SK17632001A3 - A drug for the treatment of Alzheimer's disease, method of inhibiting amyloid protein aggregation and imaging amyloid deposits - Google Patents

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

Medicinal treatment of Alzheimer's disease, inhibition of amyloid protein aggregation and method for imaging amyloid deposits

Technical field

The present invention relates to a method for inhibiting amyloid protein aggregation and for displaying amyloid deposits. More specifically, the invention relates to a method for inhibiting aggregation of amyloid protein for the treatment of Alzheimer's disease.

BACKGROUND OF THE INVENTION

Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrous proteins in patient tissues. Fibrous proteins that form accumulations or deposits are referred to as amyloid proteins. While the type of peptides or proteins in the deposits may vary, the presence of filamentous morphology and a large amount of secondary β-sheet structure is common to many types of amyloid. The amyloid deposit is formed by deposition of amyloid proteins, followed by a further combination of aggregates and / or amyloid proteins.

The presence of amyloid deposits has been shown in many diseases, each of which is associated with a particular protein, such as Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis, amyloidosis Alzheimer's disease, Down's syndrome, scrapie, CreutzfeldJakobova disease, Kuru, Gerstmann-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, isolated atrial amyloid, p 2 -microglobulin amyloid in dialysis patients, inclusion body myositis of 3 ₂ -amyloidové deposits in diseases of the dissolution of muscle, sickle cell anemia, Parkinson's disease and insulin in type II diabetes.

Alzheimer's disease is a degenerative brain disease characterized by a clinically progressive loss of memory, cognitive ability, thinking, judgment, and emotional stability, which gradually leads to mental retardation and eventually death occurs. Since Alzheimer's disease and related degenerative diseases of the brain are a major problem in a population of ever-increasing age, there is a need for methods for the treatment and diagnosis of these diseases.

A non-invasive method for detecting and quantifying amyloid patient deposits is urgently needed. Currently, the detection of amyloid deposits is performed by histological examination of biopsy or autopsy specimens. Autopsy can only be used for post-mortem diagnosis.

Direct imaging of aymloid deposits in vivo is difficult because the deposits have many of the same physical properties (e.g. density and water content) as normal tissues. Attempts at imaging amyloid deposits using magnetic resonance imaging (NMR) and computed tomography (CAT) have been disappointing and have detected amyloid deposits only in some very favorable cases. Furthermore, attempts to label amyloid deposits with antibodies, serum amyloid P protein, or other labeling molecules showed some selectivity on the periphery of the tissues but did not allow the imaging of the interior of the tissue.

Therefore, it would be useful to have a non-invasive technique for imaging and quantifying amylord deposits of a patient.

Furthermore, it would be useful to have compounds that inhibit the aggregation of amyloid proteins forming amyloid deposits.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I)

where 0

II

R ^a is hydrogen, C 1 -C 8 alkyl or -C 1 -C 8 alkyl;

n is 0 to 5 inclusive;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH,

-NH ₂ , NR ^b R ^c , -CO ₂ H, -CO ₂ C 1 -C ₆ alkyl, -NO ₂ , -OC 1 -C ₁₂ alkyl, -C 1 -C 6 alkyl, -CF ₃ , -CN, -OCH ₂ phenyl , -OCH ₂ substituted phenyl, - (CH ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl,

0

II _b 1

-0 _{(CH2) p} NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -N (Ci-6 alkyl) (CH _{2) p} NR ^b R ^c, / CH ₂ OC _{r 6} alkyl

-CH;

C1-C10-C8 alkyl

R ⁸ is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ;

R ^b and R ^c are independently hydrogen, -C 1 -C 6 alkyl, - (CH ₂ ) _m -phenyl or R ^b and

R ^c together with the nitrogen atom to which they are attached form a cyclic ring selected from the group consisting of piperidyl, pyrrollyl, imidazolyl, piperazinyl, 4-C 1 -C ₆ alkylpiperazinyl, morpholine, thiomorpholine, decahydroisoquinoline or pyrazolyl; ¹ ,

R ^d is hydrogen, -C 1 -C ₆ alkyl, -CF ₃ or phenyl;

m is 0 to 5 inclusive;

p is 1 to 5 inclusive;

A is CH or N;

R ¹ and R ² , when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment of Alzheimer's disease.

In a preferred embodiment, the group is

attached at the 4-position of the phenyl ring.

In a preferred embodiment of the compounds of formula (I): R ^a represents hydrogen; n is 2; and

R ³ and R ⁴ are hydrogen.

In a preferred embodiment of the compounds of formula (I): R ^a represents hydrogen;

R ¹ is halo;

R ² is hydrogen or halogen;

R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen; and n is 2 to 5, inclusive.

In another preferred embodiment of the compounds of formula (I)

R ^a is hydrogen;

n is 2 or 3;

R ¹ is -NR ^b R ^c ; and

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are all hydrogen.

In another preferred embodiment of the compounds of formula (I)

R ^a is hydrogen;

n is 2 or 3;

R ³ and R ⁴ are hydrogen; and

R ¹ , R ² and R ⁷ independently represent chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) ₃ N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl,

N ((CH ₂ ) ₃ CH ₃ ] ₂ , substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ .

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen;

n is 3, 4 or 5;

R ³ and R ⁴ are hydrogen; and

R ¹ , R ² and R ⁷ are independently chlorine or hydrogen.

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen; n is 2;

R ³ and R ⁴ is hydrogen Znamenaj account; and

R ⁵ , R ⁶ and R ⁸ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH ₃ , imidazolyl, -SCH ₃ , -CN, fluoro, -CH ₃ , -CF ₃ , halogen

-NH-C 1 -C ₆ alkyl, -N (C 1 -C ₆ alkyl) ₂ , -NH ₂ or pyrrolyl.

In a preferred embodiment of the compounds of formula (I): R ^a represents hydrogen; n is 2;

R ³ and R ⁴ are hydrogen; and

R ⁵ represents -CO ₂ H.

Also preferred are compounds of formula (I)

R

(CH ₂ )

where

R ^a is hydrogen;

n is 1 to 5 inclusive;

R ³ and R ⁴ are hydrogen;

R ¹ , R ¹ and R ² are independently chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH 3, fluoro, -CF 3, phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) 3 N ( CH 3) ₂ , -O-phenyl, -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl, N [(CH ₂ ) 3 CH 3] ₂ , substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ ;

R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH 3, imidazolyl, -CN, fluoro, -CH ₃ , -CF ₃ or pyrrolyl;

or a pharmaceutically acceptable salt thereof for use as a medicament for the treatment of Alzheimer's disease.

In a preferred embodiment, the compounds of formula (I) are: 2- {4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (3,4-Dichlorophenyl) ethyl] phenylamino} -5-nitrobenzoic acid;

2- {4- [4- (3,4-Dichlorophenyl) ethyl] phenylamino} -4-methoxy-5-nitrobenzoic acid;

2- {4- [2- (3,4-Dihydroxyphenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (4-Dibutylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (3,4,5-trihydroxyphenyl) ethyl] phenylamino} benzoic acid;

2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino] -4-methoxy-5-nitrobenzoic acid;

2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino] -4-imidazo-1-yl-5-nitrobenzoic acid;

2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino] -benzoic acid;

2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -benzoic acid; 2- {4- [4- (3,4-Dichlorophenyl) butyl] phenylamino] -5-nitrobenzoic acid;

2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino] -3,5-dinitrobenzoic acid;

2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino] -5-nitro-benzoic 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-nitrobenzoic acid;

2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid;

2- {4- [2- (4-Chloro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -5-nitrobenzoic acid;

5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid; 2- (4-Phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid;

2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} terephthalic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid;

4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methanesulfonyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-imidazol-1-yl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-nitro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-nitro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid;

5-Cyano-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,6-difluoro-benzoic acid;

6- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -2,3-difluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-methyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -3,5-difluoro-benzoic acid;

2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -3-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -6-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-pyrrol-1-yl-benzoic acid;

2- {4- [2- (4-Benzyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (3-dimethylamino-propoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-diethylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (2-ethoxy-1-ethoxymethyl-ethyl) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-pyrrol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Styryl-phenyl) -ethyl] -phenylamino) -benzoic acid;

2- (4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino) -benzoic acid;

2- {4- [2- (4-ethyl-biphenyl-4-yl) -ethyl) -phenylamino} -benzoic acid;

2- {4- [2- (4-octyl-phenyl) -ethyl] -phenylamino) -benzoic acid; 2- (4- {2- [3- (3,5-Dichloro-phenoxy) -phenyl] -ethyl) -phenylamino) -benzoic acid;

2- (4- {2- [4- (2-Chloro-6-fluoro-benzyloxy) -phenyl] -ethyl) -phenylamino) -benzoic acid;

2- {4- [2- (4-pyrazol-1-yl-phenyl) -ethyl] -phenylamino) -benzoic acid;

2- {4- [2- (4-Diphenylamino-phenyl) -ethyl] -phenylamino) -benzoic acid;

2- (4- {2- [4- (3,4-Dichloro-benzyloxy) -phenyl] -ethyl) -phenylamino) -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-amino-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -5-trifluoromethyl-benzoic acid;

2- (4- [2- (3,4-dichlorophenyl)] phenylamino) -5-nitrobenzoic acid;

2- {4- [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] phenyl] amino-benzoic acid;

2- {4- [3- (4-diethylaminophenyl) propyl] phenylamino) benzoic acid;

2- {4- [3- (4-nitrophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (3-nitrophenyl) propyl] phenylamino) benzoic acid; 2- {4- [3- (4-Aminophenyl) propyl] phenylamino) benzoic acid;

2- {4- [3- (3-Aminophenyl) propyl] phenylamino} benzoic acid 2- {4- [2- (4-aminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (4-Dipropylaminophenyl) ethyl] phenylamino} -benzoic acid, monohydrochoride;

2- {4- [2- (4-diethylaminophenyl) ethyl] phenylamino} -benzoic acid, monohydrochoride, monohydrate;

2- {4- (3- (3-dipropylaminophenyl) propyl] phenylamino} -benzoic acid;

2- {4- [3- (3-dimethylaminophenyl) propyl] phenylamino} benzoic acid;

2- (4- [3- (4-ethylaminophenyl) propyl] phenylamino} benzoic acid;

2- (N- {4- [3- (4-diethylaminophenyl) propyl] phenyl} -N-ethylamino) benzoic acid;

2- {4- [2- (3-Dibenzylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [3- (3-diethylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [2- (3-Aminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [3- (4-dimethylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [2- (4-Acetylaminophenyl) ethyl] phenylamino} benzoic acid;

2- (4- [2- (3-acetylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (3-dipropylaminophenyl) ethyl] phenylamino} benzoic acid, monohydrochloride;

2- {4- [2- (3-Dibutylaminophenyl) ethyl] phenylamino} benzoic acid monohydrochloride;

2- {4- [3- (4-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-yl-phenyl) -ethyl] -phenylamino} -benzoic acid monohydrochloride;

2- {4- [3- (4-Dipropylamino-phenyl) -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- (ΙΗ-pyrrol-1-yl) phenyl] propyl} phenylamino) benzoic acid;

2- {4- [3- (4-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (4-diethylcarbamoylphenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-carboxyphenyl) propyl] phenylamino} benzoic acid 2- {4- [3- (4-diethylaminomethylphenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-propylaminophenyl) propyl} phenylamino} benzoic acid;

2- {4- [3- (3-propylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-Pyrrolidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (3-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (4- [2-diethylaminoethylamino] phenyl) propyl] phenylaminobenzoic acid;

2- {4- [2- (4-hydroxycarbonylmethylamino) phenyl] ethyl] phenylamino} benzoic acid;

2- {4- [2- (4- [2-diethylaminoethylamino] phenyl) ethyl] phenylamino} benzoic acid;

2- {4- [3- (4-Morpholinophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-Piperazinylphenyl) propyl] phenylamino) benzoic acid; and 2- [4- (3,4-dichlorophenyl) phenylamino] benzoic acid.

The invention also provides the following compounds in which benzoic acid is replaced by pyridylcarboxylic acid, for example 4- [4- (3,4-dichlorophenyl) phenylamino] -3-hydroxycarbonylpyridine.

The invention also provides compounds of formula (I)

where ||

R ^a is hydrogen, C 1 -C ₆ alkyl or -C 1 -C ₆ alkyl;

n is 0 to 5 inclusive;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH,

-NH ₂ , NR ^b R ^c , -CO ₂ H, -CO ₂ C 1 -C ₆ alkyl, -NO ₂ , -OC 1 -C ₁₂ alkyl, -C 1 -C 6 alkyl, -CF ₃ , -CN, -OCH ₂ phenyl , -OCH ₂ substituted phenyl, - (CH ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl,

-O (CH ₂ ) _p NR ^b R ^c , -CNR ^b R ^c , alkyl) (CH ₂ ) _p NR ^b R ^c ,

-NHCR ^b , -NH (CH 2) p NR R ^b R ^c , -N (C 1 -C ₆ 13 yC 1 O ₆ -C 1 -C 6 alkyl-CH 2 _;

C 1 -C 6 -C 8 alkyl

R ⁸ is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ;

R ^b and R ^c are independently hydrogen, -C 1 -C 6 alkyl, - (CH 2) m -phenyl, or R ^b and R ^c together with the nitrogen atom to which they are attached form a cyclic ring selected from the group consisting of piperidyl, pyrrollyl, imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholine, thiomorpholine, decahydroisoquinoline or pyrazolyl;

R ^d is hydrogen, -C 1 -C ₆ alkyl, -CF 3 or phenyl;

m is 0 to 5 inclusive;

p is 1 to 5 inclusive;

A is CH or N;

R ¹ and R ² , when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof, for use as a medicament for inhibiting aggregation of amyloid proteins to form amyloid deposits.

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen;

n is 2; and

R ³ and R ⁴ are hydrogen.

In another preferred embodiment of the compounds of formula (I)

R ^a is hydrogen;

R ³ and R ⁴ are hydrogen; and n is 2 to 5, inclusive.

In another preferred embodiment of the compounds of formula (I)

R ^a is hydrogen;

n is 2;

R ³ and R ⁴ are hydrogen; and

R ¹ , R ² and R ⁷ independently represent chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) 3N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl,

N [(CH ₂ ) ₃ CH ₃ ] ₂ , substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ .

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen;

n is 3, 4 or 5;

R ³ and R ⁴ are hydrogen; and

R ¹ , R ² and R ⁷ are independently chlorine or hydrogen.

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen;

n is 2;

R ³ and R ⁴ are hydrogen; and

R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH ₃ , imidazolyl, -CN, fluoro, -CH ₃ , -CF ₃ , halogen, -NH-C 1 -C ₆ alkyl, -N (C 1 -C 6 alkyl) ₂ , -NH _2, or pyrrolyl.

In a preferred embodiment of the compounds of formula (I):

R ^a is hydrogen;

n is 2;

R ³ and R ⁴ are hydrogen; and

R ⁵ represents -CO ₂ H.

The invention also provides compounds of formula (I)

where

R ^a is hydrogen;

n is 1 to 5 inclusive;

R ³ and R ⁴ are hydrogen;

R ¹ , R ⁷ and R ² are independently chlorine,

-N (CH ₂ CH ₃ ) ₂ , -OH, —CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) ₃ N (CH ₃ ) ₂ , -O-phenyl , -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl, N [(CH ₂ ) ₃ CH ₃ ] ₂ , substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ ;

R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH ₃ , imidazolyl, -CN, fluoro, -CH ₃ , -CF ₃ or pyrrolyl;

R ⁸ is COOH or tetrazolyl;

or a pharmaceutically acceptable salt thereof, for use as a medicament for inhibiting aggregation of amyloid proteins to form amyloid deposits.

The most preferred compounds of the present invention are compounds of formula (II):

COOH and pharmaceutically acceptable salts thereof, wherein

R ¹ is halo;

R ² is H or halogen; and R ⁶ are as defined for formula (I).

Another preferred group of compounds of the present invention are compounds of formula (III):

and pharmaceutically acceptable salts thereof, wherein

R ¹ is halo;

R ² is H or halogen; and R ⁶ are as defined for formula (I).

Another preferred group of compounds of the present invention are compounds of formula (IV):

and pharmaceutically acceptable salts thereof, wherein

R ¹ is halo;

R ² is H or halogen; and R ⁶ are as defined for formula (I).

In a preferred embodiment, the invention provides novel compounds of formula (I) which are:

2-} 4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid;

2- {4- [4- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid;

2- {4- [2- (3,4-Dihydroxy) ethyl] phenylamino} -benzoic acid; 2- {4- [2- (4-Dibutylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (3,4,5-trihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-methoxy-5-nitrobenzoic acid;

2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-imidazo-1-yl-5-nitrobenzoic acid;

2- {4- [2 - [- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid;

2- (4- [4- (3,4-dichlorophenyl) butyl] phenylamino} benzoic acid 2- (4- [4- (3,4-dichlorophenyl) butyl] phenylamino} -5-nitro acid benzoic acid;

2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino} -3,5-dinitrobenzoic acid;

2- {4- [5- (3,4-Dichloro-phenyl) -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-nitro18 acid

benzoic acid;

5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid; 2- (4-Phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -terephthalic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid;

4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methanesulfonyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-imidazol-1-yl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-nitro-benzoic acid;

2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-nitro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid;

5-Cyano-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,6-difluoro-benzoic acid;

6- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -2,3-difluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-methyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-fluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3,5-difluoro-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-pyrrol-1-yl-benzoic acid;

2- {4- [2- (4-Benzyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4 {2- [4- (3-dimethylamino-propoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-diethylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (2-ethoxy-1-ethoxymethyl-ethyl) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-pyrrol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- [2- (4-styryl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4'-Ethyl-biphenyl-4-yl) -ethyl] -phenylamino} -benzoic acid; .

2- {4- [2- (4-octyl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- (2- [3- (3,5-dichloro-phenoxy) -phenyl] -ethyl} -20-phenylamino) -benzoic acid;

2- (4- {2- [4- (2-Chloro-6-fluoro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-pyrazol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Diphenylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (3,4-Dichloro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2 - [(3,4-dichlorophenyl) propyl] phenylamino} -5-nitrobenzoic acid;

2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid;

2 - [[4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] aminobenzoic acid; or 2- [4- (3,4-dichlorophenyl) phenyl] aminobenzoic acid.

The following compounds are also an object of the present invention:

2- {4- [4- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid;

2- {4- [2- (3,4-Dihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (3,4,5-trihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-methoxy-5-nitrobenzoic acid;

2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-imidazo-1-yl-5-nitrobenzoic acid;

2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino-benzoic acid; 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -521

nitrobenzoic acid;

2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -3,5-dinitrobenzoic acid;

2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -5-nitrobenzoic acid; 1 2- (4- [5- (3,4-dichlorophenyl) 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-nitrobenzoic acid;

5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-amino-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl)] -phenylamino} -5-nitrobenzoic acid;

2- (4-Phenethyl-phenylamino) -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; .

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino}-terephthalic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid;

4- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid;

2- {4- [2- (3,4-Dichloro-methanesulfonyl-benzoic acid);

2- {4- [2- (3,4-Dichloro-imidazol-1-yl-benzoic acid);

2- {4- [2- (3,4-Dichloro-nitro-benzoic acid);

2- {4- [2- (3,4-Dichloro-nitro-benzoic acid);

2- {4- [2- (3,4-dichloro) acid

nitrobenzoic acid;

5-cyano-2- {4- [2- (3,4

phenylamino} benzoic acid;

2- {4- [2- (3,4-dichloro) acid

difluoro-benzoic acid;

6- {4- [2- (3,4-dichloro) acid

difluoro-benzoic acid;

2- {4- [2- (3,4-dichloro) acid

fluoro-benzoic acid;

2- {4- [2- (3,4-dichloro) acid

fluoro-benzoic acid;

2- (4- [2- (3,4-dichloro) acid)

-methyl-benzoic;

2- {4- [2- (3,4-dichloro) acid

fluoro-benzoic acid;

2- {4- [2- (3,4-dichloro) acid

difluoro-benzoic acid;

2- {4- [2- (3,4-dichloro) acid

-trifluoromethylbenzoic acid;

2- {4- [2- (3,4-dichloro) acid

trifluoromethyl-benzoic acid;

2- {4- [2- (3,4-Dichloro-trifluoromethyl-benzoic acid);

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-phenyl) -ethyl] -phenylamino} -5-phenyl) -ethyl] -phenylamino} -6-phenyl) -ethyl] -phenylamino} - 4 phenyl) -ethyl] -phenylamino} -3 dichloro-phenyl) -ethyl] phenyl) -ethyl] -phenylamino} -4,6-phenyl) -ethyl] -phenylamino} -2,3-phenyl) -ethyl] -phenylamino} -6-phenyl) -ethyl] -phenylamino} -3-phenyl) -ethyl] -phenylamino} -3-phenyl) -ethyl] -phenylamino} -4-phenyl) -ethyl] -phenylamino} -3,5-phenyl) -ethyl] -phenylamino} -3 • phenyl) -ethyl] -phenylamino} -6-phenyl) -ethyl] -phenylamino} -5 • phenyl) -ethyl] -phenylamino} -523

pyrrol-1-yl-benzoic acid;

2- {4- [2- (4-Benzyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (3-dimethylamino-propoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-diethylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid 2- {4- [2- (4-octyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (2-ethoxy-1-ethoxymethyl-ethyl) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (4-pyrrol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- (4-Styryl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- {4- [2- ^(1-ethyl 4-biphenyl-4-yl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (4-octyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2- [3- (3,5-Dichloro-phenoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- (4- {2- [4- (2-chloro-6-fluoro-benzyloxy) -phenyl] -ethyl} -phenylamino-benzoic acid;

2- {4- [2- (4-pyrazol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- [2- (4-Diphenylamino-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (4- {2- [4- (3,4-Dichloro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-amino-benzoic acid;

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -524 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-trifluoromethyl-phenyl) -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) propyl] phenylamino} benzoic acid 2- {4- [2- ( 4-Aminophenyl) ethyl] phenylamino} benzoic acid 2- {4- [2- (4-dipropylaminophenyl) ethyl] phenylamino} benzoic acid monohydrochloride;

2- {4- [2- (4-diethylaminophenyl) ethyl] phenylamino} benzoic acid monohydrochloride monohydrate;

2- (4- [3- (3-dipropylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (3-dimethylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-ethylaminophenyl) propyl] phenylamino} benzoic acid;

2- (N- {4- [3- (4-diethylaminophenyl) propyl] phenyl} -N-ethylamino) benzoic acid;

2- {4- [2- (3-Dibenzylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [3- (3-diethylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [2- (3-Aminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [3- (4-dimethylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [2- (4-Acetylaminophenyl) ethyl] phenylamino} benzoic acid;

2- (4- [2- (3-acetylaminophenyl) ethyl] phenylamino} benzoic acid;

2- {4- [2- (3-Dipropylaminophenyl) ethyl] phenylamino} benzoic acid, monohydrochloride;

2- {4- [2- (3-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid monohydrochloride;

2- {4- [3- (4-Acetylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (3-Acetylaminophenyl) propyl]] phenylamino} benzoic acid;

2- {4- [3- (3-diethylaminophenyl) ethyl] phenylamino} benzoic acid monohydrochloride;

2- {4- [2- (3-Piperidin-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid monohydrochloride;

2- {4- [3- (4-Dipropylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- (3- (4-Dibutylamino-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (3-Dibutylamino-phenyl) -propyl] -phenylamino} -benzoic acid;

2- (4- {3- [4- (1H-pyrrol-1-yl) phenyl] propyl} phenylamino) benzoic acid;

2- {4- [3- (4-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (4-diethylcarbamoylphenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-Carboxyphenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-diethylaminomethylphenyl) propyl] phenylamino} benzoic acid, 26 2- {4- [3- (4-propylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (3-propylaminophenyl) propyl] phenylamino} benzoic acid;

2- {4- [3- (4-Pyrrolidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

2- {4- [3- (3-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid;

{5 - [(1-butyl-1,2,3,4-tetrahydro-6-quinolyl) methylidene] -4-oxo-2-thioxothiazolidin-3-yl} acetic acid;

{5 - [(1-butyl-2,3-dihydro-1H-indol-5-yl) methylidene] -4-oxo-2-thioxothiazolidin-3-yl] acetic acid;

3- {5 - [(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl) methylidene] -4-oxo-2-1-oxothiazolidin-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-dichlorophenyl) phenyl] aminobenzoic acid.

The invention also provides the following compounds wherein the terminal phenylalkyl group is attached at the 2- or 3-position of the central phenyl ring, that is, the compound of formula Ia:

Typical 2- and 3-substituted compounds are: 2- {3- [2- (3,4-dichlorophenyl) ethyl] phenylamino} -benzoic acid; 2- {2- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (3- [3- (4-diethylaminophenyl) propyl] phenylamino} benzoic acid;

2- (3- [3- (4-di-n-propylaminophenyl) propyl] phenylamino} benzoic acid;

2- (3- [3- (4-n-propylaminophenyl) propyl] phenylamino} -benzoic acid;

2- (3- [3- (4- [2-diethylaminoethylamino] phenyl) propyl] phenylamino} benzoic acid;

2- (2- [3- (4-hydroxycarbonylmethylamino) phenyl) propyl] phenylamino} benzoic acid;

2- {2- [2- (3- [2-diethylamino-ethylamino] -phenyl) -ethyl] -phenylamino} -benzoic acid;

2- (3- [3- (4-Morpholinophenyl) propyl] phenylamino} benzoic acid;

2- (3- [3- (4-piperazinylphenyl) propyl] phenylamino} -benzoic acid;

2- (3- [2- (4-chlorophenyl) ethyl] phenylamino} benzoic acid, 2- {3- [3- (3,4-dichlorophenyl) propyl] phenylamino} benzoic acid, and 2- (4- [4- (4- (4-Methylpiperazinyl} phenyl) butyl] phenylamino} benzoic acid.

The invention also provides pharmaceutical compositions of the novel compounds in admixture with a pharmaceutically acceptable diluent, carrier or excipient.

The invention also provides a method for displaying amyloid deposits, comprising:

(a) administering to the patient a detectable amount of a labeled compound of formula (I) or a pharmaceutically acceptable salt thereof:

R 'where ||

R ^a is hydrogen, C 1 -C ₆ alkyl or -C 1 -C ₆ alkyl; n is 0 to 5 inclusive;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH -NH 2, NR ^b R ^c , -CO 2 H, -CO ₂ C 1 -C ₆ alkyl, -NO ₂ , -OC x -C ₁₂ alkyl, -Ο C ₈ alkyl, -CF ₃ , -CN, -OCH ₂ phenyl, -OCH ₂ substituted phenyl, (CH ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl,

O ll ll

-0 _(CH2) p NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -N (CiC6alkyl) _{(CH2) p} NR ^b R ^c, / CH ₂ OC _in C ₆ alkyl

-CH;

^x _CH2 OC _{r 6} alkyl

R ^a is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ;

R ^b and R ^c are independently hydrogen, -C 1 -C 6 alkyl, - (CH ₂ ) _m -phenyl, or R ^b and R ^c together with the nitrogen atom to which they are attached form a cyclic ring selected from the group consisting of piperidyl, pyrrollyl, imidazolyl , piperazinyl, 4-ΟχC ₆ alkyl-piperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl;

R ^d is hydrogen, -C 1 -C ₆ alkyl, -CF ₃ or phenyl; m is 0 to 5 inclusive;

p is 1 to 5 inclusive;

A is CH or N;

R ¹ and R ² , when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof;

(b) waiting for a sufficient period of time to associate the labeled compound with amyloid deposits; and (c) detecting a labeled compound associated with amyloid deposits.

In a preferred embodiment of the invention, Alzheimer's disease is suspected for the patient.

In a preferred embodiment of the invention, the labeled compound is a radiolabelled compound.

In a preferred embodiment of the invention, the labeled compound is detected by MRI.

The present invention also provides the following preferred compounds:

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid;

2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid;

2 - [[4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] amino} -benzoic acid;

2- {4- [3- (4-diethylaminophenyl) propyl] phenylamino} benzoic acid;

and pharmaceutical preparations thereof.

The invention also includes pharmaceutically acceptable acid addition salts, amides and prodrugs of the compounds.

DETAILED DESCRIPTION OF THE INVENTION

The term alkyl refers to a straight or branched chain hydrocarbon having from 1 to 12 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert. butyl, sec. butyl, pentyl, hexyl, octyl, decyl and 1,1-dimethyloctyl.

Preferred alkyl groups are C 1 -C ₈ alkyl and especially C 1 -C ₆ alkyl.

The term alkoxy refers to an alkyl group attached to an oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, tert-butoxy, propoxy and isobutoxy. Preferred alkoxy groups are C _x -C ₁₂ alkoxy, in particular Ci-C _alkoxy.

The term halogen refers to chlorine, fluorine, bromine and iodine. The term substituted means that one or more hydrogen atoms in the molecule are replaced by another atom or group of atoms. The substituents include, for example, halogens, in particular chlorine, -OH, -CF ₃ , -NO ₃ , -NH ₂ , -NH (C 1 -C ₆ alkyl), -N (C 1 -C ₆ alkyl) ₂ ,

C 1 -C 6 alkyl, -OC 1 -C 6 alkyl, -CN, -CF ₃ , -CO ₂ H and -CO ₂ C 1 -C ₆ alkyl.

The term substituted phenyl refers to a phenyl ring in which from 1 to 4 hydrogen atoms are independently replaced by a substituent, which is preferably selected from the list above. Typical substituted phenyl groups are 4-chlorophenyl, 3,4-dibromophenyl, 3-fluoro-4-methylphenyl, 3,4-dichlorophenyl, 3,4-methylenedioxyphenyl and 4-dimethylaminophenyl.

Symbol ¹¹ - represents a covalent bond.

The substituents represented by R ^1, R ^3, and R ^a, for example, an amine (NR ^b R ^c) and acylamino (-NHCOR ^b). R ^b and R ^c can be hydrogen, alkyl and phenylalkyl and substituted phenylalkyl, and the usual NR ^b R ^c groups include methylamino, diethylamino, isobutylpropylamino, benzylamino and 3,4-dimethoxybenzylamino. Examples of acylamino groups are formamide, acetamide, 2-phenylacetamide and 2- (3-nitrophenyl) acetamide groups. R ¹ , R ³ and R ⁵ can be aminoalkoxy (-O (CH 2) p NR R ^b R ^c ) such as N-methylaminomethoxy and 2- (N-benzylamino) ethoxy, also as aminoalkylamino (-NH (CH 2) p NR R ^b R) ^c ) such as 3- (dimethylamino) propylamino and 2- (N-ethyl-N-benzylamino) ethylamino. Substituents such as R ¹ , R ³ and R ⁵ may further have cyclic structures, for example when NR ^b R ^{c is a} substituent a and R ^b and R ^c together with the hydrogen atom to which they are attached form a cyclic ring selected from the group consisting of imidazole , pyrrole, piperidine, piperazine, 4-C 1 -C ₆ alkylpiperazine, morpholine, thiomorpholine, pyrazole and decahydroisoquinoline.

Substituents such as R ¹ , R ² , R ⁵ , R ⁶ and R ⁷ may also be -CH = CH-phenyl (i.e. styryl), phenoxy, O-substituted phenyl such as 3-iodophenoxy, 2,4, 6-trihydroxyphenoxy, 2-fluoro-3-nitrophenoxy, also as -O-benzyl and -O-substituted benzyl such as 2-trifluoromethylbenzyloxy and 4-aminobenzyloxy.

The term pharmaceutically acceptable salt, ester, amide and prodrug as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention that are medically suitable for use involving tissue contact a patient without undesirable toxicity, irritation, allergic reaction and the like, to achieve a favorable benefit / risk ratio, and which are effective for the desired use, also as zwitterionic forms, if possible, of the compounds of the present invention. The term salts refers to the relatively non-toxic, addition salts of the compounds of the present invention with inorganic and organic acids. These salts may be. prepared in situ during the final isolation and purification of the compounds, or by autonomously reacting the purified compound in the form of the free base with a suitable anroganic or organic acid and isolating the compound thus formed. Examples of salts are hydrobromide, hydrochloride, sulfate, acid sulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and lauryl sulfonate and the like. These salts may include alkali metal or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium. methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example, Berge, S. M. et al., Pharmaceutical Salts, J; Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference).

Examples of pharmaceutically acceptable, non-toxic esters of the compounds of the present invention include C ₁ -C ₆ alkyl esters in which the alkyl group has a straight or branched chain. Acceptable esters also include C ₅ -C ₇ cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C ₄ alkyl esters are preferred. Esters of the compounds of the present invention may be prepared by conventional methods, such as by reacting a carboxylic acid of formula I with an alcohol such as ethanol or benzyl alcohol.

Examples of pharmaceutically acceptable, non-toxic amides of the compounds of the present invention include amides derived from ammonia, primarily C 1 -C ₆ alkylamines and secondary C 1 -C ₆ dialkylamines in which the alkyl group has a straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, Ci-C ₃ alkyl primary amides and C ₂ ~ C dilkyl secondary amides are preferred. The amides of the compounds of the present invention can be prepared by conventional methods.

The term prodrug refers to compounds that are rapidly transformed in vivo to compounds of the original formulas. For example, by hydrolysis in blood. A thorough discussion is given in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Syriosium Šerieš, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association Press, 1987, which are incorporated herein by reference.

Further, the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The compounds of the present invention may exist in various stereoisomeric forms due to the presence of asymmetric centers in the compounds. It is intended that all stereoisomeric forms of the compounds, as well as mixtures thereof, including racemic mixtures, form part of the present invention.

In a first step of the imaging method of the present i

of the invention is a compound of formula (I) administered to a patient in a detectable amount. The compound is usually part of a pharmaceutical composition and is administered to a tissue or patient by methods well known in the art.

According to the present invention, the compounds may be administered either orally, rectally, parenetally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intrapetironeally, intravesically, topically (in the form of powders, ointments or drops) or as buccal or nasal sprays.

Compositions suitable for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by coating agents such as lecithin, by providing the desired particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dosing agents.

Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parbens, chlorobutanol, phenol, sorbic acid and the like. It may also be appropriate to use isotonicity agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be.

I have been obtained using absorption delaying agents such as aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is admixed with at least one conventional inert ingredient (or carrier), such as sodium citrate or calcium phosphate, or (a) a filler or extender such as starch, lactose, sucrose, glucose, mannitol, and silicic acid. ; (b) a binder such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) a humectant such as glycerol; (d) a disintegrant, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates. and sodium carbonate; (e) a solution retarding agent such as paraffin; (f) an absorption accelerator, such as. are, for example, quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) absorbents, such as kaolin and bentonite; and (i) glidants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents.

Solid compositions of a similar type may also be employed as fillers in solid and soft gelatin capsules, using ingredients such as lactose or milk sugar, high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared in the form of a coating, such as an enteric coating and other coatings well known in the art. These coatings may contain light-impermeable agents and may have. also such a composition that they release the active compound or compounds in some part of the intestinal tract after a period of time. Examples of such formulations are polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the above ingredients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3butylene glycol, dimethyl oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances and the like.

In addition to inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and odor control agents.

The suspensions may contain, in addition to the active agents, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of such substances, and the like.

The compositions for rectal administration are preferably lace, which may be prepared by mixing the compounds of the present invention with suitable non-irritating ingredients or carriers, such as cocoa butter, polyethylene glycol or lace wax, which are solid at room temperature but liquid at body temperature and therefore they dissolve in the rectum or vagina and release the active compound.

Dosage forms for topical administration of the compounds of the present invention include ointments, powders, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservative, buffer, or propellant that is suitable. Ophthalmic formulations, eye ointments, powders and solutions are also within the scope of the present invention.

In a preferred embodiment of the invention, the labeled compound is administered to the patient in a detectable amount, and after a period of time sufficient to associate the compound with amyloid deposits, the labeled compound is non-invasively detected in the patient. In another embodiment of the invention, the labeled compound of formula I is administered to a patient, allowing sufficient time to associate the compound with amyloid deposits, and then taking a sample from the patient and detecting the labeled compound in the tissue outside the patient. In a third embodiment of the invention, a tissue sample is taken from the patient and the labeled compound of formula I is applied to the tissue sample. After a period of time sufficient to associate the compound with amyloid deposits, the compound is detected.

Administration of a labeled compound to a patient may be local or systemic. For example, a labeled compound may be administered to a patient so that it is distributed throughout the body. Alternatively, the labeled compound may be administered to a specific organ or tissue of interest. For example, it may be. desirable quantification of amyloid deposits in the brain to diagnose or monitor the progression of Alzheimer's disease in a patient.

The term tissue as used herein refers to a portion of the patient's body. Examples of tissues are the brain, heart, blood vessels, and arteries. A detectable amount is the amount of labeled compound required for detection by a selected detection method. The amount of labeled compound administered to a patient to facilitate detection can be readily determined by those skilled in the art. For example, an increasing amount of labeled compound may be administered to a patient until the compound is detected by a selected detection method. The labeling agent is bound to the compound to allow its detection.

The term patient refers to a human or other animal. It will be easy for those skilled in the art to determine the time sufficient to associate the compound with amyloid deposits. The time required can be readily determined by administering to the patient a detectable amount of a labeled compound of Formula I and then detecting the labeled compound at various times after administration.

The term associated refers to the chemical interaction between the labeled compound and amyloid deposits. Examples of association are covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes.

Various methods for detecting labeled compounds will be apparent to those skilled in the art. For example, magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT) can be used to detect radiolabeled compounds. The labeling agent that is bound to the compound is selected according to the selected method. For example, if PET is selected as the detection method, the compound must contain a positron emitting atom, such as ¹¹ C or ¹⁸ F.

Another embodiment of a labeling reagent of the compound of formula I represents that it is ¹³ C or ¹⁹ N ^{1 S} F which can be detected using magnetic resonance imaging (MRI) which is also sometimes called nuclear magnetic resonance. Furthermore, labeled compounds of formula I can also be detected by MRI using paramagnetic contrast agents.

Another example of detection is electron paramagnetic resonance (EPR). In this case, EPR probes well known in the art, such as nitrogen oxides, can be used.

Imaging of amyloid deposits can also be performed quantitatively so that the size of amyloid deposits can be determined.

The present invention also provides a method for inhibiting the aggregation of amyloid deposits forming amyloid deposits, wherein said method comprises administering to a patient in need of an inhibition of amyloid protein aggregation an amount of an amyloid protein inhibiting compound of Formula I. Those skilled in the art will be able to determine; an amyloid inhibiting amount by administering a compound of formula I to a patient in increasing doses until the amyloid deposits are reduced or arrested. Growth rate can be assessed by imaging or harvesting tissue from the patient and observing the patient's amyloid deposits.

A patient in need of inhibition of amyloid protein aggregation is a patient with a disease or disorder in which amyloid proteins aggregate. Examples of such diseases and disorders are Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorhagia with disease, , Gerstmann-StrausslerScheinker syndrome, medullary thyroid carcinoma, isolated atrial amyloid, β ₂ -microglobulin amyloid dialysed patients, inclusion body myositis, β ₂ amyloid deposits in muscle breakdown diseases, sickle cell disease and insulin cervical anemia.

The present invention also provides compounds of formula I wherein one or more of the atoms of the compound is replaced by a radioisotope (labeled compound). The radioisotope may be any radioisotope. However, ³ H, ¹²³ I, ¹²⁵ I, ¹³¹ I, ^1X C and ^1S F are also preferred. Methods for introducing radioisotopes into compounds will be known to those skilled in the art. For example, a compound in which one carbon atom is ⁿ C or ¹⁴ C can be readily prepared.

The compounds of the present invention can be administered to a patient at doses ranging from about 0.1 to about 1000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is sufficient. However, the particular doses employed may be varied. The dose may depend on many factors, including the requirements of the patient, the severity of the disease being treated, and the pharmacological activity of the compound used. Determination of the optimum dose is easy for the person skilled in the art.

The examples below illustrate particular embodiments of the invention and do not limit the scope thereof.

DETAILED DESCRIPTION OF THE INVENTION

synthesis

Compounds of formula I may be prepared by several methods as illustrated in Schemes 6-9. Schemes 1 through 5 illustrate synthesis methods that can be used to obtain starting amines (IV), (VIII), (XV) and (XXI).

In Scheme 1, olefin (III) is obtained from the substituted aldehyde (I) and nitrophenylacetic acid (II) by heating in piperidine at 150 ° C. Under standard hydrogenation conditions, such as Raney nickel, the desired amine (IV) is obtained.

Scheme 2 shows the synthesis of an amine (VIII) that contains three methylene chains. Condensation of the aldehyde (I) and nitro-ketone (V) in the presence of sodium hydroxide gives the desired α, β42 unsaturated ketone, from which compound (VII) is obtained under standard hydrogenation conditions (Raney nickel) and then the desired amine under Wolff-Kishner conditions (VIII).

Scheme 3 is very similar to Scheme 2, except that the aldehyde (I) is fused with a substituted aniline (IX).

Scheme 4 illustrates standard Wittig conditions in which the starting compounds (XII) and (XIII) are obtained through aldol condensations and ylide reactions, respectively. Reaction of the aldehyde (XII) and bromophosphorane (XIII) in the presence of a base such as butyllithium leads to a diene (XIV). Standard reducing conditions (e.g., Raney nickel) applied to compound (XIV) yields the desired amine (XV).

Scheme 5 illustrates the synthesis of an amine (XXI) that contains a 5-methylene chain. The Wittig reaction of bromophosphorane (XVII), which is prepared from the respective substituted bromide (XVI), and nitroaldehyde (XIX), obtained from the Swern oxidation of the corresponding alcohol (XVIII), using a base (e.g. LHDMS), yields an olefin (XX). Reduction (XX) using standard conditions (Raney nickel) affords the amine (XXI).

Scheme 6 illustrates one method for obtaining compounds of formula I. By both the Buchwald coupling reaction (method A) followed by saponification and the Ullman reaction (method B), compounds of formula I may be isolated from amines such as (IV), (VIII) and (XV). Compounds of formula I which contain hydroxyl groups, such as those of Examples 4 and 6, require demethylation of the hydroxyl protecting groups with reagents such as boron tribromide in the last step of the synthesis.

Protecting groups will also be used when reactive functional groups such as amino or carboxylic acids are present to avoid unwanted side reactions. Carboxy groups are usually converted to esters (e.g. tert-butyl, benzyl) and amino groups are usually acylated (e.g. acetyl or trimethylsilyl). These and other protecting groups are well known in organic chemistry and are described in detail in Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, New York (2nd edition, 1991). All references are incorporated herein by reference.

Scheme 7 illustrates the synthesis of compounds of Formula I by reacting amines such as (IV), (VIII) and (XXI) with the fluoro-nitro intermediate (XXIV) in the presence of a base (e.g., LHMDS or Et ₃ N) to give the ester (XXV) . This ester can be saponified using standard conditions such as sodium hydroxide.

In Scheme 8, the amine (XV) can be reacted with a readily available fluorine substituted carboxylic acid (e.g. (XXVI) or (XXVII)) in the presence of various bases (such as DBU or triethylamine) to give compounds of Formula I.

Scheme 9 illustrates coupling of the amine (VIII) with a readily available methyl ester (XXVIII) in the presence of a base such as imidazole to give the ester (XXIX). This ester can then be saponified in a conventional manner to give compounds of formula I.

Scheme 10 illustrates the synthesis of the fluoro intermediate (XXIV), which is obtained by nitrating the readily available methyl ester ( ₂ ) to yield (XXVIII). Reaction (XXVIII) with potassium cyanide affords compound (XXIV).

Scheme 11 illustrates the synthesis of compounds related to Example 18. Reaction of potassium salts of ortho-substituted benzoic acids (XXVI) with substituted anilines (XXVII) in the presence of potassium carbonate and cupric acetate affords various iodo-substituted aminobenzoic acids (XXVIII). Reaction (XXVIII) with substituted boric acids and palladium chloride gives the desired substituted aminobenzoic acids ( ₂ ).

It will be appreciated that several compounds of Formula I of the present invention can be prepared from other compounds of Formula I, using standard organic reactions such as oxidation, reduction, alkylation, condensation, elimination and similar well known synthesis methods. For example, compounds of formula I wherein A ^a is hydrogen are simply alkylated to give compounds wherein R ^a is C 1 -C 6 alkyl. Compounds where R ¹ is NH 2 are simply acylated by reaction with an acid halide or an acid anhydride to form a compound. to obtain compounds wherein R is -NHCOR ^b . Similarly, compounds wherein R ¹ is NO 2 are simply reduced to give compounds where R ¹ is NH 2. Benzoic acids (where R ⁸ is COOH) are readily converted to esters and amides, as well as salts and other prodrugs, using well known methods. For example, benzoic acid can be reacted with oxalyl chloride to give an acid chloride which is then simply reacted with a sulfonamide such as methanesulfonamide to give the corresponding compounds of the present invention wherein R ⁸ is -CONHSO ₂ CH ₃ .

Preparation of amines

Scheme 1

Grade B

Ra-Ni / THF or Pd-C / DMF r0 = \> r ⁷ / == \

// (IV) n ₂

Scheme 2

Scheme 3

Scheme 4

n-BuLi / THF (χπ) Ο ™)

Scheme 5

(XVIII) (XDQ

Coupling reaction

Scheme 6

Method A, Step C

conceive).

Scheme Ί

is an ester-forming group such as alkyl or benzyl.

Scheme 8

Scheme 9

Compound of Formula I

Synthesis of the fluoro intermediate

Scheme 10

COOMe

COOMe (xxvmy)

Scheme 11

COOH COOK ' ^Br I ^ COj / MeOH (XXVI)

Κ ^ ΟΟβ, Cu (Ac) 2

(Xxvm)

Example 1

Preparation of 2- {4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} -benzoic acid

Step A (Scheme 1): Preparation of 1,2-dichloro-4- [2- (4-nitrophenyl) ethenyl] benzene

A mixture of p-nitrophenylacetic acid (51.23 g, 0.28 mol) a

3,4-Dichlorobenzaldehyde (49.50 g, 0.28 mol) in piperidine (50 mL) was heated to 150-160 ° C for 5 hours under a nitrogen atmosphere. After cooling the reaction mixture, the precipitate was triturated in boiling methanol (MeOH) (50 mL) and then cooled to -5 ° C for 12 hours. The crystalline precipitate was filtered off, rinsed with cold MeOH and dried at room temperature in a vacuum oven overnight to give an orange solid, 22.71 g (0.077 mol, 27%), which was the desired product.

MP: 190-191 ’C.

MS: 294.9 (M < ^{+ >} ).

Step B (Scheme 1): Preparation of 4- [2- (3,4-dichlorophenyl) ethyl] benzenamine

A sample of 1,2-dichloro-4- [2- (4-nitrophenyl) ethenyl] benzene (98.0 g, 0.33 mol) in tetrahydrofuran (THF) (1.6 L) was reduced in the presence of Raney nickel (Ra). -Ni) (20 g) at 25 ° C to 40 ° C (ΔΡ = 13.5 psi) under a hydrogen atmosphere.

The reaction mixture is filtered and the filtrate is concentrated in vacuo to give an orange solid, 85.0 g (0.32 mol, 95.8%), which is the desired product. Mp 68 70 ’C.

MS: 266.1 (M < ^{+ >} ).

Step C (Scheme 6): Preparation of 2- {4- [2- (3,454 dichlorophenyl) ethyl] phenylamino} -benzoic acid

Method A

A mixture of 4- [2- (3,4-dichlorophenyl) ethyl] benzenamine (28.37 g, 106.59 mmol), methyl 2-bromobenzoate (19.10 g, 88.82 mmol), cesium carbonate (40, 52 g, 124.35 mmol), tris (dibenzylideneacetone dipalladium (O) (2.44 g, 2.67 mmol) and (S) - (2,2'-bis (di-p-tolylphosphino-1,1'-) binaftyl (98%, (S) -tol-BINAP) (2.71 g,

4.00 mmol) (Ligand / Pd = 1.5) in anhydrous toluene (300 mL) was heated to 100 ° C for 34 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ether, filtered through celite and rinsed thoroughly with ether. The filtrate was evaporated to dryness to give a brown residue (68 g). The resulting residue was dissolved in ethanol (EtOH) (50 mL) and THF (100 mL), and then 5N NaOH (aq) (200 mL) was added and the mixture was heated to reflux for 16 hours. The solvent was removed in vacuo. The residue was acidified with concentrated HCl to pH 3. The resulting precipitate was collected by filtration, triturated with boiling MeOH-HaO (4: 1) and dried in vacuo at room temperature for 16 hours to give Example 1 as an orange solid (31). , 95 g, 0.083 mol, 77.6%). Mp.175.0-177.0 ° C.

Calcd for C 21 H 17 N 1 O 2 Cl 2: C, 65.30; H, 4.44; N, 3.63.

Found: C, 65.40; H, 4.54; N, 3.50.

Method B

A mixture of 2-chlorobenzoic acid (5.4 g, 0.034 mol), 4- [2- (3,4-dichlorophenyl) ethyl] benzenamine (10.0 g, 0.037 mol), anhydrous potassium carbonate (16.9 g, 0 , 12 mol), copper powder (4.94 g, 0.077 mol) and cuprous chloride (0.37 g, 0.0037 mol) in dry dimethylformamide (DMF) (85 ml) were heated to reflux for 24 hours. hours at 150 ° C.

The reaction mixture was poured into hot H ₂ O (150 mL) and heated to 90 ° C on a hot plate. Activated charcoal is added and the mixture is stirred at 90 ° C for 5 minutes. Filter the warm brown mixture through filter paper. The cold filtrate was then acidified with concentrated HCl (pH 1) and the precipitate was collected by filtration, triturated with boiling MeOH-H ₂ O (1: 2) and dried in vacuo at room temperature for 16 hours to give Example 1 as an orange solid (2.3 g, 0.006 mol, 17.5%). Mp 165.0-173.0 ° C.

Analysis for C ₂₁ Hi ₇ N iO ₂ C1 _2: C, 65.30; H, 4.44; N, 3.63. Found: C, 65.68; H, 4.58; N, 3.60.

Example 2: Preparation of 2- {4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} -5-nitrobenzoic acid

Step C (Scheme 6): Preparation of 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid methyl ester

A mixture of 4- [2- (3,4-dichlorophenyl) ethyl] benzenamine (600 mg,

2.25 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (489 mg, 1.88 mmol), cesium carbonate (857 mg, 2.62 mmol), tris (dibenzylideneacetone dipalladium (O) (51 mg, 0.056) mmol) and (S) - (2,2'-bis (di-p-tolylphosphino-1,1'-binaphthyl (98%, (S) -tolBINAP)) (58 mg, 0.085 mmol) (Ligand / Pd = 1 5) in anhydrous toluene (16 ml) was heated at 10 ° C for 12 hours under nitrogen, cooled, diluted with ether, filtered through celite, and rinsed thoroughly with ether. of the brown residue.

Purification rapid chromatography (Silica gel, 5% EtOAc / hexanes) is obtained 540 mg (1.21 mmol) 64%), which is a desired product. T mp 107 -108 ° C. Analysis for C ₂₂ H ₁₈ N ₂ Cl ₂ O ₄ Calcd: C, 59.34; H, 4.07; N,

6.29. found: C, 59.03; H, 4.04; N, 5.99.

Preparation of 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid

A solution of 2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid methyl ester (340 mg, 0.76 mmol) and 1 N NaOH (aq) (4.0 mL) in EtOH (4.0 mL) and THF (4.0 mL) were heated at reflux for 16 h. The solvent was removed in vacuo. The residue was diluted with H ₂ O and acidified with concentrated HCl to pH 1. The mixture was then extracted with methylene chloride, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow solid, 329 mg (0.76 mmol). , 100%), which is the desired product. Mp 214-217 ° C.

Analysis for C ₂ H ₁₆ N ₂ Cl ₂ O _4: C, 58.49; H, 3.74; N, 6.50. Found: C, 58.24; H, 3.81; N, 6.28.

Example 3

Preparation of 2- {4- [4- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-methoxy-5-nitro-benzoic acid

To a cold (-78 ° C) solution of 4- [2- (3,4-dichlorophenyl) ethyl] phenylamine (0.836 g, 3.14 mmol) in THF (20 mL) was added dropwise LHDMS (6.28 g). mL, 1 M in THF, 6.28 mmol). The reaction mixture was stirred at -78 ° C for 10 minutes. A solution of 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (0.72 g, 3.14 mmol) in THF (30 mL) was added dropwise and the solution was stirred for 30 minutes at -78 ° C. The reaction mixture was allowed to gradually warm to room temperature and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (EtOAc) and acidified with 5N HCl (pH 3). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown residue. To a solution of this residue in EtOH (20 mL) and THF (40 mL) was added 5N NaOH (50 mL), and the mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue acidified with concentrated HCl (pH 3). The precipitate was collected by filtration, triturated with boiling MeOH-H ₂ O (1: 1) and dried in a vacuum oven for 16 hours to give Example 3 as an orange solid (0.70 g, 1.51 mmol, 48 %). Mp 208-209 ° C. Analysis for C ₂₂ H 18 N ₂ O ₅ Cl ₂ : calculated: C, 57.28; H, 3.93; N, 6.07. Found: C, 57.43; H, 3.69; N, 5.86.

Example 4

Preparation of 2- {4- [2- (3,4-dihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid

Step A (Scheme 1): Preparation of 1,2-dimethoxy-4- [2- (4-nitrophenyl) ethenyl] benzene

The title compound was prepared from pnitrophenylacetic 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 give a yellow solid, 13.4 g (0.047 mol, 34%), which is the desired product. Mp: 133-134 ° C.

Analysis for C ₁₆ H ₅ NiO ₄ : calculated: C, 67.36; H, 5.30; N, 4.91. Found: C, 66.81; H, 5.27; N, 4.84.

Step B (Scheme 1): Preparation of 4- [2- (3,4-dimethoxyphenyl) ethyl] phenylamine

1,2-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 dimethylformamide (DMF) (120 ml) at 25 ° C under a hydrogen atmosphere. The reaction mixture was concentrated in vacuo to give a solid. The solid is recrystallized from MeOH (400 mL) to give white crystals, 6.8 g (0.026 mol, 63%), which are the desired product. MP: 115-116 [deg.] C.

Calcd for C16H19N1O2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.60; H, 7.39; N, 5.35.

Step C (Scheme 6): Preparation of 2- {4- [2- (3,4-dimethoxyphenyl) ethyl] phenylamino} benzoic acid

The title compound was prepared from 4- [2- (3,4-dimethoxy-phenyl) -ethyl] -phenylamine (9.25 g, 0.036 mol), 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 cuprous chloride in dry DMF (75 mL) using the procedure described in Example 1, Step C, Method B. After crystallization with MeOH (H ₂ O), 4.5 g (0.012 mol, 33%) of the desired product is obtained. Mp: 137-139 ° C.

Calcd for C23H23N1O4: C, 73.19; H, 6.14; N, 3.71. Found: C, 73.47; H, 6.03; N, 3.78.

Step D: Preparation of 2- {4- [2- (3,4-dihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid

To a solution of 2- {4- [2- (3,4-dimethoxy-phenyl) -ethyl] -phenylamino} -benzoic acid (0.28 g, 0.74 mmol) in CH ₂ Cl ₂ (20 mL) was added at room temperature. Bbr ₃ (3.5 mL, 1 M in CH ₂ Cl ₂ , 3.5 mmol) was added to the room under nitrogen. The reaction mixture was stirred at room temperature for 2 hours and then poured into ice water (50 mL). This mixture was extracted with EtOAc and the organic layer was washed twice with water, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give 0.24 g (0.69 mmol, 93%) of the desired product. . Mp 215-217 ° C.

Analysis for C ₂₁ H ₁₉ NO ₄ : Calculated: C, 72.19; H, 5.48; N, 4.00. Found: C, 71.80; H, 5.46; N, 3.99.

Example 5

Preparation of 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid

Step A (Scheme 1): Preparation of 1,1-dibutylamino-4- [2- (4-nitrophenyl) ethenyl] benzene

The title compound was prepared from p-nitrophenylacetic acid (9.92 g, 0.055 mol) and 4-dibutylamino-benzaldehyde (14.32 g, 0.055 mol) in piperidine (5 mL) using the procedure described in Example 1, Step A. This procedure yielded a red solid, 4.12 g (0.012 mol, 16%), which is the desired product.

MS: 352.2, (M < ⁺ &^gt;); 353.2, (MH < ^{+ >} ).

Step B (Scheme 1): Preparation of 4- [2- (4,4-dibutylaminophenyl) ethyl] phenylamine

The title compound was prepared from 1,1-dibutylamino-4- [2- (4-nitrophenyl) ethenyl] benzene (4.1 g, 11.63 mmol) and Ra-Ni (2.0 g) in MeOH (100 g). ml) at 21 ° C to 32 ° C (ΔΡ = 3.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a colorless oil, 3.49 g (10.76 mmol). , 92.6%), which is the desired product.

MS: 325.3 (MH ⁺ ).

Step C (Scheme 6): Preparation of 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid

The title compound was prepared from 2-chlorobenzoic acid (1.46 g, 9.36 mmol), 4- [2- (4,4-dibutylaminophenyl) ethyl] phenylamine (3.31 g, 10.20 mmol), anhydrous carbonate potassium (4.27 g, 30.88 mmol), copper powder (1.25 g, 19.65 mmol) and copper (I) chloride (0.092 g, 0.93 mmol) in dry DMF (30 mL) using the procedure as described in Example 1, Step C, Method B. This procedure yielded 0.39 g (0.87 mmol, 8.6%) of the desired product. Mp = 115-117 ° C.

Analysis for C 29 H ₃₆ N ₂ O 2: C, 78.34; H, 8.16; N, 6.30. Found: C, 78.15; H, 8.07; N, 6.10.

Example 6

Preparation of 2- {4- [2- (3,4,5-trihydroxyphenyl) ethyl] phenylamino} benzoic acid

Step A (Scheme I): Preparation of 1,2,3-trimethoxy-5- [2- (4-nitrophenyl) ethenyl] benzene

The title compound was prepared from pnitrophenylacetic acid (18.6 g, 0.10 mol), 3,4,5-trimethoxybenzaldehyde (19.6 g, 0.10 mol) and piperidine (5 mL) using the procedure described in Example 1. Step A. This procedure yielded a solid, 13.0 g (0.041 mol, 41%), which is the desired product. Mp: 192-195 ° C.

Step B (Scheme 1): Preparation of 4- [2- (3,4,5-trimethoxyphenyl) ethyl] phenylamine

The title compound was prepared from 1,2,3-trimethoxy-5- [2- (4-nitrophenyl) ethenyl] benzene (9.5 g, 0.03 mol) and Ra-Ni (1.0 g) in THF ( 50 mL) at 21-26 ° C (ΔΡ = 9.6 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a brown powder, 6.6 g (0.023 mol, 74%). ), which is the desired product. T.t.91-93 C.

Step C (Scheme 6): Preparation of 2- {4- [261] methyl ester

- (3,4,5-trimethoxyphenyl) ethyl] phenylamino} -benzoic acid

The title compound was prepared from 4- (2- (3,4,5-trimethoxyphenyl) ethyl] phenylamine (0.75 g, 2.61 mmol), methyl 2-bromobenzoate (0.47 g, 2.17 mmol), carbonate cesium (0.99 g, 3.04 mmol), tris (dibenzylideneacetone dipalladium (0) (0.06 g, 0.065 mmol) and (S) - (-0-2.2 ^1- bis (di-p-tolylphosphino- 1.1 ^1-binaphthyl (98% (5 ') Tol-BINAP) (0.066 g, 0.098 mmol) (ligand / Pd - 1.5) in anhydrous toluene (100 mL) using the procedure described in Example 1, Step C , method A, to give a yellow oil, 0.69 g (1.63 mmol, 76%), which was the desired product.

Calcd for C25H27N105: C, 71.24; H, 6.46; N, 3.32. Found: C, 71.53; H, 6.24; N, 3.14.

Preparation of 2- (4- [2- (3,4,5-trimethoxyphenyl) ethyl] phenylamino} -benzoic acid

To a solution of 2- (4- (2- (3,4,5-trimethoxyphenyl) ethyl] phenylamino} benzoic acid methyl ester (0.62 g, 1.47 mmol) in THF-EtOH (2: 1, 6 mL) was added IN NaOH solution (4 mL) and the reaction mixture was heated to reflux for 5 hours, then concentrated in vacuo to remove the organic solvent, the residue acidified with concentrated HCl (pH 3) and the precipitate collected by filtration, triturated with boiling MeOH-H ₂ O (4: 1) and dried in vacuo at room temperature for 16 hours to give the title compound as a white solid, 0.59 g (1.45 mmol, 98.5%). 0147.0 ° C.

Analysis calculated for: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.54; H, 6.43; N, 3.15.

Step D: Preparation of 2- (4- (2- (3,4,5-trihydroxyphenyl) ethyl] phenylamino) benzoic acid

The title compound was prepared from 2- {4- [2- (3,4,5-trimethoxy-phenyl) -ethyl] -phenylamino} -benzoic acid (0.50 g, 1.23 mmol) in CH ₂ Cl ₂ (40 mL) and Bbr ₃ (10 mL, IM in CH ₂ C1 _2, 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%) , which is the desired product. Mp: 160.0-162.0 ° C. Analysis for C21H3.9N3.O5.1,44 _H2O: C, 64.46; H, 5.64; N, 3.58. Found: C, 64.07; H, 5.27; N, 3.39.

Example 7

Preparation of 2- (4- [2 - [- (3,4-dichlorophenyl) propyl] phenylamino} -4-methoxy-5-nitrobenzoic acid

Step A '(Scheme 2): Preparation of 3- (3,4-dichlorophenyl) -1 (4-nitro-phenyl) propenone

Sodium hydroxide (7.3 g, 0.18 mmol) was dissolved in water (80 ml) and 95% EtOH (80 ml) and the mixture was cooled to 10 ° C in a ₂ 0 Ladha one portion was added 3,4- dichlorobenzaldehyde (31.8 g, 0.18 mol). After addition, the mixture was warmed to 15 ° C. 1- (4-Nitrophenyl) ethanone (30.0 g, 0.18 mol) was added at this temperature, with vigorous stirring. After stirring for 5 minutes, the reaction mixture was diluted with 95% EtOH (300 mL). The resulting light brown mixture was stirred at room temperature for 30 minutes, then treated with ice-H ₂ O for 2 hours. The light brown solid was filtered off, washed with H ₂ O and air dried. The solid was dissolved in hot THF (1.5 L) and treated with activated carbon. The resulting mixture was filtered and the filtrate was diluted with 95% EtOH (500 mL). This solution was filtered and dried in an oven (40 ° C) to give the title compound as a light brown solid, 38.56 g (0.12 mol, 66%). Mp 220-223 ° C.

Calcd for C15H9Cl2NO3: 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 ¹ (Scheme 2): Preparation of 1- (4-amino-phenyl) -3- (3,4-dichlorophenyl) propan-1-one

3- (3,4-Dichlorophenyl) -1- (4-nitro-phenyl) propanone (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) in a hydrogen atmosphere.

The reaction mixture was concentrated in vacuo and recrystallized from MeOH (100 mL) to give a pale yellow solid, 23.5 g (0.080 mol, 75%), which was the desired product. T.t.127-129 C. Calcd for C15H13Cl2NO: C, 61.24; H, 4.45; N, 4.76; Cl, 24.10. Found: C, 60.91; H, 4.60; N, 4.70; Cl, 23.98.

Step C '(Scheme 2): Preparation of 4- [3- (3,4-dichlorophenyl) propyl] phenylamine

A mixture of 1- (4-aminophenyl) -3- (3,4-dichlorophenyl) propan-1-one (20.0 g, 0.068 mol), ΝΗ ₂ ΝΗ _2- Η ₂ Ο (16 mL), and KOH (85% 5.6 g) in ethylene glycol (160 ml) was refluxed under nitrogen for 16 hours. After cooling to room temperature, the reaction mixture was poured into ice-H ₂ O and extracted with CH ₂ Cl ₂ (2 L). The layers were separated and the organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give an oil. Purification by flash chromatography (silica gel, CH ₂ Cl ₂₎ gave an oil, 14.00 g (0.05 mol, 73%) of the desired product.

Analysis for C ₁₅ H ₁₅ Cl ₂ N: 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.

Preparation of 2,4-Difluoro-5-nitrobenzoic acid methyl ester

Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentle mixing to concentrated sulfuric acid 98% (125 mL) in a vial beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was gently stirred for 40 minutes at room temperature. The reaction mixture was then poured into ice-H ₂ O (1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated and the organic layer was washed successively with 1N NaCl, saturated NaHCO ₃ , H ₂ O, and brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow residue. This residue was washed with 10% EtOAc / hexane, filtered and dried to give a pale yellow solid, 29.0 g (0.133 mol, 82%). Tt78-80 C.

Anal. Calcd for C ₈ H ₅ F ₂ NO ₄ : C, 44.25; H, 2.32; N, 6.45. found: C, 44.18; H, 2.39; N, 6.14.

Preparation of 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester

A mixture of sodium (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 the mixture was stirred at 0 ° C to 5 ° C for 20 minutes. The reaction mixture was then allowed to warm to room temperature and stirred for 2 hours. The mixture was then filtered to give an off-white precipitate. Recrystallization of CHC1 ₃ (70 ml) gave the title compound as an off-white crystalline solid, 1.825 g (0.008 mmol,

17%). Analysis for C ₉ H ₈ FiNiO ₅ : Calcd: C, 47.17; H, 3.52; N,

6.11. Found: C, 47.09; H, 3.47; N, 6.00.

Preparation of 2- {4- [3- (3,4-Dichloro-phenyl) -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 Et ₃ N (0.46 mL) in CH ₃ CN (30 mL) was heated to reflux for 120 hours. The reaction mixture was cooled to room temperature, diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ . The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a solid. Recrystallization with MeOH gave 0.67 g (1.37 mmol, 42%) of the desired product.

Analysis for C ₂₄ H ₂₂ N ₂ Cl ₂ O ₅ · 0.42 H ₂ O: calculated: C, 58.01; H, 4.63; N, 5.64. Found: C, 57.61; H, 4.51; N, 5.94.

Preparation of 2- {4- [3- (3,4-dichlorophenyl) 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) was added 1 N NaOH (aq) (2.5 ml) and the mixture was stirred at room temperature for 36 hours. The solvent was removed and the residue acidified to pH 3 with concentrated HCl. The precipitate was collected by filtration and dried under vacuum for 16 hours. Recrystallization with MeOH gave the title compound as an orange solid, 0.21 g (0.043 mol, 70%). T.t.200-201 C.

Analysis for C ₂₃ H ₂₀ N ₂ O ₅ Cl ₂ · 0.2H ₂ O: calculated: C, 57.68; H, 4.29; N, 5.85; Cl, 14.81. Found: C, 57.71; H, 4.34; N, 5.58; Cl, 14.56.

Example 8

Preparation of (4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-imidazol-yl-5-nitrobenzoic acid

Preparation of 2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-imidazol-yl-5-nitrobenzoic acid methyl ester

A mixture of 2,4-difluoro-5-nitrobenzoic acid methyl ester (1.63 g, 7.5 mmol), imidazole (0.56 g, 8.25 mmol) and Et ₃ N (1.14 mL, 8.25 mmol) ) in CH ₃ CN (50 mL) was stirred for 16 hours at room temperature. To this dark orange solution was added 4- [3- (3,4-dichlorophenyl) propyl] phenylamine (2.10 g, 7.5 mmol) and triethylamine (Et ₃ N) (1.14 mL, 8.25 mmol). ) and the mixture was heated at reflux overnight. The reaction mixture was cooled and concentrated in vacuo to give a residue. This residue was diluted with CH ₂ Cl ₂ and washed with a saturated K ₂ HCO _{3 solution} . The organic layer was dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo to give a crude oil. Purification by flash chromatography (silica gel, 10% EtOAc / hexane) afforded 1.0 g (1.90 mmol, 25%) of the desired product. MS: 524.1 (M < ^{+ >} ).

Preparation of 2- {4- [2- [- (3,4-dichlorophenyl) propyl] phenylamino} -4-imidazol-1-yl-5-nitrobenzoic acid

The title compound was prepared from 2- {4- [2 - [- (3,4-dichloro-phenyl) -propyl] -phenylamino} -4-imidazo-1-yl-5-nitrobenzoic acid methyl ester (1.0 g, 1.9 mmol) 1N NaOH (2.0 mL) in THF (30 mL) using the procedure described in Example 8. This procedure yielded an orange solid, 0.30 g, (0.6 mmol, 32%) which was desired product.

Analysis for C25H20CI2N4O4.0,2 _H2O: 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.

Example 9 i.

Preparation of 2- {4- [3- (3,4-dichloro-phenyl) -propyl] -phenylamino} -benzoic acid

Preparation of 2- {4- [3- (3,4-dichlorophenyl) propyl] phenylamino} -benzoic acid

The title compound was prepared from 4- (3- (3,4-dichlorophenyl) propyl] phenylamine (600 mg, 2.14 mmol), 2-bromobenzoic acid methyl ester (380 mg, 1.78 mmol), cesium carbonate (812 mg, 2). , 49 mmol), tris (dibenzylideneacetanedipalladium (O) (49 mg,

0.053 mmol) and (S) - (2,2'-bis (di-p-tolylphosphino-1,1'-binaphthyl (98%, (S) -tol-BINAP)) (54 mg, 0.080 mmol) (Ligand / Pd = 1.5) in anhydrous toluene (15 mL), using the procedure described in Example 2, Step C. This procedure yields a yellow oil, 0.61 g (1.47 mmol, 69%) which is desired product.

MS: 414 (M < ^{+ >} ), 416 (MH < ^{+ >} ).

Analysis for C 23 H 21 Cl 2 O 2 N. 0.4 H ₂ O: calculated: C, 65.25; H, 5.23; N, 3.30. Found: C, 65.76; H, 5.18; N ,. 3.10.

Preparation of 2- (4- [3- (3,4-dichlorophenyl) propyl] phenylamino} -benzoic acid

The title compound was prepared from 2- {4- [3- (3,4-dichloro-phenyl) -propyl] -phenylamino} -benzoic acid methyl ester (0.41 g, 0.99 mmol), 1 N NaOH (4.0 mL) in EtOH (4). mL) and THF (4 mL) using the procedure described in Example 2. This yielded a yellow solid, 0.32 g (0.80 mmol, 81%), which was the desired product. Mp 120-126 ° C.

Analysis for C 22 H 19 Cl 2 O 2 N. 0.75 _H2O: C, 64.04; H,

5.00; N, 3.39. Found: C, 64.17; H, 4.69; N, 3.18.

Example 10

Preparation of 2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino} benzoic acid

Preparation of (trans) -3- (3,4-dichlorophenyl) -2-propenal

A mixture of 3,4-dichlorobenzaldehyde (140.0 g, 0.8 mol) and acetaldehyde (300 mL) was cooled to 5 ° C. Potassium hydroxide (5.1 g, 0.091 mol) was dissolved in hot MeOH (40 mL) and the resulting solution was added to the above mixture while maintaining an internal temperature of 25-30 ° C. The mixture was stirred in an ice-H ₂ O bath for 40 minutes and then treated with acetic anhydride (400 mL). After addition, the mixture was heated to 100 ° C and stirred for 30 minutes and then cooled to 30 ° C. To this mixture was added 12N HCl / H ₂ O (102 mL / 1.2 L) and the resulting mixture was heated to reflux for 30 minutes and then cooled to room temperature. The heterogeneous mixture was filtered and washed with H ₂ O to give a brown solid. The crude product was dissolved in EtOAc and washed with H ₂ O, dried (Na ₂ SO 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 C ₉ H ₆ Cl ₂ O: calculated: C, 53.77; H, 3.01; Cl, 35.27. Found: C, 53.75; H, 3.10; Cl, 35.58.

Preparation of (trans), (trans) -1,2-dichloro-4- [4- (4-nitrophenyl) -1,3-butadienyl] benzene

A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) and triphenylphosphine (244.0 g, 0.93 mol) in CHC1 ₃ (1.5 1) was heated at reflux overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove CHCl ₃ , then suspended with Et 2 O and mixed vigorously. The suspension was filtered and the off-white solid was washed with Et ₂ O and dried at 80 ° C for 16 hours to give 433.0 g (0.91 mol, 98%) of bromo - [(4-nitrophenyl) methyl] triphenylphosphorane. A solution of bromo [(4-nitrophenyl) methyl] triphenylphosphorane (100.0 g, 0.23 mol) in dry THF (500 mL) was cooled to 5 ° C. Add n-butyllithium (n-BuLi) (2.4 M, 96 mL, 0.23 mol) dropwise while maintaining the internal temperature between 5 ° C and 10 ° C. The cooling bath was then removed and the reaction was allowed to warm to room temperature. After 4 hours a solution of (trans) -3- (3,4-dichlorophenyl) -2-propenal (36.2 g, 0.18 mol) in THF (100 mL) was added dropwise and the resulting mixture was stirred at room temperature. for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. Purification by flash chromatography (silica gel, 20% EtOAc / hexane) afforded 16.0 g (0.05 mol, 28%) of the desired product. T. t. Mp 125-135 ° C.

Analysis for C ₁₆ H ₁₁ Cl ₂ NO ₂ : 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.

Preparation of 4- [4- (3,4-dichloro-phenyl) -butyl] -phenylamine

The title compound was prepared from (trans), (trans) -1,2-dichloro-4- [4- (4-nitrophenyl) -1,3-butadienyl] benzene (15.42 g, 0.048 mol), Ra-Ni (1 g) at 20 ° C to 26 ° C (ΔΡ = 19.3 psi) under an atmosphere of hydrogen in THF (75 mL) and MeOH (75 mL), using the procedure described in Example 1, Step B. This procedure yields a solid, 10.97 g (0.037 mol, 78%), which is the desired product. T.t.50-52 C.

Analysis for C 18 H 18 N 1 Cl 2. Calcd. C, 65.32; H, 5.82; N, 4.76. Found: C, 65.43; H, 5.84; N, 4.61.

Preparation of 2- (4- [4- (3,4-dichlorophenyl) butyl] phenylamino} benzoic acid ¹

The title compound, mp 98-105 ° C, was prepared from 4- [4- (3,4-dichlorophenyl) butyl] phenylamine (0.50 g, 1.7 mmol), 2-chlorobenzoic acid (0.24 g, 1, 56 mmol), anhydrous potassium carbonate (0.71 g, 5.15 mmol), copper powder (0.21 g, 3.28 mmol) and copper (II) chloride (0.015 g, 0.15 mmol) in dry DMF (5 mL) ) using the procedure described in Example 1, Step C, Method B.

Example 11

Preparation of 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -5-nitrobenzoic 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 Et ₃ N (2.80 mL) in acetonitrile (110 mL) was heated at reflux for 48 hours. The reaction mixture was cooled and concentrated in vacuo to remove the solvent. The residue was dissolved in CH ₂ C1 ₂ and washed with dilute HCl. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a crude solid. Purification by flash chromatography (silica gel, CH ₂ Cl ₂ ) gave 1.40 g (0.003 mol, 30%) of the desired product.

Analysis for C ₂₃ H ₉ N ₂ O ₄ Cl ₂ : 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.

Example 12

Preparation of 2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino} -3,5-dinitrobenzoic acid

To a cold (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 ( A solution of 2-fluoro-2,5-dinitrobenzoic acid (1.15 g, 5.0 mmol) in acetonitrile (15 mL) was added dropwise. After stirring for 30 minutes at 0 ° C, the reaction mixture was neutralized with dilute HCl and extracted with EtOAc, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a crude residue. Recrystallization with EtOH afforded a bright orange solid, 2.06 g (4.1 mmol, 82%), which is the title compound.

Analysis for C 23 H 19 Cl 2 N 3 O 6: calculated: 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

Preparation of 2- {4- [5- (3,4-dichlorophenyl) pentyl] phenylamino} -5-nitrobenzoic acid

Preparation of bromo [(3,4-dichlorophenyl) methyl] triphenylphosphorane

A mixture of 4-bromomethyl-1,2-dichlorobenzene (2.40 g, 0.01 mol) and triphenylphosphine (5.24 g, 0.02 mol) in toluene (30 mL) was stirred at room temperature for 16 hours. The solid is filtered off, rinsed with toluene and oven dried at room temperature to give a white powder, 3.95 ((0.0078 mol, 78%), which is the desired product.

^X H NMR [dimethylsulfoxide (DMSO): ppm]: 7.89 to 7.61 (m, 15 H), 7.50 (d, J = 8.3 Hz, IH), 7.04 (t, J = 2 3 Hz, 1H), 6.97 (m, 1H), 5.20 (d, J = 15.9 Hz, 2H).

Preparation of 4- (4-nitrophenyl) butyraldehyde

To a cold solution (-70 ° C) of oxalyl chloride (2.0 M in CH ₂ Cl ₂ , 14.1 mL, 28.2 mmol) was added dimethylsulfoxide (DMSO) (4.40 g ·, 56.32) dropwise. mmol) in CH ₂ Cl ₂ (20 mL).

The resulting reaction mixture was then stirred for 30 minutes at -70 ° C under a nitrogen atmosphere. Add dropwise a solution of 4- (4-nitrophenyl) butan-1-ol (5.00 g, 25.6 mmol) in CH ₂ C1 ₂ (3 ml) and the reaction-mixture was stirred for 1 hour at 70 ° C . Et ₃ N (16 mL, 115 mmol) was added and the reaction mixture was then allowed to gradually warm to room temperature and stirred for 30 minutes. The mixture was then quenched with H ₂ O and extracted with EtOAc. The organic layer was washed with 0.1 N HCl, H ₂ O, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a light brown oil. Purification by flash chromatography (silica gel, 50% EtOAc / hexane) afforded 3.20 g (16.56 mmol, 65%) of the desired product.

1 H NMR (DMSO: ppm): 9.75 (s, 1H), 8.12 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H 2.72 (t, J = 7.7 Hz, 2H), 2.47 (t, J = 7.1 Hz,

2H), 1.94 (m, 2H).

Preparation of 1,2-dichloro-4- [5- (4-nitrophenyl) -1-pentenyl] benzene

A solution of bromo [(3,4-dichlorophenyl) methyl] triphenylphosphorane (3.95 g, 7.9 mmol) in dry THF (20 mL) was cooled to 0 ° C. LHDMS (1.0 in THF, 9 mL, 9.0 mol) was added dropwise to maintain the temperature at 0 ° C. After stirring for 30 minutes, a solution of 4- (4-nitrophenyl) butyraldehyde (1.45 g, 7.5 mmol) in THF (5 mL) was added dropwise and the mixture was allowed to warm to room temperature over 2 hours. The mixture was then quenched with H ₂ O and extracted with EtOAc. The organic layer was washed with 0.1 N HCl, H ₂ O, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a light brown oil. Purification by flash chromatography (silica gel, 10% EtOAc / hexane) gave 2.5 g (7.4 mmol, 99%) of the desired product. MS: 335 (M < ^{+ >} ), 337 (MH < ^{+ >} ).

Preparation of 4- [5- (3,4-dichlorophenyl) pentyl] phenylamine

The title compound was prepared from 1,2-dichloro-4- [5- (4-nitrophenyl) -1-pentenyl] benzene (2.5 g, 7.4 mmol), Ra-Ni (1 g).

in THF (50 mL) at rt 25 C until 40 ° C (ΔΡ = 9.9 psi) for using the procedure described in Example 1, Step B. This the procedure yielded 1.06 g (3.4 mmol, 46% ·) , which is a desired product. ^X H NMR (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, J = 7.7 Hz, 2H), 2.31 (t, J = 7.6) Hz, 2H), 1.6-1.5 (m, 4H), 1.5-1. 4 (m, 2H).

Preparation of 2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -5-nitrobenzoic acid

To a cold (-78 ° C) solution of 4- [5- (3,4-dichlorophenyl) pentyl] -phenylamine (0.231 g, 0.75 mmol) in THF (2 mL) was added dropwise LHDMS (2.25 mL). , 1 M in hexane, 225 mmol). The reaction mixture was stirred at -78 ° C for 10 minutes. A solution of 2-fluoro-5-nitrobenzoic acid (0.139 g, 0.75 mmol) in THF (2 mL) was added dropwise and this solution was stirred for 30 minutes at -78 ° C. The reaction mixture was allowed to gradually warm to room temperature and stirred for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc and acidified with 1N HCl (pH 3). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown residue. Purification by flash chromatography (silica gel, 2% MeOH / CH ₂ Cl ₂ ) followed by recrystallization with MeOH afforded 265 mg (0.56 mmol, 75%) of the desired product. Mp 147-148 ° C. Analysis for C24H22CI2N2O4.0,37 _H2O: C, 60.05; H, 4.77; N, 5.84. Found: C, 59.67; H, 4.64; N, 5.51.

Example 14

Preparation of 2- {4- [5- (3,4-dichlorophenyl) pentyl] phenylamino} -4-methoxy-5-nitrobenzoic acid

Preparation of 2- {4- [5- (3,4-Dichloro-phenyl) -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,

IM in THF, 6.28 mmol) and 2-fluoro-4-methoxy-5-nitrobenzoic acid methyl ester (172 g, 0.75 mmol) in THF (5 mL) using the procedure described in Example 13. Purification by flash chromatography ( silica gel, 10% EtOAc / hexane) yielded 145 mg (0.28 mmol, 37%) of the desired product. MS: 515.2 (M ⁺ ), 517.2 (MH ⁺ ).

Preparation of 2- {4- [5- (3,4-dichlorophenyl) pentyl] phenylamino} -4-methoxy-5-nitrobenzoic acid

The title compound was prepared from 2- {4- [5- (3,4-dichloro-phenyl) -pentyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid methyl ester (145 mg, 0.28 mmol) and 1 N NaOH (aq) (0.56 mL) in THF (1.2 mL) using the procedure described in Example 2. Purification by flash chromatography (silica gel, 10% MeOH / CH ₂ Cl ₂ ) followed by recrystallization with MeOH yielded 58 mg (0, 12 mmol, 41%) of the desired product. Mp 192-193 ° C.

Calcd for C25H24Cl2N2O5: C, 56.95; H, 4.81; N,

5.56. Found: C, 59.29; H, 4.58; N, 5.36,

Example 15

Preparation of 2- {4- [3- (3,4-dichlorophenyl) propyl] phenylamino} -5-nitrobenzoic acid

Preparation 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, 1.25 mmol), cesium carbonate (569 mg, 1M). , 75 mmol), tris (dibenzylideneacetonipalladium (0) (34 mg, 0.037 mmol) and (S) - (2,2'-bis (di-p-tolylphosphino-1,1'-binaphthyl) (98%, (S}) -tol-BINAP) (38 mg, 0.056 mmol) (Ligand / Pd = 1.5) in anhydrous toluene (15 mL) using the procedure described in Example 2, Step C. This procedure yielded an orange solid (0, 51 g, 1.11 mmol, 74%), which is the desired product, mp 117-118 ° C.

MS: 457.1 (M < ⁺ &^gt;); 459.1 (MH ⁺ ).

Preparation of 2- {4- [3- (3,4-dichlorophenyl) propyl] phenylamino} -5-nitrobenzoic acid

The title compound was prepared from 2- {4- [3- (3,4-dichloro-phenyl) -propyl] -phenylamino} -5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2N NaOH (5.0 mL) in EtOH (2 mL) and THF (4 mL) using the procedure described in Example 2. This procedure yielded an orange solid, 0.49 g (1.10 mmol, 100%), which was the desired product. T.t.153-155 C.

MS: 443.2 (M ⁺ ), 445.2 (MH ⁺ ).

Example 16

Preparation of 2- (4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid

Preparation of 2- (4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid methyl ester

The title compound was prepared from 4- [2- (3,4-dimethyl-phenyl) -ethyl] -benzenamine (1.0 g, 4.43 mmol), 2-bromo-5-nitrobenzoic acid methyl ester (0.96 g, 3, 69 mmol), cesium carbonate (1.68 g, 5.17 mmol), tris (dibenzylideneacetone dipalladium (O) (101 mg, 0.11 mmol) and (S) - (2,2'-bis (di- p-tolylphosphino-1,1'-binaphthyl (98%, (S) -tol-BINAP) (113 mg, 0.17 mmol) (Ligand / Pd = 1.5) in anhydrous toluene (32 mL) using the procedure described in Example 2, step C. This procedure yields a yellow solid (1.31 g, 3.24 mmol, 73%) which is the desired product, mp 115-117 ° C.

MS: 405 (M < ^{+ >} ).

Analysis for C24H24O4N2.0,25 H ₂ 0: C, 71.27; H, 5.98; N, 6.93. Found: C, 70.48; H, 6.03; N, 6.85.

Preparation of 2- (4- [2- (3,4-dimethylphenyl) ethyl] phenylamino} -5-nitrobenzoic acid

The title compound was prepared from 2- (4- (2- (3,4-dimethyl-phenyl) -ethyl) -phenylamino} -5-nitrobenzoic acid methyl ester (1.12 'g, 2.76 mmol), 1N NaOH (50 mL) ) in EtOH (50 mL) and THF (50 mL) using the procedure described in Example 2. This procedure yielded a yellow solid, 1.03 g (2.63 mmol, 81%), which is the desired product. 214-216 ° C.

Analysis for C 23 H 22 O 4 N 2. 0.25 _H2O: C, 69.99; H, 5.74; N, 7.18. Found: C, 69.90; H, 5.82; N, 6.81.

Example 17

Preparation of 2 - [[4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] aminobenzoic acid

Step A (Scheme 1): Preparation of trans-1-chloro-2-trifluoromethyl-4- [2- (4-nitrophenyl) ethenyl] benzene

A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) a

4-chloro-3-trifluoromethylbenzaldehyde (47.85 g, 0.23 mol) in piperidine (19.5 g, 0.23 mol) was heated under an atmosphere

1 · nitrogen at 150 ° C to 160 ° C for 1 hour. The reaction mixture was cooled to 80 ° C to 100 ° C and i-PrOH (150 mL) was added at reflux. The mixture was cooled to room temperature and then placed in the refrigerator for 5 hours. The crystalline precipitate is filtered off, rinsed with cold iPrOH and dried at room temperature in a vacuum oven overnight to give trans-1-chloro-2-trifluoromethyl-4- [2- (4-nitrophenyl) ethenyl] -benzene as an orange solid,

22.53 g (68.75 mmol, 30%). T.t.173-174 C.

MS: 327.0 (M < ^{+ >} ).

Step B (Scheme 1): Preparation of 4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] benzenamine

The title compound was prepared from trans-1-chloro-2-,

-trifluoromethyl-4- [2- (4-nitrophenyl) ethenyl] benzene (22.53 g, 0.069 mol) and Ra-Ni (22 g) in THF (0.5 L) at 18 ° C to 29 ° C (ΔΡ = 20.5 psi) under a hydrogen atmosphere using the procedure described in Example 1, Step B. This procedure yielded a white solid, 20.0 g (66.73 mmol, 97%), which is the desired product. Mp 62-64 ° C.

MS: 298.1 (M < ^{+ >} ).

Preparation of 2- ([4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] aminobenzoic acid

To a cold solution of 4- [2- (4-chloro-3-trifluoromethylphenyl) -1-ethyl] benzenamine (4.33 g, 14.45 mmol) in THF (50 mL) at -78 ° C was added dropwise LHMDS (43.35 mL, 43.35 mmol) (1 / THF). The reaction mixture was stirred for 10 minutes at -78 ° C. A solution of 2-fluorobenzoic acid (2.02 g, 14.45 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at -78 ° C for 2 hours, then warmed to room temperature and stirred for an additional 3 hours. The reaction mixture was concentrated in vacuo (40 ° C) to remove the organic solvent. This residue was acidified to pH 3 with 3N HCl (aq). The precipitate was collected by filtration, rinsed with 10% HCl (40 mL) and dried in vacuo overnight to give the compound as a light solid, 4.3 g (10.24 mmol, 70%), which was the desired product. MP: 150-152 ° C.

Analysis for CC22H17O2NÍC1F3.0,59 _H2O: C, 61.39; H, 4.26; N, 3.25. Found: C, 61.01; H, 4.34; N, 3.30.

Example 18

Preparation of 2- [4- (3,4-dichlorophenyl) phenylamino] benzoic acid

Preparation of the potassium salt of o-bromobenzoic acid

To a solution of o-bromobenzoic acid (201.03 g, 1.0 mol) in MeOH (500 mL) was added K ₂ CO ₃ (69 g, 1.0 mol). The mixture was concentrated to give the desired product (239.1 g, 1.0 mol, 100%).

Preparation of 2 - [(4-iodophenyl) amino] benzoic acid

A mixture of o-bromobenzoic acid potassium salt (47.8 g, 0.2 mol), 4-iodoaniline (43.8 g, 0.2 mol), K ₂ CO ₃ (13.8 g, 0.1 mol) and copper acetate (2.87 g, 6%) in diglyme (100 mL) was heated to reflux for 30 min. The reaction mixture was diluted with H ₂ O (1.0 L) and filtered. The filtrate was acidified with dilute AcOH. The resulting precipitate was collected by filtration, washed with H ₂ O and dried under vacuum at 50 ° C for 16 hours. Recrystallization from EtOAc gave the desired product as a solid (29.7 g, 0.087 mol, 44%). Mp 205-206 ° C. Analysis for C _{3 0} Hi NiO ₂ I: C, 45.05; H, 2.97; N, 4.13. Found: C, 45.05; H, 2.97; N, 3.92.

Preparation of 2- [4- (3,4-dichlorophenyl) phenylamino] benzoic acid

A mixture of 3 ', 4-dichlorophenylborite (880 mg, 2.3 mmol), 2 - [(iodophenyl) amino] benzoic acid (339 mg, 1 mmol), PdCl ₂ .dppf.CH ₂ Cl ₂ [1, 1'bis (diphenylphosphine) ferrocenepalladium (II) chloride, complexed with dichloromethane (1: 1)] (67 mg, 0.082 mmol), K ₂ CO ₃ (829 mg, 6 mmol) and H ₂ O (2 mL) in dioxane (15 mL) was heated to reflux for 1 hour. The reaction mixture was diluted with EtOAc and filtered. The filtrate was treated with 1N HCl, washed with H ₂ O, brine, dried (Na ₂ SO ₄ ), and concentrated in vacuo to give a yellow solid. Purification by flash chromatography (silica gel, 10% MeOH / CH ₂ Cl 2) afforded 272 mg (0.76 mmol, 76%) of the title compound. Mp> 220 ° C.

Analysis calculated for:? _{9? 13? 2} ? 1? ₁₂ : Calcd: C, 63.23; H, 3.71; N, 3.88. Found: C, 62.95; H, 3.73; N, 3.63.

The following compounds of the present invention were prepared according to the general procedures outlined above.

Example 19

2- {4- [3- (4-Diethylaminophenyl) propyl] phenylamino) benzoic acid

MS: 403 (M < ^{+ >} ).

Calcd for C ₂₆ H ₃₀ N ₂ O ₂ 0.40 mol H ₂ O: C, 69.31; H, 6.87; N, 6.12. Found: C, 69.29; H, 7.04; N, 6.35.

Example 20

2- {4- [3- (4-Nitrophenyl) propyl] phenylamino) benzoic acid T.1.150-153 ’C.

MS: 376 (M < ^{+ >} ).

Example 21

2- (4- [3- (3-nitrophenyl) propyl] phenylamino) benzoic acid mp 166-167 ° C; MS: 376 (M < ^{+ >} ).

Calcd for C ₂₂ H ₂₀ N ₂ O ₄ · 2.20 mol H ₂ O: C, 63.51; H, 5.91; N, 6.73. Found: C, 63.56; H, 5.45; N, 6.46.

Example 22

2- {4- [3- (4-Amino-phenyl) -propyl] -phenylamino-benzoic acid, mp 110-112 ° C. MS: 347 (M ⁺ 1 < ^{+ >} ).

Example 23

2- {4- [3- (3-Aminophenyl) propyl] phenylamino) benzoic acid, mp 109 ° C. MS :. 333, (M ⁺ 1 < ^{+ >} ).

I. > 'I

Example 24

2- {4- [2- (4-Aminophenyl) phenylamino) benzoic acid

Mp 98-201 ° C. MS: 333 (M ⁺ 1 < ^{+ >} ).

Calcd for C ₂₁ H ₂₀ N ₂ O ₂ · 0.1 mol H ₂ O: 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, 8.27.

Example 25

2- {4- [2- (4-Dipropylamino-phenyl) -ethyl] -phenylamino} -benzoic acid, monohydrochloride, mp 176-177 ° C; MS: 417 (M ⁺ 1 < ^{+ >} ).

Calcd for C27H32N2O2: C, 71.59; H, 7.34; 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 ⁺ 1 ⁺ ).

Calcd for C25H26N2O2.HCl.H2O: 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 ⁺ 1 < ^{+ >} ).

Analysis for C28H34N2O2.0,2 _H2O: 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} benzoic acid

MP: 115-117 ° C.

MS: 374 (M ⁺ ), 375 (M ⁺ 1 ⁺ ).

Analysis for C24H26N2O2.0,1 _H2O: 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-ethylaminophenyl) propyl] phenylamino} benzoic acid m.p. 133 ° C.

7.02;

MS: 375 (M ⁺ 1 < ^{+ >} ).

Analysis for C 24 H ₂₆ N ₂ O ₂ 0.1 wt H ₂ O: C, 76.61; H, 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) benzoic acid MS: 431 (M ⁺ 1 ⁺ ).

Calcd for C28H34N2O2: C, 78.10; H, 7.96; N, Found: C, 78.02; H, 8.17; N, 6.50.

Example 31

2- {4- [2- (3-Dibenzylaminophenyl) ethyl] phenylamino} benzoic acid

MP: 95.5 to 97.5 ° C.

Calcd for C35H32N2O2: C, 82.00; H, 6.29; N, Found: C, 81.81; H, 6.58; N, 5.44.

Example 32

2- {4 -, [3- (3-diethylaminophenyl) propyl] phenylamino} benzoic acid

MS: 403 (M ⁺ 1 < ^{+ >} ).

Analysis for C26H30N2O2.0,1 _H2O: C, 77.23; H, N, 6.93. Found: C, 77.14; H, 7.82; N, 6.88.

Example 33 ¹

2- {4- [2- (3-Aminophenyl) ethyl] phenylamino} benzoic acid, mp 182-184 ° C. MS: 333 (M ⁺ 1 < ^{+ >} ).

Analysis for C21H20N2O2.0,25 _H2O: C, 74.87; H, N, 8.43. Found: C, 74.86; H. 6.16; N, 8.32.

Example 34

2- {4- [3- (4-Dimethylamino-phenyl) -propyl] -phenylamino} -acetic acid

6.51.

5.46.

7.53;

6.13;

benzoic acid

MS: 375 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₂₄ H ₂₆ N ₂ O ₂ · 0.1 H ₂ O: calculated: C, 76.61; H, 7.02; N, 7.44. Found: C, 76.52; H, 7.22; N, 7.49.

Example 35

2- {4- [2- (4-Acetylaminophenyl) ethyl] phenylamino} benzoic acid

MP: 224 ’C.

MS: 375 (M ⁺ 1 < ^{+ >} ).

Example 36

2- {4- [2- (3-Acetylamino-phenyl) -ethyl] -phenylamino} -benzoic acid, m.p. 213-215 ° C.

MS: 375 (M ⁺ 1 < ^{+ >} ).

Example 37

2- {4- [2- (3-Dipropylaminophenyl) ethyl] phenylamino} benzoic acid, monohydrochloride.

T.1.189-193 'C. MS: 417 (M ⁺ 1 < ^{+ >} ).

Analysis for C 7 H ₂ O ₃₂ N _{2 second} HCl: 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 acid, monohydrochloride.

T. t. 175-180 ° C. MS: 445 (M < ^{+ >} ).

Analysis for C 9 H ₃₆ N ₂ O ₂ .HCl _2: 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

2- {4- [3- (4-Acetylaminophenyl) propyl] phenylamino} benzoic acid

Tt176-178 C. MS: 389 (M ⁺ 1 < ^{+ >} ).

Example 40

2- {4- [3- (3-Acetylaminophenyl) propyl] phenylamino} benzoic acid,

T. t. 140-145 ° C. MS: 389 (M ⁺ 1 < ^{+ >} ).

Example 41

2- (4- [2- (3-diethylaminophenyl) ethyl] phenylamino} benzoic acid, monohydrochloride.

Tt166-171 C. MS: 389 (M ⁺ 1 < ^{+ >} ).

Calcd for C 25 H 28 N 2 O 2 · HCl: 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-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid, monohydrochloride, mp 187-193 ° C. MS: 401 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₂₆ H 28 N ₂ O ₂ . HCl: Calcd: C, 71.46; H, 6.69; N, 6.41; Cl, 8.11. Found: C, 71.28; H, 6.73; N, 6.35; Cl, 8.30.

Example 43

2- {4- [3- (4-Dipropylaminophenyl) propyl] phenylamino} benzoic acid

MS: 431 (M ⁺ 1 < ^{+ >} ).

Analysis for C28H ₃₄ N ₂ O 2: 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 acid

MS: 459 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₃ oH ₃₈ N ₂ 0 _2: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.40; H, 8.50; N, 6.19.

Example 45

I

2- {4- [3- (3-Dibutylaminophenyl) propyl] phenylamino} benzoic acid

MS: 459 (M ⁺ 1 < ^{+ >} ).

Calcd for C ₃₀ H ₃₈ N ₂ O ₂ : C, 78.56; H, 8.35; N, 6.11. Found: C, 78.40; H, 8.43; N, 6.11.

Example 46

2- (4- {3- [4- (ΙΗ-Pyrrol-1-yl) phenyl] propyl} phenylamino) benzoic acid

Tt131-136 C. MS: 397 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₂₆ H ₂₄ N ₂ O ₂ · 0.2 H ₂ O: calculated: 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-yl-phenyl) -propyl] -phenylamino} -benzoic acid

MS: 415 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₂₇ H ₃₀ N ₂ O ₂ .0,2 _H2O: 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

Tt57-62 C. MS: 431 (M ⁺ 1 < ^{+ >} ).

Analysis for Ο ₂₇ Ο ₃₀ Ν ₂ Ο ₃ .0,3 H ₂ O: calculated: 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

Tt236-239 C. MS: 375 (M < ^{+ >} ).

Example 50

2- {4- [3- (4-Diethylaminomethylphenyl) propyl] phenylamino} benzoic acid

Λ ’'

Ttl37 C. MS: 417 (M ⁺ 1 < ^{+ >} ).

Example 51

2- {4- [3- (4-Propylaminophenyl) propyl] phenylamino} benzoic acid

MS: 389 (M ⁺ 1 < ^{+ >} ).

Analysis for C25H28N2O2.0,2 _H2O: C, 76.58; H, 7.30; N, 7.14. Found: C, 76.61; H, 7.29; N, 7.03.

Example 52

2- {4- [3- (3-Propylaminophenyl) propyl] phenylamino} benzoic acid

MS: 389 (M ⁺ 1 < ^{+ >} ).

Analysis for C25H28N2O2.0,1 H ₂ 0: C, 76.93; H, 7.28; N, 7.18. Found: C, 76.85; H, 7.44; N, 7.06.

Example 53

2- {4- [3- (4-Pyrrolidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid

Tt171-177 C. MS: 401 (M ⁺ 1 < ^{+ >} ).

Analysis for C 26 H 8 N ₂ O _{2 2} H ₂ 0: 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-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid

Tt59-61 C. MS: 415 (M ⁺ 1 < ^{+ >} ).

Analysis for C27H30N2O2.0,3 _H2O: C, 77.22; H, 7.34;

N, 6.67. found: C, 77.18; H, 7.25; N, 6.49.

Example 55

{5 - [(1-Butyl-1,2,3,4-tetrahydro-6-quinolyl) methylidene] -4-oxo-2-thioxothiazolidin-3-yl} acetic acid,

Mp 222-224 ° C. MS: 391 (M ⁺ 1 < ^{+ >} ).

Example 56

{5 - [(1-butyl-2,3-dihydro-1H-indol-5-yl) methylidene] -4-oxo-2-thioxothiazolidin-3-yl} acetic acid

Mp > 250 ° C. MS: 377 (M ⁺ 1 < ^{+ >} ).

Analysis for C ₁₈ H ₂₀ N ₂ O ₃ S ₂ · 0.4 H ₂ O: calculated: 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-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-thiazolidin-3-yl} butanoic acid mp 152-154 ° C. MS: 417 (M ^+), 418 (M ^+), 419 (M ^{+ +).}

Analysis for C ₂ H ₂₆ N ₂ O ₃ with a _second O, 2H ₂ O: Calculated: 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, mp 98-99 ° C. MS: 414 (M < ^{+ >} ).

Example 60

N- (2- {4- [3- (3,4-dichlorophenyl) -propyl] -phenylamino} -benzoyl) -methanesulfonamide was prepared by reacting the product of Example 9 with methanesulfonamide. T.t.53-61 C.

Analysis for C 23 H 22 Cl 2 N 2 O 3 S. 0.13 _H2O: C, 57.58; H,

Λ '

4.68; N, 5.84. Found: C, 57.20; H, 4.66; N, 5.51.

Example 61

2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid

T.t.214-216 C.

Anal Ο ₂ 3Η ₂₂ Ν2Ο ₄ .0.25 H ₂ 0: C, 69.99; H, 5.74; N, 7.18. Found: C, 69.90; H, 5.82; N, 6.81.

Example 62

2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -5-nitro-benzoic acid

Mp 239-244 ° C. MS: 439 (MH < ^{+ >} ).

Example 63

2- {4- [2- (4-Chloro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid, m.p. 207-209 ° C.

Calcd for C ₂ H ₁₆ ClF ₃ N ₂ O ₄ : C, 56.85; H, 3.47; N, 6.03. Found: C, 56.75; H, 3.71; N, 5.83.

Example 64

5-Amino-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid is prepared by reacting the product of Example with hydrogen in the presence of Raney nickel. Mp 13 7-142 ° C.

Analysis for C ₂ H ₁₈ C 1 ₂ N2O2.0,96 mol THF: Calcd: C, 63.94; H,

4.72; N, 6.00. Found: C, 64.33; H, 4.91; N, 6.35.

Example 65

5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid

T.t.198-202 C.

Analysis for C ₂ H ₁₈ N ₂ O ₄ .0,11 H ₂ 0: C, 69.22; H, 5.04; N, 7.69. Found: C, 69.59; H, 5.27; N, 7.22.

Example 66

2- {4- [2- (4-Fluoro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -benzoic acid, m.p. 148-150 ° C.

Calcd for C ₂ H ₁₇ F ₄ NO 2: C, 65.51; H, 4.25; N, 3.47. found: C, 65.51; H, 4.13; N, 3.46.

Example 67

2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid

T.t.203-208 C.

Analysis for C _{2 4} F2N2O iHi _6: 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- (1H-tetrazol-5-yl) -phenyl] -amine was prepared according to the method described in Example 1, using a tetrazolfluoro intermediate which is synthesized from commercially available 2-fluorobenzonitrile and sodium azide using standard reaction conditions. MP: Ί29 precipitate, 152-157 ° C.

Analysis for C2iHi ₇ Cl ₂ N ₅ .0,15 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] -acetic acid 90

phenylamino} -5-nitro-benzoic acid

T.t.190-193 C.

Calcd for C ₂ H ₁₆ F ₄ N ₂ O ₄ : 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 C ₂₁ H ₁₉ NO ₂ : calculated: 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-phenyl) -ethyl] -phenylamino} -5-fluoro-benzoic acid

T. t. 180-182 ° C.

For C 21 H 16 Cl ₂ FNO ₂ .0.06 H ₂ O: calculated: C, 62.23; H,

4.01; N, 3.46. Found: C, 61.83; H, 4.04; N, 3.29.

Example 72

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -nicotinic acid

Mp.168-171 ° C.

Calcd for C20H16Cl2N2O2: 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

T.t.192,5-194,5 C.

Calcd for C ₂₁ H 17 ClN ₂ O ₄ : 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

T.t.210-212 C.

Analysis for C ₂ iHi ₇ ClN ₂ O ₄ 6 .0,2 H ₂ 0: 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, m.p. 153-160 ° C.

Analysis for C ₂₂ H ₉ Cl ₂ NO ₂ .0.61 H ₂ O: Calculated: 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-nitrobenzoic acid

T.t.236-238 C.

Example 77

2- {4- [2- (2,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid

MP: 200.5 to 202.5 ° C.

Analysis for C ₂₁ H ₁₆ Cl ₂ N ₂ O ₄ : calculated: 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-phenyl) -ethyl] -phenylamino} -6-trifluoromethyl-benzoic acid

T.t.130-132 C.

Analysis for C ₂₂ H ₁₆ Cl ₂ F ₃ NO ₂ : 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.

I

Example 80

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-dimethylamino-benzoic acid

T.t.75-80 C.

Example 81

2- {4- [2- (3,5-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid

Mp.191-194 ’C.

Calcd for C ₂₁ H 17 Cl ₂ NO ₂ : 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) -phenyl] -ethyl} -benzoic acid was prepared according to the method of Example 1 using decahydroisoquinoline-aldehyde prepared from trans- decahydroisoquinoline and parafluorobenzaldehyde under standard reaction conditions, mp 202-206 ° C.

Analysis for C30H34N2O2.0,12 _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 above methods, or using standard methods of combinatorial synthesis by reacting halogen-substituted benzoate esters with substituted aniline to give the corresponding diarylamine, and then saponifying to give benzoic acid of formula I. Reactions are carried out on a scale of 0.15 mmol following way. Solutions of each halobenzoate reactant (0.18 M) in toluene are placed in 7.1 cm ³ reaction flasks. Each aniline reactant was dissolved in anhydrous toluene to give 0.15 M solutions. The Distriman pipette was used to add halobenzoate containing 1 ml ml (0.15 mmol, 1 eq.) Of each solution to the prepared flasks (1.2 eq.) Aniline (0.18 mmol, reactants.) Catalyst solution was prepared by dissolving 0.025 M Pd ₂ (dba) ₃ (dipalladium-tridibenzylidene acetone) and 0.075 M BINAP (2.2 bis (diphenylphosphino) -1,1'-binaphyl) in toluene and 0.25 ml catalyst solution were added to each reaction flask. cesium (68 mg, 0.21 mmol, 1.40 eq.) was added to each reaction flask and the flasks were sealed and placed in an oven with shaker and heated at 100 ° C for 48 hours. The solid residue is suspended in 400 μΐ of ethyl acetate and filtered to remove the entire catalyst.The filtrates are concentrated to dryness by evaporation to give the desired compounds of formula I in which part of the benzoic acid is esterified (for example benzyl or methyl ester) The esters are dissolved in 500 μΐ of THF / ethanol (1: 1 v / v). to which 300 μ) of 5 M sodium hydroxide is added. The solutions are shaken for 5 hours at 60 ° C and then cooled and concentrated to dryness by evaporation of the solvents to give the desired compounds of formula I. Typical compounds prepared in this manner are listed below. The structure of the compounds is usually confirmed by mass spectral analysis.

Example 83

2- (3 ', 5'-Dichloro-3-methyl} -biphenyl-4-ylamino) -benzoic acid MS: 371; Mol. Mass: 372.2495.

Example 84

2- (3 ', 5'-Dibromo-3-methyl-biphenyl} -4-ylamino) -benzoic acid MS: 459: Mol. Mass: 461.1515,

I

Example 85

2- (4-1,3-Benzodioxol-5-yl-2-methyl-phenylamino) -benzoic acid

MS: 347; Mol. Mass: 347.3683.

Example 86

2- ⁽¹ 2,2, 4'-trichloro-biphenyl-4-ylamino) -benzoic acid MS: 391; Mol. Mass: 392.6678.

Example 87

2- (2-chloro-3 ^1, 4'-Difluoro-biphenyl-4-ylamino) -benzoic acid MS: 359; Mol. Mass: 359.7578.

Example 88

2- ^{(3-bromo-1-chloro} 2-biphenyl-4-ylamino) -benzoic acid MS: 401; Mol. Mass: 402.6737.

Example 89

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid

Example 90

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid

Example 91

3- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid

Example 92

5- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid

I,

Example 93

2- {4- (2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid

Example 94

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,5-dimethoxy-benzoic acid

Example 95

2- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid

Example 96

3- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -benzoic acid

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

4- (4- (2 - [(4aS, 8aR) -4- (octahydro-isoquinolin-2-yl) -phenyl] -ethyl} -phenylamino) -benzoic acid

Example 100

2- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -5-methoxy-benzoic acid

Example 101

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} -benzoic acid

Example 104

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid

Example 105

4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -nicotinic acid

Example 106

2- [2- (4-Fluoro-3-trifluoromethyl-phenyl) -2,3-dihydro-1H-isoindol-5-ylamino] -benzoic acid

Example 107

2- {4- [2- (3-Fluoro-4-methyl-phenyl) -ethyl] -phenylamino} -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

Example 110

I

4- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -3-methoxy-6-nitrobenzoic acid

Example 111

4- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -3-methoxy-benzoic acid

Example 112

2- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid

Example 113 {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenyl} - (2-methoxy-5-nitrophenylamine)

Example 114

2- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -3-nitro-benzoic acid

Example 115

3- (4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -benzoic acid

Example 116

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, sodium salt, m.p. 107-108 ° C.

Example 118

I

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid, potassium salt; Mp> 200 ° C.

Example 119

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid, calcium salt (1: 1); Mp> 220 ° C.

Example 120

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoate-2-hydroxy-1,1-hydroxymethyl-ethyl-ammonium; T.t.l85-187 C.

Example 121

2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -5-methoxy-benzoic acid; T.t.155-158 C.

Example 122

2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -benzoic acid; T.t.l84-185 C.

Example 123

2- {3- [2- (4-Chloro-phenyl) -ethyl] -phenylamino} -benzoic acid, mp 155-157 ° C.

Example 124

2- {3- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 182-184 ° C.

Example 125

2- {4- [2- (2,4-Dimethoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; T.t.l80-181 C.

Example 126

2- {4- [2- (2-Chloro-phenyl) -ethyl] -phenylamino} -benzoic acid m.p. 140-143 C.

Example 127

2- {4- [2- (2-Hydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid

MP: Mp 218-219 ° C.

Example 128

2- {4- [2- (3-Chloro-phenyl) -ethyl] -phenylamino} -benzoic acid m.p. 152-154 ’C.

Example 129

2- [4- (2-Biphenyl-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 [deg.] C.

Example 131

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} -acetic acid 100

benzoic acid

MP: 214-215 ’C.

Example 133

2- {4- [2- (3,4,5-Trimethoxy) -phenyl) -ethyl] -phenylamino} t acid

benzoic acid

T.1.146-147 ’C.

Example 134

2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid m.p. 153-154 C.

Example 135

2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -benzoic acid

T.t.106-108 ’C.

Example 136

2- {4- [2- (4- {2-Hydroxycarbonylphenylamino} phenyl) ethyl] phenylaminobenzoic acid

MS 451 (M + ¹ ).

Example 137

2- (3 ', 5'-Dichloro-biphenyl-4-ylamino) -benzoic acid m.p. ≫ 220 ° C.

Example 138

4- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -2-methoxy-5-nitro-benzoic acid

MP: 74-78 ’C.

Example 139

2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -5101 acid

fluoro-benzoic acid

MP: 122-123 ’C.

Example 140

5-Amino-2- {4- [5- (3,4-dichloro-phenyl) -pentyl] -phenylamino} -benzoic acid m.p. 182-184 ’C.

Example 141

N- (2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoyl) trifluoromethanesulfonamide MS.531 (M ').

Example 142

N- (2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoyl) -benzenesulfonamide; MS 539.

Example 143

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -5-trifluoromethyl-benzoic acid, mp 190-192 ° C. MS 453 (M &^lt; + & gt ^; ).

Example 144

4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino-isophthalic acid

M.p.264-266 ’C.

Example 145

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-trifluoromethyl-benzoic acid, mp 134-136 ° C; MS 454 (M < ^{+ >} ).

102

Example 146

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid MS 454 (M ⁺ ).

Example 147

2 - ({4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenyl} -methylamino) -5-dimethylamino-benzoic acid mp.128-131 ° C.

Example 148

2 - ({4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenyl} -methylamino) -benzoic acid MS 400 (M ⁺ ).

Example 149

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-dipropylamino-benzoic acid

MS 485 (M < ^{+ >} ).

Example 150

5-Dibutylamino-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid MS 513 (M ⁺ ).

Example 151

2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-diethylamino-benzoic acid, m.p. 106-110 ° C.

Example 152

2,2 ¹ - [1,2-ethanediylbis (4,1-phenylenimino)] bis103 acid

-benzoic acid

Example 153

4- [3- [4- (diethylamino) phenyl] propyl] -N- (2-methoxy-5-nitrophenyl) benzenamine

Example 154

2- {3- [2- (4-Chloro-phenyl) -ethyl] -phenylamino} -benzoic acid

Example 155

2- (3- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid

Example 156

2- (3- [3- (4-diethylaminophenyl) propyl] phenylamino} benzoic acid

Example 157

2- {3- [3- (4-Di-n-propylaminophenyl) propyl] phenylamino} benzoic acid

The following Examples 158-163 illustrate the use of the compounds of the present invention as starting materials and intermediates in the synthesis of other compounds and derivatives of the present invention. The examples illustrate the reduction of nitro groups to amino groups, alkylation of amino groups, and esterification of carboxyl groups. These reactions are shown in the following general scheme 12.

104

Scheme 12 ° ² X><c_{", and} H - <^ j reduction coo

COOH esterification

COOE alkylation

wherein R ^b and R ^c are as defined above, and E is an ester-forming group such as C 1 -C 6 alkyl (for example methyl, 2,2,2-trichloroethyl), benzyl, diphenylmethyl and the like.

Example 158

2- {4- [3- (4-Nitrophenyl) propyl] phenylamino} benzoic acid

105

To a slurry of 4- [3- (4-nitrophenyl) propyl] aniline (4.08 g, 15.9 mmol) and 2-bromobenzoic acid (3.52 g, 17.5 mmol) in i-PrOH (100 mL) Cu (OAc) ₂ (87 mg, 0.478 mmol) and KOAc (3.44 g, 35.0 mmol) were added at room temperature. The resulting mixture was heated at reflux for 23 hours and then cooled to room temperature. After removal of the solvent under reduced pressure, the residue was diluted with water (100 mL) and alkylated with 1.0 M aqueous NaOH to pH 9.0. The aqueous layer was washed with Et ₂ O (20 mL, twice) and acidified with 1.0 M aqueous HCl to pH 3.0. The resulting precipitate was suction filtered and dried at 60 ° C under vacuum to give the title compound as a beige solid (5.75 g, 96% yield). Tt150-153 C.

MS (Fab): 376 (MH &lt; ^{+ &gt;} ).

Example 159

2- {4- [3- (4-Aminophenyl) propyl] 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 DMF (40 mL) was added 10% Pd-C (300 mg) at room temperature under argon. Hydrogen gas (1 atm) was introduced into the flask and the mixture was stirred for 14 hours at room temperature. The reaction mixture was filtered through a pad of Celite to remove Pd-C and concentrated in vacuo. The residue was diluted with MeOH (about 50 mL) and concentrated in vacuo. This procedure is repeated 3 times to remove any trace of DMF. The residue was re-diluted with MeOH and the insoluble matter was removed by filtration. Removal of the filtrate solvent in vacuo yielded an oil which was diluted with CH ₃ CN (50 mL) and water (100 mL) was slowly added dropwise. The precipitate was filtered and dried at 60 ° C under vacuum to give the title compound as a white solid (2.34 g, 85% yield). Tt110-112 C. MS (Fab): 347 (MH &lt; ^{+ &gt;} ).

106

Example 160

2- {4- [3- (4-Aminophenyl) propyl] phenylamino} -benzoic acid methyl ester

To a solution of 2- {4- [3- (4-aminophenyl) propyl] phenylamino} benzoic acid (Example 159) (2.34 g, 6.75 mmol) in MeOH (50 mL) was added concentrated H ₂ SO ₄ ( 1.0 mL) at room temperature. The mixture was stirred at reflux for 3.0 days. Quench the reaction with Et ₃ N (10 mL) at 5 ° C and remove the solvent under reduced pressure. The residue was diluted with water (20 mL) and extracted with Et ₂ O (20 mL, 4 times). The combined ether layer was washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and purified by column chromatography to give the crude title compound as a yellow amorphous material (2.59 g). This material was used without further purification.

Example 161

2- {4- [3- (4-Diethylaminophenyl) propyl] phenylamino} benzoic acid methyl ester and 2- {4- [3- (4-ethylaminophenyl) propyl] phenylamino} benzoic acid methyl ester

To a solution of the crude ester described above (2.59 g, approx. 6.75 mmol) and CH ₃ CHO (2.0 mL, 35.1 mmol) in CH ₃ CN (50 mL) was added NaBH ₃ CN (1, 70 g (27.0 mmol) at 5 ° C and the suspension was stirred for 30 minutes while monitoring the pH and adding 1.0 M aqueous HCl to keep the mixture slightly acidic (pH 3.0-4.0). The reaction mixture was warmed to room temperature for 1.0 hour and then basified with 1.0 M NaOH solution to pH 9.0. The reaction mixture was concentrated under reduced pressure to remove CH ₃ CN and the resulting aqueous solution

107 was acidified with an aqueous solution of 1.0 M HCl to pH 3.0. The aqueous solution was extracted with CHCl ₃ (20 mL, 3 times) and the combined extract was washed with brine (5 mL). After drying over anhydrous Na ₂ SO ₄ , the solvent is removed under reduced pressure and purified by column chromatography (silica gel 60N, n-hexane / CHCl ₃ / Et ₃ N 50: 98: 2). The dialkylated product was first eluted as a yellow amorphous material (1.07 g, 38%).

MS (Fab): 417 (MH &lt; ^{+ &gt;} ).

The monoalkylated product is then eluted as a yellow amorphous material (0.79 g, 30%).

MS (Fab): 389 (MH &lt; ^{+ &gt;} ).

Example 162

2- {4- [3- (4-Diethylaminophenyl) propyl] phenylamino} benzoic acid

To an emulsion of 2- {4- [3- (4-diethylaminophenyl) propyl] phenylamino} benzoic acid methyl ester (1.68 g, 4.03 mmol) in EtOH (50 mL) at room temperature was added a 3 M aqueous solution of KOH ( 4.0 mL, 12.0 mmol) and then heated at reflux for 40 min. The reaction mixture was cooled to room temperature and neutralized with 1.0 M aqueous HCl to pH 9.0. The mixture was concentrated under reduced pressure to remove EtOH and the resulting aqueous solution was extracted with CHCl ₃ (50 mL, 3 times). The combined extract was washed with brine (10 mL) and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and purified by column chromatography (silica gel 60N, conc. NH ₄ OH / MeOH / CHCl ₃ 0.2: 2: 100 to 0.5: 5: 100) to give a yellow oil. This oil was diluted with acetone and the solution was concentrated under reduced pressure at room temperature to give the title compound as an amorphous solid (1.62 g, 99% for 0.2 hydrate).

108

MS (Fab): 403 (MH &lt; ^{+ &gt;} ).

Analysis for C26H30N2O2.0,20 _H2O: 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} benzoic acid

The title compound was prepared from 2- {4- [3- (4-ethylamino-phenyl) -propyl] -phenylamino} -benzoic acid methyl ester (from Example 161), EtOH (10 mL), and 3 M KOH (1.0 mL) using the procedure This procedure yielded a yellow solid, 253 mg, which is the desired product (90% for 0.1 hydrate).

MS (Fab): 375 (MH &lt; ^{+ &gt;} ).

Analysis for C24H26N2O2.0,10 _H2O: C, 76.61; H, 7.02; N, 7.44. Found: C, 76.62; H, 7.06; N, 7.36.

Biological examples

Representative compounds of formula I have been evaluated in several in vitro and in vivo assays which are used to assess clinical utility for the treatment of Alzheimer's disease.

Amyloid tests

BASSR (β-amyloid self-deposition radiodest)

Test for growth inhibitors of self-setting amyloid fibers.

109

Materials

Stock solutions:

Assay buffer or - 50 mM sodium phosphate, pH 7.5, 100 mM

NaCl, 0.02% NaN _3.1 M urea (filtered and stored at 1 ° C). and

Soluble β- (1-40) peptide (Bachem, Torrance, CA) - 2.2 mg / ml in deionized H ₂ O (storage in aliquots at -20 ° C, ice storage after dissolution) settles itself after 1 week storage. Usually, the solution should be stored until no delay is found in the test.

¹²⁵ I-labeled Αβ (1-40) - 150K-350K cpm / μΐ in 100% acetonitrile 0.1% trifluoroacetic acid (TFA) - 1% β-mercaptoethanol (aliquots stored at -20 ° c). ¹²⁵ I-labeled β (1-40) can be prepared as described by H. LeVine, III, in Neurobiol. Aging, 16: 755 (1995), which is incorporated herein by reference, or may be purchased from Amersham, Arlington Heights, Illinois.

Final Test Conditions: 30 μΜ soluble Αβ (1-40) in deionized water in assay buffer + 20K-50K cpm ¹²⁵ labeled Αβ (1-40) per test. The test compound is dissolved in dimethylsulfoxide (DMSO), usually at a stock solution concentration of 5-50 mM, so that a final DMSO concentration of <1% v / v is achieved. in the test.

Test: The reaction mixture for 50 tests (on ice) consists of 0.1 to

0.2 μΐ ¹²⁵ I-labeled Αβ (1-40) + 1 μΐ soluble Αβ (1-40) +

13.5 μΐ test buffer per test. The following are the amounts of the components of the reaction mixture sufficient for 50 test wells:

110

5-10 μΐ ¹²⁵ Ι-labeled β (1-40) (dry);

675 μΐ of test buffer;

μΐ of soluble Αβ (1-40)

Test Method: (1) Mixing the above ingredients to prepare a reaction mixture that is stored on ice.

(2) Pipette 14.5 μΐ of the reaction mixture into each of the 50 wells on polypropylene 96-well (U-bottom wells) plates on ice (Costar 3794).

(3) Add 1.7 μΐ of diluted test compound to each well in column 8, including the control solvent. Serial 3-fold dilution from 1 mM (100 μΜ final horse) in assay buffer - urea = 7 dilution + zero. Thus, each 96-well plate contains 11 samples + 1 control consisting of Congo red (0.039-5 μΜ final horse in 2-fold steps).

(4) Coat the plate with aluminum foil (Beckman 538619) and incubate for 10 minutes on ice.

(5) The temperature is raised to 37 ° C and incubated for 3 to 5 hours (depending on the amount of peptide).

(6) Remove the aluminum foil and add 200 μΐ of ice-cold urea assay buffer per well, collect the radiolabeled fibers by vacuum filtration through 0.2 μπ GVWP filters in 96-well plates (Millipore MAGV N22, Bedford, MA). The radioactivity on the filters is determined using a standard method well known to those skilled in the art.

BASST (β-amyloid self-settling T-thioflavin test) III

Test for growth inhibitors of self-setting amyloid fibers.

Materials' i

Stock solutions:

Assay buffer - 50 mM sodium phosphate, pH 7.5, 100 mM

NaCl, 0.02% NaN _3.1 M urea (filtered and stored at 4 ° C).

Soluble Αβ (1-40) peptide (Bachem, Torrance, CA) - 2.2 mg / ml in deionized H ₂ O (stored at -20 ° C, kept on ice after dissolution) settles itself after 1 week storage. Usually, the solution should be stored until no delay is found in the test.

Final Test Conditions: 30 μΜ soluble Αβ (1-40) in deionized water in assay buffer. The test compound is dissolved in dimethylsulfoxide (DMSO), usually at a stock solution concentration of 5-50 mM such that a final DMSO concentration of <1% v / v is achieved. in the test.

Test: The reaction mixture for 50 tests (on ice) consists of 1 μΐ soluble Αβ (1-40) + 13.5 μΐ assay buffer per test.

The following are the amounts of the components of the reaction mixture sufficient for 50 test wells:.

675 μΐ of test buffer;

μΐ of soluble Αβ (1-40).

Test method:

(1) mixing the above ingredients to prepare a reaction mixture that is stored on ice.

112 (2) 14.5 μΐ of the reaction mixture is pipetted into each of the 50 wells of a polystyrene 96-well (U-bottom well) microtiter plate on ice (Corning 25881-96).

(3) Add 1.7 μΐ of diluted test compound to each well in column 8, including the control solvent. Serial, 3- · ^1- fold dilution from 1 mM (100 μΜ final horse.) In assay buffer - urea = 7 dilution + zero. Thus, each 96-well plate contains 11 samples + 1 control consisting of Congo red (0.039-5 μΜ final horse in 2-fold steps).

(4) Coat the plate with aluminum foil and incubate for 10 minutes on ice.

(5) The temperature is raised to 37 ° C and incubated for 3 to 5 hours (depending on the amount of peptide).

(6) Remove aluminum foil and add 250 μΐ 5 μΜ thioflavin T (ThT) (T-3516, Sigma-Aldrich) in 50 mM glycine NaOH, pH 8.5, per well. The fluorescence is read on a plate reader (ex = 440 nm / 20 nm; em = 485 nm / 20 nm) for 5 minutes.

ΒΑΡΑ (β-amyloid peptide aggregation)

This assay is used to measure inhibition of β-amyloid peptide aggregation by a compound.

The aim of this assay is to provide a more efficient method for testing the level of β-amyloid aggregation using a final filtration-based assay. In this assay, hexafluoroisopropanol (HFIP) is used to decompose the amyloid peptide into monomeric form and a concentration of 33 μΜ is used that is sufficient to aggregate at pH 6.0 for several hours.

113

techniques

Aggregation of β-amyloid peptide, pH 6.0 (ΒΑΡΑ)

25 μΐ 50 mM phosphate buffer, pH 6.0, 10 μΐ 0.5 mg / ml Αβ (1-40) peptide in 20% HFIP + 0.1 μΙ / assay radioactive are added to a 96-well plate (Costar 3794). labeled ¹²⁵ I Αβ (140) [ ¹²⁵ ΙΑβ (1-40)], and 1 μΐ of the test compound from a concentration of 50 mM with a DMSO concentration of <1%. The plate is then incubated for 2-4 hours at room temperature. The reaction is terminated by the addition of 200 μΐ 50 mM phosphate buffer, pH 6.0, and the mixture is filtered through a 0.2 μπ 96-well filter plate (Millipore MAGU N22). Wash the filter plate with 100 μΐ of the same phosphate buffer. Aggregation is detected on a Microbeta counter after impregnating Meltilex filters (1450-441) and corrected for background.

BATYM test

methods:

The desired Αβ (1-42) California Peptide) is dried from a hexafluoroisopropanol (HFIP) stock solution. Αβ (1-42) is dissolved in dimethylsulfoxide (DMSO) and then mixed with phosphate buffered saline (PBS) (pH 7.4). The mixed Αβ (1-42) solution is filtered through a 0.2 µm Omnipore membrane filter (Millipore, Bedfors, MA). Test compound in DMSO (50-fold concentrate) is added to each well (0.5 μΐ / well) of a 96-well plate. Add Αβ (1-42) solution (24.5 μΙ / well) to each well. The plate is centrifuged at

114

1000 x g for 5 minutes and incubated at 37 ° C for 1 day (Αβ (1-42); final concentration 100 μΜ).

After incubation, a solution of thioflavin T (ThT) (30 μΜ) in glycine-NaOH buffer (pH 8.5, 50 mM) is added to each well and fluororescent (ex = 440/20 nm, em = 485/20 nm) measured. using a plate fluorescence reader. Inhibitory activity is calculated from the fluorescence reduction using the formula:

Inhibition% = {F (Αβ) -F (Αβ-Compound)} / {F (Αβ) -F (Solvent + Compound)} x 100

IC ₅₀ is calculated using a curve fitting program using the following equation. Data were obtained from two different experiments performed in triplicate.

Inhibition (x) = 100-100 / {l + x / SC ₅ O) ^n}, x = concentration of tested compound (M);

IC 50 = (M);

n = Hill coefficient.

Representative compounds of formula I have an inhibitory activity (IC ₅₀ ) of from 0.1 μΜ to more than 100 μΜ in the above tests.

The results of these assays for specific and representative compounds of the present invention are shown in Table 1 below.

115

Table 1: Inhibitory activity of compounds of formula I β-amyloid

Pri k. no. BASSR (IC ₅₀ = pM) BASST (IC ₅₀ = pM) BATYM (IC _S0 = pM) ΒΑΡΑ (IC ₅₀ = pM) 1 10 (P)> 100 (P) (6x)> 100 (Q)> 100 (R) > 100 (S), 52 (T) > 100 (Z) 2,4,30,10 (P) 3 (Q) > 100 (R) 11 (S), 11 (T) 6 (Z) 50,58.8 (P) 57.8 (Q) 60 (P),> 100 (P) 86 (Q) > 60 (R), > 60 (S), 11 (T) 2 2.2,4.1,4.1, 12,4.5 1.5 (P) 6:52 (P) 70 (P) 3 4.5,5.5 (all 3 V_v_ _shape ) (P) 15 (ppt), 5 (Q) 2 (P) 3 (Q) 11.7 (P) > 60 (P) 4 30. > 100 (3) 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 18,13,12,20 2 8.83 39 8 15,15,18,15 3, > 100 7.17 9 20 (ppt), 30, 52.40 (P) 1.2 (L) 20.1,28.2 (P) 38.6 (R) 75 (L) 10 70.50 4 75.7 67 11 18 (ppt), 20 (ppt), 20 (2x),> 100 (P)> 100,21, 30 (0) 1.1.3 (P) l, 0.8 (Q) 5.62 (P) 23 (P) 9 (Q) 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. _shape ) 15 100 (3x) P 100,16 (V. _shape ) 12,15,11 (Q) 1 (P) 1.2 (Q) 8.52 (P) 07.07 (Q) > 60 (P) 7 (Q) 16 18,7.5,10 (P) 70,32,42 (0) 3,0,3 (P) 1.1,0.8,0.6 (0) 12 (L) 10.3 (Q) 13 (P) 17 > 100 (ppt) (2x) 6.2 64.5 > 60 (Q), 41 (R) 18 > 100 (5 x) (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

116

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 (A) 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 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. _shape ) 66 > 100 (ppt) > 100 (ppt) 2.1 50.1 > 100 67 41 4 13.3 > 60 68 > 100> 100 1 > 100 110 69 2 (V. _shape ), 3.5 (ppt) 0.8 11.7 58 70 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

117

75 > 100 2.2 46.2 > 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. 70,30,40 1,0.3,0.3,0.3 9.14 51 80 > 100 4 24.8 > 60 81 > 100 15 48.4 73 82 > 100> 100> 100 2,0.3,0.3 83 > 100 > 100 9,47,29 84 > 100 > 100 5,40,21 85 > 100 18 8,77,45 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 11.8 > 100> 100 6 > 60 119 > 100 3 > 60 120 > 100 3 > 60 121 > 100> 100 1 122 > 100 2 > 100 > 60 123 > 100 (3χ), 14 4.18> 100, > 100 (Q) 3.3 3.2,4 (Q) 70.8 85.2 (Q) > 60 (Q) 124 > 100 10 62.7 125 82 10 > 100 80 126 > 100,> 100 30,100 (Q) 10.4 (Q) 84 73.9 (Q) 63 > 60 (Q) 127 > 100 (ppt) 10 > 100 67 128 > 100 (ppt) (4x) 11,> 100 (3X) 15,20,10,7.5 (Q) 15,> 100 (3X) (Q) 10,41,6 7.3.3 (Q) 75 > 60 (Q) 60 > 60 (Q) T 129 l (V _shape ) (2x)> 100 (ppt) 10,3,2,2 > 100 > 102 130 > 100 (3) 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 31.2 > 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 (4x) 40.30 > 100 2> 60> 60 144 15.25 40 > 100 114 145 10,40,30 4 56.8 9 146 > 100 30 > 100 > 60 147 > 100 10 93.4 > 60

118

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

The letter in parenthesis after a certain value indicates a particular batch of test compound. The terms P, Q, R, S, T and Z refer to different batches of the same compound. For example, designation 10 (P) indicates that the test compound was from lot P. If the lot is not listed, it was lot P.

The abbreviation ppt denotes precipitation and means that a precipitate formed at the indicated concentration. The term V-shape means that inhibition was observed after precipitation.

A value followed by a number and x (i.e. 4x) means that the compound was tested 4 times and the result was always the same.

The compounds of the present invention also have good activity in standard in vivo assays commonly used to evaluate agents useful in the art. treating diseases associated with amyloid aggregation, particularly Alzheimer's disease and other amyloidases. In one assay, amyloid is induced in the spleen of mice by subcutaneous injection of silver nitrate, Freund's complete adjuvant and intravenous injection of amyloid enhancing factor. Silver nitrate is administered every day to day 11. Test compounds are administered to mice daily from day 1 to day 11. On day 12, animals are sacrificed and their spleens are removed, treated histologically, stained with Congo red, and area percent microscopically determined.

119 spleens occupied by birefringent, Congolese red colored amyloid. The compounds of the present invention evaluated by this assay show an inhibition of amyloid deposition in the spleen by 70% relative to untreated controls.

I '

Another in vivo assay in which the compounds of the present invention were evaluated utilizes transgenic mice. Mice bearing the transgene for the prion promoter human β-amyloid precursor protein have been described by Hsiao et al. These transgenic mice develop β-amyloid deposits at approximately 9 months of age. At 15 months, the diffuse and compact senile plaques are abundant, primarily in the neocortex, the olfactory bulbus and the hippocampe. The compounds of the present invention are administered orally to mice from the age of 8 months (just prior to amyloid deposits) and administration continues for several months (up to 14-18 months of age). The animals are then sacrificed and their brains removed. The amount of amyloid in the brain is evaluated both histologically and biochemically. Compounds of the present invention evaluated using this model show an inhibition of amyloid accumulation in the cortex and hippocampus by 49% relative to untreated controls.

The above data show that representative compounds of the present invention are active in standard assays used to measure inhibition of protein aggregation. The compounds exhibit excellent specificity as demonstrated, for example, in the BASST assay, as well as in the BATYM and ΒΑΡΑ assays. The compounds are useful for clinically inhibiting amyloid protein aggregation and for displaying amyloid deposits for diagnostic purposes. The compounds will be used for the preparation

120 pharmaceutical compositions and the following examples illustrate their usual composition.

Example 164

Tablet formulation

component number Compound of Example 1 50 mg lactose 8 0 mg Corn starch (for mixture) 10 mg Corn starch (for paste) 8 mg Magnesium stearate (1%) 2 mg The compound of Example 1 is admixed with lactose and corn starch (for the mixture) and is carried out kneading to obtain

homogeneous powder. The corn starch (for paste) is suspended in 6 ml of water and heated under mixing to obtain a paste. The paste is added to the powder mixture and the mixture is granulated. The wet granules are sieved through sieves no. 8 and dried at 50 ° C. The mixture is lubricated with 1% magnesium stearate and compressed into tablets. The tablets are administered to a patient at a dose of 1 to 4 / day to prevent amyloid protein aggregation and to treat Alzheimer's disease.

Example 165: Parenteral Solution.

To a solution of 700 ml of propylene glycol and 200 ml of water for injection was added 20.0 g of Compound # 1. 19 (Example 19). The mixture was stirred and the pH adjusted to 5.0 with hydrochloric acid. Adjust the volume to 1000 ml with water for injections. The solution is sterilized, filled into 5.0 ml ampoules each containing 2.0 ml (40 mg of Compound No. 19), and these ampoules are

121 are closed under a nitrogen atmosphere. The solution is injected into a patient suffering from medullary thyroid cancer in need of treatment.

Example 166: A patch preparation of mg of 2- {4- [3- (3,4-dichlorophenyl) propyl] phenylamino} benzoic acid was mixed with 1 ml of propylene glycol and 2 mg of an acrylate-based adhesive polymer containing a resin crosslinker. The mixture is applied to an impermeable container (30 cm ² ) and adhered to the patient for long-term treatment of amyloid polyneuropathy.

The invention and the method of its implementation and use have been described to the fullest extent sufficient for its implementation and use. It will be appreciated that preferred embodiments of the invention have been described and that there are modifications which do not depart from the scope of the present invention as defined in the appended claims.

Claims (42)

PATENT CLAIMS A compound of formula (I) wherein O II R ^a is hydrogen, C 1 -C 8 alkyl or -C 1 -C 8 alkyl; n is 0 to 5 inclusive; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH, -NH 2, NR ^b R ^c , -CO 2 H, -CO ₂ C 1 -C ₆ alkyl, - NO ₂ , -OC _x -C ₁₂ alkyl, -C 1 -C 8 alkyl, -CF ₃ , -CN, -OCH ₂ phenyl, -OCH ₂ substituted phenyl, - (CH ₂ ) _m -phenyl, -O-phenyl, -O -substituted phenyl, -CH = CH-phenyl, X o o> i „L -O _{(CH2) p} NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -N (Ci-6 alkyl) (CH _{2) p} NR ^b R ^c, / C ^ alkyl OCpCg ^x CH ₂ OC _{r 6} alkyl, R ⁸ is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ; R ^b and R ^c are independently hydrogen, -C-Cgalkyl, - (CH _{2) m} ^- phenyl, or R ^b and R ^c together with the nitrogen to which they are attached form a cyclic ring selected from the group consisting of 123 piperidinyl, pyrrolyl, imidazolyl, piperazinyl, 4-C _x -C6alkylpiperazinyl, morpholino, thiomorpholino, decahydroisoquinoline, or pyrazolyl; R ^d is hydrogen, -C 1 -C 8 alkyl, -CF ₃ or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R ¹ and R ² , when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of Alzheimer's disease. A compound according to claim a pharmaceutically acceptable salt wherein R ^a is hydrogen; n is 2; and R ³ and R ⁴ are hydrogen. A compound according to claim a pharmaceutically acceptable salt, wherein R ^a is hydrogen; R ¹ is halogen; R ³ and R ⁴ are hydrogen; and n is 2 to 5, inclusive. A compound according to claim a pharmaceutically acceptable salt wherein R ^a is hydrogen; n is 2; R ³ and R ⁴ are hydrogen; and the formula or its 1 of formula (I) or a compound thereof 1 of formula (I) or a compound thereof R ¹ , R ² and R ⁷ independently represent chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) ₃ N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl, 124 N— r N [(CH ₂ ) 3 CH 3] 2, substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ . A compound according to claim 1 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen; n is 3, 4 or 5; R ³ and R ⁴ are hydrogen; and R ¹ , R ² and R ⁷ are independently chlorine or hydrogen. A compound according to claim 1 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen; n is 2; R ³ and R ⁴ are hydrogen; and R ⁵ , R ⁶ and R ⁸ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH 3, imidazolyl, -CN, fluoro, -CH ₃ , -CF ₃ , halogen, -NH-C 1 -C 6 alkyl, - N (C 1 -C 6 alkyl) ₂ , -NH ₂ or pyrrolyl. A compound according to claim 1 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen; n is e 2; R ³ and R ⁴ are hydrogen; and R ⁵ represents -CO ₂ H. 8. Compound of formula (I) 125 where R ^a is hydrogen; n is 1 to 5 inclusive; R ³ and R ⁴ are hydrogen; R ¹ , R ⁷ and R ² are independently chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) ₃ N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) 7 CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl, N [(CH ₂ ) 3 CH 3 ₁₂ , substituted phenyl, -OCH ₂ substituted phenyl, pyrrazolyl or -N (phenyl) ₂ ; R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH ₃ , imidazolyl, -CN ', fluoro, -CH ₃ , -CF _3, or pyrrolyl; R ⁸ is COOH or tetrazolyl; or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment of Alzheimer's disease. Compounds of formula (I) or pharmaceutically acceptable salts thereof for use according to claim 1, wherein the compound of formula (I) is: 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -5-nitrobenzoic acid; 2- {4- [4- (3,4-Dichlorophenyl) ethyl] phenylamino} -4-methoxy-5-nitrobenzoic acid; 2- {4- [2- (3,4-dihydroxyphenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4,5-trihydroxyphenyl) ethyl] phenylamino} benzoic acid; 126 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid; 2- {4- [3- (3,4-dichlorophenyl) propyl] phenylamino) -4-imidazo-1-yl-5-nitrobenzoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid; 2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino-benzoic acid 2- {4- [4- (3,4-dichlorophenyl) butyl] phenylamino} -5-nitro benzoic acid; 2- {4- [4- (3,4-Dichlorophenyl) butyl] phenylamino} -3,5-dinitrobenzoic acid; 2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -5-nitrobenzoic acid; 2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid; 2- [4- (3,4-dichlorobenzyl) phenylamino] benzoic acid; 2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid; 2- {4- [2- (3,4-difluorophenyl) ethyl] phenylamino} -5-nitrobenzoic acid; 2- {4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenylamino} benzoic acid; 2- [4- (2-Biphenyl-4-ylethyl) phenylamino] -5-nitrobenzoic acid; 5-nitro-2- (4-phenethylphenylamino) benzoic acid; 2- (4-phenethylphenylamino) benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; 2- {4- [2- (3,4-Dichlorophenyl) 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; 127 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methanesulfonyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -5-imidazol-1-yl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-nitrobenzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-nitrobenzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -3-nitrobenzoic acid; 5-Cyano-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -4,6-difluoro-benzoic acid; 6- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -2,3-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -6-fluoro-benzoic acid; 2- {4- [2- (3,4-dichlorophenyl) ethyl] phenylamino} -3-fluorobenzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -3-methyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3,5-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino] -5-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-pyrrol-1-yl-benzoic acid; 128 2- {4- [2- (4-Benzyloxyphenyl) ethyl] phenylamino} benzoic acid 2-4- {2- [4- (3-dimethylaminopropoxy) phenyl] ethyl} phenylamino) benzoic acid; 2- {4- [2- (4-diethylaminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Phenoxyphenyl) ethyl] phenylamino] benzoic acid; 2- {4- [2- (4-octyloxyphenyl) ethyl] phenylamino-benzoic acid; 2- (4- {2- [4- (2-ethoxy-1-ethoxymethylethyl) phenyl] ethyl} phenylamino) benzoic acid; 2- {4- [2- (4-pyrrol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Styrylphenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Dibutylaminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-ethyl-biphenyl-4-yl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octylphenyl) ethyl] phenylamino] benzoic acid; 2- (4- {2- [3- (3,5-dichlorophenoxy) phenyl] ethyl} phenylamino) benzoic acid; 2- (4- {2- [4- (2-chloro-6-fluorobenzyloxy) phenyl] ethyl} phenylamino) benzoic acid; 2- {4- [2- (4-pyrazol-1-ylphenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Diphenylaminophenyl) ethyl] phenylamino} benzoic acid; 2- (4- {2- [4- (3,4-Dichlorobenzyloxy) phenyl] ethyl} phenylamino) benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-amino-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichlorophenyl)] phenylamino} -5-nitrobenzoic acid; 129 2- {4- [2 - [(3,4-dichlorophenyl) propyl] phenylamino} -5-nitrobenzoic acid; 2- {4- [2- (3,4-dimethylphenyl) ethyl] phenylamino} -5-nitrobenzoic acid; 2 - [[4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] aminobenzoic acid; α, ¹ 2- [4- (3,4-dichlorophenyl) phenyl] aminobenzoic acid. 10. Compound of formula (I) R ^a is hydrogen, C 1 -C 8 alkyl or -C 1 -C 8 alkyl; n is 0 to 5 inclusive; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH, _-NH2, NR ^b R ^c, -CO ₂ H, -CO ₂ C ₆ alkyl, -NO _Z, -OC-C ₂ alkyl, -C Cgalkyl, -CF _3, -CN, -OCH ₂ phenyl , -OCH ₂ substituted phenyl, - (CH ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl, OO _b ll _b ll _b -O _{(CH2) p} NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -N (Ci-6 alkyl) (CH _{2) p} NR ^b R ^c, / C1-4C1-C6 alkyl CH; 'CH ₂ OC 1 -C ₆ alkyl R ⁸ is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ; 130 R ^b and R ^c are independently hydrogen, _-C-C6 alkyl, - (CH _{2) m} ^_ phenyl or R ^b and R ^c together with the nitrogen to which they are attached form a cyclic ring selected from the group consisting of piperidinyl, pyrrolyl , imidazolyl, piperazinyl, 4-C 1 -C 6 alkylpiperazinyl, morpholine, thiomorpholine, decahydroisoquinoline or pyrazolyl; R ^d is hydrogen, -C 1 -C 6 alkyl, -CF ₃ or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R and R, when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof, for use as a medicament for inhibiting aggregation of amyloid proteins to form amyloid deposits. A compound according to claim a pharmaceutically acceptable salt, wherein R ^a is hydrogen; n is 2; and R ³ and R ⁴ are hydrogen. A compound according to claim a pharmaceutically acceptable salt wherein R ^a is hydrogen; R ³ and R ⁴ are hydrogen; and n is 2 to 5, inclusive. 10 of formula (I) or a compound thereof 10 or formula A compound according to claim a pharmaceutically acceptable salt, wherein R ^a is hydrogen; n is e 2; R ³ and R ⁴ are hydrogen; and of formula (I) or thereof 131 R ¹ , R ² and R ⁷ independently represent chlorine, -N (CH ₂ CH ₃ ) 2 z -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) ₃ N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) 7 CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) 2, pyrrolyl, -CH = CH-phenyl, N [(CH ₂ ) 3 CH 3] 2, substituted phenyl, -OCH ₂ -substituted phenyl, pyrrazolyl or -N (phenyl) ₂ A compound according to claim 10 of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R ^a is hydrogen; n is 3, 4 or 5; R ³ and R ⁴ are hydrogen; and R ¹ , R ² and R ⁷ are independently chlorine or hydrogen. A compound according to claim 10 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen; n is 2; R ³ and R ⁴ are hydrogen; and R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH 3, imidazolyl, -CN, fluoro, -CH ₃ , -CF 3, halogen, -NH-C 1 -C 6 alkyl, -N (C 1 -C 6) ₆ alkyl) ₂ , -NH ₂ or pyrrolyl. A compound according to claim 10 of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a is hydrogen; n is e 2; R ³ and R ⁴ are hydrogen; and R ⁵ represents -CO ₂ H. 132 A compound of formula (I) wherein R ^a is hydrogen; n is 1 to 5 inclusive; R ³ and R ⁴ are hydrogen; R ¹ , R ⁷ and R ² are independently chlorine, -N (CH ₂ CH ₃ ) ₂ , -OH, -CH ₃ , fluoro, -CF ₃ , phenyl, hydrogen, -OCH ₂ phenyl, -O (CH ₂ ) 3N (CH ₃ ) ₂ , -O-phenyl, -O (CH ₂ ) ₇ CH ₃ , -CH (CH ₂ OCH ₂ CH ₃ ) ₂ , pyrrolyl, -CH = CH-phenyl, N [(CH ₂₎ ) ₃ CH _{3] 2,} substituted phenyl, _{-OCH2-substituted} phenyl, pyrazolyl, or -N (phenyl) _2; R ⁵ and R ⁶ are independently hydrogen, -CO ₂ H, -NO ₂ , -OCH ₃ , imidazolyl, -CN, fluoro, -CH ₃ , -CF ₃ or pyrrolyl; R ⁸ is COOH or tetrazolyl; A is CH or N; R ¹ and R ² , when adjacent, may be non-ethylenedioxy; or a pharmaceutically acceptable salt thereof for use as a medicament by inhibiting aggregation of amyloid proteins to form amyloid deposits. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to claim 17, wherein the compound of formula (I) is: 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino-benzoic acid; 2- {4- [2- (3,4-Dichlorophenyl) ethyl] phenylamino) -5-nitrobenzoic acid; 2- {4- [4- (3,4-Dichlorophenyl) ethyl] phenylamino] -4-methoxy-5-nitrobenzoic acid; 2- {4- [2- (3,4-Dihydroxy) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Dibutylaminophenyl) ethyl] phenylamino} 133 benzoic acid; 2- {4- [2- (3,4,5-trihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-methoxy-5-nitrobenzoic acid; 2- {4- [2 - [- (3,4-Dichlorophenyl) propyl] phenylamino} -4-imidazo-1-yl-5-nitrobenzoic acid; 2- {4- [2 - [- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid; 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -benzoic acid 2- (4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino] -5- nitro-benzoic acid; 2- (4- [4- (3,4-dichlorophenyl) butyl] phenylamino} -3,5-dinitrobenzoic acid; 2- {4- [5- (3,4-dichlorophenyl) pentyl] phenylamino} -5-nitrobenzoic acid; 2- (4- [5- (3,4-dichlorophenyl) pentyl] phenylamino} -4 methoxy-5-nitrobenzoic acid; 2- [4- (3,4-Dichloro-benzyl) -phenylamino] -benzoic acid; 2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- {4- [2- (4-chloro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -5-nitro-benzoic acid; 5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid; 2- (4-Phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -terephthalic acid; 134 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid; 4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methanesulfonyl-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-imidazol-1-yl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-nitro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-nitro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid; 5-Cyano-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,6-difluoro-benzoic acid; 6- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -2,3-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-methyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3,5-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6135 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; I 2- {4- [2- (4-Benzyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2- [4- (3-dimethylamino-propoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-diethylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octyloxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2- [4- (2-ethoxy-1-ethoxymethyl-ethyl) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-pyrrol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Styryl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4'-Ethyl-biphenyl-4-yl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2- [3- (3,5-Dichloro-phenoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- (4- (2- [4- (2-chloro-6-fluoro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-pyrazol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Diphenylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 136 2- (4- {2- [4- (3,4-Dichloro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2 - [(3,4-dichlorophenyl) propyl] phenylamino} -5-nitrobenzoic acid; 2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid; 2- ([4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] aminobenzoic acid; or 2- [4- (3,4-dichlorophenyl) phenyl] aminobenzoic acid. 19. 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) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4,5-trihydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -4-methoxy-5-nitrobenzoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -4-imidazo-1-yl-5-nitrobenzoic acid; 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -benzoic acid 20. Compounds: 2- (4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -5-nitro-benzoic acid; 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -3,5-dinitrobenzoic acid; 2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino} -5-nitrobenzoic acid; 137 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-nitrobenzoic acid; 2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid; 2- {4- [2- (4-Chloro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -5-nitrobenzoic 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-amino-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid; or 2- {4- [2- (3,4-dichlorophenyl)] - phenylamino} -5-nitrobenzoic acid. 21. Compounds: 2- (4-Phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} terephthalic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid; 4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methanesulfonyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5138 imidazol-1-yl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-nitro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-nitro-benzoic acid; I 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid. 22. Compounds: 5-Cyano-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,6-difluoro-benzoic acid; 6- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -2,3-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-fluoro-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-methyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3,5-difluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-trifluoromethyl-benzoic acid; 2- {4- [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; 139 2- {4- [3- (4-Aminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (3-Aminophenyl) propyl] phenylamino-benzoic acid; 2- {4- [2- (4-Aminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (4-Dipropylaminophenyl) ethyl] phenylamino} -benzoic acid monohydrochoride; 2- {4- [2- (4-diethylaminophenyl) ethyl] phenylamino} -benzoic acid, monohydrochoride, monohydrate; 2- {4- [3- (3-Dipropylaminophenyl) propyl] phenylamino} -benzoic acid; 2- {4- [3- (3-dimethylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-ethylaminophenyl) propyl] phenylamino} benzoic acid; 2- (N- (4- [3- (4-diethylaminophenyl) propyl] phenyl} -N-ethylamino) benzoic acid; 2- {4- [2- (3-Dibenzylaminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [3- (3-diethylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [2- (3-Aminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [3- (4-dimethylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [2- (4-Acetylaminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (3-Acetylaminophenyl) ethyl] phenylamino} benzoic acid; 2- {4- [2- (3-Dipropylaminophenyl) ethyl] phenylamino} benzoic acid, monohydrochloride; 2- {4- [2- (3-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid monohydrochloride; 2- {4- [3- (4-Acetylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (3-Acetylaminophenyl) propyl] phenylamino} 140 benzoic acid; 2- {4- [3- (3-diethylaminophenyl) ethyl] phenylamino} benzoic acid monohydrochloride; 2- (4- [2- (3-piperidin-1-ylphenyl) ethyl] phenylamino} benzoic acid monohydrochloride; 2- {4- [3- (4-dipropylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-Dibutylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (3-Dibutylaminophenyl) propyl] phenylamino} benzoic acid; 2- (4- (3- [4- (ΙΗ-pyrrol-1-yl) phenyl] propyl} phenylamino) benzoic acid; 2- {4- [3- (4-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid; 2- {4- [3- (4-diethylcarbamoylphenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-carboxyphenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-diethylaminomethylphenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-propylaminophenyl) propyl} phenylamino} benzoic acid; 2- {4- [3- (3-propylaminophenyl) propyl] phenylamino} benzoic acid; 2- {4- [3- (4-Pyrrolidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid; 2- {4- [3- (3-Piperidin-1-yl-phenyl) -propyl] -phenylamino} -benzoic acid; {5 - [(1-butyl-1,2,3,4-tetrahydro-6-quinolyl) methylidene] -4-oxo-2-thiazolidin-3-yl} acetic acid; {5 - [(1-butyl-2,3-dihydro-1H-indol-5-yl) methylidene] -4-oxo-2-thiazolidin-3-yl} acetic acid; 141 3- {5 - [(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl) methylidene] -4-iso-2-thiazolidin-3-yl} propanoic acid; 4- (5 - [(1-butyl-1,2,3,4-tetrahydroquinolin-6-yl) methylidene] -4-oxo-2-thiazolidin-3-yl] butanoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -5-, methyl-benzoic acid; N- (2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoyl) -methanesulfonamide; 2- {4- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -5-nitro-benzoic acid; 2- {4- [2- (4-Chloro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid; 5-amino-2- {4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 5-Nitro-2- (4-phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (4-Fluoro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenyl} - [2- (1H-tetrazol-5-yl) -phenyl] -amine; 2- {4- [2- (4-Fluoro-3-trifluoromethyl-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- (4-Phenethyl-phenylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-fluoro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -nicotinic acid; 2- {4- [2- (3-Chloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 142 2- {4- [2- (4-Chloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methyl-benzoic acid; 2- {4- [2- (2-chloro-phenyl) -ethyl] -phenylamino} -5-nitrobenzoic acid; 2- (4- [2- (2,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -6-trifluoromethyl-benzoic acid; 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-dimethylamino-benzoic acid; 2- {4- [2- (3,5-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2 - [(4aS, 8aR) -4- (octahydro-isoquinolin-2-yl) -phenyl] -ethyl} -benzoic acid; 2- ⁽¹ 3, ¹ 5-dichloro-3-methyl} biphenyl-4-ylamino) -benzoic acid; 2- (3 ', ^{5-dibromo-1-methyl} 3-biphenyl} -4-ylamino) benzoic acid; 2- (4-1,3-Benzodioxol-5-yl-2-methyl-phenylamino) -benzoic acid; 2- ⁽¹ 2,2, ^{1-trichloro-4-biphenyl-4-ylamino)} -benzoic acid; 2- (2-chloro-3 ^1, 4'-Difluoro-biphenyl-4-ylamino) -benzoic acid; 2- (3'-Bromo-2-chloro-biphenyl-4-ylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-nitro-benzoic acid; 3- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 5- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -isophthalic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} 143 benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4,5-dimethoxy-benzoic acid; 2- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -3-nitro-benzoic acid; 3- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 5- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -isophthalic acid; 2- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 4- (4- {2 - [(4aS, 8aR) -4- (octahydro-isoquinolin-2-yl) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -5-methoxy-benzoic acid; 2- {4- [2- (3-Methoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3-Bromo-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3-Fluoro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; 4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -nicotinic acid; 2- [2- (4-fluoro-3-trifluoromethyl-phenyl) -2,3-dihydro-1H-isoindol-5-ylamino] -benzoic acid; 2- {4- [2- (3-Fluoro-4-methyl-phenyl) -ethyl] -phenylamino} -benzoic acid. 23. Compounds: 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-trifluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-pyrrol-1-yl-benzoic acid; 2- {4- [2- (4-Benzyloxy-phenyl) -ethyl] -phenylamino} -44 benzoic acid; 2- (4 {2- [4- (3-dimethylamino-propoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-diethylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; I 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-Sphenyryl-phenyl) -ethyl] -phenylamino} -benzoic acid. 24. Compounds: 2- {4- [2- (4-Dibutylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- [2- (4'-Ethyl-biphenyl-4-yl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-octyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- {2- [3- (3,5-Dichloro-phenoxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- (4- {2- [4- (2-Chloro-6-fluoro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2- (4-pyrazol-1-yl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Diphenylamino-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- (4- (2- [4- (3,4-Dichloro-benzyloxy) -phenyl] -ethyl} -phenylamino) -benzoic acid; 2- {4- [2 - [(3,4-dichlorophenyl) ethyl] phenylamino} -5-aminobenzoic acid; 145 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- (3,4-dichlorophenyl) phenyl] aminobenzoic acid. 25. 2- {4- [2 - [(3,4-Dichlorophenyl) ethyl] phenyl} aminobenzoic acid or a pharmaceutically acceptable salt thereof. 26. 2- {4- [3 - [(3,4-Dichlorophenyl) propyl] phenylamino} benzoic acid or a pharmaceutically acceptable salt thereof. 27. A compound selected from the group consisting of: 2- (4- [3- (4-diethylamino-phenyl) -propyl] -phenylamino} -5-nitro-benzoic acid; 4- (4- [3- (4-diethylamino-phenyl) -propyl] -phenylamino} -benzoic acid; 4- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -3-methoxy-benzoic acid; 2- {4- [2- (3-Chloro-4-methyl-phenyl) -ethyl] -phenylamino} -5-methoxy-benzoic acid; {4- [2- (3-chloro-4-methyl-phenyl) -ethyl] -phenyl} - (2-methoxy-5-nitro-phenylamine; 2- (4- [3- (4-diethylamino-phenyl) -propyl] -phenylamino} -3-nitro-benzoic acid; 3- {4- [3- (4-Diethylamino-phenyl) -propyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dimethoxy-phenyl) -ethyl] -phenylamino} 146 benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid, sodium salt; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino) -benzoic acid; potassium salt; 2- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid, calcium salt (1: 1); 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoate-2-hydroxy-1,1-hydroxymethyl-ethyl-ammonium; 2- {4- [4- (3,4-Dichloro-phenyl) -butyl] -phenylamino} -5-methoxy-benzoic acid; 2- (4- [2- (3,4-Difluoro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {3- [2- (4-chloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {3- [2- (3,4-Dimethyl-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (2,4-Dimethoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (2-chloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (2-hydroxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3-Chloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- [4- (2-Biphenyl-4-yl-ethyl) -phenylamino] -benzoic acid; 2- {4- [2- (2,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 3- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 4- (4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4,5-trimethoxy) -phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (4-Phenoxy-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [5- (3,4-Dichloro-phenyl) -pentyl] -phenylamino}-147 benzoic acid; 2- (3 ', 5'-Dichloro-biphenyl-4-ylamino) -benzoic acid; 4- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -2-methoxy-5-nitro-benzoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -5-fluoro-benzoic acid; 5-amino-2- {4- [5- (3,4-dichloro-phenyl) -pentyl] -phenylamino} -benzoic acid; N- (2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoyl) trifluoromethanesulfonamide; 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; 4- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino-isophthalic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -4-1-fluoromethyl-benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -3-trifluoromethyl-benzoic acid; 2 - ({4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenyl} -methylamino) -5-dimethylamino-benzoic acid; 2 - ({4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenyl} -methylamino) -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-dipropylamino-benzoic acid; 5-Dibutylamino-2- (4- [2- (3,4-dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -5-diethylamino-benzoic acid; 2,2 ^1- [1,2-ethanediylbis (4,1-phenylenimino)] bis-benzoic acid; 148 4- [3- [4- (diethylamino) phenyl] propyl] -N- (2-methoxy-5-nitrophenyl) benzenamine. 28. A method of administering formula (I) to a patient: Imaging of amyloid deposits comprising: a detectable amount of the labeled compound or a pharmaceutically acceptable salt thereof Where || R ^a is hydrogen, C ₁ -C ₆ alkyl or -C 1 -C ₆ alkyl; n is 0 to 5 inclusive; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH, -NH 2, NR ^b R ^c , -CO 2 H, -CO ₂ C 1 -C ₆ alkyl, - NO ₂ , -OC 1 -C ₁₂ alkyl, -C ₁ -C ₈ alkyl, -CF ₃ , -CN, -OCH ₂ phenyl, -OCH ₂ substituted phenyl, (CK ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl, 0 0 _b ll h ll _b - 0 _{(CH2) p} NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -Ν (ΟχCealkyl) (CH 2) _p NR ^b R ^c, / CH ₂ OC _r -C ₆ alkyl, -CH OC = CH _{2 R 6} alkyl R ⁸ is COOH, tetrazolyl, -SO 2 R ^d, or -CONHSO 2 R ^d ; R ^b and R ^c are independently hydrogen, -C 1 -C ₆ alkyl, - (CH ₂ ) _m -phenyl or R ^b and R ^c together with the nitrogen atom to which they are attached, 149 form a cyclic ring selected from the group consisting of piperidyl, pyrrollyl, imidazolyl, piperazinyl, 4-C _1-6 alkylpiperazinyl, morpholine, thiomorpholine, decahydroisoquinoline or pyrazolyl; R ^d is hydrogen, -C 1 -C 6 alkyl, -CF ₃ or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R ¹ and R ² , if adjacent, may be. methylenedioxy; or a pharmaceutically acceptable salt thereof; (b) waiting for a sufficient period of time to associate the labeled compound with amyloid deposits; and (c) detecting a labeled compound associated with amyloid deposits. 29. The method of claim 28, wherein the patient has or is suspected of having Alzheimer's disease. 30. The method of claim 28 wherein the labeled compound is a radiolabeled compound. The method of claim 28, wherein the labeled compound is detected by MRI. 32. Compounds: 2- {4- [2- (3,4-Dichloro-phenyl) -ethyl] -phenylamino} -benzoic acid; 2- {4- [2- (3,4-Dichlorophenyl) ethyl] phenylamino} -5-nitrobenzoic acid; 2- {4- [3- (3,4-Dichloro-phenyl) -propyl] -phenylamino} -benzoic acid; 150 2 - [[4- [2- (4-chloro-3-trifluoromethylphenyl) ethyl] phenyl] amino} -benzoic acid; and 2- {4- [3- (4-diethylaminophenyl) propyl] phenylamino} benzoic acid. 33. A pharmaceutical composition comprising a compound of claim 19 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor. 34. A pharmaceutical composition comprising a compound of claim 20 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor. 35. A pharmaceutical composition comprising a compound according to claim 21 admixed with a pharmaceutically acceptable diluent, excipient or carrier therefor. 36. A pharmaceutical composition comprising a compound of claim 22 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor. 37. A pharmaceutical composition comprising a compound of claim 23 admixed with a pharmaceutically acceptable diluent, excipient or carrier therefor. 38. A pharmaceutical composition comprising the compound of claim 24 blended 151 with a pharmaceutically acceptable diluent, excipient or carrier for the compound. 39. A pharmaceutical composition comprising a compound of claim 25 admixed with a pharmaceutically acceptable diluent, excipient or carrier therefor. 40. A pharmaceutical composition comprising a compound of claim 26 admixed with a pharmaceutically acceptable diluent, excipient or carrier therefor. 41. A pharmaceutical composition comprising a compound of claim 32 admixed with a pharmaceutically acceptable diluent, excipient or carrier therefor. A compound of formula I Where || R ^a is hydrogen, C 1 -C ₆ alkyl or -C 1 -C ₆ alkyl; n is 0 to 5 inclusive; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, -OH, _-NH2, NR ^b R ^c, -CO ₂ H, -CO ₂ C ₆ alkyl, -NO _2, -OC-C ^ alkyl, C _x -C ₈ alkyl, -CF _3, -CN, -0CH _2- phenyl, -OCH ₂ substituted phenyl, (CH ₂ ) _m -phenyl, -O-phenyl, -O-substituted phenyl, -CH = CH-phenyl, 152 - Ο (CH ₂₎ p NR ^b R ^c, R ^c -CNR ^{b, b} -NHCR, -NH (CH 2) p NR ^b R ^c, -N (CXC ₆ alkyl) (CH _{2) p} NR ^b R c, / C OCJ ^ -C ^ alkyl, -CH ₂ CH _r OC ₆ alkyl R ⁸ is COOH, tetrazolyl, -SO 2 R ^d or -CONHSO 2 R ^d ; R ^b and R ^c are independently hydrogen, -C 1 -C 6 alkyl, - (CH ₂ ) _m -phenyl or R ^b and R ^{0 together} with the nitrogen atom to which they are attached form a cyclic ring selected from the group consisting of piperidyl, pyrrollyl, imidazolyl, piperazinyl, 4-C _1-6 alkylpiperazinyl, morpholine, thiomorpholine, decahydroisoquinoline or pyrazolyl; R ^d is hydrogen, -C 1 -C ₆ alkyl, -CF ₃ or phenyl; m is 0 to 5 inclusive; p is 1 to 5 inclusive; A is CH or N; R ¹ and R ² , when adjacent, may be methylenedioxy; or a pharmaceutically acceptable salt thereof. 43. A pharmaceutical composition comprising a compound of claim 42 admixed with a pharmaceutically acceptable diluent, excipient, or carrier therefor.