US 5,854,218 A · Sialyl Le.sup.x analogues as inhibitors of cellular adhesion

Abstract

The present invention relates to analogues of sialyl Le.sup.x that inhibit cellular adhesion between a selectin and cells that express sialyl Le.sup.x on their surfaces, as well as methods and compositions using the same, intermediates and methods for the preparation of the cellular adhesion inhibitor compounds and their intermediates. A contemplated intermediate or inhibitor compound has a structure that corresponds to that of Formula A, ##STR1##

Drawings

Drawings are temporarily unavailable. Open the PDF at USPTO

Drawings

Claims5

Dependent claims

A compound having the formula ##STR22## wherein:

Z is ##STR23## R.sup.5 is selected from the group consisting of hydrogen, benzyl, methoxybenzyl, dimethoxybenzyl and C.sub.1 -C.sub.6 acyl;
R.sup.6 is selected from the group consisting of hydrogen, a linking group for a lipid, a lipid, a linking group with attached lipid, C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl, C.sub.1 -C.sub.6 alkyl C.sub.1 -C.sub.5 alkylene .omega.-carboxylate and .omega.-tri(C.sub.1 -C.sub.4 alkyl/phenyl)silyl C.sub.2 -C.sub.4 alkylene, or OR.sup.6 together form a C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl carbamate;
R.sup.7 is methyl or hydroxymethyl;
and
X is selected from the group consisting of C.sub.1 -C.sub.6 acyloxy, C.sub.2 -C.sub.6 hydroxylacyloxy, hydroxy, halo and azido.

2 more elements

A method of preparing a pharmaceutical agent, said pharmaceutical agent having the formula:

##STR26## wherein:
Y is selected from the group consisting of C(O), SO.sub.2, HNC(O), OC(O) and SC(O);
R.sup.1 is selected from the group consisting of a linking group for a lipid, a lipid, a linking group with attached lipid, an aryl, a substituted aryl and a phenyl C.sub.1 -C.sub.3 alkylene group, wherein said aryl group has one five-membered aromatic ring, one six-membered aromatic ring or two fused six-membered aromatic rings, which rings are selected from the group consisting of hydrocarbyl, monooxahydrocarbyl, monothiahydrocarbyl, monoazahydrocarbyl and diazahydrocarbyl rings, and said substituted aryl group is said aryl group having a substituent selected from the group consisting of a halo, trifluoromethyl, nitro, C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.12 alkoxy, amino, mono-C.sub.1 -C.sub.12 alkylamino, di-C.sub.1 -C.sub.12 alkylamino, benzylamino, C.sub.1 -C.sub.12 alkylbenzylamino, C.sub.1 -C.sub.12 thioalkyl and C.sub.1 -C.sub.12 alkyl carboxamido groups;
R.sup.2 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl, C.sub.1 -C.sub.6 alkyl C.sub.1 -C.sub.5 alkylene .omega.-carboxylate, .omega.-tri(C.sub.1 -C.sub.4 alkyl/phenyl)silyl C.sub.2 -C.sub.4 alkylene, monosaccharide and disaccharide, or OR.sup.2 together form a C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl carbamate;
R.sup.4 is an alkyl group;
R.sup.7 is methyl or hydroxymethyl;
and
X is selected from the group consisting of C.sub.1 -C.sub.6 acyloxy, C.sub.2 -C.sub.6 hydroxylacyloxy, hydroxy, halo and azido;
said method comprising:
(a) preparing a lactone intermediate selected from the group consisting of lactones of formula ##STR27## wherein Z is a member selected from the group consisting of hydrogen and C.sub.1 -C.sub.6 acyl;
(b) treating said lactone intermediate with an alkoxide to form an ester intermediate having the formula ##STR28## wherein:
R.sup.4 is an alkyl group derived from said alkoxide;
and
(c) deprotecting, fucosylating and attaching a Y--R.sup.1 to provide said pharmaceutical agent.

11 more elements

A pharmaceutical composition comprising a pharmaceutically acceptable diluent having dissolved or dispersed therein a cellular adhesion-inhibiting amount of a compound of the formula ##STR29## wherein:

Z is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 acyl and ##STR30## Y is selected from the group consisting of C(O), SO.sub.2, HNC(O), OC(O) and SC(O);
R.sup.1 is selected from the group consisting of a linking group for a lipid, a lipid, a linking group with attached lipid, an aryl, a substituted aryl and a phenyl C.sub.1 -C.sub.3 alkylene group, wherein said aryl group has one five-membered aromatic ring, one six-membered aromatic ring or two fused six-membered aromatic rings, which rings are selected from the group consisting of hydrocarbyl, monooxahydrocarbyl, monothiahydrocarbyl, monoazahydrocarbyl and diazahydrocarbyl rings, and said substituted aryl group is said aryl group having a substituent selected from the group consisting of a halo, trifluoromethyl, nitro, C.sub.1 -C.sub.12 alkyl, C.sub.1 -C.sub.12 alkoxy, amino, mono-C.sub.1 -C.sub.12 alkylamino, di-C.sub.1 -C.sub.12 alkylamino, benzylamino, C.sub.1 -C.sub.12 alkylbenzylamino, C.sub.1 -C.sub.12 thioalkyl and C.sub.1 -C.sub.12 alkyl carboxamido groups;
R.sup.2 is selected from the group consisting of hydrogen, a linking group for a lipid, a lipid, a linking group with attached lipid, C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl, C.sub.1 -C.sub.6 alkyl C.sub.1 -C.sub.5 alkylene .omega.-carboxylate, .omega.-tri(C.sub.1 -C.sub.4 alkyl/phenyl)silyl C.sub.2 -C.sub.4 alkylene, monosaccharide and disaccharide, or OR.sup.2 together form a C.sub.1 -C.sub.18 straight chain, branched chain or cyclic hydrocarbyl carbamate;
R.sup.4 is an alkyl group;
R.sup.5 is selected from the group consisting of hydrogen, benzyl, methoxybenzyl, dimethoxybenzyl and C.sub.1 -C.sub.6 acyl;
R.sup.7 is methyl or hydroxymethyl;
and
X is selected from the group consisting of C.sub.1 -C.sub.6 acyloxy, C.sub.2 -C.sub.6 hydroxylacyloxy, hydroxy, halo and azido.

5 more elements

Dependencies are inferred from the claim text.

Description34,146 words

Summary1,640 words

#The present invention relates to compounds that inhibit cellular adhesion, and more particularly relates to analogue compounds of sialyl Lewis.sup.x (sialyl Le.sup.x or SLe.sup.x) that inhibit selectin-mediated cellular adhesion, compositions containing and processes for using the same, and processes for preparing those analogues.

#Vascular endothelial cells and blood platelets play key roles in a number of biological responses by selectively binding certain cells, for instance phagocytic leukocytes, in the bloodstream. For example, endothelial cells preferentially bind monocytes and granulocytes prior to their migration through the blood vessel wall and into surrounding tissue in an inflammatory response.

#Certain inflammation-triggering compounds are known to act directly on the vascular endothelium to promote the adhesion of leukocytes to vessel walls. Cells then move through the walls and into areas of injury or infection.

Brief description of the drawings7 figures

#FIG. 1 shows a reaction scheme for the preparation of compound 62.

#FIG. 2 shows a reaction scheme for the preparation of compound 73.

#FIG. 3 shows a reaction scheme for the preparation of compound 78.

Detailed description32,420 words

#A. The Compounds

#The nomenclature used to describe the oligosaccharide moieties of the present invention follows the conventional nomenclature. Standard abbreviations for individual monosaccharides are used. For instance, 2-N-acetylglucosamine is represented by GlcNAc, 2-N-acetylgalactosamine is GalNAc, fucose is Fuc, fructose is Fru, galactose in Gal, glucose is Glc, and mannose is Man. Unless otherwise indicated, all sugars except fucose (L-isomer) are D-isomers in the cyclic configuration (e.g., pyranose or furanose). The two anomers of the cyclic forms are represented by .alpha. and .beta..

#The monosaccharides are generally linked by glycosidic bonds to form oligo- and polysaccharides. The orientation of the bond with respect to the plane of the rings is indicated by .alpha. and .beta.. The particular carbon atoms that form the bond between the two monosaccharides are also noted. Thus, a .beta. glycosidic bond between C-1 of galactose and C-4 of glucose is represented by Gal.beta.1.fwdarw.4Glc. For the D-sugars (e.g., D-GlcNAc, D-Gal, D-NeuAc and D-Man) the designation .alpha. means the hydroxyl attached to C-1 (C-2 in NeuAc) is below the plane of the ring and .beta. is above the ring. In the case of L-fucose, the .alpha. designation means the hydroxyl is above the ring and .beta. means it is below.

Facts

Application

08/730,553Filed 15 Oct 1996 · continuation in part

Priority

14 May 1993

Granted

29 Dec 1998

Term ended

14 May 2013

Estimated · how

20 years from earliest known nonprovisional domestic filing. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination. Patent term adjustment is unavailable; no adjustment was added.

Classification11 codes

A61K 31/702
Carbohydrates; Sugars; Derivatives thereof: oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic…
A61K 31/70
Medicinal preparations containing organic active ingredients: carbohydrates; Sugars; Derivatives thereof
B82Y 5/00
Nanobiotechnology or nanomedicine
C07H 3/04
Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms: disaccharides

Family

Serial62,120Parent of this continuation-in-part · filed 14 May 1993

Serial241,645Parent of this continuation-in-part · filed 12 May 1994

Serial345,072Parent of this continuation-in-part · filed 28 Nov 1994

Serial485,453Parent of this continuation-in-part · filed 7 Jun 1995

US 5,604,207 AParent of this continuation-in-part

US 5,854,218 AThis patent

From the US filing history. Foreign family members aren’t listed.

Sialyl Le.sup.x analogues as inhibitors of cellular adhesion

Life of this patent

Sialyl Le.sup.x analogues as inhibitors of cellular adhesion

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims5

Description34,146 words

Drawings

Classification11 codes

Life of this patent

Description34,146 words