Bifunctional molecules with antibody-recruiting and entry inhibitory activity against the human immunodeficiency virus

Patent metadata

Field	Value
Publication number	US-9562038-B2
Application number	US-201113988251-A
Country	US
Kind code	B2
Filing date	Nov 17, 2011
Priority date	Nov 18, 2010
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-HI's, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-HI's bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. Compounds and methods are described herein.

First claim

The invention claimed is:

1. A compound according to the chemical structure:

Where

is an antibody binding terminus (moiety) comprising a moiety according to the chemical structure;

wherein said DNP group is a dinitrophenyl group linked through the amino group or a thio group to the amino acid;
Y′ is H or NO 2 ;
X is O, CH 2 , NR 1 , S(O), S(O) 2 , —S(O) 2 O, —OS(O) 2 , or OS(O) 2 O;
R 1 is H, a C 1 -C 3 alkyl group, or a —C(O)(C 1 -C 3 ) group;
Xs is OH or NHAc;
X R is O or S;
X M is O or S;
X′ is CH 2 , O, N—R 1 ′ or S;
R 1′ is H or C 1 -C 3 alkyl;
Z is a bond, a monosaccharide, disaccharide, oligosaccharide, glycoprotein or glycolipid;
Xs is OH or NHAc;
X b is a bond, O, CH 2 , NR 1 or S;
X″ is O, CH 2 , NR 1 ; and

is a linker molecule which chemical links ABT to R Y and which optionally includes a connector group CT;

optionally substituted is an aromatic or heteroaromatic group;
R Y is an optionally substituted heteroaryl, or is an optionally substituted aryl group wherein said optionally substituted heteroaryl or said optionally substituted aryl group is selected from the group consisting of imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, indole, quinoline, pyridone, pyridazine, pyrazole, triazine, tetrazole, isoindole, indolizine, purine, indazole, isoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline, phenacene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine, pyridopyrimidine; thiophene, benzothiophene; furan, pyran, cyclopentapyran, benzofuran, isobenzofuran; thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridoxazine, furopyridine, furopyrimidine, thienopyrimidine, phenyl, naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, 2-thiazole, 4-thiazole, 5-thiazole, isothiazolyl, oxazole, 2-oxazole, 4-oxazole, 5-oxazole, isoxazolyl, furanyl, 2-furan, 3-furan or thiophenyl, 2-thiophene, 3-thiophene, a bicyclic aryl, benzyl, anthracenyl, and phenanthrenyl;
X 2 is —(CH 2 ) n O—(C 1 -C 6 alkyl), —(OCH 2 ) n O—(C 1 -C 6 alkyl), H, —(CH 2 ) n OH, —(CH 2 ) n COOH, optionally substituted C 1 -C 6 alkyl, —(CH 2 ) n C(O)—(C 1 -C 6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n NR 1 R 2 , —(CH 2 ) n C(O)—NR 1 R 2 , —(CH 2 O) n H, —(CH 2 O) n COOH, —(CH 2 O) n C(O)—(C 1 -C 6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , NO 2 , CN or halogen;
X 3 is H, —(CH 2 ) n OH, —(CH 2 ) n COOH, optionally substituted C 1 -C 6 alkyl, —(CH 2 ) n O—(C 1 -C 6 alkyl), —(CH 2 ) n C(O)—(C 1 -C 6 alkyl), —(CH 2 ) n NR 1 R 2 , —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(CH 2 O) n H, —(CH 2 O) n COOH, —(OCH 2 ) n O—(C 1 -C 6 alkyl), —(CH 2 O) n C(O)—(C 1 -C 6 alkyl), —(OCH 2 ) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , NO 2 , CN, halogen or a monocyclic aryl or heteroaryl group which itself is optionally substituted;
R 1 is H or a C 1 -C 3 alkyl group;
R 1 and R 2 are each independently H or a C 1 -C 6 alkyl group;
i is 1 or 0;
k is 0, 1, 2 or 3;
n is 0, 1, 2, 3, 4, 5, 6;
Y 3 is H or a C 1 -C 3 alkyl group; and
R N is H or a C 1 -C 3 alkyl group which is optionally substituted with one or two hydroxyl groups or up to three halogen groups,
or a pharmaceutically acceptable salt, enantiomer, solvate or polymorph thereof, wherein the term “substituted” shall mean substituted at a carbon or nitrogen position with hydroxyl, carboxyl, cyano (C≡N), nitro (NO 2 ), halogen, C 1 -C 10 alkyl, substituted phenyl, benzyl, benzoyl, C 1 -C 6 alkoxy, aryl ester, C 1 -C 6 alkylene ester, where substitution occurs on the alkylene group, rather than at the ester function, aryl, a five- or six-membered cyclic alkylene amine, a C 1 -C 6 alkyl amine, a C 1 -C 6 dialkyl amine which alkyl groups may be substituted with one or two hydroxyl groups, an amido group substituted with one or two C 1 -C 6 alkyl groups, carboxamide, which is substituted with one or two C 1 -C 6 alkyl groups, C 1 -C 6 alkyl or aryl alkanol or C 1 -C 6 alkyl or aryl alkanoic acid.

2. The compound according to claim 1 according to the formula:

where

is a monocyclic or bicyclic aryl or heteroaryl group according to the chemical structure:

Where W is H, —(CH 2 ) n OH, —(CH 2 )—COOH, C 1 -C 6 alkyl, —(CH 2 ) n O—(C 1 -C 6 alkyl), —(CH 2 ) n C(O)—(C 1 -C 6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(CH 2 O) n OH, —(CH 2 O) n COOH, —CH 2 O) n O—(C 1 -C 6 alkyl), —(CH 2 O) n C(O)—(C 1 -C 6 alkyl), —(CH 2 O) b NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , NO 2 , CN, halogen (F, Cl, Br, I) or a monocyclic aryl or heteroaryl group which itself is optionally substituted;
W′ is H, —(CH 2 ) n OH, —(CH 2 ) n COOH, C 1 -C 6 alkyl, —(CH 2 ) n O—(C 1 -C 6 alkyl) or halogen;

 is a group according to chemical structure:

Where W 2 is H, —(CH 2 ) n OH, —(CH 2 ) n COOH, C 1 -C 6 alkyl, —(CH 2 ) n O—(C 1 -C 6 alkyl), —(CH 2 ) n C(O)—(C 1 -C 6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(CH 2 O) n OH, —(CH 2 O) n COOH, C 1 -C 6 alkyl, —(CH 2 O) n O—(C 1 -C 6 alkyl), —(CH 2 O) n C(O)—(C 1 -C 6 alkyl), —(CH 2 O) n NHC(O)—R 1 , —(CH 2 O) n C(O)—NR 1 R 2 , NO 2 , CN or halogen;
X in

 is a group —(CH 2 ) n′ NHC(O)—, —(CH 2 ) n′ NH—, —(CH 2 ) n′ O—, —(CH 2 ) m —, —(CH 2 ) n′ S—,
—(CH 2 ) n′ S(O)—, —(CH 2 ) n′ SO 2 — or —(CH 2 ) n′ NH—C(O)—NH— which links

 to the linker;

Y is O, S or N—R where R is H or a C 1 -C 3 alkyl group;
X 2 is —(CH 2 O) n O—(C 1 -C 6 alkyl), H, —(CH 2 ) n OH, —(CH 2 ) n COOH, C 1 -C 6 alkyl, —(CH 2 ) n O—(C 1 -C 6 alkyl), —(CH 2 ) n C(O)—(C 1 -C 6 alkyl), —(CH 2 ) n NHC(O)—R 1 , —(CH 2 ) n C(O)—NR 1 R 2 , —(CH 2 O) n OH, —(CH 2 O) n COOH, C 1 -C 6 alkyl, —(CH 2 O) n C(O)—(C 1 -C 6 alkyl), —(CH 2 O) n NHC(O)—R 1 or —(CH 2 O) n C(O)—NR 1 R 2 , NO 2 ;
R 1 and R 2 are each independently H or a C 1 -C 6 alkyl group;
Y 3 is H or a C 1 -C 3 alkyl group disposed out of or into the plane on the chiral c

Assignees

• Spiegel David
• Parker Christopher
• Univ Yale

Inventors

• Spiegel David
• Parker Christopher

Classifications

• A61P31/18

  for HIV · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title