Compounds, compositions, and methods for stimulating neuronal growth and elongation

• US 6,544,987 B2
• Filed: 12/01/2000
• Issued: 04/08/2003
• Est. Priority Date: 12/01/1999
• Status: Expired due to Fees

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc.
• Inventors: Guo, Chuangxing, Dong, Liming, Villafranca, Jesus Ernest, Hou, Xinjun J., Vanderpool, Darin
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/726,314
• Publication Number:
  US 20020061881A1
• Time in Patent Office: 858 Days
• Field of Search: 514/227.5, 514/227.8, 514/231.2, 514/231.5, 514/316, 514/317, 514/318, 514/319, 544/59, 544/60, 544/106, 544/111, 546/192, 546/193, 546/195
• US Class Current: 514/231.5
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 207/48 Sulfur atoms
• CPC Class Codes: C07D 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 279/12 not condensed with other rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention concerns methods, pharmaceutical compounds, and compositions for stimulating neuroite outgrowth in nerve cells leading to nerve regeneration. These methods, compounds and compositions inhibit rotamase enzyme activity associated with binding proteins.

Claims

1. A compound of formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein;

A is C₃-C₅ alkylene optionally substituted with one or more suitable substituents excluding 6-membered fused aryl groups and optionally any one of the CH₂ groups of the alkylene group may be replaced by O, S, SO or SO₂;

B is

 

where E and G are independently Ar, H, C₁-C₆ straight or branched alkyl, C₁-C₆ straight or branched alkenyl, C₁-C₆ straight or branched alkyl or alkenyl that is substituted with a C₅-C₇ cycloalkyl, C₁-C₆ straight or branched alkyl or alkenyl that is substituted with a C₅-C₇ cycloalkenyl, or Ar substituted with C₁-C₆ straight or branched alkyl or alkenyl, wherein, in each case, one or two of the CH₂ groups of the alkyl or alkenyl chains may be replaced by 1-2 moieties selected from

the group consisting of oxygen, sulfur, SO, SO₂, and

 

where J is H, C₁-C₆ straight or branched alkyl, or C₁-C₆ straight or branched alkenyl; and

K is Ar or substituted 5-7 membered cycloalkyl with substituents at positions 3 and 4 which are independently selected from the group consisting of H, OH, —

O—

(CH₂)_m-alkyl, —

O—

(CH₂)_m-alkenyl and carbonyl, wherein m is 1-4;

where Ar is selected from the group consisting of unsubstituted and substituted phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and monocyclic and bicyclic heterocyclic ring systems with each ring having 5 or 6 ring atoms optionally, 1-4 heteroatoms independently selected from O, N and S;

wherein when substituted, the substituents are from one to three substituents independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C₁-C₆ straight or branched alkyl, C₂-C₆ straight or branched alkenyl, O—

(C₁-C₄ straight or

branched alkyl), O—

(C₂-C₄ straight or branched alkenyl), O-benzyl,

O-phenyl, 1,2-methylenedioxy, amino, carboxyl and phenyl; and

n is an integer from 0 to 4;

D is C₁-C₆ straight or branched alkyl, C₁-C₆ straight or branched alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with C₁-C₄ straight or branched alkyl or C₁-C₄ straight or branched alkenyl, [(C₂-C₄)-alkyl or (C₂-C₄)-alkenyl)]-Ar, or Ar excluding benzyl; and

X is NR¹⁰ or O, where R¹⁰ is H, C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy.

2. A compound as claimed in claim 1, where:

A is selected from an unbranched C₃-C₅ alkylene group wherein any one of the CH₂ groups of the alkylene groups is optionally substituted by S;

Bis

 

wherein E is selected from H, benzyl, 3-pyridyl, 2-phenylethyl and 3-phenylpropyl;

G is selected from phenyl, 3-pyridyl, 3-phenylpropyl, 3-phenoxyphenyl and 4-phenoxyphenyl; and

n is 0-4;

D is selected from phenyl, 4-methylphenyl, 4-methoxyphenyl, 2-thienyl, 2,4,6-triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino)-naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, 4-nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, 1,1-dimethylpropyl and E-styrenyl; and

X is selected from NH and O.

6. A pharmaceutical composition for treating a neurological disorder in a patient comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition according to claim 6, further comprising a neurotrophic factor.

8. A method of treating a neurological disorder in a patient, comprising:

administering to the patient a therapeutically effective amount of a compound as claimed in claim 1.

9. A method according to claim 8, wherein the neurological disorder is selected from the group consisting of neuralgias, muscular dystrophy, bell'"'"'s palsy, myasthenia gravis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries.

3. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

4. A compound of formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein;

J′ and

K′

taken together with the adjacent nitrogen atom form a heterocycle ring which may contain another heteroatom;

M is selected from the group consisting of —

OR₁,

R₁ is substituted or unsubstituted alkyl, alkenyl, aryl excluding benzyl, cycloalkyl, heteroaryl, heterocycloalkyl, or cycloalkenyl, or C(R¹¹)(R¹²)(R¹³), wherein R¹¹ and R¹² each independently is substituted or unsubstituted alkyl, or R¹¹ and R¹² together with the atom to which they are bound form a cycloalkyl, and R¹³ is H, OH, substituted or unsubstituted alkyl, aryl, heteroaryl, heterocycloalkyl, or (CH₂)_n—

O—

W¹, where n is 0, 1, 2, or 3, W¹ is R² or C(O)R², and R² is subs or unsubstituted alkyl;

R′

is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, hydroxyl, and amino;

or

R₁ and R′

taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle;

R″

is hydrogen or substituted or unsubstituted alkyl;

or

R₁ and R″

taken together with the adjacent nitrogen atom form a substituted or unsubstituted heterocycle;

L′

is

 

wherein X′

is selected from the group consisting of S, O and N;

Y′

is selected from O, NH, S, a direct bond, and NR_f, wherein R_f is substituted or unsubstituted alkyl;

or

X′ and

Y′

taken together with the adjacent carbon atom form a heterocycle ring;

B′

is

 

where n is an integer from 0 to 4;

E′

a G′

H are independently, substituted or unsubstituted alkyl, aryl, heteroaryl, heterocycloalkyl, alkenyl, cycloalkyl, or cycloalkenyl, wherein, in each case, one or two of the CH₂ groups of the alkyl or alkenyl chains may be replaced by 1-2 moieties selected from the group consisting of oxygen, sulfur, SO and SO₂, or

 

where Q′

is H, or substituted or unsubstituted alkyl or alkenyl; and

Q is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R_a and R_b are independently hydrogen, substituted or unsubstituted alkyl or cycloalkyl;

Z is O, NH, CH₂ or NR_e, wherein R_e is substituted or unsubstituted alkyl; and

R_c and R_d are independently hydrogen,

wherein E′

, G′

, Q′

, Q, and n are as defined above.

10. A pharmaceutical composition for treating a neurological disorder in a patient comprising a therapeutically effective amount of a compound as claimed in claim 4 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition according to claim 10, further comprising a neurotrophic factor.

12. A method of treating a neurological disorder in a patient, comprising:

administering to the patient a therapeutically effective amount of a compound as claimed in claim 4.

13. A method according to claim 12, wherein the neurological disorder is selected from the group consisting of neuralgias, muscular dystrophy, bell'"'"'s palsy, myasthenia gravis, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, multiple sclerosis, ALS, stroke and ischemia associated with stroke, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries.

5. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

14. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, prodrug, or pharmaceutically active metabolite thereof.

15. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.