Analgesic combination of muscarinic agonists

Details Analgesic combination of muscarinic agonists Analgesic combination of muscarinic agonists

2002-03-01

2004-12-07

Wang, Shengjun (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S282000, C514S629000, C514S570000, C514S406000, C514S473000

Reexamination Certificate

active

06828328

ABSTRACT:

This invention relates to the combination of muscarinic agonists with narcotic analgesics, non-steroidal anti-inflammatory drugs or other analgesic drugs and to their use as antinociception (pain relief) agents. In particular, the invention relates to a combination of a specific class of M4 selective muscarinic agonists with narcotic analgesics, non-steroidal anti-inflammatory drugs or other analgesic drugs.
Both narcotic analgesics (e.g. morphine) and non-steroidal anti-inflammatory drugs (NSAIDs) are well-known analgesics. Use of narcotic analgesics is limited by their ability to produce tolerance and addiction and their side effect profile. Side effects of narcotic analgesics include constipation, respiratory depression and nausea. NSAIDs are generally well tolerated but less efficacious analgesic agents.
Muscarinic agents have been shown to be effective analgesic agents in animal models with an efficacy similar to morphine but with much greater potency. The concept of using muscarinic agonists as potential analgesic agents for use in humans has been around for about five decades. Despite this there have been no muscarinic agonists approved for the treatment of pain. The primary reason for this has been their unacceptable side effect profile. A lack of understanding of the muscarinic receptor subtype mediating antinociception versus the side effects has further hampered work in this area. Recently however it has been shown that agonists which act selectively at the M4 receptor may provide good antinociception with an improved side effect profile (Ellis et al., The Journal of Pharmacology and Experimental Therapeutics, 288(3), 1999).
A class of M4 selective muscarinic agonists with reduced cholinergic side effects is described in WO 00/11001. These compounds are members of classes of azaadamantanes, azanoradamantanes and azahomoadamantanes.
Despite the work done in this field there remains a need for anti-nociceptive compositions having an improved analgesic profile without increasing side effects.
The present invention brings a solution in that it has now been found that a class of M4 selective muscarinic agonists when used in combination with additional analgesics enables an analgesic effect to be reached with concomitant reduction of undesirable side-effects compared to those side-effects experienced when either the M4 selective muscarinic agonists or the additional analgesics are administered alone in a concentration able of reaching the same analgesic effect. The additional analgesics may be narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAID's) or other analgesics. In particular embodiments, the class of M4 selective muscarinic agonists when used in combination with narcotic analgesics, non-steroidal anti-inflammatory drugs (NSAID's) or other analgesics produces synergism or super-additivity in the analgesic profile without increasing side effect liabilities.
The present invention relates thus to a composition comprising at least one M4 selective muscarinic agonist selected from the azacyclic ring system having the formula I
including geometrical isomers, enantiomers, diastereomers, racemates, acid addition salts, salts thereof with a pharmaceutically acceptable acid, and prodrugs thereof, wherein
Q is
X is —CH
2
—, —NH—, —O— or —S—;
V, W, Y and Z independently are CH or N;
n and m independently are 0, 1, 2, 3 or 4;
R
1
and R
2
are at any position on the azacyclic ring, including the point of attachment of the heterocycle Q, and independently are hydrogen, —OH, halogen, —NH
2
, carboxy, straight or branched C
1-10
-alkyl, C
1-10
-alkenyl, or C
1-10
-alkynyl, straight or branched C
1-10
-alkoxy, or straight or branched C
1-10
-alkyl substituted with —OH, —CN, —CHO, —OH, —OR
3
, —SR
3
, —NH
2
, —NHR, —NR
3
R
4
, —NO
2
, —SOR
3
, —SO
2
R
3
, —COR
3
, —CO
2
R
3
, —CONH
2
, —CONHR
3
, —CONR
3
R
4
, or —CH═NOR
3
; or
R
1
and R
2
independently are phenyl, phenoxy, henzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, —CN, C
1-10
-alkyl, C
1-10
-alkoxy, or C
1-10
-alkylthio;
R is hydrogen, halogen, —CN, —CHO, —OH, —OR
3
, —SR
3
, —NH
2
, —NHR
3
, —NR
3
R
4
, —NO
2
, —SOR
3
, —SO
2
R
3
, —COR
3
, —CO
2
R
3
, —CONH
2
, —CONHR
3
, —CONR
3
R
4
, or —CN═NOR
3
; or
R is phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl, each of which are unsubstituted or substituted with halogen, —CN, C
1-15
-alkyl, C
1-10
-alkoxy, or C
1-10
-alkylthio; or
R is a 5 or 6 membered saturated, partly saturated or aromatic heterocyclic ring containing one to three heteroatoms; and
R
3
and R
4
independently are straight, branched, or cyclic C
1-15
-alkyl, C
2-15
-alkenyl, C
2-15
-alkynyl, or combinations thereof, or R
3
and R
4
independently are phenyl, phenoxy, benzoyl, benzyl or benzyloxycarbonyl groups, each of which are unsubstituted or substituted with H, halogen, —CN, C
1-15
-alkyl, C
1-10
-alkoxy, C
1-10
-alkylthio, or aryl; or
R
3
and R
4
independently are 5 or 6 membered saturated, partly saturated or aromatic heterocyclic rings containing one to three heteroatoms; and
further comprising one or more additional analgesics.
In preferred embodiments, the one or more additional analgesics produce a synergistic or super-additive effect (“synergistic analgesics or super-additive”).
In a preferred embodiment, the present invention relates to a composition as defined above wherein in formula I of the M4 selective muscarinic agonist n and m both are 1 and the azazyclic ring system has the structural formula:
wherein
Q is:
X is S,
Y and Z are N, and
R is OR
3
or SR
3
.
In a more preferred embodiment, the present invention relates to a composition as defined above wherein R
3
of the M4 selective muscarinic agonist is —CH
3
, —CH
2
CH
3
, —CH
2
CH
2
CH
3
or —CH
2
CH(CH
3
)
2
.
In a still more preferred embodiment, the invention relates to a composition comprising at least one M4 selective muscarinic agonist selected from the group consisting of, 3-(5-Aza-2-chlorotricyclo[3.3.1.1<3,7>]dec-2-yl)-4-chloro-1,2,5-thiadiazole, 3-(5-Azatricyclo-[3.3.1.1<3,7>]dec-2-yl)-4-chloro-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1<3,7>]dec-2-yl)-4-methoxy-1,2,5-thiadiazole, 3-(5-azatricyclo-[3.3.1.1<3,7>]dec-2-yl)-4-ethoxy-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1<3,7>]dec-2-yl)-4-propoxy-1,2,5-thiadiazole, 3-(5-azatricyclo[3.3.1.1<3,7>]dec-2-yl)-4-butoxy-1,2,5-thia-diazole, 3-(5-azatricyclo-[3.3.1.1<3,7>]dec-2-yl)-4-(cyclopropylmethoxy)1,2,5-thiadiazole, 3-(5-azatricyclo-[3.3.1.1<3,7>]dec-2-yl)-4-(2-methyl-propoxy)-1,2,5-thiadiazole, 4-[4-(propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1<3,7>]decane, 4-[4-(methylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1<3,7>]decane, 4-[4-(ethylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1<3,7>]decane, 4-[4-(butylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1<3,7>]decane, 4-[4-(2-methyl-propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1<3,7>]decane, 4-[4-(cyclopropylmethylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo-[3.3.1.1<3,7>]decane and
further comprising one or more additional analgesics.
In a most preferred embodiment, the invention relates to a composition comprising the M4 selective muscarinic agonist 4-s-[4-(propylsulfanyl)-1,2,5-thiadiazol-3-yl]-1-azatricyclo[3.3.1.1<3,7>]decane and further comprising one or more additional analgesics.
In a further preferred embodiment of the invention, the compositions further comprise a pharmaceutically acceptable carrier.
In another embodiment, the invention relates to a method of inducing analgesia, the method comprising co-administration of at least one M4 selective muscarinic agonist selected from the azacyclic ring system having the formula I
including geometrical isomers, enantiom

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