Pharmaceutical compositions for inhibition of cytokine production and secretion

• US 6,166,048 A
• Filed: 04/20/1999
• Issued: 12/26/2000
• Est. Priority Date: 04/20/1999
• Status: Expired due to Fees

• Current Assignee: Targacept, Inc. (Catalyst Biosciences, Inc.)
• Original Assignee: Targacept, Inc. (Catalyst Biosciences, Inc.)
• Inventors: Bencherif, Merouane
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US09/295,181
• Time in Patent Office: 616 Days
• Field of Search: 514/351, 514/345, 514/357
• US Class Current: 514/351
• CPC Class Codes: A61K 31/4406 only substituted in position 3, e.g. zimeldine nicotinic acid A61K31/455
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• 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: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Pharmaceutical compositions incorporate compounds that affect cytokine production and/or secretion. Such compounds include aryl substituted olefinic amine compounds, pyridyloxylalkylamines and phenoxyalkylamines, and aryl substituted amine compounds, such as 3-aminophenyl amine compounds. Such pharmaceutical compositions can be used for treating a wide variety of conditions, diseases and disorders, and particularly those associated with dysfunction of cytokine production and/or secretion. Of particular interest are pharmaceutical compositions useful for preventing and treating conditions, diseases and disorders associated with undesirably high levels of cytokine production and/or secretion. Such pharmaceutical compositions are useful for treating the effects of inflammatory bowel disease, inflammation, arthritis, cachexia in neoplastics diseases or associated with AIDS, and autoimmune diseases.

Claims

1. A method for inhibiting cytokine production and/or secretion, the method comprising administering an effective amount of a compound having the formula:

##STR4## where X and X'"'"' are individually carbon or nitrogen bonded to a substituent species characterized as having a sigma m value greater than 0, less than 0 or 0, A, A'"'"' and A" individually are substituent species characterized as having a sigma m value greater than 0, less than 0 or 0;

B'"'"' is selected from the group consisting of oxygen, nitrogen-containing moiety, sulfur,

space="preserve" listing-type="equation">--(CE'"'"'E")--(CE'"'"'E")--,

space="preserve" listing-type="equation">--CE'"'"'E"--X"--, ##STR5##

space="preserve" listing-type="equation">--C.tbd.C--

wherein X" is oxygen, nitrogen-containing or sulfur;

m is an integer and n is an integer such that the sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8;

E^I, E^II, E^III, E^IV, E^V and E^VI individually represent hydrogen, lower alkyl or halo substituted lower alkyl;

Z'"'"' and Z" individually are hydrogen or lower alkyl; and

the wavy line in the structural moiety indicates that the compound can have a cis (Z) or trans (E) form.

2. The method of claim 1, whereby X'"'"' is nitrogen.

3. The method of claim 1, whereby sigma m is greater than 0.1.

4. The method of claim 1, whereby sigma m is less than -0.1.

5. The method of claim 1, whereby at least one of E^I, E^II, E^III, E^IV, E^V and E^VI is not hydrogen.

6. The method of claim 1, whereby m plus n is 2 or 3.

7. The method of claim 1, whereby A is hydrogen.

8. The method of claim 1, whereby A, A'"'"' and A" are all hydrogen.

9. The method of claim 1 whereby one or two of the substituents designated as E^I, E^II, E^III, E^IV, E^V and E^VI are non-hydrogen substituents.

10. The method of claim 9, whereby E^I, E^II, E^III, E^IV, E^V and E^VI are hydrogen and whereby E^VI is non-hydrogen.

11. The method of claim 9 whereby E^I and E^II are hydrogen.

12. The method of claim 1 whereby B'"'"' is ##STR6##

13. The method of claim 1 whereby B'"'"' is oxygen.

14. The method of claim 1 whereby the compound has a trans (E) form.

15. The method of claim 1 wherein at least one of Z'"'"' and Z" are hydrogen.

16. The method of claim 1 wherein Z'"'"' is hydrogen and Z" is methyl.

17. The method of claim 1, whereby the effective amount does not exceed about mg/24hour/patient and the concentration of the compound within the plasma does not exceed 500 pg/ml.

18. The method of claim 1, whereby the method is used to treat autoimmune disorders.

19. The method of claim 1 wherein the compound is selected from the group consisting of (3E) and (3Z)-N-methyl-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and (3Z)-N-methyl-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and (5Z)-N-methyl-6-(3-pyridyl)-5-hexen-3-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-4-penten-2-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and (4Z)-N-methyl-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and (1Z)-N-methyl-1-(3-pyridyl)-1-octen-4-amine, (1E) and (1Z)-N-methyl-1-(3-pyridyl)-5-methyl-1-hepten-4-amine, (5E) and (5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and (5Z)-N-methyl-6-(3-pyridyl)-5-hexen-2-amine, (5E) and (5Z)-N-methyl-6-(3-pyridyl)-5-methyl-5-hexen-3-amine, (3E) and (3Z)-4-(3-pyridyl)-2-methyl-3-buten-1-amine, (3E) and (3Z)-4-(3-pyridyl)-3-methyl-3-buten-1-amine, (5E) and (5Z)-6-(3-pyridyl)-5-hexen-3-amine, (4E) and (4Z)-5-(3-pyridyl)-2-methyl-4-penten-2-amine, (4E) and (4Z)-5-(3-pyridyl)-3-methyl-4-penten-2-amine, (4E) and (4Z)-5-(3-pyridyl)-4-penten-2-amine, (4E) and (4Z)-5-(3-pyridyl)-1,1,1-trifluoro-4-penten-2-amine, (4E) and (4Z)-5-(3-pyridyl)-4-methyl-4-penten-1-amine, (4E) and (4Z)-5-(3-pyridyl)-4-methyl-4-penten-2-amine, (1E) and (1Z)-1-(3-pyridyl)-1-octen-4-amine, (5E) and (5Z)-6-(3-pyridyl)-5-methyl-5-hexen-2-amine, (5E) and (5Z)-6-(3-pyridyl)-5-hexen-2-amine, (5E) and (5Z)-6-(3-pyridyl)-5-methyl-5-hexen-3-amine. (3-(3-pyridyloxy)propyl)methylamine, (3-(3-pyridyloxy)propyl)amine, (3-(5-bromo-(3-pyridyloxy)propyl)methylamine, (1-methyl-3-(3-pyridyloxy)propyl)methylamine, (3-(5-ethoxy-(3-pyridyloxy)propyl)methylamine, (3-(6-methyl-(3-pyridyloxy)propyl)methylamine, (3-(5-chloro-(3-pyridyloxy)propyl)methylamine, (3-(2-bromo(3-pyridyloxy)propyl)methylamine, (1-methyl-3-(5-methoxy-(3-pyridyloxy)propyl))methylamine, (4-(3-pyridyloxy)butyl))methylamine, (3-phenoxypropyl)methylamine and (3-(3-aminophenoxy)propyl)methylamine, (3-(4-methoxyphenoxy)propyl)methylamine.