Therapeutic compounds and methods

• US 6,710,075 B2
• Filed: 11/08/2002
• Issued: 03/23/2004
• Est. Priority Date: 07/05/2000
• Status: Expired due to Term

• Current Assignee: The Government of The State of Sarawak Malaysia
• Original Assignee: The Government of The State of Sarawak Malaysia
• Inventors: Yu, Jin, Meurer-Grimes, Barbara Martha, Vairo, Gino Luigi
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US10/291,863
• Publication Number:
  US 20030181514A1
• Time in Patent Office: 501 Days
• Field of Search: 514/452, 514/468, 549/379, 549/458
• US Class Current: 514/452
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 319/12 not condensed with other rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides compounds having a cyclopentabenzofuran core and the use of such compounds in therapy as well as compositions comprising said compounds.

Claims

1. A compound of Formula (I):

wherein;

each R⁴-R¹⁰ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;

X is OR⁸ or NR⁹R¹⁰;

R¹¹ and R¹² are each independently hydrogen or, OR⁴ and R¹¹, and/or OR⁵ and R¹² together form a methylenedioxy group; and

Y is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted CH₂-(C₃-C₈ cycloalkyl), optionally substituted 5-6 membered heterocyclyl and optionally substituted CH₂-(5-6 membered heterocyclyl);

or a salt, isomer or prodrug thereof.

2. The compound according to claim 1 wherein R⁴ and Y are independently selected from the group consisting of optionally substituted C₃-C₈ cycloalkyl, optionally substituted benzoyl, optionally substituted benzyl, optionally substituted CH₂-(C₃-C₈ cycloalkyl) and C-1 linked saccharide.

3. The compound according to claim 1 wherein the optionally substituted C₃-C₈ cycloalkyl group is optionally substituted C₅-C₆-cycloalkyl and the optionally substituted CH₂-(C₃-C₈ cycloalkyl) group is optionally substituted CH₂-(C₅-C₆ cycloalkyl).

4. The compound according to claim 1 wherein Y is an optionally substituted 5-6 membered heterocyclyl group or an optionally substituted C₅-C₆ cycloalkyl group.

5. The compound according to claim 4 having Formula (i)

or isomer thereof,

wherein:

each R¹-R¹⁰ is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;

X is OR⁸ or NR⁹R¹⁰, and

R¹¹ and R¹² are each independently hydrogen or OR⁴ and R¹¹, and/or OR⁵ and R¹² together form a methylenedioxy group.

6. The compound according to claim 1 or 5 wherein R⁸ is selected from the group consisting of hydrogen, C_1-6 alkyl, phenyl, benzyl and C-1 linked saccharide.

7. The compound according to claim 1 or 5 wherein R⁹ and R¹⁰ are independently selected from the group consisting of hydrogen, C_1-6 alkyl, phenyl and benzyl.

8. The compound according to claim 1 or 5 wherein R¹¹ and R¹² are both hydrogen.

9. The compound according to claim 5 wherein each of R¹R⁷ are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, acetyl and C-1 linked saccharide.

10. The compound according to claim 5 wherein R¹ and R² are both hydrogen.

11. The compound according to claim 5 wherein R³ is methyl.

12. The compound according to claim 5 wherein at least one of R³-R⁵ is methyl, ethyl or propyl.

13. The compound according to claim 12 wherein at least one of R³-R⁵ is methyl.

14. The compound according to claim 12 wherein at least two of R³-R⁵ are methyl, ethyl or propyl.

15. The compound according to claim 14 wherein at least two of R³-R⁵ are methyl.

16. The compound according to claim 14 wherein all of R³-R⁵ are methyl, ethyl or propyl.

17. The compound according to claim 16 wherein all of R³-R⁵ are methyl.

18. The compound according to claim 1 or 5 wherein R⁶ and R⁷ are both hydrogen.

19. The compound according to claim 1 or 5 wherein X is OR⁸ and where R⁸ is selected from the group consisting of hydrogen, methyl, ethyl and propyl.

20. The compound according to claim 19 wherein R⁸ is methyl.

21. The compound according to claim 1 or 5 wherein X is NR⁹R¹⁰ where R⁹ and R¹⁰ are both hydrogen or methyl;

or R⁹ and R¹⁰ are different but at least one of R⁹ or R¹⁰ is hydrogen and the other is C_1-6 alkyl.

22. The compound according to claim 21 wherein C_1-6 alkyl is methyl, ethyl or propyl.

23. The compound according to claim 5 having Formula (ii):

or isomer thereof.

24. The isomer of the compound of claim 23 having the following NMR spectral characteristics:

¹H NMR (CDCl₃, ppm)

3.49, s, 3H;

3.56, dd, 11.7, 2 Hz, 1H;

3.61, m, 1H, 3.61, 2H;

3.65, s, 3H;

3.71, s, 3H;

3.87, s, 3H;

3.89, dd, 14.2, 6.7 Hz, 1H;

4.13, t, 11.2 Hz, 1H 4.23, brt, 11.3 Hz, 1H;

4.28, d, 14.2 Hz, 1H;

4.59, s, 1H;

5.03, d, 6.7 Hz, 1 Hz;

5.28, s, 1H;

6.28, d, 2 Hz, 1H;

6.43, d, 2 Hz, 1H;

6.68, brd, 9 Hz, 2H;

6.84, m, 2H;

7.06, m, 2H, 7.06, m, 1H;

7.10, brd, 9 Hz, 2H;

¹³C NMR (CDCl₃), (ppm)

50.03, 52.06, 55.03, 55.05, 55.1, 55.9, 59, 63.3, 68.3, 70.6, 79.6, 92.8, 93.4, 93.9, 94, 95.2, 101.9, 109.6, 112.7, 126.2, 126.6, 127.8, 127.8, 128.9, 136.7, 157.1, 158.8, 160, 160.6, 170.6.

25. The isomer of the compound of claim 23 having the following NMR spectral characteristics:

¹H NMR (CDCl₃, ppm)

3.5, s, 3H;

3.61, dd, 10.4, 4.4 Hz, 1H;

3.66, m, 1H;

3.66, s, 3H;

3.72, m;

3.72, s, 3H;

3.78, dd, 11.7, 2.4 Hz, 1H;

3.86, s, 3H;

3.9, dd, 14, 6.8 Hz, 1H;

4.02, t, 11.2 Hz, 1H;

4.12, ddd, 11, 6.8, 2-8 Hz, 1H;

4.28, d, 14 Hz, 1H;

4.60, S, 1H;

5.04, d, 6.8 Hz, 1 H;

5.26, S, 1H;

6.29, d, 2 Hz, 1H;

6.45, d, 2 Hz, 1H;

6.69, brd, 9 Hz, 2H;

6.86, m, 2H;

7.06, m, 2H;

7.06, m, 1H;

7.10, brd, 9 Hz, 2H;

¹³C NMR (CDCl₃), (ppm)

50, 52, 55, 55, 55, 55.8, 59.6, 62.5, 67.6, 71.4, 79.6, 92.8, 93.4, 94.3, 95.2, 101.8, 109.4, 112.8, 126.2, 126.6, 127.5, 127.5, 128.9, 136.6, 157.1, 158.8, 159.8, 160.2, 170.7.

26. A composition comprising a compound of claim 1 together with a pharmaceutically acceptable carrier excipient or diluent.

27. The composition according to claim 26 wherein the compound is of Formula (i) as defined in claim 5 or (ii) as defined in claim 23.

28. A method for the treatment of cancer or a cancerous condition wherein the cancer or cancerous condition is selected from the group consisting of leukemia, sarcoma, breast, colon, bladder, pancreatic, endometrial, head and neck, mesothelioma, myeloma, oesophagal/oral, testicular, thyroid, cervical, bone, renal, uterine, prostate, brain, lung, ovarian, skin, liver and bowel and stomach cancers, tumours and melanomas, comprising the administration of a treatment effective amount of a compound according to claim 1 to a subject in need thereof.

29. The method according to claim 28 wherein the compound is of Formula (i) as defined in claim 5 or (ii) as defined in claim 23.

30. A method for the treatment of a disease state or condition associated with cellular hyperproliferation wherein the disease state or condition is selected from the group consisting of atherosclerosis, restinosis, rheumatoid arthritis, osteoarthritis, inflammatory arthritis, psoriasis, periodontal disease and virally induced cellular hyperproliferation, comprising the administration of a treatment effective amount of a compound of claim 1 to a subject in need thereof.

31. The method according to claim 30 wherein the compound is of Formula (i) as defined in claim 5 or (ii) as defined in claim 23.

32. A composition comprising the isomer according to claim 24 or 25 together with a pharmaceutically acceptable carrier, excipient or diluent.

33. A method for the treatment of cancer or a cancerous condition wherein the cancer or cancerous condition is selected from the group consisting of leukemia, sarcoma, breast, colon, bladder, pancreatic, endometrial, head and neck, mesothelioma, myeloma, oesophagal/oral, testicular, thyroid, cervical, bone, renal, uterine, prostate, brain, lung, ovarian, skin, liver and bowel and stomach cancers, tumours and melanomas, comprising the administration of a treatment effective amount of the isomer according to claim 24 or 25 to a subject in need thereof.

34. A method for the treatment of a disease state or condition associated with cellular hyperproliferation wherein the disease state or condition is selected from the group consisting of atherosclerosis, restinosis, rheumatoid arthritis, osteoarthritis, inflammatory arthritis, psoriasis, peridontal disease and virally induced cellular hyperproliferation, comprising the administration of a treatment effective amount of the isomer a according to claim 24 or 25 to a subject in need thereof.