Substituted isoquinolines as ultra short acting...

Details Substituted isoquinolines as ultra short acting... Substituted isoquinolines as ultra short acting...

1999-12-22

2001-01-23

Seaman, D. Margaret (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S138000, C546S140000, C546S144000, C546S150000

Reexamination Certificate

active

06177445

ABSTRACT:

This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/EP98/01652 filed Mar. 23, 1998, which claims priority from both GB 9706117.0 filed Mar. 25, 1997 and GB 9724987.4 filed Nov. 27 1997.
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, MIR.
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 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 q and t are independently from 0 to 4; X
1
and X
2
are independently halogen; h
a
and h
b
are independently from 0 to 2; Z
1
and Z
2
are independently hydrogen, C
1-6
alkyl, C
2-6
alkenyl or C
2-6
alkynyl with the proviso that Z
1
and Z
2
are not both hydrogen; Y
1
, Y
2
,Y
3
and Y
4
are independently hydrogen, halogen or C
1-3
alkoxy; m and p are independently 1 to 6; n and r are independently 0 to 4; with the proviso that if h
a
and h
b
are both 0, then r is 0 and n is 0 to 2; R
1
to R
14
are independently hydrogen, halogen, C
1-3
alkoxy, or R
2
and R
3
together with the carbon atoms to which they are bonded, R
5
and R
6
together with the carbon atoms to which they are bonded, R
9
and R
10
together with the carbon atoms to which they are bonded and R
12
and R
13
together with the carbon atoms to which they are bonded, may independently form a methylenedioxy or ethylenedioxy moiety contained in a five or six-membered ring; W
1
and W
2
are carbon; and A is a pharmaceutically acceptable anion.
The compounds of Formula (I) contain two substituted isoquinoiinium 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 bond between the carbons attached to (CH
2
)
q
and (CH
2
)
t
, indicated as ({overscore (------)}), may be a single or double bond.
The compounds of Formula (I) may exhibit structural asymmetry in several ways. For example, a preferred sub-class of the compounds of Formula (I) is wherein n and r are different. A more preferred sub-class includes those wherein n is 1 and r is 0, i.e., one head contains a benzyl substitution whereas the other head contains a phenyl substitution.
Suitable aliphatic linkers include those where q and t are the same and are 0, 2 or 3. Preferred linkers include succinate, butenedioate, particularly fumarate, octanedioate and decanedioate. Particularly preferred aliphatic linkers comprise succinate or fumarate moieties, i.e., where q and t are each 0.
A preferred sub-class of the compounds of Formula (I) includes those where the aliphatic linker is halogenated, i.e., where h
a
and h
b
are independently from 1 to 2. Preferred halogens are chlorine, bromine or fluorine, especially chlorine and fluorine. Particularly preferred halogen substitutions are monochloro, monofluoro and difluoro. The most preferred sub-class includes compounds where the aliphatic linker contains a succinate moiety and where the halogen substitution is difluoro or where the aliphatic linker contains a fumarate moiety and the halogen substitution is monochloro or monofluoro. The position of the halogen substitution may also confer asymmetry to the compounds of Formula (I). For example, it is preferred that the halogen substitution be situated proximal to the left head when n is 1 and r is 0, i.e., the left head contains a benzyl substitution and the right head contains a phenyl substitution.
Suitable compounds of Formula (I) include those wherein Y
1
, Y
2
, Y
3
and Y
4
are each independently hydrogen or methoxy. Preferably Y
1
and Y
3
are hydrogen and Y
2
and Y
4
are methoxy. Further suitable compounds of Formula (I) include those wherein R
1
-R
14
are each independently hydrogen or C
1-3
alkoxy. Preferably R
1
, R
4
, R
7
, R
8,
R
11
and R
14
are hydrogen and R
2
, R
3
, R
5
, R
6
, R
9
, R
10
, R
12
and R
13
are C
1-3

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