Pyrazoline Dihydroquinolones, Pharmaceutical Compositions, and Uses
This disclosure relates to pyrazoline dihydroquinolone derivates, pharmaceutical compositions, and uses. In certain embodiments, the compounds are selective NMDA receptor inhibitors and are useful in therapeutic methods related thereto. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound of the following formula: Formula (I) or salts, esters, or prodrugs thereof, as provided herein.
1 . A compositions comprising a compound of the following formula:
or salts, esters, or prodrugs thereof, wherein
rings A, B, or C are each individually and independently aryl, cycloalkyl, or heterocyclyl;
dotted line represents a single or double bond;
n, m, or p are each individually and independently 0, 1, 2, 3, or 4;
V is (C═Y)Z, SO 3 H, SO 2 NH, or OSO 3 H;
W is at each occurrence CH 2 , CF 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CF 2 CH 2 , CH 2 CF 2 , CH, CH═CH, C═O, O, S, or NH;
q is 1, 2, or 3;
X or Y are each individually and independently O, S, NH, N-alkyl, two hydrogens, or two fluoros;
Z is halogen, OH, O-alkyl, O-alkanoyl, NH, N-alkyl, N-alkanoyl, SH, S-alkyl, or S-alkanoyl wherein Z is optionally substituted with one or more the same or different R 10 ;
R 1 , R 3 , and R 7 are at each occurrence individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 , R 3 , and R 7 are optionally substituted with one or more, the same or different R 10 ;
R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ; and
R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2 . The composition of claim 1 wherein the compound has formula IA or IB,
or salts, esters, or prodrugs thereof.
3 . The composition of claim 2 , wherein the compound of Formula IA or D3 is in greater than 55%, 65%, 75%, 85%, or 95% enantiomeric excess or diastereomeric excess.
4 . The composition of claim 1 , wherein W is CH 2 and q is 2.
5 . The composition of claim 1 , wherein X is two hydrogens, Y is O, and Z is halogen, OH, O-alkyl, or O-alkanoyl.
6 . The composition of claim 1 , wherein X is O, Y is two hydrogens, and Z is halogen, OH, O-alkyl, or alkanoyl.
7 . The composition of claim 1 , wherein X is O, Y is F2, and Z is halogen, OH, O-alkyl, alkanoyl, or NH2.
8 . The composition of claim 1 , wherein rings A, B, and C are phenyl.
9 . The composition of claim 8 , wherein the A ring is para-substituted with R 7 , wherein R 7 is a halogen.
10 . The composition of claim 8 , wherein the B ring is para-substituted with R 3 , wherein R 3 is a halogen.
11 . The composition of claim 8 , wherein R 1 is hydrogen, R 3 and R 7 are halogen.
12 . A compound of claim 1 , selected from:
4-(5-(4-chlorophenyl)-3-(4-(4-chlorophenyl)-2-oxo-1,2-dihydroquinolin-3-yl)-4, 5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid;
(S)-4-(5-(4-chlorophenyl)-3-(4-(4-chlorophenyl)-2-oxo-1,2-dihydroquinolin-3-yl)-4, 5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid;
4-(3-(4-(4-bromophenyl)-2-oxo-1,2-dihydroquinolin-3-yl)-5-(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobut-2-enoic acid; and
4-(4-chlorophenyl)-3-(5-(4-chlorophenyl)-1-(4-hydroxybutanoyl)-4,5-dihydro-1H-pyrazol-3-yl)quinolin-2(1H)-one.
13 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
14 . The method of treating or preventing a cognitive, psychiatric, or neurodegenerative disease or condition by administering to a person in need of such treatment an effective amount of a pharmaceutical composition as described in claim 13 .
15 . The method of claim 14 , wherein the disease or condition is cognitive impairment, a neurodegenerative disease, pain, depression, schizophrenia, attention deficit hyperactivity disorder, ischemia, or addiction.
16 . The method according to claim 14 , wherein the neurodegenerative disease is Alzheimer's disease, mild cognitive impairment, or Parkinson's disease.
17 . The method of claim 14 , wherein the pharmaceutical composition is administered in combination with a second active agent.
18 . The method of claim 15 , wherein the second active agent is an antidepressant or antipsychotic.