Derivatives of indoles as inhibitors of factor xa

 

The invention relates to new indole derivative of the formula I

where two of R1a, Rlb, Rlc, Rldindependently from each other denote H, F, I, Cl, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-With4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6c, n is 1-2, and are the same or different, and two other mean N; where all residues R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different; one of R2and R3means -(CH2)p-CO-R8and the other denotes H, F, Cl, Br, or -(CH2)p-CO-R8; p is 0, 1 or 2; R8means-NR9R10, -OR10; A represents the bivalent residue of(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4; R4means phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom; all of them stereoisomerism f is ivania blood and can be used in pharmaceutical compositions for the inhibition of factor XA, for the treatment of thromboses, cardiac infarction, angina pectoris and other Described method of producing compounds 1. 4 c. and 12 C.p. f-crystals, 2 tab.

Description text in facsimile form (see graphic part)

Claims

1. Derivatives of indole of the formula I

where two of R1a, Rlb, Rlc, Rldindependently of one another represent hydrogen, F, I, CL, Br, (C1-C4)alkyl, phenyl, phenyl-(C1-C4)alkyl, (C1-C4)alkoxy, phenyl-(C1-C4)alkoxy, phenyloxy, HE, -NR5aR5b, -SOn-R6cwhere n is 1-2, and are the same or different, and two of the residues Rla, Rlb, Rlc, Rldrepresent hydrogen;

R5arepresents hydrogen, (C1-C4)alkyl, ((C1-C4)alkoxy)carbonyl;

R5brepresents hydrogen, (C1-C4)alkyl;

R6cis a (C1-C4)alkyl;

phenyl that is present in the residues Rla, RlbRlc, Rlddenotes unsubstituted phenyl residue or a phenyl residue, which is substituted by one or two identical or different Zam>the CoE remains R5a, R5b, R6cif present in the molecule more than once, are independent from each other and may be each the same or different;

one of the residues R2and R3represents -(CH2)P-CO-R8and the other is hydrogen, F, Cl, Br, or -(CH2)P-CO-R8where p is 0, 1 or 2;

R8represents-NR9R10, -Or SIG10;

R9represents hydrogen, aminocarbonyl-(C1-C4)alkyl, (C1-C4)alkyl, ((C1-C4)alkoxy)carbonyl-(C1-C4)alkyl-, hydroxycarbonyl-(C1-C4)alkyl;

R10represents hydrogen, -(C1-C10)alkyl, phenyl, naphthyl, phenyl-(C1-C4)alkyl, naphthyl-(C1-C4)alkyl, pyridyl, where the remainder -(C1-C10)alkyl and each phenyl and nattily residue is unsubstituted or substituted one, two or three identical or different residues R11and where peredelnyj residue is unsubstituted or substituted R14on the nitrogen atom;

R11represents-N(R12)2, -OR12, -CO-N(R13)2, (C1-C14)alkyl, chinoline, which is authorized R14the nitrogen atom, R15b, pyridyl, which is unsubstituted or substituted R14the nitrogen atom, phenyl, which is substituted one, two or three identical or different residues R15b, naphthyl, which is substituted one, two or three identical or different residues R15bpiperidinyl, which is substituted or unsubstituted -(C1-C6)alkyl, where the remains of R11if present in the molecule more than once, are independent from each other and can be identical or different;

each residue R12is independently hydrogen, (C1-C4)alkyl, phenyl, naphthyl;

each residue R13is independently hydrogen, (C1-C4)alkyl, phenyl, naphthyl;

R14represents -(C1-C6)alkyl, substitution of these residues on the nitrogen atom of the heterocyclic residue leads to the formation of positively charged groups with X-as counterion; or R14is axicorp, such substitution on the nitrogen atom of the heterocyclic residue leads to the formation of N-oxide; and where the remains of R14if present in the molecule more than one R is Wallpaper -(C1-C6)alkyl, (C1-C4)alkoxy, F, I, Br, Cl, NO2, -(CH2)t-C(=NR17)-Other17, -(CH2)t-NH-C(=NR17)-Other17, hydroxy, -(CH2)t-CO-OR18, -(CH2)t-CO-N(R18)2, -(CH2)t-N(R16)2, -(CH2)t-N+(R16a)3X-where alkyl may be substituted by 1, 2 or 3 times by fluorine, and where the remains of R15bif present in the molecule more than once, are independent from each other and can be identical or different;

each residue R16regardless of the value of another residue R16represents hydrogen and (C1-C6)alkyl, and where the group containing the remains of R16if present in the molecule more than once, are independent from each other and can be identical or different;

each residue R16aregardless of the value of another residue R16arepresents a (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)quinil, phenyl-(C1-C6)alkyl, where the phenyl is present in R16Ameans unsubstituted phenyl residue, and where the group containing the remains of R16aif present in the molecule more than od regardless of the value of another residue R17represents hydrogen, a hydroxy-group and, in addition, the group - (CH2)t-C(=NR17)-Other17two residue R17together with the group C(=N)-NH, to which they are attached, may form a ring dihydroimidazole;

Andrepresents a divalent residue -(C1-C4)alkyl, which is saturated or which contains a triple bond, or -(C1-C4)alkyl-CO-NH-, where the nitrogen is associated with R4;

R4represents phenyl, which is substituted by one residue R15bor pyridyl, which is unsubstituted or substituted14on the nitrogen atom;

R15crepresents -(CH2)t-N(R16)2, -(CH2)t-CN, -(CH2)t-NH-C(=NR17)-Other17, -(CH2)t-C(=NR17)-Other17, -(CH2)t-CS-other17and where the group containing the remains of R17if present in the molecule more than once, are independent from each other and can be identical or different;

each residue R18regardless of the value of another residue R18represents hydrogen or (C1-C4)alkyl;

t is 0, 1, 2, 3; numbers t, if present in a mole>is a physiologically acceptable anion,

all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts.

2. The compound of formula I under item 1, where a represents the bivalent residue of(C1-C4)alkyl-, all stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

3. The compound of formula I under item 1 and/or 2, where R4represents phenyl, which is substituted by one residue R15call his stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

4. The compound of formula I according to one or more of the paragraphs.1-3,15Crepresents -(CH2)t-C(=NR17)-Other17all his stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

5. The compound of formula I according to one or more of the paragraphs.1-4, where a represents a methylene residue-CH2-, a R4represents phenyl, which is substituted by-C(=NR17)-Other17in the meta-position, all his stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

6. The compound of the formula I one or nesby ratios, and its physiologically acceptable salt.

7. The compound of formula I according to one or more of the paragraphs.1-6, where R2represents hydrogen, CL or Br, all stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

8. The compounds of formula I according to one or more of the paragraphs.1-7, where the remains of Rlcand Rldrepresent hydrogen, all of his stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

9. The compound of formula I according to one or more of the paragraphs.1-8, where one of the residues Rlaand Rlbrepresents hydrogen and the other chosen from the series consisting of hydrogen, methyl, F, Cl, Br, I, hydroxyl group, -(C1-C4) alkoxy, phenyl-(C1-C4) alkoxy and-other5aall his stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

10. The method of obtaining the compounds of formula I according to one or more of the paragraphs.1-9, including the condensation of the compounds of formula VII with the compound of the formula HR8’with obtaining the compounds of formula VIII and optional conversion of the compounds of formula VIII to the compound of the formula I

where the residues R8’40refers to a group-A-R4and where the group-COR41that are the same or different, represent groups of carboxylic acids or their derivatives, and where the group Rla, Rlb, Rlcand Rldhave the meanings as defined in the PP.1-9, or a functional group can also be present in protected form.

11. Pharmaceutical composition for inhibiting the activity of factor XA for the inhibition of blood clotting, for the prevention or treatment of thromboembolic conditions, thrombosis, cardiac infarction, angina pectoris, restenosis or reocclusion, comprising the compound of the formula I according to one or more of the paragraphs.1-9 and/or their physiologically acceptable salts together with a pharmaceutically acceptable carrier.

12. The compound of formula I according to one or more of the paragraphs.1-9 and/or its physiologically acceptable salts for use as pharmaceuticals for inhibiting the activity of factor XA, for inhibition of blood coagulation, for the prevention or treatment of thromboembolic conditions, thrombosis, cardiac infarction, angina pectoris, restenosis or reocclusion, comprising the compound of the formula I according to one or more of the paragraphs.1-9 and/or I on one or more of the paragraphs.1-9 and/or its physiologically acceptable salts for use as an inhibitor of factor XA.

14. The compound of formula I according to one or more of the paragraphs.1-9 and/or its physiologically acceptable salts for use as an inhibitor of blood coagulation.

15. The compound of formula I according to one or more of the paragraphs.1-9 and/or its physiologically acceptable salts for use in the treatment or prevention of thromboembolic conditions.

16. The compound of formula I according to one or more of the paragraphs.1-9 and/or its physiologically acceptable salts for use in the treatment or prevention of thrombosis, cardiac infarction, angina pectoris, restenosis or reocclusion.

 

Same patents:

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to arylpiperazines General formula I

< / BR>
where is phenyl, pyridyl or pyrimidyl; each R3- H, halogen, NO2, СООR, where R is H, C1-6alkyl, CN, CF3WITH1-6alkyl, -S - C1-6alkyl, -SO-Cl - C1-6alkyl, -SO2-Cl-C1-6alkyl, C1-6alkoxy and up to10aryloxy, n= 1, 2, or 3; R is a direct bond; And - piperazinil, X1and X2IS N; Y IS-SO2-; Z IS - N(OH)-CHO; Q - CH2-; R1- H, C1-6alkyl, C5-7cycloalkyl until10aryl, until10heteroaryl until1-2aralkyl or until12heteroallyl, R4- H, C1-6alkyl, and others; R2- H, C1-6alkyl, or together with R1- carbocyclic or heterocyclic Spiro 5-, 6 - or 7-membered ring containing at least one heteroatom selected from N, O or S, and the group Q can be associated either with R1or R2with the formation of 5,- 6 - or 7-membered alkyl or heteroalkyl ring that includes one or more O, S or N

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 compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to new compounds derived from benzo(5,6)-cyclohepta-(1,2)-pyridine of the formula I, where R1means of groups a), b), C), d), e), f), i) k) l) m) n) o) p), r), s); R2and R3together form a bond when the value of R1- group a) or group m) or mean hydrogen for the other R1; R4the hydrogen for the other R1or bromine when the value of R1group o) or group f); R5the hydrogen for the other R1or bromine for R1group r or group s), and their pharmaceutically acceptable salts or solvate

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to new arylpiperazine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, esters, where Y is O; Q is CH; X, Z and Z' each independently represent CH or N; m=0-1; n=0-4; R1and R2independently selected from H, F, Cl, Br, OCH3OC2H5, OCH2CF3CH3WITH2H5, CF3isopropylate; R3represents H; R4and R5represent H or phenyl, except that R1represents H, R2represents H, Cl or CF3, R3, R4and R5=N, Y=0, and Q=CH, if m=0 and n=1; and also except that R1represents H, R2is OCH3, R3, R4and R5=H, Y=0, Q=CH, if m=0 and n=2

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 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to new salts of pyridinium General formula (I) or their pharmaceutically acceptable salts, where R1is-R4- R5or-N(R7)N(R7R9, R4choose from the group of-N(R7R6O-, N(R7R6N(R7), -OR6O-,

-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

The invention relates to the derivatives of pyridazine General formula I, in which R1represents phenyl or pyridyloxy group which may be substituted by 1-3 substituents selected from halogen and lower alkoxygroup; R2represents a phenyl group which may be substituted at the 4th position of the lower alkoxygroup, lower alkylthiol, lower alkylsulfonyl or lower alkylsulfonyl group and in other positions 1 or 2 substituents selected from halogen atoms, lower CNS groups, lower alkylthio, lower alkylsulfonyl groups and lower alkylsulfonyl groups;3represents a hydrogen atom; a lower CNS group; halogenated lower alkyl group; a lower cycloalkyl group; phenyl, pyridyloxy or fenoxaprop, which may be substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, lower CNS groups, carboxyl groups, lower alkoxycarbonyl groups, nitro, amino, lower alkylamino and lower alkylthio; unsubstituted or substituted lower alkyl group piperidino, piperidinyl, piperazine derivatives or morpholinopropan; unsubstituted or zameshannuu lower alkylamino group piperazinylcarbonyl group; A represents a linear or branched lower alkylenes or lower alkynylamino group having 1-6 carbon atoms; or And can mean single bond when R3represents the lower cycloalkyl or halogenated lower alkyl group; X represents an oxygen atom or a sulfur atom; provided that the following combinations are excluded: R1and R2represent 4 metoksifenilny, X represents an oxygen atom, a represents a single bond, and R3represents a hydrogen atom or 2-chloraniline group; or their salts

The invention relates to substituted 3,5-diphenyl-1,2,4-triazole and their use as pharmaceutical agents, which form chelate complexes with metal
Up!