3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles

• US 4,804,663 A
• Filed: 02/05/1986
• Issued: 02/14/1989
• Est. Priority Date: 03/27/1985
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Kennis, Ludo E. J., Vandenberk, Jan
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US06/826,517
• Time in Patent Office: 1,105 Days
• Field of Search: 544/278, 544/282, 544/284, 544/54, 514/259, 514/258, 514/224.2
• US Class Current: 514/259.41
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 497/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

3-Piperdinyl-1,2-benzisothiazoles and 3-piperidinyl-1,2-benzisoxazoles and their pharmaceutically acceptable acid addition salts having useful antipsychotic properties and being useful in the treatment of a variety of complaints in which serotonin release is of predominant importance.

Claims

1. A chemical compound having the formula ##STR17## or a pharmaceutically acceptable acid addition salt thereof, wherein R is hydrogen or C_1-6 alkyl;

R¹ and R² are each independently members selected from the group consisting of hydrogen, halo, hydroxy, C_1-6 alkyloxy and C_1-6 alkyl;

X is O or S;

Alk is C_1-4 alkanediyl; and

Q is a radical of formula ##STR18## wherein Y¹ and Y² are each independently O or S;

R³ is a member selected from the group consisting of hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C_1-10 alkylcarbonyl)oxy, amino, mono- and di(C_1-6 alkyl)amino, (C_1-10 alkylcarbonyl)amino, phenylmethoxy and azido;

R⁴ is hydrogen or halo;

or a radical of formula ##STR19## wherein R⁵ is hydrogen or C_1-6 alkyl;

Z is --S--, --CH₂ -- or --CR⁶ ═

CR⁷ --;

said R⁶ and R⁷ being each independently hydrogen or C_1-6 alkyl; and

A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ --, said R⁸ and R⁹ being each independently hydrogen, halo, amino or C_1-6 alkyl.

2. A chemical compound according to claim 1, wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, hydroxy, amino or azido and R⁴ is hydrogen;

or Q is a radical of formula (b) wherein R⁵ is C_1-6 alkyl and A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or C_1-6 alkyl.

3. A chemical compound according to claim 2, wherein R is hydrogen, R¹ is hydrogen or halo and R² is hydrogen, halo, hydroxy or C_1-6 alkyloxy.

4. A chemical compound according to claim 3, wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo or methyl and Y¹ is O;

or Q is a radical of formula (b) wherein --Z--A-- is --S--CH₂ --CH₂ --, --S--(CH₂)₃ --, --S--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, --CH═

CH--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, or --CH₂ --CH₂ --CH₂ --CH₂ --.

5. A chemical compound according to claim 4, wherein R¹ is hydrogen, and R² is hydrogen, halo, hydroxy or methoxy.

6. A chemical compound according to claim 1 wherein the compound is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]-pyrimidin-4-one or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

7. A pharmaceutical composition for treating psychotic diseases, comprising an inert carrier and as an active ingredient a pharmaceutically effective amount of a chemical compound having the formula ##STR20## or a pharmaceutically acceptable acid addition salt thereof, wherein R is hydrogen or C_1-6 alkyl;

R¹ and R² are each independently members selected from the group consisting of hydrogen, halo, hydroxy, C_1-6 alkyloxy and C_1-6 alkyl;

X is O or S;

Alk is C_1-4 alkanediyl; and

Q is a radical of formula ##STR21## wherein Y¹ and Y² are each independently O or S;

R³ is a member selected from the group consisting of hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C_1-10 alkylcarbonyl)oxy, amino, mono- and di(C_1-6 alkyl)amino, (C_1-10 alkylcarbonyl)amino, phenylmethoxy and azido;

R⁴ is hydrogen or halo;

or

a radical of formula ##STR22## wherein R⁵ is hydrogen or C_1-6 alkyl;

Z is --S--, --CH₂ -- or --CR⁶═

CR⁷ --;

said R⁶ and R⁷ being each independently hydrogen or C_1-6 alkyl; and

A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ --, said R⁸ and R⁹ being each independently hydrogen, halo, amino or C_1-6 alkyl.

8. A pharmaceutical composition according to claim 7 wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, hydroxy, amino or azido and R⁴ is hydrogen;

or Q is a radical of formula (b) wherein R⁵ is C_1-6 alkyl and A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or C_1-6 alkyl.

9. A pharmaceutical composition according to claim 8 wherein R is hydrogen, R¹ is hydrogen or halo and R² is hydrogen, halo, hydroxy or C_1-6 alkyloxy.

10. A pharmaceutical composition according to claim 9 wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo or methyl and Y¹ is O;

or Q is a radical of formula (b) wherein --Z--A-- is --S--CH₂ --CH₂ --, --S--(CH₂)₃ --, --S--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, --CH═

CH--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, or --CH₂ --CH₂ --CH₂ --CH₂ --.

11. A pharmaceutical composition according to claim 10 wherein R¹ is hydrogen, and R² is hydrogen, halo, hydroxy or methoxy.

12. A pharmaceutical composition according to claim 7 wherein the compound is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.

13. A method of treating warm-blooded animals suffering from psychotic diseases which comprises the administration thereto of a pharmaceutically effective amount of a chemical compound having the formula ##STR23## or a pharmaceutical acceptable acid addition salt thereof, wherein R is hydrogen or C_1-6 alkyl;

R¹ and R² are each independently members selected from the group consisting of hydrogen, halo, hydroxy, C_1-6 alkyloxy and C_1-6 alkyl;

X is O or S;

Alk is C_1-4 alkanediyl; and

Q is a radical of formula ##STR24## wherein Y¹ and Y² are each independently O or S;

R³ is a member selected from the group consisting of hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, nitro, cyano, hydroxy, (C_1-10 alkylcarbonyl)oxy, amino, mono- and di(C_1-6 alkyl)amino, (C_1-10 alkylcarbonyl)amino, phenylmethoxy and azido;

R⁴ is hydrogen or halo;

or a radical of formula ##STR25## wherein R⁵ is hydrogen or C_1-6 alkyl;

Z is --S--, --CH₂ -- or --CR⁶ ═

CR⁷ --;

said R⁶ and R⁷ being each independently hydrogen or C_1-6 alkyl; and

A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ --;

said R⁸ and R⁹ being each independently hydrogen, halo, amino or C_1-6 alkyl.

14. A method according to claim 13 wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy, trifluoromethyl, hydroxy, amino or azido and R⁴ is hydrogen;

or Q is a radical of formula (b) wherein R⁵ is C_1-6 alkyl and A is a bivalent radical --CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ -- or --CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or C_1-6 alkyl.

15. A method according to claim 14 wherein R is hydrogen, R¹ is hydrogen or halo and R² is hydrogen, halo, hydroxy or C_1-6 alkyloxy.

16. A method according to claim 15 wherein Q is a radical of formula (a) wherein R³ is hydrogen, halo or methyl and Y¹ is O;

or Q is a radical of formula (b) wherein --Z--A-- is --S--CH₂ --CH₂ --, --S--(CH₂)₃ --, --S--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, --CH═

CH--CR⁸ ═

CR⁹ -- wherein R⁸ and R⁹ are each independently hydrogen or methyl, or --CH₂ --CH₂ --CH₂ --CH₂ --.

17. A method according to claim 16 wherein R¹ is hydrogen, and R² is hydrogen, halo, hydroxy or methoxy.

18. A method according to claim 13 wherein the compound is 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.