Substituted oxindoles

• US 5,502,072 A
• Filed: 11/26/1993
• Issued: 03/26/1996
• Est. Priority Date: 11/26/1993
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Masamune, Hiroko
• Primary Examiner(s): Haley, Jacqueline
• Application Number:
  US08/164,973
• Time in Patent Office: 851 Days
• Field of Search: 548/486, 514/418, 514/300, 546/113
• US Class Current: 514/418
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

The present invention relates to novel substituted oxindoles of the formula I as defined below and related compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds as inhibitors of phosphodiesterase ("PDE") type IV. The compounds of this invention are useful in the treatment of AIDS, asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic, dermatitis, shock, other inflammatory diseases, and other conditions where the action of phosphodiesterase type IV is implicated.

Claims

1. A compound of the formula:

##STR23## wherein X is N or CR⁴ ;

R¹ is (C₁ -C₄)alkyl or phenyl-(C₁ -C₆)alkyl;

R² is (C₁ -C₁₀)alkyl, phenyl-(C₁ -C₆)alkyl, (C₃ -C₇) cycloalkyl, or (C₆ -C₁₂) polycycloalkyl;

or R¹ and R², taken together with the oxygens to which they are attached, represent a methylene or ethylene bridge which forms a 5 or 6 membered ring;

R³ is hydrogen, (C₁ -C₆)alkyl, (C₁ -C₆)alkyloxycarbonyl, (C₁ -C₆)alkyloxy, (C₁ -C₆) alkoxycarbonyl-(C₁ -C₆)alkyl, --CONR¹⁰ R¹¹ ;

or -(C₁ -C₆)alkyl-CONR¹⁰ R¹¹ ;

R¹⁰ and R¹¹ are independently selected from hydrogen and (C₁ -C₆)alkyl, or R¹⁰ and R¹¹, taken together with the nitrogen to which they are attached, form a pyrrolidine or piperidine ring;

R⁴, R⁵, R⁶ and R⁷ are independently selected from hydrogen, halogen, (C₁ -C₈) alkoxy, (C₃ -C₇) cycloalkyloxy, hydroxy, (C₂ -C₆) acyloxy, nitro, NR⁸ R¹², SO₂ NR⁸ R¹², (C₁ -C₆)alkyl, (C₁ -C₆) alkylcarbonyl, phenyl-(C₁ -C₆)alkoxy, and (C₆ -C₁₂) polycycloalkoxy or any combination of R⁴ and R⁵, R⁵ and R⁶, or R⁶ and R⁷ which together form --OCH₂ O-- or --OCH₂ CH₂ O--, such that, when taken together with the carbons to which they are attached, they form, respectively, a 5- or 6-membered ring;

R⁸ and R¹² are independently selected from hydrogen and (C₁ -C₆)alkyl, or R⁸ and R¹², taken together with the nitrogen to which they are attached, form a pyrrolidine or piperidine ring;

R⁹ is hydrogen or (C₁ -C₆)alkyl;

the broken line represents an optional double bond; and

the wavy lines indicate that the compounds exist as (E) and/or (Z) stereoisomers when the broken line is a double bond;

with the proviso that (a) if R¹ and R² are both methyl, X is CH, R⁹ is hydrogen, and the broken line is a double bond, then (i) at least one of R³, R⁵, R⁶, and R⁷ is other than hydrogen;

(ii) at least one of R⁵, R⁶ and R⁷ is other than hydrogen or R³ is other than methyl; and

(iii) at least one of R³ and R⁷ is other than hydrogen or at least one of R⁵ and R⁶ is other than O--CH₃ ;

(b) if R³ is hydrogen, R⁹ is hydrogen, X is CH, the broken line is a double bond, and R¹ and R² together represent a methylene bridge, then at least one of R⁵, R⁶ and R⁷ is other than hydrogen; and

(c) if R¹ and R² are both methyl, X is CH, R⁹ is hydrogen, and the broken line is a single bond, then at least one of R⁵ and R⁶ is other than O--CH₃, or R⁷ is other than hydrogen, or R³ is other than COCH₃ ;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein:

R¹ is methyl or ethyl and R² is (C₁ -C₆)alkyl, phenyl-(C₁ -C₆)alkyl, (C₃ -C₇) cycloalkyl, or (C₆ -C₁₂) polycycloalkyl;

or

R¹ and R², taken together with the oxygens to which they are attached, represent a methylene or ethylene bridge which forms a 5 or 6 membered ring.

3. A compound according to claim 1 wherein X is CH or N, R¹ is methyl, R² is norbornyl, R³ is hydrogen, methyl, ethyl, --COOC₂ H₅, --CONH₂, methoxy or --CH₂ COOC₂ H₅, R⁶ is hydrogen, bromo, methoxy or chloro, and R⁵ is hydrogen, hydroxy, cyclopentyloxy, methoxy, bromo, chloro, amino, or --SO₂ NH₂, or R⁵ and R⁶ together form --OCH₂ O--, R⁷ is hydrogen, and R⁹ is hydrogen or methyl.

4. A compound according to claim 1 selected from the group consisting of:

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-1,3-dihydro-1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-1,3-dihydro-1-ethyl- 1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-1,3-dihydro-1-methyl- 1α

,2α

(Z),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-1,3-dihydro-1-ethyl- 1α

,2α

(Z),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-6-chloro-1,3-dihydro-1-methoxy- 1α

,2α

(Z),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-6-chloro-1,3-dihydro- 1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-bromo-1,3-dihydro- 1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-bromo-1,3-dihydro-1-methyl- 1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-chloro-1,3-dihydro-1-methyl- 1α

,2α

(Z),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-5-cyclopentyloxy-1,3-dihydro-1-ethyl- 1α

,2α

(E),4α

!-2H-indol-2-one;

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-6-methoxy-1,3-dihydro-1-methyl 1α

,2α

(E),4α

!-2H-indol-2-one; and

3- 3-(Bicyclo 2.2.1!hept-2-yloxy)-4-methoxyphenyl!methylene!-2,3-dihydro-N,N-dimethyl-2-oxo- 1α

,2α

(E),4α

!-1H-indole-5-sulfonamide.

5. A pharmaceutical composition for inhibiting the effects of phosphodiesterase type IV in a mammal, including a human, comprising a phosphodiesterase type IV inhibiting amount of a compound of claim 1, and a pharmaceutically acceptable carrier.

6. A method of inhibiting the effects of phosphodiesterase type IV in a mammal, including a human, comprising administering to said mammal a phosphodiesterase type IV inhibiting amount of a compound of claim 1.

7. A pharmaceutical composition for treating a condition selected from the group consisting of asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases in a mammal, including a human, comprising an amount of a compound of claim 1, effective in inhibiting the action of phosphodiesterase type IV, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition for treating a disorder in a mammal, including a human, the treatment of which is effected or facilitated by blocking the action of phosphodiesterase type IV, comprising an amount of a compound of claim 1, effective in treating such disorder, and a pharmaceutically acceptable carrier.

9. A method of treating a disorder in a mammal, including a human, the treatment of which is effected or facilitated by blocking the action of phosphodiesterase type IV, comprising administering to said mammal an amount of a compound of claim 1, effective in treating such a disorder.