US 4,703,042 AGranted

Orally active heparin salts containing multivalent cationic units

OwnerNicholas S. Bodorinventor

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Abstract

The invention provides novel orally active salts of the formula ##STR1## in which .circle. is the skeleton of a polyol, n is the number of OH's in the polyol (3 to 24); p is .gtoreq.3 and .ltoreq.n; r is the available valence of the heparin unit and .gtoreq.3 and .ltoreq.7; sr is equal to pv; and R.sup.+ is ##STR2## in which R.sup.iv is C.sub.1 -C.sub.3 alkyl; R' and R" are C.sub.1 -C.sub.7 alkyl, the same or different, or combined so that --NR'R" represents the residue of a saturated monocyclic secondary amine; R"' is identical to the corresponding portion of a natural amino acid; the alkylene groups contain 1 to 3 carbon atoms; and R.sup.v is H, --CONH.sub.2 or --COO(C.sub.1 -C.sub.7 alkyl). The salts are stable lipoidal "ion pairs" or complexes which can be absorbed through the gastrointestional wall and which slowly release heparinic acid to achieve long-lasting anticoagulant activity. Novel quaternary salts which are intermediates to the heparin salts of the invention are also disclosed.

Claims53

Dependent claims

A salt of the structural formula ##STR255## wherein .circle. is the skeleton of a polyol, said polyol being a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses, an oligosaccharide selected from the group consisting of disaccharides, trisaccharides and cyclodextrins, a C.sub.3 -C.sub.15 aliphatic polyhydroxy compound of a C.sub.5 -C.sub.18 alicyclic polyhydroxy compound, said skeleton being the portion of said polyol remaining after removal of all hydroxy substituents therefrom;

n is a number from 3 to 24 which represents the total number of hydroxy groups in said polyol;
p is a number .gtoreq.3 and .ltoreq.n;
r is the available valence of the heparin unit and is .gtoreq.3 and .ltoreq.7;
s is the number which when multiplied by r is equal to pv;
v is the number which when multiplied by p is equal to rs;
R.sup.+ is ##STR256## wherein the --COO--, --CH.sub.2 COO--, --CH.sub.2 OCOO-- and R.sup.v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring;
R.sup.iv is C.sub.1 -C.sub.3 alkyl;
R' and R", which can be the same or different, are each C.sub.1 -C.sub.7 alkyl, or R' and R" are combined with the adjacent nitrogen atom such that ##STR257## represents the residue of a saturated monocyclic secondary amine;
R"' is a radical identical to the corresponding portion of a natural amino acid;
the alkylene groups can be straight or branched and contain 1 to 3 carbon atoms;
and R.sup.v is H, --CONH.sub.2 or --COO(C.sub.1 -C.sub.7 alkyl).

8 more elements

A salt of the structural formula ##STR266## wherein .circle. is the skeleton of a polyol, said polyol being a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses, an oligosaccharide selected from the group consisting of disaccharides, trisaccharides and cyclodextrins, a C.sub.3 -C.sub.15 aliphatic polyhydroxy compound or a C.sub.5 -C.sub.18 alicyclic polyhydroxy compound, said skeleton being the portion of said polyol remaining after removal of all hydroxy substituents therefrom;

n is a number from 3 to 24 which represents the total number of hydroxy groups in said polyol;
p is a number .gtoreq.3 and .ltoreq.n;
R.sup.+ is ##STR267## wherein the --COO--, --CH.sub.2 COO--, --CH.sub.2 OCOO-- and R.sup.v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring;
R.sup.iv is C.sub.1 -C.sub.3 alkyl;
R' and R", which can be the same or different, are each C.sub.1 -C.sub.7 alkyl, or R' and R" are combined with the adjacent nitrogen atom such that ##STR268## represents the residue of a saturated monocyclic monocyclic secondary amine;
R"' is a radical identical to the corresponding portion of a natural amino acid;
the alkylene groups can be straight or branched and contain 1 to 3 carbon atoms;
R.sup.v is H, --CONH.sub.2 or --COO(C.sub.1 -C.sub.7 alkyl);
X.sup.- is the anion of a pharmaceutically acceptable organic or inorganic acid;
t is the valence of the acid anion;
and q is the number which when multiplied by t is equal to p.

8 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/808,689Filed 17 Dec 1985 · continuation
Priority: 21 May 1984
Granted: 27 Oct 1987
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 213/80
Acids; Esters: in position 3
C07D 213/55
Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals:…
C07D 213/82
Amides; Imides: in position 3
C07D 295/15
With the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted…