Bicyclic heteroaromatic compounds as lh agonists and pharmaceutical composition

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

 

The invention relates to compounds with agonistic or agonistically activity against glycoprotein hormone, in particular to the compounds with agonistic activity against luteinizing hormone (LH). In addition, the invention relates to derivatives of bicyclic heteroaromatic compounds containing pharmaceutical compositions and to the use of these compounds in medical therapy, particularly when used to control conception.

The gonadotropins play a significant role in many body functions, including meabolism, temperature regulation and reproductive process. Pituitary gonadotropin FSH, for example, plays a pivotal role in promoting 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). Currently LH used clinically in combination with FSH for ovarian stimulation, i.e. ovarian hyperstimulation for in vitro fertilization (IVF) and induction of ovulation in infertile anovular women (Insler V., Int.J.Fertility 33:85-97, 1988, Navotg and Rosenwaks, J.Vitro Fert.Embryo Transfer 5:3-13, 1988), and in the case of male hypogonadism and male infertility.

The gonadotropins act on specific cells of the genital glands to initiate differentiation and steroidogeneza aicn the s and testes. These pituitary and placental hormones mediated by specific plasma membrane receptors, which are members of the large family of G-proteinsathome 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 a source of human urine, and have a low purity (Morse et al., Amer.J.Reproduct.Immunol. and Microbiology 17:143, 1988). Alternatively, they can be obtained as recombinant gonadotropins.

As in the case of other therapeutic proteins, gonadotropins, you must enter or subcutaneously or intramuscularly. It would be an undoubted advantage, however, to activate the receptor by using small molecules that could be introduced through, for example, oral or dermal routes of administration.

The present invention describes the obtaining of such low molecular weight analogues of hormones that selectively activate one of gonadotropinum receptors. This should be seen as 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 the th salt, or their MES

where R1is NR5R6, OR5, SR5or R7preferably R1is R7;

R5and R6independently selected from H, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil, (3-8C)cycloalkyl, (2-7C)geterotsiklicheskie, (1-8C)alkylsulphonyl, (6-14C)arylcarbamoyl, (6-14C)aryl or (4-13C)heteroaryl, or R5and R6combined in a (2-7C)geteroseksualnoe ring;

R7is (3-8C)cycloalkyl, (2-7C)heteroseksualci, (6-14C)aryl or (4-13C)heteroaryl, preferably R7is (6-14C)aryl or (4-13C)heteroaryl;

R2is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted by one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)(di)alkylamino, (1-8C)alkoxy, (2-8C)alkenyl or (2-8C)quinil;

R3is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil, (3-8C)cycloalkyl,-(2-7C)heteroseksualci or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted by one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy, preferably R3is (1-8C)alkyl, more preferably (1-4C)alkyl, even more preferably R3is isopropyl or tert-butyl;

S submitted the S, O or N(R4);

R4is H, (1-8C)alkyl, (1-8C)alkylaryl, (6-14C)arylcarbamoyl or (6-14C)aryl(1-8C)alkyl;

Y represents CH or N, preferably Y represents N;

Z represents NH2or HE;

A represents S, N(H), N(R9), Or the connection;

R9can be selected from the same groups as described for R2and is N, O or communication.

Alkyl group, Alchemilla group or Alchemilla group, if present in R5and/or R6in the above formula may be optionally substituted by one or more substituents selected from hydroxyl, (6-14C)aryl, (1-8C)alkoxy, (1-8C)alkylcarboxylic, (6-14C)arylcarboxylic, (1-8C)alkoxycarbonyl, (6-14C)aryloxyalkyl, (1-8C)alkylsulphonyl, (6-14C)arylcarbamoyl, amine, (1-8C)alkylaminocarbonyl, (6-14C)arylenecarborane, (1-8C) alkylcarboxylic, (6-14C)arylcarboxamide, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino.

If R7is (6-14C)aryl or (4-13C)heteroaryl, the aryl may be optionally substituted in the ortho and/or meta position by one or more substituents selected from R8, (6-14C)aryl, (4-13C)heteroaryl, (2-7C)geterotsiklicheskie, (3-8C)cycloalkyl, other8, OR8and/or SR8where R8is (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylaryl, (6-14C) arylcarbamoyl, (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil, lilina group which may be optionally substituted by one or more substituents, chosen from hydroxyl, (1-8C)alkoxy, (2-7C)heteroseksualci((1-8C)alkoxy, (3-8)cycloalkyl((1-8C)alkoxy, (6-14C)aryl((1-8C)alkoxy, (4-13C)heteroaryl((1-8C)Ala)hydroxy, (2-7C)heterocyclyl, (3-8C) cycloalkyl, (6-14C)aryl, (4-13C)heteroaryl, (1-8C) alkoxycarbonyl, (6-14C)aryloxyalkyl, (1-8C)alkylcarboxylic, (1-14C)arylcarboxylic, (1-8C)alkylsulphonyl, (6-14C)arylcarbamoyl, amino, (1-8C)alkylaminocarbonyl, (6-14C)arylenecarborane, (1-8C)alkylcarboxylic, (6-14C)arylcarboxamide, (6-14C)(di)arylamino and/or (1-8C)(di)alkylamino. Preferably the substituents at the aryl in R7selected from other8or or8. R8preferred is (1-8C)alkylaryl, (6-14C)arylcarbamoyl, (1-8C)alkyl. The most preferred substituents in the alkyl group are (2-7C)heteroseksualci, (1-6C)(di)alkylamino and Amin.

Alkyl group, Alchemilla group or alkylsilane group, if present in R9or R2in the above formula, optionally can be substituted by one or more substituents selected from (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkylsulphonyl, (6-14C)arylcarbamoyl, (1-8C)alkylcarboxylic, (6-14C)arylcarboxylic, (6-14C)aryloxyalkyl and/or (1-8C)alkoxycarbonyl.

Alkyl group, Alchemilla group or Alchemilla group, if present in R3in the above formula, optional the part may be substituted by one or more substituents, chosen from hydroxyl, (1-8C)alkoxy, (6-14C)aryloxy, (3-8C)cycloalkyl((1-8C)Ala)hydroxy, (2-7C)heteroseksualci((1-8C)Ala)hydroxy, (6-14C)aryl((1-8C)Ala)hydroxy, (4-13C)heteroaryl((1-8C)Ala)hydroxy, (2-7C)geterotsiklicheskie, (6-14C)aryl, (4-13C)heteroaryl, (1-8C)alkoxycarbonyl, (6-14C)aryloxyalkyl, (1-8C)alkylcarboxylic, (6-14C)arylcarboxylic, (1-8C)alkylsulphonyl, (6-14C)arylcarbamoyl, amino, (1-8C)alkylaminocarbonyl, (6-14C)arylenecarborane, (1-8C)alkylcarboxylic, (6-14C)arylcarboxamide, (6-14C)(di)arylamino or (18C)(di)alkylamino.

Preferred compounds according to the invention are compounds of General formula I where X is S and/or Z represents NH2. Among these preferred compounds, especially preferred are those in which X is S and Z is NH2even more preferred compounds are those where, in addition Y is N. preferred are compounds in which, in addition to the above definitions of X, Z and Y, R1defined as representing (6-14C)aryl, and (4-13C)heteroaryl. Most preferably a is S.

Overprescriptive compounds of the invention are derivatives of bicyclic heteroaromatic compounds having General formula I, where

R1is (6-14C)aryl or (4-13C)heteroaryl,

R 2is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted by one or more substituents selected from (1-8C)alkyl, (1-8C)alkylthio, (1-8C)alkoxy, (2-8C)altira or (2-8C)quinil,

R3is (1-8C)alkyl, (2-8C)alkenyl, (2-8C)quinil, (3-8C)cycloalkyl, (2-7C)heteroseksualci or (6-14C)aryl or (4-13C)heteroaryl, both optionally substituted by one or more substituents selected from (1-8C)alkyl, (1-8C)(di)alkylamino or (1-8C)alkoxy,

X is S, Z is NH2And is S and N is(N), or link.

These compounds have the General structure

R1is (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy, halogen, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulfur;

R2is (1-8C)alkyl, (6-10C) aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy, or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulphur,

R3is (1-8C)alkyl, possibly substituted with halogen, (1-4C)alkoxy, (1-4C)alkoxycarbonyl mono - or three(6-10C)cycloalkyl, (6-10C)aryl, (5-6C)heteroaryl, (5-7C)heterocyclization, with whom containing a series as nitrogen heteroatom, oxygen or sulfur; (3-8C)cycloalkyl, (2-7C)heteroseksualci or (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C) alkoxy;

In is N(H), or bond; Y represents CH or N.

The most preferred compounds are compounds of General formula I, more preferably of General formula II, where In is N or, most preferably, when B represents n, R2and/or R3preferably represent (1-8C)alkyl, more preferably (1-4C)alkyl, and Y preferably represents n

Particularly preferred compounds according to the invention are those in which R3is isopropyl or tert-butyl, with tert-butyl is preferred.

Of the invention exclude compounds that represent methyl-5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate or ethyl-5-amino-4-(4-chlorophenyl)-2-methylthieno[2, 3-d]pyrimidine-6-carboxylate.

Excluded from the claimed scope of the claims of the compounds described in the publication is Phosph.Sulf.Sil.Rel.Chem: 60, 223-231, 1991; J.Chem.Res., Synop.(6):290-291, 1998, and Sulfur Lett. 9:101-108, 1989.

The term (1-8C)alkyl, how it is used in the definition of formulas I and II, means a branched or unbranched alkyl group having 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl and octyl (1-6C). Alkyl groups are preferred, the most preferred is (1-3C)alkyl.

The term (2-8C)alkenyl means a branched or unbranched alkenylphenol group having 2-8 carbon atoms, such as ethynyl, 2-butenyl etc.

The term (2-8C)quinil means a branched or unbranched alkylamino group having 2-8 carbon atoms, such as ethinyl and PROPYNYL.

The term (3-8C)cycloalkyl means cycloalkyl group having 3-8 carbon atoms, represents cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term (2-7C)heteroseksualci means geterotsyklicescoe group having 3-8 carbon atoms, preferably 3-5 carbon atoms, and containing at least one heteroatom selected from N, O and S. Preferred are N or O. Most preferred piperidine, morpholine and pyrrolidine.

The term (1-8C)alkoxy means CNS group having 1-8 carbon atoms, where the alkyl fragment has the same meanings as defined in the above. (1-6C)CNS group are preferred, most preferred is (1-3C)alkoxygroup.

The term (1-8C)alkoxycarbonyl means alkoxycarbonyl group in which the alkyl group contains 1-8 carbon atoms and has the same meanings as defined above.

The term (1-8C)(di)alkylamino means (di)alkylamino having 1-8 carbon atoms, where the alkyl group has the same meanings as defined above.

The term (6-14C)(di)arylamino means (di)killingray with 6-14C carbon atoms, aryl fragment has the same meanings as defined above.

The term (1-8C)alkylthio means allylthiourea having 1-8 carbon atoms, alkyl fragment has the same meanings as defined above.

The term (6-14C)aryl means an aromatic hydrocarbon group having 6-14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, antracol, which optionally may be substituted by one or more substituents, such as, but not limited to, hydroxy, halogen, nitro, trifluoromethyl, cyano, (1-8C) alkylcarboxylic, (1-8C)alkylaminocarbonyl or (1-8C)(di)alkylamino, while the alkyl fragments have the same meanings as defined above. The preferred aromatic hydrocarbon group is phenyl.

The term (6-14C)aryloxyalkyl means ar is oxycarbonyl group, in which the aryl group contains 6 to 14 carbon atoms and has the same meanings as defined above.

The term (6-14C)aryl(1-8C)alkyl means arylalkyl group having 7-22 carbon atoms, where alcalina group represents a (1-8C)alkyl group, and aryl group represents a (6-14C)aryl, as defined previously. Preferred arylalkyl groups are phenyl(1-8C)alkyl group, such as benzyl.

The term (4-13C)heteroaryl means a substituted or unsubstituted aromatic group having 3-13 carbon atoms, preferably 4 to 9, 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 and pyridyl.

The term “attached” (2-7C)heterocyclicamines ring in the definition NR5R6where R5and R6together with the nitrogen atom to which they are bound represent a ring means a ring containing a nitrogen atom, and optionally having up to 2-7 carbon atoms, with the specified ring may contain unsaturated communication or od is n or more heteroatoms, selected from N, O and/or S. Examples of such rings are azetidin, pyrrolidine, piperidine, piperazine, morpholine and thiomorpholine.

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

The term (2-7C)heteroseksualci(1-8C)alkoxy means geterotsyklicescoe group containing 3-8 carbon atoms, as defined above, attached to a (1-8C)CNS group, where CNS fragment has the meaning given above.

The term (3-8C)cycloalkyl(1-8C)alkoxy means cycloalkyl group containing 3-8 carbon atoms, as defined above, attached to a (1-8C)CNS group, where CNS fragment has the meaning given above.

The term (6-14C)aryl(1-8C)alkoxy means an aryl group containing 6-14 carbon atoms, as defined above, attached to a (1-8C)CNS group, where CNS fragment has the meaning given above.

(4-13C)Heterokedasticity represent analogues (6-14C)arielalexisxrp, including at least one heteroatom selected from N, O and S.

The term (1-8C)alkylaryl means alkylcarboxylic group, the alkyl group contains 1-8 carbon atoms and has the same meanings as defined above.

The term (6-14C)arylcarbamoyl means arylcarbamoyl group, aryl group which contains 6 to 14 carbon atoms and has the same value is e, as specified above.

The term (1-8C)alkylcarboxylic means alkylcarboxylic, the alkyl group contains 1-8 carbon atoms has the same meanings as defined above.

The term (6-14C)arylcarboxylic means arylcarboxamide, aryl group which contains 6 to 14 carbon atoms and has the same meaning as defined above.

The term (1-8C)alkylaminocarbonyl means alkylaminocarbonyl group, an alkyl group which contains from 1 to 8 carbon atoms and has the same meaning as defined above.

The term (6-14C)arellanobond means arylaminomethylene group, aryl group which contains 6 to 14 carbon atoms and has the same meaning as defined above.

The term (1-8C)alkylcarboxylic means alkylcarboxylic, an alkyl group which contains from 1 to 8 carbon atoms and has the same meaning as defined above.

The term (6-14C)arylcarboxamide means arylcarboxamide, aryl group which contains 6 to 14 carbon atoms and has the same meaning as defined above.

The term (2-7C)heterocyclizations means geterotsyklicescoe group containing 3-8 carbon atoms, as defined above, attached to an oxygen atom.

The term (3-8C)cycloalkane means cycloalkyl group containing 3-8 carbon atoms, the AK previously defined, attached to the oxygen atom.

The term (6-14C)aryloxy means an aryl group containing 6-14 carbon atoms, as defined above, attached to an oxygen atom. (4-13C)Heterokaryosis represent analogues (6-14C)aryloxy, including at least one heteroatom selected from N, O and S.

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

The invention additionally relates to pharmaceutical compositions comprising a derivative of bicyclic heteroaromatic compounds or salts thereof having the General formula I.

Pharmaceutical compositions that include ethyl-5-amino-4-phenyl-2-ethoxycarbonylmethylene[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate or ethyl-5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, fall under the scope of the present invention. Thus, the compounds according to the invention can be used in therapy. An additional aspect of the invention relates to the use of bicyclic heteroaromatic compounds having General formula I, to obtain drugs for the control of fertility. Preferably these compounds are used to activate LH prescriptions is ora.

Derivatives of bicyclic heteroaromatic compounds of this invention can possess one or more chiral carbon atoms. Therefore, the compound can be obtained in the form of chiral pure compounds or as mixtures of diastereomers and/or antimirov. Methods of obtaining pure chiral compounds is well known in this field, such as crystallization or chromatography.

For therapeutic use of salts of compounds of formula I are salts in which the counterion is pharmaceutically acceptable. However, the acid additive salts of the bases corresponding to the formula I, may also find use, for example, to get or purification of pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or 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 hydrochloric acid, and organic acids such as citric acid, tartaric acid, acetic acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid and the like.

Appropriate ways of wedenesday formula I or their pharmaceutically acceptable salts, also referred to in this description as an 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 required will depend on therapeutic action that you want to achieve (the 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 you want to enter this drug.

Usually when parenteral require lower doses than with other methods of administration, which are more dependent on absorption. However, the dosage for humans is preferably of 0.0001 to 25 mg per 1 kg of body weight. The desired dose may be present in a single dose or in multiple podos entered via the appropriate time intervals during the day, or, in the case of a recipient female, in the form of a dose for injection with a suitable daily intervals during the menstrual cycle. Dosage, as well as the mode of administration may vary, for recipients, male and female.

In the case of in vitro or ex vivo applications, that is them as IVF applications, compounds of 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 containing bicyclic heteroaromatic compound according to formula I, including but not limited to pharmaceutical compositions containing ethyl-5-amino-4-phenyl-2-ethoxycarbonylmethylene[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate or ethyl-5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, 6-acetyl-5-amino-4-phenyl-2-(2-oxopropyl)thieno[2,3-d]pyrimidine, 5-amino-6-benzoyl-4-phenyl-2-phenylcarbonylamino[2,3-d]pyrimidine or 5-amino-6-(4-chlorobenzoyl)-4-phenyl-2-[(4-chlorophenyl)carbonylmethyl]thieno[2,3-d]pyrimidine 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 should not have a harmful impact on recipients.

Pharmaceutical compositions include suitable for oral, rectal, nasal, local (including dermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermally the infusion. The composition can be obtained by any means known in the pharmaceutical field, for example, using techniques such as described in Gennaro et al., Remington''s Pharmaceutical Sciences (18thed., Mack Publishing company, 1990, in particular, see Part 8: Pharmaceutical Preparations and Their Manufacture (Part 8: Pharmaceutical preparations and their receipt).

These include the stage of introduction of the active ingredient in the composition with any auxiliary agent. Auxiliary agent(s), also referred to as auxiliary ingredients include conventional in the art (Gennaro, above), such as fillers, binders, diluents, disintegrant, lubricants, colorants, flavoring agents and wetting agents.

Pharmaceutical compositions suitable for oral administration may be present in the form of a discrete formulation of dosage forms, such as pills, tablets or capsules, or in the form of powder or granules, or in the form of a solution or suspension. The active ingredient can also be present in the form of a bolus or paste. The composition optionally can be recycled in suppositories or enemas for rectal administration.

For parenteral administration suitable compositions include aqueous and non-aqueous sterile injection. The composition may be present in the containers for a single dose or multiple doses, n is the sample in sealed containers or ampoules, and can be stored in dried by freezing (liofilizirovannom), requiring only the addition of sterile liquid carrier, for example water, before use.

Compositions or formulations suitable for administration by nasal inhalation, include finely divided powders or mist of liquid that can be generated using the supplied dispenser aerosol packaging, dispensers or air injectors.

Derivatives of bicyclic heteroaromatic compounds of the invention can also be entered in the form of implantable pharmaceutical devices, consisting of a core of active substance enclosed in controlling the rate of release of the membrane. Such implants are used subcutaneously or topically, and they will release the active ingredient with approximately constant speed over a relatively large time intervals, for example from weeks to years. Methods of obtaining implantable pharmaceutical devices as such are known in this field, such as 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 exhibit modified properties of stability and can be entered in various ways.

p> Compounds of the present invention, where B=NH, represented by formula (I-a)can usually be obtained in accordance with known in this field by the condensation reaction of the acid of formula (III) with the amine of formula (IV).

The above interaction is usually carried out at room temperature in a suitable solvent, for example in an aprotic solvent such as N,N-dimethylformamide or dichloromethane, using agent combinations, such as tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethylurea (TBTU) or hexaphosphate postreproductive (PyBrOP), and a tertiary base, for example N,N-diisopropylethylamine.

Similarly, compounds of formula (I), where I=O, represented by the formula (1-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 (III) and alcohols of the formula (V).

The compounds of formula (I), where represents the relationship represented by formula (I-c)can be obtained by condensation of pyridylcarbinol (VI), where W = CN or C(O)(OEt), with compounds of the General structure (VII) in a suitable solvent, such as ethanol, methanol or tetrahydrofuran, at elevated temperature (50° (C) in the presence of a base, such as ethoxide sodium, sodium methoxide, potassium carbonate or potassium hydroxide./p>

Alternatively, the compounds of formula (I-c), where X = S, represented by formula (I-d) can be obtained from thioamides structure (VIII), where W is as defined above, and compounds of the formula (IX), where V = halogen such as bromide or chloride, using the above method.

Such cyclization described in the literature, see, for example, Wherein, Ameseal and Vchernenko, J.Org.Chem. USSR (Engl.Transl.), 20:1828, 1984, Z.H.Khalil and A.A.Geies, Phosph.Sulf.Silic.Relat.Elem. 60:223, 1991.

A suitable method of obtaining the intermediate acid (III) is known in this field saponification under the action of bases ethyl esters of General formula (X). Saponification occurs in the presence of a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide, in a mixture of water-dioxane at elevated temperature (80°C to the boiling temperature under reflux).

The compounds of formula (X) can be obtained by cyclization of pyridylcarbinol (VI) HXCH2C(O)OEt, as described above in the synthesis of compounds (I-c). In some cases it is possible to allocate the intermediate is not subjected to cyclization product that cichlisuite for re-processing base. Alternatively, the compounds of formula (X), where X=S, can also be obtained by OSU the same way, as described for the synthesis of derivatives (I-d), the cyclization of (VIII) with VCH2C(O)OEt (IX), where V is as defined above.

Such cyclization exist in the literature. For example, thieno-cyclization described A.A.Santilli, D.H.Kim and S.V.Wanser, J.Heterocycl.Chem., 8:445, 1971; S.Kohra, Y.Tominaga and A.Hosomi, J.Heterocycl.Chem., 25:959, 1988; H.Vieweg, U.Krasselt, N.Bohm, J.Prantz and G.Wagner, Pharmazie 45:731, 1990; H.Vieweg and G.Wagner, Pharmazie 46:51, 1991; G.Wagner. H.Vieweg and S.Leitner, Pharmazie 48:588, 1993. Pyrolitically described, for example, D.H.Kim and A.A.Santiili, J.Heterocycl.Chem., 6:819, 1969.

The compounds of formula (VI), where W is as defined above, can be synthesized according to literature methods, for example, described A.A.Santilli, D.H.Kim and S.V.Wanser, J.Heterocycl.Chem., 8:445, 1971. In a typical embodiment, amide of the General structure (XI) is treated l3at elevated temperature (80°C to the boiling temperature under reflux). Adding a suitable solvent, for example dioxane, and/or adding or PCl5or N,N-dimethylaniline to the reaction mixture can lead to a shorter interaction time and higher outputs chloride (VI).

In another approach, the amide (XI) can be processed at elevated temperature (preferably, the boiling point under reflux) SOCl2giving the compounds of formula (VI), as described in the literature and D.H.Kim A.A.Santilii, J.Heterocycl.Chem. 6:819, 1969.

the value of the formula (VIII), where W is as defined above, can be obtained by treating the derivative (XI) sulfureous agent, for example P2S5or reagent Losson (Lawesson), in a suitable solvent, such as pyridine, at an elevated temperature (preferably at the boiling point under reflux), see Z.H.Khalil, Phosph.Sulf.Silic.Relat.Elem. 60:223, 1991.

In addition, compounds of General formula (VIII), where Y=CH and a is a link represented by formula (VIII-a)can be synthesized by cyclization of α,β-unsaturated ketones of the formula (XII) and thioacetamide (XIII).

In a typical experiment, the compounds (XII) and (XIII) is subjected to vzaimodeistvie in a solvent such as ethanol, methanol or tetrahydrofuran, at an elevated temperature (preferably at the boiling point under reflux in the presence of a base, such as piperidine, triethylamine, sodium methoxide or ethoxide sodium. Such cyclization is known in the literature: H.Vieweg, V.Hanfeld, S.Leitner and G.Wagner, Pharmazie 44:639, 1989; H.Vieweg and G.Wagner, Pharmazie 46:51, 1991.

Alternatively, the compounds of formula (VIII-a, W=CN) can be synthesized based on α,β-unsaturated dinitriles General structure (XIV) and thioacetamide (XV)as described G.A.H.Elgemeie, Heterocycles 31:123, 1990.

The compounds of formula (XI), where Y=N, presents what armoloy (XI-a), can be obtained using several approaches based on the literature data.

For example, derivatives of the formula (XI-a), where R1=(6-14)aryl or (4-13C)heteroaryl, can be synthesized by the condensation of ethyl esters (XVI), where W is as defined above, with an aldehyde (XVII) and compound (XVIII), which can be estimatedin (XVIII-a), smokeview (XVIII-b), monosubstituted guanidine (XVIII c)disubstituted guanidine (XVIII-d) or amidine (XVIII-e).

In a typical experiment components (XVI), (XVII) and (XVIIIa-e) are suspended in a suitable solvent, for example 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 temperature under reflux). After filtration the residue is placed in water and acidified (pH 2), then the product (XI-a) precipitate (S.Kambre, K.Saito and H.Kishi, Synthesis, 287 (1979); A.M.Abd-Alfattah, S.M.Hussain and ..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 when W=C(s)OEt, aromatization occurs when adding an oxidant such as DDQ or oxygen. Such cyclization can also be carried out on a solid medium, such as a 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).

Alternatively, the derivatives of formula (XI-a), where R1is not (6-14C)aryl or (4-13C)heteroaryl can be obtained by substitution of CL in the derivatives of formula (VI-a) or the substitution of 4-SMe in the compounds of formula (XI-b).

Such substitution reactions known 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.G.Varvounis, J.Heterocycl.Chem., 30:1065, 1993; S.Tumkevicius, Liebigs Ann.Org.Biorg.Chem. 9:1703, 1995.

Pyridine General formula (XI), where Y=CH, A=S and W=CN, represented by formula (XX), receive consecutive alkylation α,β-unsaturated dinitriles General structure (XIV) with carbon disulphide and idestam the alkyl R2-I, to obtain the compounds of General formula (XIX), as described P.Milart, Tetrahedron 54:15643-156556, 1998. Subsequent cyclization of compounds of formula (XIX) in acidic conditions, as described K.Peseke, Z.Chem., 29:442-443 (1989) gives pyridine General formula (XX).

How to determine receptor swazilan what I as well as in vitro and in vivo assays to determine biological activity of gonadotropins well known. Usually 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 of selected DNA encoding the LH receptor gene, preferably the receptor is human, Express in appropriate cell hosts. Such a cell can be a cell in the ovary of the Chinese hamster, but will also fit other cells. Preferably the cells are derived from mammals (Jia et al., Mol.Endocrin., 5:757-776, 1991).

The methods of constructing cell lines expressing recombinant LH, well known in the art (Sambrook et al., Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latest edition). The expression of the receptor is achieved by expression of DNA that encodes a desired protein. Methods site-directed mutagenesis, ligation of additional sequences, PCR and design appropriate expressing all systems, 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 about the lahcene ligation. Suitable control elements for transcription and translation included the coding sequence can be a DNA coding sequences. As is well known, currently available expression system, which is 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, avian cells, and the like.

Expressing the receptor cells are then brought into contact with a test compound to observe binding, or stimulation or inhibition of a functional response.

Alternatively, to measure the binding 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, it is also possible to carry out analyses of competitive binding.

Other analysis includes the screening of compounds agonists LH receptor by determining the stimulation of receptor-mediated camp accumulation. Thus, this method involves receptor expression on the cell surface is the surface of the host cell and the exposure of the cells to the effects of the investigated compound. Then measure the amount of camp. The level of camp will decrease or increase depending on inhibitory or stimulating effect of the compounds when binding with the receptor.

In addition to the direct measurement, for example, camp levels in cells exposed to, you can use a cell line that is in addition to transfection using the coding DNA receptor also transfection second DNA that encodes a reporting gene, expression of which corresponds to the level of camp. The genes may be cyclic amp-induced or can be designed so that they were related to the new camp-echoing elements. Usually the expression of the reporting gene can be controlled by any response element that responds to changing levels of camp. Appropriate reporting genes are, for example, LacZ, alkaline phosphatase, of Firefly luciferase and green fluorescent protein. Principles such transactivation assays well known in this field and are described, for example, Stratowa Ch., Himmler Czernilofsky, A. and A.P. (1995), Curr.Opin.Biotechnol. 6:574.

For the election of active connections study in 10-5M should lead to activity in excess of 20% of the maximum activity in the case when the links are used LH. Another criterion may be Zn is an increase EC 50that should be <10-5M, preferably <10-7M

For qualified specialist in this field will be obvious that the desired value of EC50depend on the studied compounds. For example, the connection with EC50that is less than 10-5M is usually considered as a candidate for drug selection. Preferably, this value is below 10-7M. However, the connection that has a higher value of EC50but is selective for a particular receptor, may even be the best candidate.

Screening for compounds which are antagonists of LH-receptor, can also be performed using the bioanalysis of mouse Leydig cells (Van Damme M., Robersen D. and Diczfalusy, E. (1974). Acta Endocrinol. 77:655-671, Mannaerts Century, 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, the stimulation of the LH-receptor-mediated produced testosterone can be measured in Leydig cells isolated from male mice.

To measure the in vivo activity of the compounds agonists LH receptor can be studied the induction of ovulation in immature mice. In this analysis, immature female mice can be subjected to a primary effect of FSH urine and approximately 48 hours the treated compound is honestum LH. Animals killed after processing LH agonist and the number of female germ cells in the oviduct evaluated using microscopy.

Compounds of the present invention can be applied clinically in those modes where you currently use LH or hCG. This includes replacement of LH in subjects with hypogonadal reduced function of the gonads either male or female, introduction to the middle of the cycle to induce ovulation (the induction of ovulation (0I) or controlled hyperstimulation (SLEEP)or stimulation of the yellow body.

The following examples are to illustrate the invention, and in no way should be interpreted to limit the scope of the invention.

Example 1

Ethyl-5-amino-4-(3-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

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

A mixture of sulfate S-methylisothiazoline (139 mg), 3-methoxybenzaldehyde (243 μl), ethylcyanoacrylate (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°in an ice bath, filtered and the residue was heated in water until until they received a clear solution. The solution was acidified using 2 N. Hcl to pH 2 and was cooled to 0°in an ice bath. The obtained crystals were filtered and dried in vacuum. Exit 186 mg.

Mass when ECTR-ESI: [M+H] +=274,2.

TLC: Rf=0,50, silica gel, dichloromethane/methanol=9/1 about/about.

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

To a stirred solution of 5-cyano-4-(3-methoxyphenyl)-2-methylthio-6-oxopyrimidine (305 mg) in dry dioxane (1 ml) was added l3(0.75 ml). After incubation for 3 hours at 80°the mixture was cooled to 0°in an ice bath and slowly added to crushed ice. After the termination of the exothermic reaction was added water (3 ml), the solid was filtered and dried in vacuum. Exit 244 mg.

Mass spectrum ESI: [M+H]+=292,2.

TLC: Rf=0,86, silica gel, dichloromethane.

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

Ethoxide sodium (1,4 N., 957 ml) was added to a stirred solution of ethyl-2-mercaptoacetate (92 μl) and 6-chloro-5-cyano-4-(3-methoxyphenyl)-2-methylthiopyrimidine (244 mg) in dry ethanol (4 ml). After 3 hours at 50°the mixture was cooled to 0°in an ice bath, diluted with water (5 ml) and the solids were collected by filtration and dried in vacuum. The output of 260 mg.

Mass spectrum ESI: [M+H]+=376,2.

TLC: Rf=0,44, silica gel, dichloromethane.

Example 2

Ethyl-5-amino-2-ethylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-utilizationfocused · NVG (185 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), product handling RO the l Cand subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 49 mg

Mass spectrum ESI: [M+H]+=360,2.

TLC: Rf=0,46, silica gel, dichloromethane.

Example 3

Ethyl-5-amino-2-n-pentylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-n-penalization (146 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (112 μl), processing product POCl3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 45 mg

Mass spectrum ESI: [M+H]+=402,4.

TLC: Rf=0,57, silica gel, dichloromethane.

Example 4

Ethyl-5-amino-2-n-pentylthio-4-(3-thienyl)thieno[2,3-d] pyrimidine-6-carboxylate

The cyclization of S-n-penalization (146 mg), thiophene-3-carboxaldehyde (183 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Output 4 mg

Mass spectrum ESI: [M+H]+=408,2.

TLC: Rf=0,65, silica gel, dichloromethane.

Example 5

Ethyl-5-amino-4-(3-furyl)-2-n-pentylthiophene[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-n-penalization (146 mg), 3-furaldehyde (129 μl) and ethylcyanoacrylate (112 μl), processing product l3and then inter the step with ethyl-2-mercaptoacetate carried out in accordance with the methods, described in example 1. Yield 18 mg

Mass spectrum ESI: [M+H]+=392,2.

TCX: Rf=0,60, silica gel, dichloromethane.

Example 6

Ethyl-5-amino-2-benzylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-benzisothiazolin (203 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 114 mg.

Mass spectrum ESI: [M+H]+=422,0.

TCX: Rf=0,70, silica gel, dichloromethane.

Example 7

Ethyl-5-amino-2-benzylthio-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-benzisothiazolin (203 mg), thiophene-3-carboxaldehyde (183 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 34 mg

Mass spectrum ESI: [M+H]+=428,3.

TCX: Rf=0,65, silica gel, dichloromethane.

Example 8

Ethyl-5-amino-2-benzylthio-4-(3-furyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-benzisothiazolin (203 mg), 3-furaldehyde (129 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 38 mg

+=412,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 9

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

The cyclization of S-benzisothiazolin (203 mg), 3-methoxybenzaldehyde (243 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 31 mg

Mass spectrum ESI: [M+H]+=452,2.

TLC: Rf=0,52, silica gel, dichloromethane.

Example 10

Ethyl-5-amino-2-(4-chlorobenzylthio)-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of S-p-chlorobenzenesulfonamide·Hcl (237 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 34 mg

Mass spectrum ESI: [M+H]+=456,2.

TLC: Rf=0,74, silica gel, dichloromethane.

Example 11

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

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-methoxybenzaldehyde (243 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Output mg.

Mass spectrum ESI: [M+H]+=USD 448,2.

TLC: Rf=0,12, silica gel, dichloromethane.

Example 12

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

The cyclization of sulfate S-methylisothiazoline (695 mg), thiophene-3-carboxaldehyde (910 μl) and ethylcyanoacrylate (580 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 176 mg.

Mass spectrum ESI: [M+H]+=352,2.

TCX: Rf=0,52, silica gel, dichloromethane.

Example 13

Ethyl-5-amino-4-(3-furyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-furaldehyde (129 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 32 mg.

Mass spectrum ESI: [M+H]+=336,2.

TCX: Rf=0.38 (silica gel, dichloromethane.

Example 14

Ethyl-5-amino-4-(2-forfinal-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 2-forventelige (211 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 91 mg

the Mass spectrum-ESI: [M+H] +=364,0.

TCX: Rfor =0.51, silica gel, dichloromethane.

Example 15

Ethyl-5-amino-4-(3-bromophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-bromobenzaldehyde (233 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 170 mg

Mass spectrum ESI: [M+H]+=to 426.2.

TLC: Rf=0,70, silica gel, dichloromethane.

Example 16

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

The cyclization of sulfate S-methylisothiazoline (139 mg), 4-pyridinecarboxamide (191 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. 29 mg.

Mass spectrum ESI: [M+H]+=347,2.

TLC: Rf=0,54, silica gel, dichloromethane.

Example 17

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

The cyclization of sulfate S-methylisothiazoline (139 mg), 2-pyridinecarboxamide (190 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 73 mg.

Mass when ECTR-ESI: [M+H] +=347,2.

TLC: Rf=0,50, silica gel, dichloromethane.

Example 18

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

The cyclization of sulfate S-methylisothiazoline (139 mg), thiophene-2-carboxaldehyde (189 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 106 mg.

Mass spectrum ESI: [M+H]+=381,2.

TLC: Rf=0,67, silica gel, dichloromethane.

Example 19

Ethyl-5-amino-2,4-diphenylethane[2,3-d]pyrimidine-6-carboxylate

The cyclization of benzamidine·Hcl (156 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 101 mg.

Mass spectrum ESI: [M+H]+=376,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 20

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

The cyclization of benzamidine·Hcl (156 mg), thiophene-3-carboxaldehyde (183 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 203 mg.

Mass spectrum ESI: [M+H]+=382,0.

TLC: Rf=0,65, si is yagel, dichloromethane.

Example 21

Ethyl-5-amino-4-(3-furyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of benzamidine·Hcl (156 mg), 3-furaldehyde (129 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 157 mg.

Mass spectrum ESI: [M+H]+=366,2.

TLC: Rf=0,55, silica gel, dichloromethane.

Example 22

Ethyl-5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of benzamidine·Hcl (157 mg), 3-methoxybenzaldehyde (243 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 164 mg.

Mass spectrum ESI: [M+H]+=406,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 23

Ethyl-5-amino-2-(4-chlorophenyl)-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 4-chlorobenzamidine (772 mg), benzaldehyde (1.0 ml) and ethylcyanoacrylate (1.07 ml), the product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 300 mg.

Mass spectrum ESI: [M+H]+=410,0.

TLC: Rf=0,77, silica gel, dichloromethane/heptane=3/1 (V/V).

Example 24

E. the Il-5-amino-4-phenyl-2-(2-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 2-amidinopropane·Hcl (162 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 159 mg.

Mass spectrum ESI: [M+H]+=382,0.

TLC: Rf=0,80, silica gel, dichloromethane.

Example 25

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

The cyclization of 2-amidinopropane·Hcl (162 mg), thiophene-2-carboxaldehyde (183 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. The output 139 mg.

Mass spectrum ESI: [M+H]+=388,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 26

Ethyl-5-amino-4-(3-furyl)-2-(2-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 2-amidinopropane·Hcl (162 mg), 3-furaldehyde (129 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 131 mg.

Mass spectrum ESI: [M+H]+=372,0.

TLC: Rfor =0.90, silica gel, dichloromethane.

Example 27

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

The cyclization of 2-amide is Atofina· Model HC1 (162 mg), 3-methoxybenzaldehyde (243 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 186 mg.

Mass spectrum ESI: [M+H]+=412,2.

TLC: Rf=0,61, silica gel, dichloromethane.

Example 28

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

The cyclization of 4-amidinopropane·Hcl (157 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 121 mg.

Mass spectrum ESI: [M+H]+=377,2.

TLC: Rf=0, silica gel, dichloromethane.

Example 29

Ethyl-5-amino-2-(4-pyridyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 4-amidinopropane·Hcl (157 mg), thiophene-3-carboxaldehyde (183 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Output 12 mg.

Mass spectrum ESI: [M+H]+=283,0.

TLC: Rf=0,85, silica gel, dichloromethane.

Example 30

Ethyl-5-amino-4-(3-furyl)-2-(4-pyridyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 4-amidinopropane·Hcl (157 mg), 3-fural is Egida (129 μl) and ethylcyanoacrylate (117 μl), product handling lCand subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 51 mg

Mass spectrum ESI: [M+H]+=367,0.

TLC: Rf=0,05, silica gel, dichloromethane.

Example 31

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

The cyclization of 4-amidinopropane·Hcl (157 mg), 3-methoxybenzaldehyde (243 μl) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Exit 153 mg.

Mass spectrum ESI: [M+H]+=407,2.

TLC: Rf=0,42, silica gel, dichloromethane/methanol=95/5 (V/V).

Example 32

Ethyl-5-amino-2-methylamino-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of 1-methylguanine·Hcl (110 mg), benzaldehyde (203 μl) and ethylcyanoacrylate (117 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Yield 48 mg

Mass spectrum ESI: [M+H]+=329,2.

TLC: Rf=0,85, silica gel, dichloromethane/methanol=95/5 (V/V).

Example 33

Ethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (8,35 g), benzaldehyde (12,2 ml) and atilano is Zetta (6,70 ml), product handling l3and the subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Output 7,98,

Mass spectrum ESI: [M+H]+=346,2.

TLC: Rf=0,92, silica gel, dichloromethane.

Example 34

5-Amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid

The lithium hydroxide (923 mg) was added to a stirred solution of 760 mg of ethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate (see example 33) in a mixture of dioxane/water=9/1 (V/V) and the mixture was heated at 80°C for 24 hours. The reaction mixture was poured into water and was extracted with ethyl acetate at pH 2. The organic layer was washed with water and saturated salt solution and dried over sodium sulfate. The filtrate is evaporated to dryness. Output 766 mg

Mass spectrum ESI: [M+H]+=318,0.

TLC: Rf=0,49, silica gel, dichloromethane/methanol=9/1 (V/V).

Example 35

Phenyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

To a mixed solution of 40 mg of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid, which was synthesized by the method described in example 34, in dichloromethane (2 ml) was added N,N-diisopropylethylamine (100 ml), phenol (13 mg) and hexaphosphate patrimonialization (79 mg). After 20 hours was added water (2 ml), the mixture was intensively mixed and subsequently shown is ovali through RE-filter. The organic phase was concentrated in vacuum and the residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Output 16 mg.

Mass spectrum ESI: [M+H]+=394,2.

TLC: Rf=0,32, silica gel, dichloromethane.

Example 36

n-Butyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) in n-butanol (13 ml) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Exit 7 mg.

Mass spectrum ESI: [M+H]+=374,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 37

Cyclohexyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) cyclohexanol (14 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Exit 14 mg.

Mass spectrum ESI: [M+H]+=400,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 38

Benzyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 is g), benzyl alcohol (14 ml) was carried out in accordance with the method, described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Output 10 mg

Mass spectrum ESI: [M+H]+=408,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 39

3-Bromo-2-R-methyl-1-propyl-5-amino-2-methylthio-4-phenylthieno [2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 3-bromo-2-R-methylpropan-1-I (14 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Output 5 mg

Mass spectrum ESI: [M+H]+=454,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 40

4-Methoxyphenyl-S-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of S-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 4-methoxyphenol (17 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 26 mg

Mass spectrum ESI: [M+H]+=424,2.

TLC: Rf=0,64, silica gel, dichloromethane.

Example 41

3-Methoxyphenyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-]pyrimidine-6-carboxylic acid (40 mg), 3-methoxyphenol (17 mg) was carried out in accordance with the method, described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. 29 mg.

Mass spectrum ESI: [M+H]+=424,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 42

2-Methoxyphenyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidin-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 2-methoxyphenol (17 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 19 mg

Mass spectrum ESI: [M+H]+=424,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 43

2,3-Acid-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 2,3-dimethoxyphenol (21 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=454,2.

TLC: Rf=0,36, silica gel, dichloromethane.

Example 44

2,4-Acid-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

Atrificial the 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 2,4-dimethoxyphenol (21 mg) was carried out in accordance with the method, described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 20 mg

Mass spectrum ESI: [M+H]+=454,4.

TLC: Rf=0.38 (silica gel, dichloromethane.

Example 45

3,5-Methoxyphenyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 3,5-dimethoxyphenol (21 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) in a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 18 mg

Mass spectrum ESI: [M+H]+=454,2.

TLC: Rf=0,60, silica gel, dichloromethane.

Example 46

Isopropyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) in 2-propanol (10 ml) was implemented in sootvetstsvii with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=360,2.

TCX: Rf=0,66, silica gel, dichloromethane.

Example 47

2-Thienylmethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2-d]pyrimidine-6-carboxylic acid (40 mg), 2-thiophenemethyl (17 μl) was carried out in accordance with the method, described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 18 mg

Mass spectrum ESI: [M+H]+=level of 414.2.

TCX: Rf=0,74, silica gel, dichloromethane.

Example 48

3-Thienylmethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 3-thiophenemethyl (15 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=level of 414.2.

TCX: Rf=0,74, silica gel, dichloromethane.

Example 49

2-Adamantylamine-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg), 1-adamantanemethanol (22 mg) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 15 mg

Mass spectrum ESI: [M+H]+=466, 2.

TCX: Rf=0,81, silica gel, dichloromethane.

Example 50

2-N-Pyrrolidino-1-ethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

To mix the solution of 40 mg of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid, which was synthesized by the method described in example 34, in dichloromethane (2 ml) was added N,N-diisopropylethylamine (40 μl), 1-(2-hydroxyethyl)pyrrolidine (20 ml) and tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethylurea (40 mg). After 20 hours, the solvent evaporated and the residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=100/0 (V/V)=>0/100 (V/V) as eluent. Exit 13 mg.

Mass spectrum ESI: [M+H]+=415,0.

TLC: Rf=0,07, silica gel, dichloromethane/methanol=98/2 (V/V).

Example 51

Isopropyl-5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate

Ethyl-5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate (see example 22) is first hydrolyzed to the corresponding acid (52 mg) using the method described in example 34, followed by esterification of 2-propanol (12 ml) into the corresponding ester in accordance with example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 18 mg

Mass spectrum ESI: [M+H]+=420,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 52

Phenyl-5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (52 mg), phenol (15 mg) done by ulali in accordance with the methods, described in example 51. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. The output 36 mg.

Mass spectrum ESI: [M+H]+=454,4.

TLC: Rf=0,73, silica gel, dichloromethane.

Example 53

Isopropyl-5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

Ethyl-5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate (see example 25) is first hydrolyzed to the corresponding acid (45 mg), using the methods described in example 34, followed by esterification of 2-propanol (11 μl) into the corresponding ester in accordance with example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Exit 11 mg.

Mass spectrum ESI: [M+H]+=402,2.

TLC: Rf=0,66, silica gel, dichloromethane.

Example 54

Phenyl-5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate

The esterification of 5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylic acid (45 mg), phenol (13 mg) was carried out in accordance with the methods described in example 53. The residue was chromatographically on silica gel (Isolute, 2 g) in a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Exit 13 mg.

Mass spectrum ESI: [M+H]+=436,4.

TLC: Rf=0,73, silica gel, dichloromethane.

Example 55

Isopropyl-5-the Mino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 2-aminopropanol (12 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Exit 7 mg.

Mass spectrum ESI: [M+H]+=359,2.

TLC: Rf=0,23, silica gel, dichloromethane.

Example 56

Benzyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with benzylamine (15 µl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. The output 32 mg.

Mass spectrum ESI: [M+H]+=407,2.

TLC: Rf=0,24, silica gel, dichloromethane.

Example 57

n-Butyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 1-aminobutanol (13 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Yield 18 mg

Mass spectrum ESI: [M+H]+=373,2.

TLC: Rf=0.25, silica gel, dichloromethane.

Example 58

Cyclopropyl-5-amino-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with cyclopropylamine (9 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Exit 9 mg.

Mass spectrum ESI: [M+H]+=357,2.

TLC: Rf=0,14, silica gel, dichloromethane.

Example 59

Cyclohexyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-

6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with cyclohexylamine (16 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as sa eluent. Exit 11 mg.

Mass spectrum ESI: [M+H]+=399,2.

TLC: Rf=0,32, silica gel, dichloromethane.

Example 60

4-Methoxybenzyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 4-methoxybenzylamine (18 μl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Exit 25 mg

Mass spectrum ESI: [M+H]+=437,2.

TLC: Rf=0,20, silica gel, dichloromethane.

Example 61

1-Naphthylmethyl-5-amino-2-methylthio-4-phenylthieno [2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 1-naphthylethylene (20 µl) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Output 20 mg

Mass spectrum ESI: [M+H]+=457,2.

TLC: Rf=0,32, silica gel, dichloromethane.

Example 62

Phenyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (39 mg) with aniline (909 ml) was carried out in accordance with the method described in example 35. The residue was chromatographically on silica gel (Isolute, 2 g) using dichloromethane as eluent. Yield 37 mg

Mass spectrum ESI: [M+H]+=393,0.

TLC: Rf=0,95, silica gel, ethyl acetate/pyridine/acetic acid/water=363/20/6/11 (about/about/about/about).

Example 63

2-Thienylmethyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 2-thiophenemethylamine (14 μl) was carried out in accordance with the method described in example 35, and the crude product was purified by chromatography on silica gel (Isolute, 2 g) using a mixture is heptane/dichloromethane=1/1 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=413,2.

TLC: Rf=0,23, silica gel, dichloromethane.

Example 64

1-Adamantylamine-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 1-adamantanemethylamine (22 μl) was carried out in accordance with the method described in example 35, and the crude product was purified by chromatography on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. 29 mg.

Mass spectrum ESI: [M+H]+=465,4.

TLC: Rf=0,33, silica gel, dichloromethane.

Example 65

n-Heptyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 1-aminoheptane (25 µl) was carried out in accordance with the method described in example 50. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 37 mg

Mass spectrum ESI: [M+H]+=415,2.

TLC: Rf=0,87, silica gel, dichloromethane/methanol=98/2 (V/V).

Example 66

3-Phenyl-1-propyl-5-amino~2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 3-phenyl-1-Propylamine (24 μl) and carried out is in accordance with the method, described in example 50. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. The output 32 mg.

Mass spectrum ESI: [M+H]+=435,2.

TLC: Rf=0,83, silica gel, dichloromethane/methanol=98/2 (V/V).

Example 67

1,1-Diethoxy-4-butyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with 4,4-diethoxyaniline (30 μl) was carried out in accordance with the method described in example 50. The residue was chromatographically on silica gel (2 g Isolute) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 47 mg

Mass spectrum ESI: [M+H]+=461,2.

TLC: Rf=0.38 (silica gel, dichloromethane/methanol=98/2 (V/V).

Example 68

(3R)-(-)-1-Benzyl-3-pyrrolidinone-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno [2,3-d]pyrimidine-6-carboxylic acid (40 mg) with (3R)-(-)-1-benzyl-3-aminopyrrolidine (29 μl) was carried out in accordance with the method described in example 50. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 50 mg

Mass spectrum ESI: [M+H]+=476,2.

TLC: Rf=0,21, silica gel, dichloromethane/methanol=98/2 (V/V).

Prima is 69

3-Methoxycarbonyl-1-propyl-5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxamide

The interaction of 5-amino-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylic acid (40 mg) with methyl-4-aminobutyrate (26 mg) was carried out in accordance with the method described in example 50. The residue was chromatographically on silica gel (Isolute, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Yield 39 mg

Mass spectrum ESI: [M+H]+=417,0.

TLC: Rf=0,46, silica gel, dichloromethane/methanol=98/2 (V/V).

Example 70

Isopropyl-5-amino-4-(3-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-4-(3-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate {see example 1) is first hydrolyzed to the corresponding acid (248 mg) using the method described in example 34, followed by interaction with 2-aminopropanol (111 μl) to obtain the corresponding amide in accordance with example 50. Specified in the title compound was purified by chromatography on silica gel using mixtures of dichloromethane/methanol=98/2 (V/V) as eluent, followed by crystallization from ethanol. Exit 147 mg.

Mass spectrum ESI: [M+H]+=389,0.

TLC: Rf=0,19, silica gel, dichloromethane.

Example 71

Isopropyl-5-amino-4-(3-methoxyphenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-4-(3-methox is phenyl)-2-phenylthieno[2,3-d]pyrimidine-6-carboxylate (see example 22) is first hydrolyzed to the corresponding acid (52 mg) using the method described in example 34, followed by interaction with 2-aminopropanol (13 μl) to obtain the corresponding amide in accordance with example 35. The residue was chromatographically on silica gel (Isolate, 2 g) using a mixture of heptane/dichloromethane=1/1 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=419,4.

TLC: Rf=0,17, silica gel, dichloromethane.

Example 72

Isopropyl-5-amino-4-(3-methoxyphenyl)-2-(2-thienyl)thieno[2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-4-(3-methoxyphenyl)-2-(2-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate (see example 27) is first hydrolyzed to the corresponding acid (464 mg) using the method described in example 34, followed by interaction with 2-aminopropanol (190 μl) y for receipt of the corresponding amide in accordance with example 50. Specified in the title compound was chromatographically on silica gel using mixtures of dichloromethane/methanol=98/2 (V/V) as eluent. The output 332 mg.

Mass spectrum ESI: [M+H]+=425,2.

TCX: Rf=0,23, silica gel, dichloromethane.

Example 73

Isopropyl-5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-2-(2-thienyl)-4-(3-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate (see example 25) is first hydrolyzed to the corresponding key the lot (753 mg) using the method described in example 34, followed by interaction with 2-aminopropanol (326 μl) to obtain the corresponding amide in accordance with example 50. Specified in the title compound was chromatographically on silica gel using mixtures of dichloromethane/methanol=98/2 (V/V). The output 646 mg

Mass spectrum ESI: [M+H]+=401,2.

TCX: Rf=0,29, silica gel, dichloromethane.

Example 74

Ethyl-5-amino-7-methyl-2-methylthio-4-phenylpyrrole[2,3-d]pyrimidine-6-carboxylate

(a) 5-Cyano-6-(ethoxycarbonylmethyl)(methyl)amino-2-methylthio-4-phenylpyrimidine

A mixture of sodium bicarbonate (160 mg) and ethyl-N-methylglycine·Hcl (438 and mg) in ethanol was heated at the boiling point under reflux. After 2 hours, was added 6-chloro-5-cyano-2-methylthio-4-phenylpyrimidine (100 mg, see example 1b) and the reaction mixture was heated at the boiling point under reflux for 2.5 hours.

Solids were removed by filtration, after which the product was led from the filtrate. Exit 65 mg.

Mass spectrum ESI: [M+H]+=343,2.

TLC: Rf=0,52, silica gel, dichloromethane.

(b) Ethyl-5-amino-7-methyl-2-methylthio-4-phenylpyrrole[2,3-d]pyrimidine-6-carboxylate

Ethoxide sodium (1,4 N., 52 ml) was added to a stirred solution of 5-cyano-6-(ethoxycarbonylmethyl)(methyl)amino-2-methylthio-4-phenylpyrimidine in dry ethanol (1 ml). After 3 hours at 60°With a mixture of what was gladly to 0° C in an ice bath, the solids were collected by filtration and dried in vacuum. The output 40 mg

Mass spectrum ESI: [M+H]+=343,2.

TLC: Rf=0,53, silica gel, dichloromethane.

Example 75

Ethyl-5-amino-7-benzyl-2-methylthio-4-phenylpyrrole[2,3-d]pyrimidine-6-carboxylate

Condensation of 6-chloro-5-cyano-2-methylthio-4-phenylpyrimidine (100 mg) with ethyl-N-benzylglycine (0.45 ml) and subsequent cyclization of purified 5-cyano-6-N-(ethyl-N-benzylglycine)-2-methylthio-4-phenylaminopyrimidine (chromatographically on silica gel using a mixture of heptane/dichloromethane=1/3 (V/V)=>1/0 (on/about)in the final product was carried out according to the methods described in example 74. Exit 75 mg

Mass spectrum ESI: [M+H]+=419,2.

TCX: Rf=0,78, silica gel, dichloromethane.

Example 76

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

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-phenoxybenzaldehyde (39 mg) and ethylcyanoacrylate (112 μl), processing product POCl3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/ethyl acetate=100/0 (V/V)=>80/20 (V/V) as eluent. The output of 7.0 mg

Mass spectrum ESI: [M+H]+=438,0.

TCX: Rf=0,61, silicia the ü, dichloromethane.

Example 77

Ethyl-5-amino-4-(3-n-butoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

(a) 3-n-Butoxybenzaldehyde

Diethylazodicarboxylate (3,31 ml) was added dropwise to a cooled (0° (C) to a solution of 3-hydroxybenzaldehyde (2,44 g), n-butanol (1,83 ml) and triphenylphosphine (5,51 g) in tetrahydrofuran. After stirring at room temperature for 4 hours the solution was added 2 n sodium hydroxide (150 ml) and stirring was continued for 20 minutes. The reaction mixture was extracted with dichloromethane (150 ml). The organic layer was washed with water, 1%citric acid, water and saturated salt solution, dried over sodium sulfate and concentrated in vacuum. To the crude (crude product) was added ethyl acetate (3×25 ml) and the solids were removed by filtration. The residue was chromatographically on silica gel using a mixture of heptane/ethyl acetate=100/0 (V/V)=>60/40 (V/V) as eluent. The output of 1.64,

Mass spectrum ESI: [M+H]+=179,2.

TLC: Rf=0,80, silica gel, heptane/ethyl acetate=1/1 (V/V).

(b) Ethyl-5-amino-4-(3-n-butoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-n-butoxybenzaldehyde (357 mg) and ethylcyanoacrylate (112 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate implemented the Yali in accordance with the methods, described in example 1. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/ethyl acetate=100/0 (V/V)=>80/20 (V/V) as eluent and crystallization from ethanol. Yield 78 mg

Mass spectrum ESI: [M+H]+=418,0.

TLC: Rf=0,61, silica gel, dichloromethane.

Example 78

Ethyl-4-(3-[2-acetoacetate]phenyl)-5-amino-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

(a) 3-(2-Acetoacetate)benzaldehyde

A catalytic amount of N,N-dimethylaminopyridine was added to a stirred solution of 3-(2-hydroxyethoxy)benzaldehyde (1.66 g) in acetic anhydride (9 ml) and pyridine (3 ml). After 2 hours the reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 G. hydrochloric acid, water, 5% sodium bicarbonate, water and saturated salt solution, dried over sodium sulfate and evaporated to dryness. The output of 2.16,

Mass spectrum ESI: [M+H]+=209,2.

TLC: Rf=0,60, silica gel, heptane/ethyl acetate=1/1 (V/V).

(b) Ethyl-4-(3-[2-acetoacetate]phenyl)-5-amino-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-(2-acetoacetate)benzaldehyde (357 mg) and ethylcyanoacrylate (112 μl), product handling, l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with methods described in the example 1. Re-acetylation of the crude product (acetic anhydride/pyridine=3/1 (V/V), 4 h), the concentration of the mixture and subsequent purification by chromatography on silica gel in dichloromethane gave specified in the header connection. The output of 6.0 mg

Mass spectrum ESI: [M+H]+=448, 5.

TCX: Rf=0,66, silica gel, dichloromethane/methanol=98/2 (V/V).

Example 79

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

(a) 3-(n-Octyloxy)benzaldehyde

3-Hydroxybenzaldehyde (977 mg), 1-chlorooctane (1.35 ml) and cesium carbonate (3.9 g) was stirred in dioxane at 80°C. After 60 hours, the reaction mixture was cooled to room temperature, solids were removed by filtration and washed with dichloromethane. The combined filtrates were concentrated in vacuo, dissolved in ethyl acetate and washed with water and saturated salt solution, dried over sodium sulfate, evaporated to dryness and purified by chromatography on silica gel using mixtures of dichloromethane/methanol=100/0 (V/V)=>98/2 (V/V). Yield 338 mg

Mass spectrum ESI: [M+H]+=235,2.

TCX: Rf=0,95, silica gel, dichloromethane/methanol=95/5 (V/V).

(b) Ethyl-5-amino-2-methylthio-4-(3-n-octyloxyphenyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-n-octyloxybenzoate (338 mg) and ethylcyanoacrylate (112 μl), processing product POCl3 and the subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods, described in example 1. Net specified in the title compound was obtained after chromatography on silica gel using mixtures of dichloromethane/methanol=100/0 (V/V)=>90/10 (V/V) as eluent. Output 12 mg.

Mass spectrum ESI: [M+H]+=474,2.

TLC: Rf=0,65, silica gel, dichloromethane.

Example 80

Ethyl-5-amino-4-(3-[N-benzoylamino]phenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (278 mg), 3-(2-N-benzoylamino)benzaldehyde (538 mg, synthesized from 3-hydroxybenzaldehyde (977 mg) and N-(2-chloroethyl)benzamide (1.47 g) using the method described in example 79A) and ethylcyanoacrylate (224 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Net specified in the title compound was obtained after chromatography on silica gel using mixtures of dichloromethane/etelaat=100/0 (V/V)=>80/20 (V/V) as eluent. The output of 3.9 mg

Mass spectrum ESI: [M+H]+=509,2.

TLC: Rf=0,68, silica gel, dichloromethane/methanol=95/5 (V/V).

Example 81

Ethyl-5-amino-4-(3-{2-[5-methyl-2-phenylimidazol-4-yl]ethoxy}phenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

(a) 4-Hydroxymethyl-5-|methyl-2-phenylimidazol·Hcl

2,3-Butandione (30 ml) and a solution of sodium acetate (33 g) in water (80 ml) to relax is whether the solution of benzamidine· HCl (66 g) in water (300 ml) at 0°C. After 1.5 hours, the solids were filtered off, washed with water and heated in 4 BC Hcl (750 ml). The obtained clear solution was cooled in an ice bath.

The crystals were filtered off, washed with water and dried over potassium hydroxide at 50°C. Exit 44, TPL 164-166°C.

(b) 4-Chloromethyl-5-methyl-2-phenylimidazol·Hcl

A solution of thionyl chloride (100 ml) in benzene (100 ml) was slowly added to a stirred suspension of 4-hydroxymethyl-5-methyl-2-phenylimidazole·Hcl (44 g) in benzene (150 ml). After 2 hours, was added diethyl ether and the resulting solid substance was filtered off, washed with diethyl ether and dried in vacuum. Exit 60, TPL 200-205°C.

(c) 4-Cyanomethyl-5-methyl-2-phenylimidazol

A solution of 4-chloromethyl-5-methyl-2-phenylimidazole·Hcl (40,5 g) in dimethyl sulfoxide (400 ml) was added to a stirred solution of sodium cyanide (80 g) in dimethylsulfoxide (600 ml) over 30 minutes. After 20 hours, the solids were filtered off, washed with water and dried in vacuum. Exit 14, TPL 97-100°C.

(d) 4-Ethoxycarbonylmethyl-5-methyl-2-phenylimidazol

Hydrochloric acid in ethanol (35%, 150 ml) was added to 4-cyanomethyl-5-methyl-2-phenylimidazole (20.5 g) and was heated to the boiling temperature under reflux. After 1 hour the reaction mixture was poured into water (400 ml) was added NaOH (pH>8) with p the following extraction with dichloromethane (3 times). The combined organic layers were dried over sodium sulfate and evaporated to dryness in a vacuum. The output of 17.3, TPL 119-122°C.

(e) 4-Hydroxyethyl-5-methyl-2-phenylimidazol

A solution of 4-ethoxycarbonylmethyl-5-methyl-2-phenylimidazole (19 g) in tetrahydrofuran (100 ml) was added dropwise (over 45 min) to sociallyengaged (10 g) in tetrahydrofuran (150 ml). After 2 hours of boiling the reaction mixture was left overnight at room temperature. The mixture was cooled in an ice bath was added water (40 ml) and tetrahydrofuran (50 ml). The solids were filtered off and washed with diethyl ether. Exit 20, TPL 164-167°C.

(f) 4-Chloroethyl-5-methyl-2-phenylimidazol·Hcl

A solution of thionyl chloride (50 ml) in benzene (50 ml) was slowly added (1 hour) to a stirred suspension of 4-hydroxyethyl-5-methyl-2~phenylimidazole (20 g) in benzene (250 ml) at 70°C. After 1.5 hours the reaction mixture was concentrated in vacuo, dissolved in water (500 ml) and washed with diethyl ether. Brought the pH to >8 ammonia and the mixture was extracted with diethyl ether (2 times). The combined organic layers were dried over sodium sulfate and evaporated in vacuum. The resulting oil was dissolved in ethanol. Added hydrochloric acid in ethanol (35%, 2 ml) and diethyl ether, the solid was collected by filtration and recrystallized from ethanol. The output of 7.5, TPL 188-190°C.

(g) Ethyl-5-amino-4-(3-{2-[5-methyl-2-phenylimidazol-4-yl]ethoxy}phenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (139 mg), 3-{2-[5-methyl-2-phenylimidazol-4-yl]ethoxy}benzaldehyde (496 mg, synthesized from 3-hydroxybenzaldehyde (489 mg) and 4-chloroethyl-5-methyl-2-phenylimidazole (1,03 g) using the method described in example 79A) and ethylcyanoacrylate (112 μl), processing product POCl3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Net specified in the title compound was obtained after chromatography on silica gel using mixtures of dichloromethane/ethyl acetate=100/0 (V/V)=>70/30 (V/V) as eluent. The output of 9.2 mg

Mass spectrum ESI: [M+H]+=546,2.

TLC: Rf=0,43, silica gel, dichloromethane/methanol=95/5 (V/V).

Example 82

Ethyl-5-amino-2-methylthio-4-(3-[2-N-morpholinoethoxy]phenyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (209 mg), 3-(2-N-morfolinoetilrutin (705 mg, synthesized from 3-hydroxybenzaldehyde (1,17 g) and N-(2-chloroethyl)of the research (1.44 g) using the method described in example 79A) and ethylcyanoacrylate (168 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with methods described in the note is re 1. The output of 35.2 mg

Mass spectrum ESI: [M+H]+=475,2.

TLC: Rf=0,55, silica gel, dichloromethane/methanol=95/5 (V/V).

Example 83

Ethyl-5-amino-4-(3-[2-chloroethoxy]phenyl)-2-methylthieno[2,3-d] pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (209 mg), 3-(2-hydroxyethoxy)benzaldehyde (499 mg) and ethylcyanoacrylate (168 μl), processing product POCl3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Net specified in the title compound was obtained after chromatography on silica gel using dichloromethane as eluent. The output of 1.7 mg

Mass spectrum ESI: [M+H]+=424,0.

TLC: Rf=0,45, silica gel, dichloromethane.

Example 84

Ethyl-5-amino-2-methylthio-4-(3-[2-{ethoxycarbonylmethyl}ethoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxylate

The cyclization of sulfate S-methylisothiazoline (209 mg), 3-(2-hydroxyethoxy)benzaldehyde (499 mg) and ethylcyanoacrylate (168 μl), processing product l3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Net specified in the title compound was obtained after chromatography on silica gel using dichloromethane as eluent. The output of 2.8 mg

Mass spectrum ESI: [M+H]+=508,2.

TLC: Rf=0,14, silica gel, is harmatan.

Example 85

Ethyl-5-hydroxy-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

a) 5-Ethoxycarbonyl-2-methylthio-4-phenyl-4,5-dihydro-6-oxopyrimidine

A mixture of sulfate S-methylisothiazoline (418 mg), benzaldehyde (320 μl), diethylmalonate (478 μl) and potassium carbonate (435 mg) in absolute ethanol (5 ml) was stirred at 50°C for 4 hours, the reaction mixture is evaporated to dryness, the residue was dissolved in ethyl acetate and washed with 0.5 G. hydrochloric acid, water, 5%sodium bicarbonate, water and saturated salt solution, dried over sodium sulfate and evaporated to dryness. The output 546 mg

Mass spectrum ESI: [M+H]+=293,2.

TLC: Rf=0,63, silica gel, dichloromethane/methanol=95/5 (V/V).

(b) 5-Ethoxycarbonyl-2-methylthio-4-phenyl-6-oxopyrimidine

A mixture of 5-ethoxycarbonyl-2-methylthio-4-phenyl-4,5-dihydro-6-oxopyrimidine (273 mg) and 2,S-dichloro-5,6-dicyano-1,4-benzoquinone (200 mg) in isopropanol (5 ml) was stirred for 16 hours. The reaction mixture is evaporated to dryness, the residue was dissolved in dichloromethane and stirred with 5%sodium thiosulfate for 5 minutes. The organic layer is washed with 5%sodium bicarbonate and water (2x), dried over sodium sulfate and evaporated to dryness. Net specified in the title compound was beaming after chromatography on silica gel using mixtures of dichloromethane/methanol 98/2 (V/V) as eluent is. Yield 63 mg

Mass spectrum ESI: [M+H]+=291,2.

TLC: Rf=0,50, silica gel, dichloromethane/methanol=95/5 (V/V).

(C) Ethyl-5-hydroxy-2-methylthio-4-phenylthieno[2,3-d]pyrimidine-6-carboxylate

Processing 5-ethoxycarbonyl-2-methylthio-4-phenyl-6-oxopyrimidine (63 mg) and l3(304 μl) and the subsequent interaction of the product with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Net mentioned in the title compound was obtained after chromatography on silica gel using a mixture of heptane/ethyl acetate 100/0=>60/40 (V/V) as eluent. Yield 48 mg

Mass spectrum ESI: [M+H]+=347,2.

TLC: Rf=0,72, silica gel, dichloromethane.

Example 86

Ethyl-3-amino-4,6-diphenylethane[2,3-b]pyridine-2-carboxylate

Aldorino condensation of acetophenone (2,33 ml) and benzaldehyde (2,24 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with methods described in Pharmazie, 44:639-640 (1989). Exit 65 mg.

Mass spectrum ESI: [M+H]+=375,0.

TLC: Rfor =0.6, silica gel, dichloromethane.

Example 87

Ethyl-3-amino-6-naphthyl-4-phenylthieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of 2-acetonaphthone (1.70 g) and benzaldehyde (1,12 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and then Simocatta with ethyl-2-CHLOROACETATE was carried out in accordance with the methods, described in example 86. The output of 1.05,

Mass spectrum ESI: [M+H]+=425,2.

TLC: Rf=0.75, silica gel, dichloromethane.

Example 88

Ethyl-3-amino-4-phenyl-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of 2-acetylthiophene (1.08 ml) and benzaldehyde (1,12 ml), the cyclization α,β-unsaturated ketone-2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described in example 86. The output of 767 mg

Mass spectrum ESI: [M+H]+=381,2.

TLC: Rf=0,70, silica gel, dichloromethane.

Example 89

Ethyl-3-amino-6-naphthyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of 2-acetonaphthone (1.70 g) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described in example 86. Output 1,58,

Mass spectrum ESI: [M+H]+=431,2.

TLC: Rf=0.75, silica gel, dichloromethane.

Example 90

Ethyl-3-amino-6-phenyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of acetophenone (1,17 ml) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described is example 86. Output 1,04,

Mass spectrum ESI: [M+H]+=381,2.

TLC: Rf=0,70, silica gel, dichloromethane.

Example 91

Ethyl-3-amino-6-(2-furyl)-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of 2-furaldehyde (1.01 g) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described in example 86. Exit 443 mg

Mass spectrum ESI: [M+H]+=371,2.

TLC: Rf=0,55, silica gel, dichloromethane.

Example 92

Ethyl-3-amino-4,6-di(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of 2-acetylthiophene (1.08 ml) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described in example 86. Output 1,04,

Mass spectrum ESI: [M+H]+=387,0.

TLC: Rf=0,76, silica gel, dichloromethane.

Example 93

Ethyl-3-amino-4-(3-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-carboxylate

Aldorino condensation of acetophenone (1,17 ml) and 3-methoxybenzaldehyde (1,4 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with ethyl-2-CHLOROACETATE was carried out in accordance with the methods described in example 6. The output 164 mg.

Mass spectrum ESI: [M+H]+=405,2.

TLC: Rf=0,65, silica gel, dichloromethane.

Example 94

3-Amino-2-benzoyl-4,6-diphenylethane[2,3-b]pyridine

Aldorino condensation of acetophenone (2,33 ml) and benzaldehyde (2,24 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Yield 57 mg

Mass spectrum ESI: [M+H]+=407,4.

TLC: Rf=0,65, silica gel, dichloromethane.

Example 95

3-Amino-2-benzoyl-6-naphthyl-4-phenylthieno[2,3-b]pyridine

Aldorino condensation of 2-acetonaphthone (1.70 g) and benzaldehyde (1,12 ml), cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Output 50 mg

Mass spectrum ESI: [M+H]+=457,2.

TLC: Rf=0,69, silica gel, dichloromethane.

Example 96

3-Amino-2-benzoyl-4-phenyl-6-(2-thienyl)thieno[2,3-b]pyridine

Aldorino condensation of 2-acetylthiophene (1.08 ml) and benzaldehyde (1,12 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone someshwara in accordance with the methods described in example 86. Yield 57 mg

Mass spectrum ESI: [M+H]+=413,2.

TLC: Rf=0,69, Seeley is aqel, dichloromethane.

Example 97

3-Amino-2-benzoyl-6-naphthyl-4-(2-thienyl)thieno[2,3-b]pyridine

Aldorino condensation of 2-acetonaphthone (1.70 g) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Exit 66 mg.

Mass spectrum ESI: [M+H]+=463,0.

TLC: Rf=0,67, silica gel, dichloromethane.

Example 98

3-Amino-2-benzoyl-6-phenyl-4-(2-thienyl)thieno[2,3-b]pyridine

Aldorino condensation of acetophenone (1,17 ml) and 2-thiophenecarboxaldehyde 1(of 1.03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Yield 67 mg

Mass spectrum ESI: [M+H]+=413,2.

TLC: Rf=0,71, silica gel, dichloromethane.

Example 99

3-Amino-2-benzoyl-6-(2-furyl)-4-(2-thienyl)thieno[2,3-b]pyridine

Aldorino condensation of 2-acetylfuran (1.01 g) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Exit 65 mg.

Mass spectrum ESI: [M+H]+=403,2.

TLC: Rf=0,65, silica gel, dichloromethane.

Example 100

3-Amino-2-benzoyl-4,6-di(2-thienyl)thieno[2,3-b]pyridine

Aldorino condensation of 2-acetylthiophene (1.08 ml) and 2-thiophenecarboxaldehyde (1,03 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Yield 67 mg

Mass spectrum ESI: [M+H]+=419,0.

TLC: Rf=0,57, silica gel, dichloromethane.

Example 101

3-Amino-2-benzoyl-4-(3-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine

Aldorino condensation of acetophenone (1,17 ml) and 3-methoxybenzaldehyde (1,4 ml), the cyclization α,β-unsaturated ketone with 2-cyanothioacetamide and subsequent interaction with 2-chloracetophenone carried out in accordance with the methods described in example 86. Yield 31 mg

Mass spectrum ESI: [M+H]+=437,2.

TLC: Rf=0,57, silica gel, dichloromethane.

Example 102

Isopropyl-3-amino-4,6-diphenylethane[2,3-b]pyridine-2-carboxamide

(a) 3-Amino-4,6-diphenylethane[2,3-b]pyridine-2-carboxylic acid

The lithium hydroxide (59 mg) was added to a stirred solution of 53 mg of ethyl-3-amino-4,2-diphenylethane[2,3-b]pyridine-2-carboxylate (see example 86) in a mixture of dioxane/water=9/1 (V/V) and the mixture was heated at 80°C for 72 hours. The reaction mixture was cooled to room temperature and acidified to pH 2. The crystals were collected by filtration and dried in the Aquum. Exit 33 mg.

Mass spectrum (ESI, [M+H]+=47,2.

TLC: Rf=0,05, silica gel, dichloromethane/methanol=97/3 (V/V).

(b) Isopropyl-3-amino-4,6-diphenylethane[2,3-b]pyridine-2-carboxamide

To a stirred solution of 3-amino-4,6-diphenylethane[2,3-b]pyridine-2-carboxylic kislota (33 mg) in dichloromethane was added N,N-diisopropylethylamine (36 ml), Isopropylamine (12 μl) and tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethylurea (33 mg). After 16 hours the solvent is evaporated and the residue was chromatographically on silica gel using dichloromethane as eluent. Yield 21 mg

Mass spectrum ESI: [M+H]+=388,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 103

Isopropyl-3-amino-6-naphthyl-4-phenylthieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-6-naphthyl-4-phenylthieno[2,3-b]pyridine-2-carboxylate (see example 87) is first hydrolyzed to the corresponding acid (50 mg) followed by interaction with Isopropylamine (16 μl) to obtain the corresponding amide using the methods described in example 102. Exit 17 mg.

Mass spectrum ESI: [M+H]+=438,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 104

Isopropyl-3-amino-4-phenyl-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-4-phenyl-6-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate (see example 88) is first hydrolyzed to correspond to the th acid (50 mg) followed by interaction with Isopropylamine (18 μl) to obtain the corresponding amide, using the methods described in example 102. Output 6 mg.

Mass spectrum ESI: [M+H]+=394,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 105

Isopropyl-3-amino-6-naphthyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-6-naphthyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate (see example 89) is first hydrolyzed to the corresponding acid (50 mg) followed by interaction with Isopropylamine (16 μl) to obtain the corresponding amide using the methods described in example 102. Output 16 mg.

Mass spectrum ESI: [M+H]+=444,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 106

Isopropyl-3-amino-6-phenyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-6-phenyl-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate (see example 90) is first hydrolyzed to the corresponding acid (50 mg) followed by interaction with Isopropylamine (18 μl) to obtain the corresponding amide using the methods described in example 102.

Output 16 mg.

Mass spectrum ESI: [M+H]+=394,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 107

Isopropyl-3-amino-6-(2-furyl)-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-6-(2-furyl)-4-(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate (see example 91) is first hydrolyzed to the corresponding acid (50 mg) to follow what their interaction with Isopropylamine (18 μl) to obtain the corresponding amide, using the methods described in example 102. Exit 7 mg.

Mass spectrum ESI: [M+H]+=384,0.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 108

Isopropyl-3-amino-4,6-di(2-thienyl)thieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-4,6-di(2-thienyl)thieno[2,3-b]pyridine-2-carboxylate (see example 92) is first hydrolyzed to the corresponding acid (50 mg) followed by interaction with Isopropylamine (18 μl) to obtain the corresponding amide using the methods described in example 102. Yield 35 mg

Mass spectrum ESI: [M+H]+=400,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 109

Isopropyl-3-amino-4-(3-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-carboxamide

Ethyl-3-amino-4-(-methoxyphenyl)-6-phenylthieno[2,3-b]pyridine-2-carboxylate (see example 93) is first hydrolyzed to the corresponding acid (50 mg)was then subjected to interaction with Isopropylamine (17 μl) to obtain the corresponding amide using the methods described in example 102. Yield 28 mg

Mass spectrum ESI: [M+H]+=418,2.

TLC: Rfor =0.6, silica gel, dichloromethane/methanol=97/3 (V/V).

Example 110

tert-Butyl 3-amino-6-methylthio-4-(3-methoxyphenyl)thieno[2,3-b] pyridine-2-carboxamide

(a) 1.1-Dicyano-2-methyl-2-(3-methoxyphenyl)Aten

A solution of 3-methoxyacetophenone (of 3.46 g) and malonic acid nitrile (6,89 ml) in benzene (40 ml) of relatively Asón (2.30 ml) and ammonium acetate (1.50 g) and the reaction mixture was heated at the azeotropic distillation using nozzles Dean-stark.

After 5 hours the reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water and saturated salt solution, dried (MgSO4) and concentrated in vacuum. The residue was purified flash chromatography on silica gel using a mixture of EtOAc/heptane=3/7 (V/V) as eluent. The output of 6.4,

Mass spectrum ESI: [M+H]+=199,2.

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

(b) 1,1-Di(methylthio)-3-(3-methoxyphenyl)-4,4-dicyanobutane

1,1-Dicyano-2-methyl-2-(3-methoxyphenyl)Atan (example 110A, 6.4 g), carbon disulfide (3,85 ml) and methyliodide (9,9 ml) was added to the previously obtained a suspension of sodium hydride (60% dispersion in mineral oil, 1,60 g) in DMF (200 ml). After 7 hours the reaction mixture was concentrated under reduced pressure, re-dissolved in EtOAc, washed with water and saturated salt solution, dried (MgSO4) and concentrated in vacuum. The residue was purified by chromatography on silica gel (eluent: EtOAc/heptane=3/7 (V/V). Output to 3.92,

Mass spectrum ESI: [M+H]+=303,1.

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

(C) 2-Methylthio-4-(3-methoxyphenyl)-5-cyano-6-he

A solution of 1,1-di(methylthio)-3-(3-methoxyphenyl)-4,4-dicyanobutane (example 110b, to 3.92 g) in EtOH (50 ml) was treated with 48% aq. NVG (39 ml) and the solution was heated at the boiling point under reflux for 3 hours. After ohla the tion of the reaction mixture in an ice bath (0° (C) the precipitate was filtered, washed with water and dried in vacuum. The output of 2.4,

Mass spectrum ESI: [M+H]+=273,2.

TLC: Rf=0,47, silica gel, CH2Cl2/MeOH=9/1 (V/V).

(d) tert-Butyl 3-amino-6-methylthio-4-(3-methoxyphenyl)thieno[2,3-b]pyridine-2-carboxamide

The processing of 2-methylthio-4-(3-methoxyphenyl)-5-cyano-6-she (2.4 g, example 110S) POl3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Derived - ethyl-3-amino-4-(3-methoxyphenyl)-6-methylthieno[2,3-d]pyrimidine-2-carboxylate (2.6 g) is first hydrolyzed to the corresponding acid (2.2 g) using the method described in example 34, and then was subjected to interaction with tert-butylamine (2 ml)to give the corresponding amide in accordance with example 50. 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 2,11,

Mass spectrum ESI: [M+H]+=402,3.

TLC: Rf=0,37, silica gel, heptane/EtOAc=3/2 (V/V).

Example 111

tert-Butyl 5-amino-2-methylthio-4-(N-benzoyl-Z-AMINOPHENYL)thieno[2,3-d]-pyrimidine-6-carboxamide

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

The cyclization of sulfate S-methylisothiazoline (700 mg), 3-nitrobenzaldehyde (750 mg) and ethylcyanoacrylate (560 μl), education is otcu product l 3and subsequent interaction with ethyl-2-mercaptoacetate carried out in accordance with the methods described in example 1. Purified specified in the title compound was obtained after chromatography on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent. Exit 780 mg.

Mass spectrum ESI: [M+H]+=391,3.

TLC: Rf=0,35, silica gel, heptane/EtOAc=3/2 (V/V).

(b) 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 111a, 780 mg) was dissolved in 10 ml of dioxane. Then added 10 ml of EtOH 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 10 ml of 4 M NaOH, dried (MgSO4) and concentrated under reduced pressure. Ethyl ester 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 34, followed by interaction with tert-butylamine (200 μl) for formation of the corresponding tert-butylamide (in accordance with example 50). Specified in the title compound was purified by chromatography on silica gel using a mixture of HepB is an/EtOAc=3/1 (V/V) as eluent. Yield 391 mg

Mass spectrum ESI: [M+H]+=388,0.

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

(C) tert-Butyl 5-amino-2-methylthio-4-(N-benzoyl-3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide

tert-Butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 111b, 391 mg) was dissolved in 10 ml of CH2Cl2. Then was added N,N-diisopropylethylamine (600 μl) and benzoyl chloride (210 mg) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with CH2Cl2(50 ml) and washed with saturated aqueous NaHCO3. 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=3/1 (V/V) as eluent. Exit 348 mg.

Mass spectrum ESI: [M+H]+=492,1.

TLC: Rf=0,50, silica gel, heptane/EtOAc=3/2 (V/V).

Example 112

tert-Butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-4-(3-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate (see example 1, 400 mg) is first hydrolyzed to the corresponding acid (340 mg) using the method described in example 34, followed by interaction with tert-butylamine (150 μl)to give the corresponding amide in accordance with example 50. Specified in the header of the connection behaviour is whether chromatography on silica gel using a mixture of heptane/EtOAc=3/1 (V/V) as eluent. The output of 310 mg.

Mass spectrum ESI: [M+H]+=403,0.

TLC: Rf=0,32, silica gel, heptane/EtOAc=3/2 (V/V).

Example 113

N-Methyl-N-isopropyl-5-amino-2-methylthio-4-(3-methoxyphenyl)thieno [2,3-d]pyrimidine-6-carboxamide

Ethyl-5-amino-4-(3-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate (see example 1) is first hydrolyzed to the corresponding acid (340 mg) using the method described in example 34, and then subjected to the interaction with N-methyl-N-Isopropylamine (150 μl)to give the corresponding amide in accordance with example 50. Specified in the title compound was purified by chromatography on silica gel using a mixture of heptane/EtOAc=3/1 (V/V) as eluent. Exit 271 mg

Mass spectrum ESI: [M+H]+=404,0.

TLC: Rf=0,34, silica gel, heptane/EtOAc=3/2 (V/V).

Example 114

tert-Butyl 5-amino-2-ethoxy-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide

tert-Butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide (see example 112, 1.1 g) was dissolved in triperoxonane acid (20 ml) was added 3-chloroperbenzoic acid (msrwa, of 1.23 g). After stirring for 2 hours the reaction mixture was concentrated in vacuo, re-dissolved in CH2Cl2(50 ml), washed with saturated aqueous NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The residue containing relevant is the overall 2-methylsulfoxide, then was dissolved in EtOH (10 ml) was added KO-t-Bu (1 g). After heating at the boiling point under reflux overnight the reaction mixture was acidified using 1 M Hcl, concentrated in vacuo, re-dissolved in CH2Cl2(50 ml), washed with saturated aqueous Panso3, dried (MgSO4) and concentrated under reduced pressure. Purification of the thus obtained oil was performed by chromatography on silica gel using a mixture of heptane/EtOAc=3/1 (V/V) as eluent. Exit 356 mg.

Mass spectrum ESI: [M+H]+=401,6.

TLC: Rf=0,50, silica gel, heptane/EtOAc=3/2 (V/V).

Example 115

5-Amino-2-(2-thienyl)-4-(3-methoxyphenyl)-6-(N-morpholinoethyl)thieno[2,3-d]pyrimidine

Ethyl-5-amino-4-(3-methoxyphenyl)-2-(2-thienyl)thieno[2,3-d]pyrimidine-6-carboxylate (561 mg, see example 27) is first hydrolyzed to the corresponding acid (464 mg) using the method described in example 34, and then subjected to interaction with morpholine (300 μl)to give the corresponding amide in accordance with example 50. Specified in the title compound was chromatographically on silica gel using a mixture of heptane/EtOAc=3/2 (V/V) as eluent. Output 457 mg

Mass spectrum ESI: [M+H]+=453,2.

TLC: Rf=0,16, silica gel, heptane/EtOAc=3/2 (V/V).

Example 116

tert-Butyl 5-amino-2-methylthio-4-(N-(2-tert-butylamino)acetyl)-3-aminophen is)thieno[2,3-d]pyrimidine-6-carboxamide

tert-Butyl 5-amino-2-methylthio-4-(3-AMINOPHENYL)thieno[2,3-d]pyrimidine-6-carboxamide (example 111b, 195 mg) was dissolved in 5 ml of CH2Cl2. Then was added N,N-diisopropylethylamine (300 μl) and bromocatechol (120 mg) and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with CH2Cl2(20 ml) and washed with saturated aqueous Panso3. The organic layer was then treated with tert-butylamine (2 ml). After standing overnight, the reaction mixture was again washed with a saturated aqueous solution Panso3, dried (MgSO4) and concentrated in vacuum. Purification of the residue was carried out using chromatography on silica gel (eluent: CH2Cl2/MeOH=1/0 to 9/1 (V/V)). Exit 155 mg.

Mass spectrum ESI: [M+H]+=501,2.

TLC: Rf=0,64, silica gel, CH2Cl2/MeOH=9/1 (V/V).

Example 117

tert-Butyl 5-amino-2-methylthio-4-(3-(3-(3-pyridyl)propoxy)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide

tert-Butyl 5-amino-2-methylthio-4-(3-methoxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide (400 mg, example 112) was dissolved in cold (0°C) CH2Cl2(10 ml) and added dropwise VVG3(300 μl). After stirring over night at room temperature the reaction mixture was diluted with CH2Cl2(50 ml) and washed with saturated aqueous Panso3. The organic layer was dried (MgSO4and Kon who was interaval almost dry. The remaining oil was added dropwise into the flask with stir toluene (50 ml). Thus obtained residue (360 mg)containing tert-butyl-5-amino-2-methylthio-4-(3-hydroxyphenyl)thieno[2,3-d]pyrimidine-6-carboxamide was filtered and dried in vacuo, then dissolved in THF (10 ml) and added h3(600 mg), 3-(3-pyridyl)propanol (270 mg) and azodicarbonamide (ADDP, 600 mg). After stirring over night the reaction mixture was diluted with CH2Cl2(50 ml), washed with saturated aqueous Paso3, dried (MgS4) and was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH=1/0 to 95/5 (V/V)). Exit 271 mg

Mass spectrum ESI: [M+H]+=508,2.

TLC: Rf=0,56, silica gel, CH2Cl2/MeOH=96/4 (on/about).

Example 118

In vitro test for LH bioactivity in mouse Leydig cells

In male mice luteinizing hormone (LH) induces the production of testosterone in seed Leydig cells. This activity is also found related to the chorion gonadotropin person (KCG), which binds to the same target cell receptors and LH. In vitro analysis of Leydig cells (van Damme et al., 1974; modified Mannaerts et al., 1987) is used for determination of LH bioactivity of compounds that bind to LH receptors Leydig cells, which in turn causes the production of testosterone.

For this analysis, Leydig cells isolated from the testes (testicles) Mature, aged 9 to 13 weeks, mice (strain: HSD/Cpb: SE, Harlan, The Netherlands). Thus, mice are killed and the testes quickly removed and decapsulated. Each testis is transferred into separate wells of the tablet for tissue cultures containing 0.75 ml of culture medium per well. The contents of each well is passed through a 30 cm glass tube (internal diameter 2.5 mm, narrowed to 1.2 mm in 4 places in the middle). The resulting suspension is filtered through a 30 μm nylon mesh and the filtrate is pre-incubated in 50 ml plastic test tube for 30 minutes at 37°in the incubator in a saturated water atmosphere consisting of 95% air/5% CO2. After incubation the test tube is centrifuged at 1600 N/kg over 5 minutes and the supernatant (supernatant liquid decanted. The obtained precipitation from centrifugation, re-suspended in culture medium (0.5 mg source testis/ml and retain the homogeneity of the suspension with very slow stirring on a magnetic stirrer.

This suspension of Leydig cells (100 μl) is added to the wells microtitration tablet containing 50 ál of reference compounds, the compounds or media (culture medium) per well. As reference compounds using standard samples H or hCG, from calibrated relative to International reference preparations of LH or hCG person provided by the National Institute of Biological Standards and Controls (National Institute for Biological Standards and Controls (NIBSC, London, UK). The analyzed and reference compounds are dissolved, diluted and analyzed in the same culture medium. Tablets containing the reference and test compounds are incubated for 4 hours at 37°in the incubator in a saturated water atmosphere consisting of 95% air/5% CO2. After incubation tablets, sealed and stored at -20°to measure testosterone.

Before measuring testosterone content microtitration tablets thawed at room temperature and tablets centrifuged at 150 N/kg over 5 minutes. An aliquot of 30 μl of supernatant from each well diluted culture medium (60) to obtain a suitable dilution measurement of testosterone. Aliquots (12,5 µl) of each razvedennogo test sample is then analyzed using a set for neposredstvennogo measurement of testosterone RIA. The results are presented in the table.

Example 119

Analysis of the induction of ovulation in vivo for LH bioactivity in immature female mice

Females immature mice, which stimulated follicle-stimulating hormone (FSH), ovulation may be induced luteins is the dominant hormone (LH) or holonym homatropine human (hCG), which is associated with the same LH-receptor on the follicles of Graafian. The binding of LH-receptor initiates a biochemical cascade that eventually leads to rupture of the follicle and extrusion of Mature oocytes. To measure the in vivo activity of LH-agonistic compounds immature mice by the age of 20 days (B6D2F1 strain, Broekman Institute, the Netherlands) were the primary influence of FSH urine (Humegon; of 12.5 IU/l, 0.1 ml subcutaneously) to initiate folliculogenesis. Forty-eight hours after FSH treatment animals injected investigated the connection reference connection or media (10% solution of cremophor).

The compounds (50 mg/kg in 0.1 ml) and medium (0.1 ml) is injected r.o. (oral), reference compound (500 IU/kg of hCG in 0.1 ml) is injected in the form of injections s.c. (subcutaneously). As reference compounds using standard samples of hCG, calibrated relative to International reference preparations of hCG person provided by the National Institute of Biological Standards and Controls (National Institute for Biological Standards and Controls (NIBSC, London, UK). Twenty-four hours after administration of the compounds and reference compounds or carrier animals killed by the collapse of the neck. Both ovaries excised and collected in 0.9% NaCl. Then the fallopian tubes are placed between two glass plates and examined for presence or absence of okulirovannyh the eggs under the microscope. The number okulirovannyh oocytes present in the oviduct, is an indicator of in vivo LH bioactivity. The results are presented in the table.

1. Derived bicyclic heteroaromatic compounds of General formula I or its pharmaceutically acceptable salt

where

R1is R7;

R7is (6-10C)aryl, optionally substituted in the ortho and/or meta-position by a halogen atom; other8, OR8where R8mean (1-8C)alkyl which may be substituted by a halogen atom, (1-8C)alkylaryl, (1-8C)alkylcarboxylic, phenyl, (6-10C)arylcarboxamide, 5-methyl-2-phenylimidazol-4-yl, (6S)heterocyclization, in which 1-2 heteroatom selected from nitrogen and oxygen, ethoxycarbonylmethyl(1-4C)alkoxy, amino, (6-7C)heteroaryl;or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulfur;

R2is (1-8C)alkyl or (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy; or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulfur;

R3is (1-8C)alkyl, possibly substituted (6-14C)aryl, possibly substituted with halogen, (1-4C)alkoxy,(1-4C)alkoxycarbonyl, mono - Il is three(6-10C)cycloalkyl ,(6-10C)aryl,(5-6)heteroaryl containing as heteroatoms nitrogen, oxygen or sulfur; (5-7C)heterocyclization containing 2 heteroatoms selected from nitrogen or oxygen; (3-8C)cycloalkyl, (2-7C)heteroseksualci containing 2 heteroatoms selected from nitrogen or oxygen; or (6-10C)aryl,optionally substituted by one or more substituents selected from (1-8C)alkoxy;

X represents S or N(R4);

Y represents N;

R4is H, (1-8C)alkyl, phenyl(1-8C)alkyl;

or X is S and Y is CH;

Z represents NH2or HE;

A represents S, O or a bond;

In is N(H), O, or communication;

having agonistic activity against luteinizing hormone (LH), provided that the compound does not represent methyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d] pyrimidine-6-carboxylate, ethyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate or ethyl 5-amino-4-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate.

2. Derived compound according to claim 1 where X is S and/or Z presented AET NH 2having agonistic activity against luteinizing hormone (LH).

3. Derived compound according to claim 1 or 2, where X is S, Z is NH2and R1is (6-14C)aryl or (4-13C)heteroaryl having agonistic activity against luteinizing hormone (LH).

4. Derivative compounds according to claims 1-3, where a represents N or with agonistic activity against luteinizing hormone (LH).

5. The compound according to claims 1-4, where N is having agonistic activity against luteinizing hormone (LH).

6. The compound according to claims 1-5, where R3is isopropyl or tert-butyl, having agonistic activity against luteinizing hormone (LH).

7. The compound according to claims 1-6, where Y=N, with agonistic activity against luteinizing hormone (LH).

8. Derived bicyclic heteroaromatic compounds of General formula II or its pharmaceutically acceptable salt

where

R1is (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy, halogen, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulfur;

R2presented AET (1-8C)alkyl, (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy, or (5-6C)heteroaryl containing as heteroatoms nitrogen, oxygen or sulphur,

R3is (1-8C)alkyl, possibly substituted with halogen, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, mono - or three(6-10C)cycloalkyl, (6-10C)aryl, (5-6C)heteroaryl, (5-7C)heterocyclization containing as heteroatoms nitrogen, oxygen or sulfur; (3-8C)cycloalkyl, (2-7C)heteroseksualci or (6-10C)aryl, optionally substituted by one or more substituents selected from (1-8C)alkoxy;

In is N(H), O, or communication;

Y represents CH or N;

provided that the compound does not represent methyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, ethyl 5-amino-4-phenyl-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d] pyrimidine-6-carboxylate,

ethyl 5-amino-4-(4-methoxyphenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate, methyl 5-amino-4-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate or ethyl 5-amino-4-(4-chlorophenyl)-2-methylthieno[2,3-d]pyrimidine-6-carboxylate.

9. The derivative compound of claim 8, where In is N or O.

10. The compound of claim 8 or 9, where In is the N(N).

11. Connection PP-10, where R3represents isopropyl or tertbutyl.

12. Connection PP-11, where Y is N.

13. Connection PP-12, where R2represents (1-4C)alkyl.

14. Pharmaceutical composition having agonistic activity against luteinizing hormone (LH), including derived bicyclic heteroaromatic compounds according to claims 1-13, or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable additive.



 

Same patents:

The invention relates to compounds of the formula I

in which

R1, R2in each case, independently of one another represent H, A, HE, OA or Hal,

X is R4, R5or R6, monosubstituted R7,

R4is unbranched or branched alkylene with 1-10 atoms, in which one or two CH2groups can be substituted by a group-CH=CH-,

R5is cycloalkyl or cycloalkylation containing 5-12 With atoms

R6is phenyl or vinylmation,

R7is COOH, cooa, CONH2, CONHA, CON(A)2or CN,

And is alkyl having from 1 to 6 atoms

Hal represents F, Cl, Br or I,

where at least one of the radicals R1or R2HE is a,

and their pharmaceutically acceptable salts

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of thienopyrimidine formula (I) or its salts, which have a significant GnRH antagonistic activity and can be used for prophylaxis or treatment of hormone-dependent diseases

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new biologically active chemical substances of some heterocyclic compounds of formulas I-III

I R=COOH, X=H; II, R=COOK, X=H; III R=COOC2H5X=Cl,

showing property to activate the germination of wheat seeds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt

The invention relates to organic chemistry and can find application in medicine

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

The invention relates to organic chemistry and can find application in medicine

The invention relates to an improved process for the preparation of 5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole[4,3-d]pyrimidine-7-she formulas (I) and its pharmaceutically acceptable salts by the interaction of the compounds of formula (II), where R1and R2means hydrogen or R1means hydrogen and R2means methyl, with a mixture of formic acid and formaldehyde in the presence of tetrabutylammonium bromide, and the ratio of tetrabutylammonium bromide to the original compound is from 1:60 to 1:130, preferably 1:100

The invention relates to organic chemistry and agriculture

The invention relates to organic chemistry and agriculture

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

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