ZA200109794B - Method of inhibiting amyloid protein aggregation and imaging amyloid deposits. - Google Patents

Method of inhibiting amyloid protein aggregation and imaging amyloid deposits. Download PDF

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Publication number
ZA200109794B
ZA200109794B ZA200109794A ZA200109794A ZA200109794B ZA 200109794 B ZA200109794 B ZA 200109794B ZA 200109794 A ZA200109794 A ZA 200109794A ZA 200109794 A ZA200109794 A ZA 200109794A ZA 200109794 B ZA200109794 B ZA 200109794B
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South Africa
Prior art keywords
phenyl
phenylamino
benzoic acid
ethyl
dichloro
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ZA200109794A
Inventor
Corinne Elizab Augelli-Szafran
Christopher Franklin Bigge
Shunichiro Hachiya
Takenori Kimura
Annette Theresa Sakkab
Lary Craswell Walker
Nian Zhuang
Mark Robert Barvian
Shelley Ann Glase
John Steven Kiely
Yingjie Lai
Mark James Suto
Tomoyuki Yasunaga
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Warner Lambert Co
Yamanouchi Pharma Co Ltd
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Application filed by Warner Lambert Co, Yamanouchi Pharma Co Ltd filed Critical Warner Lambert Co
Publication of ZA200109794B publication Critical patent/ZA200109794B/en

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Description

:
METHOD OF INHIBITING AMYLOID PROTEIN AGGREGATION
AND IMAGING AMYLOID DEPOSITS
FIELD OF THE INVENTION
This invention relates to a method of inhibiting amyloid protein aggregation and imaging amyloid deposits. More particularly, this invention relates to a method of inhibiting amyloid protein aggregation in order to treat
Alzheimer’s disease.
BACKGROUND OF THE INVENTION
Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrillar proteins in the tissues of a patient. The fibrillar proteins that comprise the accumulations or deposits are called amyloid proteins. While the + particular proteins or peptides found in the deposits vary, the presence of fibrillar morphology and a large amount of B-sheet secondary structure is common to many types of amyloids. An amyloid deposit is formed by the aggregation of amyloid proteins, followed by the further combination of aggregates and/or amyloid proteins.
The presence of amyloid deposits has been shown in various diseases, each with its particular associated protein, such as Mediterranean fever, Muckle-
Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer’s disease, Down's syndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler- rs
Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,
Bo-microglobulin amyloid in dialysis patients, inclusion body myositis,
Bo-amyloid deposits in muscle wasting disease, Sickle Cell Anemia, Parkinson’s
Disease, and Islets of Langerhans diabetes Type 11 insulinoma.
Po.
Alzheimer’s disease is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgement, and emotional stability that gradually leads to mental deterioration and ultimately death. Because Alzheimer’s disease and related degenerative brain disorders are a major medical issue for an increasingly aging population, the need for new treatments and methods for diagnosing the disorders are needed.
A simple, noninvasive method for detecting and quantitating amyloid deposits in a patient has been eagerly sought. Presently, detection of amyloid deposits involves histological analysis of biopsy or autopsy materials. Both methods have major drawbacks. For example, an autopsy can only be used for a postmortem diagnosis.
The direct imaging of amyloid deposits in vivo is difficult, as the deposits have many of the same physical properties (i.e., density and water content) as normal tissues. Attempts to image amyloid deposits directly using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules has provided some selectivity on the periphery of tissues, but has provided for poor imaging of tissue interiors.
Thus, it would be useful to have a noninvasive technique for imaging and quantitating amyloid deposits in a patient. In addition, it would be useful to have compounds that inhibit the aggregation of amyloid proteins to form amyloid deposits. ; SUMMARY OF THE INVENTION } 25 The present invention provides 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
R3 RS r! — RS (CH); a aX 4 R 6 rR’ R R 2
R wherein 0
I
R2 is hydrogen, C1-Cg alkyl, or -CC1-Cg alkyl; nis 0 to 5 inclusive;
RI], RZ, R3, R4, RS, RS, and R7 are independently hydrogen, halogen, -OH, -NH», NRPR€, -CO9H, -CO,C1-Cg alkyl, -NOp, -OC1-C13 alkyl, -C1-Cg alkyl, -CF3, -CN, -OCH> phenyl, -OCH»-substituted phenyl, -(CH2)p-phenyl, -O-phenyl, -O-substituted phenyl, 0 0) -CH=CH-phenyl, -O(CH2),NRbRC, -CNRYRC, -NHCRP, “NH(CHp)pNRPRE, -N(C-Cgalkyl)(CH2)pNRPRE,
CHOC Ce alkyl — :
CH, 0C,-C alkyl
R8 is COOH, tetrazolyl, -SOoRY, or -CONHSO,RY;
Rb and RC are independently hydrogen, -C 1-Cg alkyl, -(CH2)m-phenyl, or
RD and RC taken together with the nitrogen atom to which they are } attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C{-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
Rd js hydrogen, -C1-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; pis 1 to 5 inclusive;
AisCHorN;
v WO 00/76489 PCT/US00/15071
R1 and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof. ol
In a preferred embodiment, the ie (CH) group is attached at rR” 1,
R the 4-position of the phenyl ring.
In a preferred embodiment of the method, in the compounds of Formulal
RA2 is hydrogen; nis 2; and
R3 and R# are hydrogen.
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen;
R! is halo;
RZ is hydrogen or halo; :
R3, R4, RS, and RO are hydrogen; and nis 2 to 5 inclusive.
In another preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 2 or3;
R! is -NRPRC; and ; RZ, R3, R4, RS, and R7 all are hydrogen. :
In a preferred embodiment of the method, in the compounds of Formula I ; R2 is hydrogen; nis 2;
R3 and R#4 are hydrogen; and
R1, RZ, and R7 are independently chlorine, -N(CH,CH3)», -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH» phenyl,
~O(CH2)3N(CH3)p, -O phenyl, -O(CH3)7CHz, -CH(CH7 OCH, CH3)p, pyrrolyl, -CH=CH-phenyl, , -N[(CH3)3 CHz3]y, substituted phenyi, ~OCHjp-substituted phenyl, pyrrozolyl, or -N(phenyl)).
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 3,4,or5;
R3 and R4 are hydrogen; and
RL, RZ, and R7 are independently chlorine or hydrogen.
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 2;
R3 and R% are hydrogen; and
R35, RO, and R8 are independently hydrogen, -COzH, -NO», -OCH3,
Oo imidazolyl, -SCH3, -CN, fluorine, -CH3, -CF3, halogen, oO -NH-C1-Cg alkyl, -N(C1-Cgalkyl), -NH», or pyrrolyl.
In a preferred cmbodiment of the method, in the compounds of Formula .
RA2 is hydrogen; nis 2; .
R3 and R# are hydrogen; and
RS is -CO5H.
Also preferred is 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
R3 R> « Ir J 2 IN Th re RK Age
R wherein
Rais hydrogen; nis 1 to 5 inclusive;
R3 and R4 are hydrogen;
R1, R7, and R2 are independently chlorine, -N(CH,CH3)), -OH, CH3-, ) 10 fluorine, -CF3, phenyl, hydrogen, -OCH> phenyl, -O(CH2)3N(CH3)2, -O phenyl, -O(CHp)7CH3, -CH(CHOCH7,CH3)», pyrrolyl, -CH=CH-phenyl, -N[(CH3)3CH3]», substituted phenyl, -OCHy-substituted phenyl, pyrazolyl, or -N(phenyl);;
RS and RS are independently hydrogen, -CO5H, -NO», -OCH3, imidazolyl, -CN, fluorine, -CH3z, -CF3, or pyrrolyl; or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the method, compounds of Formula I are ’ 2-{4-[2-(3,4-Dichlorophenyl)ethyl}phenylamino }-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethylJphenylamino }-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)-ethylJphenylamino} benzoic acid,
2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino }-4-methoxy-
S-nitrobenzoic acid; 2- {4-13-(3,4-Dichlorophenyljpropyljphenylamine }-4-imidazo-1-yl-
S-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-
S-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-phenylaminc)-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-phenyi)-ethylj-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; : 15 + 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)-pheny!]-ethyl }-phenylamino)- benzoic acid; 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]J-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]-ethy! }-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-{4-2-[(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]phenyljamino-benzoic acid; 2-{4-[3~(4-Diethylaminophenyl)propyl]phenylamino } benzoic acid;
2-{4-[3-(4-Nitrophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3~(3-Nitrophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Aminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(3-Aminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[2-(4-Aminophenyl)ethyl}phenylamino } benzoic acid;
2-{4-[2-(4-Dipropylaminophenyl)ethylJphenylamino} benzoic acid monohydrochloride; 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride monohydrate; 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino } benzoic acid;
2-{4-[3-(3-Dimethylaminophenyl)propyl}phenylamino} benzoic acid; 2-{4-[3-(4-Ethylaminophenyl)propy!]phenylamino } benzoic acid; 2-(N-{4-[3-(4-Diethylaminophenyi)propyl]phenyl }-N-ethylamino)benzoic acid;
2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino } benzoic acid; 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino} benzoic acid; 2- {4-[3-(4-Dimethylaminophenyl)propyl]phenylamino} benzoic acid,
2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino } benzoic acid; 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino } benzoic acid; 2-{4-[2-(3-Dipropylaminopheny!)ethyl]phenylamino} benzoic acid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino } benzoic acid monohydrochloride; 2-{4-[3-(4-Acetylaminopheny!)propyl]phenylamino } benzoic acid; 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(3-Diethylaminophenyl)ethyl]phenylamino } benzoic acid monohydrochloride; : 15 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino} benzoic acid monohydrochloride; 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino} benzoic acid; : 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino} benzoic acid;
2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl} phenylamino)benzoic acid; 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Diethylaminomethylphenyl)propyl}phenylamino} benzoic acid;
2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino } benzoic acid;
’ 2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino }-benzoic acid;
2-{4-[3-(3-Piperidin-1yl-phenyl)-propyl]-phenylamino }-benzoic acid; 2-{4-[3-(4-[2-Diethylaminoethylamino]phenyl)-propyl]phenylamino}-
benzoic acid; 2-{4-[2-(4-[Hydroxycarbonylmethylamino]phenyl)ethyl]phenylamino}-
benzoic acid;
WC §0/76483 PTT/US00/15071 - 2~{4-[2-(4-[2-Diethylaminoethylamino]phenyl)ethyl]phenylamino}- benzoic acid, 2- {4-[3-(4-Morpholinophenyl)propyliphenylamine }-benzeic acid; 2-{4-[3-(4-Piperazinylphenyl)propyl|phenylamino}-benzoic acid; and 2-[4-(3,4-Dichlorophenyl)phenylamino]benzoic acid.
The invention also provides the foregoing compounds wherein the benzoic acid portion is replaced with a pyridyl carboxylic acid, for example, 4-[4-(3,4- dichlorophenyl)phenylamino]-3-hydroxycarbonylpyridine.
Also provided is 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
R3 R> rR} Jas — RS
CH rR? Lo en re RY Age
R wherein 0) i
R2 is hydrogen, C1-Cg alkyl, or -CC1-Cg alkyl; nis 0 to 5 inclusive;
RL R2, R3, R4, RS, RS, and R7 are independently hydrogen, halogen, -OH, -NH, NRbRC, -COyH, -CO,C1-Cg alkyl, -NOp, -0C;-C12 alkyl, -C1-Cg alkyl, -CF3, -CN, -OCHy phenyl, -OCHjy-substituted - phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl,
Oo 0) i
I I
-CH=CH-phenyl, -O(CH2),NRPRE, -CNRbRE, -NHCRP, -NH(CH2),NRPR®, -N(C}-Cgalkyl)(CH)pNRPRS,
/ CH,0C-Cg alkyl
CH,0C,-Cg alkyl
R8 is COOH, tetrazolyl, -SOoRY, or -CONHSO,RY;
RD and RC are independently hydrogen, -C1-Cg alkyl, -(CH2),-phenyl, or
Rb and RC taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
Rd js hydrogen, -C1-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; pis 1to 5 inclusive;
AisCHorN;
RI and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 2; and
R3 and R4 are hydrogen.
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; ] 20 R3 and R4 are hydrogen; and nis 2 to 5 inclusive. ’ In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 2;
R3 and R#4 are hydrogen; and
RL, R?, and R7 are independently chlorine, -N(CHpCHz),, -OH, CHs-, fluorine, -CF3, phenyl, hydrogen, -OCH» phenyl, -O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3, -CH(CHy OCH, CH3s)p, pyrrolyl, -CH=CH-phenyl, , -N[(CH2)3CH3]p, substituted phenyl, -OCHy-substituted phenyl, pyrazolyl, or -N(phenyl).
In a preferred embodiment of the method, in the compounds of Formula I
R2 is hydrogen; nis 3,4,0r5;
R3 and R4 are hydrogen; and
Rl, R2, and R7 are Independently chlorine or hydrogen.
In a preferred embodiment of the method, in the compounds of Formula 1
Rais hydrogen; nis 2;
R3 and R4 are hydrogen; and
RS and R6 are independently hydrogen, -COH, -NO», -OCHj3, imidazolyl, -CN, fluorine, -CHj3, -CF3, halogen, -NH-C-Cg alkyl, -N(C-Cgalkyl)y, -NHo, or pyrrolyl.
In a preferred embodiment of the method, in the compounds of Formula I
R# 1s hydrogen; : nis2;
R3 and R4 are hydrogen; and -
R5 is -CO5H.
Also provided is a preferred 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
R3 R rl Jas 3 RS
Be NS re RY Age
R wherein
RA js hydrogen; nis 1 to 5 inclusive;
R3 and R% are hydrogen;
R1,R7, and RZ are independently chlorine, -N(CH2CH3)), -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH> phenyl, -O(CH2)3N(CH3)3, -O phenyl, -O(CH5)7CH3, -CH(CH»OCH>CH3)5, pyrrolyl, -CH=CH-phenyl, -N[(CH2)3CH3]2, substituted phenyl, -OCH»-substituted phenyl, pyrazolyl, or -N(phenyl);
RS and RS are independently hydrogen, -CO,H, -NO,, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl,;
R8 is COOH or tetrazolyl; or the pharmaceutically acceptable salts thereof.
The most preferred compounds provided by the invention have Formula II . rl RS me OT
COOH and pharmaceutically acceptable salts thereof, wherein:
R! is halo;
R2isH or halo; and n and R6 are as defined above in Formula I.
Another preferred group of compounds have Formula III
Rl RS
R? AN
COOH and pharmaceutically acceptable salts thereof, wherein:
Rlijs halo;
R2 is H or halo; and n and RO are as defined above in Formula I.
Another group of preferred invention compounds have Formula IV rl RS
Oren
RZ v
Nm
N=N and pharmaceutically acceptable salts thereof, wherein:
RI is halo;
R2isHor halo; and n and RS are as defined above in Formula I.
In a preferred embodiment of the method, the novel compounds of Formula I are provided which are 2-{4-[2-(3,4-Dichlorophenyl)ethyl}phenylamino }-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-
S-nitrobenzoic acid; 2-{4-{2-(3,4-Dihydroxy-phenyl)-ethyl}-phenylamino } benzoic acid; 2-{4~[2-(4-Dibutylamino-phenyl)-ethyljphenylamino} benzoic acid;
2-{4-[2~(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino } benzoic acid; 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino }-4-methoxy- 5-nitrobenzoic acid; 2-{4-[2-[-(3 A4-Dichlorophenyl)propyljphenylamino }-4-imidazo-1-yl-
5-nitrobenzoic acid; 2-{4-[2-[-(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-pheny!)-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-pheny!}-cthyl]-phenylamine }4,5-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-trifluoromethyi- benzoic acid;
2-{4-[2~(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl- benzoic acid,
2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylaminec}-5-pyrrol-1-yl-benzoic acid; 2-{4-[2-(4-Benzyloxy-phenyl)-cthyl]-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-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]phenyljamino-benzoic acid; or 2-[4-(3,4-Dichlorophenyl)phenyl]Jaminobenzoic acid.
The present invention also provides the compounds: 2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino }-4-methoxy-
S-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-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino } -4-methoxy-
S-nitrobenzoic acid; 2-{4-[2-[-(3,4-Dichlorophenyl)propyl)phenylamino }-4-imidazo-1-yl- ’ 25 5-nitrobenzoic acid; 2-{4-[4-(3,4-Dichlorophenyl)butyl]Jphenylamino} 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;
WG 50/76485 PCT/US06/15071 .
2-[4~(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino }-5-nitro-berzoic acid; 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamine }-5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethy!]-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-[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-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)-ethyll-phenylamino}-5-methanesulfony}-
benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazoi-1-yl-
benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoic acid;
2-{4-[2-(3,4-Dichloro-pheny}l)-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-flucro-berzcic acid; 2-{4-[2-(3,4-Dichloro-phenyi)-ethyi]-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)-pheny!]-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 aéid; 2-{4-[2~(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl } -phenylamino)-benzoic i 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;
WO §0/7648% PCT/USG/15071 .
2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl} -phenylamino)- benzoic acid; 2- {4-[2-(3,4-Dichloro-pheny!)-ethyl]-phenylaminc}-5-aminc-berzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-triflucromethyl- benzoic acid; 2-{4-[2-(3,4-Dichlorophenyl)jphenylamino }-S-nitrobenzoic acid; 2-{4-[2-[(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)ethylJphenylamino } -benzoic acid; 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Nitrophenyl)propyllphenylamino} benzoic acid; 2-{4-[3-(3-Nitropheny!)propyl]phenylamino}benzoic acid;
2-{4-[3-(4-Aminephenyl)propy!lphenylamino} benzoic acid; 2-{4-[3-(3-Aminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[2-(4-Aminophenyl)ethyl]phenylamino} benzoic acid; 2-{4-[2-(4-Dipropylaminophenyl)ethyl}phenylamino } benzoic acid monohydrochloride;
2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride monohydrate; 2-{4-{3-(3-Dipropylaminophenyl)propyl]jphenylamino } benzoic acid; 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Ethylaminophenyl)propyljphenylamino} benzoic acid,
2-(N-{4-[3-(4-Diethylaminophenyl)propyl]pheny!}-N-ethylamino)benzoic acid; } 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino } benzoic acid; 2-{4-{3-(3-Biethylaminophenyl)propyl]phenylamino} benzoic acid; ’ 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino} benzoic acid;
2-{4-[3-(4-Dimethylaminophenyl)propyl}phenylamino} benzoic acid; 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino} benzoic acid; 2-{4-[2-(3-Acetylaminopheny!)ethyl]phenylaminc} benzoic acid;
2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride;
2-{4-[3-(4-Acetylaminophenyl)propyl}phenylamino } benzoic acid; 2-{4-[3-(3-Acetylaminophenyl)propyl]]phenylamino} benzoic acid; 2-{4-[3-(3-Diethylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride; 2-{4-[2-(3-Piperidin-1-ylphenyl)ethyl]phenylamino } benzoic acid monohydrochloride; 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(3-Dibutylaminophenyl)propyl}phenylamino} benzoic acid; 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl]propyl } phenylamino)benzoic acid;
2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Diethylcarbamoylpheny!)propyljphenylamino } benzoic acid; 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid;
2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyl]-phenylamino}-benzoic acid; 2-{4-[3-(3 -Piperidin-1yl-phenyl)-propyl]-phenylamino}-benzoic acid; {5-[(1-Butyl-1,2,3 4-tetrahydro-6-quinolyl)methylidene}-4-0xo0-2-
thioxothiazolidin-3-yl}acetic acid;
{5-[(1-Butyl-2,3-dihydro-1H-indol-5-yl)methylidene]-4-0x0-2-
) thioxothiazolidin-3-yl}acetic acid;
3-{5-[(1-Butyl-1,2,3 4-tetrahydroquinolin-6-yl)methylidene]-4-o0xo0-2- ) thioxothiazolidin-3-yl}propanoic acid;
4-{5-[(1-Butyl-1,2,3 4-tetrahydroquinolin-6-yl)methylidene]-4-oxo0-2-
thioxothiazolidin-3-yl}butanoic acid; or 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
Also provided are the foregoing compounds wherein the terminal phenylalkyl group is attached at the 2- or 3-position of the central phenyl ring, i.e, compounds of the Formula la rR}
Ei
Y RZ ~~ rR . Ia £0 { J RE
R RA x A RS
Typical 2- and 3-substituted compounds are: 2-{3-[2-(3,4-Dichlorophenyl)ethyl}phenylamino} -benzoic acid; 2-{2-[2-(3,4-Dichlorophenyl)ethylIphenylamino}-benzoic acid; 2-{3-[3~(4-Diethylaminophenyl)propyl]phenylamino}-benzoic acid; 2-{3-[3-(4-Di-n-propylaminopheny!)propyl]phenylamino }-benzoic acid; 2-{3~[3-(4-n-Propylaminophenyl)propyl]phenylamino}-benzoic acid; 2-{3-[3-(4-[2-Diethylaminoethylamino]phenyl)propyl]phenylamino }- benzoic acid; 2-{2-[3-(4-[Hydroxycarbonylmethylamino]phenyl)propyl]phenylamino}- benzoic acid; 2-{2-[2-(3-[2-Diethylaminoethylamino]phenyl)ethyl]phenylamino }- benzoic acid; 2-{3-[3-(4-Morpholinophenyl)propyl]phenylamino}-benzoic acid; 2-{3-[3-(4-Piperazinylphenyl)propyl]phenylamino}-benzoic acid; 2-{3-[2-(4-Chlorophenyl)ethylIphenylamino}-benzoic acid; 2-{3-[3-(3,4-Dichiorophenyl)propyljphenylainino }-benzoic acid; and 2-{4-[4-(4-{4-Methylpiperazinyl} phenyl)butyl]phenylamino}-benzoic acid. }
Pharmaceutical formulations of the novel compounds admixed with a pharmaceutically acceptable diluent, carrier, or excipient are also provided.
Also provided is 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:
R3 R3
IAN 8
Rl N R (CHy){ a A oo r4 R RO
R2 wherein 0) i
Rais hydrogen, C1-Cg alkyl, or -CC-Cg alkyl; nis 0 to 5 inclusive;
RI, R2 R3, R4, RS, RS, and R7 are independently hydrogen, halogen, -OH, -NHp, NRbPRC, -CO5H, -CO,C1-Cg alkyl, -
NO», -OC1-Cy2 alkyl, -C-Cg alkyl, -CF3, -CN, -OCH2 phenyl, -OCH,-substituted phenyl, ~(CHy)p,-phenyl, -O- phenyl, -O-substituted phenyl, 0 0)
I I
-CH=CH-pheny], -O(CHp),NRDRE, -CNRbRE, -NHCRD, -NH(CHp)pNRDRS, -N(C; -Cgalkyl)(CHp)pNRPRS,
CHOC 1-Ce alkyl — .
CH,0C, -C¢ alkyl
R38 is COOH, tetrazolyl, -SO5RY, or -CONHSO5RY; ) RD and RC are independently hydro gen, -C1-Cg alkyl, -(CH2)m- phenyl, or Rb and RC taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;
R49 is hydrogen, -C1-Cg alkyl, -CF3, or phenyl; m is 0 to § inclusive; pis 1 to 5 inclusive;
AisCHorN;
R1 and RZ, 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.
In a preferred embodiment of the method, the patient has or is suspected to have
Alzheimer’s disease.
In a preferred embodiment of the method, the labeled compound is a radio labeled compound.
In a preferred embodiment of the method, the labeled compound is detected using
MRI
The present invention also provides the preferred compounds: 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino }-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino }-5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino } benzoic acid; 2-[[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl] phenyl ]amino-benzoic : acid; 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino } -benzoic acid, . and pharmaceutical formulations thereof.
Pharmaceutically acceptable acid addition salts, amides, and prodrugs of the : foregoing compounds are also provided by this invention.
DETAILED DESCRIPTION OF THE INVENTION
The term “alkyl” means a straight or branched chain hydrocarbon having from 1 to 12 carbon atoms. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, hexyl, octyl, decyl, and 1,1-dimethyloctyl.
Preferred alkyl groups are C1-Cg alkyl, and especially C1-Cg alkyl.
The term “alkoxy” means an alkyl group attached to an oxygen atom.
Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are C;-C12 alkoxy, and especially C1-Cg alkoxy.
The term “halogen” includes chlorine, fluorine, bromine, and iodine.
The term “substituted” means that one or more hydrogen atom in a molecule has been replaced with another atom or group of atoms. For example, substituents include halogen, especially chloro, -OH, -CF3, -NO», -NH», -NH(C-Cgalkyl), -N(C1-Cgalkyl)p, C1-Cg alkyl, -OC1-Cg alkyl, -CN, -CF3, -CO2H, and -CO2C1-Cg alkyl.
The term “substituted phenyl” means a phenyl ring in which from 1 to ’ 4 hydrogen atoms have been independently replaced with a substituent, preferably one selected from the list above. Typical “substituted phenyl” groups include 4-chlorophenyl, 3,4-dibromophenyl, 3-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl, and 4-dimethylaminophenyl.
The symbol “-” means a covalent bond.
Substituent groups represented by R1, R3, and R3, for example, include amino(NRPRC) and acylamino (-NHCORY). Rb and R€ can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, and typical NRbRC groups include methylamino, diethylamino, isobutyl-propylamino, benzylamino, and 3,4- dimethoxybenzylamino. Examples of acylamino groups include formamido, acetamido, 2-phenylacetamido, and 2-(3-nitrophenyl)acetarnido. Rl R3, and R> can also be aminoalkoxy (-O(CH2),NRbR®) such as
N-methylaminomethoxy and 2-(N-benzylamino)ethoxy, as well as
WG §0/76485 PCT/USG/15071 . aminoalkylamino (-NH(CHp),NRPRE) such as 3-(dimethylamine)propylamine and 2-(N-ethyl-N-benzylamino)ethylamino. Substituent groups such as R1, R3, and RS additionally can be cyclic structures, for instance when NRPRE is part of the substituent group, and RP and RC are taken to gether with the nitrogen to which they are attached to form a cyclic ring selected from imidazole, pyrrole, piperidine, piperazine, 4-C1-Cg alkylpiperazine, morpholine, thiomorpholine, pyrazole, and decahydroisoquinoline.
Substituent groups such as R1, R2, R5, R6, and R7 also can be -CH=CH- phenyl (i.e., styryl), phenoxy, O-substituted phenyl such as 3-iodophenoxy, 2,4,6- trihydroxyphenoxy, 2-fluoro-3-nitrophenoxy, as well as -O-benzyl and -O-substituted benzyl such as 2-trifluoromethylbenzyloxy and 4-aminobenzyloxy.
The term “pharmaceutically acceptable salt, ester, amide, and prodrug” as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended : use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “salts” refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laureate, borate, benzoate, lactate, ’ phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate and laurylsulphonate salts, and the like. :
These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as, nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetracthylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, Berge S.M,, et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, nontoxic esters of the compounds of this invention include C-Cg alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods, for example by reacting a carboxylic acid of Formula I with an alcohol such as ethanol or benzyl alcohol.
Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary
C1-Cg alkyl amines and secondary Cy-Cg dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amides and
C1-C» dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods. . The term “prodrug” refers to compounds that are rapidly transformed : in vivo to yield the parent compound of the above formulas, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and
V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium
Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. : 25 In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, - ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds, as well as mixture thereof, including racemic mixtures, form part of this invention.
WG 00/76485 PCT/USHO/15071 -
In the first step of the present method of imaging, a labeled compound of
Formula I is introduced into a tissue or a patient in a detectable quantity. The compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well-known to those skilled in the art.
In the methods of the present invention, a compound can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures - 15 thereof, vegetable oils (such as olive oil), and injectable organic esters such as : ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is ‘ admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidene, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (€) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (©) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (1) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part : of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, ) dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, : polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfurning agents.
WG 00/76485 PCT/US00/15071 -
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
In a preferred embodiment of the invention, the labeled compound is introduced into a patient in a detectable quantity and after sufficient time has passed for the compound to become associated with amyloid deposits, the labeled compound is detected noninvasively inside the patient. In another embodiment of the invention, a labeled compound of Formula I is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the labeled compound in the tissue is detected apart from the patient. In a third embodiment of the invention, a tissue sample is removed from a patient and a labeled compound of Formula I is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits, the compound is detected. :
The administration of the labeled compound to a patient can be by a general or local administration route. For example, the labeled compound may be administered to the patient such that it is delivered throughout the body.
Alternatively, the labeled compound can be administered to a specific organ or tissue of interest. For example, it is desirable to Jocate and quantitate amyloid deposits in the brain in order to diagnose or track the progress of Alzheimer’s disease in a patient.
The term “tissue” means a part of a patient’s body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries. A detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen. The amount of a labeled compound to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the labeled compound can be given to a patient until the compound is detected by the detection method of choice. A label is introduced into the compounds to provide for detection of the compounds.
The term “patient” means humans and other animals. Those skilled in the art are also familiar with determining the amount of time sufficient for a compound to become associated with amyloid deposits. The amount of time necessary can easily be determined by introducing a detectable amount of a : 15 labeled compound of Formula I into a patient and then detecting the labeled compound at various times after administration.
The term “associated” means a chemical interaction between the labeled compound and the amyloid deposit. Examples of associations include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic- hydrophobic interactions, and complexes.
Those skilled in the art are familiar with the various ways to detect labeled compounds. For example, magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT) can be used to detect radiolabeled compounds. The label that is introduced into the compound will depend on the detection method desired. For example, if PET is ’ selected as a detection method, the compound must possess a positron-emitting atom, such as 11C or 18F. ) Another example of a suitable label in a compound of Formula I is an atom such as 13C, 15N, or 19F which can be detected using magnetic resonance imaging (MRI) which is also sometimes called nuclear magnetic resonance (NMR). In addition, the labeled compounds of Formula I may also be detected by
MRI using paramagnetic contrast agents.
Another example of detection is electron paramagnetic resonance (EPR).
In this case, EPR probes which are well-known in the art, such as nitroxides, can be used.
The imaging of amyloid deposits can also be carried out quantitatively so that the amount of amyloid deposits can be determined.
The present invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, by administering to a patient in need of inhibition of the aggregation of amyloid protein an amyloid protein inhibiting amount of a compound of Formula I. Those skilled in the art are readily able to determine an amyloid inhibiting amount by simply administering a compound of Formula I to a patient in increasing amounts until the growth of amyloid deposits is decreased or stopped. The rate of growth can be assessed using imaging or by taking a tissue sample from a patient and observing the amyloid deposits therein.
A patient in need of inhibition of the aggregation of amyloid proteins is a patient having a disease or condition in which amyloid proteins aggregate.
Examples of such diseases and conditions include Mediterranean fever, Muckle-
Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Alzheimer’s disease, Down’s syndrome,
Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,
B2-microglobulin amyloid in dialysis patients, inclusion body myositis,
Bo-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes
Type Il insulinoma.
Also provided by the present invention are compounds of Formula I wherein one or more atom in the compound has been replaced with a radioisotope (a labeled compound). The radioisotope can be any radioisotope. However, 3H, 1231, 1251, 1311, 11C, and 18F are preferred. Those skilled in the art are familiar with the procedure used to introduce a radioisotope into a compound. For example, a compound of Formula I wherein one carbon atom is 11C or 14C is readily prepared.
> WO 00/76489 PCT/US00/15071
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well- known to those skilled in the art.
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any manner.
EXAMPLES
SYNTHESIS
Compounds of Formula I can be prepared by several routes as illustrated in
Schemes 6 through 9. Schemes 1 through 5 show synthetic routes that can be used to obtain the desired starting amines (IV), (VIII), (XV), and (XXI).
In Scheme 1, the appropriately substituted aldehyde (I) and a nitrophenylacetic acid (II) yield olefin (JII) when heated in piperidine at 150°C.
Standard hydrogenation conditions, such as Raney nickel, give desired amine av).
Scheme 2 depicts the synthesis of amine (VIII) which contains a three methylene tether. Condensation of aldehyde (I) and nitro-ketone (V) in the } presence of sodium hydroxide gives the desired alpha, beta-unsaturated ketone, which upon standard hydrogenation conditions (Raney nickel) gives (VII) and then Wolff-Kishner conditions yields the desired amine (VIII).
Scheme 3 is very similar to Scheme 2, except that the aldehyde (I) is condensed with a substituted aniline (IX).
Scheme 4 illustrates standard Wittig conditions in which the starting materials (XII) and (XIII) are obtained via aldol condensation and ylide chemistry, respectively. Reaction of aldehyde (XII) and bromophosphorane (X11) in the presence of a base, such as butyl lithium, gives diene (XIV). Standard reduction conditions (e.g., Raney nickel) of (XIV) yields the desired amine (XV).
Scheme § illustrates the synthesis of amine (XX) which contains 2
S-methylene tether. Wittig reaction of the bromophosporane (XVII), which is formed from the corresponding substituted bromide (XVI), and nitro aldehyde (XIX), obtained from Swern oxidation of the corresponding alcohol (XV II), using a base (e.g., LHDMS) yields olefin (XX). Reduction of (XX) using standard conditions (Raney nickel) gives amine (XX1I).
Scheme 6 illustrates one route to obtain compounds of Formula I. Either by Buchwald coupling (Method A) followed by saponification or utilizing the
Ullman reaction (Method B), compounds of Formula I can be isolated from amines such as (IV), (VIII), and (XV). Compounds of Formula I that contain hydroxy groups, such as Examples 4 and 6, require demethylation of the hydroxy . protecting groups with reagents such as boron tribromide in the final step of the synthesis.
Protecting groups will also be used when reactive functional groups such as amino and carboxylic acids are present, so as to avoid unwanted side reactions.
Carboxy groups typically are converted to esters (e.g., tert-butyl, benzyl), and amino groups generally are acylated (e.g., acetyl or trimethylsilyl). These and other such protecting groups are well-known to organic chemists, and are fully described by Greene and Wuts in Protective Groups in Organic Synthesis, John
Wiley and Sons, New York (2 Ed. 1991). All citations are incorporated herein by reference.
Scheme 7 illustrates the synthesis of compounds of Formula I by reacting amines such as (IV), (VIII), and (XX1) with fluoro-nitre intermediate (XXIV), in the presence of a base (e.g., LHMDS or Et3N) to give ester (XXV). This ester can y then be saponified using standard conditions, such as sodium hydroxide.
In Scheme 8, amine (XV) can be coupled with readily available fluoro- : substituted carboxylic acids [e.g., (XX VI) or (XXVII)] in the presence of various bases (such as DBU or triethylamine) to yield compounds of Formula I
Scheme 9 depicts coupling of amine (VIII) with readily available methyl ester (XXVill) in the presence of a base, such as imidazole, to give ester {XXX}.
This ester can then be saponified as usual to give compounds of Formula I.
Scheme 10 illustrates the synthesis of fluoro-intermediate (XXIV) which is obtained by nitration of readily available methyl ester (XXX) to give (XXVIII).
Treatment of (XXVIII) with potassium cyanide gives (XXIV).
In Scheme 11, the synthesis of compounds related to Example 18 is illustrated. Reaction of the potassium salts of ortho-substituted benzoic acids (XXVI) with substituted anilines (XX VII) in the presence of potassium carbonate and cupric acetate yields various iodo-substituted aminobenzoic acids (XXVIII).
Reaction of (XXVIII) with substituted boronic acids and palladium chloride gives the desired substituted aminobenzoic acids (XXX).
It should, of course, be recognized that several invention compounds of
Formula I can be prepared from other compounds defined by Formula I, utilizing standard organic reactions such as oxidation, reduction, alkylation, condensation, elimination, and similar well-known synthetic processes. For example, compounds of Formula I wherein R2 is hydrogen are readily alkylated to form compounds wherein R3 is C1-Cg alkyl. Compounds wherein R1 is NH are readily acylated by reaction with an acid halide or acid anhydride to provide compounds wherein R1 is -NHCORD. Similarly, compounds wherein R1 is NO, are easily reduced to provide compounds wherein R1 is NHj. The benzoic acids (where R8 is COOH) are readily converted to esters and amides, as well as salts and other prodrugs by routine processes. For example, the benzoic acid can be reacted with oxalylchloride to form the acid chloride, which then readily reacts with a sulfonamide such as methanesulfonamide to produce the corresponding invention compound where R8 is -CONHSO,CHj.
Formation of Amines
Scheme
CHO + Piperidine RZ rR?
HOOC NOy ————— el 150°C, 5h ~ NO, ® Im Rr! (um
Ra-Ni/THF or
Step B | Pd-C/DMF
R2 R7 1
R mw
Scheme 2
O 7 O 2 Rr? StepA” RZ R xn
Xo +H3C No, NeOH(g) 0 rR} EtOH rl NO, ® 4%) vn .{ Ra-Ni
Step B 7
Wolff-Kischner reaction SL emer rest te rete:
Step C’ F
Rr! NHy r! NH, (vim Vin a WO 00/76489 PCT/US00/15071
Scheme 3
Rr? RR 2 Bf R3 rR’ 0 ’ R NaOH( NY a aq) 4 + NH R , CHO 2 EtOH 7) (3 -
R H,C 1 2 4 eq. ELSiH
TFA, 25°C 3 rR R
NH
Rr! 2 (VII)
Scheme 4
RZ R7
R
® Br (XD
B= | P(Ph)3 7 8 ¥ R Se) n-BuLi/THF rl \ CHO +Br(Ph);P
XID (XII
CA rl
XIV)
RaNi
THF/MeOH rl ¢
XV)
~ WO 00/76489 PCT/US00/15071
Scheme 5 2 RT 2 7 toluene R R
PPhs —— rl Br °C xv (XVI)
DMSO, (COC) on— pT —% on —( ) > ano
XviD XIX)
LHDMS
THF
Rr? R? , ’ R
Ra-Ni/H, FP
HN oN) 2 7 rl THF R xXx1 XX)
Coupling Routes
Scheme 6
Method A, Step C (1) Pd,(dba);/BINAP
Cs,CO3, toluene 100°C, 36h 2 2 rR? - 5 R
R F, n=12,3 Br R RT 3
R
NH H
R! n 9, 2 Meooc R! . § ) N COOH (xx RS aw), (vip, xvy ————mmm— 0 ——— (2) SN NaOH Formula 1 RS
EtOH/THF reflux, 16 h
Method B, Step C
CwCuCl /K,CO4/DMF 150°C, 16 h
BO
HOOC
(XxX)
Al.
Scheme 7 7 n=0,1,3 R
RZ R
NO) (a) LHDMS, THF ————— rl NH, ¢ ” > Setge t retiux
COOR 30 (IV), (VI, (XD pay 7 3
Z R
R NO n = 2 x ] 1
R H
COOR
EXV) sNNaOH
EtOH/THF 5 7 reflux, 16h R
RZ R
NO, (J
Rl
H COOH
Compound of Formula I
R is an ester forming group such as alkyl or benzyl.
Scheme 8
O
0, - COOH . g 8 : . ’ ay
O,N NO.
ON COOH RK) 2 2
XXXVI), Compound of Formula 1
DBU
CH,CN (Vid
H~~ET NH, C
R; Et;N
CH,CN xv) B reflux H COOH oon (XXVID) Compound of Formula I
Scheme 9 ~ 7 F Ir
Z i~K A iL
R No, WN
VEA® (J _N—
Rl NH + F CH,CN
COOMe Et,N, reflux (VI) XXVIID 0 7 N
RZ? R NO,
AN p 1 }
R H
(XXIX) COOMe 5N NaOH
EtOH/THF reflux, 16 h 1D 2 Rr’ N
NO,
H
RB COOH
Compound of Formula
Synthesis of Fluorc-Intermediate
Scheme 10 .
F F Me
HNO; KCN
MeOH, 10°C
F H)SO4 ¢ ’ F
COOMe COOMe COOMe (XXX) XXvVIn XXIV)
Scheme 11
COOH COOK o8 K,CO,/MeOH of TL K,CO3, Cu(Ad), —— + ————
I
XXV) XXVD XXXVI) (OOH ,
N (HO),B
TL - 1 Cl
Cl (XXVIID) (XXIX)
K,CO3, PdCL,-dppf-CH,Cl,
Dioxane
COOH
H or T :
Cl 0,0,0.¢)
wQ 00/76489 PCT/USHH/15071 -
EXAMPLE 1
Preparation of 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid
Step A (Scheme 1): Preparation of 1,2-Dichloro-4-[2-(4-nitrophenyl)ethenyl]- benzene
A mixture of p-nitrophenylacetic acid (51.23 g, 0.28 mol) and 3,4-dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) was heated to 150-160°C for 5 hours under a Ny atmosphere. After cooling the reaction mixture, the precipitate was triturated in boiling methanol (MeOH) (50 mL) and then cooled to -5°C for 12 hours. The crystalline precipitate was filtered off, rinsed with cold MeOH and dried at room temperature in a vacuum oven overnight to yield an orange solid, 22.71 g (0.077 mol, 27%) of the desired product. mp 190-191°C.
MS:294.9 (MT).
Step B (Scheme 1): Preparation of 4-[2-(3,4-Dichlorophenyl)ethyl]benzenamine
A sample of 1,2-dichloro-4-[2~(4-nitrophenyl)ethenyl]benzene (98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in the presence of Raney
Nickel (Ra-Ni) (20 g) at 25°C to 40°C (AP = 13.5 psi) under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give an orange solid, 85.0 g (0.32 mol, 95.8%) of the desired product. mp 68-70°C.
MS: 266.1 (MH).
Step C (Scheme 6): Preparation of 2-{4~[2-(3,4-Dichlorophenyl)ethyl}phenylamino }-benzoic acid .
Method A
A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (28.37 g, 106.59 mmol), methyl 2-bromobenzoate (19.10 g, 88.82 mmol), cesium carbonate (40.52 g, 124.35 mmol), tris(dibenzylideneacetone-dipaladium(0) (2.44 g, 2.67 mmol) and (5)-(2,2"-bis(di-p-tolylphosphino-1,1’-binaphthyl (98%, (S)-tol-
BINAP) (2.71 g, 4.00 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (300 mL)
was heated to 100°C for 34 hours under N. After cooling to room temperature, the reaction mixture was diluted with ether, filtered through celite and rinsed thoroughly with ether. The filtrate was evaporated to dryness to give a brown residue (68 g). The resulted residue was dissolved in ethanol (EtOH) (50 mL) and
THF (100 mL), and then SN NaOH (aq.) (200 mL) was added, and the mixture was refluxed for 16 hours. The solvent was removed in vacuum. The residue was acidified with concentrated HCI to pH 3. The resulting precipitate was collected by filtration, triturated with boiling MeOH-H»O (4:1) and dried in a vacuum at room temperature for 16 hours to give Example 1, an orange solid (31.95 g, 0.083 mol, 77.6%). mp 175.0-177.0°C.
Analysis for Co1H{7N102Cly: Caled: C, 65.30; H, 4.44; N, 3.63.
Found: C, 65.40; H, 4.54; N, 3.50.
Method B
A mixture of 2-chlorobenzoic acid (5.4 g, 0.034 mol), 4-[2-(3,4- dichlorophenyl)ethyl]benzenamine (10.0 g, 0.037 mol), anhydrous potassium carbonate (16.9 g, 0.12 mol), copper powder (4.94 g, 0.077 mol), and copper(I) chloride (0.37 g, 0.0037 mol) in dry dimethylformamide (DMF) (85 mL) was heated to reflux for 24 hours at 150°C. The reaction mixture was poured into hot
HO (150 mL) and heated to 90°C on a hot plate. Charcoal was added, and this mixture was stirred at 90°C for 5 minutes. The warm brown mixture was filtered through filter paper. The cooled filtrate was then acidified with concentrated HCI (pH 1), and the precipitate was collected by filtration, triturated with boiling
MeOH-H7O (1:2) and dried under vacuum at room temperature for 16 hours to : give Example 1, an orange solid (2.3 g, 0.006 mol, 17.5%). mp 165.0-173.0°C.
Analysis for Cp1H17N102Cly: Caled: C, 65.30; H, 4.44; N, 3.63. . Found: C, 65.68; H, 4.58; N, 3.60.
EXAMPLE 2
Preparation of 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylaminc}-5-nitrobenzoic acid
Step C (Scheme 6): Preparation of 2-{4-[2~(3,4-Dichloro-phenyl)- ethyl]phenylamino}-5-nitrobenzoic acid methyl ester
A mixture of 4-[2-(3,4-dichlorophenyl)ethyl]benzenamine (600 mg, 2.25 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (489 mg, 1.88 mmol), cesium carbonate (857 mg, 2.62 mmol), tris(dibenzylideneacetone-dipaladium(0) (51 mg, 0.056 mmol} and (8)-(2,2"-bis(di-p-tolylphosphinc-1,1’-binaphthyl (98%, (S)-tol-BINAP) (58 mg, 0.085 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (16 mL) was heated to 100°C for 12 hours under Ny. After cooling, the reaction mixture was diluted with ether, filtered through celite and rinsed thoroughly with ether. The filtrate was evaporated to dryness to give a brown residue. Purification by flash chromatography (silica gel, 5% EtOAc/hexane) yielded 540 mg (1.21 mmol, 64%) of the desired product. mp 107-108°C.
Analysis for CooHgN2ClyO4: Caled: C, 59.34; H, 4.07; N, 6.29.
Found: C, 59.03; H, 4.04; N, 5.99.
Preparation of 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid
A solution of 2-{4-[2-(3,4-dichloro-pheny!)-ethyliphenylamino}- 5-nitrobenzoic acid methyl ester (340 mg, 0.76 mmol) and IN NaOH (aq.) (4.0 mL) in EtOH (4.0 mL) and THF (4.0 mL) was heated to reflux for 16 hours.
The solvent was removed in vacuum. The residue was diluted with HO and acidified with concentrated HCI to pH 1. The mixture was then extracted with ’ methylene chloride, dried (NapSO4), filtered and concentrated in vacuo to yield a yellow solid, 329 mg (0.76 mmol, 100%) of the desired product. mp 214-217°C.
Analysis for C7 1HjgN2Clp04: Caled: C, 58.49; H, 3.74; N, 6.50.
Found: C, 58.24; H, 3.81; N, 6.28.
> WO 00/76489 PCT/US00/15071
EXAMPLE 3
Preparation of 2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino} -4-methoxy- 5-nitrobenzoic acid
To a cooled (-78°C) solution of 4-[2-(3,4-dichloro-phenyl)- ethyl]phenylamine (0.836 g, 3.14 mmol) in THF (20 mL), LHDMS (6.28 mL, 1 M in THF, 6.28 mmol) was added dropwise. The reaction mixture was allowed to stir at -78°C for 10 minutes. A solution of 2-flouro-4-methoxy-5-nitrobenzoic acid methyl ester (0.72 g, 3.14 mmol) in THF (30 mL) was added dropwise, and this solution was stirred for 30 minutes at -78°C. The reaction mixture was allowed to gradually warm to room temperature and stir for 2 hours under a Ny atmosphere.
The reaction mixture was diluted with ethyl acetate (EtOAc), and acidified with
SN HCI (pH 3). The organic layer was dried (NapSOy), filtered and concentrated in vacuo to yield a brown residue. To a solution of this residue in EtOH (20 mL) and THF (40 mL), SN NaOH (50 mL) was added, and the mixture was refluxed for overnight. The solvent was removed in vacuum, and the residue was acidified with concentrated HCI (pH 3). The precipitate was collected by filtration, triturated with boiling MeOH-H7O (1:1), and dried in a vacuum oven for 16 hours to give Example 3, an orange solid (0.70 g, 1.51 mmol, 48%). mp 208-209°C. : Analysis for C22H18N205Cly: Caled: C, 57.28; H, 3.93; N, 6.07.
Found: C, 57.43; H, 3.69; N, 5.86.
EXAMPLE 4
Preparation of 2- {4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino } benzoic acid
Step A (Scheme 1): Preparation of 1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]- benzene
The title compound was prepared from p-nitrophenylacetic acid (25.0 g, 0.14 mol), and 3,4-dimethoxybenzaldehyde (21.0 g, 0.14 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A, to yield a yellow solid, 13.4 g (0.047 mol, 34%) of the desired product. mp: 133-134°C.
Analysis of C1gH15N 04: Calcd: C, 67.36; H, 5.30; N, 4.91. Found: C, 66.81;
H, 5.27; N, 4.84.
Step B (Scheme 1): Preparation of 4-[2-(3,4-Dimethoxy-phenyl)ethyl]- phenylamine 1,2-Dimethoxy-4-[2-{4-nitrophenyDethenyllbenzene (12.1 g, 0.042 mol} was reduced in the presence of 10% Pd-C (2.0 g) in dimethylformamide (DMF) (120 mL) at 25°C under a hydrogen atmosphere. The reaction mixture was concentrated in vacuo to give a solid. The solid was recrystallized from MeOH (400 mL) to yield a white crystalline product, 6.8 g (0.026 mol, 63%) of the desired product. mp 115-116°C.
Analysis for C1gH19N1O09: Caled: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.60;
H, 7.39; N, 5.35.
Step C (Scheme 6): Preparation of 2-{4-[2-(3,4-Dimethoxy-phenyl)ethyl]- phenylamino} benzoic acid
The title compound was prepared from 4-[2-(3,4-dimethoxy-phenyl)- ethyl]phenylamine (9.25 g, 0.036 mol), 2-chlorobenzoic acid (5.2 g, 0.036 mol), anhydrous potassium carbonate (15.0 g, 0.11 mol), copper powder (0.45 g, 0.007 mol), and a catalytic amount of copper(I) chloride in dry DMF (75 mL) using the procedure described in Example 1, Step C, Method B. After crystallization with MeOH/HO0, 4.5 g (0.012 mol, 33%) of the desired product was obtained. mp: 137-139°C.
Analysis for C33Hp3N 104: Caled: C, 73.19; H, 6.14; N, 3.71. Found: C, 73.47;
H, 6.03; N, 3.78.
Step D: Preparation of 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}- henzoic acid
To a solution of 2-{4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamino}- benzoic acid (0.28 g, 0.74 mmol) in CHCl, (20 mL), BBr3 (3.5 mL, IM in
CHCl», 3.5 mmol) was added at room temperature under a No atmosphere. The reaction mixture was allowed to stir at room temperature for 2 hours and then poured into ice water (50 mL). This mixture was extracted with EtOAc, and the organic layer was washed two times with water, dried (NapSOy), filtered and concentrated in vacuo to yield 0.24 g (0.69 mmol, 93%) of the desired product. mp 215-217°C.
Analysis for C21H9gNO4: Caled: C, 72.19; H, 5.48; N, 4.00. Found: C, 71.80;
H, 5.46; N, 3.99.
EXAMPLE 5
Preparation of 2-{4-[2-(4-Dibutylamino-phenyl)-ethylJphenylamino } benzoic acid
Step A (Scheme 1): Preparation of 1,1-Dibutylamino-4-[2-(4- nitrophenyl)ethenyl]benzene
The title compound was prepared from p-nitrophenylacetic acid (9.92 g, 0.055 mol) and 4-dibutylamino-benzaldehyde (14.32 g, 0.055 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a red solid, 4.12 g (0.012 mol, 16%) of the desired product.
MS: 352.2. (M™); 353.2. (MH).
Step B (Scheme 1): Preparation of 4-[2-(4,4-Dibutylaminophenyl)ethyl}- phenylamine
The title compound was prepared from 1,1-dibutylamino-4-[2-(4- nitrophenyl)ethenyl]benzene (4.10 g, 11.63 mmol) and Ra-Ni (2.0 g) in MeOH (100 mL) at 21°C to 32°C (AP = 3.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a colorless oil, 3.49 g (10.76 mmol, 92.6%) of the desired product.
MS: 325.3 (MH).
Step C (Scheme 6): Preparation of 2-{4-[2-(4-Dibutylamino-phenyl)- ethyl]phenylamino}-benzoic acid
The title compound was prepared from 2-chlorobenzoic acid (1.46 g, 9.36 mmol), 4-[2-(4,4-dibutylaminophenyl)ethyl]phenylamine (3.31 g, 10.20 mmol), anhydrous potassium carbonate (4.27 g, 30.88 mmol), copper powder (1.25 g, 19.65 mmol), and copper(I) chloride (0.092 g, 0.93 mmol) in dry
DMF (30 mL) using the procedure described in Example 1, Step C, Method B.
This procedure yielded a 0.39 g (0.87 mmol, 8.6%) of the desired product. mp 115-117°C.
Analysis for CogHagN9 Oy: Caled: C, 78.34; H, 8.16; N, £.30. Found: C, 78.15;
H, 8.07; N, 6.10.
EXAMPLE 6
Preparation of 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino } benzoic acid
Step A (Scheme 1): Preparation of 1,2,3- Trimethoxy-5-[2-{4- nitrophenyl)ethenyl]benzene
The title compound was prepared from p-nitrophenylacetic acid (18.6 g, 0.16 mol), 3,4,5-trimethoxy-benzaldehyde (19.6 g, 0.10 mol) and piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a solid, 13.0 g (0.041 mol, 41%) of the desired product. mp:192-195°C.
Step B (Scheme 1): Preparation of 4-[2-(3,4,5-Trimethoxy-phenyl)ethyl]- phenylamine
The title compound was prepared from 1,2,3-trimethoxy-5-[2-(4- nitrophenyl)ethenyl]benzene (9.5 g, 0.03 mol) and Ra-Ni (1.0 g) in THF (50 mL) at 21-26°C (AP = 9.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a tan powder, 6.6 g (0.023 mol, 74%) of the desired product. mp 91-93°C.
Step C (Scheme 6): Preparation of 2-{4-[2-(3,4,5-Trimethoxy-phenyl)- ethyllphenylaminn}-henzoic acid methyl ester
The title compound was prepared from 4-[2-(3,4,5-trmethoxyphenyl)- ethyllphenylamine (0.75 g, 2.61 mmol), methyl 2-bromobenzoate (0.47 g, 2.17 mmol), cesium carbonate (0.99 g, 3.04 mmol), tris(dibenzylideneacetone- dipaladium(0) (0.06 g, 0.065 mmol) and (S)-(-0-2,2’-bis(di-p-tolylphosphino-1,1’- binaphthyl (98% (S)-Tol-BINAP) (0.066 g, 0.098 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (100 mL) using the procedure described in Example 1, Step C,
Method A to yield a yellow oil, 0.69 g (1.63 mmol, 76%) of the desired product.
Analysis for Co5H7N 105: Caled: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.53;
H, 6.24; N, 3.14.
Preparation of 2-{4-[2-(3,4,5- Trimethoxy-phenyl)ethyl]phenylamino} -benzoic acid
To a solution of 2-{4-[2-(3,4,5-trimethoxyphenyl)ethyl]phenylamino}- benzoic acid methyl ester (0.62 g, 1.47 mmol) in THF-EtOH (2:1, 6 mL), IN
NaOH solution (4 mL) was added, and the reaction mixture was heated to reflux for 5 hours. The reaction mixture was then concentrated in vacuo to remove the organic solvent. The residue was acidified with concentrated HCI (pH 3). This precipitate was collected by filtration, triturated with boiling MeOH-H50 (4:1) and dried in vacuum at room temperature for 16 hours to give the title compound as a white solid, 0.59 g (1.45 mmol, 98.5%). mp 146.0-147.0°C.
Analysis for Co4Hp5N105: Caled: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.54;
H, 6.43; N, 3.15.
Step D: Preparation of 2-{4-[2-(3,4,5-Trihydroxyphenyl)ethyl]phenylamino}- benzoic acid
The title compound was prepared from 2-{4-[2-(3,4,5-trimethoxy-phenyl)- ethyl]phenylamino}benzoic acid (0.50 g, 1.23 mmol) in CHCl5 (40 mL) and
BBr3 (10 mL, 1M in CH3 Cl», 10.0 mmol) using the procedure described in
Example 4, Step D. This procedure yielded a green solid, 0.25 g (0.68 mmol, 65%) of the desired product. mp: 160.0-162.0°C.
Analysis for C21H1gN105-1.44 HO: Caled: C, 64.46; H, 5.64; N, 3.58.
Found: C, 64.07; H, 5.27; N, 3.39.
EXAMPLE 7
Preparation of 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino } -4-methoxy- 5-nitrobenzoic acid
Step A’ (Scheme 2): Preparation of 3-(3,4-Dichlorophenyl)-1-(4-nitro- phenylpropenone
Sodium hydroxide (7.3 g, 0.18 mol) was dissolved in water {80 mL) and 95% EtOH (80 mL) and cooled to 10°C with an ice-HpO bath. 3,4-Dichlorobenzaldehyde (31.8 g, 0.18 mol) was added in one portion. After the addition, the mixture was warmed to 15°C. 1-(4-Nitrophenyl)ethanone (30.0 g, 0.18 mol) was added at this temperature with rigorous stirring. After stirring for 5 minutes, the reaction mixture was diluted with 95% EtOH (300 mL). The resulting tan mixture was stirred at room temperature for 30 minutes, then stirred with an ice-H7O bath underneath the flask for 2 hours. The light brown solid was filtered off, washed with HO, and air-dried. The solid was dissolved in hot THF (1.5 L) and treated with charcoal. The resulting mixture was filtered off, and the filtrate was diluted with 95% EtOH (500 mL). This solution was filtered and oven-dried (40°C) to yield a light brown solid, 38.56 g (0.12 mol, 66%) of the title compound. mp 220-223°C.
Analysis for C15HgCIpNO3: Caled: C, 55.93; H, 2.82; CI, 22.01; N, 4.35.
Found: C, 55.79; H, 2.93; Cl, 22.16; N, 4.32.
Step B’ (Scheme 2): Preparation of 1-(4-Amino-phenyl)-3-(3,4- dichlorophenyl)propan-1-one 3-(3,4-Dichlorophenyl)-1-(4-nitro-phenyl)propenone (34.56 g, 0.11 mol) was reduced in the presence of Ra-Ni (3.0 g) in THF (250 mL) at 20°C to 32°C (AP = 33.4 psi) under a hydrogen atmosphere. The reaction mixture was concentrated in vacuo and recrystallized from MeOH (100 mL) to give a light yellow solid, 23.5 g (0.080 mol, 75%) of the desired product. mp 127-129°C.
Analysis for C15H13CIoNO: Caled: C, 61.24; H, 4.45; N, 4.76; Cl, 24.10.
Found: C, 60.91; H, 4.60; N, 4.70; Cl, 23.98. :
Step C’ (Scheme 2): Preparation of 4-[3-(3,4-Dichlorophenyl)propyl]phenylamine
A mixture of 1-(4-aminophenyl)-3-(3,4-dichlorophenyl)propan-1-one (20.0 g, 0.068 mol), NHoNH»-H»O (16 mL), and KOH (85%, 5.6 g) in ethylene glycol (160 mL) was heated to reflux under a No atmosphere for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice-H>O and extracted with CH» Cl; (2 L). The layers were separated, and the organic layer was dried (NapSO4) and concentrated in vacuo to afford an oil. Purification by flash chromatography (silica gel, CHCl») yielded an oil, 14.00 g (0.05 mol, 73%) of the desired product.
Analysis for C15H5CIHN: Caled: C, 64.30; H, 5.40; N, 4.99; Cl, 25.31.
Found: C, 64.21; H, 5.59; N, 5.24; Cl, 24.87.
Preparation of 2,4-Difluoro-5-nitrobenzoic acid methyl ester
Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentle stirring to concentrated sulfuric acid 98% (125 mL) in a 1 L beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was allowed to stir gently for 40 minutes at room temperature. The reaction mixture was then poured into ice-H)O (1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated, and the organic layer was washed sequentially with 1N NaCl, saturated NaHCO3, HO and brine, dried (NapSOy), filtered and concentrated in vacuo to afford a yellow residue. This residue was washed with 10% EtOAc/hexane, filtered, and dried to yield a pale yellow solid, 29.0 g (0.133 mol, 82%). mp 78-80°C.
Analysis for CgH5FoNOy4: Calcd: C, 44.25; H, 2.32; N, 6.45. Found: C, 44.18;
H, 2.39; N, 6.14. : Preparation of 2-Fluoro-4-methoxy-5-nitrobenzoic acid methyl ester
A mixture of sodium metal (1.27 g, 0.055 mol) and MeOH ( 250 mL) was : 25 stirred at 0°C for 10 minutes. This solution was added to a solution of 2-fluoro-5- nitrobenzoic acid methyl ester (10.0 g, 0.046 mol) in MeOH (250 mL), and the mixture was stirred for 20 minutes at 0°C to 5°C. The reaction mixture was then allowed to warm to room temperature and stir for 2 hours. The mixture was then filtered to give an off-white precipitate. Recrystallization with CHCI3 (70 mL)
yielded an off-white crystalline solid, 1.825 g (0.008 mol, 17%) of the title compound.
Analysis for CoHgF1N 104: Caled: C, 47.17; H, 3.52; N, 6.11. Found: C, 47.09;
H, 3.47; N, 6.00.
Preparation of 2-{4-[3-(3 ,4-Dichlorophenyl)propyl]phenylamino }-4-methoxy- 5-nitrobenzoic acid methyl ester
A mixture of 4-[3-(3,4-dichloro-phenyl)propyljphenylamine (0.94 g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitro-benzoic acid methyl ester (0.75 g, 3.3 mmol), and EtzN (0.46 mL) in CH3CN (30 mL) was heated to reflux for 120 hours. The reaction mixture was cooled to room temperature, diluted with
CHCl and washed with saturated NaHCO3. The organic layer was dried (Na»S04) and concentrated to give a solid. Recrystallization with MeOH yielded 0.67 g (1.37 mmol, 42%) of the desired product.
Analysis for Co4Hy9N>Cly05-0.42H5 0: Caled: C, 58.01; H, 4.63. N, 5.64;
Found: C, 57.61; H, 4.51; N, 5.94.
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyljphenylamino}-4-methoxy- 5-nitrobenzoic acid
To a solution of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylaming}- 4-methoxy-5-nitrobenzoic acid methyl ester (0.30 g, 0.061 mol) in THF (5 mL),
IN NaOH (aq.) (2.5 mL) was added, and the mixture was stirred for 36 hours at room temperature. The solvent was removed, and the residue was acidified with concentrated HCI to pH 3. The precipitate was collected by filtration and dried in vacuum for 16 hours. Recrystallization with MeOH gave the title compound as an orange solid 0.21 g (0.043 mol, 70%). mp 200-201°C. ’
Analysis for Co3HogN2O5Clp-0.2H,0: Caled: C, 57.68; H, 4.29; N, 5.85;
Cl, 14.81. Found: C, 57.71; H, 4.34; N, 5.58; Cl, 14.56.
EXAMPLE 8
Preparation of 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo- 1-yl-5-nitrobenzoic acid
Preparation of 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino }-4-imidazo- 1-yl-5-nitrobenzoic acid methyl ester
A mixture of 2,4-difluoro-5-nitrobenzoic acid methyl ester (1.63 g, 7.5 mmol), imidazole (0.56 g, 8.25 mmol), and Et3N (1.14 mL, 8.25 mmol) in
CH3CN (50 mL) was stirred for 16 hours at room temperature. To this deep orange solution, 4-[3-(3,4-dichlorophenyl)propyl}phenylamine (2.10 g, 7.5 mmol) and triethylamine (Et3N) (1.14 mL, 8.25 mmol) was added, and the mixture was heated to reflux for overnight. The reaction mixture was cooled and concentrated in vacuo to afford a residue. This residue was diluted with CHCl and washed with a saturated KoHCO3 solution. The organic layer was dried (Na3SO4), filtered, and concentrated in vacuo to give a crude oil. Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 1.0 g (1.90 mmol, 25%) of the desired product.
MS: 524.1 (MH).
Preparation of 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino }-4-imidazo- 1-1-yl-5-nitrobenzoic acid
The title compound was prepared from 2-{4-[2-[-(3,4- dichlorophenyl)propyl]phenylamino }-4-imidazo-1-yl-5-nitrobenzoic acid methyl ester (1.0 g, 1.9 mmol), IN NaOH (2.0 mL) in THF (30 mL) using the procedure described in Example 8. This procedure yielded an orange solid, 0.30 g } (0.6 mmol, 32%) of the desired product.
Analysis for Cp5HpClpN404-0.2H-O: Calcd: C, 58.3 1; H, 3.99; N, 10.88;
Cl, 13.89. Found: C, 58.34; H, 4.07; N, 10.73; Cl, 13.41.
EXAMPLE 9
Preparation of 2-{4-[3-(3,4-Dichloropheny!)-propyllphenylamino }-benzoic acid
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino }~benzoic acid methyl ester
The title compound was prepared from 4-[3-(3,4-dichlorophenyl)propyl]- phenylamine (600 mg, 2.14 mmol), 2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), cesium carbonate (812 mg, 2.49 mmol), tris(dibenzylideneacetone- dipaladium(0) (49 mg, 0.053 mmol) and (S)-(2,2"-bis(di-p-tolylphosphino-1,1’- binaphthyl! (98%, (S)-tcl BINAP) (54 mg, 0.080 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (15 mL) using the procedure described in Example 2, Step C.
This procedure yielded an yellow oil, 0.61 g (1.47 mmol, 69%) of the desired product.
MS: 414 (M1), 416 (MH™).
Analysis for C93H»1Cla03N-0.4 HyO: Caled: C, 65.25; H, 5.23; N, 3.30.
Found: C, 65.76; H, 5.18; N, 3.10.
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid
The title compound was prepared from 2-{4-[3-(3,4-dichlorophenyl}- propyl]phenylamino} benzoic acid methyl ester (0.41 g, 0.99 mmol), IN NaOH (4.0 mL) in EtOH (4 mL) and THF (4 mL) using the procedure described in
Example 2. This procedure yielded a yellow solid, 0.32 g (0.80 mmol, 81%) of the desired product. mp 120-126°C.
Analysis for C2oH19ClhOoN1°0.75 HyO: Calcd: C, 64.04; H, 5.00; N, 3.39.
Found: C, 64.17; H, 4.69; N, 3.18.
EXAMPLE 10
Preparation of 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino} benzoic acid
Preparation of (trans)-3-(3,4-Dichlorophenyl)-2-propenal
A mixture of 3,4-dichlorobenzaldehyde (140.0 g, 0.8 mol) and acetaldehyde (300 mL) was cooled to 5°C. Potassium hydroxide (5.1 g, 0.091 mol) was dissolved in hot MeOH (40 mL), and the resulting solution was
+ WO 00/76489 PCT/US00/15071 added to the above cooled mixture while maintaining the internal temperature at 25°C to 30°C. The mixture was allowed to stir in ice-HO bath for 40 minutes and then treated with acetic anhydride (400 mL). After the addition, the mixture was heated to 100°C with stirring for 30 minutes and then cooled to 30°C. To this mixture, 12N HCI/HO (102 mL/1.2 L) was added, and the resulting mixture was heated to reflux for 30 minutes and then cooled to room temperature. This heterogeneous mixture was filtered and washed with H5O to afford a brown solid.
The crude product was dissolved in EtOAc and washed with HO, dried (NapSOy), and concentrated to dryness. Recrystallization from hexane/EtOAc (9:1) yielded 76.5 g (0.38 mol, 48%) of the title compound. mp: 91-93°C.
Analysis for CgHgClO: Caled: C, 53.77; H, 3.01; Cl, 35.27. Found: C, 53.75;
H, 3.10; Cl, 35.58.
Preparation of (trans), (trans)-1,2-Dichloro-4-[4-(4-nitrophenyl)-1,3- butadienyl]benzene
A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) and triphenylphosphine (244.0 g, 0.93 mol) in CHCI3 (1.5 L) was heated to reflux for overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove CHCI3 and then suspended in Et)O and stirred rigorously.
The suspension was filtered, and the off-white solid was washed with Et9O, dried ' at 80°C for 16 hours to give 433.0 g (0.91 mol, 98%) of bromo[(4- nitrophenyl)methyl}triphenylphosphorane .A solution of bromo[(4- nitrophenyl)methyljtriphenylphosphorane (100.0 g, 0.23 mol) in dry THF (500 mL) was cooled to 5°C. n-Butyl lithium (n-BuLi) (2.4 M, 96 mL, 0.23 mol) was added dropwise to maintain the temperature between 5°C to 10°C. The cooling bath was then removed, and the reaction mixture was allowed to warm to room temperature. After 4 hours, a solution of (trans)-3-(3,4-dichlorophenyl)- 2-propenal (36.2 g, 0.18 mol) in THF (100 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. Purification :
by flash chromatography (silica gel, 20% EtOAc/hexane) yielded 16.0 g (0.05 mol, 28%) of the desired product. mp 125-135°C.
Analysis for C1gH1 1CIpNO;: Caled: C, 60.02; H, 2.46; N, 4.37, Cl, 22.15.
Found: C, 59.77; H, 3.47; N, 4.40; Cl, 22.39.
Preparation of 4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamine
The title compound was prepared from (trans), (trans)-1,2-dichloro- 4-[4-(4-nitrophenyl)-1,3-butadienyl]benzene (15.42 g, 0.048 mol), Ra-Ni (1 g) at 20°C to 26°C (AP = 19.3 psi) under a hydrogen atmosphere in THF (75 mL} and
MeOH (75 mL) using the procedure described in Example 1, Step B. This procedure yield a solid, 10.97 g (0.037 mol, 78%) of the desired product. mp 50-52°C.
Analysis of C1gH17N1Clp: Caled: C, 65.32; H, 5.82; N, 4.76. Found: C, 65.43;
H, 5.84; N, 4.61.
Preparation of 2-{4-[4-(3,4-Dichlorophenylbutyl]phenylamino} benzoic acid
The title compound, mp 98-105°C, was prepared from 4-[4-(3,4- dichlorophenyl)butyl]phenylamine (0.50 g, 1.7 mmol), 2-chlorobenzoic acid (0.24 g, 1.56 mmol}, anhydrous potassium carbonate (0.71 g, 5.15 mmol), copper powder (0.21 g, 3.28 mmol), and copper(I) chloride (0.015 g, 0.15 mmol) in dry
DMF (5 mL) using the procedure described in Example 1, Step C, Method B.
EXAMPLE 11
Preparation of 2-{4-{4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro- benzoic acid
A mixture of 2-fluoro-5-nitrobenzoic acid (1.85 g, 0.01 mol), 4-[4-(3,4- } dichlorophenyl)butyl]-phenylamine (2.94 g, 0.01 mol) and Et3N (2.80 mL) in acetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture was : cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH»Cly and washed with diluted HCI. The organic layer was dried (Na3S0y), concentrated in vacuo to give a crude solid. Purification by flash
+ WO 00/76489 PCT/US060/15071 chromatography (silica gel, CH Clp) yielded 1.40 g (0.003 mol, 30%) of the desired product.
Analysis for Co3H19N2O4Cl5: Caled: C, 60.27; H, 4.18; N, 6.11; Cl, 14.47.
Found: C, 60.16; H, 4.41; N, 6.09; Cl, 15.69.
EXAMPLE 12
Preparation of 2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}- 3,5-dinitrobenzoic acid
To a cooled (0°C) solution of 4-[4-(3,4-dichlorophenyl)butyl]- phenylamine (1.47 g, 5.0 mmol) and DBU (0.75 mL, 7.5 mmol) in acetonitrile (25 mL), a solution of 2-fluoro-2,5-dinitrobenzoic acid (1.15 g, 5.0 mmol) in acetonitrile (15 mL) was added dropwise. After stirring for 30 minutes at 0°C, the reaction mixture was neutralized with dilute HCI and extracted with EtOAc, dried (NapS0y), filtered and concentrated in vacuo to afford a crude residue.
Recrystallization with EtOH yielded a bright orange solid, 2.06 g (4.1 mmol, 82%) of the title compound.
Analysis for Co3H(9ClpN30g4: Caled: C, 54.77; H, 3.80; N, 8.33; Cl, 14.06. ; Found: C, 54.68; H, 4.00; N, 8.12; Cl, 13.81. oo EXAMPLE 13
Preparation of 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid
Preparation of Bromo[(3,4-dichlorophenyl)methyl]triphenylphosphorane
A mixture of 4-bromomethyl-1,2-dichlorobenzene (2.40 g, 0.01 mol), and ) triphenylphosphine (5.24 g, 0.02 mol) in toluene (30 mL) was stirred for 16 hours at room temperature. The solid was filtered, rinsed with toluene, and oven-dried at - 25 room temperature to yield a white powder, 3.95 g (0.0078 mol, 78%) of the desired product. 1H NMR [dimethylsulfoxide (DMSO):ppm] :7.89-7.61 (m, 15H), 7.50 (d,
J=8.3 Hz, 1H), 7.04 (t, /=2.3 Hz, 1H), 6.97 (m, 1H), 5.20 (d, /=15.9 Hz, 2H).
Preparation of 4-(4-Nitrophenyl)butyraldehyde
To a cooled solution (-70°C) of oxalyl chloride (2.0 M in CH, Clg, 14.1 mi, 28.2 mmol), dimethylsuifoxide (DMSO) (4.40 g, 56.32 mmol) in
CH,Cly (20 mL) was added dropwise. The resulting reaction mixture was then stirred for 30 minutes at -70°C under a nitrogen atmosphere. A solution of 4-(A-nitrophenyl)butan-1-ol (5.00 g, 25.6 mmol) in CHCl (3 mL) was added dropwise, and the reaction mixture was stirred for 1 hour at -70°C. Et3N (16 mL, 115 mmol) was added, and the reaction mixture was then allowed to gradually warm {6 room temperature and stir for 30 minutes. The mixture was then quenched with HyO and extracted with EtOAc. The organic layers were washed with 0.1N HCl solution, HO, brine, dried (Na3SOy), filtered, and concentrated in vacuo to give a lightly brown oil. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) yielded 3.20 g (16.56 mmol, 65%) of the desired product.
IH NMR (DMSO:ppm): 9.75 (s, 1H), 8.12 (d, /=8.3 Hz, 2H), 7.30 (d, /=8.3 Hz, 2H), 2.72 (t, J=7.7 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H), 1.94 (m, 2H).
Preparation of 1,2-Dichloro-4-[5-(4-nitrophenyl)-1-pentenyl]benzene
A solution of bromo[(3,4-dichlorophenyl)methyl]triphenylphosphorane (3.95 g, 7.9 mmol) in dry THF (20 mL) was cooled to 0°C. LHDMS (1.0 M/THF, 9 mL, 9.0 mol) was added dropwise to maintain the temperature at 0°C. After stirring for 30 minutes, a solution of 4-(4-nitro-phenyl)butyraldehyde (1.45 g, 7.5 mmol) in THF (5 mL) was added dropwise, and the mixture was allowed to warm to room temperature within 2 hours. The mixture was then quenched with
H)O and extracted with EtOAc. The organic layers were washed with 0.IN HCI : solution, HyO, brine, dried (NapSQy), filtered, and concentrated in vacuo to give a lightly brown oil. Purification by flash chromatography (silica gel, 10%
EtOAc/hexane) yielded 2.5 g (7.4 mmol, 99%) of the desired product.
MS: 335 (MT), 337 (MH).
B WO 00/76489 PCT/US00/15071
Preparation of 4-[5-(3,4-Dichlorophenyl)pentyl]phenylamine
The title compound was prepared from 1,2-dichloro-4-[5-(4-nitrophenyl)- 1-pentenyl]benzene (2.5 g, 7.4 mmol), Ra-Ni (1 g) in THF (50 mL) at 25°C to 40°C (AP = 9.9 psi) using the procedure described in Example 1, Step B. This procedure yielded 1.06 g (3.4 mmol, 46%) of the desired product.
IH NMR (DMSO:ppm): 7.45 (d, /=8.3 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.12 (m, 1H), 6.74 (d, J=8.3 Hz, 2H), 6.40 (d, J=8.3 Hz, 2H), 4.73 (s, 2H), 2.50 (4,
J=7.7 Hz, 2H), 2.31 (t, J/=7.6 Hz, 2H), 1.6-1.5 (m, 4H), 1.5-1.4 (m, 2H).
Preparation of 2-{4-[5-(3,4-Dichloro-phenyl)pentyl}phenylamino }-5-nitrobenzoic acid
To a cooled (-78°C) solution of 4-[5-(3,4-dichlorophenyl)pentyl}- phenylamine (0.231 g, 0.75 mmol) in THF (2 mL), LHDMS (2.25mL, 1 M in hexane, 2.25 mmol) was added dropwise. The reaction mixture was allowed to stir at -78°C for 10 minutes. A solution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 0.75 mmol) in THF (2 mL) was added dropwise, and this solution was stirred for 30 minutes at -78°C. The reaction mixture was allowed to gradually warm to room temperature and stir for 2 hours under No atmosphere. The reaction mixture was diluted with EtOAc, and acidified with 1N HCI (pH 3). The organic layer was ) dried (NapSOy), filtered and concentrated in vacuo to yield a brown residue.
Purification by flash chromatography (silica gel, 2% MeOH/CH,Cly) then recrystallization with MeOH yielded 265 mg (0.56 mmol, 75%) of the desired product. mp 147-148°C.
Analysis for Co4Hp2CIpN204:0.37H 0: Caled: C, 60.05; H, 4.77; N, 5.84. . Found: C, 59.67; H, 4.64; N, 5.51.
WQ 00/76480 PCT/US00/15071 3
EXAMPLE 14
Preparation of 2-{4-[5-3 -4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy- 5-nitrobenzoic acid
Preparation of 2-{4~[5-(3,4-Dichlorophenyl)pentyl]phenylamino} -4-methoxy- 5-nitrobenzoic acid methyl ester
The title compound was prepared from 4-[5-(3,4- dichlorophenyl)pentyl]phenylamine (231 mg, 0.75 mmol), LHDMS (6.28 mL, 1 M in THF, 6.28 mmol) and 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (172 g, 0.75 mmol) in THF (5 mL) using the procedure described in Example 13.
Purification by flash chromatography (silica gel, 10% EtOAc/hexane) yielded 145 mg (0.28 mmol, 37%) of the desired product.
MS: 515.2 (M™), 517.2 (MH).
Preparation of 2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino }-4-methoxy- 5-nitrobenzoic acid
The title compound was prepared from 2-{4-[5-(3,4-dichlorophenyl)- pentyl |phenylamino}-4-methoxy-5-nitrobenzoic acid methyl ester (145 mg, 0.28 mmol) and IN NaOH (aq.) (0.56 mL) in THF (1.2 mL) using the procedure described in Example 2. Purification by flash chromatography (silica gel, 10%
MeOH/CH,Clp), then recrystallization with MeOH yielded 58 mg (0.12 mmol, 41%) of the desired product. mp 192-193°C.
Analysis for Cp5Hp4CloN»O4: Caled: C, 59.65; H, 4.81; N, 5.56.
Found: C, 59.29; H, 4.58; N, 5.36.
EXAMPLE 15 :
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyljphenylamino}-5-nitrobenzoic acid
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyi]phenylamino}-5-nitrobenzoic acid methyl ester
The title compound was prepared from 4-[3-(3,4-dichlorophenyl)propyl]- phenylamine (420 mg, 1.50 mmol), 2-bromobenzoic acid methyl ester (310 mg,
1.25 mmol), cesium carbonate (569 mg, 1.75 mmol), tris(dibenzylideneacetone- dipaladium(0) (34 mg, 0.037 mmol) and (S)-(2,2’-bis(di-p-tolylphosphino-1,1’- binaphthyl (98%, (S)-tol-BINAP) (38 mg, 0.056 mmol) (Ligand/Pd=1.5) in anhydrous toluene (15 mL) using the procedure described in Example 2, Step C.
This procedure yielded an orange solid 0.51 g (1.11 mmol, 74%) of the desired product. mp 117-118°C.
MS: 457.1 (M1); 459.1 (MH)
Preparation of 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid
The title compound was 2-{4-[3-(3,4-dichlorophenyl)- propyl]phenylamino}-5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2N
NaOH (5.0 mL) in EtOH (2 mL) and THF (4 mL) using the procedure described in Example 2. This procedure yielded an orange solid, 0.49 g (1.10 mmol, 100%) of the desired product. mp 153-155°C.
MS: 443.2 (M1), 445.2 (MH™)
EXAMPLE 16
Preparation of 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid
Preparation of 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid methyl ester
The title compound was prepared from 4-[2-(3,4-dimethylphenyl)ethyl]- benzenamine (1.0 g, 4.43 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (0.96 g, 3.69 mmol), cesium carbonate (1.68 g, 5.17 mmol), tris(dibenzylideneacetone-dipaladium(0) (101 mg, 0.11 mmol) and (5)-(2,2"- bis(di-p-tolylphosphino-1,1’-binaphthyl (98%, (5)-tol-BINAP) (113 mg, 0.17 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (32 mL) using the procedure described in Example 2, step C. This procedure yielded an yellow solid, 1.31 g (3-24 mmol, 73%) of the desired product. mp 115-117°C.
MS: 405 (M1)
Analysis for Co4H404N>-0.25 H»0: Caled: C, 71.27; H, 5.98; N, 6.93.
Found: C, 70.48; H, 6.03; N, 6.85.
Preparation of 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino }-5-nitrobenzoic acid
The title compound was prepared 2-{4-[2-(3,4-dimethyl-phenyl)- ethyl] phenylamino}-5-nitrobenzoic acid methyl ester (1.12 g, 2.76 mmol), IN
NaOH (50 mL) in EtOH (50 mL) and THF (50 mL) using the procedure described in Example 2. This procedure yielded a yellow solid, 1.03 g (2.63 mmol, 81%) of the desired product. mp 214-216°C.
Analysis for Co3H7904N>-0.25 HO: Caled: C, 69.99; H, 5.74; N, 7.18.
Found: C, 69.90; H, 5.82; N, 6.81.
EXAMPLE 17
Preparation of 2-[[4-[2-(4-Chloro-3-trifluromethylpbenyl)ethyliphenyl]amino- benzoic acid
Step A (Scheme 1): Preparation of frans-1-Chloro-2-trifluoromethyl-4-[2-(4- nitrophenyl)ethenyl]benzene
A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) and 4-chloro-3- trifluoromethylbenzaldehyde (47.85 g, 0.23 mol) in piperidine (19.5 g, 0.23 mol) was heated under Np atmosphere to 150°C t0160°°C for 1 hour. The reaction mixture was cooled to 80°C to 100°°C and refluxing i-PrOH (150 mL) was added.
The mixture was continued to cool to room temperature and then placed under refrigeration for 5 hours. The crystalline precipitate was filtered off, rinsed with cold i-PrOH, and dried at room temperature in a vacuum oven overnight to yield : trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene as an orange solid, 22.53 g (68.75 mmol, 30%). mp 173-174°C.
MS: 327.0 MH)
Step B (Scheme 1): Preparation of 4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]- benzenamine
The title compound was prepared from trans-1-chloro-2-trifluoromethyl-4- [2-(4-nitrophenyl)ethenyl]benzene (22.53 g, 0.069 mol) and Ra-Ni (22 g) in THF (0.5L) at 18°C to 29°C (AP =20.5 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a white solid, 20.0 g (66.73 mmol, 97%) of the desired product. mp 62-64°C.
MS: 298.1 (M™)
Preparation of 2-[[4-[2-(4-Chloro-3-trifluromethylphenyl)ethyl]phenyl]- aminobenzoic acid
To a cold solution of 4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]- benzenamine (4.33 g, 14.45 mmol) in THF (50 mL) at -78°C, was added LHMDS (43.35 mL, 43.35 mmol) (1M/THF) dropwise. Allowed the reaction mixture to stir for 10 minutes at -78°C. A solution of 2-fluorobenzoic acid (2.02 g, 14.45 mmol) in THF (50 mL) was added dropwise. The mixture was stirred for 2 hours at -78°C, then warmed to room temperature and let stir for additional 3 hours. The reaction mixture was concentrated in vacuo (40°C) to remove the organic solvent.
This residue was acidified to pH 3 with 3N HCI (aq.). This precipitate was collected by filtration, rinsed with 10% HCI (40 mL), and dried in vacuum for overnight to give as a pale solid , 4.3 g (10.24 mmol, 70%) of the desired product. mp 150-152°C.
Analysis for CopH1709NCIF3-0.59 HO: Calcd: C, 61.39; H, 4.26; N, 3.25.
Found: C, 61.01; H, 4.34; N, 3.30.
EXAMPLE 18
Preparation of 2-[4-(3,4-Dichlorophenyl)phenylamino]benzoic acid
Preparation of o-Bromobenzoic acid potassium salt ) 25 To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH (500 mL), KoCO3 (69 g, 1.0 mol) was added. The mixture was concentrated to give the desired product (239.1 g, 1.0 mol, 100%).

Claims (1)

  1. PCT/US00/15071 CLAIMS
    1. Use of a compound of Formula I R3 RS 8 R! R : (CH); a A 2 r4 RK RO 2 R wherein Oo R32 is hydrogen, C1-Cg alkyl, or -CC(-Cg alkyl; nis 0 to 5 inclusive; . Rl, RZ R3, R4,R5 RS, and R7 are independently hydrogen, halogen, -OH, -NH3, NRbR¢, -CO5H, -CO5C1-Cg alkyl, -NO», -0OC1-Cy2 alkyl, -C1-Cg alkyl, -CF3, -CN, -OCH> phenyl, -OCH»-substituted phenyl, (CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, o 0 l I -CH=CH-phenyl, -O(CH2)pNRPRC, -CNRPR¢, -NHCRD, -NH(CHp)pNRPR¢, -N(C 1-Cealkyl) (CH) NRbRE, —cH ; CH50C,-Cg alkyl R8 is COOH, tetrazolyl, -SO,RY, or -CONHSO,RY; Rb and R€ are independently hydrogen, -C-Cg alkyl, -(CH>)-phenyl, or RD and RC taken together with the nitrogen atom to which they are artached form a cyclic ring selected from piperidinyl, pyrrolyl, AMENDED SHEET
    PCT/US00/15071 ® - 107 - imidazolyl, piperazinyl, 4-C1-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; RA is hydrogen, -C-Cg alkyl, -CF3, or phenyl; m 1s 0 to 5 inclusive; pis 1 to 5 inclusive; AisCHorN; ‘R! and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating Alzheimer’s disease.
    2. Use of Claim 1 wherein R® is hydrogen; : nis 2; and . R’ and R* are hydrogen.
    3. Use of Claim 1 wherein R® is hydrogen; R’ and R* are hydrogen; and nis 2 to 5 inclusive. 4, Use of Claim 1 wherein R2 is hydrogen; nis 2; R3 and R4 are hydrogen; and R1, R2, and R7 are independently chlorine, -N(CH5CH3)s, -OH, CHj-, fluorine, -CF3, phenyl, hydrogen, -OCH> phenyl, -O(CH2)3N(CH3)p, -O phenyl, -O(CH3)7CH3, -CH(CH>OCH,CH3)3, pyrrolyl, <CH=CH-phenyl, N— , -N[(CH32)3CH3]5, substituted phenyl, -OCH,- substituted phenyl, pyrazolyl, or -N(phenyl),. AMENDED SHEET
    PCT/US00/15071 ® - 108 -
    5. Use of Claim 1 wherein R® is hydrogen; nis 3, 4, or 5; R® and R* are hydrogen; and R!, R?, and R’ are independently chlorine or hydrogen.
    6. Use of Claim 1 wherein R® is hydrogen, nis 2; R? and R* are hydrogen; and R’, RS, and R® are independently hydrogen, -CO,H, -NO,, -OCHj, imidazolyl, -CN, fluorine, -CHj3, -CF;, halogen, -NH-C,;-Cgalkyl, -N(C,-Cgalkyl),, -NH,, or pyrrolyl. k
    7. Use of Claim 1 wherein R® is hydrogen; nis 2; R® and R* are hydrogen; and R’ is -CO,H.
    8. Use of a compound of Formula I : IAN 8 R! N R 1 (CHyZ ra CA BAe r4 R RS
    2 . R wherein Ra is hydrogen; n is 1 to 5 inclusive; AMENDED SHEET
    PCT/US00/15071 ® - 109 - R3 and R4 are hydrogen; R!, R7, and R2 are independently chlorine, -N(CH>CHj3)5, -OH, CHs-, fluonne, -CF3, phenyl, hydrogen, -OCH» phenyl, -O(CH2)3N(CH3)3, -O phenyl, -O(CH3)7CHs, -CH(CH,OCH»CH3)7, pyrrolyl, -CH=CH-phenyl, -N[(CH32)3CH3]3, substituted phenyl, -OCH»-substituted phenyl, pyrazolyl, or -N(phenyl)7; RS and RS are independently hydrogen, -CO5H, -NO,, -OCHj, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R8 is COOH or tetrazolyl; or the pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating Alzheimer’s disease.
    9. Use 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; AMENDED SHEET
    PCT/US00/15071
    2-{4-[4-(3,4-Dichlorophenyl)-butyl]phenylamino}- - a 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- Co S-npitrobenzoic acid; Co 2-[4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; oo 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl}-phenylamino}-5-nitro- benzoic acid; : 2-{4-[2-(3 /4-Difluoro-phenyl)-ethyl}-phenylamino}-5-nitro- Co benzoic acid; Re 2-{4-[2-(4-Chloro-3-triflucromethyl-phenyl)-ethyl]-phenylamino}- . : benzoic acid; : . .2-[4-2-Biphenyl-4-yl-ethyl)-phenylamino}-5-nitro-benzoic acid; 5-Nitro-2-(4-phenethyi-phenylamino)-benzoic acid; : 2-(4-Phenethyl-phenyl amino)-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; : : BE | 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic Te acid; 2s © 2-{412-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5- oo - 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- oo benzoic acid; a AMENDED SHEET
    : PCT/US00/15071 ® -2-{4-[2-(3 ,A-Dichloro-phenyl)-ethyl}-phenylamino}-3-nitro- - benzoic acid; 5-Cyano-2-{4-[2~(3,4-dichloro-phenyl)-ethyl]-phenylamino}- benzoic acid;
    5 . 2-{4-[2-(3 ,A-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; oo 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; : oo : | : 2-{4-[2-(3,4-Dichloro-phenyl)-ethyi]-phenylamino}-3- trifluoromethyl-benzoic acid; 2-{4-[2-(3 s4-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- Co benzoic acid; : 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid; Co 2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl}-cthyl}- phenylamino)-benzoic acid; oo 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; AMENDED SHEET :
    PCT/US00/15071 EE
    ® 2-(4-{2-{4-(2-Ethoxy-1-ethoxymethyl-ethyl)-phenyl]-ethyl}- oo phenylamino)-benzoic acid; 2-{4-[2-(4-Pyrrol-1-yl-phenyl)-ethyl]-phenylamino} -benzoic acid; 2-{4-[2-(4-Styryl-phenyl)-cthyl]-phenylamino}-benzoic acid; 2-{4-[2-(4-Dibutylamino-pbenyl)-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; . aE 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-pheny!)-ethyl}-phenylamino }-5-amino- benzoic acid; Co 2-{4-[2-(3,4-Dichloro-pheny})-ethyl]-phenylamino}-5- trifluoromethyl-benzoic acid; Co : 2-{4-[2-(3 ,A-Dichlorophenyl)Jphenylamino}-5-nitrobenzoic acid; 2-{4-[3-(3 ,A-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3 4-Dimethyl-phenyl)-cthyl] phenylamino}-5- nitrobenzoic acid; 2-{[4-[2-(4-Chloro-3 trifluoromethylphenyl)ethyl]phenyl]amino- benzoic acid; or | ; oo . : 2-[4-(3,4-Dichlorophenyl)phenyl}aminobenzoic acid.
    AMENDED SHEET
    PCT/US00/15071 C - 113 -
    10. A method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, the method comprising administering to a subject, an amyloid protein aggregation inhibiting amount of a compound of Formula I X 8 R Ly | t 2 i I r7 R R R2 wherein Oo l R2 is hydrogen, C-Cg alkyl, or -CC-Cg alkyl; nis 0 to 5 inclusive; : Rl], RZ, R3, R4, RS, RS, and R7 are independently hydrogen, halogen, -OH, -NH», NRPRE, -CO2H, -CO,C-Cg alkyl, -NO3, -0C1-C12 alkyl, -C-Cg alkyl, -CF3, -CN, -OCH> phenyl, -OCH>-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, oO 0 i 0 _CH=CH-phenyl, -O(CH2)pNRPRE, -CNRPR, -NHCRD, -NH(CH2)pNRPRE, -N(C 1-Cgalkyl)(CH2)pNRPRE, /CH,0C-Cg alkyl CH,0C,-Cg¢ alkyl R8 is COOH, tetrazolyl, -SO2RY, or -CONHSO2RY; RD and RC are independently hydrogen, -C-Cg alkyl, -(CH7)m-phenyl, or RD and RE taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; : AMENDED SHEET
    PCT/US00/15071 RAa is hydrogen; nis 3,4, or5; R3 and R4 are hydrogen; and R], R2, and R7 are independently chlorine or hydrogen.
    15. The method of Claim 10 wherein : R2 is hydrogen; nis 2; R3 and R# are hydrogen; and RS and RS are independently hydrogen, -COoH, -NO5, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, halogen, -NH-C-Cg alkyl, -N(C -Cgalkyl)2, -NH, or pyrrolyl.
    16. The method of Claim 10 wherein R2 is hydrogen; nis 2; R3 and R# are hydrogen; and R8 is -COoH.
    17. A method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, the method comprising administering to a subject an amyloid protein aggregation inhibiting amount of a compound of Formula I R3 R> XX 8 Rr! N R (CHyg a A , 2 4 R RO
    2 . R wherein Ra is hydrogen; nis 1 to 5 inclusive; AMENDED SHEET v WO 00/76489 ’ PCT/US00/15071 R3 and R4 are hydrogen; RL, R7, and R2 are independently chlorine, -N(CHyCH3)p, -OH, CHj-, fluorine, -CF3, phenyl, hydrogen, -OCH, phenyl, : -O(CH2)3N(CH3)p, -O phenyl, -O(CH2)7CH3, : -CH(CH2OCH,CH3)y, pyrrolyl, -CH=CH-phenyl, -N[(CH2)3CH3]p, substituted phenyl, -OCHj-substituted phenyl, pyrazolyl, or -N(phenyl); RS and RO are independently hydrogen, -CO,H, -NO,, -OCHs, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R8 is COOH or tetrazolyl; AisCHorN; RI and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof.
    18. The method of Claim 17 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]Jphenylamino } -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- S-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)-butylJphenylamino}- 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)-ethyi]-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-Dichioro-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)-ethy!]-phenylamino}-5-imidazol-1- yl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro- benzoic acid;
    ¥ WO 00/76489 PCT/US00/15071
    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; S 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)-ethy!]-phenylamino } benzoic acid; 2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino }-benzoic acid, 2-(4-{2-[3-(3,5-Dichloroc-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-Dichlorophenyl)propyliphenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl] phenylamino}-5- nitrobenzoic acid; 2-[[4-[2~(4-Chloro-3-triflucromethylphenyl)ethyl]phenylJamino- i benzoic acid; or 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
    19. The compounds: 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;
    ¢ WO 00/76489 PCT/US00/15071 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino} benzoic acid; 2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl Jphenylamino } benzoic acid; 2-{4-[3 -(3,4-Dichlorophenyl)propyl]phenylamino} -4-methoxy- 5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichloropheny!)propyl}phenylamino}-4-imidazo- 1-yl-5-nitrobenzoic acid; or 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino} benzoic acid.
    20. The compounds: 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- S-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-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino} -5-amino- benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-cthyl]-phenylamino}-5- trifluoromethyl-benzoic acid; or 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid.
    21. The compounds: 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)-ethyi]-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; or 2-{4-[2-(3 ,4-Dichloro-phenyl}-ethyl}-phenylamino }-3-nitro- benzoic acid.
    22. The compounds: 5-Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}- benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl}-ethy!]-phenylamino}-4,6-difluorc- benzoic acid; 6-{4-[2~(3,4-Dichloro-phenyl)-ethylj-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-[3-(4-Diethylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(3-Nitrophenyl)propyl}phenylamino} benzoic acid; 2-{4-[3-(4-Aminophenyl)propyl]phenylamino} benzoic acid;
    2-{4-[3-(3-Aminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[2-(4-Aminophenyl)phenylamino} benzoic acid; 2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino } benzoic acid monohydrochloride; 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino} benzoic acid monohydrochloride monohydrate; 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino } benzoic acid;
    2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoic acid;
    } 2-(N-{4-[3-(4-Diethylaminophenyl)propyl phenyl }-N- ethylamino)benzoic acid; 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino} benzoic acid; 2-{4-[3-(3-Diethylaminophenyl)propyl]phenylamino} benzoic acid;
    2-{4-[2-(3-Aminophenyl)ethyl]phenylamino } benzoic acid;
    2-{4-[3-(4-Dimethylaminophenyl)propyl]phenylamino } benzoic acid; 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino} benzoic acid,
    2-{4-[2~(3-Acetylaminophenyl)ethyl]phenylamino} benzoic acid; 2-{4-[2-(3 Dipropylaminophenyl) ethyl]phenylamino } benzoic acid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl}phenylamino } benzoic acid monohydrochloride; 2-{4-[3-(4-Acetylaminopheny})propyl]phenylamino}benzoic acid: 2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[2-(3-Diethylaminopheny!)ethyl]phenylamino } benzoic acid monohydrochloride; i0 2-{4-[2-(3-Piperidin-1-yiphenyl)ethyl]phenylamino} benzoic acid monochydrochloride; 2-{4-[3-(4-Dipropylaminopheny!)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Dibutylaminopheny!)propyl]phenylamino} benzoic acid; 2-{4-[3~(3-Dibutylaminophenyl)propyl]phenylamino } benzoic acid; 2-(4-{3-[4-(1H-Pyrrol-1-yl)phenyl] propyl} phenylamino)benzoic acid; 2-{4-[3-(4-Piperidin-1-ylphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino } benzoic acid; 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino} benzoic acid; 2-{4-[3-(4-Diethylaminomethylpheny])propyllphenylamino} benzoic acid; 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino} benzoic acid; 2-{4-[3~(3-Propylaminophenyl)propyllphenylamino} benzoic acid; 2-{4-[3-(4-Pyrrolidin-1-yl-phenyl)-propyll-phenylamine }-benzoic acid; 2-{4-[3-(3-Piperidin-1yl-phenyl)-propyl]-phenylamino }-benzoic acid; {5-[(1-Butyl-1,2,3 4-tetrahydro-6-quinolyl)methylidene}-4-ox0-2- thioxothiazolidin-3-yl}acetic acid; {5-[(1-Buty}-2,3-dihydro-1H-indol-5-yl)methylidene}-4-ox0-2- thioxothiazolidin-3-yl }acetic acid;
    v WO 00/76489 PCT/US00/15071
    3-{5-[(1-Butyl-1,2,3 4-tetrahydroquinolin-6-yl)methylidene]-4- ox0-2-thioxo-thiazolidin-3-yl}propanoic acid; 4-{5-[(1-Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4- ox0-2-thioxo-thiazolidin-3-yl}butanoic acid; 2-{4-[3-(3,4-Dichloro-phenyl)-propyl]phenylamino}-5-methyl- benzoic acid; N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)- methanesulofnamime; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino }-5-nitro- benzoic acid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}- 5-nitro-benzoic acid; 5-Amino-2-{4-[2-(3 s4-Dichloro-phenyl)-ethyl]-phenylamino}- : 15 “benzoic acid; = 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid; 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}- N benzoic acid; : : 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro- benzoic acid; {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-[2-(1H-tetrazol-5-yl)- phenyl]-amine; 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino} - S-nitro-benzoic acid; 2-(4-Phenethyl-phenylamino)-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino}-5-fluoro- benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino}-nicotinic acid; ) 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino } -5-nitro-benzoic acid; 2-{4-[2-(4-Chloro-phenyl)-ethyl}-phenylamino } -5-nitro-benzoic acid;
    2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -5-methyl- benzoic acid; 2-{4-{2-(2-Chloro-phenyl)-ethyl]-phenylamino }-5-nitro-benzoic acid; 2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino }-5-nitro- benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6- trifluoromethyl-benzoic acid; 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-5-nitro-
    benzoic acid;
    2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5- dimethylamino-benzoic acid; 2-{4-[2-(3,5-Dichloro-phenyl)-ethyl}-phenylamino} -benzoic acid; 2-(4-{2-[(4aS,8aR)-4~(Octahydro-isoquinolin-2-yl)-phenyl}-ethyl}-
    phenylamino)-benzoic acid; 2-(3’,5’-Dichloro-3-methyl-biphenyl-4-ylamino)-benzoic acid; 2-(3’,5’-Dibromo-3-methyl-biphenyl-4-ylamino)-benzoic acid; 2-(4-1,3-Benzodioxol-5-yl-2-methyl-phenylamino)-benzoic acid; 2-(2,2' 4’-Trichloro-biphenyl-4-ylamino)-benzoic acid;
    2-(2-Chloro-3’,4’-difluoro-biphenyl-4-ylamino)-benzoic acid; 2-(3’-Bromo-2-chloro-biphenyl-4-ylamino)-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -5-nitro-
    benzoic acid; 3-{4-[2-(3,4-Dichloro-pheny!)-cthyl]-phenylamino}-benzoic acid; 5-{4-[2-(3,4-Dichloro-phenyi)-ethyl}-phenylamino}-isophthalic acid; . 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]}-phenylamino}-4,5- ; dimethoxy-benzoic acid;
    2-{4-[2-(3-Chloro-4-methyl-phenyl)-cthyl}-phenylamino}-3-nitro-
    benzoic acid;
    v WO 00/76489 PCT/US00/15071 3-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl}-phenylamino }-benzoic acid; 5-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}- isophthalic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 4-(4-{2-[(4a8,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl } - phenylamino)-benzoic acid; 2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-5- methoxy-benzoic acid; 2-{4-[2-(3-Methoxy-phenyl)-ethyl}-phenylamino}-benzoic acid; 2-{4-[2-(3-Bromo-phenyl)-ethyl]-phenylamino }-benzoic acid; 2-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -5-methoxy- benzoic acid; 4-{4-[2-(3,4-Dichloro-phenyl!)-ethyl]}-phenylamino} -nicotinic acid; 2-[2-(4-Fluoro-3-triflucromethyl-phenyl)-2,3-dihydro-1H-isoindol- : 5-ylamino]-benzoic acid; or 2-{4-[2-(3-Fluoro-4-methyl-phenyl)-ethyl]-phenylamino } -benzoic acid.
    23. The compounds: 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; or 2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino }-benzoic acid.
    24. The compounds: 2-{4-{2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(4’-Ethyl-biphenyl-4-yl)-ethyl}-phenylaminc } benzoic acid; . 2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-{2-[3-(3,5-Dichloro-phenoxy)-phenyi]-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- tnfluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-[(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl} phenylamino}-5- nitrobenzoic acid; 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
    v WO 00/76489 PCT/US00/15071
    25. 2-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyljamino-benzoic acid or a pharmaceutically acceptable salt thereof.
    26. 2-{4-[3-(3 ,4-Dichloropheny!)propyl]phenylamino } benzoic acid or a pharmaceutically acceptable salt thereof.
    27. A compound which is selected from: 2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino} -5-nitro- benzoic acid; 4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-benzoic acid; 4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-3- methoxy-benzoic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-5- methoxy-benzoic acid; {4-[2-(3-Chloro-4-methyl-phenyl)-ethyl}-phenyl } -(2-methoxy-5- - nitro-phenyl)-amine; 2-{4-[3-(4-Diethylamino-phenyl)-propyl}-phenylamino } -3-nitro- benzoic acid; 3-{4-[3-(4-Diethylamino-phenyl)-propyl}-phenylamino }-benzoic acid; 2-{4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenylamino }-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid monosodium; 2-{4-[2-(3,4-Dichloro-phenyl)-ethy!]-phenylamino } -benzoic acid - 25 monopotassium; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino }-benzoic acid ) calcium salt (1:1); 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino }-benzoate-2- hydroxy-1,1-bis-hydroxymethyl-ethyl-ammonium; 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-methoxy- benzoic acid;
    2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{3-[2-(4-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{3-[2~(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(2,4-Dimethoxy-phenyl)-ethyl]-phenylamino }-benzoic acid; 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(2-Hydroxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino }-benzoic acid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino}-benzoic acid;
    2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 3-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4,5-Trimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;
    2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[5-(3,4-Dichloro-phenyl)-pentyl]-phenylamino} -benzoic acid; 2-(3’,5’-Dichloro-biphenyl-4-ylamino)-benzoic acid; 4-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino} -2-methoxy-
    5-nitro-benzoic acid;
    2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino }-5-fluoro-
    benzoic acid; 5-Amino-2-{4-[5-(3,4-dichloro-phenyl)-pentyl]-phenylamino}-
    benzoic acid; N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-
    C,C,C-trifluoro-methanesuifonamide;
    N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylaminoc}-benzoyl)- benzenesulfonamide;
    2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3- trifluoromethyl-benzoic acid;
    4-{4-[2-(3 ,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic acid;
    PCT/US00/15071 C - 130 - 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino }-4- trifluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3- trifluoromethyl-benzoic acid; 2-({4-[2-(3 ,4-Dichloro-phenyl)-ethyl}-phenyl }-methyl-amino)-3- dimethylamino-benzoic acid; 2-({4-[2-(3 ,4-Dichloro-phenyl)-ethyl]-phenyl }-methyl-amino)- benzoic acid; 2-{4-[2-(3 ,4-Dichloro-phenyl)-ethyl]-phenylamino}-5- dipropylamino-benzoic acid; 5-Dibutylamino-2-{4-[2-(3,4-dichloro-phenyl)-ethyl}- phenylamino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5- .diethylamino-benzoic acid; 2,2'-[1,2-Ethanediylbis (4,1-phenyleneimino)]bis-benzoic acid; and 4-[3-[4-(Diethylamino)phenyl]propy!}-N-(2-methoxy-5- nitrophenyl)-benzinamine
    28. Use of a compound having the Formula I or a pharmaceutically acceptable salt thereof: R3 RA : 4 I° : CH Ee NE gé KP Ags R wherein o I R2 is hydrogen, C1-Cg alkyl, or -CC1-Cg alkyl; n is 0 to 5 inclusive; AMENDED SHEET
    PCT/US00/15071 ® - 131 - R1,R2, R3,R4, RS, RS, and R7 are independently hydrogen, halogen, -OH, -NH», NRPRE, -CO,H, -C02C1-Cg alkyl, -NOp, -0C1-C12 alkyl, -C1-Cg alkyl, -CF3, -CN, -OCH> phenyl, -OCH5-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, 0 eo} i -CH=CH-phenyl, -O(CH2)pNRPRE, -CNRPRE, -NHCRP, -NH(CHp)pNRORS, -N(C-Cgalkyl)(CH)pNRPRS, /CHy0C;-Cq alkyl CH,0C-Cg alkyl RS is COOH, tetrazolyl, -SOoR4, or -CONHSO2RY; RD and RC are independently hydrogen, -C-Cg alkyl, -(CH2)m-phenyl, or E RD and RC taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C1-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; Rd is hydrogen, -C1-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; AisCHorN; R! and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof, in the manufacture of a preparation for imaging amyloid deposits, by a. introducing into a patient said preparation containing a detectable quantity of said labelled compound,
    b. allowing sufficient time for the labelled compound to become associated with amyloid deposits; and
    C. detecting the labelled compound associated with the amyloid deposits. 29 Use of Claim 28 wherein the patient has or is suspected to have Alzheimer’s disease. AMENDED SHEET
    PCT/US00/15071
    30. Use of Claim 28 wherein the labelled compound is a radio labelled compound.
    31. Use of Claim 28 wherein the labelled compound is detected using MRI.
    32. The compounds: 2-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyl}amino-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyljphenylamino} - 5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino} benzoic acid; 2-[4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]phenyl}amino- benzoic acid; and 2-{4-[3-(4-Diethylaminophenyl)propyl}phenylamino}benzoic acid.
    33. A pharmaceutical formulation comprising a compound of Claim 19 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    34. A pharmaceutical formulation comprising a compound of Claim 20 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    35. A pharmaceutical formulation comprising a compound of Claim 21 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    36. A pharmaceutical formulation comprising a compound of Claim 22 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor. AMENDED SHEET
    37. A pharmaceutical formulation comprising a compound of Claim 23 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    38. A pharmaceutical formulation comprising a compound of Claim 24 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    39. A pharmaceutical formulation comprising a compound of Claim 25 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    40. A pharmaceutical formulation comprising a compound of Claim 26 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    41. A pharmaceutical formulation comprising a compound of Claim 32 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
    42. A compound of Formula I. R3 RS X 8 rR! N R % — (CH) a CA 7 4 R RO 2 R wherein . Oo R2 is hydrogen, C1 -Cg alkyl, or -CC-Cg alkyl; nis 0 to 5 inclusive; R1,R2,R3,R4, R5, RS, and R7 are independently hydrogen, halogen, -OH, -NHj, NRPRE, -CO,H, -C0,C}-Cg alkyl, -NOp, -0C;-C12 IN E v WO 00/76489 PCT/US00/15071 alkyl, -C1-Cg alkyl, -CF3, -CN, -OCH> phenyl, -OCH,-substituted phenyl, -(CH))m-phenyl, -O-phenyl, -O-substituted phenyl, oO 0) Co I -CH=CH-phenyl, -O(CH2),NRPRC, -CNRbRE, -NHCR?, -NH(CH2)pNRPRS, -N(C-Cgalkyl)(CHp),NRPRS, ,CHy0C,-Cg alkyl R8 is COOH, tetrazolyl, -SO7RY, or -CONHSO,RY; Rb and R€ are independently hydrogen, -C1-Cg alkyl, -(CH2)m-phenyl, or Rb and RC taken together with the nitrogen atom to which they are attached form a cyclic ring selected from piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C-Cg alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; Rd is hydrogen, -C]-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; pis 1 to 5 inclusive; AisCHorN; R! and R2, 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.
    PCT/US00/15071
    44. Use of a compound of Formula I as defined in Claim 10, or the pharmaceutically acceptable salts thereof, in the manufacture of a preparation for inhibiting the aggregation of amyloid proteins to form amyloid deposits.
    45. Use of Claim 44 wherein R® is hydrogen; nis 2; and R® and R* are hydrogen.
    46. Use of Claim 44 wherein R® is hydrogen; R® and R* are hydrogen; and nis 2 to 5 inclusive.
    47. Use of Claim 44 wherein R® is hydrogen, nis 2; R? and R* are hydrogen; and R!, R?, and R’ are independently chlorine, -N(CH,CHj),, -OH, CH;-, fluorine, -CF;, phenyl, hydrogen -OCH, phenyl, -O(CH,);N(CHs),, -O phenyl, -O(CH,),CHj, -CH(CH,0CH,CHys),, pyrrolyl, -CH=CH-phenyl, NT N[(CH2)3CH3] substituted phenyl, , -N[(CH2)3CH312, -OCHS,-substituted phenyl, pyrazolyl, or -N(phenyl),.
    48. Use of Claim 44 wherein R® is hydrogen; nis 3, 4, or 5; R® and R* are hydrogen; and RY R?, and R are independently chlorine or hydrogen. AMENDED SHEET
    PCT/US00/15071 C ] - 136 - 49, Use of Claim 44 wherein R® is hydrogen; nis 2; R> and R* are hydrogen; and R® and R® are independently hydrogen, -CO,H, -NO,, -OCHj, imidazolyl, - CN, fluorine, -CH;, -CF;, halogen, -NH-C,-Cgalkyl, -N(C;- Cealkyl),, -NH,, or pyrrolyl.
    50. Use of claim 44 wherein R® is hydrogen; nis 2; R® and R? are hydrogen; and R®is -CO,H.
    51. Use of a compound of Formula I as defined in Claim 17, or the pharmaceutically acceptable salts thereof, in the manufacture of a preparation for inhibiting the aggregation of amyloid proteins to form amyloid deposits. 59 Use of Claim 51 wherein the compound of Formula I is selected from the compounds listed in Claim 18.
    53. A substance or composition for use in a method of treating Alzheimer’s disease, said substance or composition comprising a compound of Formula I as defined in Claim 1, or the pharmaceutically acceptable salts thereof, and said method comprising administering an effective amount of said substance or composition to a patient having Alzheimer’s disease.
    54. A substance or composition for use in a method of treatment according to Claim 53 wherein R® is hydrogen; nis 2; and R® and R* are hydrogen. AMENDED SHEET
    PCT/US00/15071
    55. A substance or composition for use in a method of treatment according to Claim 53 wherein R® is hydrogen; R® and R* are hydrogen; and nis 2 to 5 inclusive.
    56. A substance or composition for use in a method of treatment according to Claim 53 wherein R* is hydrogen; nis 2; R® and R* are hydrogen; and R!, RZ, and R’ are independently chlorine, -N(CH,CH;),, -OH, CH;-, fluorine, -CF;, phenyl, hydrogen, -OCH, phenyl, -O(CH,)3;N(CHa),, -O phenyl, -O(CH,),CHj3, -CH(CH,OCH,CHj),, pyrrolyl, -CH=CH- phenyl , N[(CH»)3CH3]2, substituted phenyl, -OCH,-substituted phenyl, pyrazolyl, or -N(phenyl),.
    57. A substance or composition for use in a method of treatment according to Claim 53 wherein R® is hydrogen; nis 3, 4, or 5; R® and R* are hydrogen; and RY R?, and R are independently chlorine or hydrogen.
    58. A substance or composition for use in a method of treatment according to Claim 53 wherein R? is hydrogen; nis 2; R® and R* are hydrogen; and R’ RS and R® are independently hydrogen, -CO,H, -NO,, -OCHj, imidazolyl, -CN, fluorine, -CHj, -CF3, halogen, -NH-C,-Cqalkyl, -N(C,-Cgalkyl),, -NH,, or pyrrolyl. AMENDED SHEET
    PCT/US00/15071 J) -138 -
    59. A substance or composition for use in a method of treatment according to Claim 53 wherein R® is hydrogen; nis 2; R® and R* are hydrogen; and R’ is -CO,H.
    60. A substance or composition for use in a method of treating Alzheimer’s disease, said substance or composition comprising a compound of Formula I as defined in Claim 8, or the pharmaceutically acceptable salts thereof, and said method comprising administering an effective amount of said substance
    . or composition to a patient having Alzheimer’s disease.
    61. A substance or composition for use in a method of treatment according to Claim 53 wherein the compound of Formula I is selected from the compounds listed in Claim 9.
    62. A substance or composition for use in a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, said substance or composition comprising a compound of Formula I as defined in Claim 10, or the pharmaceutically acceptable salts thereof, and said method comprising administering an amyloid protein aggregation inhibiting amount of said substance or composition to a patient in need of inhibition of the aggregation of amyloid protein.
    63. A substance or composition for use in a method of treatment according to Claim 62 wherein R? is hydrogen; nis 2; and R® and R” are hydrogen. AMENDED SHEET
    PCT/US00/15071 9D) - 139 -
    64. A substance or composition for use in a method of treatment according to Claim 62 wherein R* is hydrogen; R® and R* are hydrogen; and nis 2 to 5 inclusive.
    65. A substance or composition for use in a method of treatment according to Claim 62 wherein R* is hydrogen; nis 2; R? and R? are hydrogen; and : R!, R? , and R’ are independently chlorine, -N(CH,CHj),, -OH, CH;-, fluorine, -CFs, phenyl, hydrogen -OCH, phenyl, -O(CH,);N(CHs),, -O phenyl, -O(CH,);CHj3, -CH(CH,OCH,CHj),, pyrrolyl, -CH=CH- phenyl, Cr | 2N[(CH»)3CH3]», substituted phenyl, -OCH,-substituted phenyl, pyrazolyl, or -N(phenyl),.
    66. A substance or composition for use in a method of treatment according to Claim 62 wherein R* is hydrogen; nis 3, 4, or 5; R? and R* are hydrogen; and R!, R? and R’ are independently chlorine or hydrogen.
    67. A substance or composition for use in a method of treatment according to Claim 62 wherein R® is hydrogen; nis 2; R® and R* are hydrogen; and R® and R® are independently hydrogen, -CO,H, -NO,, -OCHj, imidazolyl, - CN, fluorine, -CHj, -CF3, halogen, -NH-C,;-Cqalkyl, -N(C;- Cealkyl),, -NH,, or pyrrolyl. AMENDED SHEET
    PCT/US00/15071 J - 140 -
    68. A substance or composition for use in a method of treatment according to claim 62 wherein R* is hydrogen; nis 2; R? and R* are hydrogen; and R® is -CO,H.
    69. A substance or composition for use in a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, said substance or composition comprising a compound of Formula I as defined in Claim 17, or the pharmaceutically acceptable salts thereof, and said method comprising administering an effective amount of said substance or composition to a patient in need of inhibition of the aggregation of amyloid protein.
    70. A substance or composition for use in a method of treatment according to Claim 69 wherein the compound of Formula I is selected from the compounds listed in Claim 18.
    71. A substance or composition for use in a method of imaging amyloid deposits, said substance or composition comprising a compound having the Formula I as defined in Claim 28 or a pharmaceutically acceptable salt thereof, and said method comprising administering an effective amount of said substance or composition to a patient by a. introducing into a patient said substance or composition containing a detectable quantity of said labelled compound;
    b. allowing sufficient time for the labelled compound to become associated with amyloid deposits; and c. detecting the labelled compound associated with the amyloid deposits.
    72. A substance or composition for use in a method of treatment according to Claim 71 wherein the patient has or is suspected to have Alzheimer’s disease. AMENDED SHEET
    PCT/US00/15071 WV | - 141 -
    73. A substance or composition for use in a method of treatment according to Claim 71 wherein the labelled compound is a radio labelled compound.
    74. A substance or composition for use in a method of treatment according to Claim 71 wherein the labelled compound is detected using MRL
    75. Use according to any one of claims 1 - 9, 28 - 31, or 44 - 52, substantially as herein described and illustrated.
    76. A method according to any one of claims 10 - 18, substantially as herein described and illustrated.
    77. A substance or composition for use in a method of treatment according to any one of claims 53 - 70, substantially as herein described and illustrated.
    78. A substance or composition for use in a method of imaging or of diagnosis according to any one of claims 71 - 74, substantially as herein described and illustrated.
    79. A compound according to any one of claims 19 - 27, or 32, or 42, substantially as herein described and illustrated.
    80. A formulation according to any one of claims 33 - 41 or 43, substantially as herein described and illustrated.
    81. A new use of a compound which is defined in any one of claims 1 - 9, 28 - 31 or 44 - 52; a new non-therapeutic method of treatment; a new compound; a new formulation; or a substance or composition for a new use : in-a method of treatment or of imaging, substantially as herein described. AMENDED SHEET
ZA200109794A 1999-06-10 2001-11-28 Method of inhibiting amyloid protein aggregation and imaging amyloid deposits. ZA200109794B (en)

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CA2357450A1 (en) * 2000-09-29 2002-03-29 Warner-Lambert Company Phenoxazine analogs useful as amyloid aggregation inhibitors and treatment of alzheimer's disease and disorders related to amyloidosis
GB0225548D0 (en) 2002-11-01 2002-12-11 Glaxo Group Ltd Compounds
ES2327372B1 (en) * 2007-04-23 2010-08-24 Laboratorios Almirall S.A. NEW DERIVATIVES OF THE AMINO-NICOTINIC AND AMINO-ISONICOTINIC ACIDS.
ES2319596B1 (en) * 2006-12-22 2010-02-08 Laboratorios Almirall S.A. NEW DERIVATIVES OF THE AMINO-NICOTINIC AND AMINO-ISONICOTINIC ACIDS.
JP2010518064A (en) 2007-02-12 2010-05-27 メルク・シャープ・エンド・ドーム・コーポレイション Piperazine derivatives for the treatment of AD and related conditions
US20080253967A1 (en) * 2007-04-13 2008-10-16 Kung Hank F Halo-Stilbene Derivatives And Their Use For Binding And Imaging Of Amyloid Plaques
UY31272A1 (en) 2007-08-10 2009-01-30 Almirall Lab NEW DERIVATIVES OF AZABIFENILAMINOBENZOIC ACID
EP2135610A1 (en) 2008-06-20 2009-12-23 Laboratorios Almirall, S.A. Combination comprising DHODH inhibitors and methotrexate
NZ591896A (en) * 2008-08-29 2013-03-28 Treventis Corp Compositions and methods of treating amyloid disease
EP2239256A1 (en) 2009-03-13 2010-10-13 Almirall, S.A. Sodium salt of 5-cyclopropyl-2-{[2-(2,6-difluorophenyl)pyrimidin-5-yl]amino}benzoic acid as DHODH inhibitor
EP2228367A1 (en) * 2009-03-13 2010-09-15 Almirall, S.A. Addition salts of amines containing hydroxyl and/or carboxylic groups with amino nicotinic acid derivatives as DHODH inhibitors
EP2314577A1 (en) 2009-10-16 2011-04-27 Almirall, S.A. Process for manufacturing 2-[(3,5-difluoro-3'-methoxy-1,1'-biphenyl-4-yl)amino]nicotinic acid
EP2536405A1 (en) 2010-02-16 2012-12-26 Universita Degli Studi di Siena Non peptidic 14-3-3 inhibitors and the use thereof
KR20130115311A (en) * 2010-11-24 2013-10-21 알러간, 인코포레이티드 Modulators of s1p receptors
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BR0011728A (en) 2002-02-26
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NO20015995D0 (en) 2001-12-07
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HUP0202508A2 (en) 2002-12-28
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