Phenylindole derivatives as 5-ht2a receptor ligands

• US 6,479,480 B1
• Filed: 01/12/2001
• Issued: 11/12/2002
• Est. Priority Date: 07/24/1998
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Limited (Merck & Co., Inc.)
• Inventors: Rowley, Michael, Moyes, Christopher Richard
• Primary Examiner(s): Rao, Deepak R.
• Application Number:
  US09/743,743
• Time in Patent Office: 669 Days
• Field of Search: 540/602, 544/143, 544/373, 546/112, 546/201, 548/511, 514/217.08, 514/235.2, 514/254.09, 514/299, 514/323, 514/415
• US Class Current: 514/217.08
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 453/06 containing isoquinuclidine ring systems

Abstract

Compounds according to Formula (I) or a salt thereof are selective antagonists of the human 5-HT2A receptor useful for treatment of adverse conditions of the central nervous system:

Claims

1. A compound of formula I, or a salt thereof:

wherein

A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C_1-6 alkyl or C_1-6 alkoxy;

X and Y independently represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C_1-6 alkyl, C_1-6 alkoxy or phenyl; and

Q is selected from the structures of formula Qa to Qm;

 

in which the asterisk denotes the point of attachment to the remainder of the molecule;

Z represents oxygen, sulphur or N—

R¹;

R¹ and R² independently represent hydrogen, or C_1-6 alkyl, aryl(C_1-6)alkyl or C_3-7 heterocycloalkyl(C_1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and

R³ represents hydrogen, halogen, C_1-6 alkyl, hydroxy or C_1-6 alkoxy;

provided that at least one of R¹, R² and R³ is other than hydrogen.

2. A compound as claimed in claim 1 wherein Q represents a group of formula Qc.

3. A compound as claimed in claim 1 represented by formula II, and salts thereof:

wherein

Z¹ represents oxygen, N—

R¹ or CH—

R³.

5. A process for the preparation of a compound as claimed in claim 1, which comprises:

(A) attachment of the requisite substituent to a precursor compound of formula III;

 

wherein A, B, X and Y are as defined in claim 1, and Q¹ corresponds to a moiety of formula Q as defined in claim 1 in which R¹ and R² independently represent hydrogen;

or

(B) reducing a compound of formula V;

 

wherein A, B, X, Y and Q are as defined in claim 1;

or

(C) reducing a compound of formula VI;

 

wherein A, B, X and Y are as defined in claim 1, and Q² corresponds to a moiety of formula Q as defined in claim 1 in which R¹ and R2 independently represent a benzyloxycarbonyl group;

or

(D) reacting a compound of formula X or an acid adition salt thereof with a compound of formula XI;

 

wherein A, B, X, Y and Q are as defined in claim 1; and

(E) subsequently, where required, converting a compound of formula I initially obtained into a further compound of formula I by conventional methods.

6. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

7. A composition as claimed in claim 6 further comprising another anti-schizophrenic medicament.

8. A method for the treatment of a psychotic disorder which comprises administering to a patient in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. A compound selected from:

3-(1-methylpiperidin-3-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylpyrrolidin-2(R)-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylpyrrolidin-2(S)-ylmethyl)-2-phenyl-1H-indole;

2-methyl-3-(2-phenyl-1H-indol-3-ylmethyl)-2-azabicyclo [2.2.2]octane;

3-(2-methyl-2-azabicyclo[2.2.1]hept-3-ylmethyl)-2-phenyl-1H-indole;

3-(1,5-dimethyl-cis-pyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;

3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;

7-chloro-3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;

3-(4-methylmorpholin-3-ylmethyl)-2-phenyl-1H-indole;

3-[1-(2-phenylethyl)piperidin-3-ylmethyl]-2-phenyl-1H-indole;

3-(1-benzylpyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;

3-[1-(2-phenylethyl)pyrrolidin-2-ylmethyl]-2-phenyl-1H-indole;

2-phenyl-3-[1-(3-phenylpropyl)pyrrolidin-2(R)-ylmethyl]-1H-indole;

3-(1-benzylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;

3-[1-(2-phenylethyl)pyrrolidin-3-ylmethyl]-2-phenyl-1H-indole;

3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylpiperidin-2(S)-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylazepin-2(R)-ylmethyl)-2-phenyl-1H-indole;

3-(1-methylazepin-2(S)-ylmethyl)-2-phenyl-1H-indole;

3-(1-ethylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;

3-[1-(2-methoxyethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole;

3-(1-benzylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;

3-[1-(2-phenylethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole;

2-(3-fluorophenyl)-6-fluoro-3-(4-methylpiperazin-2(S)-ylmethyl)-1H-indole;

2-(3-fluorophenyl)-6-fluoro-3-(1-methylpiperazin-2(S)-ylmethyl)-1H-indole; and

salts thereof.