EP0871445A1

EP0871445A1 - Composition for treating pain

Info

Publication number: EP0871445A1
Application number: EP96943584A
Authority: EP
Inventors: Charles H. Mitch; Harlan E. Shannon
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1995-12-07
Filing date: 1996-12-05
Publication date: 1998-10-21
Also published as: KR19990071976A; CN1208349A; NO982562D0; CZ174698A3; CA2238815A1; WO1997020561A1; JP2000501709A; IL124419A0; NO982562L; EA199800533A1; EP0871445A4; NZ324988A; AU1279197A; PL327137A1; AU705031B2

Abstract

The present invention provides a composition and method for treating pain using a composition comprising Selected Muscarinic Compounds and one or more compounds selected from the group consisting of Nonsteroidal Antiinflammatory drugs, acetaminophen, opioids, and alpha-adrenergic compounds.

Description

COMPOSITION FOR TREATING PAIN

The present invention relates to a method for using a combination of compounds for treating pain.

This invention relates to a therapeutic combination of compounds to provide analgesic activity.

More active analgesic combinations effects are in constant demand because they offer the attractive possibility of relieving pain with reduced dosages, thereby diminishing the expected side effects and toxicity that would otherwise result from higher dosages. It would be particularly desirable to acquire a synergistic combination effect. Such a composition is the subject of the present invention.

The composition of this invention provides a surprising synergistically effective treatment for pain using compounds which are independently known in the art. The synergistic effect of the present composition provides a means for treating pain using a lower dosage of each compound in the composition, thus providing a treatment with a more desirable side effect profile.

The present invention provides a composition useful for the treatment of pain, comprising a compound selected from the group consisting of:

wherein R¹ is hydrogen, Ci-C_δ alkyl or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R² is Ci-C_δalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy;

R³ and R⁴ are independently hydrogen, C1-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C1-C₄ alkyl, hydroxy, or C₁-C₄ alkoxy, or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C1-C₄ alkoxy;

in which R⁵ represents the radical

in which R⁶ at any position on the benzene ring represents linear, branched or cyclic Ci-Cβ alkyl, C₂-C8 alkenyl or C₂- C₈ alkynyl or the radical

^N-R»

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear C_3.-C₈ alkyl, C₂-C8 alkenyl or C₂- CΘ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹,

R⁹ representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁰ or S(0)R^1:L, R¹⁰ and

R¹¹ represent linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶' _' R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- C₈ alkynyl or the radical

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear Cχ-C₈ alkyl, ₂-C₈ alkenyl or C₂- C_δ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or O₂, or OR¹²', R¹²' representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic Cτ_- C8 alkyl, C₂-C₈ alkenyl or C₂-Cg alkynyl, or R¹² represents naphthyl optionally substituted with R¹³ ' - R¹³' being defined above for R¹³;

wherein, one of R¹⁸, R¹⁹, and R²⁰ represents nitrogen and the remainder represent carbon atoms; substituted on one of the ring carbon atoms with a R²⁴ substituent represented by a non¬ aromatic azacyclic or azabicyclic ring system and independently substituted on each of the other ring carbon atoms with R²³, R²¹, or R²² substituent of low lipophilicity or a hydrocarbon having a maximum of 20 carbon atoms;

wherein one of R²⁸, R²⁹ or R³⁰ is an oxygen atom and the other two are nitrogen atoms, and the dotted circle represents aromaticity (two double bonds) thus forming a 1, 3, 4-oxadiazole or 1, 2, 4-oxadiazole nucleus; R³¹ represents a non-aromatic '927azacycle or ' 927azabicyclic ring system; and R³² represents a substituent which is convertable in vivo to an amino group;

VI; wherein R³⁴ represents a non-aromatic; non-fused 1- azabicyclic ring system; and

R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl, Br, -CF₃, -OR³⁸, - R³⁸R³⁹, -NHOR³⁸, - HNH₂, -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁶ or R³⁷ taken together form a Cι_₆alkylenedioxy ring, wherein R³⁸ is Ci-βalkyl, C₂-₆alkenyl or C₂-₆alkynyl, R³⁹ is hydrogen, Cι_g alkyl,or -COCH₃, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹

wherein R⁴³ is alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from two to six carbon atoms, alkenyl of from two to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from two to six carbon atoms, alkynyl of from two to six carbon atoms, substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms,

(CH₂)

wherein n is zero or an integer of one to eight and R⁴⁷ and R⁴⁸ are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of from one to three carbon atoms, or alkoxy of from one to three carbon atoms, or alkoxy of from one to four carbon atoms, or

wherein

R⁴⁷ and R⁴⁸ are as defined above; X is oxygen or sulfur;

R⁴⁴ is alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms alkenyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or

wherein n, R47 and R48 are as defined above R45 and R46 are each independently hydrogen, alkyl of from one to twenty carbon atoms, alkyl of from one to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to twenty carbon atoms, alkenyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to twenty carbon atoms, alkynyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of from one to four carbon atoms, alkyl of from one to four carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkoxy of from one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl of R⁴⁵ and R⁴⁶ are taken together with the nitrogen atom to which they are attached to form a ring denoted by

wherein R⁴⁹ is hydrogen, alkyl of from one to ten carbon atoms, alkyl of from one to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from two to ten carbon atoms, alkenyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms and n is as defined above,

wherein X is defined above or

wherein R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and ... represents a single or double bond with the proviso that when, ____ represents a double bond X¹ is nitrogen and when _____ represents a single bond X' is CH2;

wherein R⁵³ is selected from the group consisting

R54, R55, R56, and R57 are each independenty hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from C1-C10 alkyl, alkoxy, C1-C10 halogen or trifluoromethyl; n¹ is an interger of one or two;

wherein X is oxygen, sulfur, or -N-R^δ2, wherein R⁶² is hydrogen or alkyl of from one to ten carbon atoms; R⁵⁸ is selected from the group consisting of

R⁵⁹, R⁶⁰, and R⁶¹ are each independently hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; represents a single or double bond with the proviso that when represents a double bond R⁵⁷ and R⁶⁰ are absent;

wherein R⁶³, R⁶⁴, and R⁶⁵ are each independently hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, halogen, and trifluoromethyl; R⁶⁶ is hydrogen, hydroxy or alkoxy of from one to ten carbon atoms; and R⁶⁷ is selected from the group consisting of

wherein

R⁶⁹ is hydrogen and R⁶⁷ is hydrogen, alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms, alkenyl of from three to six carbon atoms, substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or

R⁶⁸ and R⁶⁹ are taken together with the nitrogen atom to which they are attached to form a ring denoted by

wherein n' is zero or an integer from one to eight and R⁷³ is hydrogen, alkyl of from one to ten carbon atoms, alkyl of from one to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from two to ten carbon atoms, alkenyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from two to ten carbon atoms or alkynyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms; R⁷⁰ is hydrogen, alkyl of from one to six carbon atoms, alkyl of form one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms, alkenyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or R⁷⁰ when taken together with R⁶⁸ forms a ring denoted by

wherein n is an integer from one to three and R68 are as defined above;

R⁷¹ and R⁷² are each independently hydrogen, alkyl of from one to twenty carbon atoms, alkyl of from one to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to twenty carbon atoms, alkenyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to twenty carbon atoms, alkynyl of from three to twenty carbon atoms substituted with dydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of from one to four carbon atoms, alkyl of from one to four carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkoxy of from one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl of R³ and R⁴ are taken together with the nitrogen atom to which they are attached to form a ring denoted by

wherein n' and R⁷³ are ad defined above,

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms,

in which Z is a heterocyclic group

in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being substituted by a Cι-₂ alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group R_x; or a group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of Ai and A₃ is CR₂ and the other is CR₃; and Ri, R₂ and R3 are independently selected from hydrogen, halogen, CN, OR₄, SR₄, N(R.ι)₂, NHCOR₄, NHCOOCH₃, NHCOOC₂H₅, NHOR₄, NHNH , N0₂, COR₄, COR1₃, cyclopropyl, C2-₅ straight chain alkenyl, C₂-₅ straight chain alkynyl or C₁-₅ straight chain alkyl optionally terminally substituted with OR4, (R )2» SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, H2 or NHR4; or in which Z is a group -C(R7)=NRβ in which R is a group ORQ , where Rβ is Ci-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or Rs, or a group NHR;LO or NR11R12 where Rio- Rll and R12 are independently Ci- 2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when R6 is a group OCORg or NHR10, R7 is C1-4 alkyl

in which one of X and Y represents hydrogen and the other represents Z, and Z' is a group

in which Q' represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a Cl-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3, ε represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1;

wherein R⁷⁵ represents in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1;

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is Cι_4 alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or Cι_₄alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R, 4R) -3- (3-cyclopropyl-1, 2, 4-oxadiazol-5-yl) -1- azabicyclo [2.2. lheptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of

Compound to Synergistic Analgesic of from about 1 to about

1000.

The present invention provides a method for treating pain comprising administering to a patient in need thereof, an anagesic composition comprising a compound selected from the group consisting of:

wherein R¹ is hydrogen, Cχ-C₆ alkyl or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R² is Ci-Cgalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy;

R³ and R⁴ are independently hydrogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C₁-C₄ alkyl, hydroxy, or C₁-C₄ alkoxy, or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

in which R⁵ represents the radical

in which R⁶ at any position on the benzene ring represents linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C2- CQ alkynyl or the radical ^N→

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- C_δ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹, R⁹ representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up tc 14 carbon atoms, or the radical SR¹⁰ or S{0)R^1:L, R¹⁰ and R¹¹ represent linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶'< R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic Ci-Cβ alkyl, C2-C8 alkenyl or C₂- Cβ alkynyl or the radical

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear C -Cβ alkyl, C₂-C₈ alkenyl or C₂' Cs alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or NO₂, or OR¹²', R¹² ' representing hydrogen, linear, branched or cyclic Ci-Ce alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic Cι~ Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R¹² represents naphthyl optionally substituted with R¹³ ' _' R¹³' being defined above for R¹³;

wherein one of R²⁸, R²⁹ or R³⁰ is an oxygen atom and the other two are nitrogen atoms, and the dotted circle represents aromaticity (two double bonds) thus forming a

1, 3, 4-oxadiazole or 1, 2, 4-oxadiazole nucleus; R³¹ represents a non-aromatic '927azacycle or ' 927azabicyclic ring system; and R^;i2 represents a substituent which is convertable in vivo to an amino group;

wherein R³⁴ represents a non-aromatic; non-fused 1- azabicyclic ring system; and

R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl, Br, -CF₃, -OR³⁸, -NR³⁸R³⁹, -NHOR³⁸, -NHNH , -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁵ or R³⁷ taken together form a Ci-galkylenedioxy ring, wherein R³⁸ is Cι_₆alkyl, C_2~6alkenyl or C₂-₆alkynyl, R³⁹ is hydrogen, Cι-₆ alkyl,or -COCH₃, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹

wherein

R⁴⁷ and R⁴⁸ are as defined above;

X is oxygen or sulfur;

wherein X is defined above or

wherein R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and ... represents a single or double bond with the proviso that when, _____ represents a double bond X' is nitrogen and when .. _t represents a single bond X' is CH₂;

wherein R⁵³ is selected from the group consisting

H i

CH₃

R54, R55, R56, and R57 are each independenty hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from C1-C10 alkyl, alkoxy, C1-C10 halogen or trifluoromethyl; n' is an interger of one or two;

wherein X is oxygen, sulfur, or -N-R⁶², wherein R⁶² is hydrogen or alkyl of from one to ten carbon atoms; R⁵⁸ is selected from the group consisting of

R⁵⁹ , R⁶⁰, and R⁶¹ are each independently hydrogen, alkyl of froti one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; represents a single or double bond witn the proviso that when represents a double bond R⁵⁷ and R⁶⁰ are absent;

wherein R⁶³, R⁶⁴, and R⁶⁵ are each independently hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from the group consisting of alkyl, alkoxy, thioalkoxy, halogen, and trifluoromethyl; R⁶⁶ is hydrogen, hydroxy or alkoxy of from one to ten carbon atoms; and R^G7 is selected from the group consisting of

CH₃ wherein

R⁶ⁱ³ and R⁶⁹ are taken together with the nitrogen atom to which they are attached to form a ring denoted by

n

wherein n is an integer from one to three and R68 are as defined above;

wherein n" and R⁷³ are ad defined above,

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms.

in which Z is a heterocyclic group

in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being substituted by a Cι-₂ alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group Ri; or a group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of Ai and A₃ is CR₂ and the other is CR₃; and Ri, R₂ and R₃ are independently selected from hydrogen, halogen, CN, OR4, SR₄, (R4)₂» NHCOR₄, NHCOOCH₃, NHCOOC₂H₅, NHOR₄, NHNH₂, NO₂, COR₄, COR5, cyclopropyl, C₂-₅ straight chain alkenyl, C₂-₅ straight chain alkynyl or C₁-₅ straight chain alkyl optionally terminally substituted with OR4, N(R )2/ SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR , NH2 or NHR4; or in which Z is a group -C(R7)=NRβ in which R is a group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or R11R12 where RlO- Rll and R12 are independently C__- 2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when Rζ is a group OCOR9 or NHR10, 7 is C1-4 alkyl

in which Q' represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a Cl-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3 , s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1;

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is C1-₄ alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or Cι-₄alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R, 4R) -3- (3-cyclopropyl-l, 2 , 4-oxadiazol-5-yl) -1- azabicyclo [2.2. lheptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of

Compound to Synergistic Analgesic of from about 1 to about

1000.

As noted hereinbefore, the compounds employed in the method of the present invention are known. The compounds, methods of preparing the compounds, as well as pharmaceutical formulations containing the compounds, are taught in U.S. Pat. Nos. 4,923,880, 5,110,828, 5,041,436, 5,278,170, 7,177,084, 4,992,436, 5,260,293, 4996,201, 5,066,662, 5,066,665, 5,066,663, 4,988,688, 5,106,853, 5,192,765, 5,041,455, 5,043,345, 5,260,314, 5,310,911, 5,106,851, 5,068,237, 5,318,978, 5,242,927, 5,300,516, 5,089,505, 5,302595, 5,219,871, 5,096,890, 5,164,386, 5,164,514, 5,157,160, 5,217,975, and 5,081,130 herein incorporated by reference.

It is to be understood that the invention extends to the use of each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enantiomeric, and racemic forms of the named compounds.

As used herein, the terms "Synergistic Analgesic" and "Synergistic Analgesics" refer to the group consisting of Nonsteroidal anti-inflammatory drugs (NSAIDS) , acetaminophen, alpha-adrenergic compounds, and opioids. As used herein, the term "Selected Muscarinic

Compound" and "Selected Muscarinic Compounds" refers to a compound selected from the group consisting of

wherein R¹ is hydrogen, C -C_δ alkyl or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R² is C -Cgalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy;

R³ and R⁴ are independently hydrogen, Ci-Cβ alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C₁-C₄ alkyl, hydroxy, or C -C₄ alkoxy, or phenyl-Cι~C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C -C₄ alkoxy; ^■37 -

in which R⁵ represents the radical

in which R⁶ at any position on the benzene ring represents linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- Cβ alkynyl or the radical

^N-R»

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear Ci-Cβ alkyl, C₂-C8 alkenyl or C₂- Cβ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹, R⁹ representing hydrogen, linear, branched or cyclic Cι~Cβ alkyl, C₂~Ce alkenyl or C₂~Cβ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁰ or S(0)R^1]-, R¹⁰ and R¹¹ represent linear, branched or cyclic Ci-Cs alkyl, C₂~C_δ alkenyl or C₂~Cδ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶'- R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic Ci-Cs alkyl, C₂~C_δ alkenyl or C₂- CQ alkynyl or the radical

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear C -C_δ alkyl, C₂-Cβ alkenyl or C₂- Cβ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or O , or OR¹²', R¹²' representing hydrogen, linear, branched or cyclic Ci-Cs alkyl, C₂~Ce alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic C ~ C_δ alkyl, C₂~Cβ alkenyl or C₂-C₈ alkynyl, or R¹² represents naphthyl optionally substituted with R¹³ ' - R¹³' being defined above for R¹³;

wherein one of R²⁸, R²⁹ or R³⁰ is an oxygen atom and the other two are nitrogen atoms, and the dotted circle represents aromaticity (two double bonds) thus forming a 1,3, 4-oxadiazole or 1, 2, 4-oxadiazole nucleus; R³¹ represents a non-aromatic ' 927azacycle or ' 27azabicyclic ring system; and R³² represents a substituent which is convertable in vivo to an amino group;

R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl, Br, -CF₃, -OR³⁸, -NR³⁸R³⁹, -NHOR³⁸, -NHNH₂, -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁶ or R³⁷ taken together form a Cι-₆alkylenedioxy ring, wherein R³⁸ is Ci-βalkyl, C₂-₆ lkenyl or C₂-₆ lkynyl, R³⁹ is hydrogen, C _₆ alkyl,or -COCH₃, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹ X

R«^J0-C-N-CH₂-C .= C-CH₂ -N-R 46

^R44 VII ⁴⁵

wherein n is zero or an integer of one to eight and R⁴⁷ and R^4Ϊ are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of from one to three carbon atoms, or alkoxy of from one to three carbon atoms, or alkoxy of from one to four carbon atoms, or

wherein R⁴⁷ and R⁴⁸ are as defined above; X is oxygen or sulfur; R⁴⁴ is alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms alkenyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or

wherein n, R47 and R48 are as defined above R45 and R46 are each independently hydrogen, alkyl of from one to twenty carbon atoms, alkyl of from one to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to twenty carbon atoms, alkenyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to twenty carbon atoms, alkynyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of from one to four carbon atoms, alkyl of from one to four carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkoxy of from one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl of R⁴⁵ and R⁴⁶ are taken together with the nitrogen atom to which they are attached to form a

wherein X is defined above or

wherein R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

97/20561

-44-

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and ... represents a single or double bond with the proviso that when, ________ represents a double bond X' is nitrogen and when

_______ represents a single bond X' is CH2;

wherein R⁵³ is selected from the group consisting

R⁵', R⁶⁰, and R⁶¹ are each independently hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; represents a single or double bond with the proviso that when represents a double bond R⁵⁷ and R⁶⁰ are absent;

CH₃ wherein

R^6a and R⁶⁹ are taken together with the nitrogen atom to which they are attached to form a ring denoted by

wherein n is an integer from one to three and R68 are as defined above;

wherein n' and R⁷³ are ad defined above,

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms.

in which Z is a heterocyclic group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of A and A₃ is CR₂ and the other is CR₃; and Ri, R₂ and R₃ are independently selected from hydrogen, halogen, CN, OR₄, SR₄, N(R )₂, NHCOR₄, NHCOOCH₃, NHCOOC₂H₅, NHOR₄, NHNH₂, N0₂, COR₄,

COR₅, cyclopropyl, C₂-₅ straight chain alkenyl, C₂-₅ straight chain alkynyl or C₁-₅ straight chain alkyl optionally terminally substituted with OR4, (R4>2 SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C3_.-3 alkyl and R5 is OR4, NH2 or NHR4; or in which Z is a group -C(R7)=NR6 in which R6 is a group OR8 where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or NRHR12 where Rχo, Rll and R12 are independently Ci- 2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when Rβ is a group OCOR9 or NHRχo , 7 is C1-4 alkyl

in which one of X and Y represents hydrogen and the other represents Z, and Z" is a group

in which Q' represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a Cl-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1;

wh€irein R⁷⁵ represents in which each of p and q independently represents an integer of 2 to 4, r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1;

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is Cι_₄ alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or Cι-4alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R, 4R) -3- (3-cyclopropyl-l, 2 , 4-oxadiazol-5-yl) -1- azabicyclo[2.2. lheptane; or a pharmaceutically acceptable salt or solvate thereof.

The term "low lipophilicity" refers to hydrogen, halogen, -CF₃, -OR²⁵, -NR²⁵R²⁶' ^"NHOR²⁵- -NHNH₂, -CN, COR⁸, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group; wherein R²⁵ is hydrogen, Ci-Cβ alkyl, C₂-₆ alkenyl or C₂-₆ alkynyl; R²⁶ is hydrogen, alkyl or -COCH₃, and R27 represents -OR²⁵ or -NR²⁵R²⁶-^'

The term azacyclic or azabicyclic ring system is a non-aromatic ring system containing one nitrogen atom as the sole heteroatom. Sutably, the ring system contains from 4-10 ring atoms, preferably from 5-8 ring atoms. Preferably, the ring system contains a tertiary amino nitrogen atom in a ce.ged structure. The bicyclic systems may be fused, spiro, or birdged. Preferably, the nitrogen atom is at a bridgehead in a bicyclic system. Examples of such heteroatoms include the heteroatoms described in U.S. Patent 5,260,293, columns 2-3, which has been incorporated by reference.

The term "'927 azacyclic or '927 azabicyclic" refers to a non-aromatic ring system containing one nitrogen atom as the sole heteroatom. Suitably the ring contains from 4 to 10 ring atoms. Preferably from 5-8 ring atoms. The bicyclic systems may be fused, spiro or bridged. Examples of such heteroatoms include the bicyclic heteroatoms described in U.S. Patent 5,242,927 column 2, which has been incorporated by reference. The most preferred ' 927azabicyclic or ' 927azacyclic systems include pyrrolidine, 1, 2, 5, 6- etrahydropyridine, quinuclidine or 1- azabicyclo[2.2.l]heptane ring, optionally substituted with me-hyl or hydroxy. An especially preferred '927 azabicyclic ring is quinuclidine, which is substituted by hydrogen, methyl or hydroxy at any available atom.

Groups which are converted in vivo to an amino group on the compounds claimed herein for treating pain may be ascertained by administering the compound to a human or an animal and detecting, by conventional analytical techniques, the presence of the corresponding compound having an amino substituent in the urine of a human or animal. Examples of such groups include groups which are hydrolysable in vivo to an amino group, such as amido, urethan substituents. In particular a group of the formula -NH.Q whererin Q represents CHO, COR³³ or C0₂R³³, and R³³ represents an optionally substituted hydrocarbon group. The term hydrocarbon group includes groups having up to 20 carbon atoms, suitably up to 10, and conveniently up to 8 carbon atoms. Suitable hydrocarbon groups include Cι_₈ alkyl, C₂-_δalkenyl, C₂- βalkynyl, C₃_7cycloalkyl, C₃_7cycloalkylCι_₆alkyl, aryl and arylCi-galkyl.

Suitable R³⁴ groups include the following:

wherein the broken line represents an otpional chemical bond; and R⁴¹ and R⁴² may be present at any position, including the point of attachment to the benzene ring, and independently represent hydrogen, Cι_₄alkyl, F, Br, Cl, C₁-₄ alkoxy, hydroxy, carboxy, or Cι-₄alkyoxycarbonyl or R⁴¹ and R⁴² together represent cabonyl. The nitrogen atom may be substituted by hydrogen or C₁-₄ alkyl.

The term "phenyl-Cι-C₄ alkyl" designates an alkyl group which is substituted with a phenyl group. Preferred phenyl-alkyl groups include benzyl, 1- and 2-phenylethyl, 1-, 2-, 3-phenyla propyl and 1-methyl-1-phenylethyl . The phenyl group may be optionally be substituted with from 1-3 independently selected named substituents.

The term "form together with the nitrogen atom to which they are joined, a heterocyclic radical" means that a heterocyclic radical optionally containing another heteroatom, for example, S or 0. Such groups include, but are not limited to, piperidyl, piperazynyl, morpholinyl, and pyrrolidinyl.

The term "alkyl" refers to the number of carbon atoms indicated; however, when no number is specified, the term refers to C₁-₆ alkyl. The alkyl may be linear or branched unless specified. The term "halogen" refers to chloro, bromo, and fluoro substituents.

The term "alkynyl" has its accepted meaning; however, if the number of carbon atoms are unspecified, it refers to C₂-₁₀ alkynyl. The alkynyl group may be linear or branched unless specified.

The term alkoxy refers to Cι_₄ alkoxy unless specified.

The term "analgesic dose", as used herein, represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from pain following administration to such human. The active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. While the present compounds are preferably administered orally to humans susceptible to or suffering from anxiety, the compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.

The term "NSAIDS", as used herein, represents a nonsteroidal anti-inflammatory drug which can be identified as such by the skilled artisan. For example, the Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 1308 - 1309 provide well known examples of NSAIDS. The term is intended to include, but is not limited to salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac. Especially preferred NSAIDS include aspirin, ibuprofen, and naproxen. Alternative preferred NSAIDS are indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

Particularly preferred NSAIDS include aspirin and ibuprofen. The salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic acid, and sodium salicylate. An especially preferred NSAID is ibuprofen.

The term "acetaminophen", as used herein, shall have the art accepted meaning and refers to N-(4- Hydroxyphenyl)acetamide and 4 ' -hydroxyacetanilide. The compound is claimed in U.S. Patent No. 2,998,450 and is known to the skilled artisan.

The term "central alpha-adrenergic active compounds", as used herein, represents a compound having central alpha-adrenergic receptor activity. The most preferred central alpha-adrenergic active compound is clonidine or a pharmaceutically acceptable salt thereof having the chemical name: 2- (2, 6-dichlorophenylamino) -2- imidazoline.

Clonidine is known to be useful for treating hypertension. see Physicians' Desk Reference, 45th Ed. (1991) p. 673.

The term "opioid", as used herein, represents opioid analgesics and antagonists including natural opioid analgesics, synthetic opioid analgesics, opioid antagonists and opioid agonist-antagonists. Preferred an opioid compounds are selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine. More preferred opioid compounds are selected from the group consisting of codeine, nabuphine, naloxone, and naltrexone. Preferred an opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, bro pton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine. Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, l€ivorphanol, fentanyl, and alphaprodine. Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine, and codeine. The especially particularly preferred opioid compounds are selected from morphine and codeine.

As used herein, the phrase "one or more" most preferredly refers to one; however, two, three, or more may be used.

We have discovered that a group of compounds having muscarinic cholinergic activity can be particular useful for treating pain when used in combination with non-steroidal antiinflammatory agents (NSAIDS) . More specifically, the invention provides a method of treating pain in humans using a specified known compounds (collectively referred to herein as "selected muscarinic compounds") in combination with a NSAIDS to provide a synergistic effect. The Selected Muscarinic Compounds are believed to be active based on activity at muscarinic cholinergic receptors; however, the present invention is in no way limited by the mechanism of action.

There are many NSAIDS known in the literature and to the skilled artisan. We have discovered that a group of compounds having muscarinic cholinergic activity can be particular useful for treating pain when used in combination with acetaminophen. More specifically, the invention provides a method of treating pain in humans using a specified Selected Muscarinic Compounds in combination with acetaminophen to provide a synergistic effect.

Further, we have discovered that a group of compounds having muscarinic cholinergic activity can be particularly useful for treating pain when used in combination with central alpha-adrenergic active compounds. More specifically, the invention provides a method of treating pain in humans using Selected Muscarinic Compounds in combination with a central alpha-adrenergic active compound to provide a synergistic effect.

Oral combinations of aspirin with codeine or other narcotic analgesics are known to provide additive analgesic effects in man. The Pharmacological Basis of Therapeutics, 5th edition, Macmillan Publishing Co., 1975, pp 325-358. The present invention further envisions that one or more Selected Muscarinic Compounds may be used at one time in the composition of this invention to provide the desired analgesic effect.

In the composition of this invention a Selected Muscarinic Compound and NSAIDS compound are combined in a weight ratio of Compound to NSAIDS of from about 1 to about 1000.

A preferred composition is a weight ratio of Compound to NSAIDS of from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about 1 to about 3.

In the composition of this invention a Selected Muscarinic Compound and acetaminophen are combined in a weight ratio of Selected Muscarinic Compound to acetaminophen of from about 1 to about 1000. A preferred composition is a weight ratio of Selected Muscarinic Compound to acetaminophen of from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about 1 to about 3.

The Selected Muscarinic Compounds are effective over a wide dosage range,- however, it is desirable to administer a dosage that is as low as possible. The amount of NSAIDS present in the composition is adjusted as described above in ratio to the Selected Muscarinic Compound dosage. The amount of acetaminophen present in the composition is adjusted as described above in ratio to the Selected Muscarinic compound dosage.

In the composition of this invention a Selected Muscarinic Compound selected and one or more opioid compounds are combined in a weight ratio of Selected Muscarinic Compound to opioid compound of from about 1 to about 1000.

A preferred composition is a weight ratio of Selected Muscarinic Compound to opioid compound of from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about 1 to about 3.

The amount of opioid compound present in the composition is adjusted as described above in ratio to the Selected Muscarinic Compound dosage. However, for each composition claimed herein, it will be understood that the amount of the Selected Muscarinic Compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of Selected Muscarinic Compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. While the present compounds are preferably administered orally to humans susceptible to or suffering from pain, the compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.

Transdermal formulations containing the composition claimed herein most preferably deliver the active substances in an effective amount for from about three days to about seven days. However, for chronic pain such as arthritis or cancer pain, a transdermal delivery of from about three days to up to about two weeks is desirable. Alternatively, it may be preferred to deliver the claimed compositions transdermally in an effective amount for from about one day to about three days. As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition. The Selected Muscarinic Compounds employed in the invention are not believed to act via the

GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present Selected Muscarinic Compounds as analgesic agents is believed to be based upon modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation.

Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred. The dosage administered will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of the symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 100 mg/kg of body weight SeLected Muscarinic Compound and from about 0.6 to about 200 mg/kg of NSAIDS.

Compositions suitable for internal administration contain from about one half (0.5) milligrams to about 600 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of from about 0.5% to about 95% by weight based on the total weight of the composition.

For compositions containing acetaminophen, usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 500 mg/kg of body weight Selected Muscarinic Compound and from about 0.6 to about 200 mg/kg of acetaminophen.

Typical compositions include a compound of Selected Muscarinic Compound and one or more NSAIDSs, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.

Typical compositions include a Selected Muscarinic Compound and acetaminophen, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used, as described above. A preferred composition is a weight ratio of

Selected Muscarinic Compound to central alpha-adrenergic active compound of from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio may be from about 1 to about 10. A final preferred ratio may be from about 1 to about 3.

The Selected Muscarinic Compounds are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible. The amount of central alpha-adrenergic active compound present in the composition is adjusted as described above in ratio to the Selected Muscarinic Compound dosage.

Usually, the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 500 mg/kg of body weight Selected Muscarinic ompound and from about 0.6 to about 200 mg/kg of central alpha-adrenergic active compound.

Typical compositions include a Selected Muscarinic Compound and one or more central alpha- adrenergic active compounds, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

Generally, the compositions of this invention are dispensed in unit form comprising from about 0.1 to about 300 mg in a pharmaceutically acceptable carrier per unit dosage.

The compositions of this invention may be suitable for administration to an animal. Such animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferredly, the animal is a vertebrate. Most preferredly, a composition of this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such domestic animal purposes, a composition of this invention may be administered as a feed additive.

The following models and assays are useful for illustrating the effectiveness of the compositions claimed herein.

Nociceptive pain model:

Acetic acid-induced writhing: A standard procedure for detecting and comparing the analgesic activity of different classes of analgesic drugs for which there is a good correlation with human analgesic activity is the prevention o acetic acid-induced writhing in mice. Mice, are subcutaneously administered various doses of the claimed composition and are injected injected intraperitoneally with acetic acid (0.5% solution, 10 ml/kg) 5 min prior to a designated observation period. For scoring purposes a

"writhe" is indicated by whole body stretching or contraction of the abdomen during the observation period beginning 5 min after receiving the acetic acid. Inhibition of writhing behavior is demonstrative of analgesic activity. See, Haubrich, D.R., Ward, S.J., Baizman, E., Bell, M.R. , Bradford, J., Ferrari, R., Miller, M. , Perrone, M. , Pierson, A.K., Saelens, J.K. and Luttinger, D. : Pharmacology of pravadoline: a new analgesic agent. The Journal of Pharmacology and Experimental Therapeutics 255 (1990) 511-522.

Neuropathic pain model:

Sciatic nerve ligation model: Rats are anesthetized and a nerve ligation procedure performed. The common sciatic nerve is exposed and 4 ligatures tied loosely around it with about 1 mm spacing. One day to 10 weeks after surgery, the nociceptive testing is performed. Responses to noxious heat are determined by placing the rats in a chamber with a clear glass floor and aiming at the plantar surface of the affected foot a radiant heat source from beneath the floor. Increased latency to withdraw the hindpaw is demonstrative of analgesic activity. Responses to normally innocuous mechanical stimuli is determined by placing the rats in a chamber with a screen floor and stimulating the plantar surface of the hind paw wit.h graduated von Frey hairs which are calibrated by the gre.ms of force required to bend them. Rats with sciatic nerve ligation respond to lower grams of mechanical stimulation by reflexive withdrawal of the foot than uncperated rats. This response to stimuli which are normally innocuous is termed allodynia. Increases in the grams of mechanical force required to produce foot withdrawal is demonstrative of antiallodynic activity. See, Bennett, G.J. and Xie, Y.-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1988) 87-107. See also, Lee, Y.-W., Chaplan, S.R. and Yaksh, T.L.: Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model. Neuroci Lett 186 (1995) 111-114. Formalin paw test: Rats are anesthetized and when there is a loss of spontaneous movement the rats are injected subcutaneously in the dorsal surface of the hindpaw with 50 ul of 5% formalin solution using a 30 gauge needle. Rats are then individually placed in an open Plexiglas chamber for observation, and within a maximum interval of 1 to 2 min, the animal displays recovery from anesthesia with spontaneous activity and normal motor function. Pain behavior is quantified by periodically counting the incidents of spontaneous flinching/shaking of the injected paw. The flinches are counted for 1-min periods at 1- to 2-, 5- to 6- and 5min intervals during the interval from 10 to 60 min. Inhibition of the pain behavior is demonstrative of an analgesic activity.

See, Malmberg, A.B. and Yaksh, T.L. : Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. The Journal of Pharmacology and Experimental Therapeutics 263 (1992) 136-146.

Inflammatory pain model:

Brewer's yeast-induced hyperalgesia (Randall-Selitto

Test): To assess nociceptive threshold in rats, ascending pressure is applied gradually to the paw with a motor driven weight of a Ugo Basile Analgesy Meter. Rats respond to the pressure by either pulling free of the device, struggling or vocalizing. Hyperalgesia is induced by a hind paw subplantar injection of 0.1 ml of 1% suspension of brewer's yeast in 0.9% saline. The composition of this invention is administered at varying times ( 0 - 4 hr) after injection of brewer's yeast and pressure threshold for the inflamed paw again determined at varying times. Increases in the pressure which produces a behavioral response is demonstrative of analgesic activity.

See, Haubrich, D.R., Ward, S.J., Baizman, E. , Bell, M.R., Bradford, J., Ferrari, R., Miller, M. , Perrone, M. , Pierson, A.K. , Saelens, J.K. and Luttinger, D. : Pharmacology of pravadoline: a new analgesic agent. The Journal of Pharmacology and Experimental Therapeutics 255 (1990) 511-522.

Utility Test Methods The unexpectedly enhanced analgesic activity of the composition of the invention is evidenced by tests intially conducted on mice. Male mice are fasted for 16-22 hours and weighed. Mice weighing from about 18-22 grams at the time of testing are used for the following studies. All mice are dosed sequentially by the oral route with suspensions of a composition of this invention. Doses are coded using a code unknown to the observer. A stock suspension of the test composition is prepared by mixing the active ingredients with about 40 mL of an aqueous vehicle containing about 2% Tween 80 (R) , a pharmacological dispersant and containing 100% polysorbate 80, and 1% by weight Methocel (R) MC powder, and containing 100% methylcellulose, in distilled water. The mixture may be sonicated for about 10 to about 15 seconds using an ultrasound sytem. All dosing suspensions are prepared by dilution of the stock suspension with Methocel/Tween 80. All suspensions are used within two hours of preparation.

MQvse writhing est

An accepted standard for detecting and comparing the analgesic activity of different classes of analgesic compounds for which there is a good correlation with human analgesic activity is the prevention of phenyl-p- benzoquinone induced writhing in mice. [H. Blumberg et al. Proc. Soc. Exp. biol. Med., 118, 763-766 (1965)] . Mice, treated with various doses of Selected Muscarinic Compound, composition or vehicle are injected intraperitoneally with a standard challenge dose of phenyl- p-benzoquinone 5 minutes prior to a designated observation period. The pheyl-p-benzoquinone is prepared as about 0.1 mg/ml solution in about 5% by volume of ethanol in water. The writhing dose is 1.25 mg/kg injected at a volume of about 0.25ml/10g. For scoring purposes a "writhe" is indicated by whole body stretching or contracting of the abdomen during an observation period beginning about five minutes after the phenyl-p-benzoquinone dose.

All ED50 values and their 95% confidence limits are determined using accepted numerical methods. For example, see W.F. Thompson, Bacteriological Rev.. 11, 115- 145 (1947) . The interaction of the dosages on phenyl-p- benzoquinone induced writhing in mice is demonstrated by the Loewe isobologram (S. Loewe, Pharm. Rev. 9, 237-242 (1957) .

The solid line connecting the ED50 dosages of Selected Muscarinic Compound (alone) and Synergistic

Analgesic as claimed herein (alone) represents the "ED50 addition line" which indicates the expected location of the ED50'ε for Selected Muscarinic Compound and classical analagesic combinations if simple additivity were to describe their combined effects. The 95% confidence range for the ED50 addition line is shown by the area between the broken lines above and below the ED50 addition line.

According to Loewe' s isobolic theory, if the analgesic effects are simply additive to one another, then the expected location of the ED50's of the Selected

Muscarinic Compound and Synergistic Analgesic component of each fixed dosage ratio would be contained within or overlap the region of the ED50 addition line. Combination ED50's located significantly below the ED50 addition line would represent unexpectedly enhanced analgesic activity and combination ED50's located above the line would represent unexpected diminished analgesic effect. One method to establish the significance of such unexpected enhanced or diminished activity is to calculate the best fitting polynomial regression line to the observed ED50's using standard mathematical techniques. Such experiments demonstrate that compositions comprised of a Selected Muscarinic Compound and one or more Synergistic Analgesics provides a statistically significant synergistic analgesic effect.

Preferred compounds for use in treating pain include:

OR, 4R) -3- (3-cyclopropyl-1,2, 4-oxadiazol-5-yl) -1- azabicyclo[2.2.lheptane and compounds of Formulae IV, V, v::ιι, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt thereof. Especially preferred compounds include the following: compounds of Formulae XIII, XIV, and XV.

Examples of preferred compounds include, but are not limited to, 3- [2- (δ-hydroxypyrazin)yl] -1- azabicyclo[2.2.2]octane, 3- (2-pyrazinyl) -1- azabicyclo [2.2.1]heptane, 6- (2-pyrazinyl) -1- azabicyclo[3.2.1]octane, 6- (2-pyrazinyl) -1- azabicyclo[3.2.l]octan-6-ol, 3-fluoro-3- (2-pyrazinyl) -1- azabicyclo[2.2.1]heptane, 1-methyl-3- (2- pyrazinyl)pyrrolidine, 3- [2- (3-methylpyrazin)yl] -1- azabicyclo[2.2.2]octan-3-ol, 3- [2- (3 , 6-dimethylpyrazin)yl] -1- azabicyclo[2.2.1]heptane, 3- [2- (6-allyloxypyrazin)yl] -1- azabicyclo[2.2.1]heptane,3- [2- (6-methoxypyrazin)yl] -1- azabicyclo[2.2.2]octane, 3- [2- (6-chloropyrazin)yl] -1,2,5,6- tetrahydropyridine, 3- [5- (3-octanyloxycarbonylamino-l , 2, 4- oxadiazol) -yl] -1-azabicyclo[2.2.1] eptane, 3-[5- (3- cyclohexylcarbonylamino-1, 2, 3-oxadiazol) -yl]quinuclidine, 3- [5- (3- (1- (3-n-pentyloxycarbonyl) -1-ethoxycarbonylamino) - 1,2, 4-oxadiazol) -yl] uinuclidine, 3- [5- (3-octanoylamino- 1,2, 4-oxadiazol) -yl]quinuclidine, 3- [ (l-methyl-lH-imidazol-5- yl)methyl] 1,2, 4-oxadiazol-5 (4H) -one, 4-methyl-3- [ (1-methyl- lH-imidazol-4-yl) -methyl] 1,2, 4-oxadiazol-5 (4H) -one, 4-ethyl- 3 [ (l-methyl-lH-imidazol-4-yl) -methyl] -1,2 , 4-oxadiazol-5 (4H) - one, N- [4- (hexahydro-lH-azaepin-1-yl) -2-butynyl] -N,N-dimethyl urea, N- [4-1-pyrrolidinyl) -2-butynyl] -urea, 5-acetyl-l- azabicyclo [3.1.1]heptane, 1-azabicyclo[3.1.1]hept-5- ylcarboxaldehyde, 3- (2-methyltetrazol-5-yl) -1- azabicyclo[2.2.1]heptane, 3- (2-methyl-l,2, 3-triazol-4-yl) -1- azabicyclo- [2.2.2]octane, 3- (3-cyclopropyl-l, 2, 4-oxadiazol-5- yl) -1-azabicyclo[2.2.l]heptane, and a pharmaceutically acceptable salt or solvate thereof.

Claims

We Claim:

1. A composition for treating pain comprising an analgesic dose of a Compound selected from the group consisting of:

wherein R¹ is hydrogen, Ci-Cβ alkyl or phenyl-Cι-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R² is Ci-Cgalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy; R³ and R⁴ are independently hydrogen, Cι~Cβ alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C₁-C₄ alkyl, hydroxy, or C -C₄ alkoxy, or phenyl-C₁-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

in which R⁵ represents the radical

^N-R»

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂- C₈ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹, R⁹ representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁰ or S(0)Rⁿ, R¹⁰ and R¹¹ represent linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶' - R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂- C_δ alkynyl or the radical

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂- Cβ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or

NO₂, or OR¹²', R¹ ' representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C8 alkenyl or C₂-C8 alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic Ci- Cs alkyl, C2-C8 alkenyl or C₂-C₈ alkynyl, or R¹² represents naphthyl optionally substituted with R¹³'- R¹³' being defined above for R¹³;

wherein R³⁴ represents a non-aromatic; non-fused 1- azabicyclic ring system; and R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl, Br, -CF₃, -OR³⁸, -NR³⁸R³⁹, -NHOR³⁸, -NHNH , -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁶ or R³⁷ taken together form a Cι_₆alkylenedioxy ring, wherein R³⁸ is Ci-galkyl, C₂-βalkenyl or C₂-₆alkynyl, R³⁹ is hydrogen, Cι-₆ alkyl,or -COCH₃, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹

wherein R⁴⁷ and R⁴⁸ are as defined above;

X is oxygen or sulfur; R⁴⁴ is alkyl of from one to six carbon atoms, alkyl of from one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms alkenyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or

f ΓΛ y.

wherein X is defined above or

wherem R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and ... represents a single or double bond with the proviso that when, _^____^. represents a double bond X' is nitrogen and when ________ represents a single bond X' is CH₂;

wherein R⁵³ is selected from the group consisting

R'⁵⁴, R⁵⁵, R⁵⁶, and R⁵⁷ are each independenty hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from C1-C10 alkyl, alkoxy, C1-C10 halogen or trifluoromethyl; n' is an interger of one or two;

R⁵⁹, R⁶⁰, and R⁶¹ are each independently hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; represents a single or double bond with the proviso that when represents a double bond R⁵⁷ and R⁶⁰ are absent; \ 2 -

CH₃ wherein

wherein n is an integer from one to three and R68 are as defined above;

wherein n' and R⁷³ are ad defined above,

—N

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms,

in which Z is a heterocyclic group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of A and A₃ is CR₂ and the other is CR₃; and Ri, R₂ and R3 are independently selected from hydrogen, halogen, CN, OR₄, SR₄, N(R₄)₂, NHCOR₄, NHCOOCH₃, NHCOOC₂H₅, NHOR₄, NHNH₂, N0₂, COR₄, COR₅, cyclopropyl, C₂-₅ straight chain alkenyl, C2-₅ straight chain alkynyl or C₁-₅ straight chain alkyl optionally terminally substituted with OR4, N(R4)2 SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or NHR4; or in which Z is a group -C(R7)=NR6 in which Rζ is a group OR8 , where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCORg where Rg is hydrogen or Rs, or a group NHR10 or R11R12 where Rio, Rll and R12 are independently Ci- 2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the proviso that when R6 is a group OCOR9 or NHR10, R7 is C1-4 alkyl

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is C₁-.₄ alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or Cι-₄alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R,4R) -3- (3-cyclopropyl-l,2,4-oxadiazol-5-yl)-1- azabicyclo[2.2.lheptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of Compound to Synergistic Analgesic of from about 1 to about 1000.

2. A composition as claimed by Claim 1 wherein the Compound is selected from the group consisting of Formula

IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

3. A composition as claimed by Claim 1 wherein the Synergistic Analgesic is a nonsteroidal anti-inflammatory drug. 4. A composition as claimed by Claim 3 wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

5. A composition as claimed by Claim 3 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

6. A composition as claimed by Claim 3 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

7. A composition as claimed by Claim 1 wherein the Synergistic Analgesic is an opioid.

8. A composition as claimed by Claim 7 wherein the Compound is selected from the group consisting of Formula IV,

V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

9. A composition as claimed by Claim 8 wherein the Compound is selected from the group consisting of l-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, 1-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone, 3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, l-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.1] oct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2. l]hept-3-yl-N-methoxycarboxamide,

(methoxyimino) - (1-azabicyclo [2.2.2]oct-3-yl)acetonitrile, oximino- (1-azabicyclo[2.2.2] oct-3-yl) acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

10. A composition as claimed by Claim 8 wherein the opioid is selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, bro pton' s cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine. 11. A composition as claimed by Claim 8 wherein the opioid is selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and alphaprodine.

12. A composition as claimed by Claim 8 wherein the opioid is selected from the group consisting of propoxyphene, methadone, hydrocodone, hydromorphine, and codeine. 13. A composition as claimed by Claim 1 wherein the Compound is selected from the group consisting of Formula I, II, and III; or a pharmaceutically acceptable salt or solvate thereof.

1 . A composition as claimed by Claim 1 wherein the Compound is selected from the group consisting of Formula XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

15. A composition as claimed by Claim 14 wherein the Compound is selected from the group consisting of 1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, l-azabicyclo[2.2. l]hept-3-yl cyclopropyl ketone, 3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, 1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1]oct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2.l]hept-3-yl-N-methoxycarboxamide,

(m thoxyimino) - (1-azabicyclo [2.2.2]oct-3-yl)acetonitrile, oximino- (1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof. 16. A composition as claimed by Claim 1 wherein the Synergistic Analgesic is acetaminophen.

17. A composition as claimed by Claim 15 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

18. A composition as claimed by Claim 17 wherein the Compound is selected from the group consisting of 1-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, l-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone, 3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, 1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, oximino-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

19. A composition as claimed by Claim 1 wherein the Synergistic Analgesic is an alpha-adrenergic compound.

20. A composition as claimed by Claim 19 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

21. A composition as claimed by Claim 20 wherein the Compound is selected from the group consisting of l-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, l-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone,

3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, 1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, oximino-(1-azabicyclo[2.2.2]oct-3-y1)acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

22. A method for treating pain comprising administering an analgesic dose of a composition comprising a compound a Compound selected from the group consisting of:

wherein R¹ is hydrogen, Ci-Cβ alkyl or phenyl-Cι~C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

R² is C -C6alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy;

R³ and R⁴ are independently hydrogen, C -Cts alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C₁-C₄ alkyl, hydroxy, or C₁-C₄ alkoxy, or phenyl-Cι~C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

in which R⁵ represents the radical

in which R⁶ at any position on the benzene ring represents linear, branched or cyclic C -Cs alkyl, C₂-C₈ alkenyl or C₂- C_Θ alkynyl or the radical ^N-R»

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear Ci-Cβ alkyl, C₂-C8 alkenyl or C₂- Cβ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹, R⁹ representing hydrogen, linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁰ or S(0)R , R¹⁰ and R¹¹ represent linear, branched or cyclic C -Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶'< R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- C_δ alkynyl or the radical

,14

N

-R¹⁵

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- Q alkynyl or form together with the nitrogen atom to which t ey are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or NO₂, or OR¹²', R¹²' representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C8 alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic Cι~ C(i alkyl, C₂-C₈ alkenyl or C2-C₈ alkynyl, or R¹² represents naphthyl optionally substituted with R¹³ ' > R¹³' being defined above for R¹³;

1, , 4-oxadiazole or 1, 2, 4-oxadiazole nucleus; R³¹ represents a non-aromatic '927azacycle or ' 927azabicyclic ring system; and R³² represents a substituent which is convertable in vivo to an amino group;

R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl , Br, -CF₃, -OR³⁸, -NR³⁸R³⁹, -NHOR³⁸, -NHNH₂ , -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁶ or R³⁷ taken together form a Ci-galkylenedioxy ring, wherein R³⁸ is Cι_6alkyl, C2-ealkenyl or C2-6alkynyl, R³⁹ is hydrogen, Cι_6 alkyl, or -COCH3, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹

wherein

R⁴⁷ and R⁴⁸ are as defined above;

X is oxygen or sulfur;

wherein n, R47 and R48 are as defined above R45 and R46 are each independently hydrogen, alkyl of from one to twenty carbon atoms, alkyl of from one to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to twenty carbon atoms, alkenyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to twenty carbon atoms, alkynyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of from one to four carbon atoms, alkyl of from one to four carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkoxy of from one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl of R⁴⁵ and R⁴⁶ are taken together with the nitrogen atom to which they are attached to form

wherein X is defined above or

wherein R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and ... represents a single or double bond with the proviso that when, ___^__L_ represents a double bond X' is nitrogen and when j._^ represents a single bond X' is CH₂; 53

wherein R⁵³ is selected from the group consisting

wherein X is oxygen, sulfur, or -N-R⁶², wherein R⁶² is hydrogen or alkyl of from one to ten carbon atoms; R ⁸ is selected from the group consisting of

wherein

n

wherein n is an integer from one to three and R68 are as defined above;

R⁷¹ and R⁷² are each independently hydrogen, alkyl of from one to twenty carbon atoms, alkyl of from one to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to twenty carbon atoms, alkenyl of from three to twenty carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to twenty carbon atoms, alkynyl of from three to twenty carbon atoms substituted with dydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of from one to four carbon atoms, alkyl of from one to four carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkoxy of from one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluoromethyl of R³ and R⁴ are taken together with the nitrogen atom to which they are attached to form

wherein n' and R⁷³ are as defined above,

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms,

in which Z is a heterocyclic group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of Ai and A₃ is CR₂ and the other is CR₃; and Ri, R₂ and R₃ are independently selected from hydrogen, halogen, CN, OR₄, SR₄, N(R₄)₂, NHCOR₄, NHCOOCH₃, NHCOOC2H₅, NHOR₄, NHNH₂, N0 , COR₄, COR5, cyclopropyl, C₂-₅ straight chain alkenyl, C₂-₅ straight chain alkynyl or C₁-₅ straight chain alkyl optionally terminally substituted with OR , N(R4)2# SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, H2 or NHR ; or in which Z is a group -C(R7)=NRς in which Rβ is a group OR8, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or NR11R12 where Rio, Rli and R12 are independently C]_- 2 alkyl and R7 is hydrogen or C3_.-4 alkyl, subject to the proviso that when Rζ is a group OCOR9 or NHR10 - 7 is C1- 4 alkyl ;

in which Q¹ represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a Cl-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3 , s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen s is 1;

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is C₃.-₄ alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or C _₄alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R,4R) -3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -1- a abicyclo[2.2.lheptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of

Compound to Synergistic Analgesic of from about 1 to about

1000.

23. A method as claimed by Claim 22 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof. 24. A method as claimed by Claim 22 wherein the Synergistic Analgesic is a nonsteroidal anti-inflammatory drug.

25. A method as claimed by Claim 24 wherein the nonsteroidal anti-inflammatory drug is selected from the group consisting of indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.

26. A method as claimed by Claim 24 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

27. A method as claimed by Claim 24 wherein the Compound is selected from the group consisting of Formula IV,

28. A method as claimed by Claim 22 wherein the Synergistic Analgesic is an opioid.

29. A method as claimed by Claim 28 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

30. A method as claimed by Claim 29 wherein the Compound is selected from the group consisting of l-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, 1-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone,

3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, 1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2.l]hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile, oximino- (1-azabicyclo[2.2.2]oct-3-yl) acetonitrile, and 1-azabicyclo [2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

31. A method as claimed by Claim 29 wherein the opioid is selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.

32. A method as claimed by Claim 29 wherein the opioid is selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and alphaprodine.

33. A method as claimed by Claim 29 wherein the opioid is selected from the group consisting of propoxyphene, methadone, hydrocodone, hydromorphine, and codeine.

34. A method as claimed by Claim 22 wherein the

Compound is selected from the group consisting of Formula I, II, and III; or a pharmaceutically acceptable salt or solvate thereof.

35. A method as claimed by Claim 22 wherein the Compound is selected from the group consisting of Formula XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

36. A method as claimed by Claim 35 wherein the Compound is selected from the group consisting of l-azabicyclo[2.2.2]oct-3-yl cyclopropyl ketone, l-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone, 3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, 1-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.1]oct-5-yl-N-methoxycarboxamide, l-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (1-azabicyclo[2.2.2] oct-3-yl)acetonitrile, oximino- (1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

37. A method as claimed by Claim 22 wherein the

Synergistic Analgesic is acetaminophen.

38. A method as claimed by Claim 37 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

39. A method as claimed by Claim 22 wherein the Synergistic Analgesic is an alpha-adrenergic compound.

40. A method as claimed by Claim 39 wherein the Compound is selected from the group consisting of Formula IV, V, VIII, IX, XIII, XIV, and XV; or a pharmaceutically acceptable salt or solvate thereof.

41. A method as claimed by Claim 40 wherein the Compound is selected from the group consisting of 1-azabicyclo[2.2.2] oct-3-yl cyclopropyl ketone, l-azabicyclo[2.2.l]hept-3-yl cyclopropyl ketone, 3-oxo-3- (1-azabicyclo[2.2.1]hept-3-yl)propionitrile, l-azabicyclo[2.2.2]oct-3-yl-N-methoxycarboxamide, 1-azabicyclo[3.2.lJoct-5-yl-N-methoxycarboxamide, 1-azabicyclo[2.2.1]hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (1-azabicyclo[2.2.2] oct-3-yl)acetonitrile, oximino- (1-azabicyclo[2.2.2]oct-3-yl)acetonitrile, and l-azabicyclo[2.2.2]oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

42. The use of a First Compound selected from the group consisting of

R² is Ci-Cβalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group may be optionally substituted with fluoro, hydroxy or phenyl optionally substituted with fluoro, trifluoromethyl, lower alkyl, hydroxy, or lower alkoxy;

R³ and R⁴ are independently hydrogen, Cι~Cs alkyl, C₃-C₆ cycloalkyl, phenyl optionally substituted with halogen trifluroromethyl, C -C₄ alkyl, hydroxy, or C₁-C₄ alkoxy, or phenyl-C₁-C₄ alkyl, in which the phenyl group may be substituted with halogen, C₁-C₄ alkyl or C₁-C₄ alkoxy;

in which R⁵ represents the radical

in which R⁶ at any position on the benzene ring represents linear, branched or cyclic Ci~Cs alkyl, C₂-C₈ alkenyl or C₂- C_δ alkynyl or the radical R⁷

in which R⁷ and R⁸ which may be identical or different represent hydrogen, linear Ci-Cβ alkyl, C2-C8 alkenyl or C2- Cβ alkynyl or form together with the nitrogen atom to which they are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical OR⁹, R⁹ representing hydrogen, linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁰ or S(0)Rⁿ, R¹⁰ and R¹¹ represent linear, branched or cyclic Ci-Cβ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, or R⁵ represents naphthyl optionally substituted with R⁶' - R⁶' being defined above for R⁶;

in which R¹² represents the radical

in which R¹³ at any position on the benzene ring represents linear, branched or cyclic C -CQ alkyl, C₂-C₈ alkenyl or C₂- C8 alkynyl or the radical

,14

^N~R'=

in which R¹⁴ and R¹⁵ which may be identical or different represent hydrogen, linear Ci-Cs alkyl, C₂-C₈ alkenyl or C₂- Cβ alkynyl or form together with the nitrogen atom to which t ey are attached a carbonaceous hetercyclic radical optionally containing another heteroatom, or the radical or NO₂, or OR¹²', R¹²' representing hydrogen, linear, branched or cyclic Ci-Cg alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl or aryl containing up to 14 carbon atoms, or the radical SR¹⁶ or S(0)R¹⁷, R¹⁶ and R¹⁷ represent linear, branched or cyclic Cι~ Cβ alkyl, C2-C₈ alkenyl or C₂-C₈ alkynyl, or R¹² represents naphthyl optionally substituted with R¹³ ' - R¹³ ' being defined above for R¹³;

1,3, 4-oxadiazole or 1, 2, -oxadiazole nucleus; R³¹ represents a non-aromatic '927azacycle or ' 927azabicyclic ring system; and R³² represents a substituent which is convertable in vivo to an amino group;

R³⁵, R³⁶, and R³⁷ independently represent hydrogen, F, Cl, Br, -CF₃, -OR³⁸, -NR³⁸R³⁹, -NHOR³⁸, -NHNH , -CN, COR⁴⁰, or a substituted or unsubstituted, saturated or unsaturated hydrocarbon group, provided that at least one of R³⁵, R³⁶, and R³⁷ is other than hydrogen or a hydrocarbon group, or R³⁵ and R³⁶ or R³⁷ taken together form a Ci-βalkylenedioxy ring, wherein R³⁸ is Cι_₆alkyl, C₂-₆alkenyl or C₂-₆alkynyl, R³⁹ is hydrogen, Cι_₆ alkyl,or -COCH₃, and R⁴⁰ represents OH, -OR³⁸, NHR³⁹, or -NR³⁸R³⁹

wherein

R⁴⁷ and R⁴⁸ are as defined above;

X is oxygen or sulfur;

wherein R⁴⁹ is hydrogen, alkyl of from one to ten carbon atoms, alkyl of from one to ten carbon atoms substituted with -llβ- hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from two to ten carbon atoms, alkenyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms and n is as defined above,

wherein X is defined above or

wherein R⁵⁰ is hydrogen or alkyl of from one to six carbon atoms,

wherein R⁵¹ is selected from the group consisting of

R⁵² is hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n' is zero or an integer of one or two; X' is carbon or nitrogen; and _^__JJt_represents a single or double bond with the proviso that when, _,_,_,_ represents a double bond X' is nitrogen and when __J__J___ represents a single bond X' is CH₂;

wherein R⁵³ is selected from the group consisting

R⁵⁴, R⁵⁵, R⁵⁶, and R⁵⁷ are each independenty hydrogen, alkyl of from one to ten carbon atoms, alkynyl of from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from C1-C10 alkyl, alkoxy, C1-C10 halogen or trifluoromethyl; n' is an interger of one or two;

wherein

wherein n' is zero or an integer from one to eight and R⁷³ is hydrogen, alkyl of from one to ten carbon atoms, alkyl of from one to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from two to ten carbon atoms, alkenyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from two to ten carbon atoms or alkynyl of from two to ten carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms; R⁷⁰ is hydrogen. alkyl of from one to six carbon atoms, alkyl of form one to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkenyl of from three to six carbon atoms, alkenyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, alkynyl of from three to six carbon atoms, alkynyl of from three to six carbon atoms substituted with hydroxy or alkoxy of from one to four carbon atoms, cycloalkyl of from three to six carbon atoms, or R⁷⁰ when taken together with R⁶⁸ forms a ring denoted by

n

wherein n is an integer from one to three and R68 are as defined above;

wherein n' and R⁷³ are ad defined above,

wherein X is defined above or

wherein R⁷⁴ is hydrogen or alkyl of from one to six carbon atoms,

in which Z is a heterocyclic group

in which Q represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulphur, or three nitrogen atoms, any amino nitrogen being substituted by a Cι_2 alkyl, cyclopropyl or propargyl group, and any ring carbon atom being optionally substituted by a group Ri; or a group

in which Ai, A₂ and A₃ complete a 5-membered aromatic ring and Ai is oxygen or sulphur, one of A₂ and A₃ is CR₂ and the other is nitrogen or CR₃, or A₂ is oxygen or sulphur, one of Ai and A3 is CR₂ and the other is CR₃; and Ri, R₂ and R₃ are independently selected from hydrogen, halogen, CN, OR₄, SR₄, N(R₄) , NHCOR₄, NHCOOCH3, NHCOOC₂H₅, NHOR₄, NHNH , N0₂, COR₄, COR5, cyclopropyl, C2-₅ straight chain alkenyl, C₂-₅ straight chain alkynyl or C₁-5 straight chain alkyl optionally terminally substituted with OR4, N(R4>2, SR4, CO2R4, CON(R4)2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or NH.R4; or in which Z is a group -C(R7)=NR6 in which Rβ is a group OR8, where R8 is Cι_4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a group OCOR9 where R9 is hydrogen or R8, or a group NHR10 or R11R12 where Rχo, Rll and R12 are independently Cχ_ 2 alkyl and R7 is hydrogen or Ci-4 alkyl, subject to the proviso that when Rg is a group OCORg or NHRio, R7 is C1-4 alkyl

in which Q* represents a 3-membered divalent residue completing a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by a Cl-2 alkyl, cyclopropyl or propargyl group, r represents the integer of 2 or 3, s represents an integer of 1 or 2 and t represents 0, with the proviso that when Y is hydrogen ε is 1;

R⁷⁶ is a group OR⁷⁸, where R⁷⁸ is C₁-₄ alkenyl, C₂-₄ alkynyl, a group OCOR⁷⁹ where R⁷⁹ is hydrogen or R⁷⁸, or a group NHR⁸⁰ or NR⁸¹, R⁸², where R⁸⁰, R⁸¹ and R⁸² are independently C₁-₂ alkyl; and R⁷⁷ is hydrogen or Cι_₄alkyl, subject to the proviso that when R⁷⁶ is a group OCOR⁷⁹ or a group NHR⁸⁰, R⁷⁷ is alkyl;

(3R,4R)-3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1- azabicyclo[2.2.lheptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of

First Compound to Synergistic Analgesic of from about 1 to about 1000 for a manufacture of a medicament for therapeutic application in the treatment of pain.

43. A use as claimed by Claim 42 wherein the

Synergistic Analgesic is an opioid.

44. A use as claimed by Claim 42 wherein the Synergistic Analgesic is acetaminophen. 45. A use as claimed by Claim 42 wherein the Synergistic Analgesic is a nonsteroidal anti-inflammatory drug.

46. A use as claimed by Claim 42 wherein the Synergistic Analgesic is an alpha-adrenergic compound.