Patent EA-002593-B1 (EA)
Title: N-linked sulfonamides of heterocyclic thioesters
Inventor: HAMILTON GREGORY S
IPC: A61K31/40
Filed: 1997-12-22
Abstract: 1. 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 respectfully attached, to form a 5-6 membered saturated or unsaturated heterocyclic ring, comprising any combination of CH2 and S, in any chemical-stable state of oxidation; 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, HR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; 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, HR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; C and D are independently: hydrogen, or Ar, or 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 C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or with Ar, where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups is 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, and wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, HR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; wherein Ar is an aryl or heteroaryl moiety which is substituted or unsubstituted; and R1 is selected from the group consisting of Ar, or C3-C8 cycloalkyl, or C1-C6 straight or branched chain alkyl or 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 said alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or HR2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group or C3-C8-cycloalkyl. 2. The compound of Claim 1, wherein Ar is cyclic or fused cyclic ring and comprises mono-, or bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to five positions with halo, haloalkyl, hydroxyl, nitro, trifluoromethyl, C1-C6-straight or branched chain alkyl, C2-C6-straight or branched chain alkenyl, C1-C6-alkoxy, C2-C6-alkenyloxy, phenoxy, benzyloxy, amino, thiocarbonyl, ester, thioester, cyano, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl; wherein individual ring size of the ring is 5-8 members;wherein heterocyclic ring comprises 1-4 heteroatoms, selected from the group, comprising O, N or S; wherein aromatic or tertiary alkylamines are optionally oxidized to corresponding N-oxide. 3. The compound of Claim 2, wherein mono-, or bicyclic, carbo- or heterocyclic ring is selected from the group, comprising phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pirydinyl, pirymidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl. 4. The compound selected from the group consisting of: 3-(4-Methoxyphenyl)propyl (2S)-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate; 3-(4-Methoxyphenyl)propyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate; 3-(4-Methoxyphenyl)propyl (2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarbothioate; (2,2-Phenylmethyl)ethyl (2S)-1-[(4-ethylphenyl)sulfonyl]-2-pyrrolidinecarbothioate; 2-Phenylpropyl (2S)-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate; 2-Phenylpropyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate; 3-(1-Naphtyl)propyl (2S)-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate; 3-Phenylpropyl (2S)-1-[(4-ethylphenyl) sulfonyl]-2-pyrrolidinecarbothioate; 3-(4-Methoxyphenyl)propyl-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarbothioate; 3-(4-Methoxyphenyl)propyl-1-(benzylsulfonyl)-2-pyrrolidinecarbothioate; 3-(4-Methoxyphenyl)propyl-1-(phenylsulfonyl)-2-pyrrolidinecarbothioate; 3-[4-(Trifluoromethyl)phenyl]propyl 1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarbothioate; and pharmaceutically acceptable salts, esters or solvates thereof. 5. A pharmaceutical composition comprising a neurotrophically effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. 6. A method of effecting a neuronal activity in an animal, comprising administering to said mammal a neurotrophically effective amount of the compound of Claim 1. 7. A method of Claim 6, wherein the neuronal activity selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, neurodegeneration prophylaxis and treatment of a neurological disorder. 8. A method of Claim 7, wherein the neurologic disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders related to neurodegeneration. 9. A method of Claim 8,wherein the neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis. 10. A compound of formula II:   or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and H are CH2; X is either O, or S; Y is a direct bond to Z, or a 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 is 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, HR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C2-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; 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, HR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, (C1-C6) -straight or branched chain alkyl, (C3-C6) -straight or branched chain alkenyl or alkynyl, and (C1-C4) bridging alkyl wherein said bridging alkyl forms a heterocyclic ring starting with the nitrogen of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; C a