N- methyl piperazine compounds having dopamine receptor affinity

• US 5,968,478 A
• Filed: 10/09/1997
• Issued: 10/19/1999
• Est. Priority Date: 12/12/1994
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Fu, Jian-Min, Rakhit, Sumanas
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US08/948,051
• Time in Patent Office: 740 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/1.81, 540/555, 540/557, 514/211, 514/220, 514/217, 514/183, 514/172, 514/247, 514/430, 514/431, 514/434, 544/1, 544/3, 544/7, 544/32
• US Class Current: 424/1.81
• CPC Class Codes: C07D 243/38 [b, e]- or [b, f]-condensed with six-membered rings
• CPC Class Codes: C07D 267/18 [b, e]-condensed
• CPC Class Codes: C07D 337/14 [b,f]-condensed

Abstract

Described herein are D4 receptor-selective compounds of the general formula: ##STR1## wherein X₁ is selected from CH₂, NH, O and S;

X₂ -- is selected from CH=, CH₂ --, and N=;

R₁ to R₈ are each independently selected from H, C_1-4 alkyl, halo, cyano, nitro and halo-substituted C_1-4 alkyl

and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described.

Claims

1. A compound according to formula I:

##STR8## wherein X₁ is S;

X₂ is selected from the group consisting of CH= and CH₂ --;

R₁ to R₈ are each independently selected from the group consisting of H, cyano and halo;

and acid addition salts, solvates and hydrates thereof;

wherein at least one of R₁ to R₈ is selected from the group consisting of cyano and halo, and wherein when one of R₅ -R₈ is cyano or halo, at least one of R_1-4 is also cyano or halo.

2. The compound according to claim 1 wherein R₂ is cyano and R₁ and R₃ to R₈ are H.

3. The compound according to claim 1, wherein said compound is 2-cyano-10-(4-methyl-piperazinyl)-dibenzo[b,f]thiepine.

4. A pharmaceutical composition, comprising a compound according to claim 1 in combination with a pharmaceutically effective carrier.

5. A pharmaceutical composition, comprising a compound according to claim 2 in combination with a pharmaceutically effective carrier.

6. A pharmaceutical composition, comprising a compound according to claim 3 in combination with a pharmaceutically effective carrier.

7. The compound according to claim 1, in a radiolabelled form.

8. A pharmaceutical composition for treating a condition mediated by the D4 receptor, comprising a compound according to claim 1 in an amount effective to inhibit the D4 receptor, and a pharmaceutically acceptable carrier thereof.

9. A method for the treatment of a condition mediated by the D4 receptor, comprising the step of administering to a mammal in need of such treatment, a composition according to claim 8.

10. A pharmaceutical composition for treating schizophrenia, comprising a compound according to claim 1 in an amount sufficient to produce an antischizophrenia effect, and a pharmaceutically acceptable carrier thereof.

11. A method for the treatment of schizophrenia, comprising the step of administering to a mammal in need of such treatment, a composition according to claim 10.

12. A pharmaceutical composition for treating anxiety, comprising a compound according to claim 1 in an amount sufficient to produce an antianxiety effect, and a pharmaceutically acceptable carrier thereof.

13. A method for the treatment of anxiety, comprising the step of administering to a mammal in need of such treatment, a composition according to claim 12.

14. A compound according to formula I:

##STR9## wherein X₁ is S;

X₂ is selected from the group consisting of CH= and CH₂ --;

R₁ to R₈ are each independently selected from the group consisting of H, cyano and halo;

wherein when X₂ is CH₂ --, R₇ is selected from the group consisting of of H and cyano;

and acid addition salts, solvates and hydrates thereof;

wherein said compound is in radiolabeled form.