Derivatives of benzodiazepine, the method of production thereof, and pharmaceutical composition

 

(57) Abstract:

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, >by alkyl or halogen, or pyridylethyl; X is hydrogen or halogen in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt. 5 S. and 9 C.p. f-crystals, 2 tab.

The invention relates to a derivative of benzodiazepine, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-B, and to receive them.

Many benzodiazepine derivative described in the development of psychotropic drugs as antagonists "of the benzodiazepine receptor in the Central nervous system. Recently described derivatives of benzodiazepine, which act as antagonists against the receptor CCK-A (cholecystokinin-A) and CCK-B. it is also Reported that those compounds which are selective antagonists against the receptor CCK-B, can also in response to the introduction of pentagastrin to reduce the secretion of gastric acid (V. J. Lott, and R. S. L. Chang, Eur. J. Pharmacol, Vol. 162, pp. 273-280, 1989). Examples of benzodiazepine derivatives which act as antagonists at the receptor CCK-B are, for example, in U.S. patent 4820834.

Connection with nisterooy of the substituent in position 1 benzodiazepine nucleus. The present invention includes compounds with better pharmacological properties than the compounds described in U.S. patent 4820834; preferred compounds of the present invention have a greater affinity for the receptor CCK-B and/or more selectively affect the receptor CCK-B and CCK-A than the previously described connections.

In the present invention claimed is derived benzodiazepine of formula I or its pharmaceutically acceptable salt

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where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a is 0 or 1;

R4- C1-C7-alkyl straight or branched chain or C3-C8cycloalkyl;

R5- C1-8-alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-8-alkyl, C1-8-alkyl-C3-8-cycloalkyl, pyrrolidyl, possibly substituted C1-8-acyl, carbamoyl, C1-8-alkylamino-C1-8-alkyl, or adamantylidene;

R2is phenyl, substituted C1-8-alkyl, C1-8-alkoxyl, nitro, cyano, amino, halogen, C1-8-alkylaminocarbonyl, di(C1-8)alkylaminocarbonyl, carboxy, C1-8-allmineral, carboxin is is phenyl, unsubstituted or substituted C1-8-alkyl or halogen, or pyridylethyl;

X is hydrogen or halogen in the 7-position of the benzodiazepine ring.

Examples of alkyl or cycloalkyl groups include tertbutyl, cyclopentyl and cyclohexylmethyl.

For substituted R2it is preferable substitution in metabologia.

R2most preferable is a substituted phenyl; the phenyl-containing substituent in metaprogram selected from a fluorine atom, chlorine atom, bromine atom, metoxygroup, amino, dimethylaminopropyl, nitro group, methyl group, the group - (CH2)c-COOH, ceanography, methylaminopropyl, etilenovomu, diethylaminopropyl, or 2-, 3 - or 4-pyridium, optionally containing a Deputy selected from a methyl group.

R3most preferable is a phenyl or 2-, 3 - or 4-pyridium.

Compounds of the present invention all have at least one stereogenic center and, therefore, can exist as optical isomers. It should be understood that all such isomers, as an individual, as well as mixtures, are included in the scope of claims of the present invention. Next, coelicolor cases with bases. Examples of such salts include chlorides, sulfates and acetates or salts of sodium or potassium. It should be understood that these salts are also included in the scope of claims of the present invention. In the preferred compounds of the present invention atom in position 3 of the benzodiazepine ring has an absolute configuration R (as shown in the formula (IV)

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Compounds of the present invention are antagonists of the receptor CCK-B and gastrin receptor. They can be used as drugs for treatment of diseases caused by disorders in the physiological functions controlled gastrinom, such as gastric ulcer and duodenal ulcer, gastritis, esophageal reflux, gastric cancer and colon cancer, ulcerogenic adenoma of the pancreas; in the interaction with the receptor CCK-A may not be side effects. They can be used as drugs for treatment of diseases caused by disorders in the physiological functions controlled by the Central receptor CCK-B (in particular, to eliminate fear or regulation of appetite).

Preferred compounds of the present invention are the following soedinenie.

1. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 2);

2. N-((3RS)-1-Diethylaminocarbonylmethyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (example 3);

3. N-((3RS)-1-Cyclobutanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine - 3-yl)-N'-(3-were) urea (example 1);

4. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea (example 4);

5. N-((3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3 - yl)-N'-(3-were) urea (example 7);

6. N-((3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-were)urea (example 5);

7. N-((3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-chlorophenyl) urea (example 6);

8. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 14);

9. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5- (3-pyridyl)-1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 21);

10. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5- (4-pyridyl)-1H-1,4-benzodiazepine-3-yl) -N'-(3-main-3-yl) -N'-(3-carboxyphenyl)urea (example 16);

12. N-((3R)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 17);

13. N-((3S)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 18);

14. N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2R)-2 - pyrrolidinylcarbonyl) -1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (example 10);

15. N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2S)-2 - pyrrolidinylcarbonyl)-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 8);

16. N-((3RS)-1-((2R)-1-Acetyl-2-pyrrolidinylcarbonyl)- 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 11);

17. N-((3RS)-1-((2S)-1-Acetyl-2-pyrrolidinylcarbonyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 9);

18. N-((3RS)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 12);

19. N-((3RS)-1-((2SR)-2-Cyclopentyl-2-hydroxyethyl)-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 13);

20. N-((3RS)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 19);

21. N-((3RS)-1-((2S)-2-Cyclopentyl-2-hydroxyethylaminomethyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-cyanophenyl) urea (example 49);

23. N-((3RS)-1-tert-Butylcarbamoyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-cyanophenyl) urea (example 50);

24. N-((3RS)-1-Cyclopentanecarbonyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-carboxymethyl) urea (example 31);

25. N-((3RS)-1-(1-Substituted)carbonylmethyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 51);

26. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-pyridyl) urea (example 30);

27. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(6-methyl-2-pyridyl) urea (example 29);

28. N-((3RS)-1-(3-Cyclohexyl-3-methyl-2-oxobutyl)- 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 52);

29. N-((3RS)-1-Cyclohexyloxycarbonyloxy - 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 32);

30. N-((3RS)-1-Cyclopentanecarbonyl - 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 33);

31. N-((3RS)-1-((1-Methylcyclohexyl)carbonylmethyl)- 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 34);

32. N-((3RS)-1-((1-Methylcyclopentene)carbonylmethyl)- 2,3-dinletir - 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'- (3-carboxyphenyl) urea (example 23);

34. N-((3RS)-1-Cyclopentanecarbonyl - 2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'- (3-carboxyphenyl) urea (example 22);

35. N-((3R)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)- 2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - carboxyphenyl) urea (example 24);

36. N-((3R)-1-((2R)-2 - Cyclopentyl-2-hydroxyethyl)-2,3 - dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'-(3 - carboxyphenyl) urea (example 25);

37. N-((3RS)-1-Cyclopentanecarbonyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - carboxamidine) urea (example 35);

38. N-((3R)-1-tert-Butylcarbamoyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - were) urea (example 26);

39. N-((3RS)-1-tert-Butylcarbamoyl-2,3 - dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3 - were) urea (example 27);

40. N-((3RS)-1-tert-Butylcarbamoyl-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - carboxyphenyl) urea (example 28);

41. N-((3RS)-1-tert-Amicability-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - were) urea (example 36);

42. N-((3RS)-1-tert-Amicability-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3 - carboxyphenyl) urea (example 37);

43. N-((3RS)-1-tert-Butylcarbamoyl-2,3 - dihydro-2-ox is ylmethyl-2,3 - dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3 - carboxyphenyl) urea (example 39);

45. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea (example 40);

46. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea (example 41);

47. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl) urea (example 42);

48. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl) urea (example 43);

49. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl) urea (example 44);

50. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl) urea (example 45);

51. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-formylamino) urea (example 47);

52. N-((3R)-1-((2R)-2-Hydroxy-3,3-dimethylbutyl)- 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'- (3-were) urea (example 48);

53. N-((3R)-1-((2S)-2-Hydroxy-3,3-dimethylbutyl)- 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'- (3-were) urea;

54. N-((3RS)-1-(1-Methylcyclopropyl)carbonylmethyl - 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4 - 5-(2-chlorophenyl)-1H - 1,4-benzodiazepine-3-yl)-N'-(3-were) urea (example 54);

56. N-((3RS)-1-ISO-Propylmalonate-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea (example 55);

57. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol) urea (example 56);

58. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol) urea (example 57);

59. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl) urea (example 58);

60. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl) urea (example 59);

61. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea (example 60);

62. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N - methylamino)phenyl) urea (example 61);

63. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea (example 62);

64. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5- (2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl) urea (example 63);

65. N-((3R)-1-tert-R> 66. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(4-were)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea (example 65);

67. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL) urea (example 66);

68. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'- (3-were) urea;

69. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3 - AMINOPHENYL) urea;

70. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol) urea;

71. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea;

72. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL) urea;

73. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl) -N'-(3-methylaminophenol) urea;

74. N-((3RS)-1-tert-Butylcarbamoyl-7-chloro - 2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl) -N'- (3-were) urea (example 67);

75. N-((3RS)-1-tert-Butylcarbamoyl-7-chloro - 2,3-dihydro-2 - oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl) -N'-(3-dimethylaminophenyl) moin-3-yl)-N'- (3-were) urea (example 69);

77. N-((3RS)-1-tert-Butylcarbamoyl-2,3-digidrummer - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea (example 70);

78. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N - methylamino)phenyl) urea;

79. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-diethylaminophenyl) urea.

Compounds of the present invention can be obtained according to the methods specified in figure 1.

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Reagents:

(a) NaH, dimethylformamide;

(b) R7COCH2Br;

(c) hydrogen, Pd-C or HBr;

(d) R2NCO;

(e) sodium borohydride;

(R7means R4(CH2)aor R5(CH2)a).

If R3= Pd, the original compound (I) is a known compound (M. C. Bock et al., J. Org. Chem. Vol. 52, pp. 3232-3239, 1987). For other values of R3such as pyridyl, original compound (I) can be obtained similarly to the method described by Bock et al. For simplicity, in the specific examples below, the compound (I) (R3=Pd) is called benodiazepines Side.

At stage (i), the compound (I) deprotonized strong base (usually sodium hydride), and then enter Waco can be obtained from the available carboxylic acids or carboxylic acid anhydrides according to scheme 2.

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Reagents:

(f) chloride thionyl;

(g) diazomethane;

(h) hydrogen bromide.

Next, remove protection from alcaravan benzodiazepines (2) (scheme 1). Scheme 1 shows the case when the amino group is protected by a group Z (Z = benzyloxycarbonyl), which can be removed by catalytic hydrogenolysis or acid hydrolysis.

If you use a protective group other than Z, then the stage of removing the protection can be changed accordingly. Benzodiazepine once removed to protect, process arylisocyanate (R2NCO). If, for example, R2= 3-were, it directly leads to the compound (3) as defined above (e.g., compounds 1-10 and so on). If R2includes a protected functional group (in particular, carboxylic acid, protected in the form of ester), this group can be deleted and get one of the listed compounds. The ketone (3) can be restored, for example, sodium borohydride to obtain the corresponding alcohol (4) (in particular, the compounds 18-21 and so on).

In some cases it is preferable to obtain urea in an alternative way, as shown in figure 3.

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Reagents:

(j) p-nitrophenolate previously { 1, stage (i)}, but then it is exposed to p-nitrophenylphosphate and get p-nitrophenylarsonic (5). At stage (ii) the compound obtained is reacted with an amine R2NH2with the formation of urea (3). This path is especially useful in the case where the isocyanate R2NCO is not available, and Amin R2NH2available.

These common ways to further explain the specific does not limit the present invention by examples.

Example 1.

N-((3RS)-1-Cyclobutanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 3).

1A. Prometastatic (scheme 2, steps (i) - (iii)).

To a cooled with ice to a solution cyclobutanecarbonyl acid (1.5 g, 15 mmol) in diethyl ether (10 ml) is added N,N-di-isopropylaniline (2.9 ml, 16 mmol), and then chloride thionyl (1,24 ml, 16 mmol). The mixture is stirred at a temperature of 0oC for 45 minutes, poured into ice solution diazomethane (obtained from Diazald, 14.1 g, 66 mmol) in diethyl ether and the resulting mixture for 2 h, allowed to warm to room temperature. Added dropwise a saturated solution of hydrogen bromide in diethyl ether until then, until PfP solution of potassium bicarbonate, water and saturated salt solution, filtered (phase separator Whatman PS I) and evaporated in vacuo. The crude product is purified by distillation from a cube in a cube (100oC, 5 mm RT. Art.) and get the target ketone as a colourless mobile oil (1.13 g 44%).

Range PMR (chloroform-d): 3,86 (2H, singlet), of 3.57 (1H, quintet, J = 8.5 Hz), 2,5-2,2 (6H, multiplet), 2,2-1,8 (2H, multiplet).

1B. (3RS)-3-Benzyloxycarbonylamino-1-cyclobutanecarbonyl - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

To a stirred solution of (3RS)-3-benzyloxycarbonylamino - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-it (M. G. Bock et al. J. Org. Chem. Vol. 52, pp. 3232-3239, 1987) (578 mg, obtained from 605 mg of the monohydrate after three azeotrope distillation with dimethylformamide, 1.5 mmol) in dimethylformamide (5 ml), cooled to -10oC, in an atmosphere of nitrogen was added sodium hydride (63 mg, 80% dispersion in oil, 2.1 mmol). The mixture is stirred at a temperature of -10oC for 30 minutes, and then add a solution of promotility in example 1A (398 mg, 2.25 mmol) in DMF (2 ml). Under stirring for 1 h to give the mixture to warm to room temperature, poured into dilute hydrochloric acid (100 ml) and extracted once with ethyl acetate. Organicheskuyu in vacuum. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate : petroleum ether (with T. bales. 60-80oC) 40:60.about.) and get the target benzodiazepine in the form of a glassy solid (490 mg, 68%).

Rf(ethyl acetate:petroleum ether (with T. bales. 60-80oC) 50:50) of 0.54.

Range PMR (chloroform-d): 7,8-7,2 (14H, multiplet), 6,70 (1H, doublet, J = 8 Hz), vs. 5.47 (1H, doublet, J = 8 Hz), is 5.18 (2H, singlet), 4,69 (1H, doublet, J = 7.5 Hz), 4,60 (1H, doublet, J = 7.5 Hz), to 3.36 (1H, quintet, J = 8 Hz), 2,5-1,8 (6H, multiplet).

1C. N-((3RS)-1-Cyclobutanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

To obeskislorozhennaja solution of the benzodiazepine (example 1B (490 mg, of 1.02 mmol) in glacial acetic acid (25 ml) is added the catalyst (5% palladium on coal) (200 mg). Through the suspension flow of hydrogen for 4 h, and then stop the reaction, blowing with nitrogen. The mixture is filtered and the catalyst washed with methanol. The filters are combined and evaporated under vacuum, and then the traces of the solvent is removed in a joint process of evaporation with toluene. The residue is dissolved in methylene chloride (25 ml) and stirred at room temperature. To the resulting solution was added m-tol who participate thin-layer chromatography on silica gel (eluent - the ethyl acetate: petroleum ether (with T. bales. 60-80oC) 40:60.vol.). The obtained product is dissolved in acetic acid and subjected to freeze-drying, receiving targeted benzodiazepine in the form of a white powder (203 mg, 41%, purity 95%, according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 60-80oC) 35:65) to 0.12.

Range PMR (chloroform-d): of 7.82 (2H, doublet, J = 7 Hz), 7,8-7,2 (11H, multiplet), and 7.9 (1H, doublet, J = 8 Hz), 6,99 (1H, doublet, J = 7 Hz), of 5.83 (1H, doublet, J = 8 Hz), 4,78 (2H, singlet), 3,44 (1H, quintet, J = 8.5 Hz), 2,43 (3H, singlet), 2,4-and 1.9 (6H, multiplet).

Mass spectrum (FAB + ve ion): m/e 481,8 (M+H).

Example 2.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 1).

2A. tert-Butalbitalwellbutrin (scheme 2, steps (i) - (iii)).

To ice the solution diazomethane (obtained from Diazald, 10.4 g, 49 mmol) in diethyl ether add pivaloate (2 ml, 16 mol). Give the resulting solution with stirring and heated for 3 h to room temperature, and then add a saturated solution of hydrogen bromide in ethyl acetate prior to the termination of nitrogen excretion. Washed with saturated races is iznaga oil pale brown (3,47 g, the purity of 82%, according to PMR, contains the remains of ethyl acetate).

Range PMR (chloroform-d): to 4.15 (2H, singlet), of 1.20 (9H, singlet).

2B. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (578 mg, 1.5 mmol), sodium hydride (63 mg, 80% dispersion in oil, 2.1 mmol) and bromeilles in example 2A (491 mg, purity 82%, 2.25 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 60-80oC), 50:50./about.) and get substances (700 mg, 97%).

Rf(ethyl acetate:petroleum ether (with T. bales. 60-80oC) 50:50) of 0.56.

Range PMR (chloroform-d): 7,8-7,2 (14H, multiplet), 6,74 (1H, doublet, J = 8 Hz), of 5.53 (1H, doublet, J = 8 Hz), 5,23 (2H, singlet), of 5.05 (1H, doublet, J = 18 Hz), of 4.77 (1H, doublet, J = 18 Hz), of 1.33 (9H, singlet).

2C. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 2B (700 mg, 1,45 mmol), 5% palladium on coal (approximately 300 mg) and m-tolerization any ether (with T. bales. 60-80oC) 40:60.vol.), dissolved in acetic acid and subjected to freeze-drying, receiving targeted benzodiazepine in the form of a white powder (233 mg, 33%, purity > 97% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 60-80oC) 40:60) 0,31.

Range PMR (chloroform-d): 7,72 (2H, doublet, J = 8 Hz), 7,7-7,0 (12H, multiplet), 6,87 (1H, doublet, J = 7 Hz), 5,73 (1H, doublet, J = 8 Hz), to 4.92 (1H, doublet, J = 18 Hz), 4,82 (1H, doublet, J = 18 Hz), 2,32 (3H, singlet), of 1.26 (9H, singlet).

Mass spectrum (FAB +ve ion): m/e 483,2 (M+H).

Example 3.

N-((3RS)-1-Diethylaminocarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 2).

3A. Bromoethylamine (scheme 2, steps (i) - (iii)).

2-ethylmalonic acid (2,09 g, 18 mmol) at 0oC add chloride thionyl (5,2 ml 71,5 mmol), allow the mixture to warm to room temperature and stirred for 25 minutes. The mixture is diluted with dry tetrahydrofuran, and then evaporated in vacuum at room temperature, and then subjected to azeotropic distillation with tetrahydrofuran to remove the last traces of chloride tiomila. The oil obtained is dissolved in Sura, allow the mixture to warm to room temperature and stirred for 90 minutes. Quench the reaction by adding acetic acid (x 5), alkalinized (5% solution of potassium bicarbonate and extracted with ethyl acetate (x 3). The organic extracts are combined, washed with water, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated in vacuo. Crude oil is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 60-80oC) 5:95.about.) and get desmethylimipramine liquid pale yellow (261 mg, of 1.86 mmol). To a solution of this diazoketone in ethyl acetate (10 ml) at room temperature portions add a saturated solution of hydrogen bromide in acetic acid ethyl ester as long as you do not stop the release of nitrogen. The reaction mixture is alkalinized (5% solution of potassium bicarbonate and extracted with ethyl acetate (x 2). The organic extracts are combined, washed with water, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated in vacuo. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) from 4:96 to 10:90.about.) and get the target ketone in Matera, constituting 88,8%): 3,95 (2H, singlet), 1,56 of 1.46 (4H, multiplet), 2,75-to 2.65 (1H, multiplet), 0,91-of 0.85 (6H, multiplet).

3B. (3RS)-3-Benzyloxycarbonylamino-1-diethylaminocarbonylmethyl - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (356 mg, 0,925 mmol), sodium hydride (39 mg, 80% dispersion in oil, 1.3 mmol) and bromeilles in example 3A (268 mg, 1.4 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC) 25:85.about.) and get the target benzodiazepine as colorless liquid (351 mg).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.35.

Range PMR (chloroform-d): to 7.64-7,13 (14H, multiplet), to 6.67 (1H, doublet, J = of 8.25 Hz), 5,43 (1H, doublet, J = of 8.25 Hz), 5,27 (2H, singlet), of 5.15 (1H, doublet, J = 18 Hz), 4,78 (1H, doublet, J = 18 Hz), 2,45 to 2.35 (1H, multiplet), 1,76-of 1.42 (4H, multiplet), 0,90-of 0.85 (6H, multiplet).

3C. N-((3RS)-1-Diethylaminocarbonylmethyl-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 3B (351 mg, of 0.68 mmol), 5% is chromatography on silica gel (eluent - the ethyl acetate: petroleum ether (with T. bales. 40-60oC) 35:65./about.) and get the target compound as white powder (229 mg, 68%, purity > 99% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) to 0.24.

Range PMR (chloroform-d): 7,66-6,80 (15H, multiplet), to 5.66 (1H, doublet, J = 8 Hz), to 4.73 (1H, doublet, J = 18 Hz), with 4.64 (1H, doublet, J = 18 Hz), 2,49-2,31 (1H, multiplet), and 2.26 (3H, singlet), 1,71-of 1.39 (4H, multiplet), 0,86 is 0.81 (6H, multiplet).

Mass spectrum (FAB + ve ion): m/e 497,3 (M+H).

Example 4.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-were)urea (compound 4).

4A. Bromomethylbiphenyl (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone of cyclopentanecarbonyl acid (2,05 g, 18 mmol), chloride taanila (5,2 ml, 72 mmol) and diazomethane (generated from Diazald, 9 g, 42 mmol) and purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 60-80oC) 15:85.vol.). Diazoketone then treated with a saturated solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography NTON as rolling oil, light brown (1.29 g, 37%).

Range PMR (chloroform-d): 3,99 (2H, singlet), 3,18 (1H, Quartet, J = 8 Hz), 1,98-of 1.56 (8H, multiplet).

4B. (3RS)-3-Benzyloxycarbonylamino-1-cyclopentanecarbonyl-2,3-dihydro - 5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (578 mg, 1.5 mmol), sodium hydride (63 mg, 80% dispersion in oil, 2.1 mmol) and brummelchen from example 4A (431 mg, 2.25 mmol). The crude product is purified thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC) 30:70.about.) and get the target benzodiazepine as colorless crystalline substance (682 mg, 88.5 percent).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.25.

Range PMR (chloroform-d): to 7.64-7,17 (14H, multiplet), 6,60 (1H, doublet, J = of 8.25 Hz), 5,42 (1H, doublet, J = of 8.25 Hz), 5,14 (2H, singlet), 4,78 (1H, doublet, J = 17,8 Hz), 4,63 (1H, doublet, J = 17,8 Hz), 2,92 (1H, Quartet, J = 8 Hz), 1.85 to 1.55V (8H, multiplet).

4C. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-were)urea (scheme 2, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (680 mg, 1,32 mmol), 5%-is via on silica gel (eluent - the ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35:65./about.) and obtain the target compound (463 mg, 71%). It is recrystallized from methanol and receive 161,8 mg crystalline substance (purity > 99% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.16.

Range PMR (chloroform-d): 7,66-6,80 (15H, multiplet), the 5.65 (1H, doublet, J = 8 Hz), 4,74 (1H, doublet, J = 18 Hz), of 4.67 (1H, doublet, J = 18 Hz), 2,95 - and 2.83 (1H, multiplet), of 2.28 (3H, singlet), 1,90 - of 1.53 (6H, multiplet).

Mass spectrum (WOOF, +ve ion): m/e 495,2 (M+H).

Example 5.

N-(3RS)-1-Cyclohexylcarbonyl-2.3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 6).

5A. Bromoethylethylether (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from cycloheptanone acid (3 g, 21 mmol), chloride taanila (6,24 ml, 84 mmol) and diazomethane (generated from Diazald, 12 g, 56 mmol) and purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 60-80oC) 10:90.vol.). Diazoketone then treated with a saturated solution of HBR in these the oC) from 5:95 to 10:90.about.) get the target ketone in the form of a brown oil (1.8 g, by 8.22 mmol, 39%).

Range PMR (chloroform-d): 3,98 (2H, singlet), 2,95-to 2.85 (1H, multiplet), 1,98 of 1.50 (12H, multiplet).

5B. (3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonyl-2,3-dihydro-5 - phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (578 mg, 1.5 mmol), sodium hydride (63 mg, 80% dispersion in oil, 2.1 mmol) and bromeilles in example 5A (493 mg, 2.25 mmol). The reaction ends within 30 minutes.

The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-80oC) 40:60.about.) and get the target compound in the form of a colorless crystalline substance (764 mg, 93%).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.3.

Range PMR (chloroform-d): to 7.64-7,13 (14H, multiplet), only 6.64 (1H, doublet, J = of 8.25 Hz), 5,42 (1H, doublet, J = of 8.25 Hz), 5,14 (2H, singlet), 4,79 (1H, doublet, J = 17.5 Hz), 4,63 (1H, doublet, J = 17.5 Hz), 1,65 - to 2.65 (1H, multiplet), 1,93 of 1.28 (12H, multiplet).

5C. N-(3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-were) urea (n in example 5B (787 mg, 1.5 mmol), 5% palladium on coal (600 mg) and m-tallization (0.2 ml, was 1.58 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 30:70.about.) and get the target compound in the form of solid white (53,6 mg, 10%, purity > 98% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.27.

Mass spectrum (FAB +ve ion): m/e 523,3 (M+H).

Example 6.

N-((3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-chlorophenyl) urea (compound 7) (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 5B (764 mg, of 1.41 mmol), 5% palladium on coal (600 mg) and m-chloronicotinate (180 μl, 1.48 mmol). The crude product is purified by recrystallization from hot ethyl acetate and get the target compound in the form of a crystalline substance of white color (379 mg, 69,8%) (purity > 99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7.68 per-6,89 (15H, multiplet), 5,64 (1H, doublet, J = 8 Hz), 4,74 (1H, doublet, J = 18 Hz), of 4.66 (1H, doublet, J = 18 Hz), 2,60 - 2,52 (1H, multiplet), 1.92 oxycarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepin-3-yl)-N'- (3-were) urea (compound 5).

7A. Bromomethylhexene (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from cyclohexanecarbonyl acid (1.92 g, 15 mmol), chloride taanila (4,46 ml, 60 mmol) and diazomethane (generated from Diazald, 7,16 g, 33.4 mmol). Without cleaning diazoketone treated with a saturated solution of hydrogen bromide in ethyl acetate until the cessation of hydrogen evolution. After thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether, 5:95) to obtain the target compound in the form of a yellow oil) (0,91 g, 30%).

Range PMR (chloroform-d): 4,00 (2H, singlet), a 2.75 (1H, multiplet), 1,95-of 1.20 (10H, multiplet).

7B. (3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonyl-2,3 - dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using benzodiazepin Side (385 mg, 1.0 mmol), sodium hydride (42 mg, 80% dispersion in oil, 1.4 mmol) and pommerellen from example 7A (308 mg, 1.5 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC), 35:65./about.) and get the target compound in the form of colorless 0) 0,3.

Range PMR (chloroform-d): 7,8-7,2 (14H, multiplet), of 6.65 (1H, doublet, J=8,2 Hz), 5,42 (1H, doublet, J = 8,2 Hz), is 5.18 (2H, singlet), 4,72 (1H, doublet, J = 7.5 Hz), br4.61 (1H, doublet, J = 7.5 Hz), 2.40 a (1H, multiplet), 1,9 - 1,0 (10H, multiplet).

7C. N-((3RS)-1-Cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl) -N'-(3-were) urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 7B (480 mg, 0,945 mmol), 5% palladium on coal (about 400 mg) and m-tallization (0,130 ml, 1 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35:65./about.) and get the target benzodiazepine matter white (245 mg, 52%, purity > 98% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 40:60) of 0.32.

Range PMR (chloroform-d): 7,7 (2H, doublet, J = 8 Hz), 7,65-7,00 (12H, multiplet), to 6.88 (1H, doublet, J = 7 Hz), 5,62 (1H, doublet, J = 8 Hz), of 4.67 (2H, singlet), 2,39 (1H, multiplet), of 2.21 (3H, singlet), 1,9-0,8 (10H, multiplet).

Mass spectrum (FAB + ve ion): m/e 509 (M+H).

Example 8.

The hydrochloride of N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2S)-2-pyrrolidinylcarbonyl)-modeldescription (scheme 2, stage (i)-(iii)).

To a solution of Boc-L-Proline (5.5 g, 25.6 mmol) and N-methylmorpholine (3.1 ml, of 28.2 mmol) in dry THF (80 ml) at -20oC add isobutylparaben (3.5 ml, 27,1 mmol). The mixture is stirred at a temperature of 10oC for 1 h, and then poured into ice solution diazomethane (obtained from Diazald, 18 g, 84 mmol) in diethyl ether and give the mixture for 2 hours to warm to room temperature. Excess diazomethane decompose glacial acetic acid and the resulting solution was alkalinized with 5% aqueous solution of potassium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated salt solution, filtered (phase separator Whatman IPS) and evaporated in vacuo. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35: 65. /about. and get the target compound, which is immediately used in the next stage.

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 30:70) to 0.12.

8B. (2S)-1-tert-Butyloxycarbonyl-2-paralegalpipeline.com (scheme 2, step (iii)).

To a stirred solution of diazoketone from example 8A in ethyl acetate are added dropwise to the PR

promotility sequentially washed with a saturated solution of potassium bicarbonate, water and saturated salt solution, filtered (phase separator Whatman IPS) and evaporated in vacuo. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 15:85.about.) and get the target ketone in the form of a brown oil (1.25 g, 17% in two stages).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 20:80) of 0.2.

Range PMR (chloroform-d): 4,66 figure-4.49 (1H, broad multiplet), 4,1-4,0 (2H, broad multiplet), to 3.73-to 3.50 (2H, broad multiplet), 2,40-to 1.67 (4H, multiplet), of 1.46 and 1.44 (9H, singlets).

8C. (3RS)-3-Benzyloxycarbonylamino-1-((2S)-tert-butyloxycarbonyl-2 - pyrrolidinylcarbonyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine - 2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (1.2 g, of 2.97 mmol), sodium hydride (125 mg, 80% dispersion in oil, 4.2 mmol) and bromeilles in example 8B (1,25 g of 4.46 mmol).

The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC) 35:65./about.) and obtain the target compound (798 mg, 45%).

2 (1H, multiplet), with 4.64 - and 4.40 (1H, multiplet), to 4.38 - to 4.28 (1H, multiplet), 3,60-3,44 (2H, multiplet), 2,23 - to 1.82 (4H, multiplet), of 1.44 (9H, singlet).

8D. N-(3RS)-1-((2S)-tert-Butyloxycarbonyl-2-pyrrolidinylcarbonyl)-2,3-dihydro - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'- (3-were)-urea (scheme 1, step (iii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 8C (798 mg, of 1.33 mmol), 5% palladium on coal (about 600 mg) and m-tallization (180 μl, 1.4 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35:65./about.) and get the target compound as a colourless oil (559 kg, 71,1%).

Range PMR (chloroform-d): the 7.65 for 6.81 (15H, multiplet), to 5.66 (1H, doublet, J = 9 Hz), equal to 4.97 - 4,56 (2H, multiplet), 4,40 - of 4.25 (1H, multiplet), 3,56 - to 3.38 (2H, multiplet), and 2.27 (3H, singlet), 2,21 is 1.86 (4H, multiplet), 1.44MB and of 1.42 (9H, singlets).

8E. The hydrochloride of N-(3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2S)-2-pyrrolidinylcarbonyl)-1H-1,4 - benzodiazepine-3-yl)-N'-(3-methyl-phenyl)urea.

Containing BOC-protected compound from example 8 (559 mg, 0.95 mmol) are added to a solution of hydrogen chloride in dioxane (4 M, XS) and stirred at room temperature for 30 min to Dissolve the traces of them dioxane. The resulting product is recrystallized from a mixture of chloroform/ether and receive target salt in a solid white color (245 mg, 48.5%, and the purity > 98% according to liquid chromatography high pressure).

Rf(chloroform:methanol:acetic acid, 12:2:1) 0,32.

Mass spectrum (FAB +ve ion): m/e 495,2 (M+H).

Example 9.

N-((3RS)-1-((2S)-1-Acetyl-2-pyrrolidinylcarbonyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 17).

The salt solution of the benzodiazepine (example 8E (166 mg, 0.32 mmol) in methylene chloride at 0oC in an atmosphere of nitrogen was added di-ISO populationin (of 0.11 ml, was 0.63 mmol), and then acetylchloride (22 μl, 0.32 mmol). The reaction ends after 10 minutes. The mixture is evaporated in vacuum and the residue poured into a mixture of methylene chloride and 0.3 M solution of potassium bicarbonate. The organic phase is separated, dried (over sodium sulfate), filtered (phase separator Whatman IPS) and evaporated in vacuo. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:acetic acid, 100:2 vol. /about. and get a solid white substance, which is dissolved in a mixture of acetonitrile/water and subjected to freeze-drying, prochazkova pressure).

Range PMR (chloroform-d): to $ 7.91 - 6,95 (14H, multiplet), 6,76 (1H, multiplet), 5,68-5,62 (1H, multiplet), 4,94-4,43 (3H, multiplet), 3,48 - to 3.35 (2H, multiplet), 2,35 (1H, singlet), of 2.23 (3H, singlet), 2,1 - to 1.79 (6H, multiplet).

Mass spectrum (FAB +ve ion): m/e 538,3 (M+H).

Example 10.

The hydrochloride of N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1((2R)-2-pyrrolidinylcarbonyl-1H-1,4 - benzodiazepine-3-yl)-N'-(3-were) urea (compound 14).

10A. (2R)-1-tert-Butyloxycarbonyl-2-pyramidalization (scheme 2, steps (i)-(iii)).

Get analogously to the method described in example 8A using Boc-L-Proline (4 g, and 19.4 mmol), N-methylmorpholin (2.1 ml, and 19.4 mmol) and ISO-butylchloroformate (2.7 ml of 20.5 mmol). After purification via thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35: 65./about.) get the target compound in the form of oil (1.68 g, 38%).

Range PMR (chloroform-d): the 5.45 (1H, doublet, J = 23 Hz), 4,24 (1H, doublet, J = 23 Hz), 3,51 - of 3.43 (2H, multiplet), 2,19 of - 1.83 (4H, multiplet), of 1.47 and 1.43 (9H, 2 singlets).

10B. (2R)-1-tert-Butyloxycarbonyl-2-paralegalpipeline.com (scheme 2, step (iii)).

Get similar to the methodology described in example 8B from diazoketone in example 10A (1.68 g, 7.4 mmol), the crude product is 20:80.about.) get the target ketone in the form of a brown oil (986 mg, 47,5%).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 20:80) to 0.19.

10C. (3RS)-3-Benzyloxycarbonylamino-1-((2R)-tert-butyloxycarbonyl-2 - pyrrolidinylcarbonyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i))

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (950 mg, 2,35 mmol), sodium hydride (99 mg, 80% dispersion in oil, 3,29 mmol) and pommerellen from example 10B (986 mg, of 3.57 mmol). The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC) about 40-60./about.) and obtain the target compound (1.3 g, 92%).

Range PMR (chloroform-d): a 7.62 7,18 (14H, multiplet), of 6.68 (1H, doublet, J = 8 Hz), 5,43 (1H, doublet, J = 8 Hz), 5,14 (2H, singlet), 5,09 - 4,8 (1H, multiplet), 4,65 and 4.4 (1H, multiplet), 4,37 - 4,27 (1H, multiplet), 3,49 - 3,44 (2H, multiplet), 2,22 - of 1.85 (4H, multiplet), USD 1.43 (9H, singlet).

10D. N-(3RS)-1-((2R)-tert-Butyloxycarbonyl-2-pyrrolidinylcarbonyl)-2,3 - dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea (scheme 1, step (ii)).

Get analogously to the method described in example 10, using benzodiazepine (example 10C (394 mg, of 0.65 mmol), 5% palladium on coal (about 200 mg) and m-tallization (88 μl, 0.68 m is(so Kip. 40-60oC) 40:60.about.) and get the target compound in the form of a crystalline substance (175 mg, 65%).

Range PMR (chloroform-d): 7,63 - 7,0 (13H, multiplet), 6,97 - of 6.78 (1H, multiplet), 5,64 (1H, doublet, J = 10 Hz), 4,8 - 4,7 (2H, MultiSet), 4,37 - 4,08 (1H, multiplet), 3,48 - 3,37 (2H, multiplet), 2,24 (3H, singlet), was 2.05 (3H, singlet), 2,2-of 1.76 (4H, multiplet), 1,49 and 1.34 (9H, 2 singlets).

10E. The hydrochloride of N-((3RS)-2,3-Dihydro-2-oxo-5-phenyl-1-((2R)-2 - pyrrolidinylcarbonyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were) urea.

Get similar to the methodology described in example 8E, using benzodiazepine (example 10D (175 mg, 0.3 mmol). The crude product is dissolved in acetic acid and subjected to freeze-drying, without receiving further purification of the target compound as white powder (125 mg, 78%, purity > 99% according to liquid chromatography high pressure).

Mass spectrum (FAB +ve ion): m/e 496,2 (M+H).

Example 11.

N-((3RS)-1-((2R)-1-Acetyl-2-pyrrolidinylcarbonyl)-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 16).

Receive similarly to the method shown in example 9, using salt benzodiazepine (example 10E (244 mg, 0.46 mmol), di-isopropylaniline (0.16 ml, of 0.92 mmol) and PI is ylacetic: acetic acid, 100:2 vol./about.) and get pure product which was dissolved in acetic acid and subjected to freeze-drying, obtaining the target compound as white powder (173 mg, 70%, purity >99% according to liquid chromatography high pressure).

Mass spectrum (FAB + ve ion): m/e 538,3 (M+H).

Examples 12 and 13.

N-((3RS)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 18) and

N-((3RS)-1-((2SR)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 19).

To a solution of the benzodiazepine (example 4C (240 mg, 0.49 mmol) in ethanol at 0oC add sodium borohydride (29 mg, from 0.76 mmol). The resulting mixture was stirred at 0oC for 30 minutes and then at room temperature for 90 minutes. The mixture is evaporated in vacuo and the residue purified by thin layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35:65./about.) and get two connections. Each of them dissolved in a mixture of acetonitrile/water and subjected to freeze-drying, obtaining the target compound.

The less polar product: 66 mg, 26%, purity >98%60oC) 35:65) to 0.14.

Range PMR (chloroform-d): 7,74-6,90 (14H, multiplet), is 6.78 (1H, doublet, J = 8 Hz), 5,62 (1H, doublet, J = 8 Hz), to 4.41-4,34 (1H, multiplet), 3,65-3,55 (2H, multiplet), 2,22 (3H, singlet), 1,67-1,11 (9H, multiplet).

Mass spectrum (FAB + ve ion): m/e 497,2 (M+H).

The more polar product: 95 mg, 38%, a purity of >96% according to liquid chromatography high pressure.

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 35:65) to 0.10.

Range PMR (chloroform-d): 7,73-7,0 (14H, multiplet), 6,87-of 6.78 (1H, multiplet), 5,59-to 5.56 (1H, doublet, J = 8 Hz), 4,05-3,70 (3H, multiplet), 2,24 (3H, singlet), 1,76-to 1.14 (9H, multiplet).

Mass spectrum (FAB + ve ion): m/e 497,0 (M+H).

Example 14.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 8).

14A. (3RS)-3-Benzyloxycarbonylamino-1-cyclopentanecarbonyl - 2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

To a stirred solution of (3RS)-3-Benzyloxycarbonylamino - 2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepine-2-it (R. M. Freidinger et al., European patent application 0434364 A2) (388 mg, 1 mmol) in DMF (5 ml), cooled to -10oC, in an atmosphere of nitrogen was added sodium hydride (42 mg (30% dispersion by weight of the solution of promotility from example 4A (250 mg, 1.4 mmol). Give the mixture for 1 h under stirring to warm to room temperature, then poured into dilute hydrochloric acid (100 ml). Twice extracted with a mixture of ethyl acetate, the organic extracts washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated in vacuo. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 90:10./about.) and get the target compound as a colourless solid (426 mg, 86%).

Rf(ethyl acetate) of 0.35.

Range PMR (chloroform-d): to 8.62 (1H, doublet, J = 8 Hz), 8,17 (1H, doublet, J = 8 Hz), 7,78 (1H, triplet, J = 8 Hz), 7,50 (1H, triplet, J = 8 Hz), between 7.4 to 7.15 (9H, multiplet), 6,76 (1H, doublet, J = 8.5 Hz), the 5.51 (1H, doublet, J = 8.5 Hz), 5,16 (2H, multiplet), 4,80 (1H, doublet, J = 17.5 Hz), 4,42 (1H, doublet, J = 17.5 Hz), 2,92 (1H, multiplet), and 1.9 to 1.5 (8H, multiplet).

14B. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Benzodiazepine (example 14A (426 mg, 0.86 mmol) is treated with 40% solution of hydrogen bromide in acetic acid (6 ml) and the resulting mixture was stirred at room temperature for 2 hours the Mixture daidara. The organic extract is filtered (phase separator Whatman PS I), evaporated, dissolved in methylene chloride (5 ml) and with stirring at room temperature is treated with m-trilinoleate (130 μl, 0.95 mmol) for 2 hours the Mixture was evaporated and purified by thin layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (with T. bales. 40-60oC) 70:30./about.) and get a solid yellow color, which is recrystallized from acetonitrile and receive a colorless product (73 mg, 17%).

Rf(ethyl acetate/hexane, 60:40./about.) 0,38.

Range PMR (chloroform-d): 8,6 (1H, doublet, J = 6 Hz), 7,95 (1H, doublet, J = 6 Hz), of 7.6 to 7.0 (10H, multiplet), to 6.80 (1H, doublet, J = 8.5 Hz), 5,78 (1H, doublet, J = 8.5 Hz), 5,10 (1H, doublet, J = 14 Hz), 5,00 (1H, doublet, J = 14 Hz), 2,82 (1H, multiplet), and 2.14 (3H, singlet), 1,90 of 1.50 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 496,3 (M+H).

Example 15.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(4 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 10).

15A. (3RS)-3-Benzyloxycarbonylamino-1-cyclopentanecarbonyl - 2,3-dihydro-5-(4-pyridyl)-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

A solution of (3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(4-pyridyl)- 1H-1,4-b is the iMER 14A, and after chromatographic purification (eluent - ethyl acetate) to give the product as a colourless solid (460 mg, 93%).

Rf(ethyl acetate) to 0.22.

Range PMR (chloroform-d): to 8.62 (1H, doublet, J = 7.5 Hz), 7,55 (3H, multiplet), between 7.4 and 7.1 (8H, multiplet), to 6.80 (1H, doublet, J = 8.5 Hz), 5,42 (1H, doublet, J = 8.5 Hz), 5,12 (2H, singlet), 4,72 (2H, multiplet), 2,85 (1H, multiplet), 1,9-1,4 (8H, multiplet).

15B. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(4 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Benzodiazepine (example 15A (375 mg, 0,724 mmol) is transformed into urea as described in example 14B. Product chromatographic (eluent - chloroform:methanol:acetic acid, 200:2:1, vol/about./about.) and get a solid white (59 mg, 16%).

Rf(ethyl acetate) to 0.30.

Range PMR (chloroform-d): to 8.62 (1H, doublet, J = 7.5 Hz), 7,7-7,0 (11H, multiplet), 6,8 (1H, multiplet), 5,62 (1H, doublet, J = 8.5 Hz), is 4.85 (1H, doublet, J = 16 Hz), 4,60 (1H, doublet, J = 16 Hz), 2,80 (1H, multiplet), of 2.15 (3H, singlet), 1,8-1,4 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 496,2 (M+H).

Example 16.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 11).

Benzodiazepine (example 4B (2,04 g, 4,13 mmol) hydronaut over 5% palladium on coal (1.2 g) as described in example 1C. The amine was dissolved in dry THF (15 ml) and triethylamine (0,626 ml, 4.5 mol) and cool the solution to 0oC. To the stirred solution was added n-nitrophenylacetate (0,91 g, 4.5 mmol) and stirred at room temperature for 1 h, then evaporated and subjected to chromatographicaliy (eluent - ethyl acetate/hexane, 40:60 about. /about. and receive the product in a solid yellow color (675 mg, 32%).

Rf(ethyl acetate/hexane, 60:40./about.) 0,52.

Range PMR (chloroform-d): 8,2 (1H, doublet, J = 8 Hz), 7,6-7,0 (12H, multiplet), 5,42 (1H, doublet, J = 8.5 Hz), 4,82 (1H, doublet, J = 16.5 Hz), to 4.62 (1H, doublet, J = 16.5 Hz), 2,97 (1H, multiplet), 1,9-1,4 (8H, multiplet).

16B. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl) urea (scheme 3, step (ii)).

To a stirred solution of the benzodiazepine (example 16A (175 mg, of 0.333 mmol) in DMF (5 ml) is added m-aminobenzoyl acid (72 mg, 0.52 mmol) and triethylamine (125 μl). The mixture is stirred at a temperature of 45oC for 18 h, cooled and diluted with ethyl acetate. The mixture was washed with 0.3 M hydrochloric kyaut thin-layer chromatography (eluent - the ethyl acetate:hexane:acetic acid, 60:40:2, about. /about./about.) and obtain a colorless solid matter (132 mg, 76%).

Rf(ethyl acetate:hexane:acetic acid, 60:40:2, vol/about./about.) 0,25.

Range PMR (chloroform-d): to 8.41 (1H, singlet), of 8.37 (1H, doublet, J = 7.5 Hz), 8,16 (1H, doublet, J = 7.5 Hz), 7,82 (1H, singlet), 7,7-7,2 (12H, multiplet), the 5.65 (1H, doublet, J = 8.5 Hz), of 5.81 (1H, doublet, J = 15 Hz), of 4.66 (1H, doublet, J = 15 Hz), 2,95 (1H, multiplet), 1,95 of 1.5 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 419 (M+Na - H2NC6H4COOH).

Example 17.

N-((3R)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 12).

Benzodiazepine (example 4B (1.13 g, 2.3 mmol) hydronaut as described in example 4C, and Amin chromatographic (eluent - chloroform:methanol:acetic acid, 25:2:1) and receive a yellow oil. It is dissolved in acetonitrile and stirred solution was added (S)-almond acid (335 g of 2.20 mmol), stirred for 30 minutes and add a 3.5-dichlorosalicylic aldehyde (10 mg). Leave the mix overnight, the precipitated precipitate is filtered off on a suction filter and washed with cold acetonitrile, getting a solid white color (680 mg, 59%).

Poluchennyh saturated salt solution, filter (separator phases Whatman PS I) and evaporated. The residue is dissolved in methylene chloride (5 ml) add m-tallization (110 μl, 0,852 mmol) and stirred at room temperature for 1 h the Mixture was evaporated and chromatographic (eluent - ethyl acetate/hexane, 40:60.vol.), receiving a colorless solid substance (320 mg, 76%).

Rf(ethyl acetate:hexane, 40:60.about.) 0,16.

[]D= +100,4o(chloroform, c = 0,96).

Range of PMR and mass spectrum identical to example 4C.

Example 18.

N-((3S)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 13).

Benzodiazepine (example 4B (1.98 g, 4 mmol) hydronaut as described in example 4C, and Amin chromatographic (eluent - chloroform:methanol:acetic acid, 25:2:1) and receive a yellow oil (1,15 g, 79%)). It is dissolved in acetonitrile and stirred solution was added (S)-almond acid (290 g, at 1.91 mmol) and allowed to mix overnight at room temperature. The precipitation is filtered (300 mg, 19%), the filtrate evaporated and redistribute between chloroform and 0.25 M sodium hydroxide solution. The organic phase is washed with saturated salt solution, utilitate (420 mg, 2.77 mmol) and leave the mixture was mixed at 0oC for 20 minutes and then add the 3.5 dichlorosalicylic aldehyde (5 mg) and leave the mixture was mixed overnight at room temperature. The resulting white precipitate is filtered off and washed with cold acetonitrile (800 g, 56%).

The obtained solid (780 mg, of 1.52 mmol) redistribute between chloroform and 0.25 M sodium hydroxide solution and the organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is dissolved in methylene chloride (10 ml) and add m-tallization (220 μl, 1.7 mmol) and stirred at room temperature for 1 h the Mixture was evaporated and chromatographic (eluent - ethyl acetate:hexane, 40:60.vol.), receiving a colorless solid substance (650 mg, 87%).

Rf(ethyl acetate:hexane, 40:60.about.) 0,16.

[]D= -96,0o(chloroform, c = 1,58).

Range of PMR and mass spectrum identical to example 4C.

Examples 19 and 20.

N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 20) and

N-((3R)-1-((2S)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-growing presence is anywayt by sodium borohydride in ethanol, as described in examples 12 and 13. The remainder chromatographic and receive two target compounds (eluent - ethyl acetate:hexane, 35:65./vol.).

The less polar product: 105 mg 31%.

The more polar product: 145 mg 43%.

Identical to examples 12 and 13 according to TLC, PMR and mass spectrometry.

Example 21.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(3 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 9).

21A. 2-Nitro-alpha-(3-pyridyl)benzyl alcohol.

3-Bromopyridin (of 7.90 g, 50 mmol) dissolved in dry THF (50 ml) and added dropwise n-utility (1.6 M solution, 32 ml of 51.2 mmol) at a temperature of -100oC (the temperature of the reaction mixture) and stirred the mixture at a temperature of -100oC for 15 minutes. Added dropwise a solution of 2-nitrobenzaldehyde (of 8.25 g of 54.6 mmol) in THF (20 ml), and give the mixture for 40 minutes to heat up to a temperature of 0oC. Terminate the reaction by adding water (5 ml), the mixture was evaporated and poured into a mixture of ethyl acetate and 5% aqueous solution of potassium bicarbonate. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The remainder chromatographic (eluent - ethyl acetate:hexane, 95:5 vol./vol.), the floor is St-d): scored 8.38 (1H, doublet, J = 1.5 Hz), compared to 8.26 (1H, multiplet), of 7.96 (2H, multiplet), of 7.70 (2H, multiplet), was 7.45 (1H, multiplet), 7,22 (1H, multiplet), of 6.45 (1H, singlet).

Range13C NMR (chloroform-d): 148,0, 147,9, 147,6, 138,5, 138,3, 135,2, 133,6, 128,9, 128,5, 124,5, 123,5, 68,6.

21B. 3-(2-Nitrobenzoyl)pyridine.

Chloride, oxalyl (2,3 ml of 25.8 mmol) dissolved in methylene chloride (40 ml) and added dropwise thereto over 10 minutes sulfoxide (to 3.67 ml, won with 51.75 mmol) at a temperature of -60oC. Add a solution of the alcohol from example 21A (5,22 g, 22.7 mmol) in methylene chloride (5 ml) and then triethylamine (15,8 ml, 113,3 mmol). The mixture is stirred for 5 minutes at a temperature of -60oC and then at room temperature for 12 hours Diluted with ethyl acetate and washed with 5% solution of potassium bicarbonate and a saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The remainder chromatographic (eluent - ethyl acetate/hexane, 90:10 vol. /vol.), getting solid yellow (3.25 g, 63%).

Rf(ethyl acetate) to 0.30.

Range PMR (chloroform-d): 8,90 (1H, doublet, J = 1.5 Hz), 8,82 (1H, multiplet), 8,31 (1H, doublet, J = 8 Hz), 8,18 (1H, doublet of doublets, J = 8 Hz, J = 1.5 Hz), 7,80 (2H, multiplet), to 7.50 (2H, multiplet).

Range13C NMR (chloroform-d): 192,0, other 153.9, 150,3 g, of 8.06 mmol) dissolved in a mixture of ethanol/water (1: 1 vol. /vol., 10 ml) and added iron powder (2,78 g, 48 mmol). The mixture is heated to boiling, and then add concentrated hydrochloric acid (0.17 ml) in a mixture of ethanol/water (1:1 vol./about., 2 ml). Heating continued for 1 h, and then the mixture is cooled, filtered and evaporated. The residue is poured into a mixture of 0.5 M sodium hydroxide solution and chloroform, the organic phase is separated, washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The remainder chromatographic (eluent ethyl acetate/hexane, 65:35./vol.), getting solid yellow (700 mg, 44%).

Rf(ethyl acetate) of 0.45.

Range PMR (chloroform-d): 8,72 (1H, doublet, J = 1.5 Hz), at 8.60 (1H, doublet, J = 7 Hz), 7,80 (1H, multiplet), 7,20 (3H, multiplet), 6,60 (1H, doublet, J = 8 Hz), 6.48 in (1H, triplet, J = 8 Hz), 6,12 (2H, broadened singlet).

Range13C NMR (chloroform-d): 196,3, 151,3, 149,6, 149,5, 136,4, 135,7, 134,5, 133,5, 123,0, 117,6, 115,6, 115,4.

21D. (3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(3-pyridyl)- 1H-1,4-benzodiazepine-2-it.

The target compound is obtained from the amine from example 21C (700 mg, of 3.57 mmol), using known methodology (R. M. Freidinger et al., European patent application 0434364 A2) in the form of a solid white (14 is t), 7,83 (1H, doublet, J = 7 Hz), 7,4-7,0 (5H, multiplet), 6,76 (2H, doublet, J = 8 Hz), a 5.25 (1H, doublet, J = 8 Hz), to 5.08 (2H, singlet).

21E. (3RS)-3-Benzyloxycarbonylamino-1-cyclopentanecarbonyl - 2,3-dihydro-2-oxo-5-(3-pyridyl)-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Benzodiazepine for example 21D (142 mg, 0.35 mmol) alkylate bromeilles from example 4A (90 mg, 0.49 mmol) using the method described in example 1B. The target compound is obtained after chromatographic purification (ethyl acetate/hexane, 95: 5 vol./about.) in a solid white color (164 mg, 96%).

Rf(ethyl acetate) to 0.28.

Range PMR (chloroform-d): 8,68 (1H, singlet), 8,58 (1H, doublet, J = 1.5 Hz), 7,98 (1H, doublet, J = 8 Hz), 7,88 (1H, singlet), was 7.45 (1H, multiplet), and 7.3, and 7.1 (3H, multiplet), 6,62 (1H, doublet, J = 8 Hz), lower than the 5.37 (1H, doublet, J = 8 Hz), is 5.06 (2H, singlet), 4,63 (2H, singlet), 2,80 (1H, multiplet), 1,8-1,4 (8H, multiplet).

21F. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-(3-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Benzodiazepine for example 21E (160 mg, 0.32 mmol) dissolved in methylene chloride (2 ml) at -70oC and added dropwise with stirring trichromacy Bor (1 M solution in methylene chloride, 2.0 ml). Give the mixture for 1 h, heated to whom is in a mixture of ethyl acetate and 1 M sodium hydroxide solution. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is dissolved in methylene chloride (3 ml) and for 1 h at room temperature add m-tallization (45 μl, 0.35 mmol). The mixture is evaporated and chromatographic (eluent ethyl acetate/hexane, 90:10./vol.), receiving the target compound in the form of solid white (70 mg, 44%).

Rf(ethyl acetate) to 0.28.

Range PMR (chloroform-d): 8,88 (1H, singlet), 8,80 (1H, doublet, J = 8 Hz), 7,70-7,20 (10H, multiplet), of 6.96 (1H, multiplet), 5,80 (1H, doublet, J = 8 Hz), free 5.01 (1H, doublet, J = 14 Hz), 4,80 (1H, doublet, J = 14 Hz), to 3.02 (1H, multiplet), is 2.41 (3H, singlet), a 2.0 of 1.65 (8H, multiplet)

Mass spectrum (FAB): (M+H) = 496,3.

Example 22.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 34).

22A. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (scheme 1, step (ii)).

Benzodiazepine (example 14A (180 mg, 0,363 mmol) dissolved in methylene chloride (3 ml) and cooled to -70oC in nitrogen atmosphere. Added dropwise trichromacy boron (2.2 ml, 1 M solution in methylene chloride) re. To terminate the reaction, add mixture to ice water, and then diluted with ethyl acetate and washed with 1 M sodium hydroxide solution. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated, getting the butter brown.

Methyl ester of 3-aminobenzoic acid (151 mg, 1 mmol) in methylene chloride (2 ml) at -20oC under nitrogen is treated with thiophosgene (110 mg, of 0.37 mmol) in pyridine (81 μl, 1 mmol). Mix polucheniya mixture at a temperature of -20oC for 30 minutes and add a fresh portion of pyridine (81 μl, 1 mmol), and then add Amin, the receipt of which is described above. The mixture is stirred at room temperature for 1 h, evaporated and poured into a mixture of ethyl acetate and 5% aqueous solution of potassium bicarbonate. The organic phase is washed with 10% citric acid solution, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated, and the residue chromatographic (eluent - ethyl acetate) to give a solid whitish (95 mg, 49%).

Rf(ethyl acetate) to 0.28.

Range PMR (chloroform-d): at 8.60 (1H, doublet, J = 2 Hz), 7,10-8,10 (13H, multiplet), the 5.65 (1H, doublet, J = 8 Hz), to 4.62 (2H, multiplet), and 3.8 (3H, singlet),ITIL)-1H-1,4-benzodiazepine-3-yl)-N' -(3-carboxyphenyl) urea.

Benzodiazepine (example 22A (95 mg, 0,176 mmol) dissolved in a mixture of dioxane/water (1: 1 vol./about., 2 ml), added LiOH-H2O (12 mg, 1.5 equiv.) and stirred at room temperature for 16 hours the Mixture was evaporated and poured into a mixture of chloroform and 10% citric acid. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The remainder chromatographic (eluent - chloroform:methanol: acetic acid, 100: 2:1 vol./about./about.) and get a solid white color, which is subjected to the freeze-drying process and obtain the target compound (34 mg, 37%).

Range PMR (chloroform-d): to 8.62 (1H, doublet, J = 2 Hz), of 7.1-8.2 (13H, multiplet), 5,70 (1H, doublet, J = 8 Hz), 4,58 (2H, multiplet), and 3.0 (1H, multiplet), 1,4-2,0 (8H, multiplet).

Mass spectrum (+ ve FAB): (M+H) = 526,2.

Example 23.

N-((3R)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 33).

Benzodiazepine (example 4B hydronaut and was isolated as described in example 17. The obtained salt of (S)-almond acid (430 mg, 0,838 mmol) redistribute between chloroform and 0.25 M sodium hydroxide solution and the organic phase is washed with saturated salt solution, hoteltravel the initial ester m-aminobenzoic acid (315 mg, 2.1 mmol) dissolved in methylene chloride (3 ml) and pyridine (170 μl, 2.1 mmol) and cooled to -60oC in nitrogen atmosphere. Add thiophosgene (207 mg, 0.7 mmol) and the mixture is stirred for 15 minutes, during which the temperature of the mixture is raised to -20oC. Add a fresh portion of pyridine (170 μl, 2.1 mmol), stirred at 20oC for 10 minutes, and then add Amin, the receipt of which is described above, in methylene chloride (1 ml) and stirring at room temperature continued for 2 hours Diluted with ethyl acetate and washed with 1 M hydrochloric acid solution, saturated salt solution, filtered (phase separator Whatman PS I), evaporated and chromatographic (eluent - ethyl acetate/hexane, 40: 60.vol.), receiving the intermediate ester in the form of a solid white color (375 mg, 83%).

The obtained ether dissolved in a mixture of dioxane/water (1:1 vol./about., 5 ml), added LiOH-H2O (41 mg, 1.4 equiv.) and stirred at room temperature for 16 hours the Mixture was evaporated and poured into a mixture of chloroform and 1 M hydrochloric acid. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The remainder chromatographic (eluent - ethyl acetate:hexane:acetic acid, 60:40:2 vol./about./about the tat:hexane:acetic acid, 60:40:2 vol./about./about.) 0,24.

[]D= +68,4o(ethyl acetate, c = 0,92).

Range of PMR and mass spectrum identical to example 16.

Examples 24 and 25.

N-((3R)-1-((2RS)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 35)

and

N-((3R)-1-((2R)-2-Cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 36).

Benzodiazepine according to example 23 (120 mg, 0,229 mmol) dissolved in ethanol at a temperature of 0oC for 15 minutes, treated with sodium borohydride (16 mg, 0.4 mol) and then stirred the mixture at room temperature for 2 h, evaporated and the residue chromatographic (eluent - ethyl acetate: hexane:acetic acid, 60:40:2 vol./about./about.) getting two products:

Approx. 24 = mixture 1:1 of more quickly and slower running isomer (33 mg).

Approx. 25 = net slower running isomer (46 mg) TLC (ethyl acetate: hexane:acetic acid, 60:40:2 vol./about./vol.).

Rffaster running isomer = 0,24.

Rfthe slower running isomer = 0,20.

Mass spectrum (M+H) = 527 identical for both examples.

Example 26.

N-((3R)-1-tre is ASS="ptx2">

Benzodiazepine (example 2B hydronaut and received Amin decompose the salt of its (R)-isomer and (S)-almond acid as described in example 17. Part of this salt (150 mg, 0,229 mmol) redistribute between chloroform and 0.25 M sodium hydroxide solution. The organic layer was washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is dissolved in methylene chloride and add m-tallization (42 μl, 0.33 mmol). The mixture is stirred at room temperature for 1 h, then evaporated and chromatographic (eluent - ethyl acetate/hexane, 40:60 about. /about. ), getting a solid white color, which is subjected to the freeze-drying of a mixture of acetonitrile/water (125 mg, 87%).

Data identical to the compound from example 2C.

Example 27.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 39).

27A. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepine-2-he (scheme 1, step (ii)).

(3RS)-3-Benzyloxycarbonylamino-2,3-dihydro-5-(2-pyridyl)-1H - 1,4-benzodiazepine-2-he (R. M. Freidinger et al., European patent application 0434364 A2) (2,02 g, 5 mmol) alkylate 1-pompian, 80: 20./about.) get a solid white color (2.16 g, 86%).

27B. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(4 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Part of diazepine from example 27A (502 mg, 1 mmol) dissolved in methylene chloride (2 ml) at -70oC and added dropwise trichromacy boron (6.5 ml, 1 M solution in methylene chloride) and the mixture stirred for 3 h, after which the cooling bath removed. To terminate the reaction, add water to the mixture and poured into a mixture of ethyl acetate and 1 M sodium hydroxide solution. The organic phase is washed with saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is dissolved in methylene chloride (3 ml) and for 1 h at room temperature add m-tallization (135 μl, 1.05 mmol). The mixture is evaporated and chromatographic (eluent - ethyl acetate/hexane to 75: 25./about.) and the obtained solid white recrystallized from acetonitrile (180 mg, 38%).

Rf(ethyl acetate/hexane, 60:40./about.) 0,28.

Range PMR (chloroform-d): 8,78 (1H, doublet, J = 2 Hz), of 8.27 (1H, doublet, J = 7 Hz), 7,95 (1H, multiplet), 7,65-6,9 (11H, multiplet), of 5.83 (1H, doublet, J = 8 Hz), 5,10 (1H, doublet, J = 16 Hz), 4,70 (1H,

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 40).

Benzodiazepine (example 2B hydronaut as described in example 1C, and the resulting amine (600 mg, 1,72 mmol) dissolved in dry THF (8 ml) and triethylamine (260 μl, 1.9 mmol). Added dropwise a solution of p-nitrophenylphosphate (or 0.38 g, 1.9 mmol) in THF (3 ml) and stirred the mixture at room temperature for 1 h, evaporated and chromatographic (eluent - ethyl acetate/hexane, 40:60.about.) and get a solid white color (670 mg). This substance is dissolved in DMF (10 ml) is added m-aminobenzoic acid (245 mg, about 1.75 mmol) and stirred at a temperature of 45oC for 18 hours the Mixture is evaporated and chromatographic (eluent - ethyl acetate:hexane:acetic acid, 60:40:2 vol./about./about.) and the product is recrystallized from acetonitrile, obtaining the target compound (328 mg, 38%).

Range PMR (chloroform-d): 7,8-7,0 (14H, multiplet), to 6.80 (1H, doublet, J = 7 Hz), 5,6 (1H, doublet, J = 8 Hz), 4,9 (1H, doublet, J = 18 Hz), 4,8 (1H, doublet, J = 18 Hz), of 1.40 (9H, singlet).

Mass spectrum (FAB): (M+H) = 513,4.

Example 29.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(6-methyl-3-pyridyl)urea (with the ina in example 4B (165 mg, 0,39 mmol), 5% palladium on coal (80 mg) and isocyanate, obtained as described below.

To a stirred solution of 2-amino-6-picoline (108 mg, 1 mmol) in methylene chloride (10 ml) at -20oC add thiophosgene (110 mg, of 0.37 mmol) and pyridine (79 mg, 1 mmol). Give the mixture under stirring for 30 minutes to warm to room temperature, add pyridine (79 mg, 1 mmol) and the reaction mixture is refluxed for 30 minutes. The resulting isocyanate solution is cooled to 0oC and used without further processing.

The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (with T. bales. 40-60oC) 80:20./about.) and get the target compound in the form of solid white (45 mg, 28%, purity 96% according to liquid chromatography high pressure).

Rf(ethyl acetate:petroleum ether (with T. bales. 40-60oC) 20:80) 0,20.

Range PMR (chloroform-d): 10,8 (1H, wide signal), 7,70-6,80 (13H, multiplet), 5,70 (1H, doublet, J = 8 Hz), 4,82 (1H, doublet, J = 17 Hz), and 4.75 (1H, doublet, J = 17 Hz), 2,95 (1H, quintet, J = 7 Hz), 2,60 (3H, singlet), are 1.95 and 1.75 (4H, singlet), 1.70 to a 1.45 (4H, multiplet).

Mass spectrum (FAB + ve ion): m/e 496,0 (M+H).

Example 30.

N-((3RS)-1

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (270 mg, 0.55 mmol), 5% palladium on coal (100 mg) and isocyanate, obtained as described below.

To a stirred solution of nicotinic acid (172 mg, 1.4 mmol) and di-isopropylaniline (250 μl, 1.4 mmol) in THF (15 ml) at 0oC add isobutylparaben (182 μl, 1.4 mmol). The mixture is stirred at a temperature of 0oC for 30 minutes, and then add a solution of sodium azide (97 mg, 1.5 mol) in water (1 ml) and the resulting mixture stirred for 2 h, allowing to warm to room temperature. Evaporated the mixture in vacuo, the residue is dissolved in cold ethyl acetate, washed with a cold saturated solution of potassium bicarbonate and cold saturated salt solution, filtered (phase separator Whatman PS I) and evaporated in vacuo. The residue is heated in THF (5 ml) at a temperature of 60oC for 5 minutes and get isocyanate, which is used without further purification.

The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform: methanol: acetic acid, 100:2:1 vol./about./about.) and get the target compound in the form of a crystalline substance (34 mg, 13%, purity >99% LASS="ptx2">

Range PMR (chloroform-d): 8,70-7,20 (16H, multiplet), of 5.50 (1H, doublet, J = 8 Hz), and 4.75 (1H, doublet, J = 18 Hz), of 4.67 (1H, doublet, J = 18 Hz), 3,70 (1H, multiplet), 1,90-1,20 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 482,0 (M+H).

Example 31.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxymethyl)urea (compound 24).

31A. Methyl ether 3-aminophenylarsonic acid.

To a solution of 3-aminophenylacetic acid (to 3.02 g, 20 mmol) and methanol (60 ml) is added acetyl chloride (2 ml, 28 mmol). The reaction mixture is refluxed for 6 hours to Give a mixture to cool to room temperature and the solvent evaporated in vacuum. The residue is dissolved in chloroform and washed with saturated solutions of potassium and salt, filtered (phase separator Whatman PS I) and evaporated in vacuum, obtaining the target acetate in the form of a mobile brown oil (3.0 g, 91%).

Range PMR (chloroform-d): 7,35-of 6.90 (4H, multiplet), and 4.75 (2H, singlet), of 3.80 (3H, singlet), the 3.65 (2H, singlet).

31B. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methoxymethyl)urea (scheme 1, step (ii)).

Get a similar methodology, prevedinstant, derived from the amine from example 31A in accordance with the methodology described in example 29.

The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane, 60:40./about.) and get methyl ether in a solid white color (180 mg, 97%).

Rf(ethyl acetate/hexane, 60:40./about.) 0,23.

31C. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl) -N'-(3-carboxymethyl) urea.

To a solution of diazepine for example 31B (180 mg, 0.32 mmol) in dioxane (10 ml) is added LiOH-H2O (27 mg, 0.64 mmol) in water (6 ml). The mixture is stirred for 18 h, and then add dilute hydrochloric acid (10 ml). The mixture is extracted twice with ethyl acetate, the organic extracts are combined and washed with water and a saturated solution in a vacuum. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane:acetic acid, 70: 30: 2 vol./about./about.) and get the target compound in the form of solid white (105 mg, 61%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane:acetic acid, 70:30:2 vol./about./about.) 0,20.

Range PMR (chloroform-d): 8,00 (1H, with the P> Mass spectrum (FAB + ve ion): m/e 539,1 (M+H).

Example 32.

N-((3RS)-1-Cyclohexyloxycarbonyloxy-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 29).

32A. Bromoethylethylether (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from cyclohexyloxy acid (4,27 g, 30 mmol), chloride taanila (8,7 ml, 120 mmol) and diazomethane (generate on Diazald, 14.3 g, 66 mmol) and purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 15:85.vol.). Diazoketone then treated with a saturated solution of hydrogen bromide in acetic acid ethyl ester. After tonkosloinoi chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 5:95.about.) get the target compound in the form of mobile brown oil (2.8 g, 43%).

Range PMR (chloroform-d): 3,99 (2H, singlet), 2,70 (2H, doublet, J = 8 Hz), 2,00 (1H, multiplet), 1,85-1,10 (10H, multiplet).

32B. (3RS)-3-Benzyloxycarbonylamino-1-cyclohexylcarbonyl - 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get a similar methodology, bringing the 87 mmol) and pommerellen for example (219 mg, 1 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 35:65./about.) and get the target compound in the form of a colorless crystalline substance (315 mg, 97%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.25.

Range PMR (chloroform-d): 7,50-7,00 (14H, multiplet), 6,60 (1H, doublet, J = 8 Hz), of 5.40 (1H, doublet, J = 8 Hz), 5,10 (2H, singlet), 4,78 (1H, doublet, J = 17 Hz), of 4.67 (1H, doublet, J = 17 Hz), 2,35 (2H, multiplet), of 1.85 (1H, multiplet), 1,65-0,90 (10h, multiplet).

32C. N-((3RS)-1-Cyclohexyloxycarbonyloxy-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 32B (315 mg, of 0.60 mmol), 5% palladium on coal (250 mg) and m-tallization (91 μl, 0.71 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether 40: 60.about.) and obtain the target compound, which is recrystallized from acetonitrile and get a solid white color (51 mg, 16%, purity >98% according to liquid chromatography high pressure).

Rmultiplet), 5,70 (1H, doublet, J = 8 Hz), 4,74 (1H, doublet, J = 18 Hz), of 4.67 (1H, doublet, J = 18 Hz), 2,45-of 2.20 (5H, multiplet), 1,95-0,90 (11H, multiplet).

Mass spectrum (FAB + ve ion): m/e 523,1 (M+H).

Example 33.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 30).

33A. Bromocinnamaldehyde (scheme 2, step (i) to (iii))

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from cyclopentyloxy acid (3,85 g, 30 mmol), chloride taanila (8,7 ml, 120 mmol) and diazomethane (generated from Diazald, 14.3 g, 66 mmol) and purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:petroleum ether (so Kip. 40-60oC) 15:85.vol.). Diazoketone then treated with a saturated solution of hydrogen bromide in etelaat

those. After thin-layer chromatography on silica gel (eluent - ethyl acetate: petroleum ether (so Kip. 40-60oC), 5:95.about.) get the target ketone in the form of rolling oil (2.1 g, 34%).

Range PMR (chloroform-d): 3,99 (2H, singlet), 2,80 (2H, doublet, J = 8 Hz), 2,35 (1H, multiplet), 1,95-of 1.30 (8H, multiplet).

33B. (3RS)-3-Benzyloxycarbonylamino-1-cyclopentanecarbonyl - 2,3-dihydro-5-phenyl-1H-1,4-b is Zuya benzodiazepine Side (250 mg, of 0.62 mmol), sodium hydride (26 mg, 80% dispersion in oil, 0.87 mmol) and pommerellen for example 33A (205 mg, 1 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 35:65./about.) and get the target compound in the form of a colorless crystalline substance (300 mg, 95%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.25.

Range PMR (chloroform-d): 7,70 to 6.75 (15H, multiplet), of 5.50 (1H, doublet, J = 8 Hz), 5,20 (2H, singlet), 4,74 (1H, doublet, J = 18 Hz), of 4.67 (1H, doublet, J = 18 Hz), 2,50 (2H, multiplet in), 2.25 (1H, multiplet), 1.85 to to 1.15 (8H, multiplet).

33C. N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine for example 33B (300 mg, 0.59 mmol), 5% palladium on coal (250 mg) and m-tallization (91 μl, 0.71 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether 40: 60.about.) and obtain the target compound, which is recrystallized from acetonitrile and get a solid white color (171 mg, 57%, cysteate petroleum ether, 40:60) of 0.20.

Range PMR (chloroform-d): a 7.85-6,98 (15H, multiplet), to 5.85 (1H, broadened singlet), 4,80 (2H, singlet), to 2.55 (2H, multiplet), a 2.45 (3H, singlet), 2,43-of 2.30 (1H, multiplet), 1,90-1,20 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 509,1 (M+H).

Example 34.

N-((3RS)-1-(1-Methylcyclohexyl)carbonylmethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 31).

34A. Methyl bromide(1-methylcyclohexyl)ketone (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from 1-methyl-1-cyclohexanecarboxylic acid (4,27 g, 30 mmol), chloride taanila (8,7 ml, 120 mmol) and diazomethane (generated from Diazald, 14.3 g, 66 mmol). Without intermediate purification diazoketone then treated with a saturated solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 5:95.about.) get the ketone in the form of rolling oil (1.90 g, 29%).

Range PMR (chloroform-d): of 4.25 (2H, singlet), was 2.05 (2H, multiplet), 1,70-of 1.40 (10H, multiplet), 1,25 (3H, singlet).

34B. (3RS)-3-Benzyloxycarbonylamino-1-((1 - methylcyclohexyl)methylcarbamoylmethyl)-2,3-dihydro-5-phenyl-1H-1,4 - benzodiasepin Side (250 mg, of 0.62 mmol), sodium hydride (26 mg, 80% dispersion in oil, 0.87 mmol) and bromeilles in example 34A (219 mg, 1 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 35:65./about.) and get the target compound in the form of a colorless crystalline substance (270 mg, 86%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) to 0.24.

Range PMR (chloroform-d): 7,70-7,10 (14H, multiplet), to 6.80 (1H, doublet, J = 8 Hz), of 5.55 (1H, doublet, J = 8 Hz), and 5.30 (2H, singlet), 5,10 (1H, doublet, J = 17 Hz), and 4.75 (1H, doublet, J = 17 Hz), 2,10 (2H, multiplet), 1,70-of 1.40 (10H, multiplet), of 1.30 (3H, singlet).

34C. N-((3RS)-1-(methylcyclohexyl)carbonylmethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 34B (270 mg, 0.52 mmol), 5% palladium on coal (150 mg) and m-tallization (84 μl, 0.66 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether 40: 60.about.) and obtain the target compound, which is recrystallized from acetonitrile and get crystal wisest:hexane fraction of petroleum ether, 40:60) of 0.20.

Range PMR (chloroform-d): 7,70-6,90 (15H, singlet), 5,80 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), and 4.75 (1H, doublet, J = 17 Hz), is 2.30 (3H, singlet), from 2.00 (2H, multiplet), to 1.60 and 1.35 (10H, multiplet), of 1.20 (3H, singlet).

Mass spectrum (FAB + ve ion): m/e 523,3 (M+H).

Example 35.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro - 2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxamidine) urea (compound 37).

Get by the method similar to that shown in example 16B, of the benzodiazepine (example 16A (225 mg, 0.43 mmol) and 3-aminobenzamide (87 mg, 0.64 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate) and obtain the target compound in the form of a crystalline substance (30 mg, 13%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate) to 0.20.

Range PMR (chloroform-d): 8,95(1H, singlet), of 8.27 (1H, doublet, J = 8 Hz), 8,21 (1H, doublet, J = 8 Hz), 7,65-7,20 (15H, multiplet), of 5.55 (1H, doublet, J = 8 Hz) and 4.65 (2H, singlet), 2,90 (1H, quintet, J = 8 Hz), 1.85 to a 1.50 (8H, multiplet).

Mass spectrum (FAB + ve ion): m/e 524 (M+H).

Example 36.

N-((3RS)-1-tert-Amicability-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl) -N'-(3-were) urea (compound 41).

Range PMR (chloroform-d): of 4.25 (2H, singlet), to 1.70 (1H, Quartet, J = 8 Hz), 1,30 (6N, singlet), of 0.97 (3H, triplet, J = 8 Hz).

36B. N-((3RS)-1-tert-Aminocarbonylmethyl-3-benzyloxycarbonylamino - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (500 mg, 1.25 mmol), sodium hydride (54 mg, 80% dispersion in oil, a 1.75 mmol) and pommerellen for example 36A (300 mg, 1.5 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 35:65./about.) and get the target compound in the form of colorless 40:60) of 0.20.

Range PMR (chloroform-d): of 7.90-7,30 (14H, multiplet), of 6.90 (1H, doublet, J = 8 Hz), 5,80 (1H, doublet, J = 8 Hz), of 5.40 (2H, singlet), 5,10 (1H, doublet, J = 18 Hz), and 4.75 (1H, doublet, J = 18 Hz), 1,90 (2H, multiplet), of 1.40 (6H, singlet), and 1.00 (3H, triplet, J = 8 Hz).

36C. N-((3RS)-1-tert-Amicability)-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 36B (240 mg, 0.46 mmol), 5% palladium on coal (250 mg) and m-tallization (76 μl, 0.6 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether 40: 60.about.) and obtain the target compound, which is recrystallized from acetonitrile and get crystalline substance (98 mg, 43%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.20.

Range PMR (chloroform-d): 7,50-6,80 (15H, multiplet), the 5.65 (1H, doublet, J = 8 Hz), 4,70 (1H, doublet, J = 18 Hz) and 4.65 (1H, doublet, J = 18 Hz), measuring 2.20 (3H, singlet), 1,50 (2H, Quartet, J = 8 Hz), and 1.00 (6H, singlet), 0,70 (3H, triplet, J = 8 Hz).

Mass spectrum (FAB + ve ion): m/e 497,2 (M+H).

Example 37.

N-((3RS is s 42).

37A. (3RS)-3-p-Nitrobenzisoxazole-1-tert - aminocarbonylmethyl-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get similar to the methodology described in example 16A using benzodiazepine (example 36B (325 mg, of 0.68 mmol), 5% palladium on coal (250 mg) and p-nitrophenylphosphate (150 mg, 0.75 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 35:65./about.) and get the product of the solid yellow (135 mg, 38%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.28.

Range PMR (chloroform-d): 8,10 (2H, doublet, J = 8 Hz), 7,50-7,00 (12H, multiplet), of 5.40 (1H, doublet, J = 8 Hz), is 4.85 (1H, doublet, J = 17 Hz), 4,60 (1H, doublet, J = 17 Hz), of 1.55 (2H, Quartet, J = 8 Hz), 1,10 (6H, singlet), is 0.75 (3H, triplet, J = 8 Hz).

37B. N-((3RS)-1-tert-Amicability-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (scheme 1, step (ii))

Get analogously to the method described in example 16B, using benzodiazepine (example 37A (135 mg, 0.26 mmol) and a-aminobenzoic acid (54 mg, 0,39 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of Petrotel and receive a colorless crystalline substance (30 mg, 22%, purity >97% according to liquid chromatography high pressure).

Rf(ethyl acetate: hexane fraction of petroleum ether:acetic acid, 40:60:2) 0,20.

Range PMR (chloroform-d): 8,10-6,80 (16H, multiplet), of 5.50 (1H, doublet, J = 8 Hz), 4,80 (1H, doublet, J = 18 Hz) and 4.65 (1H, doublet, J = 18 Hz), 1,40 (2H, Quartet, J = 8 Hz), and 1.00 (6H, singlet), 0,70 (3H, triplet, J = 8 Hz).

Mass spectrum (FAB + ve ion): m/e 527,1 (N+H).

Example 38.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea (compound 43).

Get similar to the methodology described in example 27B, using benzodiazepine (example 27A (185 mg, 0.38 mmol), trichromacy boron (2.5 ml, 1.0 M solution in methylene chloride) and isocyanate, which is obtained in the following way:

To a solution of 3-dimethylaminobenzoyl acid (165 mg, 1 mmol) in toluene (5 ml) is added diphenylphosphoryl (275 mg, 1 mmol) and triethylamine (101 mg, 1 mmol). The mixture is stirred at room temperature for 2 h, and then refluxed for 3 hours To a cooled mixture is added a solution of free amine in toluene (5 ml) and left to mix overnight at room temperature, evaporated, astatotilapia (phase separator Whatman PS I) and evaporated in vacuo. Clear thin-layer chromatography on silica gel (eluent - ethyl acetate) and obtain the target compound as a colourless solid (38 mg, 20%, purity >91% according to liquid chromatography high pressure).

Rf(ethyl acetate) to 0.15.

Range PMR (chloroform-d): 8,78 (1H, doublet, J = 2 Hz), of 8.27 (1H, doublet, J = 8 Hz), 7,95 (1H, multiplet), 7,65-6,6 (11H, multiplet), of 5.83 (1H, doublet, J = 8 Hz), of 5.05 (1H, doublet, J = 16 Hz), 4,60 (1H, doublet, J = 16 Hz) of 3.00 (6H, singlet), of 1.40 (9H, singlet).

Example 39.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1.4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea (compound 44).

39A. mono-Methylisophthalic.

Dimethyltotal (2.28 g, 11:7 mmol) dissolved in dioxane (25 ml) and treated with a solution LiOHH2O (510 mg, 12.1 mmol) in water (15 ml) as described in example 31B. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether:acetic acid 50:50:2) and obtain the target compound (1.1 g, 48%).

Range PMR (chloroform-d): to 8.45 (1H, singlet), 8,10 (2H, multiplet), was 7.45 (1H, multiplet), of 3.80 (3H, singlet).

39B. N-((3RS)-1-tract-BUTYLCARBAMATE-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1.4-benzodiazepine-3-yl)-N'-(3-is using benzodiazepine (example 27A (185 mg, 0.38 mmol), trichromacy boron (2.5 ml, 1.0 M solution in methylene chloride) and isocyanate, which is obtained from the acid from example 39A (250 mg, 1.4 mmol) using the procedure described in example 38. The product was then purified by chromatography (eluent - ethyl acetate) and obtain the target compound (110 mg, 56%).

Range PMR (chloroform-d): 8,30 (1H, doublet, J = 2 Hz), 7.95 is-7,00 (13H, multiplet), ceiling of 5.60 (1H, doublet, J = 8 Hz), 4,80 (1H, doublet, J = 16 Hz), 4,50 (1H, doublet, J = 16 Hz), 3,70 (3H, singlet), of 1.20 (9H, singlet).

39C. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl) -N'-(3-carboxyphenyl) urea.

Get similar to the methodology described in example 31B, using benzodiazepine (example 39B (110 mg, 0.21 mmol) and LiOHH2O (17 mg, 0.42 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:methanol:acetic acid, 75:2:1 vol./about./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and receive the product in a solid white color (20 mg, 19%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate:acetic acid, 100:2) 0,12.

Range PMR (chloroform-d): 8,50 (1H, doublet, J = 2 Hz), 8,10-to 7.35 (13H, multipl((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl) urea (compound 45).

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (400 mg, 0.8 mmol), 5% palladium on coal (400 mg) and isocyanate, obtained according to example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 60: 40./about.) and obtain the target compound, which is recrystallized from acetonitrile, and get a solid white (84 mg, 25%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 60:40) of 0.20.

Range PMR (chloroform-d): 7,60-6,50 (15H, multiplet), the 5.65 (1H, doublet, J = 8 Hz) and 4.65 (2H, singlet), and 2.8 (6H, singlet), 1,90-of 1.40 (6H, multiplet).

Mass spectrum (FAB + ve ion): m/e 524,5 (M+H).

Example 41.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl) -N'-(3-carboxyphenyl) urea (compound 46).

Get analogously to the method described in example 1C using the benzodiazepine (example 2B (380 mg, 0.8 mmol), 5% palladium on coal (300 mg) and isocyanate (3 mmol) obtained in example 38.

The crude product is purified by thin-layer chromatography on silica gel (eluent - these are the target compound as white powder (127 mg, 31%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 60:40) of 0.23.

Range PMR (chloroform-d): 7,60-6,9 (15H, multiplet), ceiling of 5.60 (1H, doublet, J = 8 Hz), 4,78 (1H, doublet, J = 18 Hz), and 4.68 (1H, doublet, J = 18 Hz), 2,80 (6H, singlet), of 1.20 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 512,5 (M+H).

Example 42.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1.4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl)urea (compound 47).

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (400 mg, 0.8 mmol), 5% palladium on coal (300 mg) and 3-methoxyphenylalanine (136 μl, 1.04 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 50:50./about.) and obtain the target compound, which is recrystallized from acetonitrile and get a white powder (265 mg, 65%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 50:50) of 0.20.

Range PMR (chloroform-d): 7,66-6,80 (15H, multiplet), of 5.75 (1H, doublet, J = 8 Hz), is 4.85 (1H, doublet, J = 8 Hz), 3,90 (3H, Singh is-dihydro-2-oxo-5-phenyl - 1H-1.4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl)urea (compound 48).

Get analogously to the method described in example 1C using the benzodiazepine (example 2B (385 mg, 0.8 mmol), 5% palladium on coal (300 mg) and 3-methoxyphenylalanine (136 μl, 1.04 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 45:55./about.) and recrystallized from acetonitrile, obtaining the target compound as white powder (249 mg, 63%, purity >99% according to liquid chromatography high pressure.

Rf(ethyl acetate:hexane fraction of petroleum ether, 50:50) of 0.23.

Range PMR (chloroform-d): 7,60-6,50 (15H, multiplet), to 5.85 (1H, doublet, J = 8 Hz), to 4.92 (1H, doublet, J = 18 Hz), 4,82 (1H, doublet, J = 18 Hz), 3,90 (3H, singlet), of 1.30 (9H, singlet).

Example 44.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl)urea (compound 49).

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (400 mg, 0.8 mmol), 5% palladium on coal (300 mg) and 3-nitrophenylhydrazine (171 μl, 1.04 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 45:55./about.) and the Council (291 mg, 69%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 50:50) to 0.22.

Range PMR (chloroform-d): 8,00-7,10 (15H, multiplet), the 5.65 (1H, doublet, J = 8 Hz), and 4.75 (1H, doublet, J = 17 Hz), of 4.67 (1H, doublet, J = 17 Hz), 2,95 (1H, multiplet), 1,90-of 1.30 (8H, multiplet).

Example 45.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl)urea (compound 50).

Get analogously to the method described in example 1C using the benzodiazepine (example 2B (385 mg, 0.8 mmol), 5% palladium on coal (300 mg) and 3-nitrophenylhydrazine (171 μl, 1.04 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 45:55./about.) and recrystallized from acetonitrile, obtaining the target compound in the form of solid pale yellow color (283 mg, 69%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 50:50) to 0.24.

Range PMR (chloroform-d): 8,10-6,90 (15H, multiplet), the 5.65 (1H, doublet, J = 8 Hz), is 4.85 (2H, singlet), 1,25 (9H, singlet).

Example 46.

N-((3R(compound 32).

46A. 1-Methylcyclopentanone acid.

To cyclohexene (25 ml, 0,246 mol) is added dropwise within 2 h, keeping the temperature at 5oC, concentrated sulfuric acid (100 ml) and formic acid (18,9 ml, 0.5 mol). Pour the mixture onto ice and extracted twice with ethyl acetate. The organic extracts are combined and washed with saturated salt solution, and then extracted with 2 m solution of caustic potash. The alkaline extract was acidified with 2 M hydrochloric acid and extracted with chloroform, filtered (phase separator Whatman PS I) and evaporated. The resulting brown oil purified by distillation from a cube in a cube (125 C/oil pump) and get the target compound as a colourless liquid (860 mg, 2%).

46B. Methyl bromide(1-methylcyclopentene)ketone (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from the acid from example 46A (860 mg, 6.7 mmol), chloride taanila (2 ml, 30 mmol) and diazomethane (generated from Diazald, 4.3 g, 20 mmol). Diazoketone further process the crude solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction petroleum everylittle), of 1.35 (3H, singlet).

46C. (3RS)-3-Benzyloxycarbonylamino-1-(1-methylcyclopentene) methylcarbamoylmethyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (202 mg, 0.5 mmol), sodium hydride (21 mg, 80% dispersion in oil, 0.70 mmol) and pommerellen for example 46B (133 mg, of 0.65 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether 40:60.about.) and get the target compound in the form of a colorless crystalline substance (190 mg, 74%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) to 0.24.

Range PMR (chloroform-d): the 7.65 7,05 (14H, multiplet), 6,55 (1H, doublet, J = 8 Hz), to 5.35 (1H, doublet, J = 8 Hz), and 5.30 (2H, singlet), of 5.05 (2H, singlet), of 4.77 (1H, doublet, J = 17 Hz), of 4.66 (1H, doublet, J = 17 Hz), 2,10-of 1.40 (8H, multiplet), of 1.20 (3H, singlet) .

46D. N-((3RS)-1-((1-methylcyclopentene)carbonylmethyl)-2,3-dihydro - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine for example 46C (190 mg, of 0.37 mmol), 5% palladium on coal (150 mg) and m-tallization (65 MK is the fraction of petroleum ether, 40: 60.about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and get a solid white color (102 mg, 54%, purity >97% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.20.

Range PMR (chloroform-d): 7,70-6,90 (15H, multiplet), 5,70 (1H, doublet, J = 8 Hz), 4,88 (1H, doublet, J = 17 Hz), 4,82 (1H, doublet, J = 17 Hz), is 2.30 (3H, singlet), 2,10-of 1.40 (8H, multiplet), 1,25 (3H, singlet).

Mass spectrum (FAB + ve ion): m/e 509,3 (M+H).

Example 47.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-formylamino)urea (compound 51).

47A. 3-Formelementname acid.

Acetic anhydride (50 ml) are added to 98% formic acid (85 ml). The mixture is stirred at room temperature for 30 minutes, and then add 3-aminobenzoic acid (10 g, 73 mmol) and the resulting mixture was stirred at room temperature for 1 h, Add water (850 ml) and leave the mixture was mixed overnight. Precipitated white precipitate is filtered off (10,66 g, 88%).

Range PMR (chloroform-d): 8,90 is 7.50 (7H, multiplet)

47B. N-((3RS)-1-tert-Butylcarbamoyl the

Benzodiazepine (example 2B hydronaut as described in example 1C, and the resulting amine (150 mg, 0.71 mmol) in toluene (2 ml) is treated with isocyanate, obtained from the acid from example 47A (410 mg, 2.5 mmol) in accordance with the methodology described in example 38. Product double-cleanse chromatography (eluent - ethyl acetate and a mixture of chloroform:methanol:acetic acid, 80: 20:1 vol./about./about.) and recrystallized from acetonitrile, getting a colourless solid (75 mg, 21%, purity >97% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 8,90-8,10 (3H, multiplet), 7,75-7,10 (14,5 H, multiplet), 6,70 (1/2H, doublet, J = 18 Hz), of 5.75 (1H, multiplet), of 4.90 (1H, multiplet), of 1.30 (9H, singlet).

Mass spectrum: (M+H)+= 512,2.

Example 48.

N-((3RS)-1-((2R)-2-Hydroxy-3,3-dimethylbutyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 52).

Benzodiazepinovye in example 26 (180 mg, 0,373 mmol) dissolved in a mixture of methanol and dichloromethane (5 ml, 1/1 vol./vol.), add CeCl37H2O (155 mg, 0,416 mmol) and stirred the mixture until complete dissolution of all solid compounds, and then cooled to a temperature of -78oC. Add sodium borohydride (20 mg, 0,529 mmol) and peremeshali for 2 h to warm to room temperature. Pour in a mixture of chloroform and saturated salt solution, the organic phase is separated, dried and evaporated. The residue is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether 40:60.about.) receive a colourless solid (105 mg, 58%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate:fraction of petroleum ether with so Kip. 60-80oC, 40:60) 0,31.

Range PMR (chloroform-d): 7,8-6,9 (15H, multiplet), 5,6 (1H, doublet, J = 8 Hz), 4,35 (1H, multiplet), 3,6 (2H, multiplet), 2,2 (3H, singlet) to 0.85 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 485,3 (M+H).

Example 49.

N-((3RS)-1-Cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl) -N'-(3-cyanophenyl) urea (compound 22)

Get analogously to the method described in example 1C using the benzodiazepine (example 4B (300 mg, 0.6 mmol), 5% palladium on coal (150 mg) and isocyanates derived from 3-cyanobenzoic acid (295 mg, 2 mmol), in accordance with the methodology described in example 30. The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:ethyl acetate, 100: 2 vol. /about.) and obtain the target compound, which is subjected to Sublim is;97% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 8,20-8,50 (4H, multiplet), 7,70-7,10 (11H, multiplet), of 5.50 (1H, doublet, J = 8 Hz), and 4.75 (1H, doublet, J = 17 Hz), of 4.66 (1H, doublet, J = 17 Hz), 1,75-of 1.35 (8H, multiplet).

Mass spectrum: (M+H)+= 506,1.

Example 50.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-cyanophenyl)urea (compound 23).

Get analogously to the method described in example 1C using the benzodiazepine (example 2B (290 mg, 0.6 mmol), 5% palladium on coal (150 mg) and isocyanates derived from 3-cyanobenzoic acid (295 mg, 2 mmol), in accordance with the method described in example 30. The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:ethyl acetate, 100: 2 vol. /about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water (36 mg, 12%, a purity of >96% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 8,20-with 8.05 (4H, multiplet), 7,70-7,10 (11H, multiplet), of 5.50 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), 4,70 (1H, doublet, J = 17 Hz) and 1.15 (9H, singlet).

Mass spectrum: (M+H)+= 494,2.

Example 51.

N-((3RS)-1-(1-Substituted)carbonylmethyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N">

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from the acid chloride of 1-adamantanecarbonyl acid (2,98 g, 15 mmol) and diazomethane (generated from Diazald, 8.7 g, 40 mmol) and then treated with saturated solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 8:92.about.) get the target compound in the form of oil pale brown (2.30 g, 60%).

Range PMR (chloroform-d): 4,20 (2H, singlet), 2,15-1,75 (15H, multiplet).

51B. (3RS)-(1-Substituted)carbonylmethyl-3-benzyloxycarbonylamino - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (202 mg, 0.5 mmol), sodium hydride (21 mg, 80% dispersion in oil, 0.7 mmol) and bromeilles in example 51A (167 mg, of 0.65 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether 40:60.about.) and get the target compound in the form of a colorless crystalline substance (130 mg, 46%).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.20.

51C. N-((3RS)-1-(1-Substituted)carbonylmethyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine for example 51B (130 mg, 0.23 mmol), 5% palladium on coal (100 mg) and m-tallization (45 μl, 0.35 mmol). The crude product is purified by thin-layer chromatography (eluent - ethyl acetate:hexane fraction of petroleum ether, 35:65./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and get a solid white (57 mg, 44%, a purity of >96% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,75-7,10 (14H, multiplet), PC 6.82 (1H, doublet, J = 8 Hz), of 5.75 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), 4,80 (1H, doublet, J = 17 Hz), is 2.30 (3H, singlet), 2,1-1,60 (15H, multiplet).

Mass spectrum (FAB + ve ion): m/e 561,3 (M+H).

Example 52.

N-((3RS)-1-(3-Cyclohexyl-3-methyl-2-oxobutyl)-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 28).

52A. Methyl-2-methyl-2-phenylpropanoate.

To a solution of methyl ester of phenylacetic CISL). The mixture was stirred at 0oC for 30 minutes, and then add itmean (4,4 ml, 70 mmol) and the mixture at the same temperature, stirred for another 30 minutes. Add an additional amount of sodium hydride (2.25 g, 80% dispersion in oil, 75 mmol) and stirred at a temperature of 0oC for 30 minutes, and then add itmean (8,8 ml, 140 mmol) and the mixture is left at room temperature for 48 hours the Reaction is interrupted, adding water, and the mixture is evaporated to remove THF. The residue is dissolved in ethyl acetate and washed with 5% solution of potassium bicarbonate, 0.3 M solution of potassium bisulfate, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated, obtaining the target compound in the form of oil (3,20 g, 26%).

Range PMR (chloroform-d): 7,70-of 7.25 (5H, multiplet), of 3.60 (3H, singlet), of 1.55 (6H, singlet).

52B. 2-Methyl-2-phenylpropane acid.

A solution of methyl ester from example 21A (3,20 g, 18 mmol) in dioxane (25 ml) is treated with a solution LiOHH2O (1.50 g, 36 mmol) in water (15 ml) as described in example 31B, obtaining the target compound as a colourless oil (1.85 g, 63%).

Range PMR (chloroform-d): 7,50-of 7.25 (6H, multiplet), of 1.55 (6H, singlet).

52C. 2-Cyclohexyl-2-methylpropanoate Kolotova nitrogen. Add 5% rhodium on the corner (2 g) and the mixture Tegaserod for 10 minutes, and then hydronaut at room temperature in a Parr apparatus under a pressure of 60 psi for 4 days. The mixture is filtered through a zeolite and the filtrate is evaporated, obtaining the target compound as a colourless oil (1.70 g, 88%).

Range PMR (chloroform-d): 1,90-1,00 (11H, multiplet), of 1.20 (6H, singlet).

52D. 1-bromo-3-cyclohexyl-3-methylbutane-2-he (scheme 2, steps (i)-(iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from the acid in example 52C (170 g, 10 mmol), chloride taanila (2 ml, 30 mmol) and diazomethane (generated from Diazald, 8.7 g, 40 mmol) and then treated with saturated solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 5:95.about.) get the target compound in the form of rolling oil is pale-brown (280 mg, 11%).

Range PMR (chloroform-d): 4,30 (2H, singlet), 2,90-1,10 (11H, multiplet), of 1.20 (6H, singlet).

52E. (3RS)-3-Benzyloxycarbonylamino-1-(3-cyclohexyl-3-methyl-2 - oxobutyl)-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Polucha mg, 80% dispersion in oil, 0.70 mmol) and pommerellen for example 52D (160 mg, of 0.65 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane A, 35: 65./about.) and get the target compound in the form of a colorless crystalline substance (70 mg, 25%).

Range PMR (chloroform-d): 7,55-7,05 (14H, multiplet), 6,55 (1H, doublet, J = 8 Hz), and 5.30 (1H, doublet, J = 8 Hz), 5,02 (2H, singlet), 4,78 (1H, doublet, J = 17 Hz), 4,58 (1H, doublet, J = 17 Hz), 1.70 to 0,90 (11H, multiplet), and 1.00 (6H, singlet).

52F. N-((3RS)-1-(3-Cyclohexyl-3-methyl-2-oxobutyl)-2,3-dihydro - 2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine for example 52E (70 mg, 0.13 mmol), 5% palladium on coal (50 mg) and m-tallization (20 μl, 0.16 mmol). The crude product is purified by thin-layer chromatography (eluent - ethyl acetate:hexane fraction of petroleum ether, 40: 60 about. /about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and get a solid white (35 mg, 50%, purity >95% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,70-6,95 (14H, multiplet), 6,60 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 the = of 551.3.

Example 53.

N-((3RS)-1-(1-Methylcyclopropyl)carbonylmethyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 54).

53A. Methyl bromide is 1-methylcyclopropyl.

To a stirred solution of methyl-1-methylcyclopropene (5 g, of 50.9 mmol) in methanol (30 ml) at a temperature of 0oC added dropwise bromine (2.6 ml, 51 mmol). The mixture is stirred at a temperature of 0oC for 2 hours, water is Added (15 ml) and the mixture is left overnight to mix at room temperature. Add a further quantity of water (45 ml) and the product extracted with diethyl ether. The organic phase is washed with 10% potassium carbonate, water and saturated salt solution, dried over calcium chloride for 30 minutes, filtered (phase separator Whatman PS I) and evaporated, obtaining the target compound in the form of transparent rolling oil (8.2 g, 91%).

Range PMR (chloroform-d): 3,95 (2H, singlet), of 1.40 (3H, singlet), of 1.30 (2H, triplet, J = 7 Hz), 0,80 (2H, triplet, J = 7 Hz).

53B. (3RS)-3-Benzyloxycarbonylamino-1-(1-methylcyclopropyl)carbonylmethyl - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using benzodiazepine is 0.75 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane A 40: 60.about.) and get the target compound in the form of a colorless crystalline substance (190 mg, 79%).

Range PMR (chloroform-d): 7,55-7,10 (14H, multiplet), of 6.65 (1H, doublet, J = 8 Hz), of 5.40 (1H, doublet, J = 8 Hz), 5,10 (2H, singlet), of 4.77 (1H, doublet, J = 17 Hz), 4,55 (1H, doublet, J = 17 Hz), of 1.40 (3H, singlet), 1,25 (2H, triplet, J = 7 Hz), 0,75 (2H, triplet, J = 7 Hz).

53C. N-((3RS)-1-(1-Methylcyclopropyl)carbonylmethyl-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get analogously to the method described in example 1C using the benzodiazepine (example 53B (190 mg, 0.4 mmol), 5% palladium on coal (200 mg) and m-tallization (65 ál, 0.5 mmol). The crude product is purified by thin-layer chromatography (eluent - ethyl acetate:hexane fraction of petroleum ether, 45:55./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and get a solid white color (150 mg, 78%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.16.

Range PMR (chloroform-d): 7,70-7,10 (14H, the mule is H, singlet), of 1.30 (2H, triplet, J = 7 Hz), of 0.90 (2H, triplet, J = 7 Hz).

Mass spectrum (FAB + ve ion): m/e 481,2 (M+H).

Example 54.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - chlorophenyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 55).

54A. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B using (3RS)-3-benzyloxycarbonylamino-7-chloro-5-(2-chlorophenyl)- 1H-1,4-benzodiazepine-2-she (241 mg, 0.51 mmol, get similar to benzodiazepine Side), sodium hydride (2 mg, 80% dispersion in oil, to 0.72 mmol) and 1-bromopinacolone (179 mg, 1 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 30:70.about.) and obtain the target compound (145 mg, 52%).

Range PMR (chloroform-d): 7,80-7,30 (12H, multiplet), to 6.80 (1H, doublet, J = 8 Hz), ceiling of 5.60 (1H, doublet, J = 8 Hz), and 5.30 (2H, singlet), a 5.25 (1H, doublet, J = 17 Hz), 4,60 (1H, doublet, J = 17 Hz), of 1.35 (9H, singlet).

54B. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - chlorophenyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get anal is on the corner (120 mg) and m-tallization (40 μl, 0.32 mmol). The crude product is purified by thin-layer chromatography (eluent - ethyl acetate:hexane fraction of petroleum ether 40:60.about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and get a solid white (45 mg, 31%).

Range PMR (chloroform-d): 7,70-6,95 (14H, multiplet), 5,80 (1H, doublet, J = 8 Hz), and 5.30 (1H, doublet, J = 17 Hz), 4,60 (1H, doublet, J = 17 Hz), is 2.40 (3H, singlet), of 1.30 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e from 517.2 (M+H).

Note: 7-chlorinated lost in the process of hydrogenolysis.

Example 55.

N-((3RS)-1-ISO-Propylmalonate-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 56).

55A. 1-bromo-3-methylbutane-2-he (scheme 2, steps (i) - (iii)).

Get by the method similar to that shown in example 3A. Intermediate diazoketone prepared from somaclonal acid (8,82 g, 100 mmol), chloride taanila (30 ml, 400 mmol) and diazomethane (generated from Diazald, 43 g, 200 mmol) and then treated with saturated solution of hydrogen bromide in acetic acid ethyl ester. After thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 6:94.about.) get the target with the H, singlet), of 3.00 (1H, septet, J = 8 Hz), 1,25 (6H, doublet, J = 8 Hz).

55B. (3RS)-3-Benzyloxycarbonylamino-1-ISO-propylmalonate - 2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get analogously to the method described in example 1B, using the benzodiazepine of the Sides (606 mg, 1.5 mmol), sodium hydride (63 mg, 80% dispersion in oil, 2.1 mmol) and pommerellen for example 55A (300 mg, 1.8 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether 40:60.about.) and get the target compound in the form of a colorless crystalline substance (250 mg, 36%).

Range PMR (chloroform-d): 7,70-7,20 (14H, multiplet), to 6.75 (1H, doublet, J = 8 Hz), of 5.50 (1H, doublet, J = 8 Hz), 5,20 (2H, singlet), is 4.85 (1H, doublet, J = 17 Hz), and 4.75 (1H, doublet, J = 17 Hz), 2,80 (1H, septet, J = 8 Hz), 1,25 (6H, doublet, J = 8 Hz).

55C. N-((3RS)-1-ISO-Propylmalonate-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get similar to the methodology described in example 27B, using benzodiazepine for example 55B (250 mg, of 0.53 mmol), trichromacy boron (3.2 ml, 1.0 M solution in methylene chloride) and m-tallization (40 μl, 0.31 mmol). The crude product is purified thin layer of chromium is Evoe connection, which is subjected to the freeze-drying of a mixture of acetonitrile-water and get a solid white color (51 mg, 21%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 50:50) of 0.16.

Range PMR (chloroform-d): 7,70-7,15 (14H, multiplet), 6,85 (1H, doublet, J = 8 Hz), 5,70 (1H, doublet, J = 8 Hz), and 4.75 (2H, singlet), 2,70 (1H, septet, J = 8 Hz), is 2.30 (3H, singlet), of 1.18 (6H, doublet, J = 8 Hz).

Mass spectrum (FAB + ve ion): m/e 469,3 (M+H).

Example 56.

N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea (compound 57).

56A. N-methyl-3-methoxycarbonylamino.

Get on the methodology described in example 1B from 3-carboxyphenylazo (2.28 g, of 13.8 mmol), sodium hydride (1,05 g of 80% dispersion in oil, 34.5 mmol) and iodomethane (2,86 ml, 45 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 60:40./about.) and get the target compound in the form of a colorless crystalline substance (2.30 g, 86%).

Range PMR (chloroform-d): 8,50 (1H, singlet), of 7.90-7,40 (4H, multiplet), of 3.95 (3H, singlet), 3,40 (3H, singlet).

is the example 56A (1.90 g, 9.8 mmol) and LiOHH2O (840 mg, 20 mmol). The target compound is a colorless crystalline substance (985 mg, 56%).

56C. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-formyl-N-methylaminophenol)urea (scheme 1, step (ii)).

Rassheplenie aminobenzothiazole in example 26 (980 mg, 2.8 mmol) in toluene (10 ml) is treated with isocyanate, obtained from the acid from example 56B (985 mg, 5.5 mmol) in accordance with the methodology described in example 38. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 75:25./about.) and obtain the target compound (960 mg, 65%).

Range PMR (chloroform-d): to 8.45 (1H, singlet), 7,65-7,05 (14H, multiplet), 6,70 (1H, doublet, J = 8 Hz), 5,70 (1H, doublet, J = 8 Hz), to 4.98 (1H, doublet, J = 17 Hz), and 4.75 (1H, doublet, J = 17 Hz), 3,20 (3H, singlet), of 1.30 (9H, singlet).

56D. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol) urea.

Benzodiazepine for example 56C (960 mg, 1.8 mmol) dissolved in acetone (15 ml) and treated with 4N hydrochloric acid (9 ml). The mixture is stirred at room temperature for 3 days, evaporated, dissolved the residue in chlorite is up. The residue is purified by thin-layer chromatography on silica gel (eluent - chloroform:methanol:acetic acid, 120: 2:1 vol./about./about.) and obtain the target compound, which is recrystallized from a mixture of acetonitrile/ether and receive solid white (400 mg, 45%, purity >99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,70-7,20 (13H, multiplet), to 6.75 (1H, singlet), of 6.65 (1H, doublet, J = 8 Hz), 6,30 (1H, doublet, J = 8 Hz), of 5.75 (1H, doublet, J = 8 Hz), is 4.85 (1H, singlet), 2,80 (3H, singlet), of 1.20 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 498,3 (M+H).

Example 57.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea (compound 58).

57A. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo - 5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-formyl-N - methylaminophenol)urea (scheme 1, step (ii)).

Get similar to the methodology described in example 27B, using benzodiazepine (example 27A (340 mg, 0.7 mmol), trichromacy boron (4,4 ml, 1.0 M solution in methylene chloride) and the isocyanate derived from the acid from example 56B (420 mg, 2.3 mmol) in accordance with the methodology described in example 38. The crude product is purified thin layer of chromium is chloroform-d): to 8.25 (1H, doublet, J = 8 Hz), 8,00 (1H, singlet), 7,60-6,80 (12H, multiplet), 6,40 (1H, doublet, J = 8 Hz), to 5.35 (1H, doublet, J = 8 Hz), to 4.62 (1H, doublet, J = 17 Hz), 4,30 (1H, doublet, J = 17 Hz), 2,90 (3H, singlet), of 0.90 (9H, singlet).

57B. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl) -N'-(3-methylaminophenol) urea.

Get on the methodology described in example 56D using benzodiazepine (example 57A (185 mg, 0.35 mmol), acetone (5 ml) and 4N hydrochloric acid (3 ml). The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:methanol:acetic acid, 120:2:1 vol./about./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and receive the product in the form of a solid white (67 mg, 38%, purity >95% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 8,30 (1H, doublet, J = 8 Hz), 7,95 (1H, doublet, J = 7 Hz), 7,60 (1H, triplet, J = 7 Hz), 7,35 (1H, triplet, J = 7 Hz), 7,20-6,85 (8H, multiplet), 6,50 (1H, singlet), 6,30 (1H, doublet, J = 8 Hz), 6,10 (1H, doublet, J = 8 Hz), of 5.40 (1H, doublet, J = 8 Hz), and 4.75 (1H, doublet, J = 17 Hz), and 4.40 (1H, doublet, J = 17 Hz), 2,60 (3H, singlet), of 0.95 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 499,3 (M+H).

Example 58.

N-((3R)-1-tert-Butylcarbamoyl-P> 58A. Methyl-3-(N-ethyl-N-methylamino)benzoate.

Get on the methodology described in example 56D, using the methyl ester from example 56A (2.35 g, 12.2 mmol), acetone (100 ml) and 4N hydrochloric acid (60 ml). The obtained amine dissolved in a mixture of methanol:acetic acid (99:1, 70 ml) at a temperature of 0oC. Add acetaldehyde (1.0 ml, 18 mmol) and NaBH3CN (1.13 g, 18 mmol). The mixture was stirred at 0oC for 2 h, evaporated, dissolved the residue in ethyl acetate, washed with 5% solution of potassium bicarbonate, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 15:85.about.) and obtain the target compound (2.15 g, 91%).

Range PMR (chloroform-d): 7,40-of 7.25 (3H, multiplet), of 6.90 (1H, multiplet), 3,90 (3H, singlet), of 3.45 (2H, Quartet, J = 7 Hz), 2,95 (3H, singlet) and 1.15 (3H, triplet, J = 7 Hz).

58B. N-(N-ethyl-N-methylamino)benzoic acid.

Get on the methodology described in example 31B, using the ester from example 58A (2.15 g, 11.1 mmol) and LiOHH2O (920 mg, 22 mmol). The target connection purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of patrilineality-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl)urea.

Split benzodiazepine according to example 26 (245 mg, 0.7 mmol) in toluene (5 ml) is treated with isocyanate, obtained from the acid from example 58B (250 mg, 1.4 mmol) in accordance with the methodology described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 45:55./about.) and obtain the target compound, which is recrystallized from acetonitrile and get a solid white color (237 mg, 64%, purity >99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,70-7,05 (13H, multiplet), to 6.58 (1H, singlet), 6,50 (1H, doublet, J = 8 Hz), 5,80 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), a 4.83 (1H, doublet, J = 17 Hz), 3,40 (2H, Quartet, J = 7 Hz), 2,95 (3H, singlet), 1,25 (9H, singlet), to 1.15 (3H, triplet, J = 7 Hz).

Mass spectrum (FAB + ve ion): m/e 526,3 (M+H).

Example 59.

N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea (compound 60).

59A. 3-Etoxycarbonyl-N-ethylformate.

Get on the methodology described in example 1B from 3-carboxyphenylazo (5.0 g, 30 mmol), sodium hydride (of 2.26 g of 80% dispersion in oil, 75 mmol) and iodine ethyl (5,2 ml, 64 mmol). Salanova ether, 50: 50./about.) and get the target connection (6,00 g, 27,1 mmol).

Range PMR (chloroform-d): 8,50 (1H, singlet), 8,00 is 7.50 (4H, multiplet), of 4.95 (2H, Quartet, J = 7 Hz), 4.00 points (2H, Quartet, J = 7 Hz), 1,50 (3H, triplet, J = 7 Hz), of 1.30 (3H, triplet, J = 7 Hz).

59B. Ethyl ester of 3-diethylaminobenzoic acid.

Get on the methodology described in example 56D, using the methyl ester from example 59A (3.50 g, 15.8 mmol), acetone (130 ml) and 4N hydrochloric acid (80 ml). Received alkylate amine by the method described in example 58A, using acetaldehyde (1.3 ml, with 23.3 mmol) and NaBH3CN (1,46 g, with 23.3 mmol). The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 10:90.about.) and obtain the target compound (1.90 g, 54%).

Range PMR (chloroform-d): 7,95-7,80 (3H, multiplet), 7,40 (1H, multiplet), of 4.90 (2H, Quartet, J = 7 Hz), 3,90 (4H, Quartet, J = 7 Hz), 1,95 (3H, triplet, J = 7 Hz), a 1.75 (6H, triplet, J = 7 Hz).

59C. 3-Diethylaminobenzoic acid.

Get on the methodology described in example 31B, using the ester from example 59B (1.90 g, 8.6 mmol) and LiOHH2O (720 mg, and 17.2 mmol). The target connection purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of the petrol is ylmethyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea (scheme 1, stage (ii)).

Split benzodiazepine according to example 26 (175 mg, 0.5 mmol) in toluene (5 ml) is treated with isocyanate, obtained from the acid in example 59C (240 mg, 1.2 mmol) according to the method described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 45:55./about.) and obtain the target compound, which is recrystallized from acetonitrile and get a solid white color (147 mg, 55%, purity >99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,70-7,05 (13H, multiplet), 6,60 (1H, doublet, J = 8 Hz), 6,50 (1H, doublet, J = 8 Hz), 5,80 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), was 4.76 (1H, doublet, J = 17 Hz), of 3.45 (2H, Quartet, J = 7 Hz), of 1.30 (9H, singlet), of 1.20 (6H, triplet, J = 7 Hz).

Mass spectrum (FAB + ve ion): m/e 540,3 (M+H).

Example 60.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea (compound 61).

60A. 3-Dimethylaminobenzonitrile.

To a solution of 3-cyanobenzaldehyde (2.50 g, 19 mmol) in a mixture of methanol:acetic acid (25 ml, 99:1) are added at a temperature of 0oC dimethylamine (2.5 ml, 50 mmol), and then NaBH3b ethyl acetate, washed with 5% solution of potassium bicarbonate, saturated salt solution, filtered (phase separator Whatman PS I) and evaporated. The residue is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:methanol, 98:2 vol./about.) and get the target connection (1,15 g, 38%).

Range PMR (chloroform-d): 7,75-of 7.60 (4H, multiplet), 3,50 (2H, singlet), to 2.35 (6H, singlet).

60B. Methyl ether 3-dimethylaminomethylphenol acid.

A solution of the nitrile from example 60A (1,15 g, 7.2 mmol) in 4 M solution of hydrogen chloride in methanol (200 ml) is stirred at a temperature of 0oC for 2 h and then at room temperature for 18 hours, water is Added (25 ml) and stirred the mixture at room temperature for 1 h, evaporated and subjected to azeotropic distillation with toluene, the residue is dissolved in chloroform, washed with 5% solution of potassium bicarbonate, filtered (phase separator Whatman PS I) and evaporated, obtaining the target compound (1.20 g, 86%).

Range PMR (chloroform-d): 8,00 is 7.50 (4H, multiplet), of 3.60 (2H, singlet), is 2.30 (6H, singlet).

60C. 3-Dimethylaminomethylphenol acid.

Get on the methodology described in example 31B, using the ester from example 60B (1.20 g, 6.2 mmol) and LiOHH2O (540 mg, 13 MMNA acid, 25:10:1) and obtain the target compound (750 mg, 68%).

60D. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea (scheme 1, step (iii)).

Benzodiazepine (example 2B hydronaut according to the method described in example 1C, and the resulting amine (192 mg, 0.55 mmol) in toluene (5 ml) is treated with isocyanate, obtained from the acid in example 60C (250 mg, 1.4 mmol) in accordance with the methodology described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:methanol:acetic acid, 20:2:1 vol./about./about.) and is recrystallized from acetonitrile and get a solid white color (50 mg, 17%, purity >99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,55-6,90 (15H, multiplet), to 6.57 (1H, doublet, J = 8 Hz), 4,80 (1H, doublet, J = 17 Hz), 4,70 (1H, doublet, J = 17 Hz), 3,40 (2H, singlet), of 2.25 (6H, singlet) and 1.15 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 526,3 (M+H).

Example 61.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)- 1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl)urea (compound 62).

The benzodiazepine (example 27A remove protection, as described in example 27B, B (250 mg, 1.4 mmol) in accordance with the methodology described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 90:10./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile/water and receive the product in a solid white color (125 mg, 42%, purity >95% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 90:10) of 0.23.

Mass spectrum (FAB + ve ion): m/e 527,3 (M+H).

Example 62.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea (compound 63).

The benzodiazepine (example 27A remove protection, as described in example 27B, and the resulting amine (200 mg, or 0.57 mmol) in toluene (5 ml) is treated with isocyanate, obtained from the acid in example 60C (250 mg, 1.4 mmol) in accordance with the methodology described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - chloroform:methanol:acetic acid, 18: 4:1 vol./about./about.) and obtain the target compound, which is recrystallized from a mixture of ethyl acetate-geksanovoi chromatography high pressure).

Range PMR (chloroform-d): 8,50 (1H, doublet, J = 8 Hz), 8,00-7,20 (12H, multiplet), to 6.80 (1H, doublet, J = 8 Hz), ceiling of 5.60 (1H, doublet, J = 8 Hz), 4,80 (1H, doublet, J = 17 Hz), 4,50 (1H, doublet, J = 17 Hz), 3,40 (2H, singlet), of 2.20 (6H, singlet), of 1.20 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 527,3 (M+H).

Example 63.

N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(2 - pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea (compound 64).

The benzodiazepine (example 27A remove protection, as described in example 27B, and the resulting amine (200 mg, or 0.57 mmol) in toluene (5 ml) is treated with isocyanate, obtained from the acid in example 59C (212 mg, 1.1 mmol) according to the method described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 75:25./about.) and obtain the target compound, which is recrystallized from acetonitrile and get a solid white color (200 mg, 65%, purity >99% according to liquid chromatography high pressure).

Range PMR (chloroform-d): at 8.60 (1H, doublet, J = 8 Hz), 8,17 (1H, doublet, J = 8 Hz), 7,70-6,90 (10H, multiplet), 6,40 (2H, multiplet), of 5.75 (1H, doublet, J = 8 Hz), of 4.90 (1H, doublet, J = 17 Hz), and 4.40 (1H, doublet, J = 17 Hz), 3,30 (2H, Quartet, J = 7 Hz), 1,20 (9HN-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea (compound 65).

Receive from the split aminobenzothiazole in example 26 (1.88 g, 5.4 mmol) in accordance with the methodology described in example 38. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 55:45./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of dioxane-water and obtain the target compound in the form of solid white (1,72 g, 62%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 60:40) of 0.21.

Mass spectrum (FAB + ve ion): m/e 512,3 (M+H).

[]D= +97,3o(chloroform, c = 0,776).

Example 65.

N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(4 - were)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 66).

65A. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 2,3-dihydro-5-(4-were)-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get from (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(4 - were)-1H-1,4-benzodiazepine-2-she (200 mg, of 0.53 mmol, get similar to benzodiazepine Side) in accordance with the methodology described in example 2B. The crude product ester, 35:65./about.) and get the target compound as a colourless liquid (252 mg, 96%).

Range PMR (chloroform-d): 7,53 (3H, multiplet), 7,41-7,13 (9H, multiplet), of 6.68 (1H, doublet, J = 8 Hz), 5,44 (1H, doublet, J = 8 Hz), is 5.18 (2H, singlet), 5,00 (1H, doublet, J = 17 Hz), of 4.67 (1H, doublet, J = 17 Hz), 2,42 (3H, singlet), of 1.35 (9H, singlet).

65B. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5-(4 - were)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Receive from the benzodiazepine (example 65A and according to the methodology described in example 14B. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 37:63.about.) and get a product that is subjected to freeze-drying of a mixture of dioxane-water and obtain the target compound in the form of solid white (118 mg, 47%, purity >98% filed liquid chromatography high pressure).

Rf(ethyl acetate:hexane, 40:60) of 0.18.

Range PMR (chloroform-d): 9,02-8,92 (3H, multiplet), 8,82-8,20 (11H, multiplet), 7,10 (1H, doublet, J = 5 Hz), 6,32 (1H, doublet, J = 8 Hz), 6,17 (1H, doublet, J = 8 Hz), 3,82 (3H, singlet), and 3.72 (3H, singlet), 2,66 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 497,3 (M+H).

Example 66.

N-((3R)-1-t

66A. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl)urea (scheme 1, step (ii)).

Split aminobenzothiazoles according to example 26 is treated with m-nitrophenylacetate as described in example 45, and receive a colorless oil (490 mg, 94%).

Data identical to those given in example 45.

66B. N-((3R)-1-tert-Butylcarbamoyl-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL) urea.

Benzodiazepine for example 66A (245 mg, 0,568 mmol) dissolved in 1 M solution of ammonium chloride (8 ml) and treated with zinc dust (620 mg), and then with vigorous stirring, slowly add ethanol (8 ml). After 1/2 h the mixture is filtered and evaporated. The residue is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 80:20./about.) and obtain the target compound, which is subjected to the freeze-drying of a mixture of acetonitrile-water and obtain the target compound in the form of solid white (115 mg, 67%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate) of 0.64.

Range PMR (chloroform-d): 7,8-7,0 (11H, multiplet), 6,9 (1H, triplet, J = 8.5 Hz), 6, the et).

[]D= +25o(methanol, c = 0,933).

Mass spectrum (FAB + ve ion): m/e 484,3 (M+H).

Example 67.

N-((3RS)-1-tert-Butylcarbamoyl-7-chloro-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 74).

67A. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get from (3RS)-3-benzyloxycarbonylamino-7-chloro-2,3-dihydro - 5-phenyl-1H-1,4-benzodiazepine-2-she (640 mg, of 1.46 mmol) are similar to benzodiazepine Side), sodium hydride (62 mg, 80% dispersion in oil, 2.04 mmol) and 1-bromopinacolone (537 mg, 3 mmol in accordance with the methodology described in example 1B. The crude product is purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 30:70.about.) and obtain the target compound (700 mg, 93%).

Range PMR (chloroform-d): 7,70-7,30 (13H, multiplet), 6,8 (1H, doublet, J = 8 Hz), ceiling of 5.60 (1H, doublet, J = 8 Hz), and 5.30 (2H, singlet), of 5.05 (1H, doublet, J = 17 Hz), 4,80 (1H, doublet, J = 17 Hz), of 1.35 (9H, singlet).

67B. N-((3RS)-1-tert-Butylcarbamoyl-7-chloro-2,3-dihydro-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Get similar techniques the solution in methylene chloride) and m-tallization (90 μl, 0.66 mmol). The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether 40:60.about.) and get a product that is subjected to freeze-drying of a mixture of acetonitrile-water and obtain the target compound in the form of solid white (83 mg, 31%, purity >98% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,70-6,95 (13H, multiplet), 5,80 (1H, doublet, J = 8 Hz), 4,90 (3H, singlet), is 2.40 (3H, singlet), 1,25 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e from 517.2 (M+H).

Example 68.

N-((3RS)-1-tert-Butylcarbamoyl-7-chloro-2,3-dihydro-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimetilfenil)urea (compound 75).

Get similar to the methodology described in example 27B, using benzodiazepine (example 67A (430 mg, 0.83 mmol), trichromacy boron (5.0 ml, 1.0 M solution in methylene chloride) and the isocyanate derived from 3-dimethylaminobenzoyl acid (400 mg, 2.4 mmol), in accordance with the methodology described in example 38. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum ether, 45:55 about. /about. and get the target compound, which is subjected to sublimation is 22%, purity >98% according to liquid chromatography high pressure).

Range PMR (chloroform-d): 7,60-6,90 (12H, multiplet), 6,50 (1H, doublet, J = 8 Hz), 6,40 (1H, doublet, J = 8 Hz), ceiling of 5.60 (1H, doublet, J = 8 Hz), and 4.75 (3H, singlet), 2,90 (6H, singlet), 2,10 (3H, singlet) and 1.15 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 546,3 (M+H).

Example 69.

N-((3RS)-1-tert-Butylcarbamoyl-7-chloro-2,3-dihydro-2-oxo - 5-(2-chlorophenyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (compound 76).

Get similar to the methodology described in example 27B, using benzodiazepine (example 54A (170 mg, 0.31 mmol), trichromacy Bor (2 ml, 1.0 M solution in methylene chloride) and m-trilinoleate (60 μl, 0.4 mmol). The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 35:65./about.) and get a product that is subjected to freeze-drying of a mixture of acetonitrile/water and get the target compound in the form of solid white (39 mg, 51%, purity >99% according to liquid chromatography high pressure).

Rf(ethyl acetate:hexane fraction of petroleum ether, 40:60) of 0.25.

Mass spectrum (FAB + ve ion): m/e 551,2 (M+H).

Example 70.

N-((3RS)-1-tert-BU).

70A. (3RS)-3-Benzyloxycarbonylamino-1-tert-butylcarbamoyl - 7-chloro-2,3-dihydro-8-methyl-5-phenyl-1H-1,4-benzodiazepine-2-he (scheme 1, step (i)).

Get from (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-8-methyl - 5-phenyl-1H-1,4-benzodiazepine-2-she (240 mg, 0.64 mmol, get similar to benzodiazepine Side) in accordance with the methodology described in example 2B. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate: hexane fraction of petroleum ether, 30:70.about.) and obtain the target compound (289 mg, 91%).

Rf(ethyl acetate: hexane fraction of petroleum ether, 30:70.about.) 0,17.

Range PMR (chloroform-d): to 7.67 (2H, multiplet), and 7.4 (9H, multiplet), 7,25 (1H, doublet, J = 8 Hz), of 6.96 (1H, singlet), 6,70 (1H, doublet, J = 9 Hz), vs. 5.47 (1H, doublet, J = 9 Hz), 5,19 (2H, singlet), to 4.98 (1H, doublet, J = 18 Hz), 4,70 (1H, doublet, J = 18 Hz), 2,46 (3H, singlet), of 1.30 (9H, singlet).

70B. N-((3RS)-1-tert-Butylcarbamoyl-2,3-dihydro-8-methyl-2 - oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea (scheme 1, step (ii)).

Receive from the benzodiazepine (example 70A (289 mg, of 0.58 mmol) by the method described in example 14B. The product was then purified by thin-layer chromatography on silica gel (eluent - ethyl acetate:hexane fraction of petroleum e and obtain the target compound in the form of solid white (106 mg, 37%, purity >98% according to liquid chromatography high pressure).

Rf(ethyl acetate: hexane fraction of petroleum ether 40:60.about.) 0,18.

Range PMR (chloroform-d): to 7.67 (2H, multiplet), 7,46 (2H, multiplet), 7,46-6,79 (9H, multiplet), of 5.68 (1H, doublet, J = 7 Hz), is 4.93 (1H, doublet, J = 11 Hz), and 4.75 (1H, doublet, J = 11 Hz), a 2.45 (3H, singlet), of 2.33 (3H, singlet), of 1.27 (9H, singlet).

Mass spectrum (FAB + ve ion): m/e 497,2 (M+H).

Connections 53, 68-73, 78 and 79 receive by methods similar to that shown in the above examples.

Compounds of the present invention are potent and selective antagonists against the receptor CCK-B and inhibit the secretion of gastric acid stimulated by pentagastrin. Methods of measuring these activities are described below.

Determination of affinity binding to the receptor CCK-B

100 SD rats without anesthesia cut off the head, the whole brain of each rat immediately remove and homogenized covered by the Teflon homogenizer in 10-fold volume of 0.32 M sucrose solution, obtained homogenized centrifuged for ten minutes with acceleration 900g in a refrigerated centrifuge and the liquid above the sediment then centrifuged for 15 minutes with scarlatinous suspension for 30 minutes and again centrifuged for 15 minutes with acceleration 11500g, the precipitate successively washed twice with 5 mm solution of buffer Tris-HCl and twice with 50 mm buffer solution Tris-HCl (in the given order with the separation in the centrifuge), washed the residue is suspended in 50 mm buffer solution Tris-HCl and the resulting suspension is kept at a temperature of -80oC until required membrane preparation.

The membrane preparation is heated to room temperature, diluted with 10 mm solution of HEPES buffer (containing 130 mm NaCl, 5 mm MgCl2, 1 mm ECTA and 0.25 mg/ml bacitracin; pH 6.5) and incubated at a temperature of 25oC for 120 minutes in the presence of [125I] BH-CCK-8 and the test compounds are then separated on a suction filter. The amount of nonspecific binding determined in the presence of 1 μm CCK-8. Number containing the label of the ligand, contacting a receptor is determined using counter gamma particles; calculate values of IC50that correspond to the concentration of test compound required to inhibit specific binding by 50%.

Determination of affinity binding to the receptor CCK-A

The pancreas of rats SD homogenized in 20-fold volume of 50 mm buffer solution Tris-HCl (pH 7,7) in the homogenizer of the type Poly rone, homogenized twice centres is JaME 50 mm solution of buffer Tris-HCl (containing 0.2% bovine serum albumin, 5 mm of magnesium chloride, 0.1 mg/ml bacitracin, 5 mm DDT; pH of 7.7) and the resulting suspension is kept at a temperature of -80oC until required membrane preparation.

The membrane preparation is heated to room temperature, diluted with buffer in the ratio of 1:10 and incubated for 30 minutes at a temperature of 37oC in the presence of [3H]L - 364,718 and test the connection then separated on a suction filter. The nonspecific binding determined in the presence of 1 μm solution of L - 364,718. Number containing the label of the ligand, contacting a receptor is determined using a liquid scintillation counter; calculate values of IC50that correspond to the concentration of test compound required to inhibit specific binding by 50%.

High affinity receptor CCK-A in the presence of antagonist gastrin/CCK-B, apparently, is undesirable because it may cause therapy to side effects, such as bile stasis and the formation of biliary calculus. Therefore, it is desirable to have a therapeutic tool was selective with respect to the receptor CCK-B. This selectivity is expressed by the ratio IC50(CCK-A)/IC50(CCK-B); the higher the ratio, the La preferred compounds of the present invention, as well as the magnitude of the relationship A/B. Many of the compounds show high affinity binding to the receptor CCK-B compared to the connection example 281 U.S. patent 4820834 (which is also known as L - 365, 260). Several compounds also exhibit a greater selectivity for the CCK-B compared with receptor CCK-A than similar data is provided for the connection example 281 U.S. patent 4820834.

Determination of the inhibition of stimulated pentagastrin secretion of gastric acid in rats

In the trachea of the rat, shot by urethane (injected intraperitoneally, of 1.25 g/kg), placed the cannula, the wall of the rat stomach cut open part of the stomach and duodenum, and in front of the stomach after dressing the cardiac orifice is placed a cannula made of polyethylene. Then the duodenum slightly dissected, cut through part of the stomach to impose a polyethylene cannula and the pylorus is preserved bandage to secure the cannula.

From the front of the stomach to the pylorus is preserved with a speed of 3 ml/min serves a physiological saline solution (pH 7.0) and determine the secretion of gastric cancer by continuous titration of the perfusion solution using a burette (AUT-201, Phi is the, the Oka pH reaches a value of 7.0, and the result is expressed by the amount of gastric acid, which is excreted within 10 minutes ( Eq/10 min). Pentagastrin is injected in the amount of 15 μg/kg/h

The secretion of gastric acid increases with the introduction of pentagastrin, reaching maximum values after 60 minutes, and then stabilized at this level. Next, intravenous drug test and determine the secretion of gastric acid; calculate values of ED50that correspond to the amount of the drug required to reduce the secretion of gastric cancer by 50% compared to the maximum level.

Examples of the values of the ED50:

ED50(µmol/kg) - ED50(µmol/kg)

Connection example 281 U.S. patent 4820834 - 4.2V

Example 4 - 0,016

Example 5 - 0,018

Example 7 - 0,047

Determination of the inhibition of stimulated pentagastrin secretion of gastric acid in dogs

Tests performed on male animals dog breeds hound (7 to 12 kg) by a standard method at the end of two months after preparation of the pocket of HEIDENHAIN. Each dog is used only once during the week.

For 18 h before proleague 15 minutes, placed in the stomach cannula with drainage by gravity, and the output of acid is determined by automatic titration of 0.05 N sodium hydroxide solution to achieve pH 7.0 (Comtite-7, "Hiranuma, Tokyo, Japan). Drugs administered orally in 3 h after start of infusion of pentagastrin (8 µg/kg/h). The impact of each connection are determined by calculation and is expressed as the percent inhibition of stimulated acid output. The maximum inhibition observed for selected examples (each result is the average of 3 to 5 animals):

Connection - Inhibition, % (dose µmol/kg)

for Example, 281 U.S. patent 4820834 - 0 (100)

for Example, a 26 - 53 (3)

for Example, 27 - 66 (3)

for Example, the 38 - 100 (3)

for Example, a 64 - 100 (3)

The experiments described show that the compounds of the present invention are potent and selective antagonists of gastrin/CCK-B and inhibit the stimulation of secretion of gastric acid caused by pentagastrin. They can therefore be used for the treatment of painful conditions in which the role of mediator played by gastrin or CCK receptor-B. Such painful conditions include disorders of the gastrointestinal system, such as gastric ulcer and duodenal ulcer, gastritis, gastroesophageal reflux syndrome Zollinger - Ellison, the sensitivity of the pancreas in relation to gastrin, sensitive is icenii disorders of the Central nervous system, such as fear and psychosis. Connections can also be used to control pain and appetite.

Compounds of the present invention and their salts can be administered orally (including sublingual), or parenterally in the form of tablets, powders, capsules, pills, injections, suppositories, ointments and patches.

The carrier or excipient in pharmaceutical manufacturing can serve as a solid or liquid non-toxic substance used in medicine, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, Kungaeva oil, peanut butter, ethylene glycol and other commonly used compounds.

Examples of compositions using the compounds of the present invention.

Examples of drugs in pill form, see table. 2.

Preparation of 20-milligramme tablets

The compound from example 4 (100 g), lactose (367 g) and corn starch (90 g) are mixed to homogeneity using a granulator (company "Ohgawara Seisakusho), the mixture is sprayed with a 10% aqueous solution of hydroxypropylcellulose (200 g) and obtain granules. After drying, the granules were sieved through 20 mesh, add 20 g of the calcium salt of carboxymethyl is produced by the company "Hata Tekkosho) and get pills, each of which weighs 120 mg.

Preparation 40-milligramme tablets

Connection example 4 (140 g), lactose (280 g) and corn starch (70 g) are mixed to homogeneity using a granulator (company "Ohgawara Seisakusho), the mixture is sprayed with a 10% aqueous solution of hydroxypropylcellulose (175 g) and obtain granules. After drying, the granules were sieved through 20 mesh, type of 14.7 g of the calcium salt of carboxymethylcellulose, and 2.8 g of magnesium stearate. The mixture is fed to a rotary tabletiruemuju machine, equipped with a pestle 7 mm x 9R (produced by the company "Hata Tekkosho) and get the pills, each of which weighs 150 mg.

Clinical dose of the compounds of the present invention should be determined by a physician, who must take into account the specific disease, the body weight of the patient, age, gender, history of disease and other factors for the patient, whose treatment. In General, the dose of oral appointment is from 1 to 1000 mg/day as a single dose or as multiple smaller doses.

1. Derivative of benzodiazepine General formula I

< / BR>
where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)a/SUB>-cycloalkyl;

R5- C1-8-alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-8-alkyl, C1-8-alkyl-C3-8-cycloalkyl, pyrrolidyl, possibly substituted C1-8-acyl, carbamoyl, C1-8-alkylamino-C1-8-alkyl, or adamantylidene;

R2is phenyl, substituted C1-8-alkyl, C1-8-alkoxyl, nitro, amino, cyano, halogen, C1-8-alkylaminocarbonyl, di(C1-8)alkylaminocarbonyl, carboxy, C1-8-allmineral, carboxyhemoglobin, carboxy(C1-8)alkyl, or pyridylethyl, possibly substituted C1-8-alkyl;

R3is phenyl, unsubstituted or substituted C1-8-alkyl or halogen, or pyridylethyl;

X is hydrogen or halogen in the 7th position of the benzodiazepine ring;

W is hydrogen or C1-8the alkyl in the 8th position of the benzodiazepine ring,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, wherein R4- C4- C7-alkyl, linear or branched.

3. Connection under item 1 or 2, characterized in that at least one of R2and R3is substituted by phenyl or pyridium.

4. Connection on p. 3, characterized in that rainbowsix points, wherein R1refers to a group-CH2CO(CH2)aR5, R2is a phenyl-containing substituent in the meta position selected from fluorine atom, chlorine atom, bromine atom, metoxygroup, amino, dimethylaminopropyl, nitro group, methyl group, the group -(CH2)cCOOH, ceanography, methylaminopropyl, methylaminopropyl, diethylaminopropyl, c = 0 - 2; R3is phenyl or 2 -, 3 - or 4-pyridium.

6. The compound according to any one of paragraphs.1 to 4, wherein R1refers to a group-CH2CHOHR4and the value for R2and R3specified in paragraph 5.

7. The compound according to any one of the preceding paragraphs, characterized in that the atom in position 3 of the benzodiazepine ring has an absolute configuration R (as shown in the formula (IV):

< / BR>
8. The compound according to any one of the preceding paragraphs, wherein W and X is a hydrogen atom.

9. Connection on p. 1, selected from the following compounds and their pharmaceutically acceptable salts:

1) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

2) N-((3RS)-1-diethylaminocarbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-('-(3-were)urea;

4) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

5) N-((3RS)-1-cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

6) N-((3RS)-1-cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

7) N-((3RS)-1-cyclohexylcarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-chlorophenyl)urea;

8) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

9) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(3-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

10) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(4-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

11) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

12) N-((3R)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

13) N-((3S)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

14) N-((3RS)-2,3-dihydro-2-oxo-5-phenyl-1-((2R)-2-pyrrolidinylcarbonyl) is methyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

16) N-((3RS)-1-((2R)-1-acetyl-2-pyrrolidinylcarbonyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

17) N-((3RS)-1-((2S)-1-acetyl-2-pyrrolidinylcarbonyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

18) N-((3RS)-1-((2RS)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

19) N-((3RS)-1-((2SR)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

20) N-((3RS)-1-((2R)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

21) N-((3RS)-1-((2S)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

22) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-cyanophenyl)urea;

23) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-cyanophenyl)urea;

24) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxymethyl)urea;

25) N-((3RS)-1-(1-substituted)carbonylmethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

26) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(6-methyl-2-pyridyl)urea;

28) N-((3RS)-1-(3-cyclohexyl-3-methyl-2-oxobutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

29) N-((3RS)-1-cyclohexyloxycarbonyloxy-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

30) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

31) N-((3RS)-1-((1-methylcyclohexyl)carbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

32) N-((3RS)-1-((1-methylcyclopentene)carbonylmethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

33) N-(3R)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

34) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

35) N-((3R)-1-(2RS)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

36) N-((3R)-1-((2R)-2-cyclopentyl-2-hydroxyethyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

37) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxamidine)urea;

38) N-((3(3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

40) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

41) N-((3RS)-1-tert-amicability-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

42) N-((3RS)-1-tert-amicability-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

43) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

44) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-carboxyphenyl)urea;

45) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

46) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

47) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl)urea;

48) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methoxyphenyl)urea;

49) N-((3RS)-1-cyclopentanecarbonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-nitrophenyl)urea;

50) N-((3RS)-1-tert-butylcarbamoyl-2,3-Digi the Idro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-formylamino)urea;

52) N-((3R)-1-((2R)-2-hydroxy-3,3-dimethylbutyl)-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

53) N-((3R)-1-((2S)-2-hydroxy-3,3-dimethylbutyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

54) N-((3RS)-1-(1-methylcyclopropyl)carboxymethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

55) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

56) N-((3RS)-1-ISO-propylmalonate-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

57) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea;

58) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea;

59) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-(N-ethyl-N-methylamino)phenyl)urea;

60) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea;

61) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

62) N-((3RS)-1-tert-butilka the(3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

64) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea;

65) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

66) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(4-were)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

67) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL)urea;

68) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

69) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL)urea;

70) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea;

71) N-((3R)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

72) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-AMINOPHENYL)urea;

73) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylaminophenol)urea;

74) N-((3RS)-1-tert-butylcarbamoyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-dimethylaminophenyl)urea;

76) N-((3RS)-1-tert-butylcarbamoyl-7-chloro-2,3-dihydro-2-oxo-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

77) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-8-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-were)urea;

78) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-[3-(N-ethyl-N-methylamino)phenyl]urea;

79) N-((3RS)-1-tert-butylcarbamoyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-diethylaminophenyl)urea.

10. The compound according to any one of paragraphs.1 to 9, with antagonist activity of gastrin or CCK receptor-Century

11. The pharmaceutical composition active antagonist of gastrin or CCK receptor, comprising an active ingredient, a derivative of benzodiazepine and pharmaceutically acceptable additives, characterized in that it contains as a derivative of benzodiazepine effective amount of the compounds of formula I under item 1.

12. A method of obtaining a benzodiazepine General formula (I) or its pharmaceutically active salts, where R1refers to a group-CH2CO(CH2)aR5and the values a, R2, R3, R5W and X are specified in paragraph 1, characterized in that exercise for working Azania in paragraph 1.

13. A method of obtaining a benzodiazepine General formula (I) or its pharmaceutically active salts, where R1refers to a group-CH2CO(CH2)aR5and the values a, R2, R3, R5W and X are specified in paragraph 1, wherein interact 3-pair-nitrophenylacetonitrile formula (VI)

< / BR>
with the amine R2- NH2.

14. A method of obtaining a benzodiazepine General formula I or its pharmaceutically active salts, where R1refers to a group-CH2CH(OH)(CH2)aR4and the values a, R2, R3, R4W and X are specified in paragraph 1, wherein interact compounds of General formula I, where R1group-CH2CO(CH2)aR5, R5- C1-7-alkyl straight or branched chain or C3-8-cycloalkyl, with regenerating agent.

Priority signs:

27.02.92 - all values radicals, in addition to compounds, where R2is phenyl, substituted nitro, di(C1-8)alkylaminocarbonyl, C1-8-allmineral or carboxyhaemoglobin, which have priority from 16.06.92 and compounds, where X is halogen, and W is C1-8-alkyl, which have priority from 26.02.93.

 

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< / BR>
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< / BR>
and their pharmaceutically acceptable salts, in which:

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