Thrombin inhibitors

 

The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts. Compounds according to the invention are inhibitors of thrombin and can be used to modulate the functioning of thrombin, as well as anticoagulants. The compounds also have a high bioavailability. 2 C. and 7 C.p. f-crystals, 2 PL.

Description text in facsimile form (see graphic part)and

Claims

1. The compound having the formula I

and its pharmaceutically acceptable salt,

where n is 1, 2 or 3;

And denotes hydrogen, C1-C6-alkyl, -SO2R1, -SO3R1, -CO2R2or -(CH2)mCO2R1where R1denotes hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, -(CH2)maryl, or-NR3R4; R2represents C1-C6-alkyl or C1-C6alkenyl; m is 1, 2 or 3; where aryl represents phenyl and R3and R4independently mean hydrogen, C1-C6-alkyl or C33-C7-cycloalkyl;

E denotes

or

where X is S, O or NR5;

Y and Z independently denote N or CR6where

R5denotes hydrogen or C1-C4-alkyl; R6denotes hydrogen or C1-C4-alkyl;

F denotes-C(NH)N(R7)2, -C(NH2)NN(R7)2or CH2N(R7), where R7denotes hydrogen;

provided that when E denotes

and F denotes-C(NH)N(R7)2excluded connections,

where n is 1 or 2;

And denotes hydrogen, C1-C6-alkyl, SO2R', -CO2R2or -(CH2)mCO2R1; R1denotes hydrogen or C1-C6-alkyl; R2represents C1-C6-alkyl; R5and R6at the same time do not represent hydrogen;

In denotes hydrogen;

C and D independently denote phenyl, unsubstituted or substituted by one or two halogen, or C3-C7-cycloalkyl.

2. Connection on p. 1, where a is selected from the group of vlur>1and R2such as specified in paragraph 1.

3. Connection on p. 2, where a is selected from the group comprising-SO2NR3R4and -(CH2)mCO2R1where m, R1, R3and R4such as specified in paragraph 1.

4. Connection on p. 2, where a is selected from the group comprising hydrogen, -SO2R1, -CO2R2, -(CH2)mCO2N -(CH2)mCO2(C1-C6-alkyl), where m is 1 or 2, and R1represents C1-C6-alkyl, -(CH2)maryl, or-NR3R4where R3and R4such as specified in paragraph 1.

5. Connection on p. 1, where C and D are independently selected from phenyl, unsubstituted or substituted by one or two halogen, or cyclohexyl.

6. Connection on p. 5, where C and D are independently selected from phenyl or cyclohexyl.

7. Connection on p. 1, where the compound is selected from the group including

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-aminomethyl-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amerzone-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-promid,

N-tert-butoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-3,4-dichlorophenylethyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-dicyclohexylamine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-aminomethyl-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amerzone-3-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-aminomethyl-3-thienyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-thienyl)methyl]amide,

N-cyclohexylsulfamic-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-allyloxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-benzylmethyl-D-cycle is-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulfonyl-D-cyclohexylethyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-cyclohexylglycine-L-prolyl-[(5-amidino-3-thienyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methyl-N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-thienyl)methyl]amide,

N-hydroxysulfonic-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-azetidin-2-carboxyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-5-methyl-2-thienyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-{(5-amidino-2-furanyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-furanyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-furanyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thiazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-1-methyl-2-pyrrolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-thienyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thiazolyl)methyl]amide,

N-(2-carboxyethyl)-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-BOC-D-diphenylalanine-L-prolyl-[(5-amerzone-2-thienyl)methyl]amide,

D-disil-[(5-amidino-2-thienyl)methyl]amide,

N-(2-carboxyethyl)-D-diphenylalanine-L-azetidin-2-carboxyl-[(5-amidino-2-thienyl)methyl]amide,

D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-(3-carboxypropyl)-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-phenyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-[(N,N-diethylcarbamoyl)methyl]-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-[(N,N-diethylcarbamoyl)ethyl]-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thiazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-thiazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thiazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-thiazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thiazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-thiazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-thiazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-thiazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thiazolyl)methyl]amide,

N-met-amidino-2-thiazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-thiazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thiazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-thiazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-thiazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-oxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-oxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-oxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-oxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-oxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-oxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-oxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-oxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-oxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-oxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-oxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-oxazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-polyaromatic-D-diphenylalanine-L-prolyl-[(4-amidino-2-oxazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(2-amidino-5-oxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-isoxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-isoxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-isoxazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-isoxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-isoxazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-isoxazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-isoxazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(2-amidino-4-isoxazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrazolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrazolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrazolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrazolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-pyrrolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrrolyl)methyl]amide,

N-aminosulfonyl-D-diphenylalanine-L-prolyl-[(5-what sulfonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrrolyl)methyl]amide,

N-methylsulphonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-pyrrolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-pyrrolyl}methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrrolyl)methyl]amide,

N-methoxycarbonyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-pyrrolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-pyrrolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(4-amidino-2-pyrrolyl)methyl]amide,

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-amidino-3-pyrrolyl)methyl]amide,

N-aminosulfonyl-D-bis-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-bis-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-bis-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-carboxymethyl-D-bis-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-aminosulfonyl-D-bis-(para-AMINOPHENYL)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-bis-(para-AMINOPHENYL)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-bis-(para-AMINOPHENYL)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-carboxymethyl-D-bis-(para-AMINOPHENYL)alanyl-L-prolyl-[(5-and the Ministry of foreign Affairs,

N-methylsulphonyl-D-bis-(para-chlorophenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methoxycarbonyl-D-bis-(para-chlorophenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-carboxymethyl-D-bis-(para-chlorophenyl)alanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-(tert-butoxycarbonyl)methyl-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-(tert-butoxycarbonyl)methyl-D-diphenylalanine-L-prolyl-[(5-hydroxyamino-2-thienyl)methyl]amide,

N-[2-(methoxycarbonyl)ethyl]-D-diphenylalanine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide

N-carboxymethyl-D-diphenylalanine-L-prolyl-[(5-hydroxyamino-2-thienyl)methyl]amide,

N-(methoxycarbonyl)methyl-D-diphenylalanine-L-prolyl-[(5-hydroxyamino-2-thienyl}methyl]amide,

N-aminosulfonyl-D-dicyclohexylamine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-methylsulphonyl-D-dicyclohexylamine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

N-carboxymethyl-D-dicyclohexylamine-L-prolyl-[(5-amidino-2-thienyl)methyl]amide,

and their pharmaceutically acceptable salts.

8. The method of modulation of thrombin, comprising the administration to a mammal an effective amount of the compounds under item 1.

9. The method according to p. 8, representing the inhibition of thrombin.

Priority points and attributes:

29.12.1998 - PP.1-9;

14.08.1999 -

 

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< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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< / BR>
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The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

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 amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to 5-[4-(6-methoxy-1-methyl-1H-benzimidazole-2-ylethoxy)benzyl] thiazolidin-2,4-dione hydrochloride
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