Cornell University

Other

Massachusetts General Hospital Corporation

The General Hospital Corporation

Burroughs Wellcome Co.

John J Savarese

Roy A Swaringen, Jr

Robert Anthony Mook

Eric C Bigham

Grady Evan Boswell

Eric Eugene Boros

Sanjay Shashikant Patel

Vincente Samano

Richard J Kitz

Sara Ginsburg

David A Yeowell

Hassan A El-Sayad

Jeff D McGilvra

Paul M Heerdt

This application describes methods of making and using physiological cysteine solutions useful for reversing a neuromuscular blockade caused by a cysteine-reversible neuromuscular blockade agent, that overcomes problems of cysteine precipitation and dimerization.

Cysteine for physiological injection

We describe ultra-short, short, and intermediate duration neuromuscular blocking compounds, reversible by cysteine or similar compounds, that are bisquaternary diesters of chlorofumaric, fumaric, or maleic acids where the quaternary groups are very different, creating a highly asymmetrical molecule where one quaternary includes an isoquinolinium ring system and the other includes a morpholinium, piperidinium, piperazinium, or pyrrolidinium system, pharmaceutical compositions, methods to use such compounds and compositions, and kits.

Asymmetrical reversible neuromuscular blocking agents of ultra-short, short, or intermediate duration

The invention provides neuromuscular blockade agents of the non-depolarizing type with few if any circulatory effects. Compounds of the invention include bis(isoquinolylalkanol) diesters of fumaric, maleic, succinic, and acetylenedicarboxylic acids; compositions suitable for parenteral administration of these compounds as a surgical adjunct to anesthesia, and methods of preparation of the compounds. Compounds of the invention can produce neuromuscular blockade of short or intermediate duration, which for various compounds can be reversed by administration of a thiol compound such as L-cysteine, D-cysteine or glutathione. For various compounds of the invention, the neuromuscular blockade effect can be reversed quickly, efficiently, and without notable side-effects.

Reversible nondepolarizing neuromuscular blockade agents and methods for their use

The invention provides novel neuromuscular blocking agents, methods of using the neuromuscular blocking agents as well as reagents, methods and kits for reversing the effects of the neuromuscular blocking agents.

Intermediate duration neuromuscular blocking agents and antagonists thereof

Ultrashort acting neuromuscular blocking agents of Formula (I) which are useful as skeletal muscle relaxants during emergency intubation procedures, routine surgery and post-operative settings are disclosed, wherein: X is a halogen; h is from 1 to 2; Y is hydrogen or methoxy; Z,and Z,are methyl; W,and W,are carbon; and A is a pharmaceutically acceptable anion.

Substituted isoquinolines as ultra short acting neuromuscular blockers

Ultra short acting neuromuscular blocking agents of Formula (I) which are useful as skeletal muscle relaxants during emergency intubation procedures, routine surgery and post-operative settings are disclosed, wherein q and t are independently from 0 to 4; X,and X,are independently halogen; h,and h,are independenity from 0 to 2; Z,and Z,are indepentdently hydrogen, C,alkyl, C,alkenyl or C,alkynyl with the proviso that Z,and Z,are not both hydrogen; Y,, Y,, and Y,and Y,are independently hydrogen, halogen or C,alkoxy; m and p are independently 1 to 6; n and r are independently 0 to 4; with the proviso the if h,and h,are both 0, then r is 0 and n is 0 to 2; R,to R,are independently hydrogen, halogen, C,alkoxy, or R,and R,together with the carbon atoms to which they are bonded, R,and R,together with the carbon atoms to which they are bonded, R,and R,together with the carbon atoms to which they are bonded, R,and R,together with the carbon atoms to which they are bonded, may independently form a methylenedioxy or ethylenedioxy moiety contained in five- or six-membered ring; W,and W,are carbon; and A is a pharmaceutically acceptable anion.

Neuromuscular blocking agents of formula (1) which are useful as skeletal muscle relaxants during surgery are disclosed. ##STR1## and X is an anion, preferably pharmaceutically acceptable.

Novel compounds

Intermediate-duration reversible neuromuscular blocking agents of the formula (I) ##STR1## where B and C are preferably para or may be meta and are each ##STR2## where W is CH.sub.2 or most preferably CH.dbd.CH R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different and are each hydrogen or lower alkoxy of 1 to 4 carbon atoms and preferably methoxy, Y is lower alkyl of 1 to 4 carbon atoms and preferably methyl, Z is hydrogen, lower alkyl of 1 to 4 carbon atoms, cyclopentyl, cyclohexyl, benzyl, or ##STR3## where ALKYL has 1 to 4 carbon atoms preferably where the O-ALKYL is at the 2, 3, 4 or 5 positions such as 4-methoxy benzyl and is most preferably 3,4-dimethoxy benzyl or 3, 4, 5-trimethoxybenzyl, n is 2, 3 or 4, most preferably 2 or 3 provided that at least one of R.sub.1 to R.sub.4 is lower alkoxy and most preferably where R.sub.1 and R.sub.4 is hydrogen and R.sub.2 and R.sub.3 are methoxy and X is a pharmaceutically acceptable anion. The neuromuscular blocking agents of formula I are useful for administration to a patient to cause skeletal muscle relaxation during surgery and are normally administered intravenously in a pharmaceutically acceptable carrier.

Bis-isoquinolinium compounds, compositions and methods of use

Short acting reversible neuromuscular blocking agents of the formula (I) ##STR1## where B and C is preferably meta or maybe para ##STR2## where m is 2, 3 or 4 and is preferably 2,

Growing community of inventors

Southbury, CT, United States of America

John J Savarese