Compounds for inhibition of ceramide-mediated signal transduction

• US 5,843,943 A
• Filed: 06/07/1995
• Issued: 12/01/1998
• Est. Priority Date: 12/29/1994
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Wasson, D. Bruce, Cottam, Howard B., Carson, Dennis A.
• Primary Examiner(s): Ford, John M.
• Application Number:
  US08/482,551
• Time in Patent Office: 1,273 Days
• Field of Search: 544/257, 544/244, 514/249, 514/84
• US Class Current: 514/249
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 473/06 with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
• CPC Class Codes: C07D 473/10 with methyl radicals in positions 3 and 7, e.g. theobromine
• CPC Class Codes: C07D 475/02 with an oxygen atom directly attached in position 4
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Novel, heterocyclic compounds having at least one ring nitrogen, disclosed side chains and, in some embodiments, an oxygen ortho to the ring nitrogen inhibit inflammatory responses associated with TNF-α and fibroblast proliferation in vivo and in vitro. The compounds of the invention neither appreciably inhibit the activity of cAMP phosphodiesterase nor the hydrolysis of phosphatidic acid, and are neither cytotoxic nor cytostatic. Preferred compounds of the invention are esters. Methods for the use of the novel compounds to inhibit ceramide-mediated intracellular responses to stimuli in vivo (particularly TNF-α) are also described. The methods are expected to be of use in reducing inflammatory responses (for example, after angioplasty), in limiting fibrosis (for example, of the liver in cirrhosis), in inhibiting cell senescence, cell apoptosis and UV induced cutaneous immune suppression.

Claims

1. A compound having the formula:

##STR11## wherein;

R₁ is a terminally substituted normal alkyl having from 1 to 7 carbon atoms, a terminally substituted alkenyl having from 2 to 7 carbon atoms, a terminally substituted ether having from 2 to 6 carbon atoms, a terminally substituted secondary amine having from 2 to 6 carbon atoms, or substituted aryl having less than 8 carbons, where A is said terminal group and is NH₂, acyloxy, SO₃ H, PO₄ H₂, NNO(OH), SO₂ NH₂, PO(OH)NH₂, SO₂ R or COOR where R is H, an alkyl having from 1 to 4 carbon atoms, an alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl;

R₂ is an alkyl, alkenyl, or aralkyl having less than 7 carbon atoms;

R₄ is H, an alkyl, alkenyl, or aryl or aralkyl having less than 7 carbon atoms, or OH or an O-alkyl having from 1 to 5 carbon atoms; and

R₅ is H, an alkyl, alkenyl, or aryl or aralkyl having less than 7 carbon atoms, or OH or an O-alkyl having from 1 to 5 carbon atoms.

2. A compound according to claim 1 wherein R₁ is --CH₂ CH₂ CH₂ --, A is COOEt, R₂ is MeCH₂ CH₂ (normal), and both R₄ and R₅ are H.

3. A compound according to claim 1 wherein R₁ is ω

-carboxyalkyl, ω

-carboxyalkenyl, or ω

-carboxyaryl, wherein the carboxyaryl further has a second substituent selected from the group consisting of NH₂, acyloxy, SO₃ H, PO₄ H₂, NNO(OH), SO₂ NH₂, PO(OH)NH₂, SO₂ R, or COOR, where R is H, an alkyl having from 1 to 4 carbon atoms, an alkenyl having from 1 to 4 carbon atoms, tetrazolyl or benzyl.

4. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a physiologically acceptable carrier.

5. A method for treating a ceramide associated condition in a host comprising administering a therapeutically effective amount of the compound of claim 1 in a physiologically acceptable carrier to the host in an amount and for a time sufficient to provide protection to the host against a ceramide associated condition being experienced in a tissue of the host.

6. The method according to claim 5 wherein the ceramide associated condition is inflammation.

7. The method according to claim 5 wherein the ceramide associated condition is fibrosis.

8. The method according to claim 5 wherein the ceramide associated condition is cell senescence or apoptosis.

9. The method according to claim 8 wherein the ceramide associated condition is radiation dermatitis, sunburn or UV induced immune suppression in skin.