Phosphorus-containing compounds and uses thereof

• US 7,091,213 B2
• Filed: 06/04/2004
• Issued: 08/15/2006
• Est. Priority Date: 02/01/2002
• Status: Active Grant

• Current Assignee: Medinol Limited (Medinol USA Incorporated)
• Original Assignee: ARIAD Gene Therapeutics, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Metcalf, lll, Chester A., Wang, Yihan, Berstein, David L., Rozamus, Leonard W.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US10/862,149
• Publication Number:
  US 20050032825A1
• Time in Patent Office: 802 Days
• Field of Search: 540/456, 514/291
• US Class Current: 514/291
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 27/02 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

This invention concerns a new family of phosphorus-containing compounds containing a moiety JQA- in which:

• A is absent or is —O—, —S— or —NR²—;
• Q is absent or (if A is —O—, —S— or —NR²—) Q may be —V—, —OV—, —SV—, or —NR²V—, where V is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, such that J is linked to the cyclohexyl ring directly, through A or through VA, OVA, SVA or NR²VA;

• • K is O or S;
  • each occurrence of Y is independently —O—, —S—, —NR²—, or a bond linking a R⁵ moiety to P;
  • each occurrence of R² and R⁵ is independently an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or H; and
  • each occurrence of R⁶ is independently —PK(YR⁵)(YR⁵), —SO₂(YR⁵) or —C(O)(YR⁵); so long as any R², or R⁵ moiety linked directly to P is not H;
  • wherein two R², R⁵ and/or R⁶ moieties may be chemically linked to one another to form a ring;
  • each occurrence of G is independently —O—, —S—, —NR²— or (M)_x;
  • each occurrence of M is independently a substituted or unsubstituted methylene moiety, and any M-M′ moiety may be saturated or unsaturated;
  • each occurrence of x is independently an integer from 1–6; and the other variables are as defined herein.

Claims

1. A compound of the formula:

5. The compound of claim 1 in which each occurrence of R² and R⁵ is an independently chosen C1–

C6 alkyl group optionally bearing one or more halo, —

OH, alkoxyl-, alkyloxyalkyloxy-, haloalkyl-, hydroxyalkoxyl-, hetrocyclic, aryl or heteroaryl substituents, except that in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

9. The compound of claim 5 in which each occurrence of R² and R⁵ is independently chosen from methyl, ethyl, n-propyl, -i-propyl, n-butyl, 2-butyl, t-butyl, phenyl, or heteroaryl, each of which optionally bearing one or more halo, —

OH, alkoxyl-, alkoxylalkoxyl-, haloalkyl-, hydroxyalkoxyl-, heterocyclic, aryl or heteroaryl substituents, and in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

13. The compound of claim 1 wherein J is chosen from the following:

14. The compound of claim 1 in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

16. The compound of claim 5 in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

18. The compound of claim 9 in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

19. The compound of claim 13 which comprises a moiety JQA- in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

20. The compound of any of claims 1–

19 in which JQA- or JA- comprises (R²Y)(Me)(P═

O)O—

in which R²Y contains 15 or fewer carbon atoms.

21. The compound of claim 20 in which JQA- comprises (R²Y)(Me)(P═

O)O—

in which R²Y—

contains 10 or fewer carbon atoms.

30. A composition comprising (a) a compound of any of claims 1 through 19, 22 through 25, or 27 through 29, and (b) a pharmaceutically acceptable vehicle, optionally containing (c) one or more pharmaceutically acceptable excipients.

31. A composition suitable for oral administration to a mammal, the composition comprising (a) a compound of any of claims 1 through 19, 22 through 25, or 27 through 29, and (b) a pharmaceutically acceptable vehicle, optionally containing (c) one or more pharmaceutically acceptable excipients.

32. A composition suitable for parenteral administration to a mammal, the composition comprising (a) a compound of any of claims 1 through 19, 22 through 25, or 27 through 29, and (b) a pharmaceutically acceptable vehicle, optionally containing (c) one or more pharmaceutically acceptable excipients.

33. A method for suppressing the immune response of a subject by administering to the subject an immunosuppressive amount of a composition of claim 30.

34. A method for treating or suppressing the rejection of transplanted tissues in a recipient, which method comprises administering to said recipient an effective amount of a composition of claim 30.

35. A method for treating graft vs. host disease, lupus, rheumatoid arthritis, diabetes mellitus, myasthenia gravis, multiple sclerosis, psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel disease, pulmonary inflammation, ocular uveitis;

adult T-cell leukemia/lymphoma;

fungal infections;

hyperproliferative restenosis;

graft vascular atherosclerosis;

cerebral vascular disease, coronary artery disease, cerebrovascular disease, arteriosclerosis, atherosclerosis, nonatheromatous arteriosclerosis, or vascular wall damage from cellular events leading toward immune mediated vascular damage, stroke or multiinfarct dementia in a subject in need thereof, which method comprises administering to said subject a therapeutically effective amount of a composition of claim 30.

36. A method for treating cancer in a subject in need thereof, which comprises administering to the subject a treatment effective amount of a composition of claim 30, wherein said cancer is selected from glioblastoma;

cancer of the prostate, breast, pancreas, lung or colon;

bone sarcoma, soft tissue sarcoma, lymphoma or a leukemia.

2. A compound of the formula:

6. The compound of claim 2 in which each occurrence of R² and R⁵ is an independently chosen C1–

C6 alkyl group optionally bearing one or more halo, —

OH, alkoxyl-, alkyloxyalkyloxy-, haloalkyl-, hydroxyalkoxyl-, hetrocyclic, aryl or heteroaryl substituents, except that in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

10. The compound of claim 6 in which each occurrence of R² and R⁵ is independently chosen from methyl, ethyl, n-propyl, -i-propyl, n-butyl, 2-butyl, t-butyl, phenyl, or heteroaryl, each of which optionally bearing one or more halo, —

OH, alkoxyl-, alkoxylalkoxyl-, haloalkyl-, hydroxyalkoxyl-, heterocyclic, aryl or heteroaryl substituents, and in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

3. A compound of the formula:

7. The compound of claim 3 in which each occurrence of R² and R⁵ is an independently chosen C1–

C6 alkyl group optionally bearing one or more halo, —

OH, alkoxyl-, alkyloxyalkyloxy-, haloalkyl-, hydroxyalkoxyl-, hetrocyclic, aryl or heteroaryl substituents, except that in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

11. The compound of claim 7 in which each occurrence of R² and R⁵ is independently chosen from methyl, ethyl, n-propyl, -i-propyl, n-butyl, 2-butyl, t-butyl, phenyl, or heteroaryl, each of which optionally bearing one or more halo, —

OH, alkoxyl-, alkoxylalkoxyl-, haloalkyl-, hydroxyalkoxyl-, heterocyclic, aryl or heteroaryl substituents, and in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

4. A compound of the formula:

8. The compound of claim 4 in which each occurrence of R² and R⁵ is an independently chosen C1–

C6 alkyl group optionally bearing one or more halo, —

OH, alkoxyl-, alkyloxyalkyloxy-, haloalkyl-, hydroxyalkoxyl-, hetrocyclic, aryl or heteroaryl substituents, except that in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

12. The compound of claim 8 in which each occurrence of R² and R⁵ is independently chosen from methyl, ethyl, n-propyl, -i-propyl, n-butyl, 2-butyl, t-butyl, phenyl, or heteroaryl, each of which optionally bearing one or more halo, —

OH, alkoxyl-, alkoxylalkoxyl-, haloalkyl-, hydroxyalkoxyl-, heterocyclic, aryl or heteroaryl substituents, and in addition, —

OR⁵ and —

NR²R⁵, may be —

OH and —

NHR⁵, respectively.

15. The compound of claim 4 in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

17. The compound of claim 8 in which QA is —

O—

, —

OVO—

, —

NH—

, —

OVNH—

, —

S—

, or —

SVS—

, where V is a lower aliphatic moiety.

22. A rapamycin or 43-epi-rapamycin in which the hydroxyl group at position 43 is replaced by a group JQA-, wherein:

A is —

O—

, —

S—

or —

NR²—

or is absent;

Q is absent or (if A is —

O—

, —

S—

or —

NR²—

) Q may be —

V—

, —

OV—

, —

SV—

, or —

NR²V—

, where V is an unsubstituted aliphatic or heteroaliphatic, an aryl, or a 5–

14 membered heteroaryl moiety having 1–

4 heteroatoms selected from nitrogen, oxygen, or sulfur, such that J is linked to the cyclohexyl ring directly, through A or through VA, OVA, SVA or NR²VA;

23. The compound of claim 22 in which each occurrence of R² and R⁵ is an independently chosen C1–

C6 alkyl group optionally bearing one or more halo, —

OH, alkoxyl-, alkyloxyalkyloxy-, haloalkyl-, hydroxyalkoxyl-, hetrocyclic, aryl or heteroaryl substituents, except that in addition, —

OR⁵ and —

NR²R⁵ may be —

OH and —

NHR⁵, respectively.

24. The compound of claim 23 in which each occurrence of R² and R⁵ is independently chosen from methyl, ethyl, n-propyl, -i-propyl, n-butyl, 2-butyl, t-butyl, phenyl, or heteroaryl, each of which optionally bearing one or more halo, —

OH, alkoxyl-, alkoxylalkoxyl-, haloalkyl-, hydroxyalkoxyl-, heterocyclic, aryl or heteroaryl substituents, and in addition, —

OR⁵ and —

NR²R⁵ may be —

OH and —

NHR⁵, respectively.

25. The compound of claim 22 in which QA is —

OVO—

, —

OVNH—

or —

SVS—

, where V is a lower aliphatic moiety.

26. The compound of any of claims 22–

25 wherein J is chosen from the following;

27. A compound of the formula:

28. A compound of the formula

29. The compound of claim 28 in which J is —

P(O)Me₂, —

P(O)Et₂, or —

P(O)Ph₂.