OA11963A - 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
OA11963A
OA11963A OA1200100327A OA1200100327A OA11963A OA 11963 A OA11963 A OA 11963A OA 1200100327 A OA1200100327 A OA 1200100327A OA 1200100327 A OA1200100327 A OA 1200100327A OA 11963 A OA11963 A OA 11963A
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phenyl
phenylamino
benzoic acid
ethyl
dichloro
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OA1200100327A
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Corinne Elizab Augelli-Szafran
Mark Robert Barvian
Christopher Franklin Bigge
Shelly Ann Glase
Shunichiro Hachiya
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Warner Lambert Co
Yamanouchi Pharma Co Ltd
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Publication of OA11963A publication Critical patent/OA11963A/en

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Abstract

The present invention provides a method of treating Alzheimer's disease using a compound of Formula (I). Also provided is a method of inhibiting the aggregation of amyloid proteins using a compound of the Formula (I) and a method of imaging amyloid deposits, as well as new compounds of Formula (I).

Description

119 6 3
METHOD OFINHIBITING AMYLOID PROTEIN AGGREGATIONAND IMAGING AMYLOID DEPOSITS
FIELD OF THE INVENTION
This invention relates to a method of inhibiting amyloid protein5 àggregation and imaging amyloid deposits. More particularly, this invention relates to a method of inhibiting amyloid protein aggregation in order to treatAlzheimer’s disease.
BACKGROUND OF THE INVENTION
Amyloidosis is a condition characterized by the accumulation of various 10 insoluble, fibrillar proteins in the tissues of a patient. The fibrillar proteins thatcomprise the accumulations or deposits are called amyloid proteins. While theparticuîar proteins or peptides found in the deposits vary, the presence of fibrillarmorphology and a large amount of β-sheet secondary structure is common tomany types of amyloids. An amyloid deposit is formed by the aggregation of 15 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 particuîar associated protein, such as Mediterranean fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloid 20 cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cérébral hemorrhage with amyloidosis, Alzheimer’s disease, Down’ssyndrome, Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,P2-microglobulin amyloid in dialysis patients, inclusion body myositis, 25 p2~amyloid deposits in muscle wasting disease, Sickîe Cell Anémia, Parkinson’sDisease, and Islets of Langerhans diabètes Type II insulinoma. 119 6 3 -2-
Alzheimer’s disease is a degenerative brain disorder characterizedclinically by progressive loss of memory, cognition, reasoning, judgement, andemotional stabîlity that gradually leads to mental détérioration and ultimatelydeath. Because Alzheimer’s disease and related degenerative brain disorders are a .major medical issue for an increasingly aging population, the need for newtreatments and methods for diagnosing the disorders are needed. À simple, noninvasive method for detecting and quantitating amyloiddeposits in a patient has been eagerly sought. Presently, détection of amyloiddeposits involves histological analysis of biopsy or autopsy materials. Bothmethods hâve major drawbacks. For example, an autopsy can only be used for apostmortem diagnosis.
The direct imaging of amyloid deposits in vivo is difïicult, as the depositshâve many of the same physical properties (i.e., density and water content) asnormal tissues. Attempts to image amyloid deposits directly usine magneticrésonance imaging (MRI) and computer-assisted tomography (CAT) nave beendisappointing and hâve detected amyloid deposits only under certain favorableconditions. In addition, efforts to label amyloid deposits with antibodies, sérumamyloid P protein, or other probe molécules has provided some selectivity on theperiphery of tissues, but has provided for poor imaging of tissue interiors.
Thus, it would be useful to hâve a noninvasive technique for imaging andquantitating amyloid deposits in a patient. In addition, it would be useful to hâvecompounds that inhibit the aggregation of amyloid proteins to form amyloiddeposits.
SUMMARY OF THE INVENTION
The présent invention provides a method of treating Alzheimer’s disease,the method comprising administering to a patient having Alzheimer’s disease atherapeutically effective amount of a compound of Formula I 119 6 3
I
wherein
Ra is hydrogen, Cj-Cg alkyl, or -CC]-Cg alkyl; nis Oto 5 inclusive;
Rl, R2, R2, R4, R5, R^, and R2 are independently hydrogen, halogen, -OH, -NH2, NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OCi-C12 alkyl, -Cj-Cg alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyî, -O-substituted phenyl,
O O 1 1 -CH-CH-phenyl, -O(CH2)pNRbRc, -CNRbRc, -NHCRb, -NH(CH2)pNRbRc,-N(C1-C6alkyl)(CH2)pNRbRc, /CT^OCj-Cg alkyl—CH ; \cH2OCrC6 alkyl r8 is COOH, îetrazolyl, -SO2R^, or -CONHSO2R^;
Rb and Rc are independently hydrogen, -Cj-Cg alkyl, -(CH2)m-phenyl, or
Rb and Rc taken together with the nitrogen atom to which they areattached form a cyclic ring selected from piperidinyl, pyrrolyl,imidazolyl, piperazinyl, 4-Cj-Cg alkylpiperazinyl, morpholino,thiomorpholino, decahydroisoquinoline, or pyrazolyl; R^ is hydrogen, -Cj-Cg alkyl, -CF3, or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; 11963 -4·. RÎ and R2, when adjacent to one another, can be methylene-dioxy;orthe pharmaceutically acceptable salts thereof.
In a preferred embodiment, the
group is attached at the 4-position of the phenyl ring.
In a preferred embodiment of the method, in the compounds of Formula IRa is hydrogen;n is 2; and R3 and are hydrogen.
In a preferTed embodiment of the method, in the compounds of Formula I10 Ra is hydrogen;
Rl is halo; R2 is hydrogen or halo; R2, R^, r5, and r6 hydrogen; andn is 2 to 5 inclusive. 15 In another preferred embodiment of the method, in the compounds of Formula 1Ra is hydrogen;n is 2 or 3;
Rl is -NRbRc; and ; R2, r3, r4 r5? and r7 ap hydrogen.
20 In a preferred embodiment of the method, in the compounds of Formula I
Ra is hydrogen;nis2; r3 and R^ are hydrogen; and R1, R2, and R7 are independently chlorine, -N(CH2CH3)2, -OH, CH3-, 25 fluorine, -CF3, phenyl, hydrogen, -00¾ phenyl, 119 6 3 -5- -O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, , -N[(CH2)3CH3]2j substituted phenyl, -OCH2-substituted phenyl, pyrrozolyl, or -N(phenyl)2.
In a preferred embodiment of the method, in the compounds of Formula IRa is hydrogen;n is 3,4, or 5;
Ri, RA and R? are independently chlorine or hydrogen.
In a preferred embodiment of the method, in the compounds of Formula IRa is hydrogen;n is 2; R^ and R^ are hydrogen; and R A r6, and R^ are independently hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -SCH3, -CN, fluorine, -CH3, -CF3, halogen,
O -NH-C]-Cg alkyl, -N(C]-Cgalkyl)2, -NH2, or pyrrolyl. in a preferred embodiment of the method, in the compounds of Formula IRa is hydrogen;nis 2; R^ and R^ are hydrogen; andR5 is -CO2H. 119 6 3 -6-
Also preferred is a method of treating Alzheimer’s disease, the methodcomprising administering to a patient having Alzheimer’s disease atherapeutically effective amount of a compound of Formula I R' i ,__ 7^“ R2
Re wherein
Ra is hydrogen;n is 1 to 5 inclusive; R^ and R^ are hydrogen;
Rl, R^, and R- are independently chlorine, -N(CH2CH3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl,-O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl,-N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl,pyrazolyl, or -N(phenyl)2; R5 and R^ are independently hydrogen, -CO2H, -NO2, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the method, coxnpounds of Formula I are2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoicacid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid;2-{4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-4-methoxy- 5-nitrobenzoic acid; 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl3-phenylamino}benzoicacid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid; 1196 3 -7- 2- {4-[3 -(3,4-Dichlorophenyl)propyl]pheny lamino} -4-methoxy- 5-nitrobenzoic acid; 2- {4-(3-(3 ,4-DicMorophenyl)propyl]phenylamino }-4-imidazo-1 -yl- 5-nitrobenzoic acid; 2- {4-[3 -(3,4-DichIorophenyl)-propyI]pheny lamino} benzoic acid;2-(4-(4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoic acid; 2- {4-(4-(3 ,4-Dichloro-phenyl)-butyl]-pheny lamino} -5-nitro-benzoic acid;2-(4-(4-(3,4-Dichlorophenyl)-butyl]phenylamino}-3,5-dinitrobenzoic acid; 2- {4-(5-(3,4-Dichlorophenyl)pentyl]phenylamino} -5-nitrobenzoic acid;2-.(4-( 5-(3,4-Dichloro-phenyl)pentyl]phenylamino}-4-methoxy- 5-nitrobenzoic acid; 2-(4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;2-(4-(2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;2-{4-(2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid; 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;2-(4-Phenethyl-phenylamino)-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino}-5-methoxy-benzoic 2-(4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylamino}-terephthalic acid;2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid; 4-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenyiamino}-isophthalic acid;2-(4-(2-(3,4-Dichloro-phenyl)-etbyl}-phenylamino}-5-inethanesulfonyl- benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -5-imidazol-1 -yl-benzoic acid; 2-(4-(2-(3,4-DicMoro-phenyl)-ethyl3-phenylamino}-6-mtro-benzoic acid;2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-nitro-benzoic acid;2-(4-(2-(3,4-Dichloro-phenyl)-ethyrj-phenylamino}-3-nitro-benzoic acid; 11963 ' -8- 5- Cyano-2- (4-(2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylanûno}-4,6-difluoro-benzoic 6- (4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoic 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]-pheny lamino} -4-fluoro-benzoic acid;2-(4-(2-(3,4-Dichloro-phenyl)-eihyl]-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]-phenylammo}-5-pyrrol-l-yl-benzoic acid; 2-{4-(2-(4-Benzyloxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4- {2-(4-(3-Dimethylammo-propoxy)-phenyl]-ethyl} -phenylamino)· benzoic acid; 2-{4-(2-(4-Diethylamino-phenyl)-ethyl]-phenylamÎno}-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-Styiyl-phenyl)-ethyl]-phenylamino}-benzoicacid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-beiizoic acid;2-{4-[2-(4'-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino}-benzoicacid; 119 6 3 -9- 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}-phenyiamino)-benzoic acid; 2- {4-[2-(4-Pyrazol-1 -yl-phenyl)-ethyl]-phenylamino } -benzoic acid; 2-{4-[2-(4-Diphenylamino-phenyl)-ethyî]-phenylamino}-benzoicacid; 2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylamino)- benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylainino}-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-îrifiuoromethylphenyl)ethyl]phenyl]arn.ino-benzoic 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid;2-(4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid;2-(4-[3-(3-Nitrophenyl)propyi3phenylanuno}benzoic acid; 2-(4-(3-(4-Aminophenyl)propyî]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)ethyl]phenylamino}benzoicacid monohydrochloride; 2-(4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoicacidmonohydrochloride monohydrate; 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenyIamino}benzoic acid;2-{4-[3-(3-Dimethylaminophenyl)propyl3phenylamino}benzoicacid;2-{4-(3-(4-Ethylaminophenyl)propyl)phenylamino}benzoicacid;2-(N-(4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid; 1196 3 -10- 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-Dimethylaniinophenyl)propyl]phenylainino}benzoicacid;2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid;2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoicacid;2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoicacid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoicacid monohydrochloride; 2-{4-[3-(4-Acetylaminophenyl)propyI]phenylamino}benzoic acid;2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoicacid; 2- {4-[3-(3-Diethylaminophenyl)ethyl]phenylanuno}benzoic acid monohydrochloride; 2-{4-[2-(3-Piperidin-l -ylphenyl)ethyl]phenyiamino} benzoic acidmonohydrochloride; 2-{4-[3-(4-Dipropylaminophenyl)propyl]phenylamino}benzoicacid;2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoicacid;2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoic acid;2-(4-{3-[4-(lH-Pyrrol-l -yl)phenyl]propyl}phenylamino)benzoic acid;2-{4-[3-(4-Piperidin- l-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)propyl3phenylamino}benzoic acid;2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acid;2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoicacid;2-{4-[3-(4-Pyrrolidin-1 -yl-phenyl)-propyi]-phenylamino}-benzoic acid; 2- {4-[3-(3-Piperidin-1 yl-phenyl)-propyl]-phenylamino} -benzoic acid;2-{4-[3-(4-[2-Diethylaminoethylamino]phenyl)-propyl]pheny]amino}- benzoic acid; 2-{4-[2-(4-[Hydroxycarbonylmethylamino]phenyl)ethyl]phenylamino}-benzoic acid; -11- 2 - {4- [2-(4- [2 -Diethyiaminoethyl amino]phenyl)ethyl]pheny lamino} -benzoic acid; 2-{4-[3-(4-Morpholinophenyl)propyl]phenylamino}-benzoic acid;2-{4-[3-(4-Piperazinylphenyl)propyl}phenylamino}-benzoic acid; and2-(4-(3,4-Dichlorophenyl)phenylamino]benzoic acid.
The invention also provides the foregoing compounds wherein the benzoicacid 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 amyloidproteins to form amyloid deposits, the method comprising administering to apatient in need of inhibition of the aggregation of amyloid protein an amyloidprotein aggregation inhibiting amount of a compound of Formula 1
wherein
O
I
Ra is hydrogen, Cj-Cg alkyl, or -CCi-Cg alkyl;n is 0 to 5 inclusive; RJ, R.2, R^, r4, r5, r6} and r7 ^g independently hydrogen, halogen, -OH, -NH2, NRbRc, -CO2H, -CO2C]-C6 -NO2, -OCpCn alkyl, -Cj-Cg alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substitutedphenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl,
O O 1 1 -CH-CH-phenyl, -O(CH2)pNRbRc,-CNRbRc, -NHCRb,-NH(CH2)pNRbRC)-N(C1-C6alkyl)(CH2)pNRbRc, 119 6 3 -12- /C^OCj-Cg alkyl—CH ;
Vh2OCj-C6 alkyl
R.8 îs COOH, tetrazolyl, -SC^R^, or -CONHSCbRA
Rb and Rc are independently hydrogen, -CpCg alkyl, -(CH2)m-phenyl, or
Rb and Rc taken together with the nitrogen atom to which they areattached form a cyclic ring selected from piperidinyl, pyrrolyl,imidazolyl, piperazinyl, 4-C}-C6 alkylpiperazinyl, moipholino,thiomorpholino, decahydroisoquinoline, or pyrazolyl;
Rd is hydrogen, -Cj-Cg alkyl, -CF3, or phenyl;m is 0 to 5 inclusive;p is 1 to 5 inclusive; A is CH or N;
Rl and R^, 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 IRa is hydrogen;n is 2; and R^ and R^ are hydrogen.
In a preferred embodiment of the method, in the compounds of Formula IRa is hydrogen; R^ and R^ are hydrogen; andn is 2 to 5 inclusive.
In a preferred embodiment of the method, in the compounds of Formula 1Ra is hydrogen;nis2; r3 and R^ are hydrogen; and 119 6 3 -13-
Rl, R.2, and R? are independently chlorine, -N(CH2CH3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl,-O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl,
YrY- II, -N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2.
In a preferred embodiment of the method, in the compounds of Formula I
Ra is hydrogen;n is 3,4, or 5; and R^ are hydrogen; and
Rl, R2, and R? are independently chlorine or hydrogen.
In a preferred embodiment of the method, in the compounds of Formula 1
Ra is hydrogen;n is 2; R^ and R^ are hydrogen; and R5 and R6 are independently hydrogen, -CO2H, -NO2, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, halogen,-NH-Cj-Cg alkyl, -N(Ci-Cgalkyl)2, -NH2, or pyrrolyl.
In a preferred embodiment of the method, in the compounds of Formula I
Ra is hydrogen;nis2; R^ and R^ are hydrogen; andR5is-CO2H.
Also provided is a preferred method of inhibiting the aggregation ofamyloid proteins to form amyloid deposits, the method comprising administering 119 6 3 -14-
to a patient in need of inhibition of the aggregation of amyloid protein an amyloidprotein aggregation inhibiting amount of a compound of Formula I
wherein
Ra is hydrogen;n is 1 to 5 inclusive; and R^ are hydrogen;
Rl, R^, and R^ are independently chlorine, -Ν(ΟΗ2ΟΗ3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl,-O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl,-N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl,pyrazolyl, or -N(phenyl)2; R5 and R^ are independently hydrogen, -CO2H, -NO2, -OCH3, imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; R 8 is COOH or tetrazolyl; or the pharmaceutically acceptable salts thereof.
The most preferred compounds provided by the invention hâve Formula II
Ry=\ R‘
fl and pharmaceutically acceptable salts thereof,wherein:
Rl is halo; R2 is H or halo; and
COOH 1196 3 -15- n and RÔ are as defined above in Formula I.
Another preferred group of compounds hâve Formula III
ΠΙ and pharmaceutically acceptable salts thereof,wherein:
Ri is halo; R^ is H or halo; and n and R^ are as defined above in Formula I. 10
Another group of preferred invention compounds hâve Formula IV
N=N
IV 15 and pharmaceutically acceptable salts thereof,wherein:
Rl is halo; R^ is H or halo; and n and are as defined above in Formula I.
In a preferred embodiment of the method, the novel compounds of Formula I areprovided which are 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid;2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid; 20 2- {4-(4-(3,4-Dichloro-phenyl)-ethyI]phenylamino} -4-methoxy- 5-nitrobenzoic acid; 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid;2-{4-[2-(4-Dibutylammo-phenyî)-ethyI]phenylamino}benzoic acid; 119 6 3 -16- 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-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-l-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-phenyî)-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]phenylammo}-5-nitrobenzoic acid; 2- {4-(5-(3,4-Dichloro-phenyl)pentyl]phenylamino} -4-methoxy- 5-nitrobenzoic acid; 2-(4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid;2-(4-(2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino} -5-nitro-benzoic acid;2-{4-[2-(4-Chloro-3-triiluoromethyl-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]-phenylanüno}-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-l-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; ( 119 6 3 -17- 2- {4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylaniino} -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]-phenylannno}-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-Dichioro-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]-phenyiamino}-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-triiluoromethyl-benzoictacid; 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-Diethylanùno-phenyî)-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-l -ethoxymethyl-ethyl)-phenyl]-ethyl} - phenylamino)-benzoic acid; 2-{4-[2-(4-Pyrrol-l -yl-phenyl)-ethyl]-phenylamino}-bsnzoic acid;2-{4-[2-(4-Styryl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl3-phenylamino}-benzoic acid; pr -18- 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]-ethyï}-phenylamino)-benzoic acid; 2-(4-{2-[4-(2-ChJoro-6-fluoro-benzyloxy)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2- {4-[2-(4-Pyrazol-1 -yl-phenyl)-ethyl3-phenylamino}-benzoic acid; . 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino}-benzoic acid;2-(4- {2-(4-(3,4-Dichloro-benzyloxy)-phenyl]-ethyl}-phenylammo)- 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-Îriiluoromethylphenyl)ethyl]phenyl]amino-benzoic acid; or 2-(4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
The présent invention also provides 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;2-{4-[2-(4-Dibutylamino-phenyl)-ethyI]phenylamino}benzoicacid;2-(4-(2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid;2-(4-(2-(-(3,4-Dichlorophenyl)propyl]phenylaniino}-4-methoxy- 5-nitrobenzoic acid; 2-{4-[2-[-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-l-yl-5-nitrobenzoic acid; 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino}benzoicacid; 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-inethoxy- 5-nitrobenzoic acid; 119 6 3 acid; acid; -19- 2-(4-(3,4-Dichloro-benzyl)-phenyîaniino]-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-trifiuoromethyl-phenyl)-ethyl]-phenylamino} -benzoic 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)-ethyl3-phenylamino}-5-amino-benzoic 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichlorophenyl)]phenyîamino}-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-meihyl-benzoic acid; 4- (4-(2-(3,4-Dichloro-phenyl)-ethyl3-phenylamino}-isophthalic acid;2-(4-(2-(3,4-Dichloro-phenyl)-ethyI}-phenylamino}-5-methanesulfonyl- benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl] -phenylamino) -5-imidazol-l -yî-benzoic acid; 2-(4-(2-(3,4-DichIoro-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)-ethyî]-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)-ethyrj-phenylamino)-4,6-difluoro-benzoic acid; acid; 6-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-2,3-difluoro-benzoic 2- (4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino) -6-fluoro-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fîuoro-benzoic acid; 119 6 3 -20- 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-fluoro-ben2oic acid;2- {4-(2-(3,4-Dichloro-phenyl)-ethyl] -phenylamino } -3,5-difluoro-benzoic acid; 2- {4-(2-(3,4-Dichloro-phenyl)-ethyl3 -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}-benzoicacid;2-{4-[2-(4-Octyloxy-phenyl)-ethyl]-phenylamino}-benzoicacid;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)-ethylj-phenylainino}-benzoic acid;2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoicacid;2-{4-[2-(4'-Ethyl-biphenyl-4-yl)-ethyl]-phenylamino} -bexizoic acid;2-{4-[2-(4-Octyl-phenyl)-ethyl]-phenylamino}-benzoicacid;2-(4-(2-(3-(3,5-Dichloro-phenoxy)-phenyl]-ethyl}-phenylamino)-benzoic 2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyI]-ethyl}-phenylamino)-benzoic acid; 2-{4-[2-(4-Pyrazol-1 -yl-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylainino}-benzoicacid; 119 6 3 -21- 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)-ethyI]-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]phenylamino}-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)propyî]phenylamino}benzoic acid;2-{4-(2-(4-Aminophenyl)ethyl]phenylamino}benzoic acid;2-{4-[2-(4-Dipropylaminophenyl)ethyl]phenylamino}benzoicacid monohydrochloride; 2-{4-[2-(4-DiethyIaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride monohydrate; 2-{4-[3-(3-Dipropylaminophenyl)propyI]phenylamino}benzoic acid; . 2- {4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoic acid; 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoicacid; 2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoic acid; 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoicacid;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}benzoicacid; 119 6 3 -22- 2- { 4- [2-(3 -Dipropylaminophenyl)ethyl]pheny lamino} benzoic acidmonohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride; 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 acidmonohydrochloride; 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-( 1 H-PyiTol-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]phenylammo}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-l-yl-phenyl)-propyl]-phenylamino}-benzoicacid; 2- {4-[3-(3-Piperidin-lyl-phenyl)-propyl]-phenylamino}-benzoic acid;{5-((1 -Butyl-1,2,3,4-tetrahydro-6-quinolyl)niethylidene]-4-oxo-2- thioxothiazolidin-3-yI}acetic acid; {5-[(l-Butyl-2,3-dihydro-lH-indol-5-yl)methylidene]-4-oxo-2- thioxothiazolidin-3-yl}acetic acid; 3- {5-[(l-Butyl-l,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid; 4- { 5-[( 1 -Butyl-1 ,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoic acid; or 2-(4-(3,4-DichlorophenyI)phenyl]aminobenzoic acid. 11963 -23-
Also provided are the foregoing compounds wherein the terminalphenylalkyl group is attached at the 2- or 3-position of the central phenyl ring, i.e.,compounds of the Formula la la
Typical 2- and 3-substituted compounds are: 2-{3-[2-(3,4-Dichlorophenyî)ethyl]phenylamino}-benzoic acid;2-{2-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid; 2- { 3 - [3 -(4-Diethyîaminopheny l)propyl]phenylamino} -benzoic acid;2-{3-[3-(4-Di-n-propylaminophenyl)propyl]phenylamino}-benzoic acid;2- {3 - [3-(4-n-Propylaminophenyl)propyl Jpheny lamino} -benzoic acid; 2- {3 -[3 -(4-[2-Diethylaminoethylamino]phenyl)propyl]pheny lamino } - benzoic acid; 2-{2-[3-(4-[Hydroxycarbonylmethylamino]phenyl)propyl]phenylainino}-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}-benzoicacid;2-{3-[2-(4-Chlorophenyl)ethyî]phenylamino}-benzoicacid;2-{3-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acid; and2-{4-[4-(4-{4-Methylpiperazinyl}phenyl)butyl]phenyiamino}-benzoic acid.
Pharmaceutical formulations of the novel compounds admixed with apharmaceutically acceptable diluent, carrier, or excipient are also provided.
Also provided is a method of imaging amyloid deposits, the methodcomprising: 119 6 3 -24- a. introducing into a patient a détectable quantity of a labeled compound having the Formula I or a pharmaceutically acceptablesait thereof:
10 15
O fi
Ra is hydrogen, Cj-Cg alkyl, or -CCj-Cg alkyl; n is 0 to 5 inclusive;
Rl, RA r3, r4, r59 r6, r7 independently hydrogen, halogen, -OH, -NH2, NRbRc, -CO2H, -CO2Cj-Cg alkyl, -NO2, -OCi-C12 alkyl, -CpCg alkyl, -CF3, -CN, -OCH2phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl,
O O fi ! -CHCH-phenyl, -O(CH2)pNRbRc, -CNRbRc, -NHCRb,-NH(CH2)pNRbRc, -NCC^CéalkylXCHilpNRbRC,
/C^OCpCg alkyl—CH \cH2OCrC6 alkyl’ r8 is COOH, tetrazolyl, -SO2R^, or -CONHSO2R^;
Rb and Rc are independently hydrogen, -Cj-Cg alkyl, -(CH2)m- phenyl, or Rb and Rc taken together with the nitrogen atomto which they are attached form a cyclic ring selected frontpiperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-Cj-Cg 20 119 6 3 -25- alkylpiperazinyl, morpholino, thiomorpholino,decahydroisoquinolme, or pyrazolyl;
Rd is hydrogen, -C] -Cg alkyl, -CF3, or phenyl;m is 0 to 5 inclusive;p is 1 to 5 inclusive; A is CH or N;
Rl and R^, when adjacent to one another, can be methylene-dioxy;or the pharmaceutically acceptable salts thereof; b. allowing sufficient tune for the labeled compound to becomeassociated with amyloid deposits; and c. detecting the labeled compound associated with the amyloiddeposits.
In a preferred embodiment of the method, the patient has or is suspected to hâveAlzheimer’s disease.
In a preferred embodiment of the method, the labeled compound is a radio labeledcompound.
In a preferred embodiment of the method, the labeled compound is detected usingMRI.
The présent invention also provides the preferred compounds: 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylarnino}-benzoicacid;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]phenyljamino-benzoic acid; 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}-benzoicacid;and pharmaceutical formulations thereof.
Pharmaceutically acceptable acid addition salts, amides, and prodrugs of theforegoing compounds are also provided by this invention. 11963 ' -26-
DETAILED DESCRIPTION OF THE INVENTION
The terni “alkyl” means a straight or branched chain hydrocaxbon havingfrom 1 to 12 carbon atoms. Représentative exemples 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 Cj-Cg alkyl, and especially CpC^ alkyl.
The term “alkoxy” means an alkyl group attached to an oxygen atom.Représentative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy,propoxy, and isobutoxy. Preferred alkoxy groups are Cj-C^ alkoxy, andespecially Cj-Cg alkoxy.
The term “halogen” includes chlorine, fluorine, bromine, and iodine.
The term “substituted” means that one or more hydrogen atom in amolécule has been replaced with another atom or group of atoms. For example,substituents include halogen, especially chloro, -OH, -CF3, -NO2, -NH2,-NH(Ci-C6alkyl), -N(C1-C6alkyl)2, CrC6 alkyl, -OCi-C6 alkyl, -CN, -CF3,-CO2H, and -CO^Cj-Cg alkyl.
The term “substituted phenyl” means a phenyl ring in which from 1 to4 hydrogen atoms hâve been independently replaced with a substituent, preferablyone 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 Rl, R^, and R^, for example, includeamino(NRbRc) and acylamino (-NHCORb). R^ and Rc can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, and typical NR^RC groups includemethylamino, diethylamino, isobutyl-propylamino, benzylamino, and 3,4-dimethoxybenzylamino. Examples of acylamino groups include formamido,acetamido, 2-phenylacetamido, and 2-(3-nitrophenyl)acetamido. Rl, R3,and R5 can also be aminoalkoxy (-O(CH2)pNR^RC) such asN-methylaminomethoxy and 2-(N-benzylamino)ethoxy, as well as 119 6 5 -27- aminoalkylamino (-NH(CH2)pNR^Rc) such as 3-(dimethylamino)propylaminoand 2-(N-ethyl-N-benzylamino)ethylamino. Substituent groups such as R^, RRand R5 additionally can be cyclic structures, for instance when NR^RC is part ofthe substituent group, and R^ and Rc are taken together with the nitrogen to which 5 they are attached to form a cyclic ring selected from imidazole, pyrrole, piperidine, piperazine, 4-Ci-Cg alkylpiperazine, morpholine, thiomorpholine,pyrazole, and decahydroisoquinoline.
Substituent groups such as R^, R^, R^, R^, and R"? also can be -CH=CH-phenyl (i.e., styryl), phenoxy, O-substituted phenyl such as 3-iodophenoxy, 2,4,6- 10 trihydroxyphenoxy, 2-fluoro-3-nitrophenoxy, as well as -O-benzyl and -O-substituted benzyl such as 2-trîfluoromethylbenzyloxy and 4-aminobenzyloxy.
The terni “pharmaceutically acceptable sait, ester, amide, and prodrug” asused herein refers to those carboxylate salts, amino acid addition salts, esters,amides, and prodrugs of the compounds of the présent invention which are, within 15 the scope of Sound medical judgement, suitable for use in contact with the tissuesof patients without undue toxicity, irritation, allergie response, and the like,commensurate with a reasonable benefit/risk ratio, and effective for their intendeduse, as well as the zwitterionic forms, where possible, of the compounds of theinvention. The term “salts” refers to the relatively nontoxic, inorganic and organic 20 acid addition salts of compounds of the présent invention. These salts can be prepared in situ during the final isolation and purification of the compounds or byseparately reacting the purified compound in its free base form with a suitableorganic or inorganic acid and isolating the sait thus formed. Représentative saltsinclude the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, 25 oxalate, valerate, oleate, palmitate, stéarate, lauréate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylatemesylate, glucoheptonate, lactobionate and laurylsuiphonate salts, and the like.These may include cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnésium, and the like, as well as, 30 nontoxic ammonium, quatemary ammonium and amine cations including, but not limited to ammonium, tétraméthylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for 1 19 6 3 1 -28- example, Berge S.M., et al., Pharmaceutical Salts, J. Pharm. Sci., 66:1-19 (1977)which is incoiporated herein by reference.)
Examples of pharmaceutically acceptable, nontoxic esters of thecompounds of this invention include Cj-Cg alkyl esters wherein the alkyl group isa straight or branched chain. Acceptable esters also include C5-C7 cycloalkylesters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkylesters are preferred. Esters of the compounds of the présent invention may beprepared according to conventional methods, for example by reacting a carboxylicacid of Formula I with an alcohol such as éthanol or benzyl alcohol.
Examples of pharmaceutically acceptable, nontoxic amides of thecompounds of this invention include amides derived from ammonia, primaryCj-Cg alkyl amines and secondary Cj-Cg dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary amines, the aminemay also be in the form of a 5- or 6-membered heterocycle containing onenitrogen atom. Amides derived from ammonia, CJ-C3 alkyl primary amides andC1-C2 dialkyl secondary amides are preferred. Amides of the compounds of theinvention may be prepared according to conventional methods.
The term “prodrug” refers to compounds that are rapidly transfonnedin vivo to yield the parent compound of the above formulas, for example, byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Deliverv Systems. Vol. 14 of the A.C.S. SymposiumSériés, and in Bioreversible Carriers in Drue Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both of whichare incoiporated herein by reference.
In addition, the compounds of the présent invention can exist in unsolvatedas well as solvated forms with pharmaceutically acceptable solvents such as water,éthanol, and the like. In general, the solvated forms are considered équivalent tothe unsolvated forms for the purposes of the présent invention.
The compounds of the présent invention can exist in differentstereoisometric forms by virtue of the presence of asymmetric centers in thecompounds. It is contemplated that ail stereoisometric forms of the compounds, aswell as mixture thereof, including racemic mixtures, form part of this invention. 119 6 3 -29-
In the fïrst step of the présent method of imaging, a labeled compound ofFormula 1 is introduced into a tissue or a patient in a détectable quantity. Thecompound is typically part of a pharmaceutical composition and is administered tothe tissue or the patient by methods well-known to those skilled in the art.
In the methods of the présent invention, a compound can be administeredeither orally, rectally, parenterally (intravenous, by intramuscularly orsubcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically,locally (powders, ointments or drops), or as a buccal or nasal spray. . Compositions suitable for parentéral injection may comprisephysiologically acceptable stérile aqueous or nonaqueous solutions, dispersions,suspensions or émulsions, and stérile powders for reconstitution into stérileinjectable solutions or dispersions. Examples of suitable aqueous and nonaqueouscarriers, diluents, solvents, or vehicles include water, éthanol, polyols(propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixturesthereof, vegetable oils (such as olive oil), and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the use of acoating such as lecithin, by the maintenance of the required particle size in thecase of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispensing agents. Prévention of the action ofmicroorganisms can be ensured by various antibacterial and antiftmgal agents, forexample, parabens, chlorobutanol, phénol, sorbic acid, and the like. It may also bedésirable to include isotonie agents, for example sugars, sodium chloride, and thelike. Prolonged absoiption of the injectable pharmaceutical form can be broughtabout by the use of agents delaying absorption, for example, aluminummonostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills,powders, and granules. In such solid dosage forms, the active compound isadmixed with at least one inert customary excipient (or carrier) such as sodiumcitrate 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, polyvinylpyrroîidone, sucrose, andacacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for .119 6 3 -30- example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain complex silicates and sodium carbonate; (e) solution retardera, as forexample parafSn; (f) absorption accelerators, as for example, quatemaryammonium compounds; (g) wetting agents, as for example, cetyl alcohol andglycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and(i) lubricants, as for example, talc, calcium stéarate, magnésium stéarate, soïidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case ofcapsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers insoft- and hard-fîlled gelatin capsules using such excipients as lactose or milksugar, as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granulescan be prepared with coatings and shells, such as enteric coatings and others wellknown in the art. They may contain opacifying agents, and can also be of suchcomposition that they release the active compound or compounds in a certain partof the intestinal tract in a delayed manner. Examples of embedding compositionswhich can be used are polymeric substances and waxes. The active compoundscan also be in microencapsulated form, if appropriate, with one or more of theabove-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceuticallyacceptable émulsions, solutions, suspensions, syrups, and élixirs. In addition to theactive compounds, the liquid dosage forms may contain inert diluents commonlyused 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 germoil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol,polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of thesesubstances, and the like.
Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening, flavoring,and perfuming agents. 119 6 3 -31-
Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland 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 süppositories whichcan be prepared by mixing the compounds of the présent invention with suitablenonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or asuppository wax, which are solid at ordinary températures but liquid at bodytempérature and therefore, melt in the rectum or vaginal cavity and release theactive component.
Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active component isadmixed under stérile conditions with a physiologically acceptable carrier and anypreservatives, buffers or propellants as may be requiréd. Ophthalmic formulations,eye ointments, powders, and solutions are also contemplated as being within thescope of this invention.
In a preferred embodiment of the invention, the labeled compound isintroduced into a patient in a détectable quantity and after sufficient time haspassed for the compound to become associated with amyloid deposits, the labeledcompound is detected noninvasively inside the patient. In another embodiment ofthe invention, a labeled compound of Formula I is introduced into a patient,sufficient time is allowed for the compound to become associated with amyloiddeposits, and then a sample of tissue ffom the patient is removed and the labeledcompound in the tissue is detected apart ffom the patient. In a third embodimentof the invention, a tissue sample is removed from a patient and a labeledcompound of Formula I is introduced into the tissue sample. After a sufficientamount of time for the compound to become bound to amyloid deposits, thecompound is detected.
The administration of the labeled compound to a patient can be by ageneral or local administration route. For example, the labeled compound may beadministered to the patient such that it is delivered throughout the body.Altematively, the labeled compound can be administered to a spécifie organ ortissue of interest. For example, it is désirable to locate and quantitate amyloid 11963 -32- deposits in the brain in order to diagnose or track the progress of Alzheimer’sdisease in a patient.
The term “tissue” means a part of a patient’s body. Examples of tissuesinclude the brain, heart, liver, blood vessels, and arteries. A détectable quantity isa quantity of labeled compound necessary to be'detected by the détection methodchosen. The amount of a labeled compound to be introduced into a patient in orderto provide for détection can readily be determined by those skilled in the art Forexample, increasing amounts of the labeled compound can be given to a patientuntil the compound is detected by the détection method of choice. A label isintroduced into the compounds to provide for détection of the compounds.
The term “patient” means humans and other animais. Those skilled in theart are also familiar with determining the amount of time sufïicient for acompound to become associated with amyloid deposits. The amount of timenecessary can easily be determined by introducing a détectable amount of alabeled compound of Formula 1 into a patient and then detecting the labeledcompound at various times after administration.
The term “associated” means a Chemical interaction between the labeledcompound and the amyloid deposit. Examples of associations include covalentbonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobie-hydrophobie interactions, and complexes.
Those skilled in the art are familiar with the various ways to detect labeledcompounds. For example, magnetic résonance imaging (MRI), positron émissiontomography (PET), or single photon émission computed tomography (SPECT)can be used to detect radiolabeled compounds. The label that is introduced into thecompound will dépend on the détection method desired. For example, if PET isselected as a détection method, the compound must possess a positron-emittingatom, such as or 18p.
Another example of a suitable label in a compound of Formula I is an atomsuch as 13C, or 19p which can be detected using magnetic résonanceimaging (MRI) which is also sometimes called nuclear magnetic résonance(NMR). In addition, the labeled corn rounds of Formula I may also be detected byMRI using paramagnetic contrast agents. 119 6 3 -33-
Another example of détection is électron paramagnetic résonance (EPR).
In this case, EPR probes which are well-known in the art, such as nitroxides, canbe used.
The imaging of amyloid deposits can also be carried out quantitatively sothat the amount of amyloid deposits can be determined.
The présent invention also provides a method of inhibiting the aggregationof amyloid proteins to form amyloid deposits, by administering to a patient inneed of inhibition of the aggregation of amyloid protein an amyloid proteininhibiting amount of a compound of Formula I. Those skilled in the art are readilyabîe to détermine an amyloid inhibiting amount by simply administering acompound of Formula I to a patient in increasing amounts until the growth ofamyloid deposits is decreased or stopped. The rate of growth can be assessedusing imaging or by taking a tissue sample from a patient and observing theamyloid deposits therein. A patient in need of inhibition of the aggregation of amyloid proteins is apatient having a disease or condition in which amyloid proteins aggregate.Examples of such diseases and conditions include Méditerranéen fever, Muckle-Wells syndrome, idiopathetic myeloma, amyloid polyneuropathy, amyloidcardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditarycérébral hemorrhage with amyloidosis, Alzheimer’s disease, Down’s syndrome,Scrapie, Creutzfeldt-Jacob disease, Kuru, Gerstmann-Straussler-Scheinkersyndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid,P2-microglobuIin amyloid in dialysis patients, inclusion body myositis,P2-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabètesType II insulinoma.
Also provided by the présent invention are compounds of Formula Iwherein one or more atom in the compound has been replaced with a radioisotope(a labeled compound). The radioisotope can be any radioisotope. However^H,12.3j, 125i} 131 1 le, and 1 ^F are preferred. Those skilled in the art are familiarwith the procedure used to introduce a radioisotope into a compound. For example, a compound of Formula 1 wherein one carbon atom is or Î4C isreadily prepared. 1196 3 -34-
The compounds of the présent invention can be administered to a patient atdosage levels in the range of about 0.1 to about 1,000 mg per day. For a normalhuman adult having a body weight of about 70 kg, a dosage in the range of about0.01 to about 100 mg per kilogram of body weight per day is sufficient. Thespécifie dosage used, however, can vary. For example, the dosage can dépend on anumber of factors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of the compound beingused. The détermination of optimum dosages for a particular patient is well-known to those skilled in the art.
The examples presented below are intended to illustrate particularembodiments of the invention and are not intended to limit the scope of thespécification, including the daims, in any manner.
EXAMPLES
SYNTHESIS
Compounds of Formula I can be prepared by several routes as illustrated inSchemes 6 through 9. Schemes 1 through 5 show synthetic routes that can be usedto obtain the desired starting amines (TV), (VIII), (XV), and (XXI).
In Scheme 1, the appropriately substituted aldéhyde (I) and anitrophenylacetic acid (II) yield olefin (III) when healed in piperidine at 150°C.Standard hydrogénation conditions, such as Raney nickel, give desired amine(IV).
Scheme 2 depicts the synthesis of amine (VIII) which contains a threemethylene tether. Condensation of aldéhyde (I) and nitro-ketone (V) in thepresence of sodium hydroxide gives the desired alpha, beta-unsaturated ketone,which upon standard hydrogénation conditions (Raney nickel) gives (VII) andthen Wolff-Kishner conditions yields the desired amine (VIII).
Scheme 3 is very similar to Scheme 2, except that the aldéhyde (I) iscondensed with a substituted aniline (IX).
Scheme 4 illustrâtes standard Wittig conditions in which the startingmaterials (XII) and (XIII) are obtained via aldol condensation and ylide chemistry,respectively. Reaction of aldéhyde (ΧΠ) and bromophosphorane (XIII) in the 1196 3 -35- presence of a base, such as butyl lithium, gives diene (XIV). Standard réductionconditions (e.g., Raney nickel) of (XIV) yields the desired amine (XV).
Scheme 5 illustrâtes the synthesis of amine (XXI) which contains a 5-methylene tether. Wittig reaction of the bromophosporane (XVII), which isformed from the corresponding substituted bromide (XVI), and nitro aldéhyde(XIX), obtained from Swem oxidation of the corresponding alcohol (XVIII),using a base (e.g., LHDMS) yields olefin (XX). Réduction of (XX) using standardconditions (Raney nickel) gives amine (XXI).
Scheme 6 illustrâtes one route to obtain compounds of Formula I. Eitherby Buchwald coupling (Method A) followed by saponification or utilizing theUllman reaction (Method B), compounds of Formula I can be isolated fromamines such as (IV), (VIII), and (XV). Compounds of Formula I that containhydroxy groups, such as Examples 4 and 6, require déméthylation of the hydroxyprotecting groups with reagents such as boron tribromide in the final step of thesynthesis.
Protecting groups will also be used when reactive functional groups suchas amino and carboxylic acids are présent, so as to avoid unwanted side reactions.Carboxy groups typically are converted to esters (e.g., tert-butyl, benzyl), andamino groups generally are acylated (e.g., acetyl or trimethylsilyl). These andother such protecting groups are well-known to organic chemists, and are fulîydescribed by Greene and Wuts in Protective Groups in Organic Synthesis. JohnWiley and Sons, New York (2nd Ed. 1991). Ail citations are incorporated hereinby référencé.
Scheme 7 illustrâtes the synthesis of compounds of Formula 1 by reactingamines such as (IV), (VIII), and (XXI) with fluoro-nitro intermediate (XXIV), inthe presence of a base (e.g., LHMDS or Et3N) to give ester (XXV). This ester canthen 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., (XXVI) or (XXVII)] in the presence of variousbases (such as DBU or triethylamine) to yield compounds of Formula I.
Scheme 9 depicts coupling of amine (VIII) with readily available methylester (XXVIII) in the presence of a base, such as imidazole, to give ester (XXIX). ,119 6 3 -36-
This ester can then be saponified as usual to give compounds of Formula I.
Scheme 10 illustrâtes the synthesis of fluoro-inteimediate (XXIV) which is obtained by nitration of readily available methyl ester (XXX) to give (XXVIII).Treatment of (XXVIII) with potassium cyanide gives (XXIV). 5 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 (XXVII) in the presence of potassium carbonateand cupric acetate yields various iodo-substituted aminobenzoic acids (XXVIII).Reaction of (XXVIH) with substituted boronic acids and palladium chloride gives 10 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, utilizingstandard organic reactions such as oxidation, réduction, alkylation, condensation,élimination, and similar well-known synthetic processes. For exampie, 15 compounds of Formula I wherein Ra is hydrogen are readily alkylated to formcompounds wherein Ra is Cj-Cg alkyl. Compounds wherein Rl is NH2 arereadily acylated by reaction with an acid halide or acid anhydride to providecompounds wherein R^ is -NHCOR^. Similarly, compounds wherein Rl isNC>2are easily reduced to provide compounds wherein Rl is NH2. The benzoic acids 20 (where R^ is COOH) are readily converted to esters and amides, as well as saltsand other prodrugs by routine processes. For example, the benzoic acid can bereacted with oxalylchloride to form the acid chloride, which then readily reactswith a sulfonamide such as methanesulfonamide to produce the correspondinginvention compound where R^ is -CONHSO2CH3. 119 6 3 -37-
Formation of Amines
Scheme 1
(vm)
(VH) nh2 119 6 3 -38-
Scheme 3
•119 6 3 -39-
Scheme 4
(XII)
n-BuLi/THF (ΧΙΠ)
(XV) -40-
Scheme 5
Coupling Routes
Scheme 6
Method A. Steo C(1) Pd2(dba)3/B!NAP
5 (ΧΧΠΙ) 11963
(a) LHDMS, THF or(b)CH3CNEtjN, reflux
no2
Compound of Foimula I R is an ester forming group such as alkyl or benzyl. >119 6 3 -42-
Compound of Formula 1 (XXVII) .119 6 3 -43-
Scheme 9
ΕίβΝ, reflux (vm) (xxvm)
Synthesis of Fluoro-Intermediate
(XXX)
Scheme 10
119 6 3 -44-
Scheme 11
COOH /Br
(XXVII) K2CO3, Cu(Ac)2 (XXV)
COOH
(HO)2B +
Cl (XXVIII)
Cl (XXIX) K2CO3, PdCl2dppfCH2Cl2Dioxane
Cl (XXX) 119 6 3 -45- EXAMPLE 1
Préparation of2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoic acid
Step A (Scheme 1): Préparation of 1,2-Dichloro-4-[2-(4-nitrophenyl)ethenyl]-benzene A mixture ofp-nitrophenylacetic acid (51.23 g, 0.28 mol) and 3,4-dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) was heated to150-160°C for 5 hours under a N2 atmosphère. After cooling the reaction mixture,the precipitate was triturated in boiling methanol (MeOH) (50 mL) and thencooled to -5°C for 12 hours. The crystalline precipitate was filtered off, rinsedwith cold MeOH and dried at room température in a vacuum oven ovemight toyield an orange solid, 22.71 g (0.077 mol, 27%) of the desired product.mp 190-19ΓΟ. MS-.294.9 (M+).
Step B (Scheme 1): Préparation of 4-(2-(3,4-Dichlorophenyl)ethyl]benzenamine A sample of l,2-dichloro-4-(2-(4-nitrophenyl)ethenyI]benzene (98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in the presence of RaneyNickel (Ra-Ni) (20 g) at 25°C to 40°C (ΔΡ =13.5 psi) under a hydrogenatmosphère. The reaction mixture was filtered, and the fîltrate was concentratedin 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 (M+).
Step C (Scheme 6): Préparation of 2-{4-[2-(3,4-Dichlorophenyl)ethyl]phenylamino}-benzoicacid
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), césium carbonate(40.52 g, 124.35 mmol), tris(di.benzylideneacetone-dipaladium(0) (2.44 g, 2.67 mmol) and (S)-(2,2'-bis(di-p-toIylphosphino-l,T-binaphthyl (98%, (S)-tol-BINAP) (2.71 g, 4.00 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (300 mL) «17 9 6 3 -46- was heated to 100°C for 34 hours under N2. After cooling to room température,the reaction mixture was diluted with ether, filtered through celite and rinsedthoroughly with ether. The filtrate was evaporated to dryness to give a brownresidue (68 g). The resulted residue was dissolved in éthanol (EtOH) (50 mL) andTHF (100 mL), and then 5N NaOH (aq.) (200 mL) was added, and the mixturewas refluxed for 16 hours. The solvent was removed in vacuum. The residue wasacidified with concentrated HCl to pH 3. The resulting precipitate was collectedby filtration, triturated with boiling MeOH-H^O (4:1) and dried in a vacuum atroom température 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 C2iH]7NiO2Cl2‘. Calcd: 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 potassiumcarbonate (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) washeated to reflux for 24 hours at 150°C. The reaction mixture was poured into hotH2O (150 mL) and heated to 90°C on a hot plate. Charcoal was added, and thismixture was stirred at 90°C for 5 minutes. The warm brown mixture was filteredthrough filter paper. The cooled filtrate was then acidified with concentrated HCl(pH 1), and the precipitate was collected by filtration, triturated with boilingMeOH-H2O (1:2) and dried under vacuum at room température for 16 hours togive Example 1, an orange solid (2.3 g, 0.006 mol, 17.5%). mp 165.0-173.0°C.Analysis for C21H17N1O2CI2: Calcd: C, 65.30; H, 4.44; N, 3.63.
Found: C, 65.68; H, 4.58; N, 3.60. ‘119 6 3 P< -47- EXAMPLE2
Préparation of 2-{4-(2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid
Step C (Scheme 6): Préparation 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),césium carbonate (857 mg, 2.62 mmol), tris(dibenzylideneacetone-dipaladium(0)(51 mg, 0.056 mmol) and (S)-(2,2'-bis(di-p-tolylphosphino-l,l'-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 N2. After cooling, the reactionmixture was diluted with ether, filtered through celite and rinsed thoroughly withether. The fîltrate was evaporated to dryness to give a brown residue. Purificationby flash chromatography (silica gel, 5% EtOAc/hexane) yielded 540 mg(1.21 mmol, 64%) of the desired product. mp 107-108°C.
Analysis for C22H18N2CI2O4: Calcd: C, 59.34; H, 4.07; N, 6.29.
Found: C, 59.03; H, 4.04; N, 5.99.
Préparation of 2-{4-[2-(3,4-Dichloro-phenyl)-ethyljphenylamino}-5-nitrobenzoicacid A solution of 2-{4-(2-(3,4-dichloro-phenyl)-ethyl]phenylamino}- 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 H2O andacidified with concentrated HCl to pH 1. The mixture was then extracted withmethylene chloride, dried (Na2SC>4), filtered and concentrated in vacuo to yield ayellow solid, 329 mg (0.76 mmol, 100%) of the desired product mp 214-217°C.Analysis for C21H16N2CI2O4: Calcd: C, 58.49; H, 3.74; N, 6.50.
Found: C, 58.24; H, 3.81; N, 6.28. 1196 3 -48- EXAMPLE3
Préparation of 2- {4-[4-(3,4-Dichloro-phenyl)-ethyl]phenylamino} -4-methoxy-5-nitrobenzoic acid
To a cooied (-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 Min THF, 6.28 mmol) was added dropwise. The reaction mixture was allowed to stirat -78°C for 10 minutes. A solution of 2-flouro-4-methoxy-5-nitrobenzoic acidmethyl ester (0.72 g, 3.14 mmol) in THF (30 mL) was added dropwise, and thissolution was stirred for 30 minutes at -78°C. The reaction mixture was allowed togradually warm to room température and stir for 2 hours under a N2 atmosphère.The reaction mixture was diluted with ethyl acetate (EtOAc), and acidified with5N HCl (pH 3). The organic layer was dried (Na2SC>4), filtered and concentratedin vacuo to yield a brown residue. To a solution of this residue in EtOH (20 mL)and THF (40 mL), 5N NaOH (50 mL) was added, and the mixture was refluxedfor ovemight. The solvent was removed in vacuum, and the residue was acidifiedwith concentrated HCl (pH 3). The precipitate was collected by filtration,triturated with boiling MeOH-H2Û (1:1), and dried in a vacuum oven for 16 hoursto give Example 3, an orange solid (0.70 g, 1.51 mmol, 48%). mp 208-209°C.Analysis for C22H18N2O5CI2: Calcd: C, 57.28; H, 3.93; N, 6.07.
Found: C, 57.43; H, 3.69; N, 5.86. EXAMPLE 4
Préparation of 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylammo}benzoic acid
Step A (Scheme 1): Préparation of l,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 yellowsolid, 13.4 g (0.047 mol, 34%) of the desired product mp: 133-134°C.
Analysis of C16H15NiO4: Calcd: C, 67.36; H, 5.30; N, 4.91. Found: C, 66.81;H, 5.27; N, 4.84. 11963 -49-
StepB (Scheme 1): Préparation of 4-[2-(3,4-Dimethoxy-phenyI)ethyI]-phenylamine l,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (12.1 g, 0.042 mol)was reduced in the presence of 10% Pd-C (2.0 g) in dimethylfonnamide (DMF)(120 mL) at 25°C under a hydrogen atmosphère. The reaction mixture wasconcentrated 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 thedesired product. mp 115-116°C.
Analysis for CjôHipNjC^: Calcd: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.60;H, 7.39; N, 5.35.
Step C (Scheme 6): Préparation of 2-{4-[2-(3,4-Dimethoxy-phenyl)ethyl]-phenylamino}benzoic acid
The title compound was prepared from 4-[2-(3,4-dimethoxy-phenyl)-ethyljphenylamine (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. Aftercrystallization with MeOHÆ^O, 4.5 g (0.012 mol, 33%) of the desired productwas obtained. mp: 137-139°C.
Analysis for C23H23N1O4: Calcd: C, 73.19; H, 6.14; N, 3.71. Found: C, 73.47;H, 6.03; N, 3.78.
Step D: Préparation of 2-{4-(2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}-benzoic acid
To a solution of 2-{4-[2-(3,4-dimethoxy-phenyl)-ethyl]phenylamino}-benzoic acid (0.28 g, 0.74 mmol) in CH2CI2 (20 mL), BBrç (3.5 mL, IM inCH2CI2,3.5 mmol) was added at room température under a N2 atmosphère. Thereaction mixture was allowed to stir at room température for 2 hours and thenpoured into ice water (50 mL). This mixture was extracted with EtOAc, and theorganic layer was washed two times with water, dried (Na2SC>4), filtered and 1196 3 -50- concentrated in vacuo to yield 0.24 g (0.69 mmol, 93%) of the desired product.mp215-217°C.
Analysis for C21H19NO4: Calcd: C, 72.19; H, 5.48; N, 4.00. Found: C, 71.80;H, 5.46; N, 3.99. EXAMPLE 5
Préparation of2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid
Step A (Scheme 1): Préparation of l,l-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 procedureyielded 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): Préparation of 4-(2-(4,4-Dibutylaminophenyl)ethyl]-phenylamine
The title compound was prepared nom l,l-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 (ΔΡ = 3.6 psi) under a hydrogen atmosphère using theprocedure 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 (MH4).
Step C (Scheme 6): Préparation 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), copperpowder (1.25 g, 19.65 mmol), and copper(I) chloride (0.092 g, 0.93 mmol) in dryDMF (30 mL) using the procedure described in Example 1, Step C, Method B. 11963 -51-
This procedure yielded a 0.39 g (0.87 mmol, 8.6%) of the desired product.mp 115-117°C.
Analysis for C29H36N2O2: Calcd: C, 78.34; H, 8.16; N, 6.30. Found: C, 78.15;H, 8.07; N, 6.10. EXAMPLE 6
Préparation of 2-(4-(2-(3,4,5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoicacid
Step A (Scheme 1): Préparation of 1,2,3-Trimethoxy-5-[2-(4- nitrophenyl)ethenyl]benzene
The title compound was prepared fromp-nitrophenylacetic acid (18.6 g,0.10 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 procedureyielded a solid, 13.0 g (0.041 mol, 41%) of the desired product. mp:192-195°C.
Step B (Scheme 1): Préparation of 4-(2-(3,4,5-Trimethoxy-phenyl)ethyl]-phenylamine
The title compound was prepared from l,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 (ΔΡ = 9.6 psi) under a hydrogen atmosphère using the proceduredescribed 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): Préparation of 2-(4-(2-(3,4,5-Trimethoxy-phenyl)-ethyl]phenylamino}-benzoic acid methyl ester
The title compound was prepared from 4-(2-(3,4,5-trmethoxyphenyl)-ethyl]phenylamine (0.75 g, 2.61 mmol), methyl 2-bromobenzoate (0.47 g, 2.17 mmol), césium carbonate (0.99 g, 3.04 mmol), tris(dibenzylideneacetone-dipaladium(O) (0.06 g, 0.065 mmol) and (£)-(-0-2,2'-bis(di-p-tolylphosphino-l,T-binaphthyl (98% (S)-Tol-BINAP) (0.066 g, 0.098 mmol) (Ligand/Pd — 1.5) inanhydrous 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. 1 1 9 6 3 · -52-
Analysis for C25H27N1O5: Calcd: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.53; H, 6.24; N, 3.14.
Préparation of 2-{4-[2-(3,4,5-Trimethoxy-phenyl)ethyl]phenylamino}-benzoicacid
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), INNaOH solution (4 mL) was added, and the reaction mixture was heated to refluxfor 5 hours. The reaction mixture was then concentrated in vacuo to remove theorganic solvent. The residue was acidified with concentrated HCl (pH 3). Thisprecipitate was collected by filtration, triturated with boiling MeOH-H2O (4:1)and dried in vacuum at room température for 16 hours to give the title compoundas a white solid, 0.59 g (1.45 mmol, 98.5%). mp 146.0-147.0°C.
Analysis for C24H25NiO5: Calcd: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.54; H, 6.43; N, 3.15.
Step D: Préparation 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 CH2C12 (40 mL) andBBrç (10 mL, IM in CH2C12, 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 C2iHi9NiO5-1.44 H2O: Calcd: C, 64.46; H, 5.64; N, 3.58.
Found: C, 64.07; H, 5.27; N, 3.39. EXAMPLE 7
Préparation of 2-(4-(2-(-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy·5-nitrobenzoic acid 1196 3 -53-
Step A' (Scheme 2): Préparation of 3-(3,4-Dichlorophenyl)-l-(4-nitro-phenyl)propenone
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-ILjO bath. 3,4-Dichlorobenzaldehyde (31.8 g, 0.18 mol) was added in one portion. Aller theaddition, the mixture was warmed to 15°C. 1 -(4-Nitrophenyl)ethanone (30.0 g, 0.18 mol) was added at this température with rigorous stimng. After stirring for5 minutes, the reaction mixture was diluted with 95% EtOH (300 mL). Theresulting tan mixture was stirred at room température for 30 minutes, then stirredwith an ice-H2Û bath undemeath the flask for 2 hours. The light brown solid wasfiltered off, washed with H2O, and air-dried. The solid was dissolved in hot THF(1.5 L) and treated with charcoal. The resulting mixture was filtered off, and thefiltrate was diluted with 95% EtOH (500 mL). This solution was filtered andoven-dried (40°C) to yield a light brown solid, 38.56 g (0.12 mol, 66%) of the titlecompound. mp 220-223°C.
Analysis for Ο^ΗρΟ^ΝΟβ: Calcd: C, 55.93; H, 2.82; Cl, 22.01; N, 4.35.
Found: C, 55.79; H, 2.93; Cl, 22.16; N, 4.32.
Step B' (Scheme 2): Préparation of l-(4-Amino-phenyl)-3-(3,4- dichlorophenyl)propan-1 -one 3-(3,4-Dichlorophenyl)-l-(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(ΔΡ = 33.4 psi) under a hydrogen atmosphère. The reaction mixture wasconcentrated in vacuo and reciystallized from MeOH (100 mL) to give a lightyellow solid, 23.5 g (0.080 mol, 75%) of the desired product. mp 127-129°C.Analysis for C15H13CI2NO: Calcd: 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): Préparation of 4-[3-(3,4-Dichlorophenyl)propyl]phenylamine A mixture of T(4-aminophenyl)-3-(3,4~dichlorophenyi)propan-l-one (20.0 g, 0.068 mol), ΝΗ2ΝΗ2-Η2Ο (16 mL), and KOH (85%, 5.6 g) in ethylene 119 6 3 -54- glycol (160 mL) was heated to reflux under a N2 atmosphère for 16 hours. Aftercooling to room température, the reaction mixture was poured into ice-H2Û andextracted with CH2CI2 (2 L). The layers were separated, and the organic layerwas dried (Na2SÛ4) and concentrated in vacuo to afford an oil. Purification byflash chromatography (silica gel, CH2CI2) yielded an oil, 14.00 g (0.05 mol, 73%)of the desired product
Analysis for Ο15Η15α2Ν: Calcd: 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.
Préparation 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 stining for10 minutes at room température, 2,4-difluorobenzoic acid methyl ester (21.9 g,0.127 mol) was added dropwise. After the addition, the reaction mixture wasallowed to stir gently for 40 minutes at room température. The reaction mixturewas then poured into ice-H^O (1 L) and stirred for 10 minutes. The mixture wasextracted with EtOAc. The layers were separated, and the organic layer waswashed sequentially with IN NaCl, saturated NaHCC>3, H2O and brine, dried(Na2SC>4), filtered and concentrated in vacuo to afford a yellow residue. Thisresidue was washed with 10% EtOAc/hexane, filtered, and dried to yield a paleyellow solid, 29.0 g (0.133 mol, 82%). mp 78-80°C.
Analysis for C8H5F2NO4: Calcd: C, 44.25; H, 2.32; N, 6.45. Found: C, 44.18; H, 2.39; N, 6.14.
Préparation of 2-Fluoro-4-methoxy-5-nitrobenzoic acid methyl ester A mixture of sodium métal (1.27 g, 0.055 mol) and MeOH ( 250 mL) was 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 themixture was stirred for 20 minutes at 0°C to 5°C. The reaction mixture was thenallowed to warm to room température and stir for 2 hours. The mixture was thenfiltered to give an off-white precipitate. Recrystallization with CHCI3 (70 mL) 1196 3 -55- yielded an off-white crystalline solid, 1.825 g (0.008 mol, 17%) of the titlecompound.
Analysis for C9H8F1N1O5: Calcd: C, 47.17; H, 3.52; N, 6.11. Found: C, 47.09; H, 3.47; N, 6.00.
Préparation 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)propyl)phenylamine (0.94 g, 3.3 mmol), 2-fluoro-4-methoxy-5-nitro-benzoic acid methyl ester (0.75 g, 3.3 mmol), and ΕίβΝ (0.46 mL) in'CHjCN (30 mL) was heated to reflux for120 hours. The reaction mixture was cooled to room température, diluted withCH2CI2 and washed with saturated NaHCC^. The organic layer was dried(Na2SC>4) and concentrated to give a solid. Recrystallization with MeOH yielded0.67 g (1.37 mmol, 42%) of the desired product.
Analysis for C24H22N2CI2O5O.42H2O: Calcd: C, 58.01; H, 4.63. N, 5.64;Found: C, 57.61; H, 4.51; N, 5.94.
Préparation of 2-{4-(3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-methoxy-5-nitrobenzoic acid
To a solution of 2-{4-(3-(3,4-dichlorophenyl)propyl]phenylamino}- 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 atroom température. The solvent was removed, and the residue was acidified withconcentrated HCl to pH 3. The precipitate was collected by filtration and driedin vacuum for 16 hours. Recrystallization with MeOH gave the title compound asan orange solid 0.21 g (0.043 mol, 70%). mp 200-201°C.
Analysis for C23H20N2O5CI2O.2H2O: Calcd: 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. 1196 3 P ·· -56- EXAMPLE8
Préparation of 2-{4-[2-[-(3,4-Dichlorophenyî)propyl]phenylamino}-4-imidazo-l-yl-5-nitrobenzoic acid
Préparation of 2- {4-(2-(-(3,4-Dichlorophenyl)propyl]phenylamino } -4-imidazo-l-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 ramol), and Et3N (1.14 mL, 8.25 mmol) inCH3CN (50 mL) was stirred for 16 hours at room température. To this deeporange 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 washeated to reflux for ovemight. The reaction mixture was cooled and concentratedin vacuo to afford a residue. This residue was diluted with CH2CI2 and washedwith a saturated K2HCO3 solution. The organic layer was dried (Na2SO4),filtered, and concentrated in vacuo to give a crude oil. Purification by flashchromatography (silica gel, 10% EtOAc/hexane) yielded 1.0 g (1.90 mmol, 25%)of the desired product. MS: 524.1.(M+).
Préparation of 2- {4-(2-(-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-l-l-yl-5-nitrobenzoic acid
The title compound was prepared irom 2- {4-(2-(-(3,4-dichlorophenyl)propyl]phenylamino}-4-imidazo-l-yl-5-nitrobenzoic acid methylester (1.0 g, 1.9 mmol), IN NaOH (2.0 mL) in THF (30 mL) using the proceduredescribed in Example 8. This procedure yielded an orange solid, 0.30 g(0.6 mmol, 32%) of the desired product.
Analysis for C25H2oCl2N404-0.2H20: Calcd: C, 58.31; H, 3.99; N, 10.88;
Cl, 13.89. Found: C, 58.34; H, 4.07; N, 10.73; Cl, 13.41. 1196 3 -57- EXAMPLE 9
Préparation of 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}-benzoic acid
Préparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-benzoic acidmethyl ester
The title compound was prepared &amp;om 4-[3-(3,4-dichlorophenyl)propyl]-phenylamine (600 mg, 2.14 mmol), 2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), césium carbonate (812 mg, 2.49 mmol), tris(dibenzylideneacetone-dipaladium(O) (49 mg, 0.053 mmol) and (5)-(2,2'-bis(di-p-tolylphosphino-l,l'-binaphthyl (98%, (5)-tol-BINAP) (54 mg, 0.080 mmol) (Ligand/Pd = 1.5) inanhydrous 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 desiredproduct. MS:414(M+),416(MH+).
Analysis for C23H21CI2O2NO.4 H2O: Calcd: C, 65.25; H, 5.23; N, 3.30.
Found: C, 65.76; H, 5.18; N, 3.10.
Préparation 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), INNaOH(4.0 mL) in EtOH (4 mL) and THF (4 mL) using the procedure described inExample 2. This procedure yielded a yellow solid, 0.32 g (0.80 mmol, 81%) of thedesired product. mp 120-126°C.
Analysis for C22Hi9Cl2Û2Nr0.75 H2O: Calcd: C, 64.04; H, 5.00; N, 3.39.Found: C, 64.17; H, 4.69; N, 3.18. EXAMPLE 10
Préparation of 2-{4-[4-(3,4-Dichlorophenyl)butyl]phenylamino)benzoic acid
Préparation of (iram-)-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 1196 3 ε. -58- added to the above cooled mixture while maintaining the internai température at25°C to 30°C. The mixture was allowed to stir in ice-H2O bath for 40 minutes andthen treated with acetic anhydride (400 mL). After the addition, the mixture washeated to 100°C with stirring for 30 minutes and then cooled to 30°C. To thismixture, 12N HCI/H2O (102 mL/1.2 L) was added, and the resulting mixture washeated to reflux for 30 minutes and then cooled to room température. Thisheterogeneous mixture was filtered and washed with H2O to afford a brown solid.The crude product was dissolved in EtOAc and washed with H2O, dried(Na2SC>4), 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 C9H6Cl2O: Calcd: C, 53.77; H, 3.01; Cl, 35.27. Found: C, 53.75; H, 3.10; Cl, 35.58.
Préparation of (trans), (trans)-1,2-Dichloro-4-[4-(4-nitropheny 1)-1,3-butadienyljbenzene A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) andtriphenylphosphine (244.0 g, 0.93 mol) in CHCI3 (1.5 L) was heated to reflux forovemight. The reaction mixture was cooled to room température, concentratedin vacuo to remove CHCI3 and then suspended in Et2Û and stirred rigorously.The suspension was filtered, and the off-white solid was washed with Et2Û, driedat 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 température between 5°C to 10°C. Thecooling bath was then removed, and the reaction mixture was allowed to warm toroom température. 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 theresulting mixture was stirred at room température for 16 hours. The mixture wasfiltered, and the filtrate was concentrated in vacuo to give a residue. Purification 1196 3 -59- 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 CjgHj jCHNC^'. Calcd: C, 60.02; H, 3.46; N, 4.37, Cl, 22.15.
Found: C, 59.77; H, 3.47; N, 4.40; Cl, 22.39.
Préparation of 4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamine
The title compound was prepared from (trans}, (trans)-1,2-dichloro- 4-[4-(4-nitrophenyl)-l,3-butadienyl]benzene (15.42 g, 0.048 mol), Ra-Ni (1 g) at20°C to 26°C (ΔΡ = 19.3 psi) under a hydrogen atmosphère in THF (75 mL) andMeOH (75 mL) using the procedure described in Example 1, Step B. Thisprocedure yield a solid, 10.97 g (0.037 mol, 78%) of the desired product. mp50-52°C.
Analysis of C^H^N^: Calcd: C, 65.32; H, 5.82;N, 4.76. Found: C, 65.43; H, 5.84; N, 4.61.
Préparation of 2-{4-[4-(3,4-Dichlorophenyl)butyl]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), copperpowder (0.21 g, 3.28 mmol), and copper(I) chloride (0.015 g, 0.15 mmol) in dryDMF (5 mL) using the procedure described in Example 1, Step C, Method B. EXAMPLE 11
Préparation 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 ΕίβΝ (2.80 mL) inacetonitrile (110 mL) was heated to reflux for 48 hours. The reaction mixture wascooled and concentrated in vacuo to remove the solvent. The residue wasdissolved in CH2CI2 and washed with diluted HCl. The organic layer was dried(Na2SÛ4), concentrated in vacuo to give a crude solid. Purification by flash Ί19 6? -60- chromatography (silica gel, CH2CI2) yielded 1.40 g (0.003 mol, 30%) of thedesired product.
Analysis for C23H19N2O4CI2: Calcd: 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. 5. EXAMPLE 12
Préparation of2-{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 10 (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, thereaction mixture was neutraîized with dilute HCl and extracted with EtOAc, dried(Na2SC>4), filtered and concentrated in vacuo to afford a crude residue.Recrystallization with EtOH yielded a bright orange solid, 2.06 g (4.1 mmol, 15 82%) of the title compound.
Analysis for C23H19CI2N3O6: Calcd: 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. EXAMPLE 13
Préparation of2-{4-[5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic 20 acid
Préparation of Bromo[(3,4-dichlorophenyl)methyl]triphenylphosphorane A mixture of 4-bromomethyl-l,2-dichlorobenzene (2.40 g, 0.01 mol), and triphenylphosphine (5.24 g, 0.02 mol) in toluene (30 mL) was stirred for 16 hoursat room température. The solid was filtered, rinsed with toluene, and oven-dried at 25 room température to yield a white powder, 3.95 g (0.0078 mol, 78%) of the desired product. iHNMR [dimethylsulfoxide (DMSO):ppm] :7.89-7.61 (m, 15H), 7.50 (d, >8.3 Hz, 1H), 7.04 (t, >2.3 Hz, 1H), 6.97 (m, ÎH), 5.20 (d, >15.9 Hz, 2H). 119 6 3 -61-
Preparation of 4-(4-Nitrophenyl)butyraldehyde
To a cooled solution (-70°C) of oxalyl chloride (2.0 M in CH2CI2, 14.1 mL, 28.2 mmol), dimethylsuifoxide (DMSO) (4.40 g, 56.32 mmol) inCH2CI2 (20 mL) was added dropwise. The resulting reaction mixture was thenstirred for 30 minutes at -70°C under a nitrogen atmosphère. A solution of 4-(4-nitrophenyl)butan-l-ol (5.00 g, 25.6 mmol) in CH2CI2 (3 mL) was addeddropwise, 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 graduallywarm to room température and stir for 30 minutes. The mixture was thenquenched with H2O and extracted with EtOAc. The organic layers were washedwith 0.1N HCl solution, H2O, brine, dried (Na2SC>4), filtered, and concentratedin vacuo to give a lightly brown oil. Purification by flash chromatography (silicagel, 50% EtOAc/hexane) yielded 3.20 g (16.56 mmol, 65%) of the desiredproduct lH NMR (DMSO:ppm): 9.75 (s, 1H), 8.12 (d,>8.3 Hz, 2H), 7.30 (d, >8.3 Hz,2H), 2.72 (t, >7.7 Hz, 2H), 2.47 (t, >7.1 Hz, 2H), 1.94 (m, 2H).
Préparation of l,2-Dichloro-4-[5-(4-nitrophenyl)-l-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 température at 0°C. Afterstirring for 30 minutes, a solution of 4-(4-nitro-phenyI)butyraldehyde (1.45 g, 7.5 mmol) in THF (5 mL) was added dropwise, and the mixture was allowed towarm to room température within 2 hours. The mixture was then quenched withH2O and extracted with EtOAc. The organic layers were washed with 0.1N HClsolution, H2O, brine, dried (Na2SÛ4), filtered, and concentrated in vacuo to givea 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 (M+), 337 (MH+). 119 6 3 -62-
Preparation of 4-(5-(3,4-Dichlorophenyl)pentyl]phenylamine
The title compound was prepared from l,2-dichloro-4-(5-(4-nitrophenyl)- l-pentenyljbenzene (2.5 g, 7.4 mmol), Ra-Ni (1 g) in THF ( 50 mL) at 25°C to40°C (ΔΡ = 9.9 psi) using the procedure described in Example 1, Step B. This 5 procedure yielded 1.06 g (3.4 mmol, 46%) of the desired product. iHNMR (DMSO:ppm): 7.45 (d, J=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 (t, .7=7.7 Hz, 2H), 2.31 (t, .7=7.6 Hz, 2H), 1.6-1.5 (m, 4H), 1.5-1.4 (m, 2H).
Préparation of 2- {4-(5-(3,4-Dichloro-phenyl)pentyl]phenylamino } -5-nitrobenzoic 10 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 (2.25 mL, 1 M inhexane, 2.25 mmol) was added dropwise. The reaction mixture was allowed to stirat -78°C for 10 minutes. A solution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 15 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 roomtempérature and stir for 2 hours under N2 atmosphère. The reaction mixture wasdiluted with EtOAc, and acidified with IN HCl (pH 3). The organic layer wasdried (Na2SC>4), filtered and concentrated in vacuo to yield a brown residue. 20 Purification by flash chromatography (silica gel, 2% MeOH/CH2Cl2) then recrystallization with MeOH yielded 265 mg (0.56 mmol, 75%) of the desiredproduct. mp 147-148°C.
Analysis for C24H22CI2N2O4O.37H2O: Calcd: C, 60.05; H, 4.77; N, 5.84.Found: C, 59.67; H, 4.64; N, 5.51. 119 6 3 •C' -63- EXAMPLE 14
Préparation of 2- {4- [5-(3,4-Dichloro-phenyl)pentyl)phenylamino } -4-methoxy- 5-nitrobenzoic acid
Préparation 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) yielded145 mg (0.28 mmol, 37%) of the desired produet. MS: 515.2 (M4), 517.2 (MH4).
Préparation 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)-pentyI]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 proceduredescribed in Example 2. Purification by flash chromatography (silica gel, 10%MeOH/CH2Cl2), then recrystallization with MeOH yielded 58 mg (0.12 mmol,41%) of the desired produet. mp 192-193°C.
Analysis for C25H24CI2N2O5: Calcd: C, 59.65; H, 4.81; N, 5.56.
Found: C, 59.29; H, 4.58; N, 5.36. EXAMPLE 15
Préparation of 2-(4-(3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoicacid
Préparation of 2-(4-(3-(3,4-Dichlorophenyl)propyl]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, 119 6 3 -64- 1.25 mmol), césium carbonate (569 mg, 1.75 mmol), tris(dibenzylideneacetone-dipaladium(O) (34 mg, 0.037 mmol) and (S)-(2,2'-bis(di-p-tolylphosphino-l,l'-binaphthyl (98%, (5>tol-BINAP) (38 mg, 0.056 mmol) (Ligand/Pd-1.5) inanhydrous toluene (15 mL) using the procedure described in Example 2, Step C. 5 This procedure yielded an orange solid 0.51 g (1.11 mmol, 74%) of the desiredproduct mp 117-118°C. MS: 457.1 (M4); 459.1 (MH4)
Préparation of2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoicacid 10 The title compound was 2- {4-(3-(3,4-dichlorophenyl)- propyljphenylamino}-5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2NNaOH (5.0 mL) in EtOH (2 mL) and THF (4 mL) using the procedure describedin Example 2. This procedure yielded an orange solid, 0.49 g (1.10 mmol, 100%)of the desired product. mp 153-155°C. 15 MS: 443.2 (M+), 445.2 (MH4) EXAMPLE 16
Préparation of2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid
Préparation of 2- {4-(2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino} -5-nitrobenzoic 20 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), césium carbonate (1.68 g, 5.17 mmol), tris(dibenzylideneacetone-dipaladium(0) (101 mg, 0.11 mmol) and (S>(2,2'-25 bis(di-p-tolylphosphino-l, 1 '-binaphthyl (98%, (iS)-tol-BINAP) (113 mg, 0.17 mmol) (Ligand/Pd = 1.5) in anhydrous toluene (32 mL) using the proceduredescribed 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 (M4) 1196 3 -65-
Analysis for θ24Η24θ4Ν2·0.25 H2O: Calcd: C, 71.27; H, 5.98; N, 6.93.
Found: C, 70.48; H, 6.03; N, 6.85.
Préparation of2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoicacid
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), INNaOH (50 mL) in EtOH (50 mL) and THF (50 mL) using the procedure describedin Example 2. This procedure yielded a yeliow solid, 1.03 g (2.63 mmol, 81%) ofthe desired product. mp 214-216°C.
Analysis for C23H22O4N2-O.25 H2O; Calcd; C, 69.99; H, 5.74; N, 7.18.
Found; C, 69.90; H, 5.82; N, 6.81. EXAMPLE 17
Préparation of2-[[4-[2-(4-Chloro-3-trifluromethylphenyl)ethyl]phenyI]amino-benzoic acid
Step A (Scheme 1); Préparation of rranj-l-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 N2 atmosphère to 150°C tol60°°C for 1 hour. The reactionmixture was cooled to 80°C to 100°°C and refluxing /-PrOH (150 mL) was added.The mixture was continued to cool to room température and then placed underréfrigération for 5 hours. The crystalline precipitate was filtered off, rinsed withcold /-PrOH, and dried at room température in a vacuum oven ovemight to yieldtrans- l-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene as anorange solid, 22.53 g (68.75 mmol, 30%). mp 173-174°C. MS: 327.0 (M+)
Step B (Scheme 1): Préparation of 4-[2-(4-Chloro-3-trifluoromethylphenyl)ethyl]-benzenamine 119 6 3 -66-
The title compound was prepared from irans-l-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene (22.53 g, 0.069 mol) and Ra-Ni (22 g) in THF(0.5 L) at 18°C to 29°C (ΔΡ - 20.5 psi) under a hydrogen atmosphère using theprocedure 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+)
Préparation 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 stirfor 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 température and let stir for additional 3 hours. Thereaction mixture was concentrated in vacuo (40°C) to remove the organic solvent.This residue was acidifîed to pH 3 with 3N HCl (aq.). This precipitate wascollected by filtration, rinsed with 10% HCl (40 mL), and dried in vacuum forovemight to give as a pale solid, 4.3 g (10.24 mmol, 70%) of the desired productmp 150-152°C.
Analysis for -0.59 H2O: Calcd: C, 61.39; H, 4.26; N, 3.25.
Found: C, 61.01; H, 4.34; N, 3.30. EXAMPLE 18
Préparation of 2-[4-(3,4-Dichlorophenyl)phenylamino3benzoic acid
Préparation of o-Bromobenzoic acid potassium sait
To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH(500 mL), K2CO3 (69 g, 1.0 mol) was added. The mixture was concentrated togive the desired product (239.1 g, 1.0 mol, 100%). 1196 3 -67-
Preparation of 2-[(4-lodophenyl)amino] benzoic acid A mixture of o-bromobenzoic acid potassium sait (47.8 g, 0.2 mol), 4-iodoaniline (43.8 g, 0.2 mol), K2CO3 (13.8 g, 0.1 mol), and cupric acetate(2.87 g, 6%) in diglyme (100 mL) was heated to reflux for 30 minutes. Thereaction mixture was diluted with H2O (1.0 L) and filtered. The filtrate wasacidified with diluted AcOH. The resulting precipitate was collected by filtration,washed with H2O and dried in a vacuum at 50°C for 16 hours. Recrystallizationfrom EtOAc gave the desired product, a solid (29.7 g, 0.087 mol, 44%). mp205-206°C.
Analysis for C13H1oN102I: Calcd: C,45.05; H, 2.97; N, 4.13. Found: C, 45.05;H, 2.97; N, 3.92.
Préparation of 2-(4-(3,4-Dichlorophenyl)phenylamino]benzoic acid A mixture of 3,4-dichlorophenylboronic acid (880 mg, 2.3 mmol), 2-((4- iodophenyl)amino]benzoic acid (339 mg, 1 mmol), PdCl2-dppf-CH2Cl2 (1,T- bis(diphenylphosphino)ferrocene palladium (II) chloride, complexed withdichloromethane (1:1)) (67 mg, 0.082 mmol), K2CO3 (829 mg, 6 mmol), andH2O (2 mL) in dioxane (15 mL) was heated to reflux for 1 hour. The reactionmixture was diluted with EtOAc and filtered. The filtrate was treated with INHCl, washed with H2O, brine, dried (Na2SÛ4), and concentrated in vacuum togive a yellow solid. Purification by flash chromatography (silica gel, 10%MeOH/CH2Cl2) yielded 272 mg (0.76 mmol, 76%) of the desired product.mp >220°C.
Analysis for C19Hi3O2N1Cl2: Calcd: C, 63.23; H, 3.71; N, 3.88.
Found: C, 62.95; H, 3.73; N, 3.63.
By following the general procedures described above, the followingadditional invention compounds were prepared: 11963 -68- EXAMPLE 19 2- {4-[3-(4-Diethylaminophenyl)propyl]phenylamino} benzoic acidMS: 403 (M+).
Analysis for C26H3()N2O2*0.40 mol H2O: Calcd: C, 69.31; H, 6.87; N, 6.12. 5 Found: C, 69.29; H, 7.04; N, 6.35. EXAMPLE 20 2-{4-[3-(4-Nitrophenyl)propyl]phenylamino}benzoic acid, mp 150-153°C.MS: 376 (M+). EXAMPLE 21 10 2-{4-[3-(3-Nitrophenyl)propyl]phenylamino}benzoic acid, mp 164-167°C.MS: 376 (M+).
Analysis for θ22Η2θΝ2θ4·2.20 mol H2O: Calcd: C, 63.51; H, 5.91; N, 6.73Found: C, 63.56; H, 5.45; N, 6.46. EXAMPLE 22 15 2-{4-[3-(4-Aminophenyl)propyI]phenylamino}benzoic acid, mp 110-112°C.MS: 347 (M+l+). EXAMPLE 23 2-{4-[3-(3-Aminophenyl)propyl]phenylamino}benzoicacid. mp 109°C. MS: 333 (M+I+). 20 EXAMPLE 24 2-{4-[2-(4-Aminophenyl)phenylamino}benzoic acid, mp 198-201 °C. MS: 333 (M+l+).
Analysis for C2iH2oN2Û2-O.l mol H2O: Calcd: C, 75.47; H, 6.09; N, 8.38.Found: C, 75.32; H, 6.12; N, 8.27. Found: C, 75.32; H 6.12; N, 827. 119 6 3 -69- EXAMPLE 25 2-{4-[2-(4-Dipropylaminophenyl)ethyI]phenylamino}benzoic acid
monohydrochloride. mp I76-177°C MS: 417 (M+l+).
Analysis for C27H32N2O2: Calcd: C, 71.59; H, 734; N, 6.18; Cl, 7.83. Found: C,71.31; H, 7.24; N, 6.19; Cl, 7.74. EXAMPLE 26 2-{4-[2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride monohydrate MS: 389 (M+l+).
Analysis for 025^8^02-1101-1120: Calcd: C, 67.78; H, 7.05; N, 6.32; Cl, 8.00.Found: C, 67.83; H, 7.01; N, 6.30; Cl, 7.75. EXAMPLE 27 2-{4-[3-(3-Dipropylaminophenyl)propyl]phenylamino} benzoic acid MS: 431 (M+l+).
Analysis for C28H34N2O2O.2 H2O: Calcd: C, 77.46; H, 7.99; N, 6.45.
Found: C, 77.43; H, 7.86; N, 6.40. EXAMPLE 28 2-{4-[3-(3-Dimethylaminophenyl)propyl]phenylamino}benzoicacid. mp 115-117*0. MS: 374 (M+), 375 (M+l+).
Analysis for 024^26^2^2'^ H20: Calcd: C, 76.61; H, 7.02; N, 7.44. Found: C,76.57; H, 7.21; N, 7.47. EXAMPLE 29 2-{4-[3-(4-EthylaminophenyI)propyl]phenylamino}benzoic acid, mp 133°C.MS: 375 (M+1+). 11963 -70-
Anaîysis for C24H26N2O2O.I H2O: Calcd: C, 76.61; H, 7.02; N, 7.44. Found: C,76.62; H, 7.06; N, 7.36. EXAMPLE 30 2-(N-{4-[3-(4-Diethylaminophenyl)propyl]phenyl}-N-ethylamino)benzoicacidMS: 431 (M+l4).
Analysis for C28H34N2O2: Calcd: C, 78.10; H, 7.96; N, 6.51. Found: C, 78.02;H, 8.17; N, 6.50. EXAMPLE 31 2-{4-[2-(3-Dibenzylaminophenyl)ethyl]phenylamino}benzoic acid,mp 95.5-97.5°C.
Analysis for C35H32N2O?: Calcd: C, 82.00; H, 6.29; N, 5.46. Found: C, 81.81;H, 6.58; N, 5.44. EXAMPLE 32 2-{4-[3 -(3-DiethylaminophenyI)propyl]phenylamino} benzoic acid MS: 403 (M+1+).
Analysis for C26H30N2O2O.I H2O: Calcd: C, 77.23; H, 7.53; N, 6.93. Found: C,77.14; H, 7.82; N, 6.88. EXAMPLE 33 2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoicacid. mp 182-184°C. MS: 333 (M+1+).
Analysis for C21H20N2O2O.25 H2O: Calcd: C, 74.87; H, 6.13; N, 8.43.
Found: C, 74.86; H, 6.16; N, 8.32. EXAMPLE 34 2-{4-[3-(4~Dimethylaminophenyl)propylJphenylamino}benzoicacidMS: 375 (M+l+).
Analysis for C24H26N2O2O.I H2O: Calcd: C, 76.61; H, 7.02; N, 7.44. Found: C,76.52; H, 7.22; N, 7.49. 119 6 3 -71- EXAMPLE 35 2-{4-[2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoic acid, mp 224°C.MS: 375 (M+l+). EXAMPLE 36 5 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoic acid, mp 213-215°C.MS: 375 EXAMPLE 37 2-{4-[2-(3-Dipropylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride. mp 189-193°C. 10 MS: 417 (M+l+).
Analysis for C27H32N2O2'HC1: Calcd: C, 71.58; H, 7.34; N, 6.18; Cl, 7.83.Found: C, 71.48; H, 7.35; N, 6.10; Cl, 7.66. EXAMPLE 38 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acid15 monohydrochloride. mp 175-180°C. MS: 445 (M+).
Analysis for C29H36N2O2'HC1: Calcd: C, 72.40; H, 7.75; N, 5.82; Cl, 7.37.Found: C, 72.61; H, 7.95; N, 5.78; Cl, 7.23. EXAMPLE 39 20 2-{4-[3-(4-Acetylaminophenyl)propyl]phenylamino}benzoic acid, mp 176-178°C.MS: 389 (M+l+). EXAMPLE 40 2-{4-[3-(3-Acetylaminophenyi)propyl]phenylamino}benzoic acid, mp 140-145°C.MS: 389 (M+1+). 11963 -72- EXAMPLE41 2-{4-{2-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride. mp 166-I71°C. MS: 389 (M+l4).
Analysis for C25H28N2O2’HC1: Calcd: C, 70.66; H, 6.88; N, 6.59; Cl, 8.34.Found: C, 70.48; H, 6.89; N, 6.57; Cl, 18.39. EXAMPLE 42 2-{4-[2-(3-Piperidin-l-ylphenyl)ethyl]phenylamino}benzoic acid monohydrochloride. mp 187-193°C. MS: 401 (M+1+).
Analysis for Co^^gN^OT'HCl: Calcd: C, 71.46; H, 6.69; N, 6.41; Cl, 8.11.Found: C, 71.28; H, 6.73; N, 635; Cl, 8.30. EXAMPLE 43 2-{4-[3-(4-Dipropylaminophenyl)propyI]phenylamino}benzoic acidMS: 431 (M+I+).
Analysis for C28H34N2O2: Calcd: C, 78.10; H, 7.96; N, 6.51. Found: C, 77.91;H, 8.03; N, 6.43. EXAMPLE 44 2-{4-[3-(4-Dibutylaminophenyl)propyl]phenylamino}benzoic acidMS: 459 (M+1+).
Analysis for C3QH3gN2O2: Calcd: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.40;H, 8.50; N, 6.19. EXAMPLE 45 2-{4-[3-(3-Dibutylaminophenyl)propyl]phenylamino}benzoicacidMS: 459 (M+l4).
Analysis for C30H38N2O2*. Calcd: C, 78.56; H, 835; N, 6.11. Found: C, 78.40;H, 8.43; N, 6.11. 1116 3 -73- EXAMPLE46 2-(4-{3-[4-(lH-Pyrrol-l-yl)phenyl)propyl}phenylamino)benzoic acid,mp 131-136°C. MS: 397 (M+Î+).
Analysis for C26H24N2O2O.2 H2O: Calcd: C, 78.05; H, 6.15; N, 7.00. Found: C,77.95; H, 6.17; N, 7.08. EXAMPLE 47 2- {4-[3-(4-Piperidin-1 -ylphenyl)propyl]phenylamino}benzoic acid MS: 415 (M+l·*).
Analysis for C27H30N2O2O.2 H2O: Calcd: C, 77.55; H, 7.33; N, 6.70. Found: C,77.37; H, 7.35; N, 6.63. EXAMPLE 48 2-{4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino}benzoic acid,mp 57-62°C. MS: 431 (M+l+).
Analysis for C27H30N2O3-0.3 H2O: Calcd: C, 74.39; H, 7.07; N, 6.43. Found: C,74.23; H, 6.97; N, 6.27. EXAMPLE 49 2-{4-[3-(4-Carboxyphenyl)propyl]phenylamino}benzoic acid, mp 236-239°C.MS: 375 (M+). EXAMPLE 50 2-{4-[3-(4-Diethylaminomethylphenyl)propyl]phenylamino}benzoic acid,mp 137°C. MS: 417 (M+l+). EXAMPLE 51 2-{4-[3-(4-Propylaminophenyl)propyl]phenylamino}benzoic acidMS: 389 (M+l4). 119 6 3 -74-
Analysis for C25H28N2O2O.2 H2O: Calcd: C, 76.58; H, 7.30; N, 7.14. Found: C,76.61; H, 7.29; N, 7.03. EXAMPLE 52 2-{4-[^(3-Propylaminophenyl)propyl]phenylamino}benzoicacid MS: 389 (M+l+).
Analysis for C25H28N2O2O.I H2O: Calcd: C, 76.93; H, 728; N, 7.18. Found: C,76.85; H, 7.44; N, 7.06. EXAMPLE 53 2-{4-[3-(4-Pyrrolidin-l-yl-phenyl)-propyl]-phenylamino}-benzoicacid.mp 171-177°C. MS: 401 (M+l+).
Analysis for C26H28N2O2-0.2 H2O: Calcd: C, 77.27; H, 7.08; N, 6.93. Found: C,77.09; H, 6.97; N, 6.96. EXAMPLE 54 2-{4-[3-(3-Piperidin-lyl-phenyl)-propyl]-phenylamino}-benzoic acid,mp 59-61 °C. MS: 415 (M+l+).
Analysis for C27H30N2O2O.3 H2O: Calcd: C, 77.22; H, 7.34; N, 6.67. Found: C,77.18; H, 7.25; N, 6.49. EXAMPLE 55 {5-[(l-Butyl-l,2,3,4-tetrahydro-6-quinolyl)methylidene]-4-oxo-2-thioxothiazolidin-3-yl} acetic acid, mp 222-224°C. MS: 391 (M+1+). EXAMPLE 56 { 5-[(l -Butyl-2,3-dihydro-1 H-indol-5-yl)methylidene]-4-oxo-2-thioxothiazoIidin-3-yl} acetic acid, mp >250°C. MS: 377 (M+l4). 119*3 -75-
Analysis for CigH2oN203S2'0.4 H2O: Calcd: C, 56.34; H, 5.46; N, 7.30; S, 16.71. Found: C, 56.27; H, 5.18; N, 7.31; S, 16.74. EXAMPLE 57 3- { 5 - [( 1 -Butyl-1,2,3 ,4-tetrahydroquinolin-6-yl)methylidene] -4-oxo-2-thioxo- 5 thiazolidin-3-yl}propanoic acid, mp 214-215°C. MS: 405 (M+1+). EXAMPLE 58 4- {5-[( 1 -Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}butanoic acid, mp 152-154°C. Î0 MS: 417 (M-l+), 418 (M+), 419(M+1+).
Analysis for C21H26N2O3S2O.2 H2O: Calcd: C, 59.74; H, 6.30; N, 6.64; S, 15.19. Found: C, 59.59; H, 6.16; N, 6.52; S, 15.38. EXAMPLE 59 2- {4-[3-(3,4-Dichloro-phenyl)-propyl]phenylamino} -5-methyl-benzoic acid. 15 mp 98-99°C. MS: 414 (M+). EXAMPLE 60 N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-methanesulfonamide was prepared by reacting the product from Example 9 with 20 methanesulfonamide. mp 53-61 °C.
Analysis for C23H22CI2N2O3SO.I3 H2O: Calcd: C, 57.58; H, 4.68; N, 5.84.Found: C, 57.20; H, 4.66; N, 5.51. EXAMPLE 61 2-{4-[2-(3,4-Dimethyl-phenyî)-ethyl]-phenylamino}-5-nitro-benzoicacid. 25 mp 214-216°C.
Analysis for C23H22N2O4O.25 H2O: Calcd: C, 69.99; H, 5.74; N, 7.18.
Found: C, 69.90; H, 5.82; N, 6.81. 1196 3 -76- EXAMPLE62 2-[4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-mtro-benzoic acid, mp 239-244°C.MS: 439 (MH+). EXAMPLE 63 5 2-{4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-5-nitro-benzoicacid, mp 207-209°C.
Analysis for C22H16CIF3N2O4: Calcd: C, 56.85; H, 3.47; N, 6.03.
Found: C, 56.75; H, 3.71; N, 5.83. EXAMPLE 64 1 θ 5-Amino-2-{4-[2-(3.4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid was prepared by reacting the product from Example 2 with hydrogen gas in thepresence of Raney nickel, mp 137-142°C.
Analysis for C2iHjgCl2N2O2"0.96 mol THF: Calcd: C, 63.94; H, 4.72; N, 6.00.Found: C, 64.33; H, 4.91; N, 6.35. 15 EXAMPLE 65 5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid, mp 198-202°C.
Analysis for C21H18N2O4O.11 H2O: Calcd: C, 69.22; H, 5.04; N, 7.69.
Found: C, 69.59; H, 5.27; N, 7.22. EXAMPLE 66 20 2- {4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid, mp 148-150°C.
Analysis for C22H17F4NO2: Calcd: C, 65.51; H, 4.25; N, 3.47. Found: C, 65.51;H, 4.13; N, 3.46. 1196 3 -77- EXAMPLE 67 2-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acidmp 203-208°C.
Analysis for C21H16F2N2O4: Calcd: C, 63.32; H, 4.05; N, 7.03.
Found: C, 62.94; H, 4.37; N, 6.87. EXAMPLE 68 {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-[2-(lH-tetrazol-5-yl)-phenyl]-aminewas prepared as described in Example 1, using a tetrazole fluoro intermediate thatwas synthesized from commercially available 2-fluorobenzonitrile and sodiumazide under standard reaction conditions, mp 129 shrink, 152-157°C.
Analysis for C21H17CI2N5O.I5 EtOAc-0.15 Hexane: Calcd: C, 61.80; H, 4.64; N, 16.12. Found: C, 61.61 ; H, 4.28; N, 15.83. EXAMPLE 69 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl}-phenylamino}-5-nitro-benzoicacid, mp 190-193°C.
Analysis for C22H16F4N2O4: Calcd: C, 58.93; H, 3.60; N, 6.25.
Found: C, 58.69; H, 3.42; N, 6.57. EXAMPLE 70 2-(4-Phenethyl-phenylamino)-benzoic acid, mp 173-182°C.
Analysis for C21H19NO2: Calcd: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.42; H, 5.97; N, 4.47. Found: C, 79.59; H, 6.03; N, 4.50. EXAMPLE 71 2-{4-[2-(3,4-Dichloro-phenyI)-ethyl]-phenylamino}-5-fluoro-benzoic acid,mp 180-182°C.
Analysis for C2iHi6CI2FN02-0.06 H2O: Calcd: C, 62.23; H, 4.01; N, 3.46.Found: C, 61.83; H, 4.04; N, 3.29. 1196 3 -78- EXAMPLE 72 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid. mp 168-171°C.
Analysis for C2oHigCl2N202: Calcd: C, 62.03; H, 4.16; N, 7.23.
Found: C, 62.11; H, 4.17; N, 7.07. EXAMPLE 73 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid,mp 192.5-194.5°C.
Analysis for C21H17CIN2O4: Calcd: C, 63.56; H, 4.32; N, 7.06. Found: C, 63.83;H, 4.62; N, 6.79. EXAMPLE 74 2-{4-[2-(4-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid,mp 210-212°C.
Analysis for C2iH17ClN2O4-0.26 H2O: Calcd: C, 62.82; H, 4.40; N, 6.98.Found: C, 62.51; H, 4.34; N, 6.58. EXAMPLE 75 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-methyl-benzoic acid,mp 153-160°C.
Analysis for C22H19CI2NO20.61 H2O: Calcd: C, 64.25; H, 4.96; N, 3.41.Found: C, 63.87; H, 4.64; N, 3.55. EXAMPLE 76 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid,mp 236-238°C. EXAMPLE 77 2-{4-[2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid,mp 200.5-202.5°C. 1196 3 -79-
Analysis for C2iH]gCl2N2O4: Calcd: C, 58.49; H, 3.74; N, 6.50.
Found: C, 58.33; H, 3.67; N, 6.29. EXAMPLE 78 2- {4-[2-(3,4-Dichloro-phenyî)-ethyl]-phenylamino }-6-trifîuoromethyl-benzoicacid, mp 130-132°C.
Analysis for C22H16CI2F3NO2: Calcd: C, 58.17; H, 3.55; N, 3.08.
Found: C, 58.25; H, 3.65; N, 3.05. EXAMPLE 79 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-5-nitro-benzoic acid,mp >260°C. EXAMPLE 80 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-dimethylamino-benzoicacid, mp 75-80°C. EXAMPLE 81 2-{4-[2-(3,5-Dichloro-phenyl)-ethyl3-phenylamino}-benzoic acid, mp 191-194°C.Analysis for C21H17CI2NO2: Calcd: C, 65.30; H, 4.44; N, 3.63. Found: C, 65.38;H, 4.29; N, 3.52. EXAMPLE 82 2-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl3-ethyl}-phenylamino)-benzoic acid was prepared according to Example 1 using a decahydroisoquinolinealdéhyde which was prepared from trans-decahydroisoquinoline and para-fluorobenzaldehyde under standard reaction conditions, mp 203-206°C.
Analysis for C30H34N2O2O.12 H2O: Calcd: C, 78.89; H, 7.56; N, 6.13.
Found: C, 78.49; H, 7.58; N, 5.90.
The following examples are prepared according to the foregoing methods,or by utilizing standard combinatorial synthetic methodology by reacting halosubstituted benzoate esters with a substituted aniline to form the corresponding 1196 3 -80- diarylamine, followed by saponification to the benzoic acid of Formula I. Thereactions are carried out on 0.15 mmol scale as follows. Solutions of each halobenzoate reactant (0.18 M) in toluene are placed in 2 dram reaction vials. Eachaniline reactant is dissolved in anhydrous toluene to give 0.15 M solutions. ADistriman pipet is used to add 1 mL (0.15 mmol, 1 eq) of each halo benzoatesolution to the appropriate vials containing 1 mL (0.18 mmol, 1.2 eq) of theaniline reactants. A catalyst solution is prepared by dissolving 0.025 M ofPd2(dba)3 (dipalladium-tridibenzylidene acetone) and 0.075 M of BINAP (2,2 -bis(diphenylphospbino)-l,r-binapthyl) in toluene, and 0.25 mL of the catalystsolution is added to each reaction vial. A base, generally césium carbonate(68 mg, 0.21 mmol, 1.40 eq) is added to each reaction vial, and the vials arecapped and placed in a shaker oven and heated at 100°C for 48 hours. Thereaction mixtures are then cooled, and the reaction solvents are removed byévaporation. The solid residue is suspended in 400 gL of ethyl acetate and filteredto remove ail catalyst. The filtrâtes are concentrated to dryness by évaporation toprovide compounds of Formula I, wherein the benzoic acid portion is esterified(e.g., benzyl or methyl ester). The esters are dissolved in 500 pL of THF/ethanol(1:1 v/v) to which is added 300 pL of 5 M sodium hydroxide. The solutions areshaken for 5 hours at 60°C and then cooled and concentrated to dryness byévaporation of the solvents to provide the desired compounds of Formula I.Typical compounds prepared by this method are as follows. The structure of thecompounds are generally confirmed by mass spectral analysis. EXAMPLE 83 2-(3 ',5'-Dichloro-3-methyl-biphenyl-4-ylamino)-benzoic acidMS: 371; MW: 372.2495. EXAMPLE 84 2-(3',5'-Dibromo-3-methyl-biphenyl-4-ylamino)-benzoic acidMS: 459; MW: 461.1515. 1196 3 -81- gXAMPLE 85 2-(4-1.3-Benzodioxol-5-yi-2-methyl-phenylamino)-benzoic acidMS: 347; MW: 347.3683. EXAMPLE 86 5 2-(2,2',4'-Trichloro-biphenyl-4-ylamrno)~benzoic acidMS: 391; MW: 392.6678. EXAMPLE 87 2-(2-Chloro-3,,4z-difluoro-biphenyl-4-yiamino)-benzoicacidMS: 359; MW: 359.7578. 10 EXAMPLE 88 2-(3z-Bromo-2-chloro-biphenyl-4-yiainino)-benzoic acidMS: 401; MW: 402.6737. EXAMPLE 89 2-{4-[2-(3,4-Dicbloro-phenyl)-ethyl]-phenylamino}-5-nitro-ben2oicacid 15 EXAMPLE 90 2- {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-nitro-benzoicacid EXAMPLE 91 3- {4- [2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino } -benzoic acid EXAMPLE 92 20 5- (4- [2-(3,4-Dichloro-phenyl)-ethyl3-phenylamino} -isophthalic acid EXAMPLE 93 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid EXAMPLE 94 2-{4-[2-(3,4-Dichloro-phenyl)-ethyï]-phenylamino}-455-dimethoxy-benzoic acid 119 6 3 -82- EXAMPLE 95 2- {4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-3-nitro-beiîZoic acid EXAMPLE 96 3- {4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-benzoic acid 5 EXAMPLE 97 5-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino}-isophthalic'*acid EXAMPLE 98 2- {4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylamino} -benzoic acid EXAMPLE 99 10 4-(4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoic acid EXAMPLE 100 2-{4-[3-(4-Diethylamino-phenyl)-propylJ-phenylamino}-5-methoxy-benzoic acid EXAMPLE 101 15 2- {4-[2-(3-Methoxy-phenyl)-ethyl]-phenylamino}-benzoic acid EXAMPLE 102 2-{4-[2-(3-Bromo-phenyl)-ethyl]-phenylamino}-benzoic acid EXAMPLE 103 2-{4-[2-(3-Fluoro-phenyl)-ethyl]-phenylamino}-ben2oic acid 20 EXAMPLE 104 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyiamino}-5-methoxy-benzoic acid EXAMPLE 105 4-{4-[2-(3J4-Dichloro-phenyl)-ethyl]-phenylamino}-nicotinic acid -83- EXAMPLE 106 2-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-2,3-dihydïO-lH-isoindol-5-yianiino]-benzoic acid EXAMPLE 107 5 2- {4-[2-(3-Fluoro-4-methyl-phenyl)-ethyl]-phenyIamino} -benzoic acid EXAMPLE 108 2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-5-nitro-benzoic acid EXAMPLE 109 4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-benzoic acid 10 EXAMPLE 110 4-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylamino}-3-methoxy-6-nitro-benzoic acid EXAMPLE 111 4- {4-[3-(4-Diethylamino-pheny l)-propyl]-phenylamino } -3 -methoxy-benzoic acid 15 EXAMPLE 112 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethylJ-phenylamino}-5-methoxy-benzoic acid EXAMPLE 113 {4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenyl}-(2-methoxy-5-nitro-phenyl)- 20 amine EXAMPLE 114 2- {4-[3-(4-Diethylamino~phenyl)-propyl]-phenylamino}-3-nitro-benzoicacid EXAMPLE 115 3- {4-[3-(4-Diethylamino-phenyl)-propylJ-phenylamino}-benzoic acid rt 19 6 3 -84- EXAMPLE116 2-{4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 159- .161°C. EXAMPLE 117 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid monosodium;mp 107-108°C. EXAMPLE 118 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid monopotassium;mp >200°C. EXAMPLE 119 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid calcium sait(l:I);mp>220°C. EXAMPLE 120 2-{4-[2-(3,4-Dichloro-phenyl)-ethyï]-phenylamino}-benzoate-2-hydroxy-l,l-bis-hydroxymethyl-ethyl-ammonium; mp 185-187°C. EXAMPLE 121 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-methoxy-benzoicacid;mp 155-158°C. EXAMPLE 122 2-{4-[2-(3.4-Diiluoro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 184-185°C. EXAMPLE 123 2-{3-[2-(4-Chloro-phenyl)-ethyI]-phenylamino}-benzoic acid; mp 155-157°C. EXAMPLE 124 2-{3-[2-(3,4-Dimethyl-phenyl)-ethylJ-phenylamino}-benzoic acid; mp 182-184°C. :-11963 -85- EXAMPLE 125 2-(4-(2-(2,4-Dimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 180-181°C. EXAMPLE 126 5 2-{4-(2-(2-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 140-143°C. EXAMPLE 127 2-{4-(2-(2-Hydroxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 218-219°C. EXAMPLE 128 2-{4-[2-(3-Chloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 152-154°C. 10 EXAMPLE 129 2-[4-(2-Biphenyî-4-yl-ethyl)-phenylamino]-benzoic acid; mp 200-202°C. EXAMPLE 130 2- {4-(2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 181-183°C. EXAMPLE 131 15 3-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 137-138°C. EXAMPLE 132 4-{4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 214-215°C. EXAMPLE 133 2-{4-[2-(3}4J5-Trimethoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; mp 146-20 147°C. EXAMPLE 134 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-bcnzoic acid; mp 153-154°C. si 19 6 3 -86- EXAMPLE 135 2-{4-[5-(354-Dichloro-phenyl)-pentyl3-phenylamino}-ben2oic acid; mp 106-108°C. EXAMPLE 136 5 2-{4-[2-(4-{2-HydToxycarbonylphenylamino}phenyl)ethyl]-phenylamino}-benzoic acid; MS 451 (M”l). EXAMPLE 137 2-(3/,5'-Dichloro-biphenyl-4-ylamino)-benzoic acid; mp >220°C. EXAMPLE 138 10 4-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-2-methoxy-5-nitro-benzoicacid; mp 74-78°C. EXAMPLE 139 2- {4-(3-(3 s4-Dichloro-phenyl)-propyl]-phenylamino }-5-fluoro-benzoic acid;mp 122-123°C. 15 EXAMPLE 140 5-Amino-2-{4-[5-(3,4-dichloro-phenyl)-pentyl]-phenylamino}-benzoicacid;mp 182-184°C. EXAMPLE 141 N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-C,C,C-20 trîfluoro-methanesulfonamide; MS 531 (M“). EXAMPLE 142 N-(2-{4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)-benzenesulfonamide; MS 539. ,119 6 3 -87- EXAMPLE 143 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoicacid; mp 190-192°C. MS 453 (M*1). EXAMPLE 144 5 4-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-isophthalic acid; mp 264-266°C. EXAMPLE 145 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-trifluoromethyl-benzoicacid; mp 134-136°C; MS 454 (M+). 10 EXAMPLE 146 2- {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -3 -trifluoromethyî-benzoicacid; MS 454 (M+). EXAMPLE 147 2-( {4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenyl}-methyl-amino)-5-dimethylamino- 15 benzoic acid; mp 128-131°C. EXAMPLE 148 2-( {4- [2-(3,4-Dichloro-phenyl)-ethyl] -phenyl} -methy l-amino)-benzoic acid;MS 400 (M+). EXAMPLE 149 20 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-dipropylamino-benzoicacid; MS485(M+). EXAMPLE 150 5-Dibutylamino-2- {4-(2-(3,4-dichloro-phenyl)-ethyl]-phenylamino} -benzoic acid;MS 513 (M4). 419 6 3 -88- EXAMPLE 151 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-diethylamino-benzoic acid;mp 106-110°C. EXAMPLE 152 5 2,2'-[ 1,2-Ethanediylbis (4,1 -phenyleneimino)Jbis-benzoic acid EXAMPLE 153 4-[3-[4-(Diethylamino)phenyl]propyl]-N-(2-methoxy-5-nitrophenyl)-benzinamine EXAMPLE 154 2- {3 -[2-(4-Chlorophenyl)ethyl]phenylamino} -benzoic acid 10 EXAMPLE 155 2- {3 -[3-(3,4-Dichloropheny l)propyl]phenylamino} -benzoic acid EXAMPLE 156 2-{3-[3-(4-Diethylaminophenyl)propyl]phenylamino}-benzoicacid EXAMPLE 157 15 2- {3 -[3-(4-Di-n-propylaminophenyl)propyl]phenylamino} -benzoic acid
The following Exemples 158-163 illustrate the use of inventioncompounds as starting matériels and intermediates in the synthesis of otherinvention compounds and dérivatives. The examples illustrate réduction of nitrogroups to amino groups, alkylation of amino group, and estérification of 20 carboxylic acid groups. These reactions are depicted in the following generalizedScheme 12. ί119 6 3 -89-
Scheme 12
COOH . COOE estérification alkylation
Rc
COOH where and Rc are as defined above, and E is an ester forming group such asC]-Cg alkyl (e.g., methyl, 2,2,2-trichloroethyl), benzyl, diphenylmethyl, or the 5 like. EXAMPLE 158 2-{4-[3-(4-Nitrophenyl)propyl)phenylamino}benzoicacid
To a slurry of 4-[3-(4-nîtrophenyl)propyl] aniline (4.08 g, 15.9 mmol) and 2-bromobenzoic acid (3.52 g, 17.5 mmol) in i-PrOH (100 mL) was added il 5 9 6 3 -90-
Cu(OAc)2 (87 mg, 0.478 mmol) and KOAc (3.44 g, 35.0 mmol) at roomtempérature. The resulting mixture was allowed to heat under reflux for 23 hours,then cooled to room température. After removing the solvent under reducedpressure, the residue was diluted with water (100 mL) and basifîed with aqueous1.0 M-NaOH solution to pH 9.0. The aqueous layer was washed with Et2Û(20 mL, twice) and acidified with aqueous 1.0 Μ-HCl solution to pH 3.0. Theprecipitate formed was filtered by suction and dried at 60°C in vacuo, affordingthe title compound as a beige solid (5.75 g, 96% yield). mp 150-153°C. MS (Fàb): 376 (MH+). EXAMPLE 159 2-{4-[3-(4-Aminophenyl)propy]]phenylamino}benzoic acid
To a solution of 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid (Example 158) (3.0 g, 7.97 mmol) in DMP (40 mL) was added 10% Pd-C(300 mg) at room température under argon atmosphère. Hydrogen gas (1 atm) wasintroduced into the flask and the mixture was stirred for 14 hours at roomtempérature. The reaction mixture was filtered through a Celite pad to removePd-C and concentrated in vacuo. The residue was diluted with MeOH (ca. 50 mL)and concentrated in vacuo. This operation was repeated 3 times to remove anytrace of DMF. The residue was diluted with MeOH again, and insoluble stuff wasremoved by filtration. Removing the solvent of the filtrate in vacuo afforded anoil, which was diluted with CH3CN (50 mL) and added dropwise water (100 mL)slowly. The precipitate fonned was filtered and dried at 60°C in vacuo, affordingthe title compound as a white solid (2.34 g, 85% yield). mp 110-112°C. MS (Fab): 347 (MH+). EXAMPLE 160 2-{4-[3-(4-Ammophenyl)propyl]phenylamino}benzoic acid methyl ester
To a solution of 2-{4-[3-(4-aminophenyl)propylJphenylamino}benzoic acid (Example 159) (2.34 g, 6.75 mmol) in MeOH (50 mL) was addedconcentrated H2SO4 (1.0 mL) at room température. The mixture was stirred underreflux for 3.0 days. The reaction was quenched with Et3N (10 mL) at5eC, and the 11963 -91- solvent was removed under reduced pressure. The residue was diluted with water(20 mL) and extracted with Et20 (20 mL, 4 times). The combined ether layer waswashed with water (10 mL) and brine (10 mL), and dried over anhydrousNa2SÜ4· The solvent was removed under reduced pressure and purification by 5 column chromatography afforded crude title compound as a yellow amorphousmaterial (2.59 g). This material was used without further purification. EXAMPLE 161 2-{4-[3-(4-Diethylaminophenyl)propyl]phenylamino}benzoic acid methyl esterand 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino)benzoic acid methyl ester 10 To a solution of the crude ester described above (2.59 g, ca. 6.75 mmol) and CH3CHO (2.0 mL, 35.1 mmol) in CH3CN (50 mL) was added NaBH3CN(1.70 g, 27.0 mmol) at 5°C, and the suspension was stirred for 30 minutes whilethe pH was monitored and aqueous 1.0 Μ-HCl solution was added to maintain themixture moderately acidic (pH 3.0-4.0). The reaction mixture was allowed to 15 warm up to room température over 1.0 hour and then basified with aqueous 1.0 M-NaOH solution to pH 9.0. The reaction mixture was concentrated underreduced pressure to remove CH3CN, and the resulting aqueous solution wasacidified with aqueous 1.0 Μ-HCl solution to pH 3.0. The aqueous solution wasextracted with CHCI3 (20 mL, 3 times), and the combined extract was washed 20 with brine (5 mL). After drying over anhydrous Na2SÛ4, the solvent was removed under reduced pressure and purified by column chromatography (silicagel 60N, n-hexane/CHCl3/Et3N 50:98:2). First eluted was the dialkylated productas a yellow amorphous material (1.07 g, 38%). MS (Fab): 417 (MH4). 25 Subsequently eluted was the monoalkylated product as a yellow amorphousmaterial (0.79 g, 30%). MS (Fab): 389 (MH4). EXAMPLE 162 2-{4-[3-(4-DiethylaminophenyI)propyl]phenylamino}benzoicacid -92- Το an émulsion of 2-{4-[3-(4-diethylaminophenyl)propyl]phenylamino}-benzoic acid methyl ester (1.6S g, 4.03 mmol) in EtOH (50 mL) was addedaqueous 3 M-KOH solution (4.0 mL, 12.0 mmol) at room température, then themixture was allowed to beat under reflux for 40 minutes. The reaction mixturewas cooled to room température and neutralized with aqueous 1.0 Μ-HCl solutionto pH 9.0. The mixture was concentrated under reduced pressure to remove EtOH,and the resulting aqueous solution was extracted with CHCI3 (50 mL, 3 times).The combined extract was washed with brine (10 mL) and dried over anhydrousNa2SÛ4. The solvent was removed under reduced pressure and purification bycolumn chromatography (silica gel 60N, conc NH4OH/MeOH/CHCl3 0.2:2:100to 0.5:5:100) afforded a yellow oil. This oil was diluted with acetone, and thesoluiion was concentrated under reduced pressure at room température to give thetitle compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate). MS (Fab): 403 (MH+).
Analysis for C26H30N2O2O.2O H2O: Calcd: C, 76.89; H, 7.54; N, 6.90.
Found: C, 76.73; H, 7.67; N, 7.10. EXAMPLE 163 2-{4-[3-(4-Ethylaminophenyl)propyl]phenylamino}benzoicacid
The title compound was prepared from 2-{4-[3-(4-ethylaminophenyl)-propyl]phenylamino}benzoic acid methyl ester (from Exemple 161), EtOH(10 mL), and 3 M-KOH solution (1.0 mL) using the procedure described inExample 162. This procedure yielded a yellow solid, 253 mg of the desiredproduct (90% for 0.1 hydrate). MS (Fab): 375 (MH+).
Analysis for C24H26N2O2O.IO H2O: Calcd: C, 76.61; H, 7.02; N, 7.44.
Found: C, 76.62; H, 7.06; N, 7.36. 419 6 3 -93-
BIOLOGICAL EXAMPLES
Représentative compounds of Formula I hâve been evaluated in severalin vitro and in vivo assays which are well-established as indicative of ciinicalusefulness in treating Alzheimer’s disease.
AMYLOID ASSAYS BASSR fBeta-Amvloid Self-Seeding Radioassay)
An assay for inhibitors of self-seeded amyloid fibril growth
Materials:
Stock Solutions:
Assay Buffer - 50 mM sodium phosphate, pH 7.5,100 mM NaCl, 0.02% NaN3, 1 M urea (filter and store at 4°C).
Soluble Αβ(1-40) peptide (Bachem, Torrance, CA) - 2.2 mg/mL in deionized H2O(stored in aliquots at -20°C, keep on ice when thawed) will self-seed after 1 weekstorage. Typically, the solution should be stored until no lag phase is seen in theassay. 1251-labeled Αβ (1-40) - 150K-350K cpm/gL in 100% acetonitrile - 0.1%trifluoroacetic acid (TFA) - 1% β-mercaptoethanol (aliquots stored at -20°C).Î25i.iabeied A/? (1-40) can be made in accordance with the procedure set forth byH. LeVine, III in NeurobioL Aging, 16,755, (1995), which is hereby incoiporatedby reference, or this reagent may be purchased from Amersham, ArîingtonHeights, Illinois.
Final assay conditions: 30 μΜ soluble A/? (1-40) in deionized water in assaybuffer + 20K-50K cpm I^^I-labeled Αβ (1-40) per assay. Compound to be testedis dissolved in dimethylsulfoxide (DMSO), typically 5 to 50 mM stock, such thatthe final concentration of DMSO is <1% v/v in the assay. '119 6 3 -94-
Assay: Reaction mixture for 50 assays (on ice) is comprised of 0.1 to 0.2 gL of125i_iabeled k^l-labeled J/?(l-40) + 1 gL of soluble Αβ( 1-40) + 13.5 gLassay buffer per assay. The following are the amounts of the components of thereaction mixture sufficient for 50 assay wells: 5-10 gL 125i_jabeied j^(j_40) dried down675 gL assay buffer50 gL soluble Αβ( 1-40)
Assay Method 1) Préparé reaction mixture above by mixing components and storing on ice. 2) Pipet 14.5 gL of reaction mixture into each of 50 wells on a polypropyleneU-bottom 96-well microtiter plate on ice. (Costar 3794). 3) Add 1.7 gL of diluted compound to be tested to each well in a column ofeight, including solvent control. Serial 3-fold dilutions from 1 mM (100 gMfinal) in assay buffer - urea = 7 dilutions + zéro. Each 96-well plate cantherefore accommodate 11 samples + 1 Congo Red control (0.039-5 gMfinal in 2-fold steps). 4) Seal the plate with aluminum film (Beckman 538619) and incubate for10 minutes on ice. 5) Raise the température to 37°C and incubate for 3 to 5 hours (depending onthe lot of the peptide). 6) Remove the aluminum film and add 200 gL/well of ice cold assay bufferwith urea, collecting the radiolabeled fibrils by vacuum filtration through0.2 gm pore size GVWP filters in 96-well plates (Millipore MAGV N22,Bedford, MA). Détermine the radioactivity of the filters using standardmethods well-known to those skilled in the art
BASST (Beta-Amvloid Self-seeding. ThiofiavinD
An assay for inhibitors of self-seeded amyloid fibril growth METHODS:
Materials:
Stock Solutions: 119 6 3 -95-
Assay Buffer - 50 mM sodium phosphate, pH 7.5,100 mM NaCl, 0.02% NaN3, 1 M urea (filter and store at 4°C)
Soluble Αβ (1-40) - 2.2 mg/mL in deionized HoO (store in aliquots at -20°C, keep on ice when thawed) will self-seed after 1 week storage. Typicaliy, the solution5 should be stored until no lag phase is seen in the assay.
Final assay conditions: 30 μΜ soluble Αβ (1-40) in deionized water in assaybuffer. Compound to be tested is dissolved in DMSO, typicaliy 5 to 50 mM stock,such that the final concentration of DMSO is <1% v/v in the assay.
Assay: Reaction mixture for 50 assays (on ice) comprised of 1 gL of soluble10 Αβ ( 1 -40) + 13.5 gL assay buffer per assay. The following are the amounts of the components of the reaction mixture that resuit in each of the 50 assay wells: 50 gL soluble Αβ (1-40) 675 gL assay buffer
Assay Method 15 1) Préparé the reaction mix above by mixing the components and storing on ice. 2) Pipet 14.5 gL of reaction mixture into each of 50 wells of a polystyrèneU-bottom 96-well microtiter plate (Corning 25881-96) on ice. 3) Add 1.7 gL of diluted compound to be tested to each well in a column of
20 eight, including solvent control. Serial 3-fold dilutions from 1 mM (100 gM final) in assay buffer - urea - 7 dilutions + zéro. Each 96-well plate cantherefore accommodate 11 samples + 1 Congo Red control (0.039-5 gMfinal in 2-fold steps). 4) Seal the plate with aluminum film and incubate for 10 minutes on ice. 25 5) Raise the température to 37°C and incubate for 3 to 5 hours (dépends on the lot of the peptide). 6) Remove the aluminum film and add 250 gL/well of 5 gM thioflavin T (ThT)[T-3516, Sigma-Aldrich] in 50 mM glycine-NaOH, pH 8.5. Read 11963 -96- fluorescence on a plate reader (ex = 440 nm/20 nm ; em = 485 nm/20 nm)within 5 minutes. ΒΑΡΑ fBeta-AmvIoid Peptide Aggregation)
This assay is used to provide a measure of inhibition by a compound against the aggregation behavior of the beta amyloid peptide.
The purpose of this assays is to provide a higher volume method ofassaying the amount of beta amyloid aggregation using an endpoint assay basedon filtration. In this assay, hexafluoroisopropanol (HFIP) is used to break downthe initial amyloid peptide to a monomer State and use a concentration of 33 gMwhich is high enough so that aggregation will occur at pH 6.0 in several hours. METHOPS: β-Amyloid Peptide Aggregation. pH 6.0 (ΒΑΡΑ)
In a 96-well plate (Costar 3794), we add 25 gL 50 mM Phosphate Buffer,pH 6.0,10 gL 0.5 mg/mL Αβ (1-40) peptide in 20% HFIP + 0.1 gL/assayradioiodinated 125j Αβ (1-40) [125χ Αβ(1-40)], and 1 gL of the compound to betested starting at 50 mM with a concentration of DMSO <1%. Then, we incubatefor 2 to 4 hours at room température. We stop the reaction with 200 gL of 50 mMphosphate buffer, pH 6.0, and filter it through a 0.2 gm 96-well filter plate(Millipore MAGU N22). We wash the filter plate with 100 gL of the samephosphate buffer. Aggregation was detected on a Microbeta counter afterimpregnating the filters with Meltilex (1450-441) and is corrected for background.
BATYM ASSAY METHOPS:
Required Αβ (1-42) (California Peptide) was dried from itshexafluoroisopropanol (HFIP) stock solution. The Αβ (1-42) was dissolved indimethylsulfoxide (PMSO) and then mixed with phosphate buffered saline (PBS)(pH 7.4). The mixed Αβ (1-42) solution was filtered with a 0.2 gm Omniporemembrane syringe filter (Millipore, Bedford, MA). The compound to be tested inDMSO (50 times concentrate) was put into each weil (0.5 gL/well) of a 96-well 11963 -97- plate. The Αβ (1-42) solution was added into each well (24.5 pL/well). The platewas centrifuged at 1,000 g for 5 minutes and incubated at 37°C for 1 day(Αβ 1-42; final concentration 100 μΜ).
After incubation Thioflavin T (ThT) (30 μΜ) solution in glycine-NaOH5 buffer (pH 8.5, 50 mM) was added into each well (250 pL/well), fluorescence was measured (ex = 440/20 nm, em = 485/20 nm) using a fluorescence plate reader.The inhibitory activity was calculated as the réduction of fluorescence with thefollowing formula:
Inhibition (%) ={(Ρ(Αβ)-Ρ(Αβ+οοπιροιηκ1)}/{Ρ(Αβ)-Ρ(5ο1νεηΐ + compound)} x 100 10 The IC5QS were calculated by a curve fitting program using the following équation. The data were obtained from two different experiments in triplicate.
Inhibition(x) = 100-100/ {l+(x/IC5o)n},x = Concentration of tested compound (M), IC50 = (M), 15 n = Hill coefficient.
Représentative compounds of Formula I hâve exhibited inhibitoryactivities (IC50) ranging from 0.1 μΜ to greater than 100 μΜ in the foregoingassays.
The results of these assays for spécifie and représentative compounds ofthe présent invention are shown in Table 1 below. 20 1196 3 -98-
Table 1. β-Amyloid inhibitory Activity of Compounds of Formula I
Example No. BASSR(IC50 = gM) BASST (ÎC50 = μΜ) BATYM(ÎC50 = pM) ΒΑΡΑ(IC50 = gM) 1 10 (P), >100 (P)(6x), >100(Q),>100 (R), >100 (S),52(1) >100 (Z) 2,4,30,10 (P)3(Q) >100 (R) 11 (S), 11 (D6(Z) 50, 58.8 (P)57.8 (Q) 60 (P), >100 (P) 86 (Q), >60 (R), >60 (S), H(D 2 2.2,4.1,4.1, 12,4.5 1,1.5 (P) 6.52 (P) 70 (P) 3 4.5,5,5 (ail 3 V-shaped)(P) 15 (ppt), 5 (Q) 2(P) 3(0) 11.7 (P) >60 (P) 4 30, >100 (3x) 3,4,8 26.3,30.7 67 5 70, >100 4.5 10 74 6 15,21,20,40 4,1,3 21.5 >60 7 8 18, 13,12,20 15,15,18,15 2 3, >100 8.83 7.17 39 9 20 (ppt), 30, 52,40 (P) 1,2 (P) 20.1,28.2 (P)38.6 (R) 75 (P) 10 70,50 4 75.7 67 11 18 (ppt), 20 (ppt), 20 (2x), >100 (P)>100,21,30(Q) 1,1,3 (P)1,0.8 (Q) 5.62 (P)6.78 (Q) 23 (P) 9(0) 12 20 (4x) 1,1 3.93 >60 13 21, >100, 20 (ppt), 15 (ppt), >100 0.9 6.41 6 14 18 (ppt), 8, 6 (ppt), 7 (ppt) 1.0 10.9 >10 (V-shaped) 15 100(3x)P 100,16(V-shaped)12,15,11(Q) 1(P) 1.2 (Q) 8.52 (P)7.26 (Q)7.07(0) >60 (P) 7(0) 1196 3 -99-
Tabie 1. β-Amyloid Inhibitory Activity of Compounds of Formula I (cont’d)
Example No. BASSR(ΙΟ50 = μΜ) BASST(IC50 = μΜ) BATYM(IC50 = gM) ΒΑΡΑ(IC50 = μΜ) 16 18, 7.5, 10 (P)70,32,42 (Q) 3, 0,3 (P)1.1,0.8, 0.6 (Q) 12 (P) 10-3 (Q) 13 (P) 17 >100 (ppt) (3x) 6.2 64.5 >60 (Q), 41 (R) 18 >100 (5x)(P) 30, >100 (P) >100 (P) 9, >40, 53 (P), 12 19 3,4, >100,2.2 >100,1,1,1.5 31.0,34.0 >60,43 20 4.2 6 68.6 22 21 3 4 62.7 26 22 3 9 >100 24 23 20 2 >100 17 24 >100 20 >100 91 25 >100 4 21.1 47 26 >100 1 >100 57 27 >100 3 19.8 74 28 >100 5 42.3 27 29 >100 4 38.1 30 30 30,20 4,2 75.3 38 31 >100 1 22.6 86 32 >100 1 29.2 96 33 >100 >100 >100 >10 34 45 3 45.0 48 35 >100 100 >100 154 36 >100 >100 >100 149 37 >100 0.8 30.2 25 38 20,10 (V) 3 23.4 184 39 >100 20 >100 21 40 >100 3.0 >100 53 41 >100 5 49.7 42 42 >100 2 55.6 30 43 >100 0.3 24.2 63 44 >100 1 26.5 52 45 >100 1 21.5 32 46 >100 6 34.3 47 >100 2 38.2 48 25 10 >100 49 >100 >100 >100 50 >100 >100 >100 51 85 0.8 39.1 119 6 3 -100-
Table 1. β-Amyloid Inhibitory Activity of Compounds of Formula I (cont’d)
Exemple No. BASSR (IC50 = μΜ) BASST(IC50 = gM) ΒΑΊΎΜ(IC50 = gM) ΒΑΡΑ(ΐε50 = μΜ) 52 75 0.5 36.5 53 >100 0.3 30.0 54 >100 0.4 43.9 55 12 2 5.1 101 56 >100 3 11.5 30 57 4.8 1.5 4.0 50' 58 3.5 1 5.1 60 59 >100 >100 >100 3 60 >100 3 40.7 8 61 18,7.5,10 3,0.3 12 13 62 >100 1.5 8.98 63 15,15,18 (ppt) 1 9.43 45 64 . >100 5 35 >100 65 60, 80 1.5 15.9 >100 (V-shaped) 66 >100 (ppt), 2.1 50.1 >100 67 >100 (ppt) 41 4 . 13.3 >60 68 >100, >100 1 >100 110 69 2 (V-shaped), 0.8 11.7 58 70 3.5 (ppt) 20, 100 10 >100 65 71 >100 3 >60 72 40,15,12 2,2.5 74.8 >60, >60 73 25,35,40 0.3 9.43 >60 74 6,18,19,18 0.3,0.5 8.36 >60 75 >100 2.2 462 >60 76 3 0.5 8.59 >60 77 18,15 8,0.3 9.49 >60 78 70 0.1 >100 8 79 3.1,50,38,70, 1, 0.3,0.3,0.3 9.14 51 80 70,30,40>100 4 24.8 >60 81 >100 15 48.4 73 82 83 >100, >100, >100>100 2, 0.3,0.3>100 9,47,29 84 >100 >100 5,40,21 85 >100 18 8,77,45 119 6 3 -101-
Table 1. β-Amyloid Inhibitory Activity of Compounds of Formulai (cont’d)
Example No. BASSR (IC50 = μΜ) BASST (IC50 = μΜ) ΒΑΊΎΜ (IC50 = μΜ) ΒΑΡΑ (Ι05ο = μΜ) 86 40 18 >10, 89, 37 87 >100 50 >10, 15, 32 88 >100 10 >10, 37, 27 116 >100, >100 18,30 96 117 >100 3 61.3 >100 118 >100, >100 6 >60 119 >100 3 >60 120 >100 3 >60 121 122 >100, >100>100 1 2 >100 >60 123 >100 (3 x), 14 3,3 70.8 4, 18, >100, 3.2,4 (Q) 85.2 (Q) >60 (Q) 124 >100 (Q) >100 10 62.7 125 82 10 >100 80 126 >100, >100 4,5 84 63 30, 100 (Q) 10,4(Q) 73.9 (Q) >60 (Q) 127 >100 (ppt) 10 >100 67 128 >100 (ppt) (4 x) 10,41,6 75 60 ll,>100(3x) 15,20,10,7.5 (Q) 7,3,3(Q) >60 (Q) >60 (Q) 129 15, >100(3 x)Q 1 (V-shaped)(2 10,3,2,2 >100 >102 130 x) >100 (ppt) >100 (3 x) 2, >100, 50 47.5 238 131 >100 10 93.5 >60 132 >100 10 >100 60 133 >100 >100 >100 >60 134 >100 2 36.5 >60 135 >100 1.2 31J2 >60 136 >100 3 >100 53 137 >100, >100 3 52 141 >100 7 56.7 >50 142 >100 2.1 26.9 55 143 >100 (4 x) 40,30 >100 2, >60, >60 144 15,25 40 >100 114 11963 -102-
Table 1. β-Amyloid Inhibitory Activity of Compounds of Formula I (cont’d)
Example No. BASSR(IC50 = μΜ) BASST(IC50 = μΜ) BATYM(ΐε5ο = μΜ) ΒΑΡΑ(ΐσ50 = μΜ) 145 10,40, 30 4 56.8 9 146 >100 30 >100 >60 147 >100 10 93.4 >60 148 >100 >100 149 >100 >100 >100 >60 150 >100 10 >100 76 151 >100, >100 5, >100 >100 108 154 >100 3,30 70.8 155 >100 3 44.6 156 27.8 157 25.9 A letter in parenthèses after particular value indicates the particularsynthetic lot of the compound tested. The ternis “P,” “Q,” “R,” “S,” ‘T,” and “Z”designate different lots of the same compound. For example, 10 (P) indicates thatcompound tested was from Lot P. If no lot is specified, the lot of the compound 5 was Lot P.
The abbreviation “ppt” means precipitate and indicates that a precipitateformed at the indicated concentration. In addition, the terni “V-shaped” meansthat inhibition was observed followed by précipitation. A value followed by a number and x (i.e., 4x) means that the compound10 was tested four times, and each time the resuit was the same.
The invention compounds hâve also shown good activity in standardin vivo assays commonly used to evaluate agents to treat diseases related toaggregation of amyloid proteins, especially Alzheimer’s disease and otheramyloidoses. In one assay, amyloid protein is induced into the spleen of mice by 15 subcutaneous injections of silver nitrate, Freund’s complété adjuvant, and an intravenous injection of amyloid enhancing factor. Silver nitrate is administeredeach day through Day 11. Test compounds are administered to the mice dailystarting on Day 1 through Day 11. On Day 12, the animais are sacrificed, and thespleens are removed, histologically prepared, stained with Congo red, and the 20 percent area of the spleen occupied by biréfringent, Congo red-stained amyloid is 11963 -103- quantitated microscopically. Invention compounds evaluated in this test hâveinhibited spienic amyloid déposition by up to 70% relative to untreated Controls.
Another in vivo assay in which the invention compounds hâve beenevaluated uses transgenic mice. The mice bear a human β-amyloid precursor 5 protein transgene with a prion promoter and are described by Hsiao et al., “Corrélative memory déficits, Αβ élévation, and amyloid plaques in transgenicmice,” Science 1966;274:99-102. These transgenic mice develop β-amyloiddeposits at about 9 months of âge. By 15 months, diffuse and compact senileplaques are abundant, primarily in the neocortex, olfactory bulb, and 10 hippocampus. Invention compounds are administered orally to the mice beginningat the âge of 8 months (just prior to the onset of amyloid deposits) and continuingfor several months (up to about âge 14-1S months). The animais are thensacrificed, and the brains are removed. The amount of amyloid in the brain isquantitated both histologically and biochemically. Invention compounds evaluated 15 in this model hâve inhibited amyloid accumulation in the cortex and hippocampusby up to 49% relative to untreated Controls.
The above data establishes that représentative invention compounds areactive in standard assays used to measure inhibition of protein aggregation. Thecompounds exhibit excellent specificity, for example, as shown in the BASST 20 assay, as well as the BATYM and ΒΑΡΑ assays. The compounds are thus usefulto clinically inhibit amyloid protein aggregation and to image amyloid deposits fordiagnostic use. The compounds will be used in the form of phaimaceuticalformulations, and the following examples illustrate typical compositions. 1196 3 -104- EXAMPLE 164
Tablet Formulation
Ingrédient Amount Compound of Example 1 50 mg Lactose 80 mg Comstarch (for mix) 10 mg Comstarch (for paste) 8mg Magnésium Stéarate (1%) 2mg 150 mg
The compound of Example 1 is mixed with the lactose and comstarch (formix) and blended to uniformity to a powder. The comstarch (for paste) is 5 suspended in 6 mL of water and heated with stirring to form a paste. The paste isadded to the mixed powder, and the mixture is granulated. The wet granules arepassed through a No. 8 hard screen and dried at 50°C. The mixture is lubricatedwith 1% magnésium stéarate and compressed into a tablet. The tablets areadministered to a patient at the rate of 1 to 4 each day for prévention of amyloid 10 protein aggregation and treatment of Alzheimer’s disease. EXAMPLE 165
Parentéral Solution
In a solution of 700 mL of propylene glycol and 200 mL of water forinjection is added 20.0 g of Compound No. 19 (Example 19). The mixture is 15 stirred and the pH is adjusted to 5.5 with hydrochloric acid. The volume is adjusted to 1000 mL with water for injection. The solution is sterilized, filled into5.0 mL ampoules, each containing 2.0 mL (40 mg of Compound No. 19), andsealed under nitrogen. The solution is administered by injection to a patientsuffering from medullary carcinoma of the thyroid and in need of treatment 1196 3 -105- EXAMPLE 166
Patch Formulation
Ten milligrams of 2-{4-[3-(3,4-dichlorophenyl)propyl]phenylamino}benzoic acid is mixed with 1 mL of propylene glycol and 2 mg of acrylic-based 5 polymer adhesive containing a resinous cross-linking agent. The mixture is applied to an imperméable backing (30 cm-) and applied to the upper back of apatient for sustained release treatment of amyloid polyneuropathy.
The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise, and exact terms as to enable any person 10 skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the présentinvention and that modifications may be made therein without departing from thespirit or scope of the présent invention as set forth in the daims. To particulariypoint out and distinctly daim the subject matter regarded as invention, the 15 following daims conclude this spécification.

Claims (5)

1196 3 -106- CLAIMS What is claimed is:
1. Use of a compound of Formula I
O 8 10 Ra is hydrogen, Cj-Cg alkyl, or -CCj-Cg alkyl; n is 0 to 5 inclusive; RJ, R^, r3, r4? r5? r6} anj r7 gjg independently hydrogen, halogen, -OH, -NH2,NRbRc, -CO2H, -CO2C1-C6 alkyl, -NO2, -OCi-C12alkyl, -Cj-Cg alkyl, -CF3, -CN, -OCH2 phenyl, -OCH2-substituted 15 phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, O O I B -CH=CH-phenyl, -O(CH2)pNRbRC, -CNRbRc, -NHCRb,-NH(CH2)pNRbRC-N(Ci-C6alkylXCH2)pNRbRC /CH^OCj-Cg alkyl 20 “CH ; XCH7OCj-C6 alkyl R8 is COOH, tetrazolyl, -SO2Rd, or -CONHSO2Rd; Rb and Rc are independently hydrogen, -Cj-Cg alkyl, -(CH2)œ-phenyl, or Rb and Rc taken together with the nitrogen atom to which they areattached form a cycîic ring selected from piperidinyl, pyrrolyi, -107- imidazolyl, piperazinyi, 4-C|-Cg alkylpiperazinyl, morpholino,thiomorpholino, decahydroisoquinoline, or pyrazolyl; is hydrogen, -C}-Cg alkyl, -CF3, or phenyl;m is 0 to 5 inclusive;p is 1 to 5 inclusive; A is CH or N; RÎ and R-, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof, in the manufacture of a médicament for treating Alzheimer’s disease,
2. The use of Claim 1 whereinRa is hydrogen; n is 2; and R3 and are hydrogen.
3. The use of Claim 1 whereinRa is hydrogen; R^ and are hydrogen; andn is 2 to 5 inclusive.
4. The use of Claim 1 whereinRa is hydrogen; nis 2; R^ and R^ are hydrogen; and RÏ, R^, and R? are independently chlorine, -N(CH2CH3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl,-O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, •N[(CH2)3CH3]2> substituted phenyl, -OCH2- substituted phenyl, pyrrozolyl, or -N(phenyl)2· 1196 3 -108- 5 6. 5 6. 10 10 7. 15 7. 15 8. 20 8. 20 The use of Claim 1 wherein Ra is hydrogen; n is 3,4, or 5; R3 and R^ are hydrogen; and R1, R^, and R? are independently chlorine or hydrogen. The use of Claim 1 wherein Ra is hydrogen; n is 2; r3 and R^ are hydrogen; and r5, r6s and R“ are independently hydrogen, -CO2H, -NO2, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, halogen, -NH-Cj-Cg alkyl, -N(Cj-Cgalkyl)2, -NH2, orpyirolyl. The use of Claim 1 whereinRa is hydrogen;n is 2; R3 and R^ are hydrogen; andR5 is -CO2H. Use of a compound of Formula I R- wherein Ra is hydrogen; n is 1 to 5 inclusive; I 1196 3 -109- R3 and R4 are hydrogen; Rl, R?, and R- are independently chlorine, -N(CH2CH3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -00¾ phsnyl, -O(CH2)3N(CH3)2, -O phenyl, -O(CH2>7CH3, -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, -N[(CH2)3CH332, substituted phenyl, -OCH2-substituted phenyl,pyrazolyl, or -N(phenyl)2; R3 and R^ are independently hydrogen, -CO2H, -NO2, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; Rs is COOH or tetrazolyl; or the pharmaceutically acceptable salts thereof, in the manufacture of amédicament for treating Alzheimer’s disease.
9. The use of Claim ï 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)-ethyi3phenyiamino}benzo ic acid; 2- {4- [3-(3,4-Dichlorophenyl)propy ljphenylamino } -4-methoxy- 5-nitrobenzoic acid; 2-(4-(3-(3,4-Dichlorophenyl)propyl]phenylamino}-4-imidazo-l-yl-5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;2-{4-(4-(3,4-DichlorophenyI)butyl]phenylamino}benzoicacid; 2-{4-(4-(3,4-Dichloro-phenyl)-butyl j-phenylamino} -5-nitro- benzoic acid; 1196 3 -110- 2-(4-(4-(3,4-Dichlorophenyl}-butyî]phenylamino}- 3,5-dinitrobsnzoic acid; 2-(4-(5-(3,4-Dichlorophenyl)pentyl]phenylamino}-5-nitrobenzoic acid; 2-{4-[5-(3,4-Dichloro-phenyî)pentyl]phenylamino}-4-methoxy- 5-nitrobenzoic acid; 2-(4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro- benzoic acid; 2- {4-[2-(334-Difluoro-phenyl)-ethyl]-phenylamino }-5-nitro-benzoic acid; 2-(4-(2-(4-Chloro-3 -trifluoromethyl-phenyl)-ethyl]-phenylainino} -bsnzoic acid; 2-(4-(2-Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;5-Nitro-2-(4-phenethyî-phenylamino)-benzoic acid;2-(4-Phenethyl-phenylamino)-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyi]-phenylamino}-5-methoxy- benzoic acid; 2- (4-(2-(3,4-Dichloro-pheny l)-ethyl] -phenylamino} -terephthalic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylamino}-5-methyl-benzoic acid; 4- (4-(2-(3,4-Dichloro-pheny l)-ethyl]-phenylamino} -isophthalic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyî]-phenylaniino}-5-methanesulfonyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-pheny]>ethyï]-phenylamino}-5-imidazol-l-yl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylamino}-6-nitro-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl>ethyl]-phenylamino}-4-nitro-benzoic acid; 1196 3 -111- 2-{4-[2-(3,4-Dichloro-phenyl)-sthyl]-phenylamino}-3-nitro-benzoic acid;
5- Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 5 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino}-4,6-difluoro- benzoic acid; 6- {4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylainino}-2,3-difluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-fluoro-10 benzoie acid; 2-{4-[2-(3,4-Dichloro-phenyI)-eihyl]-phenylainino}-3-iluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-methyl-benzoic acid; 15 2- {4- [2-(3,4-Dichloro-phsny l)-ethy l]-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}-3-20 trifluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl}-phenylamino}-6-trifluoromethyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyi]-phenylamino}-5-trifluoromethyl-benzoic acid; 25 2- {4- [2-(3,4-Dichloro-phenyl)-ethyî]-phenylamino}-5-pyrrol-1 -yl- benzoic acid; 2-{4-[2-(4-Benzyloxy-phenyl)-ethyl]-phenylaniino}-benzoic acid;2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}- phenylamino)-benzoic acid; 30 2-{4-[2-(4-Diethylamino-phenyl)-ethyl3-phenylamino}-benzoic acid; 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Octyloxy-phenyl)-ethyî)-phenylamino}-benzoic acid; 1196 3 -112- 2-(4- (2-[4-(2-Ethoxy-1 -ethoxymethyl-ethyl)-phenyI3-ethyl}-phenylammo)-benzoic acid; 2-{4-[2-(4-Pyrrol-l-yl-phenyl)-ethyl]-phenylaiiûno}-benzoic acid;2-{4-{2-(4-Styryl-phenyl)-ethyl}-phenyiamino}-benzoic acid; 2- {4-[2-(4-Dibutylaxnino-phenyl)-ethylj-phenylamino}-benzoi c acid; 2-{4-(2-(4z-Ethyl-biphenyî-4-yl)-ethyi]-phenylamino}-benzoic acid; 2- (4-[2-(4-Octyl-phenyï)-ethyl]-phenylamino} -benzoic acid; 2-(4- {2-(3-(3,5-Dichloro~phenoxy)-phenyl]-£thyl} -phenylamino)- benzoic acid; 2-(4-{2-[4-(2-Chloro-6-fluoro-benzyloxy)-phenyl]-eîhyl}-phenylamino)-benzoic acid; 2- {4-[2-(4-Pyrazol-1 -yl-phenyl)-ethyl]-phenylamino }-benzoic acid; 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylaniino}-benzoic acid; 2-(4-(2-(4-(3,4-Dichloro-benzyloxy)-phenyl]-eîhyl}-phenylamino)-benzoic acid; 2- {4-(2-(3,4-Dichloro-phenyl)-ethyî]-phenylamino}-5-amiiio-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichlorophenyl)]phenylamino}-5-nitrobenzoic acid;2-(4-(3-(3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyI] phenylamino}-5-nitrobenzoic acid; 2-[[4-[2-(4-Chloro-3-triiluoromethyîphenyl)ethyl]phenyl]ainino-benzoic acid; or 2-(4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid. 119 6 3 -113-
10. Use of a compound of Formula I
Ra is hydrogen, Cj-Cg alkyl, or -CCj-Cg alkyl; 10 n is 0 to 5 inclusive; Rj, R^, r3, r4, r5; po, p7 îndependently hydrogen, halogen, -OH, -NH2, NRbRc, -CO2H, -CO^-Cg alkyl, -NO2, -OC]-C12 alkyl, -Cj-Cg alkyl, -CF2, -CN, -OCH2 phenyl, -OCH2-substituted phenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, 15 0 0 1 I -CH=CH-phenyl, -0(CH2)pNRbRc, -CNRbRc, -NHCRb,-NH(CH2)pNRbRc, -N(C i -C6alkyl)(CH2)pNRbRc, /CH*)OCj-Cg alkyl—GH " ; ^CH2OCrC6 alkyl 20 R8 is COOH, tetrazolyl, -SO2Rd, or -CONHSO2Rd; Rb and Rc are îndependently hydrogen, -Cj-Cg alkyl, -(CH2)m-phersyl, or Rb and Rc taken together with the nitrogen atom to which they areattached form a cyclic ring selected from piperidinyl, pyrrolyl,imidazolyî, piperazinyl, 4-C]-Cg alkylpiperazinyî, morpholino, 25 thiomorpholino, decahydroisoquinoline, or pyiazolyl; 1196 3 -134- Rd is hydrogen, -Cj-Cg alkyl, -CF3, orphenyl;m is 0 to 5 inclusive;p is 1 to 5 inclusive; A is CH or N; Rl and R^, when adjacent to one another, can be methylene-dioxy;or the pharmaceutically acceptable salts thereof, in the manufacture of amédicament for use in a method of inhibiting the aggregation of amyloidproteins to form amyloid deposits.
11. The use of Claim 10 wherein Ra is hydrogen;n is 2; and r3 and R^ are hydrogen.
12. The use of Claim 10 whereinRa is hydrogen; R^ and R^ are hydrogen; andn is 2 to 5 inclusive.
13. The use of Claim 10 whereinRa is hydrogen; nis 2; R3 and R^ are hydrogen; and R1, R^, and R? are independently chlorine, -N(CH2CH3)2, -OH, CH3-, fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl,-O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,-CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, N[(CH2)3CH3]2, substituted phenyl, -OCH2-substituted phenyl, pyrazolyl, or -N(phenyl)2.
14. The use of Claim 10 wherein 119 6 3 5 15. 5 15. 10 -115- 10 16. 16. 15 15 17. 20 17. 20 Ra is hydrogen; n is 3, 4, or 5; r3 and P/ are hydrogen; and Rl, R-, and R^ are independently chlorine or hydrogen. The use of Claim 10 wherein Ra is hydrogen; n is 2; r3 and R^ are hydrogen; and r5 and R° are independently hydrogen, -CO2H, -NO?, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, halogen,-NH-Cj-Cg alkyl, -N(C j-Cgalkyl^, -ΝΗ2, or pyrrolyl. The use of Claim 10 wherein Ra is hydrogen; nis 2; r3 and are hydrogen; andR8 is -CO2H. Use of a compound of Formula I
R- wherein Ra is hydrogen; n is 1 to 5 inclusive; i 119 6 3 -116- r3 and R4 are hydrogen; Rl, R^, and R^ are independently chlorine, -N(CH2CH3)2, -OH, CH3-,fluorine, -CF3, phenyl, hydrogen, -OCH2 phenyl, -O(CH2)3N(CH3)2, -O phenyl, -O(CH2)7CH3,
5 -CH(CH2OCH2CH3)2, pyrrolyl, -CH=CH-phenyl, -N[(CH2)3CH3]2, substituted phenyl, -OCH2-substitüted phenyl,pyrazolyl, or -N(phenyl)2*, r5 and are independently hydrogen, -CCbH, -NO2, -OCH3,imidazolyl, -CN, fluorine, -CH3, -CF3, or pyrrolyl; 10 R &amp; is COOH or tetrazolyl; Ais CH or N; Rl and R^, when adjacent to one another, can be methyiene-dioxy;or the pharmaceutically acceptable salts thereof, in the manufacture of amédicament for use in a method of inhibiting the aggregation of amyloidproteins to form amyloid deposits.
18. The use of Claim 17 wherein the compound of Formula I is: 15 2-((4-(2-(3,4-Dichlorophenyl)ethyl]phenyl]ammo-benzoic acid; 2-{4-(2-(3,4-Dichloro-phenyl)-ethyl]phenylamino}-5-nitroheiizoic acid; 2-{4-(4-(3,4-Dichloro-phenyl)-ethyl]phenylaimno}-4-methoxy-5-nitrobenzoic acid; 20 2-{4-(2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid; 2-{4-[2-{4-Dibutylarnino-phenyl)-ethyI]phenylamino}benzoic acid;2-{4-[2-(3,4,5-Trihydroxy-phenyl)-ethyl3phenylamino}benzoic acid; 2-{4-(3-(3,4-DichlorophenyI)propyl]phenyiamino}-4-methoxy- 5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)propyI]phenylamino}-4-imidazo- l-yl-5-nitrobenzoic acid; 2-{4-[3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoicacid;2-{4-[4-(3,4-Dichlorophenyl)buÎyl]phenylamino}benzoic acid; 11963 -117- 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-nitro-benzoic acid; 2-{4-(4-(3,4-Dichlorophenyl)-buÎyl]phenylamino}- 3,5-dinitrobenzoic acid; 2-{4-(5-(3,4-Dichlorophenyl)pentyl]phenylamino} -5-nitrobenzoic acid; 2-{4-(5-(3,4-Dichloro-pbenyl)pentyl]phenylamino}-4-methoxy-5-nitrobenzoic acid; 2-(4-(3,4-Dichloro-benzyl)-phenylamino]-bexizoic acid;2-{4-[2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro- benzoic acid; 2- {4-(2-(3,4-Difluoro-phenyî)-ethyl]-phenyiamino } -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-phsnylamino)-benzoic acid;2-(4-Phenethyl-phenyîamino)-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-methyI-·benzoic acid; 4-{4-(2-(3,4-Dichloro-phenyl)-ethy]]-phenylamino}-isophthalic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-eÎhyl]-phenylamino}-5-methanesulfonyl-benzoic acid; 2- {4-(2-(3 54-Dichloro-phenyl)-ethyl]-phenylamino}-5-imidazoî-l -yl-benzoic acid; 2-{4-(2-(3,4-Dichloro-phenyI)-ethyl]-phenylamino}-6-nitro-benzoic acid; Η9ί 3 -118- 2-(4-(2-(3,4-Dichloro-p’nsnyl)-ethyl}-phenylanùno}-4-nitro-bsnzoic acid; 2- {4- [2-(3,4-Dichloro-phsnyl)-ethyl]-phsny lamino} -3-nitro-benzoic acid;
5- Cyano-2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-{4-[2-(3,4-DichIoro-phenyl)-ethyl]-phsn.ylamino}-4,6-difluoro-benzoic acid; 6- {4-[2-(3,4-DichJoro-phcnyl)-ethyl]-phenylamino}-2,3-difluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-etbyl]-phenylamino}-6-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyî)-ethy]}-phenylamino}-3-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylaniino}-3-methyl-bsnzoic acid; 2-(4-(2-(3,4-Dichloro-phcnyî)-ethyl]-phenylamino}-4-fluoro-benzoic acid; 2-{4-[2-(3,4-Dichlon>-phenyl)-ethyIj-phenylamino}-3,5-difluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyî}-phenylamino}-3-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylaniino}-6-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-pbenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyî)-ethyl]-phenylamino}-5-pyrrol-î-yl-benzoic acid; 2-{4-[2-(4-Benzyloxy-phenyl)-eîhyl]-phenylaniino}-benzoic acid;2-(4-{2-[4-(3-Dimethylamino-propoxy)-phenyl]-ethyl}- phenylamino)-benzoic acid; 2-{4-(2-(4-Diethylarnino-phenyl)-ethyl]-phenylamino}-benzoic acid; 119 6 3 -119- 2- {4-[2-(4-Phenoxy-phenyl)-etnyl]-phenylamino} -benzoic acid; 2- {4-[2-(4-OciyIoxy-phenyl)-ethyl] -phenyiamino } -benzoic acid;2-(4-{2-[4-(2-Ethoxy-l-ethoxymethyî-ethyl)-phenyl]-ethyl}- phenylamino)-benzoic acid; 5 2-{4-[2-(4-Pyrroi-l-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] -phenyiamino } -benzoic 10 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}- 15 phenylamino)-benzoic acid; 2- {4- (2-(4-Pyrazol-1 -yl-pheny l)-ethyl]-pheny lamino } -benzoic acid; 2 - {4- (2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino) -benzoic acid; 20 2-(4-{2-[4-(3,4-Dichloro-benzyloxy)-phenyl}-ethyl}- phenylamino)-benzoic acid; 2- {4-(2-((3,4-Dichlorophenyl)propyî]phenylamino} -5-nitrobenzoic acid; 2-{4-[2-(354-Dimethyl-phenyl)-ethyl] phenylamino}-5- 25 nitrobenzoic acid; 2-[[4-[2-(4-Chloro-3-trifluoroinethylphenyl)ethyl3phenyl]amino- benzoic acid; or 2-[4-(3,4-Dichlorophenyl)phenyl]aminobenzoic acid.
19. The compounds; 30 2-{4-(4-(3,4-Dichloro-phenyI)-ethyï3phenylamino}-4-methoxy- 5-nitrobenzoic acid; 2-{4-[2-(3,4-Dihydroxy-phenyl)-ethyl]-phenylamino}benzoic acid; 11963 -120- 2-{4-[2-(4-Dibutylamino-phenyl)-ethyl]phenylamino}benzoic acid;2-(4-(2-(3,4J5-Trihydroxy-phenyl)-ethyl]phenylamino}benzoic acid; 2-(4-(3-(3,4-Dichlorophenyl)propyl)phenylanùno}-4-methoxy-5-nitrobenzoic acid; 2-{4- [3 -(3,4-Dichlorophenyl)propyl]phenylamino } -4-imidazo-l-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-niÎro-benzoic acid; 2-{4- [4-(3,4-Dichlorophenyl)-butyl]phenylammo} -3,5-dinitrobenzoic acid; 2-(4-(5-(3,4-DichlorophenyI)pentyl]phenylamino}-5-nitrobenzoic acid; 2- {4- [5-(3,4-Dichloro-phenyl)pentyl]phenylamino} -4-methoxy-5-nitrobenzoic acid; 2-(4-(3,4-Dichloro-benzyl)-phenylamino]-benzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyl]-phenylamino}-5-nitro- benzoic acid; 2-(4-(2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino} -5-niîro-benzoic acid; 2-(4-[2-(4-Chloro-3-trifluoromethyl-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-(2 -Biphenyl-4-yl-ethyl)-phenylamino]-5-nitro-ben2oic acid;5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid.2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenyIammo}-5-amino- benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-trifluoromethyl-benzoic acid; or 2-(4-(2-(3,4-Dichiorophenyl)]phenylamino}-5-nitrobenzoic acid. 119 6 3 -121-
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-(354-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]-pnenylamino}-5-methanesulfonyl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-iniidazoî-î-yl-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-6-nitro-benzoic acid; 2-{4-[2-(354-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)-ethyî]-phenylamino}-benzoic acid; 2-{4-[2-(3.4-Dichloro~phenyl)-ethyl]-phsnylamino}-4,6-difluoro-benzoic acid; 6- {4-[2-(354-Dichloro-phenyl)-eihyl]-phenyiamino}-2,3-diiluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-eihyl]-phenylamino}-6-iluoro-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3-fluoro-benzoic acid; -122- 2^(4-(2-(3,4-Dichloro-phenyl)-ethyî]-phenylamino}-3-m£thyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethy]]-phenylamino}-4-fluoro-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-3,5-difluoro-benzoic acid; 2-(4-(2-(3,4-Dichioro-phenyl)-ethy 1] -phenylamino } -3-trifluoromethyl-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl}-phenylammo}-ô-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)ethyI]pheny lamino} benzoic acid monohydrochloride; 2-{4-(2-(4-Diethylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride monohydrate; 2-(4-(3-(3-Dipropylaminophenyl)propyl]phenylamino}benzoic acid; 2- (4-(3-(3-Dimethylaminophenyl)propyî]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)ethyi}phenylamino}benzoic acid;2-{4-[3-(3-Diethyiaminophenyl)propyl3phenylamino}benzoic acid;2-{4-[2-(3-Aminophenyl)ethyl]phenylamino}benzoicacid;2-{4-(3-(4-Dimethylaminophenyl)propyi]phenylamino}benz.oic acid; 2-{4-(2-(4-Acetylaminophenyl)ethyl]phenylamino}benzoicacid; 119 6 3 ecT/t -123- 2-{4-[2-(3-Acetylaminophenyl)ethyl]phenylamino}benzoÎc acid;2-{4-[2-(3-Diprapylaminophenyl)ethyl]phenylaimno}banzoic acid monohydrochloride; 2-{4-[2-(3-Dibutylaminophenyl)ethyl]phenylamino}benzoic acidmonohydrochloride; 2-{4-[3-(4-Acetylaminophenyl)propyI]phenylamino}benzoic acid;2-{4-[3-(3-Acetylaminophenyl)propyl]phenylamino}benzoic acid;2-{4-[2-(3-Diethylaminophenyl)ethyl]phenylamino}benzoic acid monohydrochloride; 2-{4-[2-(3-Piperidin-l-ylphenyl)ethyl]phenylainino}benzoic acidmonohydrochloride; 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-( 1 H-Pyrrol-1 -y l)phenyl]propyl} phenylamino)benzoic acid; 2-{4-[3-(4-Piperidin-1 -ylphenyl)propyl]phenylamino}benzoic acid;2- {4-[3-(4-Diethylcarbamoylphenyl)propyl]phenylamino jbenzoic 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]pheriylamino}benzoic acid;2-{4-[3-(3-Propylaminophenyl)propyl]phenylamino}benzoic acid;2-{4-[3-(4-Pyrrolidin-l-yl-phenyl)-propyl]-phenylamino}-benzoic acid; 2-{4-[3-(3-Piperidin-1 yl-phenyl)-propyl]-phenylamino}-benzoic acid; {5-[(î -Butyl-1,2,3,4-tetrahydro-6-quinolyl)methylidene}-4-oxo-2-thioxothiazolidin-3-yl}acetic acid; {5-[(l-Butyl-2,3-dihydro-lH-indol-5-yl)methylidene]-4-oxo-2-thioxothiazo!idin-3-yl}acetic acid; 1 Î9 6 3 -124- 3- { 5-(( 1 -Butyl-1,2.3,4-tetrahydroquinoliri-6-yl)methy iidene]-4-oxo-2-thioxo-thiazoiidin-3-yl}propanoic acid;. 4- {5-[( 1 -Butyl-1,2,3,4-tetrahydroquinolin-6-yl)methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}butanoicacid; 5 2- {4-(3-(3,4-Dichloro-phenyl)-propyl]phenylamino}-5-methyl- benzoic acid; N-(2- {4-(3-(3,4-Dichloro-pheny l)-propyl]-phenylamino } -benzoyl)-methanesulofnamime; 2-{4-[2-(3,4-Dimethyl-phenyl)-ethyI]phenylamino}-5-nitro-î 0 benzoic acid; 2-[4-(2-Biphenyî-4-yl-ethyl)-phenylamino]-5-nitro-benzoic acid;2-{4-(2-(4-Chloro-3-trifiuoromethyl-phenyl)-ethyl}-phenyiamino}- 5-nitro-benzoic acid;
5-Amino-2-{4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-Î5 benzoic acid;
5-Nitro-2-(4-phenethyl-phenylamino)-benzoic acid;2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl]-phenyiamino}- benzoic acid; 2-{4-(2-(3,4-Difluoro-phenyl)-ethyl]-phenylamino}-5-nitro-20 benzoic acid; {4-(2-(3,4-Dichloro-phenyl)-ethyl3-phenyl}-[2-(lH-tetrazol-5-yI)-phenyl]-amine; 2-{4-[2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethyl)-phenylamino}-5-nitro-benzoic acid; 25 2-(4-Phenethyl-phenylamino)-benzoic acid; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylamino}-5-fluoro- benzoic acid; 2-(4-(2-(3,4-Dichioro-phenyl)-ethyl]-phenylamino}-nicotinic acid;2-{4-(2-(3-Chloro-phenyl)-ethyl]-phenylammo}-5-nitro-benzoic 30 acid; 2-{4-(2-(4-Chloro-phenyl)-ethyî]-phenylamino}-5-iiitro-benzoic acid; 119 6 3 -125- 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylainino}-5-inethyl-bsnzoic acid; 2-{4-[2-(2-Chloro-phenyl)-ethyl]-phenyiamino}-5-niÎro-benzoic acid; 5 2- {4-(2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino}-5-nitro- benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyI)-cthyl]-phcnylamino}-6-trifluoromethyl-benzoic acid; 2-{4-(2*(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-5-nitro- 10 benzoic acid; 2-{4-(2-(3,4-Dichloro-phenyî)-ethyî]-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-yI)-phenyl]-ethyl} - 15 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-ylanüno)-bçnzoic acid; 20 2-(2-Chioro-3',4'-diiluoro-biphenyl-4-ylamino)-benzoic acid; 2-(3'-Bromo-2-chloro-biphenyl-4-ylamino)-benzoic acid; 2- {4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylaniino}-5-rntro-benzoic acid; 3- {4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -benzoic acid; 25 5- {4-(2-(3,4-Dichloro-phenyl)-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; 30 2-{4-[2-(3-Chloro-4-meihyl-phenyl)-ethyl]-phenylamino }-3-nitro- benzoic acid; 119 6 3 -126- 3- {4-[2-(3-Chloro-4-methyl-pnenyl)-eîh :.]-phenylamino}-benzoic acid; 5-{4-[2-(3-Chloro-4-metiiyl-phenyl)-ethyî]-phenylamino}-isophthalic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyî]-phenyiamino}-benzoic acid; 4- (4-{2-[(4aS,8aR)-4-(Octahydro-isoquinolin-2-yl)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-[3-(4-Diethylamino-phenyl)-propyl]-phenylaniino}-5-methoxy-benzoic acid; 2-{4-[2-(3-Methoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(3-Bronio-phenyl)-etiiyl3-phenylammo}-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)-ethyI)-phenylamino}-nicotinic acid;2-[2-(4-Fluoro-3-trifluoromeÎhyl-phenyl)-2,3-dihydro-lH-isoindol- 5-ylamino]-benzoic acid; or 2-{4-[2-(3-Fluoro-4-methyl-phenyl)-ethyl]-phenylamino}-ben2oic acid.
23. The compounds: 2-{4-[2-(3,4-Dichloro-phenyl)-ethyI3-phenylaniino}-5-trifluoromethyl-benzoic acid; 2- {4-(2-(3,4-Dichioro-phenyl)-ethyl]-phenylamino } -5-pyrrol-1 -yi-benzoic acid; 2- {4-[2-(4-Benzyloxy-phenyl)-ethyI]-phenyIamino}-benzoic acid;2-(4-{2-[4-(3-Dimethylamino-propoxy)-phsnyI]-ethyl}- phenyiamino)-benzoic acid; 2-{4-[2-(4-Diethylamino-phenyl)-ethyl]-phenylamino}-bsnzoic acid; 2-{4-[2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid;2-{4-[2-(4-Octyloxy-pheny])-ethyl]-phenylamino}-benzoicacid; 119 6 3 -127- 2-(4-(2-(4-(2-Ethoxy-l-ethoxymethyl-ethyl)-phenyl]-ethyl}-phenylamino)-benzoic acid; 2-{4-(2-(4-Pyrrol-l-yl-phenyl)-ethyl]-phenylamino}-benzoic acid;or 5 2-{4-(2-(4-Styryl-phenyl)-ethyl]-phcnylamino}-benzoic acid.
24. The compounds: 2-(4-(2-(4-Dibutylamino-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-(2-(4'-Ethyl-biphenyl-4-yI)-ethyl]-phenylamino}-benzoic 10 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)-phenyi]-ethyl}-15 phenyîamino)-benzoic acid; 2- {4- [2-(4-Pyrazol-1 -yl-pheny l)-ethyl]-phenylamino} -bsnzoic acid; 2-{4-[2-(4-Diphenylamino-phenyl)-ethyl]-phenylamino} -benzoic acid; 20 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}-5-25 trifluoromethyî-benzoic acid; 2-(4-(2-(3,4-Dichiorophenyl)]phenylamino}-5-nitrobenzoic acid;2-(4-(2-((3,4-Dichlorophenyl)propyl]phenylamino}-5-nitrobenzoic acid; 2-(4-(2-(3,4-Dimethyl-phenyl)-ethyl3 phenylamino}-5-30 nitrobenzoic acid; 2-(4-(3,4-Dichlorophenyl)phenyl]aininobenzoic acid. E*l -128- 25. 2-[4-[2-(3,4-Dichlorophenyl)ethyl]phenyi]amino-ben2oic acid or aphannaceutically acceptable sait thereof. 26. 2-{4-[3-(3,4-Dichlorophenyl)propyl]phenylamino}ben2oic acid or aphannaceutically acceptable sait thereof.
27. A compound which is selected frôm: 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-Diethylammo-phenyl)-propyl]-phenylamino}-3-methoxy-benzoic acid; 2-{4-[2-(3-Chloro-4-methyl-phenyl)-ethyl]-phenylammo}-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)-propylj-phenylainino}-3-nitro-benzoic acid; 3- {4- [3-(4-Diethylamino-phenyl)-propyl]-phenylamino} -benzoic acid; 2-{4-[2-(3,4-Dimethoxy-phenyl)-ethyl]-phenylaniino}-benzoic acid; 2-{4-[2-(3,4-Dichloro-phenyl)-ethyl]-phenylaniino}-beiizoic acidmonosodium; 2-{4-[2-(354-Dichloro-phenyl)-ethyI]-phenylamino}-benzoic acidmonopotassium; 2-{4-[2-(3,4-E>ichloro-phenyl)-ethyî]-phenylaniino}-ben2oic acidcalcium sait (1:1); 2-{4-[2-(3ADich]oro-phenyl)-ethyl]-phenylainino}-benzoate-2-hydroxy-1 J-bis-hydroxymethyl-ethy Ι-ammonium; 2-{4-[4-(3,4-Dichloro-phenyl)-butyl]-phenylamino}-5-methoxy-benzoic acid; -129- 2-(4- [2-(3,4-Diiluoro-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 5 acid; 2-(4-(2-(2 -Chloro-phenyî)-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; 10 2-(4-(2-(2,4-Dichloro-phenyl)-ethyl]-phenylamino)-benzoic acid; 3- (4- [2-(3,4-Dichloro-phenyl)-ethyl]-phenylammo } -benzoic acid; 4- (4-(2-(3,4-Dichloro-phenyl)-ethyI]-phenylamino}-benzoic acid;2-(4-(2-(3,4,5-Trimethoxy-phsnyl)-ethyl]-phenylamino}-benzoic acid; 15 2-(4-(2-(4-Phenoxy-phenyl)-ethyl]-phenylamino}-benzoic acid; 2-(4-(5-(3,4-Dichloro-phenyî)-pentyl]-phenylamino}-benzoic acid;2-(3',5'-Dichloro-biphenyl-4-yiamino)-benzoic acid; 4- (4-(3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-2-methoxy- 5-nitro-benzoic acid; 20 2-(4-(3-(3,4-Dichloro-phenyl)-propyl]-phenylamino} -5-fluoro- benzoic acid;
5- Amino-2-(4-(5-(3,4-dichloro-phenyl)-pentyl3-phenylamino}-benzoic acid; N-(2-(4-[3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl}- 25 C,C,C-trifluoro-methanesulfonamide; N-(2-(4-(3-(3,4-Dichloro-phenyl)-propyl]-phenylamino}-benzoyl)- benzenesulfonamide; 2-(4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino} -5-trifluoromethyl-benzoic acid; 30 4-(4-(2-(3,4-Dich]oro-phenyl)-ethyi]-phenylamino}-isophthalic acid; 1Î963 -130- 2- {4-(2-(3,4-Dichloro-phenyl)-ethyl]-phenylamino}-4-trifluoromethyl-benzoic acid; 2- {4-(2-(3,4-Dicbloro-phenyl)-ethyl]-phenylaniino}-3-trifluoromethyl-benzoic acid; 5 2-( {4- (2-(3,4-Dichloro-phenyl)-ethyl]-phenyl} -methyl-amino)-5- 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} -5-10 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; 15 2,2'-[l,2-Ethanediylbis (4,l-phenyleneimino)]bis-benzoic acid; and 4-[3-[4-(Diethylamino)phenyl]propyl3-N-(2-methoxy-5- nitrophenyl)-benzinamine
28. Use of a labeled compound having the Formula I or a pharmaceutically20 acceptable sait thereof:
Ra is hydrogen, Cj-Cg alkyl, or -CCi-Cg alkyl; n is 0 to 5 inclusive; 119 6 3 -131- Rl, R2, R2, R4, R5, R6, and R2 are independentiy hydrogen, halogen, -OH, -NH2, NRbRc, -CO2H, -ŒbCi-Cg alkyl, -NO2, -OC]-Ci2alkyl, -Cj-Cg alkyl, -CF3, -CN, -00¾ phenyl, -OCH2-substitutedphenyl, -(CH2)m-phenyl, -O-phenyl, -O-substituted phenyl, O O 8 B -CH=CH-phenyl, -O(CH2)pNRbRc, -CNRbRc, -NHCRb, -NH(CH2)pNRbRc,-N(C1-C6alkyl)(CH2)pNRbRc, /C^OCj-Cq alkyl—-CH ; X‘CH2OC1-C6 alkyl RS is COOH, xetrazolyl, -SO2R^, or -CONHSO2Rd; Rb and Rc are independentiy hydrogen, -CpCg alkyl, -(CH2)m-phenyl, or Rb and Rc taken together with the nitrogen atom to which they areattached form a cyciic ring selected from piperidinyi, pyrrolyl,imidazolyl, piperazinyl, 4-C]-Cg alkylpiperazinyl, morpholino,thiomorpholino, decahydroisoquinoline, or pyrazolyl; Rd is hydrogen, -CpCg alkyl, -CF3, or phenyl;m is 0 to 5 inclusive;p is 1 to 5 inclusive; A is CH or N; Rl and R2, when adjacent to one another, can be methylene-dioxy; or the pharmaceutically acceptable salts thereof, in the manufacture of a médicament for use in a method of imaging amyloid deposits.
29. The use of Claim 28 wherein the patient has or is suspected to hâveAlzheimer’s disease. 1196 3 -132-
30. The use of Claim 28 wherein the labeled compound is a radio labeled compound.
31. The use of Claim 28 wherein the labeled compound is detected usingMRI.
32. The compounds: 2-(4-(2-(3,4-Dichlorophenyl)ethyl3phenyl]amino-benzoic acid; 2- {4-(2-(3,4-Dichloro-phenyl)-ethyl)phenylamino}-5-nitrobenzoicacid; 2-{4-(3-(3,4-Dichlorophenyl)-propyl]phenylamino}benzoic acid;î 0 2-[4-[2-(4-Chloro-3 -trifluoromethy lphenyl)ethyl}phenyl]amino- benzoic acid; and 2-{4-[3-(4-Diethylaminophenyl)propyIjphenylamino}benzoic acid.
33. A phaimaceutical formulation comprising a compound of Claim 19 admixed with a phannaceutically acceptable diluent, excipient, or carrier 15 therefor.
34. A pharmaceutical formulation comprising a compound of Claim 20 admixed with a phannaceutically acceptable diluent, excipient, or carriertherefor.
35. A pharmaceutical formulation comprising a compound of Claim 2120 admixed with a phannaceutically acceptable diluent, excipient, or carrier therefor.
36. A pharmaceutical formulation comprising a compound of Claim 22 admixed with a phannaceutically acceptable diluent, excipient, or carriertherefor. -133-
37. A pharmaceutical formulation comprising a compound of Claim 23admixed with a pharmaceutically acceptable diluent, excipient, or carriertherefor.
38. A pharmaceutical formulation comprising a compound of Claim 24 5 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.
39. A pharmaceutical formulation comprising a compound of Claim 25admixed with a pharmaceutically acceptable diluent, excipient, or carriertherefor. 10 40. A pharmaceutical formulation comprising a compound of Claim 26 admixed with a pharmaceutically acceptable diluent, excipient, or carriertherefor.
41. A pharmaceutical formulation comprising a compound of Claim 32 admixed with a pharmaceutically acceptable diluent, excipient, or carrier 15 therefor.
42. A compound of Formula I.
O 20 S Ra is hydrogen, Cj-Cg alkyl, or -CCj-Cg alkyl;n is 0 to 5 inclusive; R1, R^, r3, r4, r5# r6? p7 independently hydrogen, halogen, -OH, -NH2, NRbRC, -CO2H, -CO2CI-C6 alkyl, -NO2, -OCi -CI2 119 6 3 -134- alkyl, -Cj-Cg alkyl, -CF3, -CN, -OCH2 phenyl, -OCH^-substitutsd „ ( phenyl, -(CH^m-phenyl, -O-phenyl, -O-substituted phenyl, O O . 1 S
5 -CH=CH-phenyl, -Û(CH2)pNRbRc, -CNRbRc, -NHCRb, -NH(CH2)pNRbRc, -N(Ci-C6aIkyl)(CH2)pNRbRc, /C^OCj-^ alkyl—CH . ^CH2OCrC6 alkyl R8 is COOH, tetrazolyl, -SO2Rd, or -CONHSO2Rd; Rb and Rc are independently hydrogen, -C]-Cg alkyl, -(CH2)m-phenyl, or 10 Rb and Rc taken together with the nitrogen atom to which they are attached form a cyclic ring seîected from piperidinyl, pyrrolyl,imidazolyl, piperazinyl, 4-Cj-Cg alkylpiperazinyl, morpholino,thiomorpholino, decahydroisoquinoline, or pyrazolyl; Rd is hydrogen, -Cj-Cg alkyl, -CF3, or phenyl; 15 m is 0 to 5 inclusive; p is 1 to 5 inclusive; Ais CH or N; Rl and R^, when adjacent to one another, can be methylene-dioxy;or the pharmaceutically acceptable salts thereof. 20 43. A phannaceutical formulation comprising a compound of Claim 42 admixed with a pharmaceutically acceptable diluent, excipient, or carriertherefor.
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