US2004220235A1PendingUtilityA1
Method of inhibiting amyloid protein aggregation and imaging amyloid deposits
Priority: Jun 10, 1999Filed: Jun 2, 2004Published: Nov 4, 2004
Est. expiryJun 10, 2019(expired)· nominal 20-yr term from priority
Inventors:Corinne E. Augelli-SzafranMark BarvianChristopher Franklin BiggeShelly GlaseShunichiro HachiyaJohn S. KielyTakenori KimuraYingjie LaiAnnette SakkabMark J. SutoLary Craswell WalkerTomoyuki YasunagaNian Zhuang
C07D 257/04C07D 217/02C07D 213/82A61K 31/402C07C 229/62C07C 311/51A61K 31/4164C07D 209/44C07D 233/88C07D 413/06C07C 229/64A61P 25/28C07D 295/135C07D 317/58C07C 233/43A61K 31/196C07C 229/58
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Claims
Abstract
The present invention provides a method of treating Alzheimer's disease using a compound of Formula I Also provided is a method of inhibiting the aggregation of amyloid proteins using a compound of Formula I and a method of imaging amyloid deposits, as well as new compounds of Formula I.
Claims
exact text as granted — not AI-modified1 . A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I
wherein
R a is hydrogen, C 1 -C 6 alkyl, or
n is 0 to 5 inclusive;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —OH, —NH 2 , NR b R c , —CO 2 H, —CO 2 C 1 -C 6 alkyl, —NO 2 , —OC 1 -C 12 alkyl, —C 1 -C 8 alkyl, —CF 3 , —CN, —OCH 2 phenyl, —OCH 2 -substituted phenyl, —(CH 2 ) m -phenyl, —O-phenyl, —O-substituted phenyl,
—CH═CH-phenyl, —O(CH 2 ) p NR b R c ,
—NH(CH 2 ) p NR b R c , —N(C 1 -C 6 alkyl)(CH 2 ) p NR b R c ,
R 8 is COOH, tetrazolyl, —SO 2 R d , or —CONHSO 2 R d ;
R b and R C are independently hydrogen, —C 1 -C 6 alkyl, —(CH 2 ) m -phenyl, or R b and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
R d is hydrogen, —C 1 -C 6 alkyl, —CF 3 , or phenyl;
m is 0 to 5 inclusive;
p is 1 to 5 inclusive;
A is CH or N;
R 1 and R 2 , when adjacent to one another, can be methylene-dioxy;
or the pharmaceutically acceptable salts thereof.
2 . The method of claim 1 wherein
R a is hydrogen;
n is 2; and
R 3 and R 4 are hydrogen.
3 . The method of claim 1 wherein
R a is hydrogen;
R 3 and R 4 are hydrogen; and
n is 2 to 5 inclusive.
4 . The method of claim 1 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 1 , R 2 , and R 7 are independently chlorine, —N(CH 2 CH 3 ) 2 , —OH, CH 3 —, fluorine, —CF 3 , phenyl, hydrogen, —OCH 2 phenyl, —O(CH 2 ) 3 N(CH 3 ) 2 , —O phenyl, —O(CH 2 ) 7 CH 3 , —CH(CH 2 OCH 2 CH 3 ) 2 , pyrrolyl, —CH═CH-phenyl,
—N[(CH 2 ) 3 CH 3 ] 2 , substituted phenyl, —OCH 2 — substituted phenyl, pyrrozolyl, or —N(phenyl) 2 .
5 . The method of claim 1 wherein
R a is hydrogen;
n is 3, 4, or 5;
R 3 and R 4 are hydrogen; and
R 1 , R 2 , and R 7 are independently chlorine or hydrogen.
6 . The method of claim 1 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 5 , R 6 , and R 8 are independently hydrogen, —CO 2 H, —NO 2 , —OCH 3 ,
imidazolyl, —CN, fluorine, —CH 3 , —CF 3 , halogen,
—NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —NH 2 , or pyrrolyl.
7 . The method of claim 1 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 5 is —CO 2 H.
8 . A method of treating Alzheimer's disease, the method comprising administering to a patient having Alzheimer's disease a therapeutically effective amount of a compound of Formula I
wherein
R a is hydrogen;
n is 1 to 5 inclusive;
R 3 and R 4 are hydrogen;
R 1 , R 7 , and R 2 are independently chlorine, —N(CH 2 CH 3 ) 2 , —OH, CH 3 —, fluorine, —CF 3 , phenyl, hydrogen, —OCH 2 phenyl, —O(CH 2 ) 3 N(CH 3 ) 2 , —O phenyl, —O(CH 2 ) 7 CH 3 , —CH(CH 2 OCH 2 CH 3 ) 2 , pyrrolyl, —CH═CH-phenyl, —N[(CH 2 ) 3 CH 3 ]2, substituted phenyl, —OCH 2 -substituted phenyl, pyrazolyl, or —N(phenyl) 2 ;
R 5 and R 6 are independently hydrogen, —CO 2 H, —NO 2 , —OCH 3 , imidazolyl, —CN, fluorine, —CH 3 , —CF 3 , or pyrrolyl;
R 8 is COOH or tetrazolyl;
or the pharmaceutically acceptable salts thereof.
9 . The method of claim 1 wherein the compound of Formula I is:
2-[[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl]amino-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid;
2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;
2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;
2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;
2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;
2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;
2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-1-yl-5-nitrobenzoic acid;
2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;
2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid;
2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid;
2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid;
2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid;
2-{4-[5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid;
2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid;
2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;
2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;
2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;
5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;
2-(4-Phenethyl-phenylamino)-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methoxy-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-terephthalic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid;
4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methanesulfonyl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazol-1-yl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoic acid;
5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4,6-difluoro-benzoic acid;
6-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-trifluoromethyl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-trifluoromethyl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-pyrrol-1-yl-benzoic acid;
2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}-phenylamino)-benzoic acid;
2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-(4-{2-[4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoic acid;
2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4′-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl}-phenylamino)-benzoic acid;
2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoic acid;
2-{4-[2-(4-Pyrazol-1-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;
2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-amino-benzoic acid;
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid;
2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;
2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid;
2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid;
2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl]amino-benzoic acid; or
2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
10 . A method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, the method comprising administering to a patient in need of inhibition of the aggregation of amyloid protein an amyloid protein aggregation inhibiting amount of a compound of Formula I
wherein
R a is hydrogen, C 1 -C 6 alkyl, or
n is 0 to 5 inclusive;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —OH, —NH 2 , NR b R c , —CO 2 H, —CO 2 C 1 -C 6 alkyl, —NO 2 , —OC 1 -C 12 alkyl, —C 1 -C 8 alkyl, —CF 3 , —CN, —OCH 2 phenyl, —OCH 2 -substituted phenyl, —(CH 2 ) m -phenyl, —O-phenyl, —O-substituted phenyl,
—CH═CH-phenyl, —O(CH 2 ) p NR b R c ,
—NH(CH 2 ) p NR b R c , —N(C 1 -C 6 alkyl)(CH 2 ) p NR b R c ,
R 8 is COOH, tetrazolyl, —SO 2 R d , or —CONHSO 2 R d ;
R b and R c are independently hydrogen, —C 1 -C 6 alkyl, —(CH 2 ) m -phenyl, or R b and R C taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
R d is hydrogen, —C 1 -C 6 alkyl, —CF 3 , or phenyl;
m is 0 to 5 inclusive;
p is 1 to 5 inclusive;
A is N;
R 1 and R 2 , when adjacent to one another, can be methylene-dioxy;
or the pharmaceutically acceptable salts thereof.
11 . The method of claim 10 wherein
R a is hydrogen;
n is 2; and
R 3 and R 4 are hydrogen.
12 . The method of claim 10 wherein
R a is hydrogen;
R 3 and R 4 are hydrogen; and
n is 2 to 5 inclusive.
13 . The method of claim 10 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 1 , R 2 , and R 7 are independently chlorine, —N(CH 2 CH 3 ) 2 , —OH, CH 3 —, fluorine, —CF 3 , phenyl, hydrogen, —OCH 2 phenyl, —O(CH 2 ) 3 N(CH 3 ) 2 , —O phenyl, —O(CH 2 ) 7 CH 3 , —CH(CH 2 OCH 2 CH 3 ) 2 , pyrrolyl, —CH═CH-phenyl,
—N[(CH 2 ) 3 CH 3 ] 2 , substituted phenyl, —OCH 2 -substituted phenyl, pyrazolyl, or —N(phenyl) 2 .
14 . The method of claim 10 wherein
R a is hydrogen;
n is 3, 4, or 5;
R 3 and R 4 are hydrogen; and
R 1 , R 2 , and R 7 are independently chlorine or hydrogen.
15 . The method of claim 10 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 5 and R 6 are independently hydrogen, —CO 2 H, —NO 2 , —OCH 3 , imidazolyl, —CN, fluorine, —CH 3 , —CF 3 , halogen,
—NH—C 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —NH 2 , or pyrrolyl.
16 . The method of claim 10 wherein
R a is hydrogen;
n is 2;
R 3 and R 4 are hydrogen; and
R 8 is —CO 2 H.
17 . A method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, the method comprising administering to a patient in need of inhibition of the aggregation of amyloid protein an amyloid protein aggregation inhibiting amount of a compound of Formula I
wherein
R a is hydrogen;
n is 1 to 5 inclusive;
R 3 and R 4 are hydrogen;
R 1 , R 7 , and R 2 are independently chlorine, —N(CH 2 CH 3 ) 2 , —OH, CH 3 —, fluorine, —CF 3 , phenyl, hydrogen, —OCH 2 phenyl, —O(CH 2 ) 3 N(CH 3 ) 2 , —O phenyl, —O(CH 2 ) 7 CH 3 , —CH(CH 2 OCH 2 CH 3 ) 2 , pyrrolyl, —CH═CH-phenyl, —N[(CH 2 ) 3 CH 3 ]2, substituted phenyl, —OCH 2 -substituted phenyl, pyrazolyl, or —N(phenyl) 2 ;
R 5 and R 6 are independently hydrogen, —CO 2 H, —NO 2 , —OCH 3 , imidazolyl, —CN, fluorine, —CH 3 , —CF 3 , or pyrrolyl;
R 8 is COOH or tetrazolyl;
A is N;
R 1 and R 2 , when adjacent to one another, can be methylene-dioxy;
or the pharmaceutically acceptable salts thereof.
18 - 21 . (Cancelled).
22 . The compounds:
4-{4-[2-(3,4-Dicloro-phenyl)-ethyl]-phenylamino}-nicotinic acid.
23 - 27 . (Cancelled).
28 . A method of imaging amyloid deposits, the method comprising:
a. introducing into a patient a detectable quantity of a labeled compound having the Formula I or a pharmaceutically acceptable salt thereof: wherein
R a is hydrogen, C 1 -C 6 alkyl, or
n is 0 to 5 inclusive;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —OH, —NH 2 , NR b R c , —CO 2 H, —CO 2 C 1 -C 6 alkyl, —NO 2 , —OC 1 -C 12 alkyl, —C 1 -C 8 alkyl, —CF 3 , —CN, —OCH 2 phenyl, —OCH 2 -substituted phenyl, —(CH 2 ) m -phenyl, —O-phenyl, —O-substituted phenyl,
—CH═CH-phenyl, —O(CH 2 ) p NR b R c ,
—NH(CH 2 ) p NR b R c , —N(C 1 -C 6 alkyl)(CH 2 ) p NR b R c ,
R 8 is COOH, tetrazolyl, —SO 2 R d , or —CONHSO 2 R d ;
R b and R c are independently hydrogen, —C 1 -C 6 alkyl, —(CH 2 ) m -phenyl, or R b and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
R d is hydrogen, —C 1 -C 6 alkyl, —CF 3 , or phenyl;
m is 0 to 5 inclusive;
p is 1 to 5 inclusive;
A is CH or N;
R 1 and R 2 , when adjacent to one another, can be methylene-dioxy;
or the pharmaceutically acceptable salts thereof. b. allowing sufficient time for the labeled compound to become associated with amyloid deposits; and c. detecting the labeled compound associated with the amyloid deposits.
29 . The method of claim 28 wherein the patient has or is suspected to have Alzheimer's disease.
30 . The method of claim 28 wherein the labeled compound is a radio labeled compound.
31 . The method of claim 28 wherein the labeled compound is detected using MRI.
32 - 41 . (Cancelled).
42 . A compound of Formula I.
wherein
R a is hydrogen, C 1 -C 6 alkyl, or
n is 0 to 5 inclusive;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, —OH, —NH 2 , NR b R c , —CO 2 H, —CO 2 C 1 -C 6 alkyl, —NO 2 , —OC 1 -C 12 alkyl, —C 1 -C 8 alkyl, —CF 3 , —CN, —OCH 2 phenyl, —OCH 2 -substituted phenyl, —(CH 2 ) m -phenyl, —O-phenyl, —O-substituted phenyl,
—CH═CH-phenyl, —O(CH 2 ) p NR b R c ,
—NH(CH 2 ) p NR b R c , —N(C 1 -C 6 alkyl)(CH 2 ) p NR b R c ,
R 8 is COOH, tetrazolyl, —SO 2 R d , or —CONHSO 2 R d ;
R b and R c are independently hydrogen, —C 1 -C 6 alkyl, —(CH 2 ) m -phenyl; or R b and R c taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
R d is hydrogen, —C 1 -C 6 alkyl, —CF 3 , or phenyl;
m is 0 to 5 inclusive;
p is 1 to 5 inclusive;
A is CH or N;
R 1 and R 2 , when adjacent to one another, can be methylene-dioxy;
or the pharmaceutically acceptable salts thereof.
43 . A pharmaceutical formulation comprising a compound of claim 42 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.Join the waitlist — get patent alerts
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