US2015291654A1PendingUtilityA1
3,3 disubstituted 19-nor pregnane compounds, compositions, and uses thereof
Est. expiryOct 14, 2031(~5.2 yrs left)· nominal 20-yr term from priority
Inventors:Ravindra B. UpasaniBenny C. Askew, Jr.Boyd L. HarrisonPeter DistefanoFrancesco G. SalituroAlbert Jean Robichaud
A61P 9/10A61P 25/14A61P 25/08A61P 25/04A61P 25/24A61P 25/16A61P 25/22A61P 25/18A61P 25/20A61P 25/28A61P 27/16A61P 25/00C07J 7/002C07J 31/006C07J 5/0015C07J 7/0085C07J 9/005C07J 7/008C07J 43/003
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Claims
Abstract
Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I) and (III): where R 1 , R 2 , R 3 , R 3′ , R 4 , R 6a , R 6a , R 11a , and R 11b are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress, and epilepsy.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R, —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OH, —OR B1 , —OC(═O)R B1 , —NH 2 , —N(R B1 ) 2 , or —NR B1 C(═O)R B1 , wherein each instance of R B1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 groups are joined to form an substituted or unsubstituted heterocyclic ring;
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3′ is hydrogen, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ), wherein R C1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are joined to form an substituted or unsubstituted heterocyclic ring; and R C2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
each of R 6a and R 6b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (═O) group;
each of R 11a and R 11b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OH, —OR D1 OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR C(═O)R, wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or R 11a and R 11b are joined to form an oxo (═O) group;
wherein represents a single or double bond, provided if a double bond is present in Ring B, then one of R 6a or R 6b is absent, and provided if a single bond is present in Ring B, then the hydrogen at C5 is in the alpha or beta position;
provided that the following compounds, and salts thereof, are specifically excluded:
2 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 , wherein each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form an substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OH, —OR B1 , —OC(═O)R B1 , —NH 2 , —N(R B1 ) 2 , or —NR B1 C(═O)R B1 , wherein each instance of R B1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 groups are joined to form an substituted or unsubstituted heterocyclic ring;
R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3′ is hydrogen, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —S(═O) 2 R C2 , —S(═O) 2 OR C1 , —P(═O) 2 R C2 , —P(═O) 2 OR C1 , —P(═O)(OR C1 ) 2 , —P(═O)(R C2 ) 2 , or —P(═O)(R C2 )(OR C1 ), wherein R C1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are joined to form an substituted or unsubstituted heterocyclic ring; and R C2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
each of R 6a and R 6b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (═O) group;
each of R 11a and R 11b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OH, —OR D1 OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR C(═O)R, wherein each instance of R D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 groups are joined to form an substituted or unsubstituted heterocyclic ring; or R 11a and R 11b are joined to form an oxo (═O) group;
wherein represents a single or double bond, provided if a double bond is present in Ring B, then one of R 6a or R 6b is absent, and provided if a single bond is present in Ring B, then the hydrogen at C5 is in the alpha or beta position;
3 . The compound of claim 1 , wherein R 1 is hydrogen, halogen, —OR A1 , —SR A1 , —N(R A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —SC(═O)R A2 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —NHC(═O)R A1 , —NHC(═O)OR A1 , —NHC(═O)SR A1 , —NHC(═O)N(R A1 ) 2 , —OS(═O) 2 R A2 , —OS(═O) 2 OR A1 , —S—S(═O) 2 R A2 , —S—S(═O) 2 OR A1 , —S(═O)R A2 , —SO 2 R A2 , or —S(═O) 2 OR A1 .
4 . The compound of claim 1 , wherein R 1 is hydrogen, halogen, —OR A1 , —N(R A1 ) 2 , —S—S(═O) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
5 . The compound of claim 1 , wherein R 2 is hydrogen, substituted or unsubstituted heterocyclyl, —OH, —OR B1 , —OC(═O)R B1 , —NH 2 , —N(R B1 ) 2 , or —NR B1 C(═O)R B1 .
6 . The compound of claim 1 , wherein R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.
7 . The compound of claim 1 , wherein R 3 is a group of formula:
wherein each instance of R 3a is hydrogen, halo, or —OR F1 , wherein R F1 is substituted or unsubstituted alkyl; and each instance of R 3b and R 3c is independently hydrogen, halo, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.
8 . The compound of claim 1 , wherein R 3′ is hydrogen.
9 . The compound of claim 1 , wherein R 4 is hydrogen.
10 . The compound of claim 1 , wherein each of R 6a and R 6b is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are joined to form an oxo (═O) group.
11 . The compound of claim 1 , wherein both R 6a and R 6b are hydrogen.
12 . The compound of claim 1 , wherein one of R 6a and R 6b is a non-hydrogen group.
13 . The compound of claim 1 , wherein R 6a is a non-hydrogen alpha group.
14 . The compound of claim 1 , wherein R 6a is a non-hydrogen beta group.
15 . The compound of claim 1 , wherein R 6a is halo or alkyl and R 6b is hydrogen.
16 . The compound of claim 1 , wherein R 6a and R 6b are both halo.
17 . The compound of claim 1 , wherein R 6a and R 6b are both alkyl.
18 . The compound of claim 1 , wherein R 6a and R 6b are joined to form an oxo group.
19 . The compound of claim 1 , wherein each of R 11a and R 11b is independently hydrogen, —OH, —OR D1 , —OC(═O)R D1 , —NH 2 , —N(R D1 ) 2 , or —NR D1 C(═O)R D1 , or R 11a and R 11b are joined to form an oxo (═O) group.
20 . The compound of claim 1 , wherein both R 11a and R 11b are hydrogen.
21 . The compound of claim 1 , wherein one of R 11a and R 11b is a non-hydrogen group.
22 . The compound of claim 1 , wherein R 11a and R 11b are joined to form an oxo group
23 . The compound of claim 1 , wherein the compound of Formula (I) is of the Formula (I-a1), (I-a2), or (I-a3):
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 2 , wherein the compound of Formula (III) is of the Formula (III-a1), (III-a2), or (III-a3):
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
26 . The compound of claim 2 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
27 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
28 . A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
29 . The method of claim 28 , wherein the disease or condition insomnia, depression, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety disorders, bipolar disorder, schizophrenia, depression, bipolar disorder, schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, compulsive disorders, post-traumatic stress disorder, Autism spectrum disorder, dysthymia, social anxiety disorder, obsessive compulsive disorder, pain, sleep disorders, memory disorders, dementia, Alzheimer's disease, a seizure disorder, traumatic brain injury, stroke, addictive disorders, autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndromes, or tinnitus.
30 . The method of claim 28 wherein the compound is administered orally.
31 . The method of claim 28 wherein the compound is administered chronically.Join the waitlist — get patent alerts
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