US2003176448A1PendingUtilityA1
Mitochondria protecting agents for treating mitochondria associated diseases
Est. expiryJan 26, 2018(expired)· nominal 20-yr term from priority
A61P 9/10A61P 3/10A61P 43/00A61K 31/00A61P 27/00C07D 215/20C07C 39/19C07C 69/017A61P 25/00C07D 311/72C07C 215/80C07C 217/84C07C 215/78A61P 25/16A61P 25/08A61P 25/18C07C 279/18C07C 39/11A61P 25/14A61K 31/136A61K 31/06A61K 31/155A61P 25/28C07C 39/08A61K 31/05
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Claims
Abstract
The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods related to the same. The methods of this invention involve administration of a pharmaceutically effective amount of a mitochondria protecting agent to a warm-blooded animal in need thereof, and composition of this invention contain a mitochondria protecting agent in combination with a pharmaceutically acceptable carrier or diluent. Mitochondrial associated diseases that may be treated by the present invention include (but are not limited to) Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal and cardiac ischemia, Huntington's disease and stroke.
Claims
exact text as granted — not AI-modified1 . A method for treating a mitochondria associated disease by administering to a warm-blooded animal in need thereof an effective amount of a compound having one of the following structures (I), (II), (III) or (IV):
including steroisomers, prodrugs and pharmaceutically acceptable salts thereof,
where in structure (i):
X 1 is selected from —OH, —OR a and —OCOCH 3 ;
Y 1 is selected from —OH, —R a OH, —OCOCH 3 and C 1-12 alkyl;
Z 1 is selected from —H, —NH 2 , —OH, —NO 2 , —OCOCH 3 and C 1-12 alkyl; and
each occurrence of R a is selected from C 1-6 alkyl;
where in structure (II):
R 1 and R 2 are independently selected from —H, —C(═O)C 1-3 alkyl and C 1-3 alkyl;
X 2 is optionally present and selected from —C(A 2 )(A 3 )—, —(CH 2 ) n —, —O— and —NH—;
Y 2 and Z 2 are independently selected from —H, —OH, —NH 2 , —NO 2 , —OR b , —NHCNHNH 2 , —NHR b and —NR b R c ;
A 2 and A 3 are independently selected from —H and C 1-3 alkyl;
R b and R c are independently C 1-4 alkyl; and
n is 2-9;
where in structure (III):
the dotted line represents a single or double bond;
A 1 is selected from —H and C 1-3 alkyl;
Y 3 is selected from —H, C 1-3 alkyl and —CORd;
Z 3 is selected from —H, C 1-3 alkyl and —(CH 2 ) m X 3 R d ;
X 3 is selected at each occurrence from —S—, —O— and —NH—;
R 3 is selected from —H, —CH 3 , —CH 2 CH 3 and —R d ;
R d is selected from a guanidino moiety, a cylcoguanidino moiety, and a non-steroidal anti-inflammatory drug; and
m is 1-4; and
where in structure (IV):
W 1 , W 2 and W 3 are independently selected from —H and C 1-3 alkyl;
X 4 is optionally selected from —NH—, —O— and —S—;
Y 4 is selected from —H and C 1-12 alkyl; and
R 4 is selected from —H, a guanidino moiety, a cylcoguanidino moiety, and a non-steroidal anti-inflammatory drug, or X 4 —R 4 taken together is selected from —CH 2 OH, —OC(═O)CH 3 , and C 1-3 alkyl.
2 . The method of claim 1 wherein the mitochondria associated disease is Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal or cardiac ischemia, Huntington's disease, a polyglutamine disease, dystonia, Leber's hereditary optic neuropathy, schizophrenia, a myodegenerative disorder, or myoclonic epilepsy ragged red fiber syndrome.
3 . The method of claim 2 wherein the myodegenerative disorder is mitochondrial encephalopathy, lactic acidosis or stroke.
4 . The method of claim 2 wherein the polyglutamine disease is spinalbulbar muscular atrophy, Machado-Joseph disease (SCA-3), dentatorubro-pallidoluysian atrophy (DRPLA) or spinocerebellar ataxias 1, 2 or 6.
5 . The method of claim 1 wherein the mitochondria associated disease is Alzheimer's Disease, Parkinson's Disease, diabetes mellitus, or stroke.
6 . The method of claim 1 wherein the compound has structure (I).
7 . The method of claim 6 wherein X 1 is —OH, —OCH 3 or —OCOCH 3 .
8 . The method of claim 6 wherein Z 1 is —OH, —NH 2 , —OCOCH 3 or C 1-8 alkyl.
9 . The method of claim 6 wherein Y 1 is —OH, —OCOCH 3 or —C 1-8 alkyl.
10 . The method of claim 1 wherein the compound has structure (II).
11 . The method of claim 10 wherein R 1 and R 2 are —H or —CH 3 .
12 . The method of claim 10 wherein X 2 is —C(CH 3 ) 2 —.
13 . The method of claim 10 wherein Y 2 and Z 2 are independently —H, —NH 2 or —N(CH 3 ) 2 —.
14 . The method of claim 1 wherein the compound has structure (III).
15 . The method of claim 14 wherein R 3 is —H, —CH 3 or —CH 2 CH 3 .
16 . The method of claim 14 wherein X 3 is —O—.
17 . The method of claim 14 wherein Al is —CH 3 .
18 . The method of claim 14 wherein Z 3 is —CH 3 .
19 . The method of claim 14 wherein Y 3 is —H or —CH 3 .
20 . The method of claim 14 wherein Y 3 is —COR d —.
21 The method of claim 20 wherein R d is a non-steroidal anti-inflammatory drug (NSAID).
22 . The method of claim 21 wherein the NSAID is ibuprofen, aspirin or naproxen.
23 . The method of claim 1 wherein the compound has structure (IV).
24 . The method of claim 23 wherein W 1 , W 2 and W 3 are —CH 3 .
25 . The method of claim 23 wherein Y 4 is —CH 3 .
26 . The method of claim 23 wherein X 4 -R4 taken together is —O—NSAID.
27 . The method of claim 26 wherein the NSAID is ibuprofen, aspirin or naproxen.
28 . The method of claim 23 wherein X 4 -R 4 taken together is —OH, —CH 3 , —CH 2 OH or —OCOCH 3 .
29 . The method of claim 23 wherein X 4 is —NH— and R 4 is a guanidino moiety having the structure —NHC(═NH)NH 2 .
30 . A compound having one of the following structures (I), (II), (III) or (IV):
including steroisomers, prodrugs and pharmaceutically acceptable salts thereof,
where in structure (I):
X 1 is selected from —OH, —OR a and —OCOCH 3 ;
Y 1 is selected from —OH, —R a OH, —OCOCH 3 and C 1-12 alkyl;
Z 1 is selected from —H, —NH 2 , —OH, —NO 2 , —OCOCH 3 and C 1-12 alkyl; and
each occurrence of R a is selected from C 1-6 alkyl;
where in structure (II):
R 1 and R 2 are independently selected from —H, —C(═O)C 1-3 alkyl and C 1-3 alkyl;
X 2 is optionally present and selected from —C(A 2 )(A 3 )-, —(CH 2 ) n —, —O— and —NH—;
Y 2 and Z 2 are independently selected from —H, —OH, —NH 2 , —NO 2 , —OR b , —NHCNHNH 2 , —NHR b and —NR b R c ;
A 2 and A 3 are independently selected from —H and C 1-3 alkyl;
R b and R c are independently C 1-4 alkyl; and
n is 2-9;
where in structure (III):
the dotted line represents a single or double bond;
A 1 is selected from —H and C 1-3 alkyl;
Y 3 is selected from —H, C 1-3 alkyl and —COR d ;
Z 3 is selected from —H, C 1-3 alkyl and —(CH 2 ) m X 3 R d ;
X 3 is selected at each occurrence from —S—, —O— and —NH—;
R 3 is selected from —H, —CH 3 , —CH 2 CH 3 and —R d ;
R d is selected from a guanidino moiety, a cylcoguanidino moiety, and a non-steroidal anti-inflammatory drug; and
m is 1-4; and
where in structure (IV):
W 1 , W 2 and W 3 are independently selected from —H and C 1-3 alkyl;
X 4 is optionally selected from —NH—, —O— and —S—;
Y 4 is selected from —H and C 1-12 alkyl; and
R 4 is selected from —H, a guanidino moiety, a cylcoguanidino moiety, and a non-steroidal anti-inflammatory drug, or X 4 -R 2 taken together is selected from —CH 2 OH, —OC(═O)CH 3 , and C 1-3 alkyl.
31 . The compound of claim 30 having structure (I).
32 . The compound of claim 30 having structure (II).
33 . The compound of claim 30 having structure (III).
34 . The compound of claim 30 having structure (IV).
35 . A pharmaceutical composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier.Cited by (0)
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