US2006074124A1PendingUtilityA1
Methods of treating a disorder
Est. expirySep 12, 2023(expired)· nominal 20-yr term from priority
Inventors:Andrew NapperPeter DistefanoRory CurtisJeffrey HixonThomas McdonaghL. Julie HuberJonathan M. SolomonRussell ThomasJean-Francois Pons
A61P 9/10A61P 43/00A61P 3/06A61P 3/10A61P 9/12A61K 31/403C07D 209/88C07D 471/04A61P 3/04A61K 31/497A61K 31/437C07D 209/94A61P 25/28A61K 31/404C07D 209/18A61K 31/4439A61P 35/00A61K 31/5377
48
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Claims
Abstract
Compound of formula (I) and methods of treating disorders by administering a compound of formula (I) are described herein. Examples of disorders include neoplastic disorders, fat-cell related disorders, neurodegenerative disorders, and metabolic disorders.
Claims
exact text as granted — not AI-modified1 . A method of treating or preventing a disorder, the method comprising administering to a subject an effective amount of a compound having a formula (I):
wherein,
R 1 and R 2 , together with the carbons to which they are attached, form C 5 -C 10 cycloalkyl, C 5 -C 10 heterocyclyl, C 5 -C 10 cycloalkenyl, C 5 -C 10 heterocycloalkenyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl, each of which may be optionally substituted with 1-5 R 5 ; or R 1 is H, S-alkyl, or S-aryl, and R 2 is amidoalkyl wherein the nitrogen is substituted with alkyl, aryl, or arylalkyl, each of which is optionally further substituted with alkyl, halo, hydroxy, or alkoxy;
R 3 and R 4 , together with the carbons to which they are attached, form C 5 -C 10 cycloalkyl, C 5 -C 10 heterocyclyl, C 5 -C 10 cycloalkenyl, C 5 -C 10 heterocycloalkenyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl, each of which are optionally substituted with 1-5 R 6 ;
each of R 5 and R 6 is, independently, halo, hydroxy, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C 1 -C 10 alkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 7 -C 12 heteroaralkyl, C 3 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 5 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, C 1 -C 6 alkyl amino, C 1 -C 6 dialkyl amino, mercapto, SO 3 H, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphate, C 1 -C 4 alkylenedioxy, oxo, acyl, aminocarbonyl, C 1 -C 6 alkyl aminocarbonyl, C 1 -C 6 dialkyl aminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl; alkoxyaminocarbonyl; or one of R 5 or R 6 and R 7 form a cyclic moiety containing 4-6 carbons, 1-3 nitrogens, 0-2 oxygens and 0-2 sulfurs, which are optionally substituted with oxo or C 1 -C 6 alkyl;
X is NR 7 , O, or S; Y is NR 7′ , O or S;
- - - - represent optional double bonds;
each of R 7 and R 7 ′ is, independently, hydrogen, C 1 -C 6 alkyl, C 7 -C 12 arylalkyl, C 7 -C 12 heteroarylalkyl; or R 7 and one of R 5 or R 6 form a cyclic moiety containing 4-6 carbons, 1-3 nitrogens, 0-2 oxygens and 0-2 sulfurs, which are optionally substituted with oxo or C 1 -C 6 alkyl; and
n is 0 or 1.
2 . The method of claim 1 , wherein R 1 and R 2 , together with the carbons to which they are attached, form C 5 -C 10 cycloalkyl, C 5 -C 10 heterocyclyl, C 5 -C 10 cycloalkenyl, C 5 -C 10 heterocycloalkenyl, C 6 -C 10 aryl, or C 6 -C 10 heteroaryl, each of which may be optionally substituted with 1-5 R 5 .
3 . The method of claim 1 , wherein R 1 and R 2 , together with the carbons to which they are attached, form C 5 -C 10 cycloalkenyl.
4 . The method of claim 3 , wherein R 1 and R 2 are substituted with R 5 .
5 . The method of claim 4 , wherein R 5 is, C 1 -C 6 alkyl substituted with a substituent or amino carbonyl, substituted with a substituent.
6 . The method of claim 5 , wherein the substituent is an amino substituent, or aminocarbonyl.
7 . The method of claim 1 , wherein R 3 and R 4 , together with the carbons to which they are attached, form C 6 -C 10 aryl.
8 . The method of claim 5 , wherein R 3 and R 4 are substituted with R 6 .
9 . The method of claim 6 wherein R 6 is halo or C 1 -C 6 alkyl.
10 . The method of claim 1 , wherein n is 0.
11 . The method of claim 1 wherein X is NR 7 .
12 . The method of claim 1 wherein n is 0 and X is NR 7 .
13 . The method of claim 1 , having the formula (X) below:
14 . The method of claim 13 , wherein R 6 is halo or C 1 -C 6 alkyl.
15 . The method of claim 13 , wherein R 5 is aminocarbonyl.
16 . The method of claim 13 , having the formula (XI) below:
17 . The method of claim 16 , wherein R 6 is halo or alkyl.
18 . The method of claim 16 , wherein R 5 is aminocarbonyl.
19 . The method of claim 16 , wherein wherein R 6 is halo or alkyl and wherein R 5 is aminocarbonyl.
20 . The method of claim 13 wherein the compound is 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid amide.
21 . The method of claim 20 wherein the compound comprises greater than a 60% enantiomeric excess of the enantiomer having an optical rotation of −14.1 (c=0.33 DCM).
22 . The method of claim 21 , wherein the compound conrises greater than a 90% enantiomeric excess of the enantiomer having an optical rotation of −14.1 (c=0.33 DCM).
23 . The compound of claim 1 , wherein the compound preferentially inhibits SirT1 relative to a non-SirT1 sirtuin.
24 . The compound of claim 1 , wherein the compound has at least a 5 fold preference for SirT1.
25 . The compound of claim 1 , wherein the compound has a K i for SirT1 of less than about 1 μM.
26 . The method of claim 1 wherein the disorder is a neoplastic disorder.
27 . The method of claim 26 , wherein the neoplastic disorder is a cancer.
28 . The method of claim 1 wherein the disorder is a neurodegenerative disorder.
29 . The method of claim 28 , wherein the neurodegenerative disorder is Alzheimer's Disease or Parkinson's disease.
30 . The method of claim 1 , wherein the disorder is a fat-cell related disorder.
31 . The method of claim 30 , wherein administration of the compound enhances adipogenesis in the subject.
32 . The method of claim 1 , wherein the disorder is diabetes.
33 . The method of claim 32 , wherein the subject has type I diabetes.
34 . The method of claim 32 , wherien the subject has type II diabetes.
35 . The method of claim 1 , wherein the subject is identified as being at risk of diabetes.
36 . The method of claim 35 , wherein the patient has been identified as being at risk of diabetes by having impaired glucose tolerance.
37 . The method of claim 35 , wherein the patient has been identified as being at risk of diabetes by having fasting hyperglycemia.
38 . The method of claim 1 , wherein the disorder is metabolic syndrome.
39 . The method of claim 38 , wherein the subject has atherogenic dyslipidemia.
40 . The method of claim 38 , wherein the subject is obese.
41 . The method of claim 38 , wherein the subject has insulin resistance or impaired glucose intolerance.
42 . The method of claim 38 , wherein the subject has hypertension.
43 . A compound having formula (XI),
wherein R 6 is halo or C 1 -C 6 alkyl, and
p is 0, 1, or 2; and
wherein, the compound has the same relative stereochemistry as the stereoisomer of 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid amid having an optical rotation of −14.1 (c=0.33 DCM).
44 . The compound of claim 43 , wherein R 6 is chloro or methyl.
45 . The compound of claim 43 , wherein p is 1.
46 . The stereoisomer of 6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid amid having an optical rotation of −14.1 (c=0.33 DCM).Cited by (0)
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