Indeno[;1,2-C];pyrazole derivatives for inhibiting tyrosine kinase activity

• US 6,534,655 B1
• Filed: 04/03/2000
• Issued: 03/18/2003
• Est. Priority Date: 10/06/1997
• Status: Expired due to Term

• Current Assignee: Abbvie Deutschland GmbH & Company KG (Abbvie Incorporated)
• Original Assignee: BASF AG (BASF SE)
• Inventors: Barlozzari, Teresa, Turner, Allyson, Hockley, Michael, Xu, Yajun, Rafferty, Paul, Arnold, Lee D.
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): COPPINS, JANET L
• Application Number:
  US09/541,309
• Time in Patent Office: 1,079 Days
• Field of Search: 514/338, 514/339, 546/275.7, 548/359.1
• US Class Current: 546/275.7
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Chemical compounds that are derivatives of indeno[1,2-c]pyrazole are inhibitors of tyrosine kinase activity. Several of the tyrosine kinases, whose activity is inhibited by these chemical compounds, are involved in angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell proliferation is a factor. Compounds of this invention also inhibit the induction of vascular hyperpermeability and the associated formation of edema, ascites, and exudates.

Claims

1. A method of inhibiting tyrosine kinase activity comprising the administration of a compound represented by the formula:

wherein;

X is a carbonyl;

R¹ is a hydrogen; and

R² is a pyridyl to said tyrosine kinase in sufficient concentration to inhibit the enzyme activity of said tyrosine kinase.

2. The method of claim 1 wherein said compound is in an enantiomeric form, a tautomeric form, is in a mixture with one or more other said compounds, or is both in an enantiomeric form and in a mixture with one or more other said compounds.

3. The method of claim 1 wherein said tyrosine kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase.

4. The method of claim 3 wherein said tyrosine kinase is selected from the group consisting of KDR, flt-1, TIE-2, Lck, Src, fyn, and yes.

5. The method of claim 1 wherein the activity of said tyrosine kinase affects angiogenesis.

6. The method of claim 5 wherein the inhibition of said tyrosine kinase is anti-angiogenic.

7. The method of claim 6 wherein said inhibition of said tyrosine kinase inhibits the progression of the disease state selected from the group consisting of arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collateral vascularization, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, wound healing peptic ulcer Helicobacter related diseases, fractures, diabetic retinopathy and cat scratch fever.

8. The method of claim 1 wherein the activity of said tyrosine kinase affects vascular hyperpermeability.

9. The method of claim 1 wherein said compound is represented by the formula:

wherein R² is selected from the group consisting of 3-pyridyl and 4-pyridyl.

10. The method of claim 1 wherein said compound is represented by the formula:

wherein R² and X are respectively 3-pyridyl and CO.

11. The method of claim 1 wherein X is a carbonyl and R¹ is a hydrogen, wherein the inhibition of said tyrosine activity is associated with anti-fertility or abortifacient effects.