Compounds having effects on serotonin-related systems

• US 5,576,321 A
• Filed: 06/06/1995
• Issued: 11/19/1996
• 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., Rasmussen, Kurt
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Bottino, Anthony
• Application Number:
  US08/468,900
• Time in Patent Office: 532 Days
• Field of Search: 548/408, 548/465, 546/201, 544/154, 544/373, 514/323, 514/255, 514/409, 514/422, 514/427, 514/469, 514/470, 514/414, 514/415
• US Class Current: 514/254.09
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• 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 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 Antihypertensives
• 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

space="preserve" listing-type="equation">--NH--R.sup.1 II

R¹ is piperidinyl, piperazino, morpholino or pyrrolyl, substituted with 0-1 phenyl or benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

which phenyl or benzyl group is substituted with 0-2 C₁ -C₃ alkyl, halo, trifluoromethyl or C₁ -C₃ alkoxy groups;

or R¹ is ##STR47## n and m are independently 4-5, and the group of Formula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl, substituted with pyrrolyl, furyl, thienyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinotinyl, substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein X is hydrogen or hydroxy, and D completes a pyrrolyl group.

3. A compound of claim 1 wherein r is 1-3.

4. A compound of claim 3 wherein s is 0.

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

6. 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 ##STR48## 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

space="preserve" listing-type="equation">--NH--R.sup.1 II

R¹ is piperidinyl, adamantyl, piperazino, morpholino or pyrrolyl, substituted with 0-1 phenyl or benzyl group or 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

which phenyl or benzyl group is substituted with 0-2 C₁ -C₃ alkyl, halo, trifluoromethyl or C₁ -C₃ alkoxy groups;

or R¹ is ##STR49## n and m are independently 4-5, and the group of Formula VI may be substituted with 0-1 oxo group and 0-2 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or R¹ is C₁ -C₄ alkyl, substituted with pyrrolyl, adamantyl, furyl, thienyl, pyridinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinolinyl, substituted with 0-4 C₁ -C₃ alkyl, C₁ -C₃ alkoxy or halo groups;

or a pharmaceutically acceptable salt thereof.

7. A method of claim 6 wherein the compound is a compound wherein r is 1-3, s is 0, and X is hydrogen or hydroxy.

8. 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 6.

9. A method of claim 8 wherein the compound is a compound wherein r is 1-3, s is 0, and X is hydrogen or hydroxy.

10. A method of treating anxiety which comprises the method of claim 6.

11. A method of claim 6 wherein the compound is a compound wherein r is 1-3, s is 0, and X is hydrogen or hydroxy.

12. 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 6.

13. 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 6.

14. A method of claim 8 wherein a serotonin reuptake inhibitor is also administered to the subject.