US2003013645A1PendingUtilityA1
Inhibitors of cyclophilin rotamase activity
Priority: Nov 20, 1995Filed: Jul 22, 2002Published: Jan 16, 2003
Est. expiryNov 20, 2015(expired)· nominal 20-yr term from priority
A61P 25/28A61P 25/16C12N 5/0619A61K 38/13A61P 25/00
49
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Claims
Abstract
This invention relates to the method of using neurotrophic cyclophilin inhibitor compounds having an affinity for cyclophilin-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a neurological activity in an animal, comprising:
administering to an animal an effective amount of an immunosuppressive cyclosporin represented by formula I: and pharmaceutically acceptable salts thereof wherein R 1 is MeBmt or [3-DesoxyMeBmt] or represented by formula III: wherein positions 2, 3, and 4 have the configurations S, R and R, respectively; wherein —X—Y— is connected by a double bond or a single bond; wherein:
R 2 is independently selected from the group consisting of Abu, Ala, Thr, Val, and norVal;
R 3 is Sar;
R 4 is MeLeu;
R 5 is Val;
R 6 is MeLeu;
R 7 is Ala;
R 8 is D-Ala;
R 9 is MeLeu;
R 10 is MeLeu; and,
R 11 is Val or [D-MeVal].
2 . The method of claim 1 wherein R 1 is [3-DesoxyMeBmt] for cyclosporin F.
3 . The method of claim 1 wherein R 2 is Abu for cyclosporin A.
4 . The method of claim 1 wherein R 2 is Ala for cyclosporin B.
5 . The method of claim 1 wherein R 2 is Thr for cyclosporin C.
6 . The method of claim 1 wherein R 2 is Val for cyclosporin D.
7 . The method of claim 1 wherein R 2 is norVal for cyclosporin G.
8 . The method of claim 1 wherein R 11 is Val for cyclosporin E.
9 . The method of claim 1 wherein R 11 is [D-MeVal] for cyclosporin H.
10 . The method of claim 1 wherein cyclosporin has a modified “C9 amino acid” at position R 1 .
11 . The method of claim 10 wherein the modified “C9 amino acid” at position R 1 is fluorinated MeBmt.
12 . The method of claim 1 wherein R 2 is an allyl-Gly residue.
13 . The method of claim 1 wherein R 2 is an allyl-Gly residue and wherein R 8 is a (D)-Ser residue.
14 . The method of claim 1 wherein R 3 is an optically active, N-methylated α-amino acid residue of the (D) configuration.
15 . The method of claim 1 wherein cyclosporin has a modified amino acid at position R 8 .
16 . The method of claim 15 wherein R 8 is dehydro-Ala or O-(2-hydroxyethyl) (D)Ser.
17 . The method of claim 15 wherein R 8 is a (D)-Ser residue.
18 . The method of claim 15 wherein R 8 is a modified sulfur-containing amino acid.
19 . The method of claim 15 wherein R 8 is a (D)-acyloxy-α-amino acid residue.
20 . The method of claim 15 wherein R 8 is an α-hydroxycarboxylic acid.
21 . The method of claim 15 wherein R 8 is a hydroxy-substituted serine residue.
22 . The method of claim 1 wherein —X—Y— of formula II is a double bond in a trans configuration.
23 . The method of claim 1 , wherein the neurological activity is stimulation of damaged neurons.
24 . The method of claim 1 , wherein the neurological activity is stimulation of growth of damaged peripheral nerves.
25 . The method of claim 1 , wherein the neurological activity is stimulation of growth of damaged neurons in the spinal cord.
26 . The method of claim 1 , wherein the neurological activity is stimulation of growth of motor neurons.
27 . The method of claim 1 , wherein the neurological activity is promotion of neuronal degeneration.
28 . The method of claim 1 , wherein the neurological activity is prevention of neurodegeneration.
29 . The method of claim 1 , wherein the neurological activity is treatment of neurological disorders.
30 . The method of claim 29 , wherein the neurological disorder is peripheral neuropathies caused by physical injury or disease state.
31 . The method of claim 29 , wherein the neurological disorder is physical damage to the brain.
32 . The method of claim 29 , wherein the neurological disorder is physical damage to the spinal cord.
33 . The method of claim 29 , wherein the neurological disorder is stroke associated with brain damage.
34 . The method of claim 29 , wherein the neurological disorder relates to neurodegeneration.
35 . The method of claim 29 , wherein the neurological disorder is Alzheimer's Disease.
36 . The method of claim 29 , wherein the neurological disorder is Parkinson's Disease.
37 . The method of claim 1 further including a neurotrophic factor in amounts sufficient to treat the neurological activity.
38 . The method of claim 37 wherein the neurotrophic factor is selected from the group consisting of nerve growth factor, glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor, and neurotropin-3.
39 . A method of treating a neurological activity in an animal, comprising:
administering to an animal an effective amount of a non-immunosuppressive cyclosporin of formula IV: wherein: R 1 is MeBmt or dihydro MeBmt or represented by formula III: wherein positions 2, 3, and 4 have the configurations S, R and X, respectively; wherein —X—Y— is connected by a double bond or a single bond; wherein:
R 2 is Abu or a fluorinated analog thereof;
R 3 is Sar, D-MeAla, or a fluorinated analog thereof;
R 4 is an N-methylated amino acid residue with a (C1-C9) straight or branched chain alkyl or alkenyl group; these straight or branched alkyl or alkenyl groups may be substituted by cycloalkyl (C3-C8); R 1 may also be (C3-C8) cycloalkyl or (C5-C7) cycloalkenyl; the above alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be substituted with (C1-C4) alkyl or (C1-C4) alkenyl, or hydroxy;
R 5 is Val or a fluorinated analog thereof; R 6 is MeAla, MeAbu, or a fluorinated analog thereof; R 7 is Ala or a fluorinated derivative thereof; R 8 is
(a) D-Ala or a fluorinated analog thereof; or
(b) O-acyl-D-Ser or O-acyl-D-Thr wherein the acyl group is defined as R 12 —CO — where R 12 represents hydrogen, C 1-6 alkyl, phenyl or substituted phenyl of formula V:
wherein X 1 and X 2 independently are
(a) C 1-6 alkyl;
(b) C 1-6 alkanoyl;
(c) CH 2 OH;
(d) halo;
(e) C 1-6 alkoxy;
(f) —NH 2 ;
(g) —NO 2 ;
(h) —COOH;
(i) —COOC 1-6 alkyl; or
(j) —H;
R 9 and R 10 are independently MeLeu or a fluorinated analog thereof; and, R 11 is MeVal or a fluorinated analog thereof.
40 . The method of claim 39 wherein R 4 is MeLeu, MeVal, Me homo-Ala, or [Me-(α-methyl)Thr].
41 . The method of claim 39 , wherein the neurological activity is stimulation of damaged neurons.
42 . The method of claim 39 , wherein the neurological activity is stimulation of growth of damaged peripheral nerves.
43 . The method of claim 39 , wherein the neurological activity is stimulation of growth of damaged neurons in the spinal cord.
44 . The method of claim 39 , wherein the neurological activity is stimulation of growth of motor neurons.
45 . The method of claim 39 , wherein the neurological activity is promotion of neuronal degeneration.
46 . The method of claim 39 , wherein the neurological activity is prevention of neurodegeneration.
47 . The method of claim 39 , wherein the neurological activity is treatment of neurological disorders.
48 . The method of claim 39 , wherein the neurological disorder is peripheral neuropathies caused by physical injury or disease state.
49 . The method of claim 39 , wherein the neurological disorder is physical damage to the brain.
50 . The method of claim 39 , wherein the neurological disorder is physical damage to the spinal cord.
51 . The method of claim 39 , wherein the neurological disorder is stroke associated with brain damage.
52 . The method of claim 39 , wherein the neurological disorder relates to neurodegeneration.
53 . The method of claim 39 , wherein the neurological disorder is Alzheimer's Disease.
54 . The method of claim 39 , wherein the neurological disorder is Parkinson's Disease.
55 . The method of claim 39 further including a neurotrophic factor in amounts sufficient to treat the neurological activity.
56 . The method of claim 55 wherein the neurotrophic factor is selected from the group consisting of nerve growth factor, glial derived growth factor, brain derived growth factor, ciliary neurotrophic factor, and neurotropin-3.
57 . The method of claim 39 , wherein the cyclosporin is Cyclosporin A.
58 . The method of claim 58 wherein R 4 is selected from the group consisting of MeVal, Me[homo-Ala], and Me-(α-methyl)Thr.Cited by (0)
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