Piperidine and piperazine derivatives which function as 5-ht2a receptor antagonists

• US 20030130287A1
• Filed: 11/05/2002
• Published: 07/10/2003
• Est. Priority Date: 01/11/2000
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Ackermann, Karl-August, Bartoszyk, Gerd, Greiner, Hartmug, V. Amsterdam, Christoph, Seyfried, Christoph, Pruecher, Helmut, Boettcher, Henning, Harting, Juergen
• Application Number:
  US10/169,399
• Publication Number:
  US 20030130287A1
• Time in Patent Office: Days
• US Class Current: 514/253.07
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/54 Sulfur atoms
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 217/02 with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 233/84 Sulfur atoms
• CPC Class Codes: C07D 271/12 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 285/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07D 307/91 Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 333/34 Sulfur atoms
• CPC Class Codes: C07D 333/62 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• 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 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Compounds of the formula I

in which R¹, R², X, Y and alk are as defined in claim 1, are potent 5-HT_2A antagonists and are suitable for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Huntington'"'"'s disease, eating disorders, such as bulimia, anorexia nervosa, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

Claims

1. Compounds of the formula I

2. Compounds according to claim 1

a) 8-{4-[2-(4-fluorophenyl)ethyl]piperazine-1-sulfonyl)quinoline;

b) 4-(4-fluorophenylsulfonyl)-1-[2-(4-fluorophenyl)ethyl]piperidine;

c) 2-chloro-6-{1-[2-(4-fluorophenyl)ethyl]piperidin-4-sulfonyl}pyridine;

d) 4-(2-methoxyphenylsulfanyl)-1-[2-(4-fluorophenyl)ethyl]-piperidine

e) 4-(4-methylphenylsulfinyl)-1-[2-(4-fluorophenyl)ethyl]piperidine;

f) 4-(3-cyano-1H-indole-5-sulfonyl)-1-[2-(4-fluorophenyl)ethyl]-piperazine

and their physiologically acceptable salts and solvates.

3. Process for the preparation of compounds of the formula I according to claim 1 in which X is N, characterized in that

a) a compound of the formula II

 

in which R¹ and alk are as defined in claim 1, is reacted with a compound of the formula III

R²—

Y—

L 

 

III

in which L is Cl, Br, I or a free or reactively functionally modified OH group,

and R² and Y are as defined in claim 1,

or

b) if desired one of the radicals R¹ and/or R² is converted into another radical R¹ and/or R² by, for example, cleaving an OA group to form an OH group and/or converting a CHO group into a CN group,

and/or

a resultant base of the formula I is converted into one of its salts by treatment with an acid.

4. Process for the preparation of compounds of the formula I according to claim 1 in which X is CH, characterized in that

a) a compound of the formula IV

in which R² is as defined in claim 1, is reacted with a compound of the formula V

R¹-alk-L 

 

V

in which L is Cl, Br, I or a free or reactively functionally modified OH group,

and R¹ and alk are as defined in claim 1,

and the product is subsequently oxidized,

or

b) if desired one of the radicals R¹ and/or R² is converted into another radical R¹ and/or R² by, for example, cleaving an OA group to form an OH group and/or converting a CHO group into a CN group,

and/or

a resultant base of the formula I is converted into one of its salts by treatment with an acid.

5. Compounds of the formula I according to claim 1, and their physiologically acceptable salts and solvates, as medicaments.

7. Medicament according to claim 5 or 6 for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Huntington'"'"'s disease, eating disorders, such as bulimia, anorexia nervosa, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

8. Pharmaceutical preparation comprising at least one medicament according to claim 5 or 6 and optionally vehicles and/or auxiliaries and optionally other active ingredients.

9. Use of compounds according to claim 1 and/or their physiologically acceptable salts and solvates for the preparation of a medicament having a 5-HT_2A receptor-antagonistic action.

10. Use according to claim 9 for the preparation of a medicament for the treatment of psychoses, schizophrenia, depression, neurological disorders, memory disorders, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Alzheimer'"'"'s disease, Huntington'"'"'s disease, eating disorders, such as bulimia, anorexia nervosa, premenstrual syndrome and/or for positively influencing obsessive-compulsive disorder (OCD).

6. Compounds of the formula I