WO1996034853B1 - Azocompounds for the antemortem diagnosis of alzheimer's disease and in vivo imaging and prevention of amyloid deposition - Google Patents

Abstract

Amyloid binding compounds which are derivatives of Chrysamine G, pharmaceutical compositions containing, and methods using such compounds to identify Alzheimer's brain in vivo and to diagnose other pathological conditions characterized by amyloidosis, such as Down's Syndrome are described. Pharmaceutical compositions containing Chrysamine G and derivatives thereof and methods using such compositions to prevent cell degeneration and amyloid-induced toxicity in amyloidosis associated conditions are also described. Methods using Chrysamine G derivatives to stain or detect amyloid deposits in biopsy or post-mortem tissue are also described. Methods using Chrysamine G derivatives to quantify amyloid deposits in homogenates of biopsy and post-mortem tissue are also described.

Claims

AMENDED CLAIMS [received by the International Bureau on 27 November 1996 (27.11.96); original claim 1 amended; remaining claims unchanged (5 pages)]

1. An amyloid binding compound of Formula I or a water soluble, non-toxic salt thereof:

wherein :

is either N=N, c≡c, or CR'=CR' (where R'

represents H or a lower alkyl group) ;

X is C(R")₂

(wherein R" is each independently is H, F, Cl, Br, 1, a lower alkyl group, CF₃, CH₂-CH₂F, O-CH₂-CH₂F, CH₂- CH₂-CH₂F, O-CH₂-CH₂-CH₂F, CN, (C=O)-R', N(R')₂, NO₂, (C=O)N(R')₂ O(CO)R', OR', COOR', a tri-alkyl tin, a tetrazole or oxadiazole of the form:

wherein R' is H or a lower alkyl group) or X is CH=CH, N=N, C=O, O, NR' (where R' represents H or a lower alkyl group), S, or SO₂; each R₁ and R₂ independently is H, F, Cl, Br, I, a lower alkyl group, CF₃, CH₂-CH₂F, O-CH₂-CH₂F, CH₂-CH₂-CH₂F, O-CH₂- CH₂-CH₂F, CN, (C=O)-R', N(R')₂, N0₂, (C=O) N(R')₂ O(CO)R', OR', COOR', a tri-alkyl tin, a tetrazole or oxadiazole of the form:

(wherein R' is H or a lower alkyl group), or a triazene of the form:

(wherein R₈ and R₉ are lower alkyl

groups) or

and at least one of R₂ is not H, OCH₃, CH₃, or halogen when the compound of Formula I is a diazo phenyl compound; each Q is independently selected from one of the following structures, each of which contain a carboxylic acid or an acid-like functionality:

IA, IB, IC, ID, IE, IF and IG, wherein

IA has the following structure: where

in :

each of R₃, R₄, R₅, R₆, or R₇ independently is H, F, Cl, Br, I, a lower alkyl group, CF₃, CH₂-CH₂F, O-CH₂- CH₂F, CH₂-CH₂-CH₂F, O-CH₂-CH₂-CH₂F, CN, (C=O)-R', N(R')₂, NO₂, (C=O)N(R')₂ O(CO)R', OR', COOR', a trialkyl tin, a tetrazole or oxadiazole of the form:

(wherein R' is H or a lower alkyl group), or a triazene of the form:

(wherein R₈ and R₉ are lower alkyl groups)

or

wherein at least one of R₃, R₄, R₅, R₆, or R₇ is a hydroxy, tetrazole , oxadiazole , NO₂, or carboxy in both Q ' s ; and at least one of R₁ , R₂, R₃ , R₄, or R₇ is not H when R₅ is hydroxyl and R₆ is carboxy or a lower alkyl ester thereof ; at least one of R₁ , R₂, R₃ , or R₄ is not H when R₅ is amino, R₆ is carboxy or a lower alkyl ester thereof, and R₇ is hydroxyl; at least one of R₁, R₃, R₄, or R₇ is not H when exactly two of R₂ is CH₃ or OCH₃, R₅ is hydroxyl and R₆ is carboxy or a lower alkyl ester thereof; at least one of R₁ or R₂, is not ri or CH₃ when R₃, R₄, or R₇ is CH₃, R₅ is hydroxyl and R^ is carboxy or a lower alkyl ester thereof; R₇ is not hydroxyl when R₄ is F; R₂ is not COOH when R₅ is hydroxyl and R₆ is carboxy or a lower alkyl ester thereof; at least one of R_1, R₂, R₃, R₄, or R₇ is not H when R₅ is hydroxyl and R₆ is H; R₄ is not sulfo when R₆ is COOH and R₇ is hydroxyl; R₃ and R₇ are not NH₂ or hydroxyl when R₂ is carboxy; at least one of R₁, R₂, R₃, R₄, or R₇ is not H when R₅ is hydroxyl, R₆ is carboxy or a lower alkyl ester thereof, and X of Formula I is CR'=CR'; at least one of R, or R₂ is not H or at least one of R₃, R₅, or R₇ is not H, hydroxyl, or CH₃ when X of Formula I is SO₂;

IB has the following structure:

(IB)

wherein:

each of R₁₀, R₁₁, R₁₂, R₁₃, R_14, R₁₅, or R₁₆ independently is H, F, Cl, Br, I, a lower alkyl group, CF₃, CH₂- CH₂F, O-CH₂-CH₂F, CH₂-CH₂-CH₂F , O-CH₂-CH₂-CH₂F, CN, (C=O)-R', N(R')₂, NO₂, (C=O)N(R')₂, O(CO)R', OR', COOR', a tri-alkyl tin, a tetrazole or oxaddazole of the form:

(wherein R' is H or a lower alkyl group), or a triazene of the form:

(wherein R₈ and R₉ are lower alkyl

groups) or

and wherein at least one of R_10, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅ or

R₁₆ is a hydroxy, tetrazole; oxadiazole, NO₂ or carboxy in both Q's; and at least one of R₁ or R₂ is Br or I or at least one of R₁₁-R₁₅ is not H when R₁₀ is hydroxyl and R₁₆ is (C=O)N(R')₂ or carboxy or a lower alkyl ester thereof; at least one of R₁ or R₂ is Br or I or at least one of R₁₀-R₁₄ is not H when R₁₅ is hydroxyl and R₁₆ is carboxy or a lower alkyl ester thereof; at least one of R₁ or R₂ is not H or at least one of R_11-14 is not H when X of Formula I is SO₂;

IC has the following structure: STATEMENT UNDER ARTICLE 19(1)

In response to the International Search Report, mailed on 27 September 1996, the applicants have amended the claims by replacing present pages 119-123 with substitute pages 119-123 submitted herewith. In the substituted pages, claim 1 has been amended. Claims 2-25 are as filed. The amendment to claim 1 amends the definition of R₂ on Formula I and amends the definition of the combinations of R groups on structures IA, IB to exclude those compounds disclosed in the documents cited in the search report.

Applicants have reviewed the International Search Report, and the documents cited therein and note that only claim 1 has been indicated as lacking novelty and inventive step. Applicants have amended the claims such that the documents no longer defeat the novelty or inventive step of the compounds claimed in the substitute pages.

Applicants submit that the claims contained in the substitute pages 119-123 possess novelty and inventive step over each of the documents cited in the search report.