Compounds having effects on serotonin-related systems

• US 5,741,789 A
• Filed: 06/06/1995
• Issued: 04/21/1998
• Est. Priority Date: 01/17/1995
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Krushinski, Joseph H. Jr., Rocco, Vincent P., Schaus, John M., Thompson, Dennis C., Hibschman, David J., Rasmussen, Kurt
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Kifle, Bruck
• Application Number:
  US08/467,434
• Time in Patent Office: 1,050 Days
• Field of Search: 546/201, 546/187, 546/195, 546/16, 546/17, 546/140, 546/143, 546/177, 546/101, 514/323, 514/213, 514/210, 514/278, 514/314, 540/593, 540/586, 540/597, 540/543
• US Class Current: 514/212.02
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• 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 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 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 409/12 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
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 495/10 Spiro-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

A series of hetero-oxy alkanamines are effective pharmaceuticals for the treatment of conditions related to or affected by the reuptake of serotonin and by the serotonin 1_A receptor. The compounds are particularly useful for alleviating the symptoms of nicotine and tobacco withdrawal, and for the treatment of depression and other conditions for which serotonin reuptake inhibitors are used.

Claims

1. A compound of the formula ##STR45## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl, group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR46## A is a residue which combines with the nitrogen atom to which it is attached to complete

a) an azabicyclo(octyl nonyl or decyl) group;

##STR47## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring wherein M is, substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁶ and R⁷ combine with the atom to which they are attached to complete a fluorenyl or dihydroanthracenyl group;

q represents 0-2;

Q represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein r is 0-3and s is O;

X is hydrogen or hydroxy;

A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR48## M is a residue which combines with the carbon atom to which it is attached to complete a benzopyranyl, naphthodi-hydrofuranyl, benzodihydrothienyl, or benzodihydrofuranyl group, wherein the spiro junction is not to an aromatic ring wherein M is, substituted with 0-2 C₁ -C₃ alkoxy, benzyloxy, phenyl or halo groups;

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 2.

11. A method of antagonizing or partially agonizing the serotonin 1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of claim 2.

12. A method of preventing or alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises administering to a subject in need of such treatment an effective amount of a compound of claim 2.

13. A method of treating anxiety which comprising administering to a subject in need of such treatment an effective amount of a compound of claim 2.

14. A method of treating a condition chosen from the group consisting of hypertension, cognitive disorders, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 2.

15. A method of potentiating the action of a serotonin reuptake inhibitor in increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering to a subject in need of such treatment an effective amount of a serotonin reuptake inhibitor in combination with an effective amount of a compound of claim 2.

16. A method of preventing or alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises administering to a subject in need of such treatment an effective amount of a serotonin reuptake inhibitor in combination with an effective amount of a compound of claim 2.

17. A compound of claim 2 wherein r is 1 and X is hydroxy.

18. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 17.

19. A method of antagonizing or partially agonizing the serotonin 1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of claim 17.

20. A method of treating a condition chosen from the group consisting of hypertension, cognitive disorders, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 17.

5. A method of antagonizing or partially agonizing the serotonin 1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of the formula ##STR49## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR50## A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR51## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, idenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroinndolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring,

wherein M is substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo

q represents 0-2;

Q represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

6. A method of preventing or alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises administering to a subject in need of such treatment an effective amount of a compound of formula XII ##STR52## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR53## A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR54## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, idenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroinndolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring,

wherein M is substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo

q represents 0-2;

O represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

10. A method of claim 6 wherein a serotonin reuptake inhibitor is also administered to the subject.

7. A method of treating anxiety which comprises administering to a subject in need of such treatment an effective amount of a compound of formula XII ##STR55## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR56## A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR57## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, idenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroinndolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring,

wherein M is substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo

q represents 0-2;

O represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

8. A method of treating a condition chosen from the group consisting of hypertension, cognitive disorders, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders and obesity, substance abuse, obsessive-compulsive disease, panic disorder and migraine, comprising administering to a subject in need of such treatment an effective amount of a compound of formula XII ##STR58## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR59## A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR60## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, idenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroinndolyl, naphthodihydrofuranyl, benzodihydrothienyl benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring,

wherein M is substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo

q represents 0-2;

O represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

9. A method of potentiating the action of a serotonin reuptake inhibitor in increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering to a subject in need of such treatment a serotonin reuptake inhibitor in combination with a method of antagonizing or partially agonizing the serotonin 1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of the formula ##STR61## wherein r is 0-4;

s is 0-1;

D is a residue which combines with the carbon atoms to which it is attached to complete a pyridinyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

provided that X is hydrogen or phenyl when r is 0;

R is ##STR62## A is a residue which combines with the nitrogen atom to which it is attached to complete ##STR63## M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, idenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dinhydroinndolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl, or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring,

wherein M is substituted with 0-2 C₁ -C₃ alkyl, oxo, C₁ -C₃ alkoxy, pyrrolidinyl- or piperidinyl-C₁ -C₃ alkoxy, C₁ -C₂ alkylenedioxy, phenoxy, benzyloxy, phenyl or halo groups;

p represents 0-2;

R⁶ and R⁷ independently represent phenyl groups, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo

q represents 0-2;

O represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.