Non-peptidic cyclophilin binding compounds and their use

• US 6,677,376 B1
• Filed: 09/07/2000
• Issued: 01/13/2004
• Est. Priority Date: 09/08/1999
• Status: Expired due to Fees

• Current Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Original Assignee: Guilford Pharmaceuticals Inc. (M G I Pharma Incorporated)
• Inventors: Steiner, Joseph P., Hamilton, Gregory S., Wei, Ling, Choi, Chi, Vaal, Mark J.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US09/656,898
• Time in Patent Office: 1,223 Days
• Field of Search: 564/86, 514/603, 514/9, 514/11, 514/19, 514/604, 514/605, 514/616, 514/619, 514/621, 514/622, 514/626, 514/629, 514/688, 514/689, 514/718, 514/731, 530/317
• US Class Current: 514/603
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 275/30 being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 323/62 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Abstract

The invention relates to non-peptidic compounds that possess bioactive properties, such as the ability to protect neuronal cells from otherwise lethal treatments or the ability to promote the growth or regeneration of neuronal cells. In part, the invention provides compounds that interact with or bind to a cyclophilin and compounds that have activity towards neuronal cells. Methods for using the compounds, such as administering them to cells or animals or using them to treat neurodegenerative conditions, are specifically included.

Claims

1. A complex comprising a compound of Formula II and a cyclophilin, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

2. The complex of claim 1 wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

3. The complex of claim 1, wherein the cyclophilin is a human cyclophilin.

4. The complex of claim 2, wherein the cyclophilin is a human cyclophilin.

5. A method of using a compound to bind a cyclophilin-type immunophilin protein, comprising contacting the compound with a cyclophilin, wherein the compound has the following formula:

Formula II

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each R may independently be

hydrogen, Q, or a C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

6. The method of claim 5, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

7. The method of claim 5, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

8. The method of claim 7, wherein the compound inhibits cyclophilin rotamase activity with an IC₅₀ of 1 μ

M or less.

9. The method of claim 5, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

10. The method of claim 7, wherein the compound inhibits FKBP rotamase activity with an IC₅₀ of 10 μ

M or more.

11. The method of claim 5, wherein contacting the compound with a cyclophilin occurs in vivo.

12. The method of claim 7, wherein contacting the compound with a cyclophilin occurs in vivo.

13. The method of claim 5, wherein contacting the compound with a cyclophilin occurs within a cell.

14. The method of claim 7, wherein contacting the compound with a cyclophilin occurs within a cell.

15. The method of claim 5, wherein the cyclophilin is a human cyclophilin.

16. The method of claim 7, wherein the cyclophilin is a human cyclophilin.

17. The method of claim 5, wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.

18. The method of claim 7, wherein contacting the compound with a cyclophilin occurs after administering the compound to an animal.

19. The method of claim 17, wherein the animal is human.

20. The method of claim 18, wherein the animal is human.

21. The method of claim 19, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

22. The method of claim 20, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

23. The method of claim 19, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy, diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

24. The method of claim 20, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy, diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

25. A method of using a compound of Formula II to treat or prevent a neurological disorder in an animal, comprising administering a pharmaceutically effective amount of the compound to the animal, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

26. The method of claim 25, wherein each R of R⁴ and R⁵ in said compound of Formula II may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

27. The method of claim 25, wherein the animal is human.

28. The method of claim 26, wherein the animal is human.

29. The method of claim 27, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

30. The method of claim 28, wherein the human is diagnosed with, is predisposed to, or is suspected of having a neurodegenerative condition, a neuropathic condition, or a peripheral neuropathy.

31. The method of claim 27, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy, diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

32. The method of claim 28, wherein the human has Parkinson'"'"'s disease, Alzheimer'"'"'s disease, ALS, memory loss, hair loss, hearing loss, vision loss, stroke, peripheral neuropathy, diabetic neuropathy, mitochondrial disorder, viral infection, traumatic brain injury, or a spinal cord injury.

33. A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

34. A method of preventing a neurodegenerative condition comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

35. A method of protecting nerves from damage comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

36. A method of protecting nerves from damage comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

37. A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight alkyl or alkenyl chain, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, or carbonyl oxygen, and where in said alkyl or alkenyl chain one or more carbon atoms are either optionally substituted with Q, or optionally replaced by O, S, SO, SO₂, N, or NH;

where Q, which is optionally saturated, partially saturated, or aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to five positions with halo, hydroxyl, nitro, trifluoromethyl, acetyl, aminocarbonyl, methylsulfonyl, oxo, cyano, carboxy, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.

38. A method of stimulating the growth of or regenerating damaged nerves comprising administering to an animal an effective amount of a composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, diluent, or excipient, wherein Formula II is

where R⁴ and R⁵ may independently be

—

N—

SO₂—

R,

—

SO₂—

NRR,

—

O—

R,

—

CO—

N—

R,

—

N—

CO—

R,

—

CO—

R,

wherein each of R may independently be

hydrogen, Q, or C1-C6 branched or straight chain alkyl or alkenyl, which may be substituted in one or more positions by C3-C8 cycloalkyl or cycloalkenyl, hydroxyl, carbonyl oxygen, or Q;

where Q, which is optionally aromatic, is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein each ring may be optionally substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, C1-C4 alkoxy, C1-C4 alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, and wherein the individual ring sizes are 5-6 members, and wherein each heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, or a combination thereof.