Benzo Lipoxin Analogues

• US 20100152290A1
• Filed: 02/23/2010
• Published: 06/17/2010
• Est. Priority Date: 09/10/2003
• Status: Active Grant

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Petasis, Nicos A.
• Granted Patent: US 8,115,023 B2
• Time in Patent Office: Days
• US Class Current: 514/532
• CPC Class Codes: A61J 1/14 Details; Accessories therefor A61J7/00 takes precedence; openers B65D, B67B7/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07C 69/618 having unsaturation outside the six-membered aromatic ring
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids

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.

Claims

1. A compound of general formula 1:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from a group consisting of hydrogen, alkyl, aryl, acyl or alkoxyacyl;

the integer n is zero, one or two;

the integer m is one or two;

the two substituents on ring X are ortho-, meta- or para-.

6. The compound of claim 1, wherein W is alkyl or aryloxy.

7. The compound of claim 1, wherein W is butyl.

8. The compound of claim 1, wherein W is aryloxy.

9. The compound of claim 1, wherein A is hydroxy or alkoxy.

13. A pharmaceutical composition, comprising:

a compound according to claim 1; and

a pharmaceutically acceptable carrier.

14. A method of ameliorating or treating a disease or condition associated with inflammation, autoimmune diseases and abnormal cell proliferation, the method comprising administering to a subject an effective amount of a compound according to claim 1.

15. The method of claim 14, wherein the disease is selected from rheumatoid arthritis and other forms of arthritis, asthma, psoriasis, inflammatory bowel disease, systemic lupus erythematosus, systemic dermatomyositis, inflammatory ophthalmic diseases, autoimmune hematologic disorders, multiple sclerosis, vasculitis, idiopathic nephrotic syndrome, transplant rejection and graft versus host disease.

16. The method of claim 14, wherein the 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.

17. An article of manufacture, comprising packaging material, the compound of claim 1, or a pharmaceutically acceptable derivative thereof, contained within packaging material, which is used for treatment, prevention or amelioration of one or more symptoms associated with inflammation, autoimmune disease or abnormal cell proliferation, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for treatment, prevention or amelioration of one or more symptoms associated with inflammation, autoimmune disease or abnormal cell proliferation.

2. A compound selected from a group consisting of general structures 2-7:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;

the integer n is zero, one or two;

the integer m is one or two.

3. A compound selected from a group consisting of general structures 8-13:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;

the integer n is zero, one or two;

the integer m is one or two.

4. A compound selected from a group consisting of general structures 14-19:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;

the integer n is zero, one or two;

the integer m is one or two.

5. A compound selected from a group consisting of:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc.

10. A method for preparation of a compound of the general formula 1:

by

providing a compound of formula 20, a compound of formula 21, and a compound of formula 22

wherein;

G, Q, X and Y are independently selected from a group consisting of bromo, chloro, iodo, triflyl, diazonium, iodonium, boronic acid, boronate, borinate, borate, trifluoroborate, stannyl, perfluorostannyl, silyl, zinc, magnesium or copper.

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, where M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from a group costing of hydrogen, alkyl, aryl, acyl or alkoxyacyl;

the integer n is zero, one or two;

the integer m is one or two;

the two substituents on ring X are either ortho-, meta- or para- and by;

reacting a compound of formula 20, with a compound of formula 21 in the presence of a metal catalyst, followed by reaction with a compound of formula 22 in the presence of a metal catalyst selected from a group consisting of palladium, nickel and copper;

or reacting a compound of formula 20, with a compound of formula 22 in the presence of a metal catalyst, followed by reaction with a compound of formula 21 in the presence of a metal catalyst selected from a group consisting of palladium, nickel and copper.

11. The method of claim 10, where the two coupling steps are carried out in sequence or in one pot.

12. The method of claim 10, wherein 20, 21 or 22 is connected to a polymeric chain or other solid phase material.

18. A compound represented by a structural formula selected from the group consisting of:

wherein;

A is hydroxy, alkoxy, aryloxy, amino, alkylamino, dialkylamino or —

OM, wherein M is a cation selected from the group consisting of ammonium, tetra-alkyl ammonium, and the cations of sodium, potassium, magnesium and zinc;

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 independently selected from the group consisting of hydrogen, alkyl, aryl, acyl and alkoxyacyl;

the integer n is zero, one or two; and

the integer m is one or two.

19. A method of ameliorating or treating a disease or condition associated with cancer or abnormal cell proliferation, the method comprising administering to a subject a therapeutically or prophylactically effective amount of a compound according to claim 18, or a pharmaceutically acceptable salt or prodrug thereof.

20. The method of claim 19, wherein the 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.