US4703042A
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US
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Orally active heparin salts containing multivalent cationic units
Assignee: Individual
•
Filing: 1985-12-17
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Granted: 1987-10-27
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Expires: 2005-12-17
Abstract
Abstract The invention provides novel orally active salts of the formula ##STR1## in which ○ is the skeleton of a polyol, n is the number of OH's in the polyol (3 to 24); p is ≧3 and ≦n; r is the available valence of the heparin unit and ≧3 and ≦7; sr is equal to pv; and R + is ##STR2## in which R iv is C 1 -C 3 alkyl; R' and R" are C 1 -C 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 v is H, --CONH 2 or --COO(C 1 -C 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.
Inventors
- 👤 Nicholas S. Bodor
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-06 15:02
CPC Classifications
C; C07; C07D; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/78; C07D213/79; C07D213/80; C07D213/24; C07D213/54; C07D213/55; C07D213/81; C07D213/82; C07D295/00; C07D295/04; C07D295/14; C07D295/145; C07D295/15; C07H; C07H13/00; C07H13/02; C07H13/04; C07H13/10; C07H3/00; C07H3/04; C07H3/06; C08; C08B; C08B37/00; C08B37/006; C08B37/0063; C08B37/0075
Claims Analysis
Total Claims: 55
Claim 1
Independent Claim
262 words
A salt of the structural formula ##STR255## wherein ○ 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 3 -C 15 aliphatic polyhydroxy compound of a C 5 -C 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 ≧3 and ≦n; r is the available valence of the heparin unit and is ≧3 and ≦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 + is ##STR256## wherein the --COO--, --CH 2 COO--, --CH 2 OCOO-- and R v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring; R iv is C 1 -C 3 alkyl; R' and R", which can be the same or different, are each C 1 -C 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 v is H, --CONH 2 or --COO(C 1 -C 7 alkyl).
Claim 2
Dependent Claim
262 words
A salt of the structural formula ##STR255## wherein ○ 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 3 -C 15 aliphatic polyhydroxy compound of a C 5 -C 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 ≧3 and ≦n; r is the available valence of the heparin unit and is ≧3 and ≦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 + is ##STR256## wherein the --COO--, --CH 2 COO--, --CH 2 OCOO-- and R v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring; R iv is C 1 -C 3 alkyl; R' and R", which can be the same or different, are each C 1 -C 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 v is H, --CONH 2 or --COO(C 1 -C 7 alkyl).
Claim 3
Dependent Claim
26 words
A salt as claimed in claim 1 wherein the polyol is ribose, arabinose, xylose, lyxose, ribulose, xylulose, glucose, galactose, mannose, fructose, sorbose, tagatose, mannoheptulose or sedoheptulose.
Claim 4
Dependent Claim
19 words
A salt as claimed in claim 1 wherein the oligosaccharide is sucrose, lactose, maltose, raffinose, α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.
Claim 5
Dependent Claim
20 words
A salt as claimed in claim 1 wherein the aliphatic polyhydroxy compound is a C 3 -C 8 alkyl polyol.
Claim 6
Dependent Claim
20 words
A salt as claimed in claim 4 wherein the C 3 -C 8 alkyl polyol is glycerol, erythritol or 1,2,6-trihydroxyhexane.
Claim 7
Dependent Claim
25 words
A salt as claimed in claim 1 wherein the alicyclic polyhydroxy compound is a C 5 -C 10 cycloalkyl or fused fully hydrogenated aromatic polyol.
Claim 8
Dependent Claim
15 words
A salt as claimed in claim 6 wherein the cycloalkyl polyol is a cyclohexane polyol.
Claim 9
Dependent Claim
13 words
A salt as claimed in claim 7 wherein the cyclohexane polyol is inositol.
Claim 10
Dependent Claim
18 words
A salt as claimed in claim 6 wherein the fused fully hydrogenated aromatic polyol is a decahydronaphthalene polyol.
Claim 11
Dependent Claim
65 words
A salt as claimed in claim 1 wherein R"' is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR258## --CH 2 OH, --CHOH--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR259## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH.
Claim 12
Dependent Claim
61 words
A salt as claimed in claim 1 wherein R' and R" are combined with the adjacent nitrogen atom such that ##STR260## represents the residue of a saturated monocyclic secondary amine having 5 to 7 ring atoms, optionally containing another hetero ring atom --O--, --S-- or --N-- in addition to the indicated nitrogen atom, and optionally bearing 1 to 3 methyl substituents.
Claim 13
Dependent Claim
28 words
A salt as claimed in claim 11 wherein ##STR261## is morpholino, 1-pyrrolidinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl or 1- or 3-imidazolidinyl.
Claim 14
Dependent Claim
36 words
A salt as claimed in claim 1 wherein R + is structure (a), (b) or (c); R iv is methyl; and the --COO--, --CH 2 COO-- or --CH 2 OCOO-- group is located in the 3-position.
Claim 15
Dependent Claim
40 words
A salt as claimed in claim 1 wherein R + is structure (d); R' is methyl or ethyl and R" is identical to R', or R'R"N-- represents morpholino, piperidino, 1-pyrrolidinyl or 1-piperazinyl; R iv is methyl; and alkylene is --CH--.
Claim 16
Dependent Claim
47 words
A salt as claimed in claim 14 wherein R"' is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR262## --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 or ##STR263##
Claim 17
Dependent Claim
25 words
A salt as claimed in claim 1 wherein R + is structure (e) and alkylene is --CH 2 -- or --CH 2 CH 2 --.
Claim 18
Dependent Claim
16 words
A multiplet as claimed in claim 16 wherein R v is H or --CONH 2 .
Claim 19
Dependent Claim
13 words
A salt as claimed in claim 1 wherein p is equal to n.
Claim 20
Dependent Claim
13 words
A salt as claimed in claim 1 wherein p is at least 4.
Claim 21
Dependent Claim
14 words
A salt as claimed in claim 1 wherein r is 5, 6 or 7.
Claim 22
Dependent Claim
21 words
A salt as claimed in claim 1 wherein ○ is the skeleton of inositol, n is 6 and p is 6.
Claim 23
Dependent Claim
18 words
A salt as claimed in claim 21 wherein v is 5, r is 5 and s is 6.
Claim 24
Dependent Claim
18 words
A salt as claimed in claim 22 having the structural formula ##STR264## wherein R 2 + is ##STR265##
Claim 25
Dependent Claim
257 words
A salt of the structural formula ##STR266## wherein ○ 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 3 -C 15 aliphatic polyhydroxy compound or a C 5 -C 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 ≧3 and ≦n; R + is ##STR267## wherein the --COO--, --CH 2 COO--, --CH 2 OCOO-- and R v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring; R iv is C 1 -C 3 alkyl; R' and R", which can be the same or different, are each C 1 -C 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 v is H, --CONH 2 or --COO(C 1 -C 7 alkyl); X - 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.
Claim 26
Dependent Claim
257 words
A salt of the structural formula ##STR266## wherein ○ 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 3 -C 15 aliphatic polyhydroxy compound or a C 5 -C 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 ≧3 and ≦n; R + is ##STR267## wherein the --COO--, --CH 2 COO--, --CH 2 OCOO-- and R v ring substituents can each be in the 2-, 3- or 4-position of the pyridinium ring; R iv is C 1 -C 3 alkyl; R' and R", which can be the same or different, are each C 1 -C 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 v is H, --CONH 2 or --COO(C 1 -C 7 alkyl); X - 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.
Claim 27
Dependent Claim
26 words
A salt as claimed in claim 24 wherein the polyol is ribose, arabinose, xylose, lyxose, ribulose, xylulose, glucose, galactose, mannose, fructose, sorbose, tagatose, mannoheptulose or sedoheptulose.
Claim 28
Dependent Claim
19 words
A salt as claimed in claim 24 wherein the oligosaccharide is sucrose, lactose, maltose, raffinose, α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin.
Claim 29
Dependent Claim
20 words
A salt as claimed in claim 24 wherein the aliphatic polyhydroxy compound is a C 3 -C 8 alkyl polyol.
Claim 30
Dependent Claim
20 words
A salt as claimed in claim 27 wherein the C 3 -C 8 alkyl polyol is glycerol, erythritol or 1,2,6-trihydroxyhexane.
Claim 31
Dependent Claim
25 words
A salt as claimed in claim 24 wherein the alicyclic polyhydroxy compound is a C 5 -C 10 cycloalkyl or fused fully hydrogenated aromatic polyol.
Claim 32
Dependent Claim
15 words
A salt as claimed in claim 29 wherein the cycloalkyl polyol is a cyclohexane polyol.
Claim 33
Dependent Claim
13 words
A salt as claimed in claim 30 wherein the cyclohexane polyol is inositol.
Claim 34
Dependent Claim
18 words
A salt as claimed in claim 29 wherein the fused fully hydrogenated aromatic polyol is a decahydronaphthalene polyol.
Claim 35
Dependent Claim
65 words
A salt as claimed in claim 24 wherein R"' is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR269## --CH 2 OH, --CHOH--CH 3 , --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 , ##STR270## --CH 2 SH, --CH 2 COOH or --CH 2 CH 2 COOH.
Claim 36
Dependent Claim
61 words
A salt as claimed in claim 24 wherein R' and R" are combined with the adjacent nitrogen atom such that ##STR271## represents the residue of a saturated monocyclic secondary amine having 5 to 7 ring atoms, optionally containing another hetero ring atom --O--, --S-- or --N-- in addition to the indicated nitrogen atom, and optionally bearing 1 to 3 methyl substituents.
Claim 37
Dependent Claim
28 words
A salt as claimed in claim 34 wherein ##STR272## is morpholino, 1-pyrrolidinyl, perhydro-1,2,4-oxathiazin-4-yl, 1- or 4-piperazinyl, 4-methyl-1-piperazinyl, piperidino, hexamethyleneimino, 2-methyl-1-pyrazolidinyl, 1- or 2-pyrazolidinyl, 3-methyl-1-imidazolidinyl or 1- or 3-imidazolidinyl.
Claim 38
Dependent Claim
36 words
A salt as claimed in claim 24 wherein R + is structure (a), (b) or (c); R iv is methyl; and the --COO--, --CH 2 COO-- or --CH 2 OCOO-- group is located in the 3-position.
Claim 39
Dependent Claim
39 words
A salt as claimed in claim 24 wherein R + is structure (d); R' is methyl or ethyl and R" is identical to R', or R'R"N-- represents morpholino,piperidino, 1-pyrrolidinyl or 1-piperazinyl; R iv is methyl; and alkylene is ##STR273##
Claim 40
Dependent Claim
47 words
A salt as claimed in claim 37 wherein R"' is H, --CH 3 , --CH(CH 3 ) 2 , --CH 2 --CH(CH 3 ) 2 , ##STR274## --(CH 2 ) 2 --SCH 3 , --CH 2 --CONH 2 , --CH 2 CH 2 --CONH 2 or ##STR275##
Claim 41
Dependent Claim
25 words
A salt as claimed in claim 24 wherein R + is structure (e) and alkylene is --CH 2 -- or --CH 2 CH 2 --.
Claim 42
Dependent Claim
16 words
A salt as claimed in claim 39 wherein R v is H or --CONH 2 .
Claim 43
Dependent Claim
13 words
A salt as claimed in claim 24 wherein p is equal to n.
Claim 44
Dependent Claim
13 words
A salt as claimed in claim 24 wherein p is at least 4.
Claim 45
Dependent Claim
11 words
A salt as claimed in claim 24 wherein t is 1.
Claim 46
Dependent Claim
20 words
A salt as claimed in claim 24 wherein X - is I - , Br - or Cl - .
Claim 47
Dependent Claim
21 words
A salt as claimed in claim 24 wherein ○ is the skeleton of inositol, n is 6 and p is 6.
Claim 48
Dependent Claim
31 words
A salt as claimed in claim 45, having the structural formula ##STR276## wherein X 1 - is I - , Br - or Cl - and R 2 + is ##STR277##
Claim 49
Dependent Claim
15 words
A salt as claimed in claim 46 wherein X 1 - is I - .
Claim 50
Dependent Claim
34 words
A method for eliciting an anticoagulant response in a warm-blooded animal, said method comprising orally administering to said animal an effective anticoagulant amount of a salt of formula (I) as defined by claim 1.
Claim 51
Dependent Claim
38 words
A method for eliciting an anticoagulant response in a warm-blooded animal, said method comprising administering to said animal nasally or by oral inhalation an effective anticoagulant amount of a salt of formula (I) as defined by claim 1.
Claim 52
Dependent Claim
49 words
A pharmaceutical composition of matter, in unit dosage form, for use in eliciting an anticoagulant response in a warm-blooded animal, said composition comprising, per dosage unit, an effective unit anticoagulant amount of a salt of formula (I) as defined by claim 1 and a non-toxic pharmaceutically acceptable carrier therefor.
Claim 53
Dependent Claim
12 words
A pharmaceutical composition as claimed in claim 50, suitable for oral administration.
Claim 54
Dependent Claim
12 words
A pharmaceutical composition as claimed in claim 50, suitable for nasal administration.
Claim 55
Dependent Claim
13 words
A pharmaceutical composition as claimed in claim 50, suitable for oral inhalation therapy.
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| 11.5 Years (Year 12) | 1998-10-26 | 1999-04-27 | 1999-10-27 | $7700.00 | Window Closed / Lapsed |