Selected fused pyrrolocarbazoles

• US 6,630,500 B2
• Filed: 08/22/2001
• Issued: 10/07/2003
• Est. Priority Date: 08/25/2000
• Status: Expired due to Term

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Hudkins, Robert L., Gingrich, Diane E.
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): SMALL, ANDREA D SOUZA
• Application Number:
  US09/935,285
• Publication Number:
  US 20020061920A1
• Time in Patent Office: 776 Days
• Field of Search: 548/417, 514/410
• US Class Current: 514/410
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• 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 9/08 : Vasodilators for multiple indications
• 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 487/04 : Ortho-condensed systems

Abstract

The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

Claims

1. Compounds of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

—

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH, —

CH₂OCH₂CH₃, or —

CH₂SCH₂CH₃.

3. The compounds of claims 1 or 2 wherein:

R¹ is an alkyl of 1-4 carbons, substituted with —

OH or —

OR⁴ where R⁴ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

R² is H; and

R³ is alkyl of 1-4 carbons, substituted with —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons; and

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed.

4. The compounds of claims 1 or 2 wherein:

R¹ is —

CH₂CH₂CH₂OH or —

CH₂CH₂CH₂OCOCH₂N(CH₃)₂;

R² is H; and

R³ is —

CH₂OR⁷ wherein R⁷ is alkyl of 1-4 carbons.

5. The compounds of claims 1 or 2 represented in Table I:

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or carrier.

2. Compounds of Formula II:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

—

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH, —

CH₂OCH₂CH₃, or —

CH₂SCH₂CH₃.

16. The compound of claim 2 wherein R¹ is (CH₂)₃OH, R² is H, and R³ is CH₂OCH(CH₃)₂.

17. The compound of claim 2 wherein R¹ is (CH₂)₃OCOCH₂N(CH₃)₂, R² is H, and R³ CH₂OCH(CH₃)₂.

18. A pharmaceutical composition comprising a compound of claim 16 and a pharmaceutically acceptable excipient or carrier.

19. A pharmaceutical composition comprising a compound of claim 17 and a pharmaceutically acceptable excipient or carrier.

20. A method for treating prostate disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.

21. A method for treating prostate disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 17.

22. The method of claim 20 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

23. The method of claim 21 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

24. A method for treating angiogenic disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.

25. A method for treating angiogenic disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 17.

26. The method of claim 24 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

27. The method of claim 25 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

28. A method for treating pathological disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.

29. A method for treating pathological disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 17.

30. The method of claim 28 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

31. The method of claim 29 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

32. A method for treating neurodegenerative diseases and disorders, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, stroke, ischaemia, Huntington'"'"'s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.

33. A method for treating neurodegenerative diseases and disorders, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, stroke, ischaemia, Huntington'"'"'s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 17.

34. A method for creating multiple myeloma and leukemias which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.

35. A method for treating multiple myeloma and leukemias which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 17.

36. The method of claim 34 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia or chronic lymphocytic leukemia.

37. The method of claim 35 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.

7. A method for treating prostate disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵, —

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1—

4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH,

alkyl of 1-8 carbons substituted with —

OH or —

SR⁶, wherein R⁶ is alkyl of 1-4 carbons;

—

(CH₂)_nSR⁵, wherein n is 1 and R⁵ is alkyl of 1-4 carbons;

or —

CH₂SR⁵, wherein R⁵ is alkyl of 1-4 carbons.

8. The method of claim 7 wherein the prostate disorder is prostate cancer or benign prostate hyperplasia.

9. A method for treating angiogenic disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

—

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH,

alkyl of 1-8 carbons substituted with —

OH or —

SR⁶, wherein R⁶ is alkyl of 1-4 carbons;

—

(CH₂)_nSR⁵, wherein n is 1 and R⁵ is alkyl of 1-4 carbons;

or —

CH₂SR⁵, wherein R⁵ is alkyl of 1-4 carbons.

10. The method of claim 9 wherein the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma.

11. A method for treating pathological disorders which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

—

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH,

alkyl of 1-8 carbons substituted with —

OH or —

SR⁶, wherein R⁶ is alkyl of 1-4 carbons;

—

(CH₂)_nSR⁵, wherein n is 1 and R⁵ is alkyl of 1-4 carbons;

or —

CH₂SR⁵, wherein R⁵ is alkyl of 1-4 carbons.

12. The method of claim 11 wherein the pathological disorder is neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.

13. A method for treating neurodegenerative diseases and disorders, Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, Parkinson'"'"'s disease, stroke, ischaemia, Huntington'"'"'s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy induced peripheral neuropathy, AID related peripheral neuropathy or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

—

(CH₂)_nS(O)_yR⁵;

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)yR⁶ or —

SR⁶; and

wherein

R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH,

alkyl of 1-8 carbons substituted with —

OH or —

SR⁶, wherein R⁶ is alkyl of 1-4 carbons;

—

(CH₂)_nSR⁵, wherein n is 1 and R⁵ is alkyl of 1-4 carbons;

or —

CH₂SR⁵, wherein R⁵ is alkyl of 1-4 carbons.

14. A method for treating multiple myeloma and leukemias which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula I:

wherein;

R¹ and R² are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR⁴ where R⁴ is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R³ is —

CH₂OH;

—

CH₂OR⁷;

—

(CH₂)_nSR⁵;

(CH₂)_nS(O)_yR⁵;

—

CH₂SR⁵;

or alkyl of 1-8 carbons substituted with —

OH, —

OR⁵, —

OR⁸, —

CH₂OR⁷, —

S(O)_yR⁶ or —

SR⁶; and

wherein R⁵ is alkyl of 1-4 carbons or aryl;

R⁶ is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R⁷ is H or alkyl of 1-4 carbons;

R⁸ is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R¹ is (CH₂)₃OH and R² is H, then R³ cannot be —

CH₂OH,

alkyl of 1-8 carbons substituted with —

OH or —

SR⁶, wherein R⁶ is alkyl of 1-4 carbons;

—

(CH₂)_nSR⁵, wherein n is 1 and R⁵ is alkyl of 1-4 carbons;

or —

CH₂SR⁵, wherein R⁵ is alkyl of 1-4 carbons.

15. The method of claim 14 wherein the leukemia is acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, or chronic lymphocytic leukemia.