Benzo lipoxin analogues

Patent metadata

Field	Value
Publication number	US-9573880-B2
Application number	US-201414450017-A
Country	US
Kind code	B2
Filing date	Aug 1, 2014
Priority date	Sep 10, 2003
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Benzolipoxin analogs, methods of their preparation and pharmaceutical compositions containing the compounds are provided. The compounds and compositions are useful in methods for treatment of various diseases, including, inflammation, autoimmune disease and abnormal cell proliferation.

First claim

What is claimed:

1. A compound having a structural and stereochemical formula selected from the group consisting of:

wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or OM, wherein M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation;
W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;
R a -R c are each independently hydrogen, alkyl, aryl, acyl or alkoxyacyl; and
one or more of R a -R c are not hydrogen

or a pharmaceutically acceptable salt thereof.

2. A compound having a structural and stereochemical formula selected from the group consisting of:

wherein:
A is OR wherein R is a straight-chained, branched or cyclic alkyl containing between 2 and 20 carbon atoms, aryloxy, amino, alkylamino, dialkylamino or OM, wherein M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation;
W is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide;
R a -R c are each independently hydrogen, alkyl, aryl, acyl or alkoxyacyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , having a structural and stereochemical formula:

wherein:
A is OR, wherein R is a straight-chained, branched or cyclic alkyl containing between 2 and 20 carbon atoms;

or a pharmaceutically acceptable salt thereof.

4. A compound having a structural and stereochemical formula selected from the group consisting of:

wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or OM, wherein M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation;
W is hydrogen, methyl, ethyl, propyl, isopropyl, 2-butyl, 2-methylpropyl, 2-methyl-2-propyl, alkyl containing a chain of between 5 and 20 atoms, cycloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide; and
R a -R c are each independently hydrogen, alkyl, aryl, acyl or alkoxyacyl

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein A is hydroxy or alkoxy.

6. The compound of claim 4 , wherein R a , R b , and R c are each hydrogen.

7. The compound of claim 4 , wherein A is hydroxy or alkoxy, and R a , R b , and R c are each hydrogen.

8. The compound of claim 4 , having a structural and stereochemical formula selected from the group consisting of:

wherein:
A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or OM, wherein M is an ammonium, tetra-alkyl ammonium, sodium, potassium, magnesium or zinc cation;
W is hydrogen, methyl, ethyl, propyl, isopropyl, 2-butyl, 2-methylpropyl, 2-methyl-2-propyl, alkyl containing a chain of between 5 and 20 atoms, cycloalkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, alkoxy, aryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, or sulfonamide; and

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 4 , wherein W is a straight-chained, branched or cyclic alkyl containing between 5 and 20 carbon atoms.

10. A pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 wherein the formulation is suitable for topical administration.

12. The pharmaceutical composition of claim 10 wherein the formulation is a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation, or spray.

13. The pharmaceutical composition of claim 10 wherein the formulation further comprises one or more of the group consisting of: a sterile diluent; antimicrobial agent; antioxidant; chelating agent; buffer; and agent for the adjustment of tonicity.

14. The pharmaceutical composition of claim 10 wherein the formulation is suitable for topical administration to the eye.

15. The pharmaceutical composition of claim 10 wherein the formulation is suitable for topical administration to the skin and mucous membranes, including transdermal delivery.

16. The pharmaceutical composition of claim 10 wherein the formulation is suitable for inhalation therapies.

17. The pharmaceutical composition of claim 10 wherein the formulation is a nasal solution.

18. A method of ameliorating or treating a disease or condition associated with inflammation, autoimmune diseases or abnormal cell proliferation, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition of claim 10 .

19. The method of claim 18 , wherein the disease or condition is neutrophil-mediated inflammation or neutrophil-mediated damage.

20. The method of claim 18 , wherein the disease or condition is inflammatory ophthalmic disease.

21. The method of claim 18 , wherein the disease or condition is arthritis, asthma, psoriasis, inflammatory bowel disease, or systemic dermatomyositis.

22. The method of claim 18 , wherein the disease or condition is periodontal disease.

23. The method of claim 18 , wherein the disease associated with abnormal cell proliferation is a non-small cell lung cancer, head and neck squamous cancers, colorectal cancer, prostate cancer, breast cancer, acute lymphocytic leukemia, adult acute myeloid leukemia, adult non-Hodgkin's lymphoma, brain tumors, cervical cancers, childhood cancers, childhood sarcoma, chronic lymphocytic leukemia, chronic myeloid leukemia, esophageal cancer, hairy cell leukemia, kidney cancer, liver cancer, multiple myeloma, neuroblastoma, oral cancer, pancreatic cancer, primary central nervous system lymphoma, skin cancer, and small-cell lung cancer.

24. The method of claim 18 , wherein the disease associated with abnormal cell proliferation is colorectal cancer, breast cancer or brain tumors.

25. An article of manufacture, comprising packaging material, a compound of claim 4 , or a pharmaceutically acceptable salt thereof contained within the packaging material, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment or amelioration of one or more symptoms associated with a disease or condition associated inflammation, autoimmune diseases or abnormal cell proliferation.

26. A method of ameliorating or treating a disease or condition associated with inflammation, autoimmune diseases or abnormal cell proliferation, the method comprising administering to a subject a therapeutically effective amount of a topical formulation comprising a compound of claim 4 , and a pharmaceutically acceptable carrier.

27. A substantially diastereomeric

Assignees

• Univ Southern California

Inventors

• Petasis Nicos A

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C69/732

  of unsaturated hydroxy carboxylic acids · CPC title

• A61K9/0078

  for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions · CPC title