Derivatives of n-(4-carbamimidoyl)glycinamide, intermediate compounds, method for producing and farmcampsite

 

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in interaction, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2. In addition, the compounds of formula (I) have inhibitory amylolyticus activity against complex factor VII/tissue factor and due to this property can be the active ingredient in farbkomposition. 5 C. and 7 C.p. f-crystals.

Description text in facsimile form (see drawings) T TC

Claims

1. Derivatives of N-(4-carbamimidoyl)glycinamide formulawhere E denotes hydrogen or HE; Q represents hydrogen or alkyl;
R stands for aryl, cycloalkyl or alkyl substituted radicals R1, R2and R3;
R1denotes hydrogen, COOH, COO-alkyl or aryl;
R2denotes hydrogen, aryl, cycloalkyl or heteroaryl;
R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional secure imaginalis-3-yl;
three of the radicals X1-X4independently from each other represent a group C(Ra), C(Rb) or C(Rc), and the fourth radical represents a group C(Rdor N;
Ra-Rdindependently of one another denote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, NHCO-alkyl, NHCO-aryl, NHCOO-alkyl, NHCO-alkyl-NH2, NHCO-alkyl-NH-G, aralkyl-CONH, alkyl-O-alkyl-CONH, alkyl-COOH, O-alkyl-COOH or O-alkyl-COO-alkyl, or two adjacent groups Ra-Rdtogether denote alkylenedioxy, not more than three of the radicals from Ra-Rdcan have the same value and X1cannot specify soon or SSAS-alkyl;
G denotes aminosidine group;
one of the radicals G1and G2denotes hydrogen and the other radical represents hydrogen, alkyl, HE, alkoxygroup, aroyl, alkanoyl-och2aroyl-OCH2or a group COO-Rgor OCO-Rgwhere Rgdenotes alkyl, optionally substituted with halogen, HE, alkoxygroup, COOH or COO-alkyl,
where heteroaryl represents a 5-10 membered aromatic group which contains about the forge group, which includes one or two rings and contains one or more heteroatoms N, O and/or S,
and their hydrate or solvate, and physiologically acceptable salts.

2. Connection on p. 1, where E, G2and Q represent hydrogen, R represents alkyl, aryl, aralkyl, benzhydryl, cycloalkenyl or heteroaromatic, G1denotes hydrogen, HE or COO-alkyl, X1-X4denote the group of C(Ra)-C(Rdand Ra-Rdindependently of one another denote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COO-alkyl, NHSO2-alkyl or NHSO2-aryl, and not more than three of the radicals from Ra-Rdcan have the same value and X1can not mean SSAS-alkyl.

3. Connection under item 1 or 2, where E, G1, G2and Q denote hydrogen.

4. Connection under item 1 or 3, where R denotes alkyl, in particular methyl or ethyl, substituted R1, R2and R3where, in particular, R1denotes aryl, especially phenyl or COOH, R2denotes hydrogen or aryl, especially phenyl, and R3denotes hydrogen.

5. Connection PP.1, 3, or 4, where X1-X4denote a group(R; NHSO2-aryl, especially phenylcarbonylamino; aralkyl-CONH, primarily phenylacetylamino, or O-alkyl-COOH, especially carboxymethoxy, Rbdenotes H, alkoxygroup, especially methoxy or ethoxypropan; Rcdenotes H, alkoxygroup, especially a methoxy group; or aralkylated, especially benzyloxy, and Rddenotes H or alkoxygroup, especially a methoxy group.

6. Compounds according to any one of paragraphs.1-5, for example,
(R, S)-N-benzyl-2-(4-benzyloxy-3-ethoxyphenyl)-2-(4-carbamimidoyl)ndimethylacetamide,
2-(2-phenylcarbonylamino-4-benzyloxy-5-methoxyphenyl)-N-benzyl-2-(4-carbamimidoyl)ndimethylacetamide.

7. Compounds according to any one of paragraphs.1 and 3-5, for example,
(RS)-[2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl)acetylamino]diphenylhexane acid,
(RS)- and (SR)-3-[(RS)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl)acetylamino]-3-phenylpropionate acid,
(S)-[(R)-2-(4-benzyloxy-3-methoxyphenyl)-2-(4-carbamimidoyl)acetylamino]phenylacetic acid,
(S)-[(S)-2-(4-carbamimidoyl)-2-(3,5-acid)acetylamino]phenylacetic acid,
(RS)-3-[2-[benzylcarbamoyl-(4-carbamimidoyl)methyl] -4,5-dimethoxyphenoxy]Ben the PTA,
(S)-[(R)-2-(2-phenylcarbonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoyl)acetylamino]phenylacetic acid,
(S)-[(S)-2-(2-phenylcarbonylamino-4-benzyloxy-5-methoxyphenyl)-2-(4-carbamimidoyl)acetylamino]phenylacetic acid,
(S)-[(R)-2-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-2-(4-carbamimidoyl)acetylamino]phenylacetic acid,
(S)-[(S)-2-(4-benzyloxy-5-methoxy-2-phenylacetylamino)-2-(4-carbamimidoyl)acetylamino]phenylacetic acid.

8. The compounds of formula I and their salts in PP.1-7, acting as inhibitors of the formation of coagulation factors XA, Ha and thrombin induced by factor VIIa and tissue factor, designed to obtain a pharmaceutical for the treatment and prevention of diseases associated with impaired factor in blood clotting.

9. The compounds of formula


or

where E, Q, R and X1-X4have the values listed in paragraph 1.

10. Pharmaceutical composition having inhibitory amylolyticus activity against complex of factor VIIa/tissue factor containing the active substance and farmaceuti according to any one of paragraphs.1-7.

11. The method of obtaining compounds of formula I on p. 1, characterized in that the aldehyde of the formula

subjected to interaction with isonitriles formula R1NC and 4-aminobenzamidine formula III

followed if necessary by moving the reactive functional group in the resulting compound of formula I, its derivative and the transformation of compounds of formula I into a physiologically acceptable salt or converting the salt of the compounds of formula I in free acid or base.

12. The method of obtaining compounds of formula I on p. 1, characterized in that the cyano CN present in the corresponding nitrile of the formula

turn in amidinopropane C(N-G1)NH-G2followed if necessary by moving the reactive functional group in the resulting compound of formula I, its derivative and the transformation of compounds of formula I into a physiologically acceptable salt or converting the salt of the compounds of formula I in free acid or base.

 

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< / BR>
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,

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< / BR>
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