Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-19
2001-02-13
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S307000, C546S140000, C546S144000, C546S147000
Reexamination Certificate
active
06187789
ABSTRACT:
The present invention relates to novel compounds, methods for the preparation of such compounds, pharmaceutical compositions containing them and their use as neuromuscular blocking agents of ultra-short duration.
In anesthesia, neuromuscular blocking agents are used to provide skeletal muscle relaxation during surgery and during intubation of the trachea. Neuromuscular blockers are generally classified by both the mechanism of action (depolarizing or non-depolarizing) and the duration of action (ultrashort, short, intermediate, and long). See, Bedford, R., “From the FDA”,
Anesthesiology,
82(1), 33a. 1995. Non-depolarizing neuromuscular blocking agents include long-duration agents such as d-tubocurarine, pancuronium, gallamine, diallyltoxiferine and toxiferine, intermediate-duration agents such as atracurium and vecuronium, and short-duration agents such as mivacurium. See e.g., U.S. Pat. No. 4,179,507, U.S. Pat. No. 4,701,460, U.S. Pat. No. 4,761,418 and U.S. Pat. No. 5,945,510. Conventional non-depolarizing agents typically exhibit a 20 to 180 minute duration of action when used as skeletal muscle relaxants. Presently there are no ultrashort duration, non-depolarizing neuromuscular blocking agents in clinical use.
Depolarizing agents include succinylcholine and decamethonium. Due to their depolarizing mechanism of action, these agents can have severe side effects such as cardiac arrest and death, hyperkalemia, malignant hyperthermia, severe muscle pain, cardiac arrhythmias, increased intraocular pressure and increased intragastric tension. Conventional depolarizing agents exhibit shorter durations of action, e.g., 10 to 15 minutes in humans. Succinylcholine has a rapid onset and ultrashort duration of action and is the only ultra-short acting neuromuscular blocker in clinical use. Despite its undesirable side effect profile, no other ultrashort acting agent is available and thus it is currently the preferred agent for emergency use. The ultra-short duration of action is extremely important in emergency situations. Use of longer duration agents could lead to serious brain damage and death.
Non-depolarizing agents are generally believed to be safer and more clinically desirable than depolarizing agents, and clinicians have long recognized the need for a non-depolarizing neuromuscular blocker that has an ultra-short duration of action. See, Miller, R. D.
Anesthesia and Analgesia
61(9), 721, 1982; and Belmont, M. R.,
Current Opinion in Anaesthesiology,
8, 362, 1995. However, non-depolarizing agents can exhibit side effects not specifically related to their mechanism or duration of action. For example, the long-duration agents pancuronium and gallamine have effects on the autonomic nervous system and may cause an increase in heart rate (tachycardia). Intermediate- and short-duration agents such as atracurium besylate and mivacurium chloride may also exhibit the side effect of histamine release. Histamine release has undesirable effects on blood pressure and heart rate, and some physicians believe that release of large amounts of histamine can cause life-threatening anaphylaxis in some patients.
It has now been discovered that compounds of Formula (I) include potent non-depolarizing neuromuscular blocking agents of ultra-short duration, e.g., about 5 to 15 minutes, that will provide both increased safety over known depolarizing ultrashort acting agents, e.g. succinylcholine, and a reduced capacity to release histamine over other non-depolarizing agents such as atracurium and mivacurium. In addition, they have a rapid onset of action and are reversed by treatment with known reversal agents such as neostigmine, both very important features in emergency situations and in other procedures. These agents maintain their ultrashort duration of action and rapid spontaneous recovery when administered by either bolus or continuous infusion and are without the cumulative effects observed with other neuromuscular blockers (pancuronium, vecuronium). Thus, compounds of the present invention should provide a significant advantage in the emergency, routine surgical, and post-operative settings.
Accordingly, the present invention provides compounds of Formula (I):
wherein X is halogen; h is from 1 to 2; Y is hydrogen or methoxy; Z
1
and Z are methyl; W
1
and W
2
are carbon; and A is a pharmaceutically acceptable anion.
The compounds of Formula (I) contain two substituted isoquinolinium moieties connected by an aliphatic linker. The two substituted isoquinolinium moieties can be conveniently distinguished by referring to them as the “left head” and the “right head”, where the left head contains W
1
and the right head contains W
2
. The aliphatic linker is the portion of the compound of Formula (I) denoted by the following Formula (i).
The solid and dashed lines ({overscore (------)})indicates a double or single bond.
A suitable class of compounds of Formula (I) is that wherein X is chlorine or fluorine. Particularly preferred halogen substitutions are monochloro, monofluoro and difluoro.
The aliphatic linker portion of compounds of Formula (I), as described by Formula (i), comprises a butanedioate or butenedioate moiety. Suitably, compounds of Formula (I) wherein the aliphatic linker comprises a butenedioate moiety may exist in either the E or Z configuration or as mixtures of E and Z isomers. Preferably the to butenedioate moiety of compounds of Formula (I) is a fumarate.
The term fumarate as used herein refers to a butenedioate moiety wherein the two ester carbonyl groups are oriented trans to one another.
A preferred class of compounds of Formula (I) is that wherein the aliphatic linker is a butanedioate moiety and X represents chlorine or fluorine and h is 1 or 2. A particularly preferred class of compounds of Formula (I) is that wherein the aliphatic linker is a butanedioate moiety and X represents fluorine and h is 1 or 2. Compounds of Formula (I) wherein the aliphatic linker is a butanedioate moiety, X represents fluorine and h is 2 are most preferred.
Another preferred class of compounds of Formula (I) is that wherein the aliphatic linker is a butenedioate moiety and X represents chlorine or fluorine. A particularly preferred class of compounds of Formula (I) includes those wherein the aliphatic linker is a butenedioate moiety, X represents chlorine or fluorine, h is 1 and the butenedioate moiety is a fumarate. Compounds of Formula (I) wherein the aliphatic linker is a butenedioate moiety, X represents chlorine, h is 1 and the butenedioate moiety is a fumarate are most preferred.
The compounds of Formula (I) contain four chiral centres. The carbon atoms (denoted as W
1
and W
2
) and each quaternary nitrogen atom in the isoquinolinium moieties are chiral. Each of the four chiral centres may independently exist in either the R or S configuration. Accordingly, it would be apparent to those skilled in the art that each compound within Formula (I) may exist in sixteen distinct optical isomeric forms. The scope of the present invention extends to cover each and every isomer of the compounds of Formula (I) either individually or in admixture with other isomers, and all mixtures of such isomers. Suitably W
1
is in the R configuration, the N attached to Z is in the S configuration, W is in either the R or S configuration, and the N attached to Z
2
is in either the R or S configuration. Preferably W
1
is in the R configuration, the N attached to Z
1
is in the S configuration, W
2
is in the S configuration, and the N attached to Z
2
is in either the R or S configuration. Compounds of Formula (I) wherein W
1
is in the R configuration, W
2
is in the S configuration, the N attached to Z
1
is in the S configuration and the N attached to Z
2
is in the R configuration are most preferred.
Particularly preferred compounds of Formula (I) include:
(Z)-2-Chloro-4-{3-[(1S,2R)-6,7-dimethoxy-2-methyl-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-2-isoquinolinio]propyl}-1-{3{(1R,2S)-6,7-dimethoxy-2-methyl -1-[(3,4,5-trimethoxyphenyl)methyl]-1,2,3,4-tetrahy
Bigham Eric Cleveland
Boros Eric Eugene
Boswell Grady Evan
Mook, Jr. Robert Anthony
Patel Sanjay Shashikant
Glaxo Wellcome Inc.
Makujina Shah
Morgan Lorie Ann
Seaman D. Margaret
LandOfFree
Substituted isoquinolines as ultra short acting... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted isoquinolines as ultra short acting..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted isoquinolines as ultra short acting... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2608172