Compounds having effects on serotonin-related systems

• US 5,614,523 A
• Filed: 06/06/1995
• Issued: 03/25/1997
• Est. Priority Date: 01/17/1995
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Wong, David T., Audia, James E., Krushinski, Joseph H. Jr., Rocco, Vincent P., Schaus, John M., Thompson, Dennis C., Rasmussen, Kurt
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): KIFLE, BRUCK
• Application Number:
  US08/470,512
• Time in Patent Office: 658 Days
• Field of Search: 548/469, 548/465, 548/151, 548/218, 544/238, 544/253, 544/358, 544/359, 514/252, 514/253, 514/254, 514/414-415
• US Class Current: 514/254.08
• 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 ##STR46## 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 pyrrolyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

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

R is ##STR47## R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl;

or R⁵ is C₁ -C₃ alkyl substituted with benzodioxinyl or benzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁵ is pyridinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy or halo groups;

or R⁵ is ##STR48## B is oxygen or sulfur;

Y is a residue which combines with the atoms to which it is attached to complete a triazolyl, imidazolyl, thiazolyl or pyrrolyl ring;

or a pharmaceutically acceptable salt thereof.

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

14. A compound of claim 1 wherein X is hydrogen or hydroxy;

s is 0; and

r is 0-3.

3. A method of affecting 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 pyrrolyl group;

wherein X is hydrogen, phenyl, hydroxy or methoxy;

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

R is ##STR50## R⁵ is C₁ -C₆ alkyl or C₁ -C₄ acyl;

or R⁵ is C₁ -C₃ alkyl substituted with phenyl, benzodioxinyl or benzodioxolyl,

substituted on the phenyl ring with 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R⁵ is pyridinyl, phenyl, naphthyl, tetralinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl,

substituted with 0-2 C₁ -C₃ alkyl, trifluoromethyl, C₁ -C₃ alkoxy or halo groups;

or R⁵ is ##STR51## B is oxygen or sulfur;

Y is a residue which combines with the atoms to which it is attached to complete a triazolyl, imidazolyl, thiazolyl or pyrrolyl ring;

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 the method of claim 3.

8. A method of treating anxiety which comprises the method of claim 3.

10. A method of treating a condition chosen from the group consisting of hypertension, cognitive disorders, psychosis, 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 the method of claim 3.

12. 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 the method of claim 3.

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

15. A method of claim 3 wherein the compound is a compound wherein X is hydrogen or hydroxy;

s is 0; and

r is 0-3.

16. A method of treating anxiety which comprises the method of claim 15.

17. A method of treating a condition chosen from the group consisting of hypertension, cognitive disorders, psychosis, 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 the method of claim 15.

18. A method of preventing or alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises the method of claim 15.

19. 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 the method of claim 15.

4. A method of inhibiting the reuptake of serotonin which comprises administering to a subject in need of such treatment an effective amount of a compound of formula ##STR52## wherein r is 0-3;

X is hydrogen or hydroxy;

R is ##STR53## R⁵ is phenyl, phenyl-C₁ -C₃ alkyl, or diphenyl-C₁ -C₃ alkyl, substituted with 1-2 halo, C₁ -C₃ alkoxy or trifluoromethyl groups;

or a pharmaceutically acceptable salt thereof.

5. A method of claim 4 wherein the serotonin 1A receptor of the subject is also affected by the compound.

7. A method of treating depression which comprises the method of claim 4.

9. A method of treating both anxiety and depression which comprises the method of claim 4.

11. A method of treating a condition chosen from the group consisting of obsessive-compulsive disease, obesity, migraine, pain, particularly neuropathic pain, bulimia, premenstrual syndrome or late luteal syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention-deficit hyperactivity disorder, disruptive behavior disorders, impulsive control disorders, borderline personality disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism and trichotilomania, comprising the method of claim 4.