2-[(2-(phenylamino)-1h-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide derivatives as igf-ir inibitors for treating cancer

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

 

The text descriptions are given in facsimile form.

1. The compound of formula (I):

or its pharmaceutically acceptable salt, or MES, where
R1selected from N and C1-C3of alkyl;
R2selected from H, C1-C 3of alkyl, halogeno;
R3selected from H, HE, C1-C6the alkyl groups,- C1-C6alkylene-OH, -C1-C6alkylen-phenyl (possibly substituted, halogeno) and-C1-C6alkylen-C(O)NH2;
R4selected from N, halogeno, C1-C6the alkyl groups and-O-C1-C6alkyl; or
R3and R4together with the atoms to which they are attached, form a five - or six-membered lactam;
each of R5and R6independently selected from N, halogeno, C1-C6the alkyl groups and-O-C1-C6alkyl,
or
R5and R6together with the aryl to which they are attached, form a naphthalene;
R7selected from C1-C6the alkyl group-O-C1-C6alkyl, halogen, -N-R19R19and the group-O-C1-C6alkylen-halogeno1-3;
R8selected from N, halogeno and C1-C6of alkyl;
one of R9and R10selected from the groups-C1-C6alkylen-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O-C0-C6alkylen(possibly substituted by-OH)-NR22R23,
and;
and the other of R9and R10selected from H, C1-C6the alkyl group-O-C1-C6alkyl, halogeno;
where each of Het1 and Het2 are independently represents ATI - or six-membered heterocyclic ring, with the N atom and possibly one or two additional heteroatoms, selected from N and O, and
each R14independently selected from H, HE, halogeno, C1-C6the alkyl groups,- O-C1-C6alkyl, -C(O)-C1-C6alkyl, SO2-C1-C6alkyl, -(CH2)1-4-halogen and -(CH2)1-4-SO2-C1-C6alkyl;
or
R9and R10together with the atoms to which they are attached, form a five-, six - or semiline heterocyclic ring containing one or two N atom and the remaining atoms, where at least one N atom is substituted by an R15and the atoms of the heterocyclic ring may substituted by one or more groups selected from R16and (R19)1-2;
where R15selected from N, groups With1-C4alkyl, -C1-C4alkylen-halogen, -C(O)-C0-C6alkylene-NR22R23-C(O)-C1-C6alkyl, -C1-C4alkylene-NR22R23- 1-C4alkylen-C(O)-NR22R23-C(O)-C1-C4alkylen-O-C1-C6alkyl, -C(O)-pyrrolidin and-C(O)-pyrrolidin-C1-C6alkyl;
R16selected from h, =O; and
each R19independently selected from N and C1-C6of alkyl;
R22selected from H, C1-C6the alkyl groups,- O-C1-C6alkyl and-C1-C6alkylen-O-C1-C6alkyl; the
R23selected from N and C1-C6of alkyl; or
R22and R23combined with the formation of four-, five - or six-membered heterocyclic ring containing the N atom to which they are attached, and possibly additional heteroatom selected from N and O, where the ring may substituted-HE or-C1-C6the alkyl.

2. The compound according to claim 1, where R4, R5and R6each independently selected from H, halogeno.

3. The compound according to claim 1, where R3represents N.

4. The compound according to claim 1, where R3represents methyl.

5. The compound according to claim 1, where R7represents-O-C1-C6alkyl.

6. The compound according to claim 1, where R7represents-O-methyl.

7. The compound according to claim 1, where R8represents N.

8. The compound according to claim 1, where R10represents N, and R9selected from the groups-C1-C6alkylen-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O-C0-C6alkylen(possibly substituted by-OH)-NR22R23,
and.

9. The compound according to claim 1, where R10represents N, and R9selected from
,,,and.

10. With the unity according to claim 1, where R9and R10together with the atoms to which they are attached, form a five - or six-membered heterocyclic ring, selected from
,,,
,and.

11. The compound according to claim 1, having the formula (Ia):
,
where all substituents are as defined in claim 1.

12. The compound according to claim 1, where R14represents a C1-C6alkyl.

13. The compound according to claim 1, where R4represents fluorine, R5represents N, and
R6represents fluorine.

14. The compound of the formula

or its pharmaceutically acceptable salt, or MES.

15. The compound according to claim 1, having formula (Ib):
,
where all substituents are as defined in claim 1.

16. The connection indicated in paragraph 15, where R14represents a C1-C6alkyl.

17. The compound according to claim 1, where R4represents fluorine, R5represents N, and
R6represents N.

18. The compound of the formula

or its pharmaceutically acceptable salt, or MES.

19. The compound according to claim 1, having formula (Ic):
.
g is e, all substituents are as such as defined in claim 1.

20. The compound according to claim 1, where R15represents-C(O)-CH2-(CH3)(CH3).

21. The connection of claim 10, where R4represents fluorine, R5represents N, and R6represents N.

22. The compound of the formula

or its pharmaceutically acceptable salt, or MES.

23. The compound of the formula

in the form of a monohydrate.

24. The compound according to claim 1, having the formula (Id):
,
where all substituents are as defined in claim 1.

25. The connection point 24, where R15represents-C(O)-CH2-N(CH3)(CH3).

26. The connection point 24, where R4represents fluorine, R5represents N, and R6represents N.

27. The compound of the formula

or its pharmaceutically acceptable salt, or MES.

28. The compound according to claim 1, having the formula (Ie):
,
where all substituents are as defined in claim 1.

29. Connection p, where R15represents-C(O)-CH2-N(CH3)(CH3).

30. Connection p, where R4represents fluorine, R5represents N, and R6represents fluorine.

31. The compound of the formula

or its pharmaceutically acceptable salt, or MES.

32. Pharmaceutical composition having the properties of an inhibitor of receptor IGF-1R and IR, containing an effective amount of a compound according to any one of claims 1 to 31 and a pharmaceutically acceptable carrier, diluent or excipient.

33. A method of treating a proliferative disease mediated by the activity of IGF-1R receptor, comprising introducing a therapeutically effective amount of a compound according to any one of claims 1 to 31.

34. The method according to p, where the specified proliferative disease is selected from breast cancer, sarcomas, lung cancer, prostate cancer, colorectal cancer, kidney cancer, pancreatic cancer, cancer of the blood, for neuroblastoma, glioma, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cancer of the cheeks, oral cancer, gastrointestinal stromal tumors and skin cancer.

35. The compound according to any one of claims 1 to 31 for use in the treatment of condition mediated by IGF-1R.

36. The compound according to any one of claims 1 to 31 for use in the treatment of proliferative diseases, mediated by the activity of IGF-1R receptor.

37. Connection p, where the proliferative disease is selected and the breast cancer, sarcomas, lung cancer (including non-small cell carcinoma of the lung), prostate cancer, colorectal cancer, kidney cancer, pancreatic cancer, cancer blood disorders (including multiple myeloma), for neuroblastoma, glioma, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cancer of the cheeks, oral cancer, gastrointestinal stromal tumor and skin cancer (including melanoma).

38. The use of compounds according to any one of claims 1 to 31 for the manufacture of a medicinal product for the treatment of condition mediated by IGF-1R.

39. The use of compounds according to any one of claims 1 to 31 for the manufacture of a medicinal product for the treatment of proliferative diseases, mediated by the activity of IGF-1R receptor.

40. The application of § 39, where the proliferative disease is selected from breast cancer, sarcomas, lung cancer (including non-small cell carcinoma of the lung), prostate cancer, colorectal cancer, kidney cancer, pancreatic cancer, cancer blood disorders (including multiple myeloma), for neuroblastoma, glioma, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, cancer Yai is ka, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, cancer of the cheeks, oral cancer, gastrointestinal stromal tumor and skin cancer (including melanoma).

41. Pharmaceutical composition for use for the preparation of drugs for the treatment of proliferative diseases, mediated by the activity of IGF-1R receptor selected from breast cancer, sarcomas, lung cancer (including non-small cell carcinoma of the lung), prostate cancer, colorectal cancer, kidney cancer, pancreatic cancer, cancer blood disorders (including multiple myeloma), for neuroblastoma, glioma, head and neck cancer, thyroid cancer, hepatocarcinoma, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, stomach cancer, nasopharyngeal cancer, cancer of the cheeks, oral cancer, gastrointestinal stromal tumor and skin cancer (including melanoma), where the composition comprises a compound according to any one of claims 1 to 31 in an effective amount.



 

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3 cl, 3 ex, 6 tbl

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17 cl, 2 tbl, 91 ex

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10 cl, 24 ex

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10 cl, 18 ex

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42 cl, 36 dwg, 7 tbl

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27 cl, 30 dwg, 8 ex

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21 cl, 8 tbl

FIELD: medicine.

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12 cl, 7 tbl, 10 ex

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23 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

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1 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and may be applied in treating breast cancer. Breast is resected. Coletex-Mex textile tissue is applied for 4-7 days in 7-10 postoperative days on the postoperative scar and remained breast tissues, and changed 2 times a day. For the following 4-7 days, Coletex-D hydrogel tissue is applied and coated with Coletex-SMT textile tissue in the same regiment. The applications for 8-10 hours a day are combined with radiation teletherapy to SRD 20 Gy - 25 Gy. The radiation teletherapy is combined with the applications of Coletex gel DNA hydrogel coated with Coletex-Mex textile tissues from above changed twice a day. The radiation teletherapy is followed by the application of Coletex-SMT tissue and Coletex-Mex tissues changed every 12 hours to complete rehabilitation.

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1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and may be used in integrated treatment of stomach cancer. That is ensured by pre-operative blood sampling 300 ml followed by preparing autoplasma by centrifugation. All recovered autoplasma and chemopreparations are placed into a first flask; the remained blood corpuscles and chemopreparations are placed into a second flask. The flasks are separately incubated for 40 minutes at 37°C. A colonic surgery follows. The surgery begins with the drop-by-drop intravenous introduction of the incubated blood corpuscles and chemopreparations from the second flasks. Upon completion of the surgery, before closure of an abdominal wall, drain tubes are blocked; the abdominal cavity is processed with autoplasma and chemopreparations from the first flask, and autoplasma and chemopreparations are kept in the abdominal cavity. The abdominal wall is closed. Then 3 hours upon completion of the operation, the drain tubes are opened.

EFFECT: method enables reducing rate of peritoneal metastases caused by stomach cancer and increasing survival rate of the patients due to combined surgical and intraoperative intraperitoneal chemotherapy.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 2-substituted-2,3-dihydrooxazolo[3,2-a]pyrimidin-7-ones and 2-substituted-2,3,5,6-tetrahydrooxazolo[3,2-a]pyrimidin-7-ones of formula (I): where p, n, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are described in the description. These compounds are modulators of metabotropic glutamate receptors (mGluR), particularly the mGluR2 receptor. Compounds in the present invention are therefore suitable for use as pharmaceutical agents, especially in treating and(or) preventing various disorders of the central nervous system (CNS), including, among others, acute and chronic neurodegenerative disorders, psychosis, convulsions, anxiety, depression, migraine, pain, sleep disorder and emesis.

EFFECT: improved method.

14 cl, 148 ex

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