Cis-2-[(4-heteroaryl-1-piperazinyl)alkyl] hexahydro-1H-isoindole-1,3 (2H)-diones and related compounds and their therapeutic utility

• US 5,556,858 A
• Filed: 06/06/1995
• Issued: 09/17/1996
• Est. Priority Date: 05/19/1989
• Status: Expired due to Fees

• Current Assignee: Hoechst-Roussel Pharmaceuticals Incorporated (Sanofi )
• Original Assignee: Hoechst-Roussel Pharmaceuticals Incorporated (Sanofi )
• Inventors: Bordeau, Kenneth J., Chiang, Yulin, Strupczewski, Joseph T., Helsley, Grover C., Glamkowski, Edward J., Tegeler, John J., Nemoto, Peter A.
• Primary Examiner(s): TSANG, CECILIA J
• Application Number:
  US08/467,387
• Time in Patent Office: 469 Days
• Field of Search: 544/368, 514/254
• US Class Current: 514/254.06
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/33 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 323/22 containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 45/45 by condensation
• CPC Class Codes: C07C 45/673 by change of size of the carbon skeleton
• CPC Class Codes: C07C 45/71 being hydroxy groups
• CPC Class Codes: C07C 47/575 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/755 a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 261/20 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 275/04 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 275/06 with hetero atoms directly attached to the ring sulfur atom
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• 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 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 : Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

Heteroarylpiperidines, pyrrolidines, and piperazines are useful as antipsychotic and analgesic agents the compounds are especially useful for treating psychoses by administering to a mammal a psychoses-treating effective amount of one of the compounds. Depot derivatives of the compounds are useful for providing long acting effects of the compounds. The compounds are also useful as analgesics by administering a pain-relieving effective amount of one of the compounds to a mammal.

Claims

1. A compound of the formula:

##STR132## X is --O--, --S--, --NH--, or --N(R₂);

R₂ is selected from the group consisting of lower alkyl, aryl lower alkyl, aryl, (₃ -C₁₀) cycloalkyl, aroyl, (C₂ -C₁₈) alkanoyl, (C₁ -C₁₈) alkoxycarbonyl, and phenylsulfonyl groups;

aryl is as defined hereinafter;

p is 1 or 2;

Y is hydrogen, lower alkyl, hydroxy, chlorine, fluorine, bromine, iodine, lower alkoxy, trifluoromethyl, nitro, or amino;

R₁ is --CR₂₄ R₂₇ --(CR₂₃ R₂₇)_n --, where n is 0,1,2 or 4;

or

--CHR₂₄ CH═

CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CHR₂₄ --,

--CHR₂₄ --CH═

CH--CR₂₃ R₂₄ --CHR₂₄ --,

--CHR₂₄ --CR₂₃ R₂₄ --CH.tbd.CH--CHR₂₄ --,

--CHR₂₄ --C.tbd.C--CR₂₃ R₂₄ --CHR₂₄ --, or

--CHR₂₄ --CR₂₃ R₂₄ --C.tbd.C--CHR₂₄,

the --CH═

CH-- bond being cis or trans;

R₂₃ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy, (C₁ -C₁₈)alkoxy, aryloxy, aryl (C₁ -C₁₈)alkyloxy, (C₁ -C₁₈)alkanoyloxy, hydroxy (C₁ -C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆) alkyl, phenyl (C₁ -C₆)alkyloxy, aryl (C₁ -C₁₈) alkyloxy (C₁ -C₆)alkyl or (C₁ -C₁₈)alkanoyloxy (C₁ -C₆) alkyl or ##STR133## where Z₁ is lower alkyl, --OH, lower alkoxy, --CF₃, --NO₂, --NH₂, or halogen, and p is as previously defined;

R₂₄ is hydrogen, (C₁ -C₁₈) linear alkyl, phenyl, hydroxy (C₁ -C₆)alkyl, (C₁ -C₁₈)alkoxy(C₁ -C₆)alkyl, phenyl (C₁ -C₆)alkyloxy, aryl (C₁ -C₁₈) alkyoxy(C₁ -C₆) alkyl, (C₁ -C₁₈) alkanoyloxy (C₁ -C₆)alkyl or ##STR134## where Z₁ and p are as previously defined;

R₂₇ is hydrogen or R₂₄ and R₂₇ taken together with the carbon to which they are attached form C═

O or C═

S;

and aryl is phenyl or ##STR135## where R₅ is hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; and

, any hydroxyl group attached to an aliphatic or aromatic carbon atom, or any primary or secondary nitrogen atom may be acylated with a (C₄ -C₁₈)carboxylic group, in addition, any nitrogen atom may alternatively be acylated with a (C₄ -C₁₈)alkoxycarbonyl group;

all geometric, optical, and stereoisomers thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, wherein X is --N(R₂)--.

3. The compound of claim 1, wherein R₂ is (C₁ -C₁₈)alkanoyl or (C₁ -C₁₈)alkoxycarbonyl.

4. An antipsychotic composition, which comprises the compound of claim 1 in an amount sufficient to produce an antipsychotic effect, and a pharmaceutically acceptable carrier therefor.

5. A method of treating psychoses, which comprises administering to a mammal a psychoses-treating effective amount of the compound of claim 1.

6. An analgesic composition, which comprises the compound of claim 1 in an amount sufficient to produce a pain-relieving effect, and a pharmaceutically acceptable carrier therefor.

7. A method of alleviating pain, which comprises ad- ministering to a mammal a pain-relieving effective amount of the compound of claim 1.

8. A depot pharmaceutical composition, which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1, wherein the compound contains an acylated hydroxy group, or an acylated amino group.

9. The depot pharmaceutical composition of claim 8, wherein the hydroxy group is acylated or the amino group is acylated with an (C₄ -C₁₈)alkanoyl group or an (C₄ -C₁₈)alkoxycarbonyl group.

10. The composition of claim 8, which contains a pharmaceutically acceptable oil.

11. The composition of claim 10, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

12. The composition of claim 9, which contains a pharmaceutically acceptable oil.

13. The composition of claim 12, wherein the oil is selected from the group consisting of coconut oil, peanut oil, sesame oil, cotton seed oil, corn oil, soybean oil, olive oil, and esters of fatty acids and polyfunctional alcohols.

14. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 8 sufficient to produce a long acting antipsychotic effect.

15. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 9 sufficient to produce a long acting antipsychotic effect.

16. A method for providing a long acting antipsychotic effect, which comprises injecting into a mammal an amount of the composition of claim 13 sufficient to produce a long acting antipsychotic effect.