5-membered heterocycles, medicaments containing these compounds, their use and processes for their preparation

• US 5,817,677 A
• Filed: 10/18/1996
• Issued: 10/06/1998
• Est. Priority Date: 10/20/1995
• Status: Expired due to Fees

• Current Assignee: Dr. Karl Thomae GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Dr. Karl Thomae GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Himmelsbach, Frank, Guth, Brian, Pieper, Helmut, Austel, Volkhard, Linz, Gunter, Weisenberger, Johannes
• Primary Examiner(s): POWERS, FIONA
• Application Number:
  US08/733,898
• Time in Patent Office: 718 Days
• Field of Search: 544/365, 546/187, 546/209, 546/268.7, 548/136, 514/252, 514/318, 514/326, 514/360
• US Class Current: 514/326
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

5-Membered heterocyclic compounds, of which the following compounds are exemplary:

(a) 4- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-1-(4-piperidyl)imidazole,

(b) 5- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole,

(c) 5- 4-(carboxymethoxy)phenyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole,

(d) 5- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole,

(e) 5- 4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole,

(f) 5- trans-4-(carboxymethoxy)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole,

(g) 5- 4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole,

(h) 5- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, and

(i) 4- trans-4-carboxycyclohexyl!aminocarbonyl!-1- 2-(4-piperidyl)ethyl!imidazole.

These are useful for the treatment or prevention of illnesses in which relatively small or relatively large cell aggregates occur or cell-matrix interactions play a part.

Claims

1. A 1,3,4-thiadiazole of the formula ##STR30## wherein A is a cycloalkyl group having 5 to 7 carbon atoms, which is optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R_a --N<

group, which may additionally be substituted by a cyano, aminocarbonyl, carboxyl, alkoxycarbonyl or phenylalkoxycarbonyl group or alternatively, if the substitution does not take place in the α

-position relative to a nitrogen atom, by a hydroxyl, alkoxy or phenylalkoxy group, and in which

R_a is a hydrogen atom, an alkyl group, a phenylalkyl group, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, a phenylalkoxycarbonyl group, an alkenyloxycarbonyl group having a total of 4 to 6 carbon atoms, a cycloalkoxycarbonyl group having a total of 6 to 8 carbon atoms or an R₁ --CO--O--(R₂ CH)--O--CO-- group, in which

R₁ is an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms, a phenylalkyl group, an alkoxy group having 1 to 5 carbon atoms, a cycloalkoxy group having 5 to 7 carbon atoms or a phenyl group and

R₂ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms or a phenyl group,

and additionally in the 6- or 7-membered azacycloalkyl groups thus formed a >

CH-- unit in the 4-position may be replaced by a nitrogen atom or in the 5- to 7-membered azacycloalkyl groups thus formed a --CH₂ --CH<

unit may be replaced by a --CH═

C<

unit and in the piperazinyl or homopiperazinyl rings thus formed one or two methylene groups, which are adjacent to the nitrogen atom in the 4-position, may in each case be replaced by a carbonyl group, or

a quinuclidinyl group,

B is a bond or a straight-chain or branched alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 or 3 carbon atoms, an --O(CH₂)_n --, --(CH₂)_n O--, --S(CH₂)_n --, --(CH₂)_n S--, --CONR₃ --, --R₃ NCO--, --NR₃ (CH₂)_n -- or --(CH₂)_n NR₃ -- group, in which

n is the number 1 or 2 and

R₃ is a hydrogen atom, a phenylalkyl group which is optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by an alkyl, hydroxyl or alkoxy group, or is an alkyl or pyridylalkyl group,

D is a --CO--NR₃ --, --NR₃ --CO--, --SO₂ --NR₃ --, --NR₃ --SO₂ --, --W--CO--NR₃ --, --W₁ --NR₃ --CO--, --W₁ --SO₂ NR₃ --, --W₁ --NR₃ SO₂ --, --CO--NR₃ --W₁ --, --NR₃ --CO--W₁ --, --SO₂ NR₃ --W₁ --, --NR₃ SO₂ --W₁ --, --CO--(CH₂)_n --O--, --CO--(CH₂)_n --NR₃ --, --O--W₁ --, --W₁ --O--, --S--W₁ --, --W₁ --, --W₁ --S--, --NR₃ --W₁ --, --W₁ --NR₃ --, --(CH₂)_n --O--(CH₂)_n --, --(CH₂)_n --NR₃ --(CH₂)_n --, --W-- or --W--CO-- group, in which

R₃ and n are defined as mentioned above,

W₁ is an alkylene group having 1 to 3 carbon atoms,

W₂ is an alkenylene group having 2 or 3 carbon atoms and

W is an alkylene group having 1 to 3 carbon atoms or an alkenylene group having 2 or 3 carbon atoms,

E is a phenylene group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or by alkyl, trifluoromethyl, R₃ O-- or R₃ O--CO--CH₂ --O-- groups, it being possible for the substituents to be identical or different and R₃ being defined as mentioned above,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene group, each of which may be substituted in the carbon ring system by a chlorine atom or by an alkyl or alkoxy group, it additionally being possible for one or two --CH═

N-- groups each to be replaced by a --CO--NR₃ -- group, in which R₃ is defined as mentioned above, and one of the nitrogen atoms may also be bonded to the radical F, instead of to the radical R₃, if this is not a bond,

a cycloalkylene group having 4 to 5 carbon atoms, which is optionally substituted by an alkyl, phenylalkyl or phenyl group, in which a >

CH-- unit may be replaced by a nitrogen atom and additionally a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group, or

a cycloalkylene group, having 6 or 7 carbon atoms which is optionally substituted by an alkyl, phenylalkyl or phenyl group, in which one or two >

CH-- units may each be replaced by a nitrogen atom, it additionally being possible for a methylene group adjacent to a nitrogen atom to be replaced by a carbonyl group,

F is a bond, a straight-chain or branched alkylene or alkenylene group, which is optionally substituted by a phenylalkyl, phenyl, pyridyl, R₃ O--, R₃ S--, R₃ R₃ N--, R₃ O--CO--, R₃ R₃ N--CO--, R₄ CO--NR₃ --, R₅ O--CO--NR₃ --, R₄ SO₂ --NR₃ --, R₃ R₃ N--CO--NR₃ --, R₃ O--CO--C_1-3 -alkyl or R₃ R₃ N--CO--C_1-3 -alkyl group, in which in each case the alkylene moiety may contain 1 to 5 carbon atoms and the alkenylene moiety may contain 2 to 5 carbon atoms, or a --Y--W₁ -- group, in which

R₃ and W₁ are defined as mentioned above,

R₄ is an alkyl group having 1 to 5 carbon atoms, or a phenylalkyl, phenyl or pyridyl group,

R₅ is an alkyl group having 1 to 5 carbon atoms, a phenylalkyl, cycloalkyl or cycloalkylalkyl group and

Y is an oxygen atom, a --CO--, sulphenyl-, sulphinyl-, sulphonyl-, --NR₃ --, --N(COR₄)--, --N(SO₂ R₄)--, --CO--NR₃ -- or --NR₃ --CO-- group, Y being linked to the radical E, with the proviso that a heteroatom of the radical E is not bonded to a nitrogen or sulphur atom of the above groups,

and R_b is an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms in the cycloalkyl moiety, it being possible for the above-mentioned groups each to be substituted in the alkyl and cycloalkyl moiety from position 2 by an R₃ O-- or R₃ R₃ N-- group, or is an alkenyl group having 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl-alkyl group having 3 to 7 carbon atoms in the cycloalkyl moiety, which may be substituted in the alkyl moiety from position 2 by an R₃ O-- or R₃ R₃ N-- group, R₃ in each case being defined as mentioned above, an R₁ --CO--O--(R₂ CH)-- group, in which R₁ and R₂ are defined as mentioned above, or alternatively a hydrogen atom if the R_b O--CO-- group is not directly bonded to a nitrogen atom of the radical E,

the distance between the furthest removed nitrogen atom of the group A and the COOR_b group being at least 11 bonds,

where, if nothing different has been mentioned,

the above-mentioned alkyl, alkylene or alkoxy moieties may each contain 1 to 3 carbon atoms and the above-mentioned cycloalkyl moieties may each contain 3 to 7 carbon atoms,

or a tautomer or physiologically tolerable salt thereof.

2. A 1,3,4-thiadiazole of the formula I according to claim 1, in which

A is a cycloalkyl group having 5 to 7 carbon atoms, which is optionally substituted by 1 to 4 alkyl groups, in which an unsubstituted methylene group is replaced by the R_a --N<

group, which may additionally be substituted by a cyano, aminocarbonyl, carboxyl or alkoxycarbonyl group or alternatively, if the substitution does not take place in the α

-position relative to a nitrogen atom, by a hydroxyl or alkoxy group, and in which

R_a is a hydrogen atom, an alkyl, phenylalkyl, alkoxycarbonyl or phenylalkoxycarbonyl group or an R₁ --CO--O--(R₂ CH)--O--CO-- group, in which

R₁ is an alkyl, cycloalkyl, phenyl, alkoxy or cycloalkoxy group each having 5 to 7 carbon atoms in the cycloalkyl moiety and

R₂ is a hydrogen atom or a methyl group,

and additionally in the 6- or 7-membered azacycloalkyl groups thus formed a >

CH-- unit in the 4-position may be replaced by a nitrogen atom or in the 5- to 7-membered azacycloalkyl groups thus formed a --CH₂ --CH<

unit may be replaced by a --CH═

C<

unit, or

a quinuclidinyl group,

B is a bond or an alkylene group having 1 to 5 carbon atoms, an alkenylene group having 2 or 3 carbon atoms, or a --OCH₂ --, --CH₂ O--, --SCH₂ --, --CH₂ S--, --CONR₃ --, --R₃ NCO--, --NR₃ CH₂ -- or --CH₂ NR₃ -- group, in which

R₃ is a hydrogen atom, or an alkyl, phenylalkyl or pyridylalkyl group, and an oxygen, sulphur or nitrogen atom of the radical B is not bonded directly to a nitrogen atom of the radical A or to a nitrogen atom of the 5-membered heterocycle,

D is a --CO--, --CO--NR₃ --, --NR₃ --CO--, --SO₂ --NR₃ --, --NR₃ --SO₂ --, --W--CO--NR₃ --, --W₁ --NR₃ --CO--, --W₁ --SO₂ NR₃ --, --W₁ --NR₃ SO₂ --, --CO--NR₃ --W₁ --, --NR₃ --CO--W₁ --, --SO₂ NR₃ --W₁ --, --NR₃ SO₂ --W₁ --, --CO--CH₂ --O--, --CO--CH₂ --NR₃ --, --O--W₁ --, --W₁ --O--, --S--W₁ --, --W₁ --S--, --NR₃ --W₁ --, --W₁ --NR₃ --, --CH₂ --O--CH₂ --, --CH₂ --NR₃ --CH₂ --, --W₁ -- or --W--CO-- group, in which

R₃ is defined as mentioned above,

W₁ is an alkylene group having 1 to 3 carbon atoms,

W₂ is an alkenylene group having 2 or 3 carbon atoms, and

W is an alkylene group having 1 to 3 carbon atoms or an alkenylene group having 2 or 3 carbon atoms,

E is a phenylene group which may be substituted by a fluorine, chlorine or bromine atom, or by an alkyl, trifluoromethyl, R₃ O-- or R₃ O--CO--CH₂ --O-- group, R₃ being defined as mentioned above,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group, each of which may be substituted in the carbon ring system by an alkyl or alkoxy group,

a 1,4-cyclohexylene group, in which one or two >

CH-- units may each be replaced by a nitrogen atom, it additionally being possible in each case for a methylene group adjacent to a nitrogen atom to be replaced by a carbonyl group,

a 1,3-cyclohexylene group, in which a >

CH-- unit may be replaced by a nitrogen atom, it then additionally being possible for a methylene group adjacent to the nitrogen atom to be replaced by a carbonyl group,

a 1,3-pyrrolidinylene, 2-oxo-1,3-pyrrolidinylene, 5-oxo-1,3-pyrrolidinylene or 1,4-homopiperazinylene group,

F is a bond, a straight-chain or branched alkylene group having 1 to 5 carbon atoms, which is optionally substituted by a phenyl, pyridyl, R₃ O--, R₄ CO--NR₃ --, R₅ O--CO--NR₃ --, R₄ SO₂ --NR₃ --, R₃ R₃ N--CO--NR₃ -- or a --Y--W₁ -- group, in which

R₃ and W₁ are defined as mentioned above,

R₄ is an alkyl group having 1 to 5 carbon atoms, or a phenylalkyl, phenyl or pyridyl group,

R₅ is an alkyl group having 1 to 5 carbon atoms or a phenylalkyl group and

Y is an oxygen atom, a sulphenyl, --NR₃ --, --N(COR₄)-- or --N(SO₂ R₄)-- group, Y being linked to the radical E, with the proviso that a heteroatom of the radical E is not bonded to a nitrogen or sulphur atom of the above groups, and R_b is an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms in the cycloalkyl moiety, each of which may be substituted in the alkyl and cycloalkyl moiety from position 2 by an R₃ O-- or R₃ R₃ N-- group, or is an alkenyl group having 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkylalkyl group having 3 to 7 carbon atoms in the cycloalkyl moiety, which may be substituted in the alkyl moiety from position 2 by an R₃ O-- or R₃ R₃ N-- group, R₃ in each case being defined as mentioned above, an R₁ --CO--O--(R₂ CH)-- group, in which R₁ and R₂ are defined as mentioned above, or alternatively a hydrogen atom if the R_b O--CO-- group is not directly bonded to a nitrogen atom of the radical E,

the distance between the furthest removed nitrogen atom of the group A and the COOR_b group being at least 11 bonds,

where, if nothing different has been mentioned,

the above-mentioned alkyl, alkylene or alkoxy moieties may each contain 1 to 3 carbon atoms,

or a tautomer or physiologically tolerable salt thereof.

3. A 1,3,4-thiadiazole of the formula I according to claim 1, in which

A is a cycloalkyl group having 5 or 6 carbon atoms, in which an unsubstituted methylene group in the 3- or 4-position is replaced by the R_a --N<

group, in which

R_a is a hydrogen atom, or a C_1-2 -alkyl, C_1-4 -alkoxycarbonyl or benzyloxycarbonyl group,

and additionally in the 4-piperidinyl groups thus formed a >

CH-- unit in the 4-position may be replaced by a nitrogen atom,

B is a bond, a C_1-2 -alkylene, --OCH₂ -- or --CH₂ O-- group,

D is a --CO--, --CO--NR₃ --, --NR₃ --CO--, --W--CO--NR₃ --, --CO--NR₃ --W₁ --, --NR₃ --CO--W₁, --CO--CH₂ --O--, --O--W₁ --, --W₁ --O--, --W₁ -- or --W--CO-- group, in which

R₃ is a hydrogen atom, or a C_1-4 -alkyl, benzyl or pyridylmethyl group,

W₁ is a C_1-2 -alkylene group and

W is a C_1-2 -alkylene or vinylene group,

E is a 1,4-phenylene group which may be substituted by a hydroxyl, methoxy, carboxymethoxy or methoxycarbonylmethoxy group,

a 1,4-cyclohexylene group in which one or two >

CH-- units may each be replaced by a nitrogen atom,

F is a bond, a straight-chain or branched alkylene group having 1 to 3 carbon atoms, which is optionally substituted by an R₄ CO--NR₃ --, R₄ SO₂ --NR₃ -- or --Y--W₁ -- group, in which

R₃ and W₁ are defined as mentioned above,

R₄ is a methyl, ethyl or phenyl group and

Y is an oxygen atom, or an --NR₃ -- or --N(SO₂ R₄)-- group, Y being linked to the radical E, with the proviso that a nitrogen atom of the radical E is not bonded to a nitrogen atom of the above groups, and R₃ and R₄ are defined as mentioned above,

and R_b is a C_1-5 -alkyl, cyclohexyl or benzyl group or alternatively a hydrogen atom if the R_b O--CO-- group is not directly bonded to a nitrogen atom of the radical E,

the distance between the furthest removed nitrogen atom of the group A and the COOR_b group being at least 11 bonds,

or a tautomer or physiologically tolerable salt thereof.

4. A 1,3,4-thiadiazole of the formula I according to claim 1, in which

A is a cyclohexyl group, in which an unsubstituted methylene group in the 4-position is replaced by the R_a --N<

group, in which

R_a is a hydrogen atom, a C_1-4 -alkoxycarbonyl or benzyloxycarbonyl group,

B is a bond or a C_1-2 -alkylene group,

D is a --CH₂ CH₂ --, --CO--, --CH₂ --O--, --CH₂ CH₂ --CO--, --CH═

CH--CO--, --CO--NR₃ --, NR₃ --CO--, --CH₂ CH₂ --CO--NR₃ --, --CO--NR₃ --CH₂ -- or --CO--NR₃ --CH₂ CH₂ -- group, in which

R₃ is a hydrogen atom or a pyridylmethyl group,

E is a 1,4-phenylene, 1,4-cyclohexylene, 1,4-piperidinylene or 1,4-piperazinylene group,

F is a bond, a --CH₂ --, --CH₂ CH₂ --, --O--CH₂ --, --O--CH₂ CH₂ -- or --N(SO₂ CH₃)--CH₂ -- group, and

R_b is a C_1-4 -alkyl or cyclohexyl group or alternatively a hydrogen atom if the R_b O--CO-- group is not directly bonded to a nitrogen atom of the radical E,

the distance between the furthest removed nitrogen atom of the group A and the COOR_b group being at least 11 bonds,

or a tautomer or physiologically tolerable salt thereof.

7. A pharmaceutical composition comprising a compound in accordance with claim 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable carrier.

8. A method for the treatment or prevention of venous or arterial thromboses which comprises administering to a host suffering from or likely to suffer from the formation of a thrombus an anti-thrombotic amount of a compound in accordance with claim 1, 2, 3, 4, 5 or 6.

5. A compound selected from the group consisting of:

(a) 5- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole, and

(b) 5- 4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole,

or a C_1-4 -alkyl or cyclohexyl ester thereof, or a physiologically tolerable salt thereof.

6. 5- trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole or a physiologically tolerable salt thereof.