5Imidazoquinolines and Pyrimidine Derivatives as Potent Modulators of VEGF-Driven Angiogenic Processes

• US 20120282252A1
• Filed: 07/17/2012
• Published: 11/08/2012
• Est. Priority Date: 03/26/2008
• Status: Abandoned Application

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Garcia-Echeverria, Carlos
• Application Number:
  US13/550,828
• Publication Number:
  US 20120282252A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• 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

The invention relates to the use of compounds of formula (I) or (II)

in the treatment of mammalian target of VEGF-driven angiogenic diseases, methods of use of said compounds in the treatment of said diseases in a warm-blooded animal, especially a human, pharmaceutical preparations comprising said compounds for the treatment of said diseases and said compounds for use in the treatment of said diseases.

Claims

1. A method of treating a patient suffering from a VEGF-driven angiogenic disease comprising administering a therapeutically effective amount of a compound of formula II,

2. The method according to claim 1, where the compound of the formula II is 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine.

3. The method according to claim 1, wherein said VEGF-driven angiogenic disease is resistant to the treatment with a VEGF or VEGF modulator selected from the group consisting of Bevacizumab, Ranibizumab, AVE0005, HuMV833, 2C3, CB0-P11, Sutent, Sorafenib, Vatalanib, Zactima, Midostaurin, Angiozyme, AG-013736, Lestautinib, CP-547,632, CEP-7055, KRN633, NVP-AEE788, IMC-1211, ZK260253, Semaxanib, E-7107, AS-3, Cand5 and PTC-299.

4. The method according to claim 1, wherein the disease to be treated is Rheumatoid arthritis, Synovitis, Bone and cartilage destruction, Osteomyelitis, Pannus Growth, Osteophyte formation, Hepatitis, Pneumonia, Glomerulonephritis, Asthma, Nasal polyps, Transplantation, Liver generation, Retinopathy of prematurity, Age macular degeneration, Diabetic retinopathy, Chroidal and other intraocular disorders, Leukomalacia, Thyroiditis,

Thyroid enlargement, Lympopholiferative disorders, Karposi'"'"'s sarcoma, Haematologic malignacies (e.g., haemangiomas), Obesity, Spinal cord injury, Acutemyocardial infarction, Pulmonary, cerbral and retinal oedema, or further any combinations thereof.

5. The method according to claim 1, wherein the compound of formula II is administered together with a VEGF modulator selected from the group consisting of Bevacizumab, anti-VEGF, Ranibizumab AVE0005, anti-VEGF HuMV833, anti-VEGF 2C3, anti-VEGF CB0-P11, Sutent, Sorafenib, Vatalanib, Zactima, Midostaurin, Angiozyme, AG-013736, Lestautinib, CP-547,632, CEP-7055, KRN633, NVP-AEE788, IMC-1211, ZK260253, Semaxanib, E-7107, AS-3, Cand5 and PTC-299;

and the HSP90 inhibitors CNF1010, CNF2024, tanespimycinm, alvespimycin, IPI504, SNX5422 and NVP-AUY922.

6. A pharmaceutical preparation for the treatment of a VEGF-driven angiogenic disease comprising a compound of formula II according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7. The pharmaceutical preparation according to claim 6, wherein the disease to be treated is Rheumatoid arthritis, Synovitis, Bone and cartilage destruction, Osteomyelitis, Pannus Growth, Osteophyte formation, Hepatitis, Pneumonia, Glomerulonephritis, Asthma, Nasal polyps, Transplantation, Liver generation, Retinopathy of prematurity, Age macular degeneration, Diabetic retinopathy, Chroidal and other intraocular disorders, Leukomalacia, Thyroiditis, Thyroid enlargement, Lympopholiferative disorders, Karposi'"'"'s sarcoma, Haematologic malignacies (e.g., haemangiomas), Obesity, Spinal cord injury, Acutemyocardial infarction, Pulmonary, cerbral and retinal oedema, or further any combinations thereof.

8. The pharmaceutical preparation according to claim 6, further comprising a VEGF modulator selected from the group consisting of Bevacizumab, anti-VEGF, Ranibizumab AVE0005, anti-VEGF HuMV833, anti-VEGF 2C3, anti-VEGF CB0-P11, Sutent, Sorafenib, Vatalanib, Zactima, Midostaurin, Angiozyme, AG-013736, Lestautinib, CP-547,632, CEP-7055, KRN633, NVP-AEE788, IMC-1211, ZK260253, Semaxanib, E-7107, AS-3, Cand5 and PTC-299;

and the HSP90 inhibitors CNF1010, CNF2024, tanespimycinm, alvespimycin, IPI504, SNX5422 and NVP-AUY922.

9. A combination comprising:

(a) a compound 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine (Compound C); and

(b) a VEGF or VEGFR targeting agent selected from the group consisting of Bevacizumab, anti-VEGF, Ranibizumab AVE0005, anti-VEGF HuMV833, anti-VEGF 2C3, anti-VEGF CB0-P11, Sutent, Sorafenib, Vatalanib, Zactima, Midostaurin, Angiozyme, AG-013736, Lestautinib, CP-547,632, CEP-7055, KRN633, NVP-AEE788, IMC-1211, ZK260253, Semaxanib, E-7107, AS-3, Cand5 and PTC-299; and

the HSP90 inhibitors CNF1010, CNF2024, tanespimycinm, alvespimycin, IPI504, SNX5422 and NVP-AUY922;

wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use for the treatment of a VEGF-driven angiogenic disease.

10. A combination according to claim 9, wherein the disease to be treated is Rheumatoid arthritis, Synovitis, Bone and cartilage destruction, Osteomyelitis, Pannus Growth, Osteophyte formation, Hepatitis, Pneumonia, Glomerulonephritis, Asthma, Nasal polyps, Transplantation, Liver generation, Retinopathy of prematurity, Age macular degeneration, Diabetic retinopathy, Chroidal and other intraocular disorders, Leukomalacia, Thyroiditis, Thyroid enlargement, Lympopholiferative disorders, Karposi'"'"'s sarcoma, Haematologic malignacies (e.g., haemangiomas), Obesity, Spinal cord injury, Acutemyocardial infarction, Pulmonary, cerbral and retinal oedema, or further any combinations thereof.