Arylidene-1-azacycloalkanes and arylalkyl-1-azacyclo-alkanes, their salts, medicaments containing these compounds and their use, and processes for their preparation

• US 5,466,687 A
• Filed: 03/25/1994
• Issued: 11/14/1995
• Est. Priority Date: 10/22/1992
• Status: Expired due to Term

• Current Assignee: Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Dr. Karl Thomae GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Mark, Michael, Muller, Peter, Maier, Roland, Hallermayer, Gerhard, Hurnaus, Rudolf, Eisele, Bernhard, Woitun, Eberhard, Budzinski, Ralph-Michael
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/218,092
• Time in Patent Office: 599 Days
• Field of Search: 540/598, 540/601, 540/603, 544/54, 544/96, 544/335, 546/209, 546/210, 548/146, 548/238, 548/314.7, 514/212, 514/226.8, 514/228.8, 514/326, 514/372, 514/374, 514/385, 514/399
• US Class Current: 514/217.05
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings

Abstract

The invention relates to arylidene-1-azacycloalkanes and arylalkyl-1-azacycloalkanes of the general formula ##STR1## (wherein n, m, p, A, W¹, W², X, Y, and R¹ to R¹¹ are as defined in claim 1) and the isomers, isomer mixtures and salts thereof, which have useful properties, in particular an inhibitory effect on cholesterol biosynthesis.

Claims

1. An arylidene-1-azacycloalkane or arylalkyl-1-azacycloalkane of the formula I ##STR22## wherein:

n denotes the numbers 0 or 1;

m denotes the numbers 1 or 2;

p denotes the numbers 0 or 1;

A denotes a single bond, a straight-chained or branched C_1-17 -alkylene group, a C_2-17 -alkenylene group or a C_2-4 -alkynylene group;

W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond;

X denotes a carbonyl or sulphonyl group;

Y denotes an oxygen or sulphur atom or an >

NR¹¹ group;

R¹ to R⁶ in each case denote a hydrogen atom, or

one, two or three of the groups R¹ to R⁶, which groups may be identical or different, denote a straight-chained or branched C_1-4 -alkyl group which may be substituted by a hydroxy, alkoxy, alkylthio or dialkylamino group or by a phenyl group which is optionally substituted by a halogen atom or an alkyl group, or denote an alkoxycarbonyl group and the remaining groups R¹ to R⁶ each denote a hydrogen atom;

whilst one, two or all three of the groups R¹, R³ and R⁵ may also denote a phenyl group which is optionally substituted by an alkyl group or by a halogen atom;

R⁷ denotes a hydrogen or halogen atom, or an alkyl or alkoxy group;

R⁸ and R⁹ independently of one another each denote a hydrogen atom or an alkyl group;

R¹⁰ denotes a hydrogen atom, a C_3-6 -cycloalkyl group, a phenyl group optionally substituted by a halogen atom, by a straight-chained or branched C_1-4 -alkyl group, or by a trifluoromethyl, alkoxy, cyano, nitro, alkylsulphonyl or phenyl group, or R¹⁰ denotes a phenyl group substituted by two trifluoromethyl groups, by two to five halogen atoms or by a halogen atom and an alkyl group, or R¹⁰ denotes a naphthyl or tetrahydronaphthyl group optionally substituted by a fluorine atom, or R¹⁰ denotes a pyridyl group or a thienyl group optionally substituted by a halogen atom or by an alkyl group; and

R¹¹ denotes a hydrogen atom or an alkyl group;

whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and

wherein, unless otherwise stated, the above mentioned alkyl, alkoxy, alkylthio and alkylsulphonyl groups each contain 1, 2 or 3 carbon atoms and the above mentioned halogen atoms are selected from fluorine, chlorine and bromine,

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition, suitable for the treatment of hyperlipidaemias, hypercholesterolaemias and of atherosclerosis, comprising a compound according to claim 1, 2, 3, 4 or 5 together with a pharmaceutically acceptable carrier.

7. A method for the treatment of excessive cholesterol biosynthesis, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 1, 2, 3, 4 or 5.

8. The method of claim 7 wherein the condition to be treated is hyperlipidaemia, hypercholesterolaemia or atherosclerosis.

9. The method of claim 8 wherein the condition to be treated or prevented is hyperlipidemia.

10. A method for the treatment of conditions caused by excessive cell proliferation, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 1.

11. A method for the treatment of gallstones, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 1, 2, 3, 4 or 5.

12. A method for the treatment of mycoses, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 1, 2, 3, 4 or 5.

13. The method of claim 10, which method comprises administering an effective amount of the compound 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine.

2. An arylidene-1-azacycloalkane or arylalkyl-1-azacycloalkane of the formula Ia ##STR23## wherein:

n denotes the numbers 0 or 1;

m denotes the numbers 1 or 2;

p denotes the number 0 or 1;

A denotes a single bond, a straight-chained or branched C_1-17 -alkylene group, or a C_2-4 -alkenylene or a C_2-4 -alkynylene group;

W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond;

X denotes a carbonyl or sulphonyl group;

Y denotes an oxygen or sulphur atom or an >

NR¹¹ group;

R¹ to R⁴ in each case denote a hydrogen atom, or

one or two of the groups R¹ to R⁴ independently of one another each denote a straight-chained or branched C_1-4 -alkyl group which may be substituted by a hydroxy, alkylthio or dialkylamino group or by a phenyl group itself optionally substituted by a halogen atom, or denote a phenyl group, and the remaining groups R¹ to R⁴ each denote a hydrogen atom;

R⁵ and R⁶, which may be identical or different, denote a hydrogen atom or a methyl group;

R⁷ denotes a hydrogen or halogen atom, or an alkyl or alkoxy group;

R⁸ denotes a hydrogen atom or an alkyl group;

R⁹ denotes a hydrogen atom;

R¹⁰ denotes a hydrogen atom, a C_3-6 -cycloalkyl group, a phenyl group optionally substituted by one or two halogen atoms, by a straight-chained or branched C_1-4 -alkyl group or by a trifluoromethyl, methoxy, cyano, nitro, methylsulphonyl or phenyl group, or R¹⁰ denotes a phenyl group substituted by two trifluoromethyl groups or by a halogen atom and a methyl group, or R¹⁰ denotes a phenyl group substituted by three to five fluorine atoms, or R¹⁰ denotes a naphthyl group optionally substituted by a fluorine atom, or R¹⁰ denotes a tetrahydronaphthyl or pyridyl group or a thienyl group optionally substituted by a halogen atom; and

R¹¹ denotes a hydrogen atom or an alkyl group;

whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and

wherein, unless otherwise stated, the above mentioned alkyl groups each contain 1, 2 or 3 carbon atoms and the above mentioned halogen atoms are selected from the group consisting of fluorine, chlorine and bromine,

or a pharmaceutically acceptable salt thereof.

3. An arylidene-1-azacycloalkane or arylalkyl-1-azacycloalkane of the formula Ia, in accordance with claim 2, wherein:

n denotes the numbers 0 or 1,

m denotes the numbers 1 or 2,

p denotes the numbers 0 or 1,

A denotes a single bond, a C_1-17 -straight-chained or branched alkylene or C_2-4 -alkenylene group,

W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,

X denotes a carbonyl or sulphonyl group,

Y denotes an oxygen atom or an >

NR¹¹ group,

R¹ to R⁴ in each case denote a hydrogen atom or

one or two of the groups R¹ to R⁴ independently of one another in each case denote a straight-chained or branched C_1-4 -alkyl group, and the remaining groups R¹ to R⁴ each denote a hydrogen atom,

R⁵ and R⁶, which may be identical or different, denote a hydrogen atom or a methyl group,

R⁷ denotes a hydrogen or halogen atom, or a methyl or methoxy group,

R⁸ denotes a hydrogen atom or a methyl group,

R⁹ denotes a hydrogen atom,

R¹⁰ denotes a hydrogen atom, a C_3-6 -cycloalkyl group, a phenyl group optionally substituted by one or two halogen atoms, by five fluorine atoms, by an alkyl group, by one or two trifluoromethyl groups or by a halogen atom and an alkyl group, or R¹⁰ denotes a 1-naphthyl group which is optionally substituted in the 4-position by a fluorine atom, or R¹⁰ denotes a 2-naphthyl group, a 1,2,3,4-tetrahydro-2-naphthyl group, a pyridyl or 4-biphenyl group or a thienyl group optionally substituted by a halogen atom, and

R¹¹ denotes a hydrogen atom or a methyl group,

whilst A cannot be a single bond if X denotes the sulphonyl group and R¹⁰ denotes a hydrogen atom, and

wherein, unless otherwise stated, the above mentioned alkyl moieties each contain 1, 2 or 3 carbon atoms and the above mentioned halogen atoms are selected from the group consisting of fluorine and chlorine,

or a pharmaceutically acceptable salt thereof.

4. An arylidene-1-azacycloalkane or arylalkyl-1-azacycloalkane of the formula Ia, in accordance with claim 2, wherein:

n denotes the numbers 0 or 1,

m denotes the number 1,

p denotes the numbers 0 or 1,

A denotes a single bond,

W¹ and W² each denote a hydrogen atom or together denote a carbon-carbon bond,

X denotes a carbonyl group,

Y denotes an oxygen atom,

R¹ to R⁶ in each case denote a hydrogen atom,

R⁷ denotes a hydrogen or halogen atom or a methyl group,

R⁸ and R⁹ each denote a hydrogen atom,

R¹⁰ denotes a phenyl group substituted in the 4-position by a fluorine, chlorine or bromine atom or by a trifluoromethyl group, or R¹⁰ denotes a 4-chloro-3-methylphenyl group, a 5-chloro-2-thienyl group or a cyclohexyl group,

or a pharmaceutically acceptable salt thereof.

14. A method for the treatment of conditions caused by excessive cell proliferation, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 2.

15. A method for the treatment of conditions caused by excessive cell proliferation, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 3.

16. A method for the treatment of conditions caused by excessive cell proliferation, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 4.

5. A compound selected from the group consisting of:

(1) 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

(2) 1-(4-chlorobenzoyl)-4-[4-(4,5-dihydro-6H-oxazin-2-yl)benzylidene]piperidin

(3) 4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-trifluoromethylbenzoyl)piperidine

(4) 1-(4-chloro-3-methylbenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

(5) 1-(4-fluorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

(6) 1-(5-chloro-2-thienoyl)-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

(7) 1-cyclohexanecarbonyl-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine

(8) 4-[4-(2-oxazolin-2-yl)benzyl ]-1-(4-trifluoromethylbenzoyl)piperidine

(9) 1-(4-chlorobenzoyl)-4-[4-(2-oxazolin-2-yl)benzyl]piperidine

(10) 1-(4-chlorobenzoyl)-3-[4-(2-oxazolin-2-yl)benzylidene]pyrrolidine

(11) 1-(4-chlorobenzoyl)-4-[2-fluoro-4-(2-oxazolin-2-yl)benzylidene]piperidine (12) 1-(4-chlorobenzoyl)-4-[3-methyl-4-(2-oxazolin-2-yl)benzylidene]piperidine

and the pharmaceutically acceptable salts thereof.

17. A method for the treatment of conditions caused by excessive cell proliferation, which method comprises administering to a host in need of such treatment an effective amount of a compound according to claim 5.