Derivatives of biphenyl, the method of production thereof, pharmaceutical composition, its preparation, drug

 

Describes the biphenyl derivatives of the formula (I) in which R1, R4independently of one another denote a group-C(=NH)-NH2which may be substituted by a group-HE or the group-CO-N=C(NH2)2, R3denotes H, COOR6, -O-[C(R6)2]m-COOR6X denotes [C(R6)2]n-, [C(R6)2]n-O-, -O-[C(R6)2]n-, R2, R5each represents H, R6denotes H or a, a denotes alkyl with 1-6 carbon atoms, n denotes 0, 1 or 2, m represents 1 or 2, and their salts. Describes how to obtain these compounds, and their salts, including the conversion of compounds of formula (I), where R1and/or R4mean amedieval group substituted by a hydroxy-group, other compounds of formula (I), where R1and/or R4mean amedieval group, and, if necessary, the resulting compounds of the formula (I) existing ester group, hydrolyzing to the carboxyl group and/or, if necessary, the compounds obtained in the form of a base or acid is transferred to one of their salts. Also describes a pharmaceutical composition having inhibitory effect on the blood coagulation factor XA, Osnova formula (I) and/or one of its physiologically acceptable salts and at least one solid, liquid or semi-liquid carrier or auxiliary substances and medicinal products that are inhibitors of coagulation factor XA. The technical result consists in the fact that the compounds are inhibitors of coagulation factor. 5 c. and 2 C.p. f-crystals, 1 PL.

Description text in facsimile form (see graphic part)

Claims

1. Derivatives of biphenyl of the formula I

in which R1R4each independently of the other denotes the group-C(=NH)-NH2,

which may be substituted by a group-HE or the group-CO-N=C(NH2)2;

R3- H, COOR6or-O-[C(R6)2]m-COOR6;

X - [C(R6)2]n-, -[C(R6)2]n-O-, -O-[C(R6)2]n-;

R2and R5each - H;

R6- N or A, where a is alkyl with 1-6 carbon atoms;

n = 0, 1, or 2;

m = 1 or 2

and also their salts.

2. Connection on p. 1, selected from the group including

a) 3'-(3-carbamimidoyl) biphenyl-3-carboxamide,

b)3'-(3-carbamidomethylated) biphenyl-3-carboxamide,

C) 3'-CT is methyl)biphenyl-3-carbonyl] guanidine,

d) methyl ester of [3'-amidino-5-(4-amidinophenoxy) biphenyl-3-yloxy] acetic acid,

(e) [3'-amidino-5-(4-amidinophenoxy)biphenyl-3-yloxy] acetic acid, and their salts.

3. The method of obtaining compounds of formula I on p. 1, and their salts, including the conversion of compounds of formula I, where R1and/or R4mean amedieval group substituted by a hydroxy-group, the other connection of the formula I, where R1and/or R4mean amedieval group, and, if necessary, the resulting compounds of formula I of the existing ester group, hydrolyzing to the carboxyl group and/or, if necessary, the obtained compound of formula I in the form of a base or acid is transferred to one of their salts.

4. A method of obtaining a pharmaceutical composition having inhibitory effect on the blood coagulation factor XA, characterized in that the appropriate dosage form is produced from the compounds of formula I under item 1 and/or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary substance.

5. Pharmaceutical composition having inhibitory effect on the blood coagulation factor XA, ex what about the physiologically acceptable salts.

6. The compounds of formula I on p. 1 and their physiologically acceptable salts, having inhibitory action on the blood coagulation factor XA.

7. The drug, which is an inhibitor of coagulation factor XA containing the compound of formula I under item 1 and/or one of its physiologically acceptable salts.

 

Same patents:

The invention relates to compounds of formula (I)

< / BR>
where R(2) and R(3) independently from each other denote hydrogen, Cl, Br, J, (C1-C8)-alkyl, (C3-C8-cycloalkyl or(5), R(5) - (C1-C8)-alkyl, and one of the two substituents R(2) and R(3) is always hydrogen, however, both Deputy R(2) and R(3) at the same time are not hydrogens, as well as their pharmaceutically acceptable salts

The invention relates to new orthotamine benzoylpyridine formula (1), where R(1) - H, alkyl with 1-8 C-atoms, Xand-(CH2)b-(CF2)c-CF3where a, b, C = 0; one of the two substituents R(2) and R(3) means-O-CO-R(27), respectively, and the other substituents R(2) and R(3) is R(1) where R(27) - alkyl with 1-8 C-atoms; R(4) is hydrogen, alkoxy with 1-4 C-atoms, F, Cl, Br, I; R(5) is hydrogen, and their pharmaceutically acceptable salts

The invention relates to novel ortho-substituted benzoylpyridine formula (1), where R(1) denotes H, halogen, Xand-(CH2)b-(CF2)with-CF3, a, b, C denote the zero, one of the two substituents R(2) and R(3) denotes hydroxyl, and the other of the substituents R(2) and R(3) is R(1), R(4) denotes a1-C4-alkyl, halogen, (CH2)n-(CF2)o-CF3n, mean zero, and their pharmaceutically acceptable salts

The invention relates to substituted guanidines thiophenemethylamine acid of the formula I

< / BR>
where mean:

at least one of the substituents R(1), R(2) and R(3)

- Op-(CH2)s-CqF2q+1, R(40)CO - or R(31)SOk-;

p is zero or 1;

s is zero, 1, 2, 3 or 4;

q 1,2, 3,4, 5, 6, 7 or 8;

k is zero, 1 or 2;

R(40) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms,

cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF, methyl or methoxy;

R(31) alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms, or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl or methoxy;

or

R(31) NR(41)R(42);

R(41)and R(42)

independently from each other hydrogen, alkyl with 1, 2, 3 or 4 C-atoms,

perfluoroalkyl with 1, 2, 3 or 4 C-atoms,

or

R(41)and R(42)

together 4 or 5 methylene groups, of which CH2-group may be replaced by oxygen, S, NH, N-CH3or N-benzyl;

and sootwetstwii-OgaWITHraH2raR(10);

PA zero or 1;

mA zero, 1, 2, 3, 4, 5, 6, 7 or 8;

ga zero or 1;

ha zero, 1, 2, 3 or 4;

R(10) cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl, where the phenyl is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl and methoxy;

R(4) and R(5)

independently from each other hydrogen, F, Cl, Br, I, CN, alkyl with 1, 2, 3, 4, 5, 6,

7 or 8 C-atoms, perfluoroalkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms, cycloalkyl with 3, 4, 5, 6, 7 or 8 C-atoms or phenyl which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, methoxy and NR(14)R(15);

R(14)R(15)

independently from each other H, alkyl with 1, 2, 3 or 4 C-atoms or perfluoroalkyl of 1, 2, 3 or 4 C-atoms

and their pharmaceutically tolerable salts

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1, 2, 3 or 4;

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

The invention relates to orthotamine benzoylpyridine formula (1), where R(1) denotes R(13)-SOmm denotes the number 2; R(13) denotes alkyl, one of the substituents R(2) and R(3) represents hydrogen; and the other CHR(30)R(31), R(30) represents-(CH2)g-(CHOH)h-(CH2)I-(CHOH)k-R(32), R(32) denotes hydrogen or methyl, g, h, I is equal to zero, k is 1, R(2) and R(3) represents-C(OH)R(33)R(34), R(31), R(33) R(34) denote hydrogen or alkyl, R(4) denotes alkyl, alkoxy, F, Cl, Br, I

The invention relates to compounds of formula (I), where R1, R3-R8 means XYaWZ or X YaWZ', where X Is O; Y - alkylene with 1 to 4 atoms of CH2= 0 , and W is CH2or, if W does not follow directly behind the heteroatom group HUandalso About; Z is-C(=O)R(15) or, if W does not mean Oh, also NR(16)R(17); R(15) is-N=C(NH2)2R(16) and R(17) is hydrogen or alkyl or R(16) and R(17) imply together 4 or 5 methylene groups, of which one CH2-group may be replaced by oxygen or N-(p-chlorophenyl); X' is-C(=O)NR(30); Z' is-C(= O)R(15), N-containing heterocycle with 1-5 C-atoms, and N-containing heterocycle linked through C; the other of R1, R3-R8, which do not fall under the above values, independently of one another denote VpQqU, where V - O, p=0 or 1, q=0, U is hydrogen, alkyl, and one of the substituents R5-R8 are not hydrogen

The invention relates to andinorganic formula I, a method for obtaining medicinal product based on it

The invention relates to new derivatives of 1-afterheading formula (I)

where R2, R3, R4, R5, R6, R7, R8 denote H, F, CL, Br, I, CF3XaYbZ, X stands for O, a=0,1, Y means alkylene, and one of the CH2 groups may be replaced by O-phenylene, b=zero or 1, Z denotes H, alkyl,/=O/ R/15, NR/16/ R/17/ or phenyl, which may be unsubstituted or substituted, or Z means a nitrogen-containing heterocycle with 1-5 carbon atoms, and their pharmaceutically acceptable salts

The invention relates to a derivative of benzamidine formula I, where R1denotes-C(=NH)-NH2; R2denotes H; R3refers to -[C(R5)2]m-СООR5, R3and X together represent well-CO-N-, form a 5-membered ring, with R3refers to - C = O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAr; X represents O, NR5or CH2Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-СООR5W represents a bond, -SO2-, -CO - or-СОNR5-

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 взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase ring or aryl ring

The invention relates to a derivative of biphenylamine General formula (1), where R1represents a hydrogen atom; L represents a direct bond or C1-4-alkylenes group; R2represents a carboxyl group;1-8-alkoxycarbonyl group; karbamoilnuyu group, and a nitrogen atom that is part of carbamoyl group, may be substituted mono - or di-C1-8is an alkyl group or may be a nitrogen atom in the amino acid; C1-8-alkylcarboxylic group; R3represents a hydrogen atom; X represents any of the groups-O-, -NH-CO-NH-, -N(R4)-, -CO-N(R5)-, -N(R5)-CO-, in which R4represents a hydrogen atom, a C1-10is an alkyl group, a C1-10-alkylcarboxylic group1-10-alkylsulfonyl group, R5represents a hydrogen atom, a C1-10is an alkyl group, Y represents a C4-8-cycloalkyl the group in which the methylene group in the C4-8-cycloalkyl may be substituted WITH1-8is an alkyl group WITH1-8-CNS group, carbamoyl group1-8-alkoxycarbonyl group, a carboxyl group, or the following 5-8-membered ring of formula I-1

The invention relates to new derivatives of biphenylamine formula (I)

< / BR>
where a IS-O-CmH2m-X1-

or denotes the formula (II)

,

where X1oxygen,

or formula (III)

< / BR>
R1- cycloalkyl with 5-7 carbon atoms, Ar1, CR4R5AG2, (CH3)2R6, R2is hydrogen, alkyl, hydroxyl, halogen, O - alkyl, R3is hydrogen, alkyl, R4- alkyl, trifluoromethyl, CH2HE, R5is hydrogen, alkyl, trifluoromethyl, or R4and R5may together form alkylene, R6- CH2OH, CONR7R8CH2R7R8provided that R1means associated through alkylene unsubstituted phenyl residue, or their acid additive salts with pharmacologically acceptable acids

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to substituted derivative of amidine possessing biological activity, in particular to new substituted derivative of benzamidine possessing biological activity, in particular antagonistic action on leukotriene receptors B4

The invention relates to the field of medicine and relates to farbkomposition for use as protivotromboznoe tools, including derived glucuronic acid funds for promotion of growth of vascular endothelial cells, containing derivative of glucuronic acid with high efficiency
Up!