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US 6,294,551 B1Granted
N-linked sulfonamides of heterocyclic thioesters
AssigneeGPI NIL Holdings, Inc.
InventorsGregory S. Hamilton, Jai-He Li, Wei Huang
Life of this patent
Estimating the term…
Abstract
This invention relates to neurotrophic low molecular weight, small molecule N-linked sulfonamides of heterocyclic thioesters having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.
Claims34
A compound of formula I:
- or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
- A and B are taken together, with the nitrogen and carbon atoms to which they are respectively attached, to form a 5-7 membered saturated or unsaturated heterocyclic ring containing no further heteroatoms in addition to the nitrogen to which A is attached in any chemically stable oxidation state;
- X is either O or S;
- Y is a direct bond, a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- C and D are independently:
- hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- wherein Ar is selected from the group consisting of a carbocyclic ring, quinoline, and isoquinoline;
- wherein said Ar group is substituted or unsubstituted;
- and
- R1 is selected from the group consisting of Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl.
8 more elements
A compound selected from the group consisting of:
- (2,2-Phenylmethyl)ethyl (2S)-1-[(4-ethylphenyl)sulfonyl]-2-pyrrolidinecarbothioate;
- 3-Phenylpropyl (2S)-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate;
- 3-Phenylpropyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate;
- 3-(1-Naphthyl)propyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate;
- 3-Phenylpropyl (2S)-1-[(4-ethylphenyl)sulfonyl]-2-pyrrolidinecarbothioate;
- 3-(4-Methoxyphenyl)propyl 1-[(4-methylphenyl)sulfonyl]-2-piperidinecarbothioate;
- 3-(4-Methoxyphenyl)propyl 1-(benzylsulfonyl)-2-piperidinecarbothioate;
- 3-(4-Methoxyphenyl)propyl 1-(phenylsulfonyl)-2-piperidinecarbothioate;
- 3-[4-(Trifluoromethyl)phenyl]propyl 1-[(4-methylphenyl)sulfonyl]-2-piperidinecarbothioate;
- and a pharmaceutically acceptable salt, ester, or solvate thereof.
7 more elements
A compound of formula II:
- or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
- E, F, G, and H are independently CH2;
- X is either O or S;
- Y is a direct bond to Z, a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- C and D are independently:
- hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- wherein Ar is selected from the group consisting of a carbocyclic ring, quinoline, and isoquinoline;
- wherein said Ar group is substituted or unsubstituted;
- and
- R1 is selected from the group consisting of Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl.
8 more elements
A compound of formula III:
- or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
- E, F, and G are independently CH2;
- X is either O or S;
- Y is a direct bond to Z, a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- Z is a direct bond, or a C1-C6 straight or branched chain alkyl, or a C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- C and D are independently:
- hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more position(s) with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups are optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl;
- wherein Ar is selected from the group consisting of a carbocyclic ring, quinoline, and isoquinoline;
- wherein said Ar group is substituted or unsubstituted;
- and
- R1 is selected from the group consisting of Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl which is substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR2 wherein R2 is selected from the group consisting of hydrogen, (C1-C6)-straight or branched chain alkyl, and (C3-C6)-straight or branched chain alkenyl or alkynyl.
8 more elements
Dependencies are inferred from the claim text.