Derivatives of amino acids and pharmaceutical compositions containing them as active ingredients

 

The invention relates to amino acid derivatives of the formula Ior its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain. The values of the radicals R1-R4listed in the description. 5 C. and 13 C.p. f-crystals, 41 PL.

Description text in facsimile form (see graphic part). T T TV

Claims

1. Amino acid derivative of the formula (I)where R1means 1)1-C15alkyl, 2)1-C8alkoxy, 3) phenyl, 4)3-C8cycloalkyl, 5) heterocyclic ring, 6)1-C4alkyl, substituted heterocyclic ring, or 7)2-C4alkenyl, substituted phenyl, C3-C8cycloalkyl or heterocyclic ring, where all these phenyl,3-C8cycloalkyl and heterocyclic ring in R1can be substituted by 1-3 substituents selected from the group ub>2-C5acyl, (vi) halogen, (vii)1-C4alkoxycarbonyl, and (viii) - NR6R7(where R6and R7taken together with the nitrogen atom to which they are attached, represent a 5 to 7 membered saturated heterocyclic ring necessarily containing one nitrogen atom or one oxygen atom); And a represents a simple bond, -CO-; R2is hydrogen; D - C1-C4alkylen; E represents 1), 2) -S-3) IS a SO-;
R3means 1) carbocyclic ring, 2)1-C4alkyl, substituted carbocyclic ring;
J denotes the J1or J2where J1- -NR16- (where R16is hydrogen or C1-C4alkyl), J2means 1) -NR17- (where R17- C1-C4alkyl substituted with one hydroxy or -(C1-C4alkylene)-O-(C2-C5the acyl), 2) -NR20-NH21- (where R20and R21independently is hydrogen or C1-C4alkyl), 3) -NR22-(C1-C4alkylene)-NR23- (where R22and R23independently - hydrogen);
R4means R4-1, R4-2or R4-3where R4-11) With the1-C8alkyl, 2) carbocyclic ring, 3)1-C8alkyl, substituted by 1-3 substituents selected from the group -, every R4-1and R23taken together with the nitrogen atom to which they are attached, may represent a heterocyclic ring, where the specified carbocyclic ring in R4-1and specified heterocyclic ring represented by each of R4-1and R23taken together with the nitrogen atom to which they are attached may be substituted by 1-3 substituents selected from the group including (i)1-C4alkoxy; R4-2means 1) carbocyclic ring, 2) a heterocyclic ring or 3)1-C8alkyl, substituted by 1-3 substituents selected from the group comprising: (i) carbocyclic ring, provided that when J represents-NR16- every R4-2and R16taken together with the nitrogen atom to which they are attached, may represent a heterocyclic ring, where at least one ring of the above carbocyclic ring and heterocyclic ring in R4-2and the heterocyclic ring represented by each of R4-2and R16taken together with the nitrogen atom to which they are attached is substituted by one hydroxy or a group - O-(C1-C4alkylene)-O-(C1-C4alkyl) and can be optionally substituted 1-si and R4-3represents - L-M, where L denotes 1) carbocyclic ring which may be substituted by 1-3 substituents, 2) heterocyclic ring which may be substituted by 1-3 substituents, or 3) -(C1-C4alkylen) - carbocyclic ring or heterocyclic ring which may be substituted by 1-3 substituents, provided that when J represents-NR16- every L and R16taken together with the nitrogen atom to which they are attached, may represent a heterocyclic ring which may be substituted by 1-3 substituents; M represents 1) carbocyclic ring or heterocyclic ring which may be substituted by 1-3 substituents (provided that, when specified carbocyclic ring is phenyl, such a ring is substituted by at least one Deputy, and that, when the specified heterocyclic ring is a 5 - to 7-membered saturated heterocyclic ring in which the nitrogen atom in the specified heterocyclic ring is linked to the group L, as shown

and which may contain another nitrogen atom or one oxygen atom, then this ring is substituted by at least one Deputy, 2)1-C4alkyl, substituted the but 1-3 substituents, (ii) heterocyclic ring which may be substituted by 1-3 substituents, 3) -NR38- carbocyclic ring which may be substituted by 1-3 substituents, where R38is hydrogen or C1-C4alkyl), 4) -NR39- (C1-C4alkylen)-carbocyclic ring which may be substituted by 1-3 substituents, where R39is hydrogen or C1-C4alkyl or C2-C5acyl which may be substituted by 1-3 halogen atoms, or 5)- - - carbocyclic ring which may be substituted by 1-3 substituents where the Deputy (deputies) of the said carbocyclic ring in L and M, and the heterocyclic ring represented by each of L and R16taken together with the nitrogen atom to which they are attached, are selected from (i)1-C4of alkyl, (ii) hydroxy, (iii)1-C4alkoxy, (iv) halogen, provided that when j is j1, R4is not R4-1,
or its non-toxic salt or its hydrate.

2. Connection on p. 1, where R1- C1-C15alkyl or C1-C8alkoxy.

3. Connection on p. 1, where R1- 1) phenyl, 2)3-C8-cycloalkyl, 3)2-C4alkenyl, substituted phenyl or3-C81- 1) a heterocyclic ring, 2)1-C4alkyl, substituted heterocyclic ring, 3)2-C4alkenyl, substituted heterocyclic ring, all of these heterocyclic rings may be substituted.

5. Connection on p. 1 or 4, where R1indicates 1) a 5 - to 15-membered mono - or biheterocyclic ring containing 1-2 nitrogen atom and 1 to 2 oxygen atom or one sulfur atom, 2)1-C4alkyl, substituted 5 - to 15-membered mono - or biheterocyclic ring containing 1-2 nitrogen atom and 1 to 2 oxygen atom or one sulfur atom, 3)2-C4alkenyl, substituted 5 - to 15-membered mono - or biheterocyclic ring containing 1-2 nitrogen atom and 1 to 2 oxygen atom or one sulfur atom, all of these heterocyclic rings may be substituted.

6. Connection on p. 1 or 5, where E denotes-O-, -S-, -SO-.

7. The compound according to any one of paragraphs. 1-5, where E denotes-O - or-S-.

8. The compound according to any one of paragraphs. 1-7, where R3- carbocyclic ring or1-C4alkyl, substituted carbocyclic ring.

9. The compound according to any one of paragraphs. 1-7, where R3- C3-C10cycloalkyl or1-C4alkyl, substituted C3-C10cyclooctylamino-3-cyclohexylacetophenone,
(2) (2R)-N-(4-hydroxybenzyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(3) (2S)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(4) (2R)-N-(1-benzylpiperidine-4-ylmethyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(5) (2R)-N-(3-methoxyethoxy-4-methoxybenzyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(6) (2R)-N-(1-(4-methoxybenzyl)piperidine-4-ylmethyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(7) (2R)-N-methyl-N-(1-benzylpyrrolidine-3-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(8) (2R)-N-(1-(4-methoxybenzyl)piperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(9) (2R)-N-(1-(4-methoxybenzoyl)piperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(10) (2R)-N-(1-(4-terbisil)piperidine-4-ylmethyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(11) tert-butyl ether N - ((1R)-2-cyclohexylmethyl-1-(4-benzylpiperazine-1-ylcarbonyl)ethyl) - carbamino acid,
(12) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-diphenylbutylpiperidine-1-ylcarbonyl)ethyl) - carbamino acid,
(13) (2R)-N-(2-benzylamino)-2-tert-butoxycarbonyl the Nile)piperazine-1-ylcarbonyl)ethyl)-carbamino acid,
(15) (2R)-N-(1-(4-terbisil)piperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(16) (2R)-N-(1-(4-perbenzoic)piperidine-4-yl)-2-tertbutoxycarbonyl-3-cyclohexylacetophenone,
(17) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-(pyridin-2-yl)piperazine-1-ylcarbonyl)ethyl) - carbamino acid,
(18) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-pyridin-4-yl)piperazine-1-ylcarbonyl)ethyl) - carbamino acid,
(19) (2R)-N-(4-(morpholine-4-ylmethyl)phenyl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(20) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-phenylaminopyrimidine-1-ylcarbonyl)ethyl) - carbamino acid,
(21) (2R)-N-(4-(N'-methyl-N'-phenylamino)benzyl)-2-tertbutoxycarbonyl-3-cyclohexylacetophenone,
(22) (2R)-N-((4-methoxyphenyl)amino)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(23) (2R)-N-amino-N-benzyl-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(24) (2S)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(25) (2R)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclopentylpropionic,
(26) (2R)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclomethicone,
(28) (2R)-N-(2-acetoxyethyl)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(29) (2R)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylmethyl-3-methylbutanoic,
(30) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-(N'-benzyl-N'-triptoreline)piperidine-1-ylcarbonyl)ethyl) - carbamino acid, or
(31) tert-butyl ether N-((1R)-2-cyclohexylmethyl-1-(4-(N'-benzyl-N'-methylamino)piperidine-1-ylcarbonyl)ethyl) - carbamino acid,
or its non-toxic salt or its hydrate.

11. Connection under item 1 or 2, which is
(1) (2R)-N-(I-(4-methylbenzyl)piperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexylacetophenone,
(2) (2RS)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-4-cyclohexylthiophthalimide, or
(3) (2R)-N-(1-benzylpiperidine-4-yl)-2-tert-butoxycarbonylamino-3-cyclohexyldimethylamine,
or its non-toxic salt or its hydrate.

12. Connection under item 1 or 3, which is
(1) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(2-phenoxyethylamine)propanamide,
(2) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(3-phenoxybenzamine)propanamide,
(3) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexyloxycarbonyl)propanamide,
(5) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(4-tert-butoxycarbonylmethylene)propanamide,
(6) (2R)-N-(1-benzylpiperidine-4-yl)-3-cilexetil-2-(3-tert-butoxycarbonylmethylene)propanamide, or
(7) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl (1 phenylcyclohexylpiperidine) propanamide,
or its non-toxic salt or its hydrate.

13. Connection on p. 1 or 4, which is
(1) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(2) (2R)-N-(4-hydroxybenzyl)-3-cyclohexylmethyl-2-((2RS)-3-tert-butoxycarbonylmethyl-2-alarmonline)propanamide,
(3) (2R)-N-(4-hydroxybenzyl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)-propanamide,
(4) (2R)-N-(1-benzylpiperidine-4-ylmethyl)-3-cyclohexylmethyl-2-((4R) -3-tert-butoxycarbonylmethyl-4-ylcarbonyl) propanamide,
(5) (2R)-N-(3-hydroxy-4-methoxybenzyl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(6) (2R)-N-(1-(4-methoxybenzyl)piperidine-4-ylmethyl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(7) (2R)-N-methyl-N-(1-benzylpyrrolidine ethoxybenzyl)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(9) (2R)-N-(1-(4-methoxybenzoyl)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(10) (2S)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethoxy-2-((4R-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(11) (2R)-N-(2-benzylamino)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(12) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-benzylpiperazine-1-ylcarbonyl)ethyl)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl,
(13) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-diphenylbutylpiperidine-1-ylcarbonyl)ethyl)-3-tert-butoxycarbonyl-thiazolidin-4-ylcarbonyl,
(14) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(4-methoxyphenyl)piperazine-1-ylcarbonyl)ethyl-3-tert-butoxycarbonyl-thiazolidin-4-ylcarbonyl,
(15) (2R)-N-(1-(4-terbisil)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-alcuronium)propanamide,
(16) (2R)-N-(1-(4-perbenzoic)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(17) (4R)-N - ((1R)-2-cyclohexylmethyl-1-(4-pyridine-2-)yl piperazine-1-ylcarbonyl)ethyl)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl,
(18) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-pyridin-4-is-4-yl)-3-cyclohexyl-methylthio-2-((3RS)-4-tert-butoxycarbonylamino-3-yl-carbylamine)propanamide,
(20) (2R)-N-(4-(morpholine-4-ylmethyl)phenyl)-3-cyclohexyl-methylthio-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl) propanamide,
(21) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-phenyl-aminopyridine-1-ylcarbonyl)ethyl)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl,
(22) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4RS)-3-tert-butoxycarbonyl-1,3-targetrotation-4-ylcarbonyl)propanamide,
(23) (2R)-N-(4-N'-methyl-N'-phenylamino)benzyl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(24) (2R)-N-((4-methoxyphenyl)amino)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl) propanamide,
(25) (2R)-N-amino-N-benzyl-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl) propanamide,
(26) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4S)-3-tert-butoxycarbonylmethyl-4-yl, carbylamine)propanamide,
(27) (2S)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(28) (2S)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4S)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl) propanamide,
(29) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclopentylmethyl-2-((4R)-3-tert-butoxide-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(31) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonyl-5,5-dimethylthiazolidine-4-ylcarbonyl) propanamide,
(32) (2R)-N-(2-acetoxyethyl)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(33) (2R)-N-(1-antipeptide-4-yl)-3-cyclohexyl-methylthio-3-methyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)butanamide,
(34) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(N'-benzyl-N'-triptoreline)piperidine-1-ylcarbonyl)ethyl)-3-tertbutoxycarbonyl-4-ylcarbonyl,
(35) (2R)-N-(-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2RS, 4S)-3-tert-butoxycarbonyl-2-methylthiazolidine-4-ylcarbonyl) propanamide,
(36) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(N'-benzyl-N' methylamino)piperidine-1-ylcarbonyl)ethyl)-3-tert-butoxycarbonyl-thiazolidin-4-ylcarbonyl,
(37) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2RS)-3-tert-butoxycarbonylmethyl-2-ylcarbonyl) propanamide,
(38) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(3-tert-butoxycarbonylmethyl-2-ylcarbonyl-amino)propanamide,
(39) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(((4R)-3-tert-butoxycarbonylmethyl-4-ylmethyl)amino) propanamide,
(40) (2R)-
(41) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(42) (2R)-N-(1-benzylpiperidine-4-ylmethyl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(43) (2R)-N-(1-(4-methoxybenzyl)piperidine-4-ylmethyl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl) propanamide,
(44) (2R)-N-(1-(4-methoxybenzyl)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl) propanamide,
(45) (2R)-N-(3-hydroxy-4-methoxybenzyl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl) propanamide,
(46) (2R)-N-methyl-N-(1-benzylpyrrolidine-3-yl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(47) (2S)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethoxy-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(48) (2R)-N-(2-benzylamino)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(49) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-benzile-perazin-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(50) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-phenyl-aminopiperidin-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(51) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-5,5-dimethylthiazolidine-4-ylcarbonyl)-propanamide,
(52) (2R)-N-(1-benzylpiperidine-4-yl)-3-IIN-4-yl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl) propanamide,
(54) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-diphenyl-methylpiperazin-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(55) (2R)-N-(1-(4-perbenzoic)piperidine-4-yl)-3-cyclohexylmethyl-2-((4B)-thiazolidin-4-ylcarbonyl)propanamide,
(56) (2R)-N-(1-(4-terbisil)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(57) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(4-methoxyphenyl)piperazine-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(58) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(pyridin-2-yl)piperazine-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(59) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-(pyridin-4-yl)piperazine-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarbonyl,
(60) (2R)-N-(4-(morpholine-4-ylmethyl)phenyl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(61) (2R)-N-(4-(N'-methyl-N'-phenylamino)benzyl)-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl)propanamide,
(62) (2R)-N-amino-N-benzyl-3-cyclohexylmethyl-2-((4R)-thiazolidin-4-ylcarbonyl) propanamide,
(63) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(((4R)-thiazolidin-4-ylmethyl)amino)propanamide,
(64) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-isopropoxycarbonyl-4-ylcarbonyl) propanamide,
(65) (2R)-N-(1-benzile the
(66) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-2,2-dimethylthiazolidine-4-ylcarbonyl)-propanamide,
(67) (2R)-N-(I-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S, 4S)-1-tert-butoxycarbonyl-4-ftorpirimidinu-2-ylcarbonyl)propanamide,
(68) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S)-1-tert-butoxycarbonyl-4,4-debtorprovidian-2-ylcarbonyl)-propanamide,
(69) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-(2-methylpropanesulphonic)thiazolidin-4-ylcarbonyl)propanamide,
(70) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexyl-methylthio-2-((4R)-3-methoxycarbonylmethylene-4-ylcarbonyl)propanamide,
(71) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-Jaloliddin-4-ylcarbonyl)-propanamide,
(72) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-(3-methylbutyryl)thiazolidin-4-ylcarbonyl-amino)propanamide
(73) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexyl-methylthio-2-((4R)-3-(2-methylpropionyl)thiazolidin-4-ylcarbonyl)propanamide,
(74) (2R)-N-(2-hydroxyethyl)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(75) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-benzyl-aminopiperidin-1-ylcarbonyl)ethyl)-3-tert-BU-methylbutyryl)thiazolidin-4-ylmethyl)amino) propanamide,
or its non-toxic salt or its hydrate. 14. Connection on p. 1 or 4, which is
(1) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S)-1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-2-ylcarbonyl) propanamide,
(2) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S)-1-tert-butoxycarbonylamino-2-ylcarbonyl)propanamide,
(3) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4S)-3-tert-butoxycarbonyloxyimino-4-ylcarbonyl)propanamide,
(4) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S)-1-tert-butoxycarbonylamino-2-ylcarbonyl-amino)propanamide,
(5) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((2S, 4RS)-1-tert-butoxycarbonyl-4-methylthiopyrimidin-2-ylcarbonyl)propanamide,
(6) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-thio-2-((3S)-4-tert-butoxycarbonylmethyl-3-ylcarbonyl) propanamide,
(7) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-(3-tert-butoxycarbonylamino-4-ylcarbonyl)propanamide,
(8) (2R)-N-(1-(4-methylbenzyl)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(9) (2RS)-N-(1-benzylpiperidine-4-yl)-4-cyclohexylthio-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl-4-ylcarbonyl) propanamide,
(11) (2S)-N-(1-benzylpiperidine-4-yl)-3-cyclohexyl-methoxy-2-((4S)-3-tert-butoxycarbonyloxyimino-4-ylcarbonyl) propanamide,
(12) (2R)-N-(2-benzylamino)-3-cyclohexylmethyl-2-((4R)-3-isopropoxycarbonyl-4-ylcarbonyl)propanamide,
(13) (2R)-N-(2-benzylamino)-3-cyclohexylmethyl-2-((4R)-3-(3-methylbutyryl)thiazolidin-4-ylcarbonyl)propanamide,
(14) (2R)-N-(1-(4-hydroxybenzyl)piperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-3-tert-butoxycarbonylmethyl-4-ylcarbonyl)propanamide,
(15) (4R)-N-((1R)-2-cyclohexylmethyl-1-(4-benzylaminopurine-1-ylcarbonyl)ethyl)-3-(3-methylbutyryl)thiazolidin-4-ylcarbonyl,
(16) (4R)-N-(1R)-2-cyclohexylmethyl-1-(4-benzylaminopurine-1-ylcarbonyl)ethyl)-3-isopropoxycarbonyl-4-ylcarbonyl or
(17) (2R)-N-(1-benzylpiperidine-4-yl)-3-cyclohexylmethyl-2-((4R)-2,2-dimethyl-3-(3-methylbutyryl)thiazolidin-4-ylcarbonyl) propanamide, or its non-toxic salt or its hydrate.

15. Pharmaceutical composition having inhibitory effect on calcium channel N-type, comprising as an active ingredient derived amino acids of the formula (I) under item 1, its non-toxic salt or its hydrate.

16. Inhibitor calcium channel N-type, including ka

17. Pharmaceutical composition for prevention and/or treatment of cerebral infarction, transient cerebral circulation, encephalomyelopathy after heart surgery, spinal angiopathy, hypertension with stroke, neurosis, epilepsy, asthma or pollakiuria containing as an active ingredient derived amino acids of the formula (I) under item 1, its non-toxic salt or its hydrate.

18. Pharmaceutical composition for treating pain, comprising as an active ingredient derived amino acids of the formula (I) under item 1, its non-toxic salt or its hydrate.

 

Same patents:

The invention relates to a new group of individual compounds of the formula I

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where R denotes optionally substituted aryl, aryl(ness.)alkyl, (ness.)alkenyl, (ness.)quinil or N-containing heterocyclyl; R2and R3each independently of one another denotes hydrogen or optionally substituted (ness.)alkyl, aryl(ness.)alkyl, cycloalkyl(ness.)alkyl, or R2and R3together denote (NISS

The invention relates to the field of medicine

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

-ketoamide inhibitors of 20s proteasome" target="_blank">

The invention relates to a method for suppression of disorders of cell proliferation, infectious diseases, and immunological diseases in mammals, particularly humans, by using compounds of the following General formula:

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where X2is a AG or AG-X3where X3includes-C=O, CH2CO - or (CH2)nwhere n=0-2, and where AG represents phenyl, substituted phenyl, indole, substituted indoles and any other heteroaryl;

R1and R2independently selected from the side chains known natural-amino acids and not natural amino acids, hydrogen, 1-10 carbon linear and branched alkyl, 1-10 carbon linear and branched substituted alkyl, aryl and substituted aryl, 1-10 carbon linear and branched substituted aryl, alkoxyaryl, 3-8 carbon cycloalkyl, heterocycle and substituted heterocycle, or heteroaryl and substituted heteroaryl

The invention relates to compounds of formula I (the values of the radicals defined in the description), their prodrugs and their pharmaceutically acceptable salts

The invention relates to a method for producing esters of L-carnosine and their salts, including the interaction of L-carnosine with the lower alcohol in an anhydrous environment of the corresponding alcohol by cooling, in the presence of an acid catalyst, followed by the selection of the target product and its purification
The invention relates to the neurotropic agent, representing the (RS)-N-pantoyl-aminobutyric acid or its pharmaceutically acceptable salt: sodium, potassium, calcium, magnesium or zinc, as well as two means of obtaining it, which is or condensing RS-pantolactone salt-aminobutyric acid in alcohol followed by treatment of the salts with organic or mineral acid or a cation exchange resin in the H+form; or in condensing RS-pantolactone salt-aminobutyric acid in alcohol followed by treatment received calcium or magnesium salt of an inorganic salt or cation exchange resin in the corresponding salt form

The invention relates to a series peptidergic heterocyclic compounds, intermediates used in their receiving and containing pharmaceutical compositions

The invention relates to new chemical substances with the General formula M'nM(H-1GluTrp)mn2Oh, where M' is a cation of an alkali metal, M is a cation d-metal or alkaline-earth metal, GluTrp - anion glutamylation, n is the number of atoms of alkali metal, m is the number of water molecules

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2

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

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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 derivatives isothiazolinones acid of the formula I, where R stands for a group-OR1or-SR2in which R1means alkyl with 1-6 carbon atoms, a substituted once residues selected from the group comprising halogenoalkanes with 1-6 carbon atoms and 1 to 5 halogen atoms, dialkylamino with 1-6 carbon atoms in each alkyl part, phenylalkyl with 1-4 carbon atoms in the CNS parts and pyrrolidinyloxyl with 1-4 carbon atoms in the CNS part, and twice by hydroxyl, or so, m and n is 2, R3means phenyl, R4means alkyl with 1-4 carbon atoms, R2means alkyl with 1-6 carbon atoms, or R2means phenylalkyl with 1-2 carbon atoms in the alkyl part, with the phenyl portion may be substituted with halogen

The invention relates to a new derivative of solidilin formula (I) where one of X, Y and Z represents C=O or C=S, and one of the remaining X, Y and Z denotes a group With=, and the other group C=S; R1, R2and R3are Deputy or X, Y and Z, or nitrogen atom and may be the same or different and denote hydrogen, halogen, hydroxy, nitro, etc., the group -(CH2)n-O - and may be joined through the nitrogen atom, or X, Y, Z, n is 1-4, Ar denotes a phenylene or naftilan, R4denotes hydrogen or forms a bond with group a, And denotes nitrogen or CR5, R5denotes hydrogen, halogen or forms a bond with R4In means O or S, when a is CR5and means that, when a is N, its tautomeric forms, stereoisomers, polymorphic forms, pharmaceutically acceptable salt and solvate

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to the derivatives of pyrrolidine formula I

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where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
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R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient
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