Indole derivatives as 5-HT receptor antagonist

• US 5,990,133 A
• Filed: 10/16/1997
• Issued: 11/23/1999
• Est. Priority Date: 02/02/1995
• Status: Expired due to Fees

• Current Assignee: Smithkline Beecham PLC (GSK plc)
• Original Assignee: Smithkline Beecham PLC (GSK plc)
• Inventors: Forbes, Ian Thomson, Wyman, Paul Adrian, Mulholland, Keith Raymond, Davies, David Thomas, Jones, Graham Elgin, Gaster, Laramie Mary, Duckworth, David Malcolm
• Primary Examiner(s): Rotman, Alan L.
• Application Number:
  US08/875,506
• Time in Patent Office: 768 Days
• Field of Search: 546/277.1, 514/337
• US Class Current: 514/337
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• 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
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

A compound of formula (I) or a salt thereof: ##STR1## wherein: P¹ is pyridyl;

P² is phenyl;

A is a bond or a chain of 1 to 5 atoms optionally substituted by C_1-6 alkyl;

R¹ and R² groups are each independently hydrogen, C_1-6 alkyl optionally substituted by NR¹² R¹³, C_2-6 alkenyl, C_2-6 alkynyl, cyano, halogen, CF₃, NR¹² R¹³, CHO, OCF₃, COR¹⁴, CH₂ OR¹⁴ or OR¹⁴ where R¹², R¹³ and R¹⁴ are independently hydrogen or C_1-6 alkyl;

n and m are independently 0, 1 or 2;

R³ is hydrogen or C_1-6 alkyl;

R⁴ is a group of formula (i): ##STR2## in which: R⁶ and R⁷ are independently hydrogen, C_1-6 alkyl optionally substituted by one or more fluorine atoms, C_1-6 alkylthio, C_1-6 alkoxy or halogen.

Claims

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

##STR11## wherein;

P¹ is pyridyl;

P² is phenyl;

A is a bond or a chain of 1 to 5 atoms optionally substituted by C_1-6 alkyl;

R¹ and R² groups are each independently hydrogen, C_1-6 alkyl optionally substituted by NR¹² R¹³, C_2-6 alkenyl, C_2-6 alkynyl, cyano, halogen, CF₃, NR¹² R¹³, CHO, OCF₃, COR¹⁴, CH₂ OR¹⁴ or OR¹⁴ where R¹², R¹³ and R¹⁴ are independently hydrogen or C_1-6 alkyl;

n and m are independently 0, 1 or 2;

R³ is hydrogen or C_1-6 alkyl;

R⁴ is a group of formula (i);

##STR12## in which;

R⁶ and R⁷ are independently hydrogen, C_1-6 alkyl optionally substituted by one or more fluorine atoms, C_1-6 alkylthio, C_1-6 alkoxy or halogen, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 which is:

1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[(4-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline,

1-[(3-Pyridyl)-3-phenyl carbamoyl]-5-methylthio-6-trifluoromethyl indoline,

1-[(3-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluromethylindoline,

1-[(4-Pyridyl)-4-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[(2-Pyridyl)-3-phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[4-Methyl-3-(3-Pyridyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[2-Fluoro-5-(3-pyridyl) phenyl carbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-(3-Fluoro-5-(4-methyl-3-pyridyl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

6-Chloro-5-methyl-1-(4-methyl-3-(pyrid-3-yl)-phenylcarbamoyl) indoline,

1-(4-Methyl-3-(pyrid-3-yl) phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl indoline,

1-(3-Fluoro-5-(pyrid-3-yl)phenylcarbamoyl)-5-thiomethyl-6-trifluoromethyl-indoline,

1-(4-Chloro-3-(pyrid-3-yl)phenylcarbamoyl)-5-methoxy-6-trifluoromethylindoline,

1-[4-Methyl-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[5-Bromo-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[4-t-Butyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[4-Methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-Fluoro-4-methoxy-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-Bromo-4-methyl-5-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[3-(4-Methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

1-[5-Ethyl-3-(pyrid-3-yl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

6-Chloro-5-methyl-1-[4-methyl-3-(4-methyl-3-pyridyl)phenyl carbamoyl] indoline,

1-[3-(pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methoxy-6-trifluoromethyl-indoline,

1-[3-(Pyrid-3-ylaminocarbonyl )-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl-indoline,

1-[3-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline,

1-[4-(Pyrid-3-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline,

1-[4-(Pyrid-4-ylaminocarbonyl)-phenylcarbamoyl]-5-methylthio-6-trifluoromethyl indoline,

1-[3-(3-pyridylcarbonyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[3-(Pyrid-3-yl-aminosulphonyl)-phenylcarbamoyl]5-methoxy-6-trifluoromethyl-indoline, 5-Methylthio-6-trifluoromethyl-1-[4-(pyrid-4-yl-methylamino carbonyl)phenyl carbamoyl] indoline,

Trans-5-Methylthio-6-trifluoromethyl-1-{4-[2-ethenyl-(4-pyridyl)]-phenyl carbamoyl}-indoline,

5-Methylthio-6-trifluoromethyl-1-{4-[2-ethyl(4-pyridyl)]phenyl carbamoyl}indoline,

5-Methylthio-6-trifluoromethyl-1-[4-(pyrid-3-ylmethyl)amido phenyl carbamoyl]indoline,

5-Methylthio-6-trifluoromethyl-1-[3-(pyrid-4-ylmethyl) amidophenylcarbamoyl] indoline,

5-Methylthio-6-trifluoromethyl-1-[4-(pyrid-2-ylmethyl) amidophenylcarbamoyl] indoline,

1-[4-Fluoro-3-(3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethyl indoline,

1-[4-Chloro-3-(4-methyl-3-pyridyl)phenylcarbamoyl]-5-methoxy-6-trifluoromethylindoline,

and pharmaceutically acceptable salts thereof.

3. A compound according to claim 1 in which A is a bond.

4. A compound according to claim 1 in which R² is hydrogen, halogen, methyl, CF₃ or OCF₃.

5. A compound according to claim 1 in which R³ is hydrogen.

6. A compound according to claim 1 in which R⁶ is trifluoromethyl or halogen and R⁷ is C_1-6 alkoxy , C_1-6 alkylthio or C_1-6 alkyl.

7. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.

9. A method of antagonizing 5HT_2C receptors by administering to patient in need thereof, a compound of claim 1.

10. A method of treating CNS disorders by administering to a patient in need thereof, a compound of claim 1.

11. A method of treating anxiety or depression by administering to a patient in need thereof, a compound of claim 1.

12. A compound of claim 1 which is 1-[3-Fluoro-5-(3-pyridyl)phenylcarbomoyl]-5-methoxy-6-trifluoromethyl indoline.

13. A method of treating anxiety or depression by administering to a patient in need thereof, a compound of claim 12.

14. A pharmaceutical composition which comprises a compound according to claim 12 and a pharmaceutically acceptable carrier or excipient.

8. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:

(a) the coupling of a compound of formula (II);

##STR13## with a compound of formula (HI);

space="preserve" listing-type="equation">D--R.sup.4 '"'"' (III)

wherein A, P¹ and P² are as defined in formula (I) , C and D contain the appropriate functional group(s) necessary to form the moiety -NR³ '"'"'CO when coupled, the variables R¹ '"'"', R² '"'"', R³ '"'"' and R⁴ '"'"' are R¹, R², R³ and R⁴ respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R¹ '"'"', R² '"'"', R³ '"'"' and R⁴ '"'"', when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt thereof;

or

(b) the coupling of a compound of formula (IV);

##STR14## with a compound of formula (V);

##STR15## wherein P¹, P², R¹ '"'"', R² '"'"', R³ '"'"' and R⁴ '"'"' are as defined above and E and G contain the appropriate functional group(s) necessary to form the A moiety when coupled and thereafter optionally and as necessary and in any appropriate order, converting any R¹ '"'"', R² '"'"', R³ '"'"' and R⁴ '"'"', when other than R¹, R², R³ and R⁴ respectively to R¹, R², R³ and R⁴, interconverting R¹, R², R³ and R⁴ and forming a pharmaceutically acceptable salt.