Details for Patent: 6,670,340
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Title: | 6-Mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block |
Abstract: | Disclosed is a 6-mercapto-cyclodextrin derivative having general formula (I) wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C.sub.1-6)alkylene, optionally substituated with 1-3 OH groups, or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p --; o and p are independently 0-4; X is COOH, CONHR.sub.1, NHCOR.sub.2, SO.sub.2 OH, PO(OH).sub.2, O(CH.sub.2 --CH.sub.2 --O).sub.q --H, OH or tetrazol-5-yl; R.sub.1 is H or (C.sub.1-3)alkyl; R.sub.2 is carboxyphenyl; q is 1-3; or pharmaceutically acceptable salts thereof. The 6-mercaptocyclodextrin derivative is highly suitable for use in the reversal of drug-induced neuromuscular block. ##STR1## |
Inventor(s): | Zhang; Mingiang (Montreal, CA), Palin; Ronald (Banton, GB), Bennett; David Jonathan (The Grange, GB) |
Assignee: | Akzo Nobel (Arnhem, NL) |
Filing Date: | Aug 19, 2002 |
Application Number: | 10/148,307 |
Claims: | 1. A 6-mercapto-cyclodextrin derivative having the general formula I ##STR25## wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C.sub.1-6)alkylene, optionally substituted with 1-3 OH groups, or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p ; o and p are independently 0-4; X is COOH, CONHR.sub.1, NHCOR.sub.2, SO.sub.2 OH, PO(OH).sub.2, O(CH.sub.2 --CH.sub.2 --O).sub.q --H, OH or tetrazol-5-yl; R.sub.1 is H or (C.sub.1-3)alkyl; R.sub.2 is carboxyphenyl; q is 1-3; or pharmaceutically acceptable salts thereof; with the exclusion of 6-per-deoxy-6-per-(2-hydroxyethylthio)-.beta.-cyclodextrin; 6-mono-deoxy-6-mono-(2-hydroxyethylthio)-.beta.-cyclodextrin; 6-per-deoxy-6-per-(2-hydroxyethylthio)-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(carboxymethylthio)-.beta.-cyclodextrin; 6-mono-deoxy-6-mono-(carboxymethylthio)-.beta.-cyclodextrin; 6A,6B-dideoxy-6A,6B-bis((o-carboxyphenyl)thio)-.beta.-cyclodextrin; 6A,6B-dideoxy-6A,6B-bis(carboxymethylthiol)-.beta.-cyclodextrin and 6-per-deoxy-6-per-(2,3-dihydroxypropylthio)-.beta.-cyclodextrin. 2. The 6-mercapto-cyclodextrin derivative according to claim 1, wherein R, m and n are defined as in claim 1 and X is COOH or SO.sub.2 OH; or a pharmaceutically acceptable salt thereof. 3. The 6-mercapto-cyclodextrin derivative according to claim 1, wherein m is 0; n is 8; R is (C.sub.1-6)alkylene or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p ; o and p are independently 0-4; and X is COOH or SO.sub.2 OH; or a pharmaceutically acceptable salt thereof. 4. A 6-mercapto-cyclodextrin derivative according to claim 1 selected from the group consisting of: 6-per-deoxy-6-per-(2-carboxyethyl)thio-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(3-carboxypropyl)thio-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(4-carboxyphenyl)thio-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(4-carboxyphenylmethyl)thio-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(2-carboxypropyl)thio-.gamma.-cyclodextrin; and 6-per-deoxy-6-per-(2-sulfoethyl)thio-.gamma.-cyclodextrin; or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition comprising a 6-mercapto-cyclodextrin derivative having the general formula I ##STR26## wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C.sub.1-6)alkylene, optionally substituted with 1-3 OH groups, or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p ; o and p are independently 0-4; X is COOH, CONHR.sub.1, NHCOR.sub.2, SO.sub.2 OH, PO(OH).sub.2, O(CH.sub.2 --CH.sub.2 --O).sub.q --H, OH or tetrazol-5-yl; R.sub.1 is H or (C.sub.1-3)alkyl; R.sub.2 is carboxyphenyl; q is 1-3; or a pharmaceutically acceptable salt thereof, with the exclusion of 6-per-deoxy-6-per-(2-hydroxyethylthio)-.beta.-cyclodextrin; 6-mono-deoxy-6-mono-(2-hydroxyethylthio)-.beta.-cyclodextrin; 6-per-deoxy-6-per-(2-hydroxyethylthio)-.gamma.-cyclodextrin; 6-per-deoxy-6-per-(carboxymethylthio)-.beta.-cyclodextrin; 6-mono-deoxy-6-mono-(carboxymethylthio)-.beta.-cyclodextrin; 6A,6B-dideoxy-6A,6B-bis((o-carboxyphenyl)thio)-.beta.-cyclodextrin; 6A,6B-dideoxy-6A,6B-bis(carboxymethylthiol)-.beta.-cyclodextrin and 6-per-deoxy-6-per-(2,3-dihydroxypropylthio)-.beta.-cyclodextrin, in admixture with pharmaceutically acceptable auxilliaries. 6. A kit for providing neuromuscular block and its reversal comprising (a) a neuromuscular blocking agent, and (b) a 6-mercapto-cyclodextrin derivative according to the general formula I ##STR27## wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C.sub.1-6)alkylene, optionally substituted with 1-3 OH groups, or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p ; o and p are independently 0-4; X is COOH, CONHR.sub.1, NHCOR.sub.2, SO.sub.2 OH, PO(OH).sub.2, O(CH.sub.2 --CH.sub.2 --O).sub.q --H, OH or tetrazol-5-yl; R.sub.1 is H or (C.sub.1-3)alkyl; R.sub.2 is carboxyphenyl; q is 1-3; or a pharmaceutically acceptable salt thereof. 7. The kit according to claim 6, wherein the neuromuscular blocking agent is selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mivacurium, (cis)atracurium, tubocurarine and suxamethonium. 8. The kit according to claim 6, wherein the neuromuscular blocking agent is rocuronium. 9. A method for reversal of drug-induced neuromuscular block in a patient, which comprises parenterally administering to said patient an effective amount of a 6-mercapto-cyclodextrin derivative according to the general formula I ##STR28## wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C.sub.1-6)alkylene, optionally substituted with 1-3 OH groups, or (CH.sub.2).sub.o -phenylene-(CH.sub.2).sub.p ; o and p are independently 0-4; X is COOH, CONHR.sub.1, NHCOR.sub.2, SO.sub.2 OH, PO(OH).sub.2, O(CH.sub.2 --CH.sub.2 --O).sub.q --H, OH or tetrazol-5-yl; R.sub.1 is H or (C.sub.1-3)alkyl; R.sub.2 is carboxyphenyl; q is 1-3; or a pharmaceutically acceptable salt thereof. |