Methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis

• US 6,846,839 B1
• Filed: 06/16/1999
• Issued: 01/25/2005
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Fong, Annie, Tang, Peng Cho, Sun, Li, Shawver, Laura Kay, Hirth, Klaus Peter
• Primary Examiner(s): Myers, Carla J.
• Assistant Examiner(s): Spiegler, Alexander H.
• Application Number:
  US09/333,703
• Time in Patent Office: 2,050 Days
• Field of Search: 514/397, 514/359, 514/361, 514/362, 514/363, 514/364, 514/365, 514/372, 514/374, 514/378, 514/381, 514/383, 514/414, 514/418
• US Class Current: 514/397
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 455/06 containing benzo [a] quinolizine ring systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: G06F 13/4045 where the bus bridge performs an extender function

Abstract

The present invention relates to methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis. More specifically, this invention relates to methods for treating diseases and disorders, such as rheumatoid arthritis, endometriosis, ocular neovascularization, solid tumor growth and metastases, and excessive scarring during wound healing, with indolinone compounds.

Claims

1. A method of identifying one or more indolinone compounds of Formula I

that inhibit growth factor-stimulated cell proliferation comprising the following steps:

(a) contacting cells with one or more indolinone compounds;

(b) contacting said cells with one or more growth factors selected from the group consisting of VEGF, PDGF, and FGF;

(c) monitoring an inhibitory effect on growth factor stimulated cell proliferation; and

(d) identifying indolinone compounds of formula I that inhibit growth factor-stimulated cell proliferation,

wherein,

R₁ is H or alkyl;

R₂ is O or S;

R₃ is H;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

A is selected from the group consisting of a 4,5,6,7-tetrahydroindole, thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4,-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, wherein said group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

n is 0-3;

R is selected from the group consisting of H, alkyl, and aryl; and

R′

is selected from the group consisting of H, alkyl, and aryl, where the alkyl is optionally substituted with a six-membered heteroaliphatic ring, and where the six-membered ring is optionally substituted at one or more positions with substituents selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, NO₂, and (CH₂)_nCO₂R.

2. The method of claim 1, wherein said cells are endothelial cells and are contacted with VEGF in step (b).

3. The method of claim 1, wherein said cells are smooth muscle cells and are contacted with PDGF in step (b).

4. The method of claim 1, wherein said cells are endothelial cells and are contacted with FGF in step (b).

5. A method of identifying one or more indolinone compounds of Formula I

that are active in an adjuvant arthritis model in rats comprising the following steps:

(a) administering said one or more indolinone compounds to said rats;

(b) monitoring in said rats one or more effects selected from the group consisting of ear nodulation, tail nodulation, nose swelling, paw swelling and ballanitis; and

(c) identifying indolinone compounds of formula I that are active in an adjuvant arthritis model in rats.

wherein,

R₁ is H or alkyl;

R₂ is O or S;

R₃ is H;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

A is selected from the group consisting of a 4,5,6,7-tetrahydroindole, thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4,-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, wherein said group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

n is 0-3;

R is selected from the group consisting of H, alkyl, and aryl; and

R′

is selected from the group consisting of H, alkyl, and aryl, where the alkyl is optionally substituted with a six-membered heteroaliphatic ring, and where the six-membered ring is optionally substituted at one or more positions with substituents selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, NO₂, and (CH₂)_nCO₂R.

6. The method of claim 5, wherein said one or more compounds are administered at a concentration in the range of from about 1 to about 1000 mg/m²/day.

7. A method of inhibiting VEGF, FGF, or PDGF stimulated cell proliferation in vein endothelial cells or smooth muscle cells comprising administering to a patient in need of such treatment a composition comprising a therapeutically effective amount of one or more compounds of formula I which inhibit VEGF, FGF, or PDGF stimulated cell proliferation in vein endothelial cells or smooth muscle cells,

wherein said composition optionally includes one more pharmaceutically acceptable excipients in at least one of parenteral, oral, or topical formulation:

wherein,

R₁ is H or alkyl;

R₂ is O or S;

R₃ is H;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

A is selected from the group consisting of a 4,5,6,7-tetrahydroindole, thiophene, pyrrole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4,-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, where said group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

n is 0-3;

R is selected from the group consisting of H, alkyl, and aryl; and

R′

is selected from the group consisting of H, alkyl, and aryl, where the alkyl is optionally substituted with a six-membered heteroaliphatic ring, and where the six-membered ring is optionally substituted at one or more positions with substituents selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, NO₂, and (CH₂)_nCO₂R.

8. A method of treating arthritis comprising administering to a patient in need of such treatment a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more compounds of formula I which treat arthritis,

wherein,

R₁ is H or alkyl;

R₂ is O or S;

R₃ is H;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

A is selected from the group consisting of a 4,5,6,7-tetrahydroindole, thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4,-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, where said group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

n is 0-3;

R is selected from the group consisting of H, alkyl, and aryl; and

R′

is selected from the group consisting of H, alkyl, and aryl, where the alkyl is optionally substituted with a six-membered heteroaliphatic ring, and where the six-membered ring is optionally substituted at one or more positions with substituents selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, NO₂, and (CH₂)_nCO₂R.

9. A method of inhibiting VEGF, FGF, or PDGF stimulated cell proliferation in vein endothelial cells or smooth muscle cells in vitro, comprising:

a) contacting said cells with one more compounds of formula I which inhibit VEGF, FGF, or PDGF stimulated cell proliferation in vein endothelial cells or smooth muscle cells in vitro,

wherein said composition optionally includes one more pharmaceutically acceptable excipients in at least one of parenteral, oral, or topical formulation;

wherein,

R₁ is H or alkyl;

R₂ is O or S;

R₃ is H;

R₄, R₅, R₆, and R₇ are each independently selected from the group consisting of hydrogen alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

A is selected from the group consisting of a 4,5,6,7-tetrahydroindole, thiophene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, 2-sulfonylfuran, 4-alkylfuran, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4,-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3,4-thiatriazole, 1,2,3,5-thiatriazole, and tetrazole, where said group is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, alkaryl, alkaryloxy, halogen, trihalomethyl, S(O)R, SO₂NRR′

, SO₃R, SR, NO₂, NRR′

, OH, CN, C(O)R, OC(O)R, NHC(O)R, (CH₂)_nCO₂R, CONRR′

, and (CH₂)_nONRR′

;

n is 0-3;

R is selected from the group consisting of H, alkyl, and aryl; and

R′

is selected from the group consisting of H, alkyl, and aryl, where the alkyl is optionally substituted with a six-membered heteroaliphatic ring, and where the six-membered ring is optionally substituted at one or more positions with substituents selected from the group consisting of alkyl, alkoxy, halogen, trihalomethyl, NO₂, and (CH₂)_nCO₂R;

b) measuring the activity of VEGF, FGF, or PDGF; and

c) comparing said activity of VEGF, FGF, or PDGF to cells that have not been contacted with one more compounds of formula I.