Tricyclic benzodiazepines, pharmaceutical composition containing the same and methods for hypertension treatment

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

 

Technical field of invention

This application takes priority of provisional patent application No. 60/116358, filed January 19, 1999, which entered into the description by reference.

This invention relates to new tricyclic antagonists of vasopressin receptors. More specifically, the compounds of this invention interrupts the binding of the peptide hormone vasopressin to its receptor and therefore are useful for treating conditions associated with vascular resistance and heart failure.

Background of the invention

Vasopressin is nonapeptides (consisting of 9 peptides) hormone secreted mainly the posterior lobe of the pituitary gland. The hormone exerts its activity through membranosvyazannye subtypes of receptors V-1 and V-2. The function of vasopressin include the uterus, the bladder and the smooth muscle, stimulating the breakdown of glycogen in the liver; the release of corticotropin from the anterior pituitary; the induction of platelet aggregation, and modulation of the Central nervous system behavior and response to stress. V-1 receptor mediates the effects of vasopressin on the contraction of smooth muscle, hepatic breakdown of glycogen and the Central nervous system. V-2 receptor, supposedly discovered only in the kidney, assistanceerectile action of vasopressin via stimulation of adenylate cyclase.

Elevated levels of vasopressin in plasma, as it turned out, participate in the pathogenesis of congestive heart failure (R.A. Van Zwieten, Progr. Pharmacol. Clin. Pharmacol. 1990, 7, 49). Progress in the treatment of congestive heart failure was the fact that antagonists of V-2 receptor nonapeptide vasopressin induced Alvarez (release of water) at low osmolality and decreased total peripheral vascular resistance in the minds of dogs with congestive heart failure (N. Ogawa, J. Med. Chem. 1996, 39, 3547). In certain pathological conditions the content of vasopressin in plasma may increase to levels not match the osmotic pressure that leads to renal water retention and hyponatremia. Hyponatremia associated with swelling (cirrhosis, congestive heart failure, renal failure), may be accompanied by a syndrome of abnormal secretion of antidiuretic hormone (syndrome of inappropriate secretion of antidiuretic hormone - SIADH). Treatment of rats with impaired secretion SIADH using V-2 antagonist of vasopressin corrected observed them hyponatremia (G. Fujisawa, Kidney Int. 1993, 44(1), 19). Thanks in part to reduce the action of vasopressin on the receptor V-1 on the vascular network, V-1 antagonists of vasopressin reduces blood pressure, which is a potential JV is a method for treating hypertension. Thus, antagonists of vasopressin receptors could be useful as therapeutic agents for treating conditions hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis and water retention.

Brief description of the invention

This invention relates to compounds represented by following General formula (I) and (II):

where m takes integer values from 1 to 2 so that "NO" in the compound of formula (II) represents a stable five - or six-membered monocyclic aromatic ring system consisting of carbon atoms and one heteroatom, which heteroatom is selected from N, O or S and which may be joined at any heteroatom or carbon atom, provided that the resulting ring system is stable; for example, thiophene, furan, pyrrole or pyridine;

A is selected from-C(O)-, SO2or CH2, And preferably represents-C(O)-;

Y is selected from CH2or SN as part of the olefin;

X is selected from CH2CH as part of the olefin, NH3, S, or O;

provided that if Y is with the battle of CH 2then X represents (CH2)2;

Z is selected from N or CH;

R1selected from hydrogen, alkyl, alkoxygroup, halogen, aminoalkyl or nitro;

AG is selected from naphthyl, where the naphthyl optionally substituted with one to three substituents, independently selected from C1-C8of alkyl, C1-C8alkoxygroup, fluorinated C1-C8the alkyl (preferably of trifloromethyl), fluorinated C1-C8alkoxygroup (preferably cryptometer), halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino (preferably-NH-C1-C4of alkyl, C1-C4dialkylamino (preferably N-[(C1-C4the alkyl]2where the alkyl groups may be the same or different); or phenyl, where phenyl optionally substituted with one to three substituents, independently selected from C1-C8of alkyl, C1-C8alkoxygroup, fluorinated C1-C8the alkyl, fluorinated C1-C8alkoxygroup, C1-C8aralkyl (in which optionally alkyl or aryl are independently substituted and the alkyl part may be substituted by at least one fluorine atom, and/or the aryl portion may be independently substituted one to three substituents, selected and from halogen, C1-C4of alkyl, C1-C6ancilliary or hydroxyl group), C1-C8urlcategory (which is not necessarily CNS or aryl are independently substituted, and CNS part may be substituted by at least one fluorine atom, and/or the aryl portion may be independently substituted one or two substituents selected from halogen, C1-C4of alkyl, C1-C6ancilliary or hydroxyl group), halogen, ceanography, hydroxyl group, amino -, nitro-, C1-C4alkylamino-, C1-C4dialkylamino (where the alkyl groups may be the same or different), C1-C8alkylsulfonyl, C1-C8allylthiourea, C1-C8alkylsulfonyl, heteroaryl, the second phenyl (where the second phenyl is optionally substituted with one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkoxygroup, fluorinated C1-C4the alkyl, fluorinated C1-C4alkoxygroup, halogen, ceanography, hydroxyl group, amino-, nitro - C1-C4alkylamino-, C1-C4dialkylamino [where the alkyl groups may be the same or different], C1-C4alkylsulfonyl, C1-C4ancilliary or C1 -C4alkylsulfonyl;

R2selected from hydrogen, NR4COAr, NR4CO-heteroaryl, NR4Ar, CH=CH-Ar, - CF=CH-Ar, - CH=CF-Ar, CCl=CH-Ar, CH=CCl-Ar, - CH=CH-heteroaryl, CF=CH-heteroaryl, CH=CF-heteroaryl, -CCL=CH-heteroaryl, CH=CC1-heteroaryl, co2-AG, co2-heteroaryl, SCH2-Ar or NR4CH2Ar; preferably R2represents NR4COAr; most preferably R2represents NHCOAr;

R3selected from hydrogen, acyl, alkyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl;

R4selected from hydrogen or C1-C4of alkyl; preferably R4represents hydrogen or methyl; most preferably R4represents hydrogen; and

R5selected from hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine, fluorine, hydroxyl group, dialkylamino (in which the alkyl groups may be the same or different), trifloromethyl or cryptometer;

and their pharmaceutically acceptable salts.

The compounds of this invention are antagonists of vasopressin receptor, are useful as antitumor funds (aquaretics) and, in General, for the treatment of cardiovascular diseases.

One embodiment of the present invention is a compound of formula (III):

where

R1selected from hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, halogen, amino, C1-C4the alkyl or nitro;

R2represents NHCOAr;

R3selected from hydrogen, acyl, alkyl, alkoxycarbonyl, alkylsulfonyl or arylsulfonyl; and

R5selected from hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine, fluorine, hydroxyl group, dialkylamino, trifloromethyl or cryptometer;

all other variables take the values defined above; and pharmaceutically acceptable salts.

To the class of the present invention includes a connection that

X is selected from CH2CH as part of the olefin, S, or O;

Z represents CH;

AG represents phenyl, where phenyl optionally substituted with one to three substituents, independently selected from C1-C8of alkyl, C1-C8alkoxy, fluorinated C1-C8the alkyl, fluorinated C1-C8alkoxygroup, C1-C8aralkyl (in which optionally alkyl or aryl are independently substituted and the alkyl part may be substituted by at least one fluorine atom, and/or the aryl portion may be independently substituted one or two substituents selected from halogen, C1-C4/sub> of alkyl, C1-C6ancilliary or hydroxyl group), C1-C8urlcategory (where optional CNS or aryl are independently substituted, and CNS part may be substituted by at least one fluorine atom, and/or the aryl portion may be independently substituted one or two substituents selected from halogen, C1-C4of alkyl, C1-C6ancilliary or hydroxyl group), halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C8alkylamino-, C1-C4dialkylamino (in which the alkyl groups may be the same or different), C1-C8alkylsulfonyl, C1-C8allylthiourea, C1-C8alkylsulfonyl, heteroaryl, the second phenyl (where the second phenyl is optionally substituted with one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkoxygroup, fluorinated C1-C4the alkyl, fluorinated C1-C4alkoxygroup, halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino-, C1-C4dialkylamino [in which the alkyl groups may be the same or different], C1-C4alkylsulfonyl, C1-C4ancilliary or C1-C4 alkylsulfonyl;

and all other variables take the values defined above;

and its pharmaceutically acceptable salts.

One of the embodiments of the present invention is a compound of formula (IV):

where

X is selected from the group consisting of CH2, S and O;

R1selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, halogen, amino-C1-C4-alkyl and nitro;

R5selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine, fluorine, trifloromethyl and cryptometer;

R6selected from the group comprising phenyl (where the phenyl optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkoxygroup, fluorinated C1-C4the alkyl, fluorinated C1-C4alkoxygroup, halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino-, C1-C4dialkylamino [in which the alkyl groups may be the same or different], C1-C4alkylsulfonyl, C1-C4ancilliary or C1-C4alkylsulfonyl); aralkyl (in which the alkyl or aryl portion is optionally independently replaced the seal, and the alkyl part may be substituted by at least one fluorine atom [preferably one] and/or the aryl portion may be independently substituted one or two substituents selected from halogen [preferably fluorine or chlorine], C1-C4the alkyl [preferably C1-C2the alkyl], C1-C6ancilliary [preferably C1-C4] or hydroxyl group) and urlcategory (where CNS or aryl portion is optionally independently substituted, and CNS part may be substituted by at least one fluorine atom [preferably one], and/or the aryl portion may be independently substituted one or two substituents selected from halogen [preferably fluorine or chlorine], C1-C4the alkyl [preferably C1-C2the alkyl], C1-C6ancilliary [preferably C1-C4] or hydroxyl group); and

R7independently selected from the group comprising hydrogen, fluorine, chlorine, hydroxyl group, C1-C6alkyl (preferably C1-C4more preferably C1-C2), C1-C6alkoxygroup (preferably C1-C4more preferably C1-C2and combinations thereof, where R7can represent from one to four independently selected g is PP;

and all other variables take the values defined above;

and its pharmaceutically acceptable salts.

The following compounds represent an additional embodiment of the present invention:

10-[4-[[(2-Biphenyl) carbonyl]amino]benzoyl]-10,11-dihydro-5H-piperidino[2,1-C][1,4]benzodiazepine;

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-

(tetrahydropyridine)[2,1-C][1,4]benzodiazepine;

(RS)-2-Phenyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(12H)-ylcarbonyl)phenyl]-benzamide;

(S)-2-(4-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-Phenyl-4-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-(3-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepin-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-Phenyl-5-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a] [1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-(4-Methylthieno)-4-fluoro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2,6-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ilıca is bonyl)phenyl]-benzamide;

(RS)-2,3-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(R)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[2-methoxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2,3,4,5-Titrator-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Chloro-5-trifluoromethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Fluoro-3-chloro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-(Deformality)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]-5-oxovanadate-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[2-hydroxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazine,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[3-hydroxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Methyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-fluoro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N - [4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8,9-dimethoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(9-chloro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepin(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8,9-debtor-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(8-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(8-chloro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(10-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(10-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)for 3,5-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Iodine-3-methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino [4,3-a] [1,4]-benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)for 3,5-Dichloro-N-(3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Methyl-3-iodine-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Forfinal-N-[4-(1,3,4,12A-tetrahydro-6N[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-dimethylamino-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-N)-ylcarbonyl)phenyl]-benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

and their pharmaceutically acceptable salts.

Another embodiment of the present invention is an intermediate compound of formula (V):

Another embodiment of the present invention is an intermediate compound of formula (VI):

Illustrating the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described above. Illustrating the invention is a pharmaceutical composition made by mixing any of the compounds described above and a pharmaceutically acceptable carrier. An illustrative example of the present invention is a method of obtaining a pharmaceutical composition comprising mixing any of the compounds described above and a pharmaceutically acceptable carrier.

An example of the present invention is a method of treating congestive heart failure in the subject, who needs it, including an introduction to the subject a therapeutically effective amount of any(Oh) of the compounds or pharmaceutical compositions described above.

Additional illustrative example of the invention is the fast way to treat congestive heart failure, where a therapeutically effective amount of compound is from about 0.1 to about 300 mg/kg/day.

An additional illustration of the invention is a method of treatment of a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis or delay water from the entity that needs it, including an introduction to the subject a therapeutically effective amount of any(Oh) of the compounds or pharmaceutical compositions described above. Preferably, a therapeutically effective amount of the compounds introduced for the treatment of any of these States, ranging from 0.1 to about 300 mg/kg/day.

This invention also includes the use of any of the compounds described above, for preparing a medicinal product for the treatment of a condition selected from hypertension, congestive heart failure, cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis or delay water, the entity that needs it.

Detailed description of the invention

D. the TES invention provides tricyclic benzodiazepine compounds which are useful as antagonists of vasopressin. More specifically, the compounds of formulas (I) and (II) inhibit the binding of vasopressin with the receptor V-1 and V-2 and, therefore, useful for treating conditions with increased vascular resistance. Examples of conditions with increased vascular resistance include, but are not limited to, congestive heart failure, edema, state water retention, etc. More specifically, this invention relates to compounds of formula (I) and (II):

and their pharmaceutically acceptable salts;

where A, X, Y, Z, R1, R2, R3and m take the values defined above.

Tricyclic benzodiazepine compounds of this invention are antagonists of vasopressin receptor, and in the preferred embodiment the connection active when administered orally. As shown by the results of the pharmacological studies described below, the compounds demonstrate the ability to block the binding of vasopressin with recombinant V-1 and V-2 and lower blood pressure, increased under the action of arginine-vasopressin, in animal models.

The compounds of this invention can be represented also in the form of pharmaceutically acceptable salts. For use in medicine approach is whether the compounds of this invention, called " non-toxic “pharmaceutically acceptable salts”. However, other salts may be useful for obtaining the compounds of this invention or their pharmaceutically acceptable salts. Typical examples of organic and inorganic acids include, but are not limited to, hydrochloric, Hydrobromic, yodiewonderdog, perchloro, sulphuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, almond, methansulfonate, hydroxyethanesulfonic, benzosulfimide, oxalic acid, pambou, 2-naphthalenesulfonate, p-toluensulfonate, cyclohexanesulfamic, salicylic, and some saccharine triperoxonane acid.

When the compounds according to this invention contain at least one chiral center, they may exist as enantiomers. When compounds contain two or more chiral centers, they may additionally exist as diastereomers. You should imagine that all such isomers and mixtures thereof are included in the scope of this invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs of, and assumes that such modifications are included in this invention. In addition, some of the connections on the frame of the invention with water may form a solvate, implying that such a solvate is included in the scope of this invention.

The term “subject” in this description refers to an animal, preferably a mammal, most preferably to the person who was the object of treatment, observation or experiment.

The term “therapeutically effective amount”, as used herein, refers to an amount of active compound or pharmaceutical agent that gives the biological or medical response in a tissue system, animal or human study(CSOs) by the researcher, veterinarian, medical doctor or other Clinician, which includes relieving symptoms of the disease or disorder to be treated.

Unless another value, the terms “alkyl” and “alkoxygroup”as used herein by themselves or as part of a substituent, include straight and branched chain, cyclic groups (with side carbon chains or without them), containing from 1 to 8 carbon atoms or any number within this interval. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. CNS radicals are simple the oxygen-containing esters, formed from the above-described alkyl groups, straight or branched chain or cyclic alkyl groups. Cycloalkyl and cycloalkyl groups contain from 3 to 8 ring carbon atoms and preferably from 5 to 7 ring carbon atoms. Similarly, alkeline and alkyline groups include alkenes and alkynes with a straight or branched chain or cyclic alkenes, and alkynes containing from 1 to 8 carbon atoms or any number within this interval.

The terms “AG” and “aryl”, as used herein, are synonymous and refer to unsubstituted or substituted aromatic group, such as phenyl and naphthyl. When AG or aryl group is substituted, it may contain from one to three substituents that are independently selected from C1-C8of alkyl, C1-C8alkoxygroup, fluorinated C1-C8the alkyl (for example, trifloromethyl), fluorinated C1-C8alkoxygroup (for example, cryptometer), halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino (i.e.- NH-C1-C4of alkyl, C1-C4dialkylamino (ie-N-[(C1-C4alkyl]2where the alkyl groups may be the same or different), or phenyl, where phenyl is optionally someseni is one to three substituents, independently selected from C1-C8of alkyl, C1-C8alkoxygroup, fluorinated C1-C8the alkyl, fluorinated C1-C8alkoxygroup, C1-C8aralkyl (in which optionally alkyl or aryl are independently substituted and the alkyl part may be substituted by at least one fluorine atom, and/or the aryl portion may be independently substituted one or two substituents selected from halogen, C1-C6ancilliary or hydroxyl group), C1-C8urlcategory (which is not necessarily CNS or aryl are independently substituted, and CNS part may be substituted by at least one fluorine atom and/or the aryl portion may be independently substituted one or two substituents selected from halogen, C1-C6ancilliary or hydroxyl group), halogen, ceanography, hydroxyl group, amino-, nitro - C1-C8alkylamino-, C1-C4dialkylamino (in which the alkyl groups may be the same or different), C1-C8alkylsulfonyl, C1-C8allylthiourea, C1-C8alkylsulfonyl, heteroaryl, the second phenyl (where the second phenyl is optionally substituted with one or two substituents, independently in the swear of C 1-C4of alkyl, C1-C4alkoxygroup, fluorinated C1-C4the alkyl, fluorinated C1-C4alkoxygroup, halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino [in which the alkyl groups may be the same or different], C1-C4alkylsulfonyl, C1-C4ancilliary or C1-C4alkylsulfonyl.

The term “NO” or “heteroaryl”, as used herein, refers to a stable unsubstituted or substituted five - or six-membered monocyclic aromatic ring system or a nine - or deletechannel benzo-condensed heteroaromatic ring system which consists of carbon atoms and one to three heteroatoms selected from N, O or S. the Heteroaryl group may join via any heteroatom or carbon atom, if this results in the formation of a stable structure. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothiazol, benzisoxazole, benzoxazole, benzimidazolyl, indolyl, benzothiazolyl, benzotriazolyl, benzothiazolyl Il is chinoline. Preferred heteroaryl groups include pyridinyl, thiophenyl, furanyl and chinoline. When the heteroaryl group is substituted, it may contain from one to three substituents that are independently selected from C1-C8of alkyl, halogen, aryl, heteroaryl, alkoxygroup, alkylamino, dialkylamino, arylamino, nitro-, hydroxyl groups.

The term “aralkyl” refers to an alkyl group, substituted aryl group (for example, benzyl, ventilation). Similarly, the term “arakaki” refers to CNS group, substituted aryl group (for example, benzyloxycarbonyl). The term “aminoalkyl” refers to an alkyl group, a substituted amino group (i.e.,- alkyl-NH2). The term “alkylamino” refers to the amino group, substituted alkyl group (i.e.- NH-alkyl). The term “dialkylamino” refers to the amino group which is disubstituted by alkyl groups, where the alkyl groups may be the same or different (i.e.- N-[alkyl]2). The term “allylthiourea” refers to alkylthiophenes the group of simple ether (that is,- S-alkyl).

The term “acyl”, as used herein, refers to an organic radical containing from 2 to 6 carbon atoms (branched or straight chain) and derived from an organic acid by removal hidroxil the Oh group.

The term “halogen” will include iodine, bromine, chlorine and fluorine.

In all cases, when in the name of Deputy appears the term “alkyl” or “aryl” or their roots, serving as a prefix (e.g., aralkyl, dialkylamino), this should be interpreted as enabling constraints described above for the terms “alkyl” and “aryl”. The specified number of carbon atoms (for example, C1-C6) will independently relate to the number of atoms in the alkyl or cycloalkyl fragment or the alkyl portion of a larger substituent in which there is alkyl as the root of the prefix.

It is implied that the definition of any substituent or variable in a particular location in a molecule is independent of its definitions in other positions in the molecule. It is clear that the deputies and schema substitution in the compounds of this invention can be selected by a skilled person in this field to provide compounds that are chemically stable and which can be easily synthesized by methods known in this field, as well as the methods described in this invention.

One of the embodiments of the present invention is a compound of formula (IV):

where

X is selected from the group consisting of CH2, S and O;

R1in the bran from the group consisting of hydrogen, C1-C4of alkyl, Ci-C4alkoxygroup, halogen, amino-C1-C4-alkyl and nitro;

R5selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine, fluorine, trifloromethyl and tripometer;

R6selected from the group comprising phenyl (where the phenyl is optionally substituted with one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkoxygroup, fluorinated C1-C4the alkyl, fluorinated C1-C4alkoxygroup, halogen, ceanography, hydroxyl group, amino-, nitro-, C1-C4alkylamino-, C1-C4dialkylamino [in which the alkyl groups may be the same or different], alkylsulfonyl, C1-C4ancilliary or C1-C4alkylsulfonyl); aralkyl (in which the alkyl or aryl portion is optionally independently substituted and the alkyl part may be substituted by at least one fluorine atom [preferably one], and/or the aryl portion may be independently substituted one or two substituents selected from halogen [preferably fluorine or chlorine], C1-C4the alkyl [preferably C1-C2the alkyl], C1-C6ancilliary [predpochtitelno C 1-C4] and urlcategory (in which CNS or aryl portion is optionally independently substituted, and CNS part may be substituted by at least one fluorine atom [preferably one], and/or the aryl portion may be independently substituted one or two substituents selected from halogen [preferably fluorine or chlorine], C1-C4the alkyl [preferably C1-C2the alkyl], C1-C6ancilliary [preferably C1-C4] or hydroxyl group); and

R7independently selected from the group comprising hydrogen, fluorine, chlorine, hydroxyl group, C1-C6alkyl (preferably C1-C4and more preferably C1-C2), C1-C6alkoxygroup (preferably C1-C4and more preferably C1-C2and combinations thereof, where R7can represent from one to four independently selected groups.

It is implied that the term “composition”, as used herein, covers the product containing the specified ingredients in the specified amounts, as well as any product that is obtained, directly or otherwise, in the combinations listed ingredients in the listed amounts.

The applicability of the compounds for the treatment of disorders of povyshennoj the vascular resistance can be determined according to the procedures described in this description. Thus, this invention provides a method of treatment of disorders of the vascular resistance in the subject, who needs it, including the introduction of any of the compounds defined in the present description, in a quantity effective for the treatment of disorders vascular resistance. The compounds can be administered to a patient who needs treatment, any convenient method of administration, including, but without limiting them alone, oral, nasal, sublingual, ocular, cutaneous, rectal, vaginal and parenteral (i.e. subcutaneous, intramuscular, intradermal, intravenous, and so on).

In the present invention are also pharmaceutical compositions comprising one or more compounds of this invention in combination with a pharmaceutically acceptable carrier.

To prepare the pharmaceutical compositions of the present invention, one or more compounds of the formula (I) or (II) or its salt as the active ingredient is thoroughly mixed (are) according to standard methods of preparation of pharmaceutical compounds with a pharmaceutical carrier which can take a variety of forms, depending on the desired form of the drug for administration (e.g. oral or parenteral administration, such as intramuscular introduction the s). Suitable pharmaceutically acceptable carriers well known in this field. Descriptions of some of these pharmaceutically acceptable carriers can be found in the publication of The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.

Methods of obtaining pharmaceutical compositions are described in several publications, for example: Pharmaceutical Dosage Forms: Tablets. Second Edition. Revised and Expanded. Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; published by Marcel Dekker, Inc.

In the preparation of pharmaceutical compositions of this invention in liquid dosage form for oral, local or parenteral administration can be any of the usual pharmaceutical media and fillers. So, for liquid dosage forms, such as suspensions (i.e. colloidal solutions, emulsions and dispersions and solutions, suitable carriers and additives include, but are not limited to, pharmaceutically acceptable wetting agents, dispersants, flocculants, thickeners, additives for pH control (i.e. buffers), additives for regulating the osmotic pressure, dyes, flavorings, fragrances, preservatives (i.e. additives to control growth of microorganisms, and so on), as well as liquid media.

But not all of the listed components BU the ut are required for each liquid dosage forms.

Suitable carriers and additives for solid preparations of oral administration, such as, for example, powders, granules, capsules, capley (caplets), gelatin capsules, pills and tablets (each of the forms includes preparations of immediate release, delayed release and sustained release of the active substance), include, but are not limited to, diluents, additives, promotes granulation, lubricants, binding agents, to facilitate sliding if swallowed tools, leavening agents, etc. Because of the ease of introduction of tablets and capsules represent the most advantageous standard dosage form for oral administration, and in this case obviously apply solid pharmaceutical carriers. If necessary, the tablets may be coated with sugar, gelatin, film or intersolubility coating using standard methods.

The pharmaceutical compositions described in this invention will contain per unit of standard forms, such as tablet, capsule, powder, preparation for injection, teaspoonful and so on, the amount of active ingredient needed to deliver an effective dose as described above. The pharmaceutical compositions described in this invention will contain one unit of the standard form, e.g. a tablet, is apsule, the powder preparation for injection, suppository, teaspoonful and so on, from about 0.03 mg to 100 mg/kg (preferably from about 0.1-30 mg/kg), and can be taken in a dose of about 0.1-300 mg/kg/day, preferably about 1-50 mg/kg/day and more preferably from about 0.03 to 10 mg/kg/day). Preferably for the method of treatment of disorders vascular resistance described in this invention and applying any of the compounds described above, the dosage form will contain a pharmaceutically acceptable carrier containing from about 0.01 to 100 mg, more preferably about 5 to 50 mg of the compound, and can be made in any form that is acceptable for the selected mode of administration. However, the dosage can vary depending on the needs of patients, the severity of the condition to be treated, and used for the connection. Can be used daily or introduction, or postperovskite dosing.

Preferably such compositions are standard dosage forms, such as tablets, pills, capsules, powders, granules, pellets, sterile solutions or suspensions for parenteral administration, metered aerosol or liquid sprays, drops, ampoules, devices for autoinjection or candles; introduction to oral, nasal, under the tongue, eye, dermal, parenteral, recta is Ino, vaginally, by inhalation or by means of insufflation. Alternatively, the composition may be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the active compound, such as decanoate, can be used to obtain a basic preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, for example the standard ingredients to obtain tablets, such as diluents, binders, adhesives, disintegrating agents, lubricants, additives that prevent bonding, and means to facilitate sliding. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat or potato starch, which can be hydrolyzed), lactose (granulated, dried by spraying or anhydrous), sucrose, thinners on the basis of sucrose (sugar confectionery, sucrose plus about 7-10 wt. percent invert sugar, sucrose plus about 3 wt. percent of modified dextrins; sucrose plus invert sugar, about 4% (wt.) inverted sugar, from about 0.1 to 0.2% (wt.) corn starch and magnesium stearate), dextrose, hexahydro-g is chaoxianzu (Inositol), mannitol, sorbitol, microcrystalline cellulose (i.e AVICELTM- microcrystalline cellulose available from FMC Corp.), the dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate, etc. Suitable binding agents and adhesives include, but are not limited to, Arabian gum, guargum, tragakant, sucrose, gelatin, glucose, starch and cellulose (methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, hypromellose, hydroxypropylcellulose and the like), water soluble or dispersible binders (i.e. alginic acid and its salts, magnesium aluminosilicate, hydroxyethyl cellulose [i.e TYLOSETMavailable from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and Pregelatinised starch), etc. Suitable leavening agents include, but are not limited to, starches (corn, potato etc), sodium chromalveolata, Pregelatinised starches, clays, aluminum silicate magnesium, cellulose (such as cross-linked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch and so on), resin (agar, guerova gum, gum fruit of the carob, gum karaya, pectin and tragakant), stitched polyvinylpyrrolidon is he, etc. Suitable lubricants and antiadhesive include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, tal, waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax (carbowax) 4000, carbowax (carbowax) 6000, sodium oleate, sodium benzoate, sodium acetate, nutriceuticals, magnipapillata and other Appropriate means, to facilitate the sliding, include, but are not limited to, talc, corn starch, silicon dioxide (silicon dioxide CAB-O-SILTMavailable from Cabot, silica SYLOIDTMavailable from W.R. Grace/Davison, and silicon dioxide AEROSILTMavailable from Degussa) and the like Sweeteners and flavorings can be administered in solid dosage forms that require grinding, to improve the readability of the dosage form when administered orally. Additionally, in the solid dosage form can be administered or applied to its surface dyes and coatings for easy identification of the medicinal product or for aesthetic purposes. These carriers are injected into the drug with a pharmaceutically active substance to provide accurate, appropriate doses of pharmaceutically active substances with therapeutic profile of release of the active substance.

Usually these carriers are mixed with the pharmaceutically active substance DL is receiving solid composition prior formulations, containing a homogeneous mixture of the pharmaceutically active compounds of this invention or its pharmaceutically acceptable salt. Typically, the prior recipe will be one of the three traditional methods: (a) wet granulation, (b) dry granulating and (C) dry mixing. When these compositions preliminary formulations are called homogeneous, this means that the active ingredient is dispersed evenly throughout the composition so that the composition can easily be divided into dosage forms equal efficiency, such as tablets, pills and capsules. Such a solid composition prior formulation is further divided into standard dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the present invention. Tablets or pills containing compositions can also be prepared in the form of multi-layer tablets or pills to ensure a supported release or dual-release products. For example, the tablet or pill dual release may contain internal dosed component and an outer dosage component, the latter is a wrapper for the first. Two components can be separated intersolubility layer, which prevents the decomposition of W is Luke and allows the inner component to pass intact into the duodenum or to escape the slow way. For such intersolubility layers or coatings can be used various materials, such materials include a number of polymeric materials, such as shellac, cellulose acetate (i.e. cellulose-acetate-phthalate, cellulose-acetate-trimellitate (trimetllitate)), polyvinylacetate, hypromellose-phthalate, hypromellose-acetate-succinate, copolymers of methacrylate and acrylate, copolymere methacrylate and methyl methacrylate and other slow release Tablets can also be obtained by coating a film or wet granulation using membrane not easily soluble or insoluble substances in the solution (which in the method of wet granulation acts as a binding agent) or low-melting solids in the form of a melt (which in the method of wet granulation may include the active ingredient). The above-mentioned materials include natural and synthetic polymeric waxes, hydrogenated oils, fatty acids and alcohols (i.e. beeswax, Carnauba wax, cetyl alcohol, cetylstearyl alcohol and the like), esters formed by the metal Soaps of fatty acids and other suitable materials that can be used for granulation, coating, introduction in some form or other restrictions solubility active and is gradient for the achievement of sustained or prolonged release of the product.

Liquid form, which can be new compositions of this invention for oral administration or for injection include, but are not limited to, aqueous solutions, syrups with improved taste, aqueous or oil suspensions and emulsions improved taste with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable suspendresume additives for aqueous suspensions include synthetic and natural resins, such as the Arabian gum, agar, alginate (i.e. propylaniline, sodium alginate and the like), guargum, gum karaya, gum carob, pectin, tragakant and xantanovu gum, cellulose such as sodium carboxymethyl cellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, and combinations thereof, synthetic polymers such as polyvinylpyrrolidone, carbomer (i.e. carboxypolymethylene) and polyethylene glycol; clays, such as bentonite, hectorite, attapulgite and thick; and other pharmaceutically acceptable suspiciouse supplements such as lecithin, gelatin, etc. Suitable surfactants include, but are not limited to, nutritional (soduim docusate), Matricaria that, Polysorbate, octoxynol-9, nonoxynol-10, Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, poloxamer 188, poloxamer 235 and combinations thereof. Suitable deflocculant or dispersing additives include lecithins pharmaceutical grades. Suitable flocculants include, but are not limited to, neutral electrolytes (i.e. sodium chloride, potassium chloride and the like), vysokozaraznoe insoluble polymer particles and polyelectrolytes, water-soluble divalent and trivalent ions (i.e. calcium salts, alum or sulphates, citrates and phosphates (which can be used simultaneously in drugs as pH buffers and as flocculants). Suitable preservatives include, but are not limited to, parabens (i.e. methyl, ethyl, propyl and butyl), sorbic acid, thimerosal (thymerosal), Quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol etc. There are many liquid media that can be used in liquid pharmaceutical dosage forms, however, the carrier liquid used in a particular dosage form, must be compatible with suspendresume(them) additive(s). For example, nonpolar liquid media, such as a complex fatty esters and oil liquid media, it is best to apply with such suspendresume additives, as the AB with low products HLB (hydrophilic-lipophilic balance), stearalkonium, water-insoluble resin, water-insoluble film-forming polymers, etc. And Vice versa, polar liquids such as water, alcohols, polyhydric alcohols and glycols, it is best to use with such suspendresume additives as surfactants with a high products HLB, acid clay, gum, water soluble cellulose derivatives, water-soluble polymers and the like For injecting the desired sterile suspensions and solutions. Liquid forms that are useful for parenteral administration include sterile solutions, emulsions and suspensions.

Isotonic preparations, which usually contain suitable preservatives are used in those cases when it is desirable intravenous.

In addition, the compounds of this invention can be administered nasal using local application of suitable nasal carriers or using the compositions in the form of transdermal patches for dermal applications, which are well known to a qualified specialist in this field. For injection of therapeutic doses in the form of a transdermal delivery system, its introduction should be continuous rather than intermittent throughout the administration of the medicine.

The compounds of this invention can also be administered in the form of a liposomal delivery system, such as a small unilamellar (one is lainie) bubbles large unilamellar bubbles, multilamellar (multilayer) bubbles, etc. Liposomes can be obtained from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholine etc.

The compounds of this invention can also be delivered using monoclonal antibodies used as individual carriers that are associated with the molecules of the compounds of this invention. The compounds of this invention can also contact soluble polymers are used as carriers of drugs targeted application. Such polymers may include, but are not limited to, polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethyleneterephtalate, substituted Palmitoyl balance. In addition, the compounds of this invention can be contacted with the polymers degrade by biological method and useful for achieving controlled release of drugs, for example, homopolymers and copolymers (which means polymers containing two or more chemically distinct repeating monomer unit) of lactide (which includes lactide (d-, 1 - and meso-lactic acid), glycolide (including glycolic acid), ε -caprolactam is she, p-dioxanone (1,4-dioxane-2-one), trimethylantimony (1,3-dioxane-2-one), alkyl derivatives of trimethylhexanoate, δ -valerolactone, β -butyrolactone, γ -butyrolactone, ε -decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxan-2-it (including its dimer 1,5,8,12-tetrachloroethylene-7,14-dione), 1,5-dioxan-2-it, 6,6-dimethyl-1,4-dioxane-2-it, with complex prioritaire, polyacetate, policyidreference, polycyanoacrylate and sewn or amphipatic copolymers of hydrogels and mixtures thereof.

In those cases where the means of obtaining the compounds according to the invention lead to mixtures of stereoisomers, these isomers may be separated by standard techniques such as preparative chromatography. The compound can be obtained in racemic form, or individual enantiomers may be obtained either enantiospecific synthesis or by separation. The connection can, for example, be separated into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by formation of salts.

Compounds can also be separated by formation of diastereomeric esters or amides, followed by separation by chromatography and remove side of chiral substances. Alternatively, compounds can be separated by the use of chiral HPLC columns.

In the process of implementing any of the methods for producing the compounds of this invention may be necessary and/or desirable to protect sensitive or reactive groups on any of the examined molecules. This can be achieved using conventional protective groups, which are described in the publications of Protective Groups in Organic Chemistry, ed. J.F.W. McOmie. Plenum Press, 1973; T.W. Green & P.G.M. Wuts, Protective Groups In Organic Synthesis, John Wiley & Sons, 1991. The protective group can be removed at a subsequent stage using methods known in this field.

The compounds of this invention can be administered in any of the above compositions and schemes of medicine established in this area, when the subject in need of treatment of disorders vascular resistance.

A daily dose of the pharmaceutical compositions of this invention may vary in a wide range - from about 0.01 to 30000 mg / day for an adult, however, the dosage will preferably be in the range of from about 0.01 to about 1000 mg per day for an adult. For oral administration the compositions preferably are offered in the form of tablets containing 0,01, 0,05, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic control of the dosage to the subject, the underlying treatment. An effective quantity of a drug is usually provided at the dose level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably the dosing interval is from about 0.03 to about 100 mg/kg body weight / day, most preferably from about 0.03 to about 10 mg/kg of body weight per day. The compounds can be administered 1 to 4 times a day.

The optimal dose intended for insertion, can be easily determined by a skilled person in this field and will vary depending on the specific applicable connection, the method of administration, strength of the drug and the stage of the disease. In addition, factors associated with a particular subject to be treated, including the age of the subject, weight, diet and time of administration, will lead to the need for regulation of the dosage to the appropriate therapeutic level.

In the schemes and examples, this specification uses the following abbreviations:

EAP or BZl = Benzyl

BOC = Tert-Butoxycarbonyl

THIEF-CL = Bis(2-oxo-3-oxazolidinyl)fatfingered

CBZ = Benzyloxycarbonyl

CF = the Connection

DCM = Dichloromethane

DIC = Diisopropylcarbodiimide

DIEA = Diisopropylethylamine

DMAP = 4-Dimethylaminopyridine

DMF = N,N-Dimethylformamide

DMSO = dimethyl Sulfoxide

EDC = Ethyldimethylamine incarnational

Et2O = Diethyl ether

EtOAc = ethyl Acetate

EtOH = Ethanol

HBTU = Hexaphosphate 2-(1H-Benzotriazol-1-yl)-

1,1,3,3-tetramethylurea

NOUT = Hydroxybenzotriazole

HPLC = high performance liquid chromatography

i-Pr = Isopropyl

LAH = Alumoweld lithium

Me = Methyl

Meon = Methanol

Mg/kg = Milligrams per kilogram

NMM = N-Methylmorpholine

NT = He tested

Ph = Phenyl

PPT = Precipitate

RT or rt = Room temperature

TEA = Triethylamine

THF = Tetrahydrofuran

TFU = Triperoxonane acid

Z = Benzyloxycarbonyl

The method of naming the compounds of the present invention is consistent with the current rules of nomenclature. The letter “R” or “S” denotes the absolute configuration (rules Kahne-Ingold-Prelog - Cahn-Ingold-Prelog). For example, structural names are usually obtained in accordance with the following system:

Accordingly, the compound 4 has the following title:

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide.

Especially preferred compounds include the compounds shown in table 1.

The compounds of this invention where X and Y are methylene, can be obtained with regard to the availa able scientific C with the scheme AA. The anhydride of N-carboxyanhydrides acid and pipecolinic acid is subjected to the condensation reaction at a high temperature in DMF to obtain the intermediate amide AA3. Amide AA3 is subjected to reduction with lithium aluminum hydride in boiling THF and then combine with the acid chloride of the acid HA obtaining 4-nitrobenzamide AA. The nitro-group is subject to recovery of zinc to the corresponding amine and then the combination with the acid chloride of the acid HA with the final product A. For compounds in which X represents O or S and Y is a methylene, an intermediate cyclic amino acid corresponding to AA1, can be obtained in accordance with the method of publication of the U. Larsson and R. Carlson, Acta Chimica Scandinavica 1994, 48, 517-525. For compounds in which X represents CH and Y is CH (olefin), intermediate cyclic amino acid corresponding to AA1, can be obtained in accordance with the method of publication of F. Rutjes, Tetrahedron Lett. 1997, 38, 677-680.

3-Cl RS
TABLE II
ExampleXR1R5R6R7Config.
5ON4'-OH-PhHS
6ON3-CLPh4-OHS
7ON3-Cl3'-OH-PhHS
8ON3-ClPh5-OHS
9ON3-Cl4-Me-2-thi4-FRS
10ON3-ClMe6-MeRS
11ON3-ClMe3-MeRS
12ONN4'-Me-PhHRS
13ON3-ClPhHR
14ON3-OMePhHRS
15ON2-OMePhHRS
16ON3-ClF3,4,5-F3

17AboutN3-CLCl5-FRS
18AboutN3-ClF3-ClRS
19AboutN3-ClSCHF2HRS
20ONNPhHRS
21ON - (5-oxo)3-ClPhHRS
22ON2-HEPhHRS
23ON3-OHPhHRS
24ON3-ClMeHRS
25ON3-Cl4'-Me-PhHRS
26ONNMeHRS
27ON3-IUMeH RS
28ON3-IU4'-Me-PhHRS
29ON3-IUPhHRS
30ON3-F4'-Me-PhHRS

TABLE III
ExampleXR1R5R6R7Config
3SNHPhHRS
31S8-OMeHPhHRS
32S8-FHPhHRS
33S8,9-(OMe)2HPhHRS
34S9-ClHPhHRS
35S8,9-(F)2H PhHRS
36S8-MeHPhHRS
37S8-ClHPhHRS
38S8-F3-ClPhHRS
39S10-MeHPhHRS
40S10-OMeHPhHRS
41SH3-ClH3,5-MeRS
42SH3-ClI3-MeRS
43SH3-ClH3,5-Cl2RS

44SN3-C1Me3-1RS
45SNN2'-FPhHRS
46SN3-NMe2 PhHS
47SN3-C1PhHS

The compounds of formula (III) can be obtained analogously to the compounds (I) using derivatives of Anthranilic acid, i.e. 2-amino-3-thiophencarboxylic acid or 2-amino-3-pyridineboronic acids and their regioisomers. Derivatives of Anthranilic acid can be converted into the corresponding derivatives of the anhydride of N-carboxyanhydrides acid by standard methods (condensation with carbonyl diimidazol) and then be used as shown in Scheme AA.

The compounds of this invention in which X represents O and Y represents a methylene, can be obtained as shown in the diagram AB. In aziridine AS introducing a protective group through interaction with benzylchloride obtaining AV and then subjected to interaction with 2-chloroethanol obtaining serine-derived AV. With connection AV remove a protective group by hydrogenolysis and then cyclist in the presence of triethylamine to obtain the research AV. The acylation AV 2-nitrobenzotrifluoride with subsequent recovery by cyclization using as a catalyst of iron gives benzodiazepine AV. This bis-lactam p will gorhaut reduction with lithium aluminum hydride, isolated in the form of his ditawarkan salt and subjected to acylation of 2-chloro-4-nitrobenzofurazan to connect AV. Recovery AS powdered zinc, followed by acylation of 2-biphenylcarboxylic results oxazine 4.

The compounds of this invention in which X represents S and Y represents a methylene, can be obtained in accordance with the scheme of AC. Aminoethanol and 3-bromopyruvate subjected to condensation and cyclist obtaining AC1. The resulting Imin restore using nutritionpolicy obtaining thiazine AC2. The acylation AC2 2-nitrobenzotrifluoride and subsequent reduction using iron yields a bis-lactam AC4. The intermediate product AC4 may be subjected to further processing as shown, for example, in the diagram AB to obtain the final target casinovip connections.

Reagents purchased from Aldrich Chemical Company.1H NMR spectra in the region of strong fields recorded on a spectrometer Bruker AC-360 at 360 MHz, the binding constants are given in Hertz. The melting temperature determined with the apparatus of the Mel-Temp II and have not been adjusted. Microanalysis performed in the laboratory Rob-ertson Microlit Laboratories, Inc., Madison, New Jersey, and the results are presented in percentage from the calculation of the mass of the each element relative to the total molecular weight. In those cases, when the product is obtained as a salt, free base get known in the art methods, such as principal ion-exchange purification. The spectra of nuclear magnetic resonance (NMR) for hydrogen atoms recorded in the specified solvent and Tetra-methylsilane (TMS) as internal standard spectrometer Bruker AM-360 (360 MHz). Values are expressed in parts per million shift in the lower region relative to TMS. Mass spectra (MS) were obtained on a Micromass spectrometer/Hewlett Packard Series 1050 (MH+) using the methods of ionization elektrorazpredelenie. Unless another source used in the examples of substances obtained from readily available commercial sources or synthesized by methods known qualified specialists in the field of chemical synthesis. Deputies, which vary between examples represent hydrogen, unless a different value.

EXAMPLE 1

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-piperidino[2,1-C][1,4]benzodiazepine · Hcl(1)

The mixture of the anhydride of N-carboxyanhydrides acid (1.1 g, 0,0068 mol) and pipecolinic acid (1.0 g, 0,0078 mol) in dimethylformamide (5 ml) is heated to 150° C and maintained at this temperature for 18 hours, cooled to room temperature and poured into ice water (10 ml). White precipitate is filtered off, washed with the ice water and dried in vacuum, the result AA3 (1.0 g). The solution AA3 in THF (10 ml) at room temperature is treated with lithium aluminum hydride (13.4 ml, 1.0 M in THF, of 0.013 mol), refluxed for 4 hours and cooled to room temperature. The resulting mixture was slowly quenched with water (5 ml) and sodium hydroxide (5 ml) and the product extracted with EtOAc (50 ml). The organic layer was washed with saturated sodium bicarbonate solution (20 ml), dried (sodium sulfate) and evaporated, the result A in the form of solids (0,53 g). The solution A, DCM (15 ml) and TEA (0.34 g, 0,0034 mol) at room temperature is treated AA (0.54 g, 0,0029 mol) and stirred for 18 hours. The reaction mixture was diluted with DCM (50 ml), washed with saturated sodium bicarbonate solution (15 ml), dried (sodium sulfate) and evaporated, the result A in the form of a glassy substance (0,83 g). The mixture A, Meon (29 ml) and ammonium chloride (0.75 g) is treated with powdered zinc (5,2 g, 0.08 mol) and then refluxed for 2 hours. The reaction mixture is cooled to room temperature, filtered through celite and the filtrate concentrated. The residue is treated with 10% acetic acid (1 ml), neutralized with saturated sodium bicarbonate solution and the product extracted with EtAc (50 ml). The organic layer was washed with water (15 ml), dried (sodium sulfate) and evaporated, resulting in what are square A in the form of a white solid (0,59 g). The solution A, DCM (9 ml) and TEA (0.24 g, 0,0024 mol) at room temperature is treated AA (0,44 g, 0.002 mol) and stirred for 18 hours. The reaction mixture was diluted with DCM (50 ml), washed with saturated sodium bicarbonate solution (20 ml), dried (sodium sulfate) and evaporated, get a solid yellow color. The solid product was then purified HPLC with reversed phase (0,01% TFU/MeCN, C18 Column), the result is a white solid substance. The solid product is treated with Hcl (1,0 N., 1.0 ml) and evaporated, the result A in the form of a reddish-brown powder: so pl. 191-193° C.1H NMR (DMSO-d6) 1,2 (m, 2 H), and 1.6 (m, 5H), 2,3 (t, J=4, 1H), 2,4 (m, 1H), and 2.7 (t, J=4, 1H), 2,9 (d, J=4, 1H), 3,4 (d, J=6, 1H), 3,8 (d, J=6, 1H), 4.8V (d, J=6, 1H), 6,4 (d, J=3, 1H), 6,7-7,0 (m, 7H), and 7.1 to 7.4 (m, 8H), and 7.8 (d, J=3, 1H); MC m/e 502,3 (MH+).

EXAMPLE 2

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-(tetrahydropyridine)[2,1-C][1,4]benzodiazepine (2)

1H NMR (Dl3) 1,1 (m, 1H), 2,9 (m, 1H), 2,3 (m, 1H), and 2.7 (m, 1H), 2,9 (m, 2H), 3,1 (m, 1H), 3,9 (m, 1H), 4,7 (m, 1H), 5,6 (ush, s, 2H), 6,7 (m, 1H), and 7.1 (m, 4H), 7,2-7,6 (m, N), 10,31 (s, 1H); MC m/e 500,3 (MH+).

EXAMPLE 3

(RS)-2-Phenyl-N-4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide (3)

1H NMR (DMSO-d6) to 2.5 (m, 5H), 2,9 (m, 1H), 3,2 (m, 2H), 3,8 (d, J=6, 1H), 4,1 (d, J=6, 1H), 4,7 (m, 1H), 6,7 (m, 1H), 7,0-7,2 (m, 4H), to 7.3 and 7.6 (m, 11N); MC m/e 520,5 (MH+).

EXAMPLE 4

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxa is Ino [4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · HCl (4)

The solution AS (49 g, 0.48 mol), DCM (1.0 l) and E3N (48.6 g, 1 EQ.) when 0° treated With a solution of benzylbromide (96 g, 1 EQ.) in DCM (100 ml), adding it dropwise within 1 hour. The ice bath removed and the mixture is stirred for 20 hours. The mixture was washed with water (200 ml), 20% citric acid (150 ml) and saturated salt solution (100 ml). The organic layer is dried (Na2SO4), evaporated and dried in high vacuum, the result is AS in the form of an amber oil (87,4 g, 77%). The solution AS (87,4 g), DCM (1.5 l) and 2-chloroethanol (225 ml, 10 EQ.) at room temperature, treated F3·Et2O (14 ml), stirred for 48 hours and diluted with water (1 l). The layers are separated and the organic layer dried (Na2SO4), evaporated and dried in high vacuum, the result is AS in the form of an amber oil (114 g, 99%). The mixture AW (114 g, 0.36 mol), Meon (2 l), Hcl (1 N., 360 ml) and 10% Pd-C (10 g) hydronaut at a pressure of 50 pounds per square inch (344,75 kPa) at room temperature in a Parr apparatus for 7 hours. The mixture is filtered through celite and the filtrate is evaporated and dried, the result is AS in the form of white crystals (79,2 g, 99%). The mixture AV (79,2 g), Meon (8 l) and Et3N (73 g, 2 EQ.) boil with a reverse refrigerator for 7 hours, cooled to room temperature and evaporated to dryness. The resulting residue is dissolved in DCM (1.2 l) and the organic layer is raybaut saturated salt solution (2× 300 ml), dried (Na2SO4), evaporated and dried in high vacuum, the result is AV as a dark amber oil (29 g, 56%). The solution AS (29 g, 0.20 mol), DCM (3 l) and Et3N (26,3 g, 1.3 EQ.) when 0° treated With a solution of 2-nitrobenzotrifluoride (45,4 g, 1.1 EQ.) in DCM (500 ml), adding it dropwise within one hour. The ice bath removed and the mixture is stirred for 18 hours. The resulting mixture was diluted with water (250 ml) and the layers separated. The organic layer is dried (Na2SO4), evaporated and purified flash chromatography on silica gel (EtOAc), the result AS in the form of a solid (53 g, 90%). The mixture AV (50 g, to 0.17 mol), Asón (1 l) and iron (60 g, 5 EQ.) refluxed for 20 hours, cooled to room temperature and filtered, washing the Asón. The filtrate is evaporated and cooled brown residue is treated with ice water (150 ml). The dark solid is filtered off and dried, the result is AS in the form of a solid reddish-brown substance (24.6 g, 62%). The solution AS (20 g, 0,087 mol) and THF (600 ml) at 0° treated With LAH (1 N. in THF, Fluka, 270 ml, 3.1 equiv.) adding it dropwise over 1 hour, and the ice bath removed. The mixture is stirred for 18 hours, cooled to 0° and treated successively with water (24 ml), NaOH (1 N., 36 ml) and THF (500 ml). The resulting mixture is filtered, the filtrate dried (Na2SO 4) and evaporated, the result is an amber oil. The oil is purified flash chromatography (1:1 hexane/EtOAc),the result is the product racemic tricyclic diamine in the form of pale yellow crystals (10,9 g, 61%). To a solution of diamine (6.2 g, being 0.030 mol) in Meon (40 ml) was added with stirring D-di-p-toluylene acid (5.8 g, 1 EQ.). Once dissolved, add Et2O (80 ml), the result is a cloudy solution, to which are added dropwise Meon to restore transparency. Solution close and leave for three days, get the crystals. The crystals are filtered, washed with chilled Et2O and dried, the result is 3.4 g resolved salt (58%). This product is partitioned between EtOAc and NaOH (1 ad), thoroughly mix, and the layers separated. The organic layer is washed with water and saturated salt solution, dried (Na2SO4) and evaporated, the result AS in the form of a white solid (1.52 g, 52%; side enantiomer was not detected using NMR with chemical shift Pirkle (Pirkle shift reagent)). A solution of compound IV (2.0 g, 0,0099 mol), DCM (20 ml) and Et3N (1.8 ml, 1.3 EQ.) when 0° treated With a solution of 2-chloro-4-nitrobenzotrifluoride (2.4 g, 1.1 EQ.) in DCM (10 ml), warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with DCM, washed with water, dried (Na2SO44OH/1% MeOH/DCM), the result AS in the form of a white foam (3.8 g, 99%). The foam solution and the Meon (100 ml) is treated with NH4Cl (2.6 g, 5 EQ.) and powdered zinc (22,7 g, 35 EQ.), refluxed for 2 hours and cooled to room temperature. The mixture is filtered through celite and the filtrate evaporated to a solid residue. The solid residue partitioned between EtOAc and water, and the aqueous phase is extracted once with EtOAc. The combined organic extracts washed with saturated salt solution, dried (Na2SO4) and evaporated, the result AS in the form of a white solid (3.6 g, 99%). A solution of 2-biphenylcarbonic acid (2.2 g, to 0.011 mol), DCM (15 ml), DMF (0.1 ml) and oxalicacid (1/0 ml, 1 EQ.) stirred for 2.5 hours and then added to the solution AS (3,6), DCM (20 ml) and Et3N (1.8 ml). The resulting mixture is stirred for 3 hours, diluted with DCM (100 ml) and washed with 10% Panso3, water and saturated salt solution. The organic layer is dried (Na2SO4), evaporated and purified flash chromatography on silica gel (0.1% of NH4OH/1% MeOH/DCM), the result is a white solid substance (about 2 g). The obtained solid product is dissolved in Meon (25 ml), treated with HCl/Et2O (1 N., 15 ml) and the solution is evaporated, the result is 4 (1,0 Hcl· 1,3 N2O&x000B7; 0,25 Et2O) as a white solid (2.5 g): so pl.>210° C (decomp.); MS m/e 538 and 540 (MH+); []

D
23
+215,5° (0,278, Meon). Elemental analysis: calculated for C32H28lN3O3·1,0 Hcl· 1,3 N2O· 0,25 Et2O (616,46): 64,30; N To 5.58; N 6,82; C1 11,50. Found: 64,40; N 5,44; N 6,70; C1 11.90.

EXAMPLE 5

(S)-2-(4-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (5)

White powder:1H NMR (CD3OD) 2,61 (s, 1H), 3,1 (m, 1H), 3,3 (m, 3H), 3,8 (dt, J=6 Hz, 2H), 4,1 (m, 2H), 4,4 (d, J=9 Hz, 1H), 4,9 (m, 4H), 6,7 (d, J=4 Hz, 1H), PC 6.82 (s, 2H), of 7.0 to 7.7 (m, N); MS m/e 554 and 556 (MH+).

EXAMPLE 6

(S)-2-Phenyl-4-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (6)

White powder:1H NMR (CD3OD) at 2.59 (s, 1H), 3,1 (m, 1H), 3,3 (m, 3H), 3,8 (dt, J=6 Hz, 2 H), 4,1 (m, 2H), 4,4 (d, J=9 Hz, 1H), 4,9 (m, 4H), 6,8 (m, 2H), of 7.0 to 7.7 (m, 13H); MS m/e 554 and 556 (MH+).

EXAMPLE 7

(S)-2-(3-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (7)

White powder:1H NMR (CD3OD) 2,60 (s, 1H), 3,1 (m, 1H), 3,3 (m, 3H), 3,8 (dt, J=6 Hz, 2H), 4,1 (m, 2H), 4,3 (d, J=9 Hz, 1H), 5,0 (m, 4H), 6,7 (d, J=4 Hz, 1H), 6,9 (d, J=4 Hz, 1H), and 7.1 to 7.7 (m, 13H); MS m/e 554 and 56 (MH+).

EXAMPLE 8

(S)-2-Phenyl-5-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (8)

White powder:1H NMR (CD3OD) at 2.59 (s, 1H), 3,1 (m, 1H), 3,3 (m, 3H), 3,8 (dt, J=6 Hz, 2H), 4,1 (m, 2H), 4,4 (d, J=9 Hz, 1H), 5,0 (m, 4H), 6,91 (s, 2H), 7,0 (d, J=4 Hz, 1H), 7,12 (s, 1H), of 7.2 to 7.7 (m, 11N); MS m/e 554 and 556 (MH+).

EXAMPLE 9

(RS)-2-(4-Methylthieno)-4-fluoro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (9)

White powder:1H NMR (CD3OD) and 2.14 (s, 3H), 2,59 (s, 1H), 3,1 (m, 1H), 3,3 (m, 3H), 3,8 (dt, J=6 Hz, 2H), 4,1 (m, 2H), 4,4 (d, J=9 Hz, 1H), 4,9 (m, 3H), 6,9 (d, J=4 Hz, 2H), of 7.0 to 7.7 (m, N), a 7.62 (s, 1H); MS m/e 576 and 578 (MH+).

EXAMPLE 10

(RS)-2,6-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (10)

White powder:1H NMR (CD3OD) of 1.4 (m, 1H), 2,30 (C, 6N), the 3.2 to 4.1 (m, 7H), 4.2V (d, J=9 Hz, 2H), and 4.5 (m, 1H), 4,9 (m, 2H), 6,9 (d, J=4 Hz, 2H), of 7.0 to 7.7 (m, 7H), 7,83 (s, 1H); MS m/e 490 and 492 (MH+).

EXAMPLE 11

(RS)-2,3-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (11)

White powder:1H NMR (CD3OD) of 2.28 (s, 3H), 2,31 (s, 3H), 3,1 (m, 1H), 3,3-4,1 (m, 8H), 4,4 (d, J=9 Hz, 1H), 5,0 (m, 2H), 7,0-7,5 (m, 8H), 7.5 (d, J=4 Hz, 1H), 7,6 (d, J=4 Hz, 1H), 7,82 (s, 1H); MS m/e 490 and 492 (MH+).

EXAMPLE 12

(RS)-2-(4-Were)-N-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino-[4,3-a] [1,4]benzodiazepine-N)-ylcarbonyl)phenyl]benzamide · TFU (12)

White powder;1H NMR (CD3OD) of 2.30 (s, 3H), 3.0 a (m, 1H), 3,5 (m, 4H), and 3.8 (m, 2H), 4,1 (m, 2H), 4,5 (d, J=9 Hz, 1H), 5,1 (m, 2H), 6,9 (d, J=4 Hz, 1H), of 7.2 to 7.7 (m, N); MS m/e 518 (MH+).

EXAMPLE 13

(R)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (13)

White powder: MS m/e 538 and 540 (MH+).

EXAMPLE 14

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12A-tetrahydro-6N[1,4]-oxazino[4,3-a] [1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · Hcl (14)

White powder: MS m/e tune 534.6 (MH+).

EXAMPLE 15

(RS)-2-Phenyl-N-[2-methoxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino [4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (15)

Reddish-brown powder: MS m/e tune 534.6 (MH+).

EXAMPLE 16

(RS)-2,3,4,5-Titrator-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (16)

Yellow powder: MS m/e 535 and 537 (MH+).

EXAMPLE 17

(RS)-2-Chloro-5-trifluoromethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl) phenyl]benzamide · TFU (17)

White powder: MS m/e 565 and 567 (MH+).

EXAMPLE 18

(RS)-2-Fluoro-3-chloro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino [4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (18)

White powder: MS m/e 514 and 516 (MH+).

EXAMPLE 19

(RS)-2-(Deformality)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-1(N)-ylcarbonyl)-phenyl]benzamide · TFU (19)

White powder: MS m/e 544 and 546 (MH+).

EXAMPLE 20

(RS)-2-Phenyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · TFU (20)

White powder: MS m/e 504,6 (MH+).

EXAMPLE 21

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]-5-oxovanadate-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (21)

White powder: MS m/e 552 and 554 (MH+).

EXAMPLE 22

(RS)-2-Phenyl-N-[2-hydroxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a] [1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (22)

Reddish-brown powder: MS m/e 520,6 (MH+); TPL 188-195° C (decomp.).

EXAMPLE 23

(RS)-2-Phenyl-N-[2-hydroxy-4-(1,3,4,12A-tetrahydro-6N[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (23)

Reddish-brown powder: MS m/e 520,6 (MH+); TPL 185-188° C (decomp.).

EXAMPLE 24

(RS)-2-Methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (24)

White powder: MS m/e 476 and 478 (MH+).

EXAMPLE 25

(RS)-2-(4-Were)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[I/4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (25)

White flakes: MS m/e 552 and 554 (MH+).

EXAMPLE 26

(RS)-2-Methyl-N-[4-(1,3,4,12A-tetrahydro-6N[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · TFU (26)

White powder: MS m/e 442,5 (MH+).

The USE of the 27

(RS)-2-Methyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (27)

White powder: MS m/e 456,5 (MH+).

EXAMPLE 28

(RS)-2-(4-Were)-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (28)

Cream coloured powder: MS m/e 532,6 (MH+).

EXAMPLE 29

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a] [1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · TFU (29)

White powder: MS m/e 518,6 (MH+).

EXAMPLE 30

(RS)-2-(4-Were)-N-[3-fluoro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide · TFU (30)

Cereal cream colour: MS m/e 536,6 (MH+).

Synthesis AC4

In a round bottom flask with a volume of 1 l load 2-aminoethanethiol hydrochloride (5,24 g, 0.046 mol), sodium bicarbonate (9,70 g, 2.5 EQ.), 4.0 g of molecular sieves 3(activated in a microwave oven) and 200 ml of dry methanol. The indicator bromocresol purple, 50 mg type for pH control, via the reaction mixture is passed a stream of nitrogen and the mixture remain in a nitrogen atmosphere. Add ethylbromide (10 g, 0,051 mol) via syringe at such a speed that the pH of the reaction mixture remained above 6 (dark olive color of the reaction mixture). Adding conducted for about 3 hours. The reaction is ionic mixture incubated for another 30 minutes and one portion add cyanoborohydride sodium (5.8 g, 2 EQ.).

The reaction mixture is acidified to pH 4 and maintain this pH value within 3 hours cautious addition of 6.0 M Hcl. The color of the reaction mixture remains yellow, the pH control indicator paper Panpeha®. Then add an excess of hydrochloric acid to obtain a pH of 1-2, after the cessation of gas evolution, the mixture is filtered through celite and evaporated in vacuum. The residue is dissolved in 200 ml of water and extracted once with diethyl ether, the ethereal solution drop. The aqueous solution is alkalinized (pH 8-9) by adding 6 N. aqueous sodium hydroxide solution and extracted 5 times with 50 ml diethyl ether. The combined organic extracts are dried over magnesium sulfate and filtered. The saturation of the resulting solution of gaseous Hcl leads to the deposition of ester amino acids, which is separated by filtration. White crystals are dried in a vacuum oven, receiving 7.9 g (0,037 mol) AC2 (spectral data are consistent with literature data (U. Larsson, and R. Carlson, Acta Chem. Scand. 48 (1994), 517-525). In a flask with a volume of 100 ml dissolve AC2 (8,66 g 0,041 mol) in 50 ml of dioxane containing 5 ml of water. Sodium bicarbonate (12.0 g, 0.14 mol) is added in one portion and added dropwise 6,82 g (being 0.036 mol) of 2-nitrobenzotrifluoride. The addition requires about 45 minutes. The system can withstand 4 hours at room temperature, diluted with 200 ml of saturated solution with the Lee and extracted with ether (4 x 50 ml). The combined organic fractions are dried over anhydrous magnesium sulfate and evaporated, to obtain 12.0 g (0,037 mol) of a viscous yellow oil (AC3), which is used without further purification. In a flask with a volume of 200 ml equipped with a reflux condenser, download AC3 (12.0 g, 0,037 mol) and 10 g of iron filler. The reaction mixture is refluxed for 4 hours and decanted into 500 ml of cold water. After stirring for 20 minutes to precipitate falls a white solid. It is filtered off, washed with a large amount of cold water and dried in a vacuum oven, the result AC4 in the form of a white solid (7.0 g, 0,028 mol).1H NMR (DMSO-d6) to 2.65 (DD, J=14.4 and 5.8 Hz, 1H), 2,74-only 2.91 (m, 2H), and 3.16 (dt, J=12,6 and 4.7 Hz, 1H), 3.33 and-to 3.41 (m, 1H), 4,19 (DD, J=9, 9 and 5.8 Hz, 1H), 4,58 (DD, J=14.1 and a 4.3 Hz, 1H), 7,11 (d, J=8.0 Hz, 1H), 7,25 (t, J=7.7 Hz, 1H), 7,54 (t, J=7.2 Hz, 1H), 7,80 (d, J=8.0 Hz, 1H); MS m/e 249 (MH+).

EXAMPLE 31

(RS)-2-Phenyl-N-[4-(8-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (31)

White powder: MS m/e 550,7 (MH+).

EXAMPLE 32

(RS)-2-Phenyl-N-[4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (32)

White flakes: MS m/e 538,6 (MH+); so pl. 177-180° C.

EXAMPLE 33

(RS)-2-Phenyl-N-[4-(8,9-dimethoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl is)phenyl]-benzamide · HCl (33)

White powder; MC m/e 550,7 (MH+).

EXAMPLE 34

(RS)-2-Phenyl-N-[4-(9-chloro-1,3,4,12A-tetrahydro-6N[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (34)

White flakes: MC m/e 554 and 556 (MH+).

EXAMPLE 35

(RS)-2-Phenyl-N-[4-(8,9-debtor-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (35)

White powder: MC m/e 556,6 (MH+); so pl. 194-199° C.

EXAMPLE 36

(RS)-2-Phenyl-N-[4-(8-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (36)

White flakes: MC m/e 534,7 (MH+); so pl. 191-196° C.

EXAMPLE 37

(RS)-2-Phenyl-N-(4-(8-chloro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (37)

White flakes: MC m/e 554 and 556 (MH+).

EXAMPLE 39

(RS)-2-Phenyl-N-[3-chloro-4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4] thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (38)

White flakes: MS m/e 572 and 574 (MH+).

EXAMPLE 39

(RS)-2-Phenyl-N-[4-(10-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (39)

White powder: MS m/e 534,7 (MH+).

EXAMPLE 40

(RS)-2-Phenyl-N-[4-(10-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (40)

White powder: MS m/e 550,7 (MH+).

EXAMPLE 41

(RS)for 3,5-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-and[1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · HCl (41)

White powder: MS m/e 506 and 508 (MH+).

EXAMPLE 42

(RS)-2-Iodine-3-methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (42)

Yellow powder: MS m/e 618 and 620 (MH+).

EXAMPLE 43

(RS)for 3,5-Dichloro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (43)

White powder: MS m/e 547 and 549 (MH+).

EXAMPLE 44

(RS)-2-Methyl-3-iodine-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (44)

Reddish-brown powder: MS m/e 618 and 620 (MH+).

EXAMPLE 45

(RS)-2-Forfinal-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (45)

White powder: MS m/e 538,6 (MH+).

EXAMPLE 46

(S)-2-Phenyl-N-[3-dimethylamino-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide · Hcl (46)

White powder: MS m/e 563,7 (MH+).

EXAMPLE 47

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide · Hcl (47)

White powder: so pl. 192-197° C; MS m/e 554 and 556 (MH+);+173,4 (0,154, Meon). Elemental analysis: calculated for C32H28lN3O2S· 1,0 Hcl· 1,0 H2O (608,58): 63,15; N 5,13; N 6,90; Cl 11,65. Found: 63,29; N 4,99; N Is 6.78; Cl 11,40.

EXAMPLE 48

0-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-1,2-metanarrative[2,1-C][1,4]benzodiazepine · TFU (48)

White powder: MS m/e 500,3 (MH+).

EXAMPLE 49

As a specific example of a composition for oral delivery, 100 mg of compound 9 of example 1 is prepared in a mixture with sufficient finely powdered lactose, so to get the total amount of 580 to 590 mg to fill the volume all the hard gelatin capsules.

EXAMPLE 50

TEST the BINDING of RECOMBINANT RECEPTOR VASOPRESSIN IN VITRO

Compounds tested on their ability to substitute containing3H-arginine vasopressin of V-1 or V-2 receptor, human cells SOME 293. Buffer for testing - 50 mm Tris-CL, 5 mm gl2, 0.1% bovine serum albumin (pH 7.5)containing 5 μg/ml Aprotinin, leupeptin, pepstatin, 50 μg/ml bacitracin and 1 mm Pefabloc.3H-vasopressin is a3H-arginine-8-vasopressin (68,5 Ci/mmol, final concentration in the experience of 0.65 to 0.75 nm). In wells of 96-well round-bottom polypropylene tablets add buffer, tested the connection, the membrane containing the cloned V-1 or V-2 receptor) and3H-vasopressin. The reaction tablets leave at room temperature for one hour. Samples filtered through a plate Unifilter GF/C (pre-soaked in 0.3 polyethylenimine). Tablets washed 5 times with cold saline containing 0.05% Tween 20. After suck the bottom filter plate seal and each filter add 0,025 ml of Microscint-20. The upper part of the tablet, sealed and calculate. Nonspecific binding is determined by addition of 1.25 μm arginine-8-vasopressin in these wells.

EXAMPLE 51

The TREATMENT of VASOPRESSIN-INDUCED HYPERTENSION IN RATS

Hypotensive activity of the compounds was determined on shot model vasopressin-induced hypertension. Male rats of the Long Evans with normal pressure weighing from 350 to 450 g is subjected to anesthesia using pentobarbital (35 mg/mg, intraperitoneally) and support throughout the experience intraperitoneal infusion of 10 mg/kg/hour. Arginine vasopressin injected at a speed of 30 ng/mg/min intravenously to induce a state of stable hypertension (increase in average blood pressure by approximately 50 MND). Compound is administered in increasing doses and the average value of the maximum decrease in arterial blood pressure recording. ED50determined from the linear part of the dependence “dose-effect” for each animal.

This model is slightly modified to assess the bioavailability of these compounds. Instead intravenous dosing of increasing doses of substances to animals injected with one dose directly into the duodenum. Then hypotensive effects control for 60 minutes and calculate the maximum percentage about the stop.

TABLE IV
The results of in vitro
ConnectionV2 Bdg IC50(PM)VI Bdg (% ing. 0.1 ám)V2 cAMP IC50(µm)
1931%0,21
21429%0,46
31042%0,71
42(of 0.82 μm)0,011
5929%not tested
6349%not tested
7111%not tested
82732%not tested
91118%not tested
10915%not tested
11811%not tested
126(0,030 µm)not tested
1332(2,8 µm)not tested
14 936%not tested
151369%not tested
162520%not tested
17(63%/0.1 ám)13%not tested
181815%not tested
192724%not tested

(43%/0.1 ám)
20869%not tested
21(59%/0.1 ám)2%not tested
22667%not tested
231033%not tested
241634%not tested
251260%not tested
26(65%/0.1 ám)58%not tested
27137%not tested
281014%not tested
296 3%not tested
301474%not tested
314327%/10 µmnot tested
322044%/10 µmnot tested
33(19%/0.1 ám)6%/10 Μmnot tested
34(41%/0.1 ám)1%/10 µmnot tested
353815%/10 µmnot tested
361876%not tested
372275%not tested
38189%not tested
39(37%/0.1 ám)(of 0.77 μm)not tested
40(12%/0.1 ám)(of 4.3 μm)not tested
41(38%/0.1 ám)5%not tested
42(62%/0.1 ám)0%not tested
43(47%/0.1 ám)11%not tested
442%not tested
45(69%/0.1 ám)15%not tested

46478%not tested
4711of 0.85 μm)not tested

TABLE V

Results lower blood pressure experience in vivo
ConnectionI.D. Dose (mg/kg)Reduction in blood pressure (%)
11067%
310100%
410100%

Although in the above description presents the principles of the present invention with illustrative examples, it should be understood that the practice of the present invention includes all of the usual variations, adaptations and/or modifications that are included in the scope of the following claims and their equivalent.

EXAMPLE 52

Pharmacological safety of the compounds according to the invention

Cardiovascular system

Compounds of the present invention had no significant impact on shot sa is PAC rat Long Evans in cumulative dose up to 30 mg/kg

Respiratory system

In rats, the introduction of single oral doses of 10 and 50 mg/kg of the compounds of the present invention caused a weak but significant change in the inhaled volume. Due to this effect, we changed the time of inhalation and exhalation, as well as the peak values of the inhaled and exhaled streams.

Central nervous system

In rats introduction oral compounds of the present invention was not observed noticeable behavioral symptoms at doses up to 100 mg/kg, whereas at doses of 100 mg/kg was observed relaxation of skeletal muscles from mild to strong and calm.

These data demonstrate the low toxicity of the compounds of the present invention.

1. Tricyclic benzodiazepine of formula (I)

where

And means-C(O)-;

Y represents CH2or SN as part of the olefin;

X is CH2CH as part of the olefin, S, O or NR3where R3means C1-C8alkyl; provided that when Y represents CH as part of the olefin, and X represents CH as part of the olefin;

Z is selected from the group consisting of N or CH;

R1selected from the group consisting of hydrogen, C1-C8-alkyl, C1-C8-alkoxygroup or halogen;

R2means GRU is PU NR 4COAr, where R4means hydrogen, and AG denotes phenyl, which is optionally substituted with one to three substituents, independently selected from C1-C8of alkyl, halogen, hydroxyl group, fluorinated C1-C8ancilliary second or phenyl, where the second phenyl optionally substituted by the Deputy, is selected from C1-C4of alkyl, halogen or hydroxyl group; and

R5selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine, fluorine, a hydroxyl group, and di-C1-C4-alkylamino;

and their pharmaceutically acceptable salts.

2. The compound according to claim 1 of formula (III)

where

Y represents CH2or SN as part of the olefin;

X is CH2CH as part of the olefin, S, O or NR3where R3means C1-C4alkyl; provided that when Y represents CH as part of the olefin, and X represents CH as part of the olefin;

R1selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup and halogen;

R2means NHCOAr;

R5selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine and fluorine; and

the, Ah, and Z are defined as indicated in claim 1;

and its pharmaceutically acceptable salts.

3. The compound according to claim 2, where

Y represents CH2or SN as part of the olefin;

X is CH2CH as part of the olefin, S, or O; provided,

if Y represents CH as part of the olefin, and X represents CH as part of the olefin;

Z represents CH;

AG denotes phenyl, which is optionally substituted with one to three substituents, independently selected from C1-C8of alkyl, halogen, hydroxyl group, fluorinated C1-C8allylthiourea, or the second phenyl, where the second phenyl optionally substituted by the Deputy, is selected from C1-C4of alkyl, halogen and hydroxyl groups;

and its pharmaceutically acceptable salts.

4. The compound of formula (IV)

where

X is selected from the group consisting of CH2, S and O;

R1selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup and halogen;

R5selected from the group consisting of hydrogen, C1-C4of alkyl, C1-C4alkoxygroup, chlorine and fluorine, a hydroxyl group, and di-C1-C4-alkylamino;

R6means phenyl, where phenyl is neo Astelin substituted C 1-C4by alkyl, halogen or hydroxyl group; and

R7independently selected from the group comprising hydrogen, fluorine, chlorine, hydroxyl group, C1-C6alkyl, and combinations thereof, where R7can mean from one to three independently selected groups;

and its pharmaceutically acceptable salts.

5. The compound according to claim 1, selected from the group comprising the following compounds:

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-piperidino[2,1-C][1,4]benzodiazepine;

10-[4-[[(2-Biphenyl)carbonyl]amino]benzoyl]-10,11-dihydro-5H-(tetrahydropyridine)[2,1-C][1,4]benzodiazepine;

(RS)-2-Phenyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(S)-2-(4-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-Phenyl-4-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-(3-Hydroxyphenyl)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(S)-2-Phenyl-5-hydroxy-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-FeNi is]benzamide;

(RS)-2-(4-Methylthieno)-4-fluoro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2,6-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2,3-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(R)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methoxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[2-methoxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2,3,4,5-Titrator-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Chloro-5-trifluoromethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Fluoro-3-chloro-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(Deformality)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-alkabo who yl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]-5-oxovanadate-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[2-hydroxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[3-hydroxy-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-methyl-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Methyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Phenyl-N-[3-methyl-4-(1,3,4,12A-tetrahydro-6N-[1,4]-oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-(4-Were)-N-[3-fluoro-4-(1,3,4,12A-tetrahydro-6N-[1,4]oxazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)-phenyl]benzamide;

(RS)-2-Hairdryer is l-N-[4-(8-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[4-(8,9-dimethoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(9-chloro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-phenyl-N-[4-(8,9-debtor-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(8-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(8-chloro-1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(RS)-2-Phenyl-N-[3-chloro-4-(8-fluoro-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(10-methyl-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Phenyl-N-[4-(10-methoxy-1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)for 3,5-Dimethyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Iodine-3-methyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)for 3,5-Dichloro-N-[3-chlor-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Methyl-3-iodine-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(RS)-2-Forfinal-N-[4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

(S)-2-Phenyl-N-[3-dimethylamino-4-(1,3,4,12A-tetrahydro-6N-[1,4]-thiazino[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]-benzamide;

(S)-2-Phenyl-N-[3-chloro-4-(1,3,4,12A-tetrahydro-6N-[1,4]thiazino-[4,3-a][1,4]benzodiazepine-11(N)-ylcarbonyl)phenyl]benzamide;

and their pharmaceutically acceptable salts.

6. Pharmaceutical composition having anti-hypertensive activity, including an active agent and a pharmaceutically acceptable carrier, wherein the active agent it contains a compound according to any one of claims 1 to 5.

7. The pharmaceutical composition according to claim 6, obtained by mixing the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 6, obtained by granulating the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

9. A method of treating hypertension in a subject in need of such treatment, comprising administration to the subject a therapeutically effective amount of an active agent, wherein the active agent is a compound according to claim 1.

10. The method according to claim 9, where a therapeutically effective to icesto compound is from about 0.1 to about 300 mg/kg/day.

11. A method of treating hypertension in a subject in need of such treatment, comprising administration to the subject a therapeutically effective amount of an active agent, wherein the active agent is a compound according to claim 4.

12. The method according to claim 11, where a therapeutically effective amount of compound is from about 0.1 to about 300 mg/kg/day.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

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

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

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

The invention relates to the field of production of new heterocyclic o-dicarbonitriles

The invention relates to a new method for the preparation of 3-substituted cephalosporins of the formula (I):

where R1is a para-nitrobenzyl or allyl, X is a halogen; comprising the stage of: a) cyclization trimethylphosphine the compounds of formula (IIIA):

where R1is a para-nitrobenzyl or allyl, R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; in a solvent to form compounds of the formula (II):

where R1is a para-nitrobenzyl or allyl; R2selected from the group comprising FROM1-6alkyl, C6-10aryl, C6-10arils1-6alkyl and dithienyl; and (b) interaction of the compounds of the formula (II) with acid

The invention relates to polycyclic, thiazolidin-2 - ildenafil amines and their physiologically acceptable salts and physiologically functional derivatives

The invention relates to a method for producing [1,2,4]triazolo[3,4-b][1,3]benzothiazol-3(2H)-thione of the formula

including fusion [1,2,4]triazolo[3,4-b][1,3]benzothiazole with excess sulfur in for 5-20 minutes at a temperature of 180-200With subsequent isolation of the target product

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to tetrahydro-gamma carbolines formula (I), where R1, R2D, Alk and n are such as defined in the claims

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, chemical technology, herbicides.

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

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

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

(IVa)

or (IVb) ,

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

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to the field of organic chemistry, namely to new individual compounds of class benzoxazines that exhibit fluorescent properties and can be used as starting products for the synthesis of new heterocyclic systems, as well as substances for sample labeling and additives for reflective paints

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to new cyclic diamine compounds of the formula I, where

< / BR>
represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to new heterocyclic o-dicarbonitrile formula (I), where

< / BR>
The compounds obtained can be used to obtain hexatriene-fluorophores

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

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