH2Ra wherein Ra means the group -CO(OR') wherein R' means (C1-C8)-alkyl; R2 means hydrogen atom, the group -CORb wherein Rb means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R3 means (C1-C8)-alkyl, (C3-C8)-cycloalkyl, phenyl, pyridyl, furfuryl or thiophenyl; A means tri-linked fragment of ring of the formula: wherein R6 and R7 mean hydrogen atom or tetra-linked fragment of ring of the following formulae: wherein R4' means hydrogen atom or benzyloxy-group; R5' means hydrogen atom; R6' means hydrogen atom, (C1-C8)-alkyl or nitro- (NO2)-group; R7' means hydrogen atom, (C1-C8)-alkyl, or R6' and R7' mean in common the following fragment of ring: -CRi=CRj-CH=CH- wherein Ri and Rj mean hydrogen atom; R5'' means hydrogen, chlorine atom or (C1-C8)-alkyl; R6'' means hydrogen atom; R7''n means hydrogen atom, amino- (NH2)-group or (C1-C8)-alkyl; R4''', R6''' and R7''' mean hydrogen atom; R8 means (C1-C8)-alkyl or (C3-C8)-cycloalkyl; X means anion of inorganic or organic acid, or their acid-additive compounds. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof. These new compounds show affinity to opiate μ-receptor and can be used, in particular, as analgesic agents.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

12 cl, 2 dwg, 32 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes new 7-azaindoles of the general formula (I): wherein n = 1 or 2; R1 means mono- or multi-unsaturated, linear or branched (C2-C10)-alkenyl, linear or branched, unsubstituted (C1-C10)-alkyl that can be monosubstituted with (C1-C6)-alkoxy-group, naphthyl, pyridinyl, (C3-C6)-cycloalkyl, phenyl that, in turn, can be substituted with (C1-C6)-alkyl, halogen atom, (C1-C6)-alkoxy-group or hydroxy-group, or radical of the formula: ; R2 and R3 are similar or different being only one of them can mean hydrogen atom and mean (C1-C5)-alkyl possibly substituted with -O-(C1-C6)-alkyl or pyridyl, phenyl possibly substituted twice with -F, -Cl, -Br, -O-(C1-C3)-alkyl or monosubstituted with -COOH or -COO-(C1-C3)-alkyl, pyridyl possibly twice substituted with -Cl, -Br, or group of formulae: or , or R2 and R3 in common with N-atom mean: or under condition that if n = 1 then they don't mean simultaneously: R1 - (C1-C6)-alkyl; R2 - hydrogen atom (H) or (C1-C6)-alkyl, and R3 or wherein R and R' mean independently -Cl or -Br. These compounds possess inhibitory activity with respect to activity of phosphodiesterase 4. Also, invention relates to a medicinal agent comprising these compounds, methods for its preparing and using these compounds for preparing medicinal agents.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and drug.

17 cl, 6 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to a new physiologically active composition effecting on nicotine receptors and prepared in the form of tablets, granules, capsules, suspensions, solutions and injections. As an active component the composition comprises pharmaceutically effective amount of substituted 1-oxo-1,2-dihydro[2,7]-naphthyridine of the general formula (1)

or its salt, N-oxide or hydrate wherein R1 represents hydrogen atom, inert substitute, optionally substituted (C1-C5)-alkyl, optionally substituted amino-group; R2 and R3 represent independently of one another hydrogen atom, nitrile group, formyl group, inert substitute, optionally substituted (C1-C5)-alkyl, carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group; R4 at carbon atoms of pyridine moiety represents: hydrogen atom, halogen atom, inert substitute, optionally substituted hydroxy-(C1-C5)-alkyl, optionally substituted amino-group, optionally substituted hydroxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group, optionally substituted carbamoyl group; R4 at nitrogen atom of pyridine moiety forms pyridinium salt with pharmacologically acceptable anion and represents inert substitute. Also, invention relates to new substituted 1-oxo-1,2-dihydro[2,7]naphthyridines of the general formula (1) or their salts, N-oxides or hydrates wherein R1 and R4 have value given in cl. 1, and R2 and R3 represent independently of one another carboxyl group, optionally substituted (C1-C6)-alkyloxycarbonyl group or optionally substituted carbamoyl group. Also, invention relates to a method for their preparing and to a method for modulating activity of nicotine receptor and using compounds of the general formula (1) by cl. 1 for preparing physiologically active composition, and as ligands of nicotine receptors for aims of experimental investigations of physiological processes as "pharmacological tools". Also, invention relates to a set for preparing the composition.

EFFECT: improved preparing method, valuable properties of compounds and compositions.

7 cl, 2 sch, 2 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the general formula (I) or (II) wherein R1 represents hydrogen atom; R2 is taken among the group consisting of aryl and heteroaryl; R3 is taken among the group consisting of halogen atom, nitro-, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl, trifluoromethoxy-group, -NH2, -NH-(C1-C6)-alkyl and -N-(C1-C6)-alkyl)2; b is a whole number from 0 to 4; R4 is taken independently among the group consisting of halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxycarbonyl, phenyl (wherein phenyl group can be substituted optionally with one-three substitutes taken independently among RD), phenylsulfonyl, heteroaryl (wherein heteroaryl can be substituted optionally with one-three substitutes taken independently among RD), heterocycloalkyl, -NH2, -NHRA, -N-(RA)2,

wherein each RD is taken independently among halogen atom, hydroxy-, carboxy-, oxo-group, (C1-C4)-alkyl, (C1-C4)-alkylthio, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, (C1-C4)-alkylcarbonyl, trifluoromethyl, trifluoromethoxy-group, -NH2. -NHRA, -N-(RA)2, -C(O)N(RA)2, -SO2N(RA)2, acetylamino-, nitro-, cyano-group, formyl, (C1-C6)-alkylsulfonyl, carboxy-(C1-C6)-alkyl and aralkyl; c = 0; a means a whole number from 0 to 1; Y is taken among the group consisting of a residue -(C1-C)-alkyl, -C(O)-, -(C2-C6)-alkenyl)-carbonyl, -carbonyl-(C1-C6)-alkyl)-, -C(S)-, -C(O)NH-(C1-C6)_alkyl), -C(O)-(C3-C7)-cycloalkyl)- and (C3-C7)-cycloalkyl)-C(O)-; represents phenyl;

is taken among the group consisting of phenyl, heteroaryl and cycloalkyl under condition that when R1 represents hydrogen atom, R3 represents hydrogen atom, b = 0, c = 1, Y represents -CH2-, represents phenyl and represents phenyl then R2 is not trimethoxyphenyl, and its pharmaceutically acceptable salts. Also, invention describes a pharmaceutical composition designated for inhibition of activity of phosphodiesterase comprising a pharmaceutically acceptable vehicle and compound by cl. 1, method for preparing pharmaceutical composition, methods for treatment of sexual dysfunction by using compound by cl. 1 or pharmaceutical composition, method for increasing the concentration of cGMP in penis tissue and method for treatment of state when inhibition of activity of phosphodiesterase shows the favorable effect. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 7 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new urea-substituted imidazoquinolines of the formula (1):

wherein R, R1, R2 and n have values given in the description, and to pharmaceutical preparations based on these compounds. Proposed compounds possess effect of immunomodulators initiating biosynthesis of different cytokines. Also, invention relates to methods for treatment of different states, among them viral diseases and neoplastic pathologies.

EFFECT: improved method for induction, valuable properties of compounds.

47 cl, 11 tbl, 142 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes derivatives of imidazo-3-ylamine of the general formula (I):

wherein X and Y mean CH or nitrogen atom (N) under condition that X and Y don't mean nitrogen atom (N) simultaneously; R1 means tert.-butyl, (CH2)nCN wherein n means 4, 5 or 6, phenyl substituted optionally with (C1-C4)-alkyl, (C1-C4)-alkoxy-group, (C4-C8)-cycloalkyl, 1,1,3,3-tetramethylbutyl or CH2Ra wherein Ra represents hydrogen atom, branched or linear (C1-C8)-alkyl, phenyl substituted optionally with halogen atom, (C1-C4)-alkoxy-group, CO(OR') wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl, PO(OR')2 wherein R' means linear (C1-C4)-alkyl or branched (C3-C5)-alkyl; R2 means hydrogen atom, CORb wherein Rb represents branched or linear (C1-C4)-alkyl; R3 means methyl, ethyl, tert.-butyl, (C3-C8)-cycloalkyl, phenyl monosubstituted optionally at position 3, 5 or 6 or optionally multisubstituted at position 4 and additionally at position 2 and/or 3, and/or 5, and/or 6 with halogen atom, hydroxyl group (OH), (C1-C4)-alkyl or (C1-C4)-alkoxy-group, naphthyl, optionally substituted (C1-C4)-alkoxy-group, di-(C1-C4)-alkylamino-group, pyrrole substituted optionally with (C1-C4)-alkyl, benzylsulfonyl, COOCH3, pyridyl substituted optionally with (C1-C4)-alkyl, OH, hydroxy-(C1-C4)-alkyl, furan substituted optionally with (C1-C4)-alkyl, nitro-group (-NO2), halogen-substituted phenyl, CH2COOCH3, COOH, thiophene substituted optionally with halogen atom, (C1-C4)-alkyl, (C1-C4)alkylsulfanyl, -NO2, phenoxy-group, thiophene, alkynylphenyl, unsubstituted anthracene or quinoline substituted optionally with halogen atom under condition that R3 doesn't means cyclohexyl-unsubstituted phenyl or phenyl monosubstituted with carboxylic acid amide at position 3 if R1 means tert.-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, monosubstituted phenyl, 2,6-dimethylphenyl or benzyl, and R2 means simultaneously hydrogen atom or -CO-(methyl) and under condition that R2 doesn't mean hydrogen atom if R1 means benzyl simultaneously and R3 means methyl or R1 means simultaneously CH2C(O)-tert.-butyl and R3 means unsubstituted phenyl, in forms of bases or pharmaceutically acceptable salts, and a method for their preparing and a medicinal agent based on thereof. Described compounds possess analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds and agent.

7 cl, 2 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

The invention relates to new nitrogen-containing heterocyclic compounds, in particular to derive hinzelin or benzodiazepina.beloe acid formula

(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract
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