Tetrahydroisoquinoline derivatives as modulators of dopamine D.sub.3 receptors

• US 6,046,210 A
• Filed: 11/03/1998
• Issued: 04/04/2000
• Est. Priority Date: 05/11/1996
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham PLC (GSK plc)
• Original Assignee: Smithkline Beecham PLC (GSK plc)
• Inventors: Stemp, Geoffrey, Johns, Amanda
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US09/180,156
• Time in Patent Office: 518 Days
• Field of Search: 546/146, 514/307
• US Class Current: 514/307
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 217/04 with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• 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 413/12 linked by a chain containing hetero atoms as chain links

Abstract

This invention relates to compounds of formula (I): ##STR1## which are useful as modulators of D₃ receptors, in particular in the treatment of psychoses.

Claims

1. A compound of formula (I):

##STR11## wherein;

R¹ represents a substituent selected from;

a hydrogen or halogen atom;

a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, C_1-4 alkyl, C_1-4 alkoxy, arylC_1-4 alkoxy, C_1-4 alkylthio, C_1-4 alkoxyC_1-4 akyl, C_3-6 cycloalkylC_1-4 alkoxy, C_1-4 alkanoyl, C_1-4 alkoxycarbonyl, C_1-4 alkylsulphonyl, C_1-4 alkylsulphonyloxy, C_1-4 alkylsulphonylC_1-4 alkyl, arylsulphonyl, arylsulphonyloxy, arylsulphonylC_1-4 alkyl, C_1-4 alkylsulphonamido, C_1-4 alkylamido, C_1-4 alkylsulphonamidoC_1-4 alkyl, C_1-4 alkyamidoC_1-4 alkyl, arylsulphonamido, arylcarboxamido, arylsulphonarnidoC_1-4 alkyl, arylcarboxamidoC_1-4 alkyl, aroyl, aroylC_1-4 alkyl, or arylC_1-4 alkanoyl group;

a group R³ OCO(CH₂)_p, R³ CON(R⁴)(CH₂)_p, R³ R⁴ NCO(CH₂)_p or R³ R⁴ NSO₂ (CH₂)_p where each of R³ and R⁴ independently represents a hydrogen atom or a C_1-4 alkyl group or R³ R⁴ forms part of a C_3-6 azacyloalkane or C_3-6 (2-oxo)azacycloalkane ring and p represents zero or an integer from 1 to 4;

or a group Ar² --Z, wherein Ar² represents an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring and Z represents a bond, O, S, or CH₂ ;

R² represents a hydrogen atom or a C_1-4 alkyl group;

q is 1 or 2;

Ar and Ar¹ each independently represent an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered aromatic heterocyclic ring; and

Y represents a bond, --NHCO--, --CONH--, --CH₂ --, or --(CH₂)_m Y¹ (CH₂)_n --, wherein Y¹ represents O, S, SO₂, or CO and m and n each represent zero or 1 such that the sum of m+n is zero or 1;

or a salt thereof.

2. A compound according to claim 1 wherein q represents 1.

3. A compound as claimed in claim 1 wherein Y represents a bond.

4. A compound as claimed in claim 1 wherein Ar represents unsubstituted phenyl.

6. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises:

(a) reacting a compound of formula (II);

##STR12## wherein R¹ and q are as defined in claim 1;

with a compound of formula (III);

##STR13## wherein R², Y, Ar and Ar¹ are as defined in claim 1;

(b) reacting a compound of formula (IV);

##STR14## wherein R¹ and R² are as defined in claim 1;

with a compound of formula (V);

space="preserve" listing-type="equation">Ar.sup.1 --Y--ArCOX Formula (V)

wherein Y, Ar and Ar¹ are as defined in claim 1 and X is a halogen atom or the residue of an activated ester;

(c) preparing a compound of formula (I) wherein R¹ is Ar² --Z and Z is a bond, reacting a compound of formula (VI);

##STR15## wherein one R^1a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron compound or a metal function, and when q is 2 the other R^1a is R¹ ;

with a compound Ar² --W¹, wherein W¹ is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W¹ is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;

(d) preparing a compound of formula (I) wherein R¹ is Ar² --Z and Z is O or S, reacting a compound of formula (VII);

##STR16## wherein one R^1b represent a group ZH and when q is 2 the other R^1b represents R¹ ;

with a reagent serving to introduce the group Ar² ;

(e) preparing a compound of formula (I) where Y is a bond, reaction of a compound of formula (VIII);

##STR17## wherein R¹, R², Ar and W are as defined in claim 1, with a compound Ar¹ --W¹, wherein W¹ is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M, or W¹ is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;

(f) interconverting one compound of formula (I) to a different compound of formula (I); and

optionally thereafter forming a salt of formula (I).

7. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof and a physiologically acceptable carrier therefor.

8. A method of treating a condition which requires modulation of a dopamine receptor which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 or a physiologically acceptable salt thereof.

9. The method according to claim 8 wherein the dopamine receptor is a dopamine D₃ receptor.

10. The method according to claim 8 wherein a dopamine antagonist is required.

11. The method according to claim 8 wherein the condition is a psychotic condition.

5. A compound of formula (I) which is:

7-Methoxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Hydroxy-N-4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline 2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline N-(4-(4-Phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

7-Methylsulfonyloxy-N-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquimoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-methoxy-1,2,3,4-terrahydroisoquinoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethydsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Cyanophenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

7-(4-(3,5-Dimethyl)isoxazolyl)sulfonyloxy-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Acetyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Methoxy-2-(4-(4-(6-methyl)-3-pyridyl)benzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Aminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydoisoquinoline;

2-(4-(4-(3-Methylsulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(1-Methyl-4-pyrazolyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4(-(5-Methyl-1,2,4-oxadiazolyl)benzoylamino)butyl)-7-triuoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-Pyrimidyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-(1-(2-Oxo)pyrrolidinyl)phenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Aminosulfonylphenyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(5-(1-Oxo)indanyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(3-(6-(1-Pyrrolyl)pyridyl)carboxamido)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-(5-Methyl-1,2,4-oxadiazolyl)-phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-(5-Methyl-1,3,4-oxadiazolyl)phenylbenzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(3-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Methylaminocarbonyl)phenyl)benzoylamino)butyl-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Pyridyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(2-Thienyl)benzoylamino)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(2-(5-(2-Pyridyl)thienylcarboxamido)butyl)-7-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-pyridyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(2-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(Phenylbenzoylamino)butyl)-7-(3-cyanophenyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-Phenylbenzoylamino)butyl)-7-(3-thienyl)sulfonyloxy-1,2,3,4-tetrahydroisoquinoline;

7-Methoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Ethoxycarbonylmethyl-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-(2-Cyanophenoxy)-2-(4-(4-phenylbenzoylamino)butyl-1,2,3,4-tetrahydroisoquinoline;

7-Bromo-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

7-Cyano-2-(4-(4-phenylbenzoylamino)butyl)-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluoromethoxy-1,2,3,4-tetrahydroisoquinoline;

2-(4-(4-(4-Acetylphenyl)benzoylamino)butyl)-7-trifluommethyl-1,2,3,4-tetrahydroisoquinoline;

or a salt thereof.