MXPA98004519A

MXPA98004519A - Composition to treat do

Info

Publication number: MXPA98004519A
Application number: MXPA/A/1998/004519A
Authority: MX
Inventors: Howard Mitch Charles; Edgar Shannon Harlan
Original assignee: Eli Lilly And Company; Mitch Charles H; Shannon Harlan E
Priority date: 1995-12-07
Filing date: 1998-06-05
Publication date: 1999-04-06

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 Anti-inflammatory drugs without steroids, acetaminophen, opioids and alpha-adrenérgic compounds.

Description

-CO-M-P ^ -OS «-ICI - Ó ^ N --- ^ P-A -._ R_A___TRATAR! (____ D_____O____L____O_R DESCRIPTION DK THE INVENTION 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 effects of active analgesic combinations are in constant demand because they offer the attractive possibility of alleviating pain with reduced doses, thus decreasing the expected side effects and toxicity that would otherwise result from high doses. It would be particularly desirable to acquire a synergistic, combination effect. Such a composition is the object of the present invention. The composition of this invention provides a surprising synergistically effective treatment for pain using compounds, which are known independently in the art. The synergistic effect of the present composition provides a means to treat RBP pain: 27502 using a low dose of each compound in the composition, thereby 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 R 1 is hydrogen, C 1 -C 6 alkyl or phenyl C 1 -C alkyl, in which the phenyl group can be substituted with halogen, C 1 -C alkyl or C 1 -C 4 alkoxy; • R2 is an alkyl group of Ci-Cß, C3-C6 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group can be optionally substituted with fluoro, hydroxy or substituted phenyl optionally with fluoro, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R3 and R4 are independently hydrogen, Ci-Cß alkyl, C3-C6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C? -C alkyl, hydroxy, or C? -C-alkoxy, or phenyl-C? -C4 alkyl, in which the phenyl group can be substituted with halogen, Ci-C4 alkyl or C? -C4 alkoxy; in which R represents the radical wherein R6 at any position on the benzene ring represents an alkyl group of C _ _ C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the tC radical wherein R7 and R8, which may be identical or different, represent hydrogen, C?-C8 alkyl, C2-Cß alkenyl or linear C2-C alqu alkynyl or form, together with the nitrogen atom to which they are attached , a carbonaceous heterocyclic radical optionally containing another hetero atom, or radical OR9, R9 representing hydrogen, Ci-Cβ alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14 carbon atoms, or radical SR10 or S (0) R1X, R10 and R11 represent an alkyl group of C? -C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, represents naphthyl optionally substituted with Rc being defined in the above by R6; in which R, 12 represents the radical wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical wherein R14 and R15, which may be identical or different, represent hydrogen, alkyl, C? -C8, C2-C8 alkenyl or linear C2-C8 alkynyl or form together with the nitrogen atom to which are attached a carbonaceous heterocyclic radical optionally containing another heteroatom, or the radical or N02, or OR12 ', R12' which represents hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or linear, branched or cyclic C 2 -C 8 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR 16 or S (0) R 17, R 16 and R17 represent a C1-C8 alkyl group, straight-chain, branched cyclic C2-C2-C2 alkenyl alkenyl, 12 represents naphthyl optionally substituted with R13, 13 'being defined in the above by R13; wherein, one of R18, R19 and R20 represents nitrogen and the remainder represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic azacyclic or azabicyclic ring system and independently substituted at each of the other carbon atoms on the ring with the substituent R23, R21 or R22 of low lipophilicity or a hydrocarbon having a maximum of 20 carbon atoms; wherein one of R2ß, R29 or R30 is an oxygen atom and the other two are nitrogen atoms, and the dotted circle represents aromaticity (two double bonds) thereby forming a 1,3,4-oxadiazole or 1 nucleus; 2,4-oxadiazole; R31 represents a non-aromatic ring system 927azacyclo or 927azabicyclic; and R32 represents a substituent which is converted in vi to an amino group; where R34 represents a ring system 1-non-aromatic azabicyclic; not merged; and R35, R36 and R37 independently represent hydrogen, F, Cl, Br, -CF3, -OR3β, -NR38R39, -NHOR38, -NHNH2, -CN, COR40, or a substituted or unsubstituted, saturated or unsaturated idrocarbon group, with the provided that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form an alkylenedioxy ring of C? -6, wherein R38 is an alkyl group of C? ? _6, C2-6 alkenyl or C2_6 alkynyl, , 39 e s h idrogen, a l l l of C 1 - 6 -COCH3 and R 40 repre s to OH, -OR38, NHR39 or -NR38R39 wherein R43 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to six carbon atoms, alkenyl of two to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, wherein n is zero or an integer from one to eight and R47 and R48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy from one to four carbon atoms, or where R, 47, 4 < 8 are as defined in the above; X is oxygen or sulfur; R44 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl from three to six carbon atoms, alkenyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or wherein n, R47 and R48 are as defined above, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four carbon atoms, alkyl from one to four carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkoxy 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 indicated by wherein R49 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to ten carbon atoms, alkenyl of two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R, 50 is hydrogen or alkyl of one to six carbon atoms, wherein R, 51 is selected from the group consisting of , 52 is hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; n 'is zero or a whole number of one or two; X 'is carbon or nitrogen; and ... represents a single or double bond with the condition that when ... represent a double bond X 'is nitrogen and when ... represents a single bond X' is CH2; where R is selected from the group consisting R54, R55, R56 and R57 are each independently hydrogen, alkyl of one to ten carbon atoms, alkynyl of two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from C? -C_o alkyl , alkoxy, Ci-Cio halogen or trifluoromethyl; n 'is a whole number of one or two; -R5ß wherein X is oxygen, sulfur or -N-R62, wherein R62 is hydrogen or alkyl of one to ten carbon atoms; R58 is selected from the group consisting of or? -.

R59, R60 and R61 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that when it represents a double bond R57 and R60 are absent; wherein R, R, 6 * "4 and R 65 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from the group it consists of alkyl, alkoxy, thioalkoxy, halogen and trifluoromethyl, R66 is hydrogen, hydroxy or alkoxy from one to ten carbon atoms, and R67 is selected from the group consisting of R68-N-C-M-CHJ-C-? E C-CH2-N-R71 wherein R69 is hydrogen and R67 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms , cycloalkyl 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 indicated by wherein n 'is zero or an integer from one to eight and R73 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with nidroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkyne from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon'; substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, cycloalkyl of three to six carbon atoms, carbon, or R70 when taken together with R68 forms a ring indicated by where n is an integer from one to three and Rb8 are as defined in the above; R71 and R72 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four carbon atoms, alkyl from one to four carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkoxy from one to four carbon atoms; carbon, 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 indicated by ) ii ' where n 'and R73 are as defined in the above, where X is defined in the above or wherein R74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 is CR2 and the other one 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, C0R4, COR5, cyclopropyl, straight chain alkenyl of C2 -5, C2-5 straight chain alkynyl or chain alkyl linear of C? _5 optionally substituted terminally with OR4, N (R) 2, SR4, C02R4, CON (R) 2 or one, two or three halogen atoms, in which each R is independently hydrogen or C1 alkyl -3 and R5 is OR4, NH2 or NHR4; or wherein Z is a group -C (R) = NR6 in which Re is an OR8 group, where Rβ is C? -4 alkyl, C2.4 alkenyl, C2.4 alkynyl, an OCOR9 group where R9 is hydrogen or R8, or a group NHR10 or R ?? 2 2 where Rio, Rn and R12 are independently C alquilo _2 alkyl and R is hydrogen or C? -4 alquilo alkyl, subject to the proviso that when R6 is an OCOR9 or NHR10 group, R7 is C alquilo alquilo alkyl; in which one of X and Y represents hydrogen and the other represents Z, and Z 'is a group wherein Q 'represents a divalent 3-membered residue that completes an aromatic ring of 5 members and comprises two or three nitrogen atoms, any amino nitrogen being substituted by an alkyl group of C? -2, cyclopropyl or propargyl, 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; in dop-ie R 75 represents in which each of p and q independently represents an integer from 2 to 4, r represents a integer from 2 to 4, s represents 1 or 2 and t represents 0 or 1; R76 is an OR78 group, where R78 is C? -4 alkenyl, C2.4 alkynyl, an OCOR79 group where R79 is hydrogen or R78, or a group NHR80 or NR81, R82, where R80, R81 and R82 are independently alkyl of C? _2; and R77 is hydrogen or C? _4 alkyl, subject to the proviso that when R, 76 is an OCOR group 79 or an NHR80 group, R77 is alkyl; (3R, 4R) -3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -1-azabicyclo [2.2.1] heptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of a Compound to a Synergistic Analgesic from about 1 to about 1000. The present invention provides a method for treating pain comprising administering to a patient in need thereof, an analgesic composition which comprises a compound selected from the group consisting of: wherein R 1 is hydrogen, Ci-Cß alkyl or phenyl-C?-C 4 alkyl, in which the phenyl group can be substituted with halogen, C?-C-alkyl or C?-C-alkoxy; R2 is an alkyl group of Ci-Cβ, C3-C6 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group can be optionally substituted with fluoro, hydroxy or optionally substituted phenyl with fluoro, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R3 and R4 are independently hydrogen, Ci-Cß alkyl, C3-C6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C?-C4 alkyl, hydroxy, or C?-C alco alkoxy, or phenyl-C alquilo-alkyl. C ~ C4, in which the phenyl group can be substituted with halogen, C? -C4 alkyl or C? -C alkoxy; in which R represents the radical wherein R6 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical NR "in which R7 and R8 may be identical or different, represent hydrogen, C?-C8 alkyl, C2-Cß alkenyl or linear C2-C8 alkynyl or form together with the nitrogen atom to which a radical is attached carbonaceous heterocyclic optionally containing another heteroatom, or the radical OR9, R9 representing hydrogen, Ci-Cg alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C2 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR10 or S (0) Ru ,. R10 and Ru represent an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C alqu alkynyl, or R5 represents naphthyl optionally substituted with R6 ', R6' being defined in the above by R *; in which R, 1 2 represents the radical wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical wherein R14 and R15 may be identical or different, they represent hydrogen, Ci-Cß alkyl, C2-C8 alkenyl or linear C2-C alqu alkynyl or form together with the nitrogen atom to which a carbonaceous heterocyclic radical containing optionally another heteroatom, or the radical or N02, or OR12 ', R12' representing hydrogen, C? -C? alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14? carbon atoms, or the radical SR, 1160 or S (0) R, 1i7 ', R, 1i6B and RL represent an alkyl group of C? -C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or R12 represents optionally substituted naphthyl. with R13 ', R13' being defined in the foregoing by R13; where, one of RiB, R13 and R? represents nitrogen and the rest represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic azacyclic or azabicyclic ring system and independently substituted at each of the other carbon atoms on the ring with the substituent R23, R21 or R22 of low lipophilicity or a hydrocarbon having a maximum of 20 carbon atoms; where 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 ring system 927azacyclo or 927azabicyclic; and R32 represents a substituent which is converted in vi to an amino group; wherein R34 represents a non-aromatic 1-azabicyclic ring system; not merged; and 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, with the condition that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form an alkylenedioxy ring of C? -6, wherein R38 is an alkyl group of C? -6, C2-6 alkenyl or C2-6 alkynyl, R39 is hydrogen, C? -6 alkyl or -COCH3 and R40 represents OH, -OR38, NHR39 or "-NR38R39 wherein R, 43 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to six carbon atoms, alkenyl of two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, wherein n is zero or an integer from one to eight and R47 and R48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy of one to four carbon atoms, or wherein R47 and R48 are as defined in the foregoing; X is oxygen or sulfur; R44 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or wherein n, R47 and R48 are as defined above, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four carbon atoms, alkyl from one to four atoms of carbon substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of 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 indicated by wherein R49 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to ten carbon atoms, alkenyl of two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R50 is hydrogen or alkyl of one to six carbon atoms, where R51 is selected from the group consisting of , 52 is hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; n 'is zero or a whole number 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 R, 53 is selected from the group consisting R54, R55, R56 and R57 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from Ci-Cio alkyl, alkoxy, Halogen of C -Cio or trifluoromethyl; n 'is a whole number of one or two; wherein X is oxygen ', sulfur or -N-R, 62, wherein R 62 is hydrogen or alkyl of from one to ten carbon atoms,, 58 is selected from the group consisting of R59, R60 and R61 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that when representing a double bond R57 and R60 are absent; wherein 63, 64, 65 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl 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 from one to ten carbon atoms; and R 67 is selected from the group consisting of wherein R69 is hydrogen and R67 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl 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 indicated by wherein n 'is zero or an integer from one to eight and R73 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or R70 when taken together with R68 forms a ring indicated by where n is an integer from one to three and R68 are as defined, in the above; R71 and R72 are each independently hydrogen, alkyl - from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four atoms of carbon, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of 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 bound to form a ring indicated by where n 'and R, 73 are as defined in the above, where X is defined in the above or wherein R74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 is CR2 and the other one is CR3; and Ri, R2 and R3 are independently selected from hydrogen, halogen, CN, 0R4, SR4, N (R4) 2, NHCOR4, NHCOOCH3, NHC00C2H5, NH0R4, NHNH2, N02, C0R4, C0R5, cyclopropyl, straight chain alkenyl of C2 -5, straight chain alkynyl of C2.5 or straight chain alkyl of C1-5 optionally substituted terminally with 0R4, N (R4) 2, SR4, C02R4, CON (R4) 2 or one, two or three atoms of halogen, in which each R4 is independently hydrogen or C1-3 alkyl and R5 is 0R4, NH2 or NHR4; or wherein Z is a group -C (R7) = NR6 in which Re is a group 0R8, where R8 is C1-4 alkyl, C2- alkenyl, C2-4 alkynyl, an OCOR9 group where Rg is hydrogen or R8, or a group NHR10 or NR11R12 where Rio, Rn and R i 2 are independently C? _2 alkyl and R7 is hydrogen or C? -4 alkyl, subject to the proviso that when R6 is an OCOR9 group or NHR10, R7 is C? -4 alkyl in which one of X and Y represents hydrogen and the other represents Z, and Z 'is a group wherein Q 'represents a 3-membered divalent residue which completes a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, 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; where R, 75 represents wherein each of p and q independently represents an integer from 2 to 4, r represents an integer from 2 to 4, s represents 1 or 2 and t represents 0 or 1; R76 is an OR78 group, where R78 is C? -4 alkenyl, C2_4 alkynyl, an OCOR79 group where R79 is hydrogen or R, 7.8 or an NHR group 80 NR, 8e1, 82 where R, RBi and R? they are independently C? -2 alkyl; and R77 is hydrogen or C? -4 alkyl, subject to the proviso that when R76 is an OCOR79 group or an NHR80 group, R77 is alkyl; (3R, 4R) -3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -l-azabicyclo [2.2.1] heptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of a Compound to an Analgesic Synergistic from about 1 to about 1000. As noted above, the compounds employed in the method of the present invention are known. The compounds, methods for preparing the compounds, as well as also pharmaceutical formulations containing the compounds, are taught in U.S. Patent Nos. 4,923,880, 5,110,828, 5,041,436, 5,258,170, 7,177,084, 4,992,436, 5,260,293, 4,996,201, 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, 5,068,437, 5,318,978, 5,242,927, 5,300,516, 5,089,505, 5,302,595, 5,219,871, 5,096,890, 5,164,386, 5,164,514, 5,157,160, 5,217,975 and 5,081,130, incorporated herein by reference . This 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 and racemic enantomeric forms of the named compounds.

As used herein, the terms "Synergistic Analgesic" and "Synergistic Analgesics" refer to the group consisting of anti-inflammatory drugs without steroids (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 R 1 is hydrogen, C 1 -C 6 alkyl or phenyl C 1 -C 4 alkyl, in which the phenyl group can be substituted with halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R2 is an alkyl group of C6-C6, C3-C3 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group can be optionally substituted with fluoro, hydroxy or substituted phenyl optionally with fluoro, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R3 and R4 are independently hydrogen, Ci-Cß alkyl, C3-C6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C?-C4 alkyl, hydroxy, or C?-C 4 alkoxy, or phenyl-C alquilo-alkyl ? -C4, in which the phenyl group can be substituted with halogen, C1-C4 alkyl or C? -C alkoxy; in which R represents the radical wherein R6 at any position on the benzene ring represents an alkyl group of Ci-Cβ, C2-Ca alkenyl or straight, branched or cyclic C2-C8 alkynyl or radical N-R "in which R7 and R8 may be identical or different, represent hydrogen, C-Cg alkyl, C2-C8 alkenyl or linear C2-C8 alkynyl or form together with the nitrogen atom to which a radical is attached carbonaceous heterocyclic optionally containing another heteroatom, or the radical OR9, R9 representing hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14 carbon atoms , or the radical SR10 or S (0) R1X, R10 and R11 represent an alkyl group of C? -C8, C2-C8 alkenyl or linear, branched or cyclic C2-C2 alkynyl, or R5 represents naphthyl optionally substituted with R6 ', R6' being defined in the foregoing by R in which R, 12 represents the radical wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical ? H N-R » wherein R14 and R15 may be identical or different, represent hydrogen, Ci-Ca alkyl, C2-C8 alkenyl or linear C2-C8 alkynyl or form together with the nitrogen atom to which a carbonaceous heterocyclic radical containing optionally another heteroatom, or the radical or N02, or OR12 ', R12' representing hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14? carbon atoms, or the radical SR16 or S (0) R17, R16 and R17 represent an alkyl group of Ci-Cs, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or R12 represents optionally substituted naphthyl with R13 ', R13' being defined in the foregoing by R13; wherein, one of R10, R1 * and R * 'J represents nitrogen and the remainder represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic azacyclic or azabicyclic ring system and independently substituted on each of the other carbon atoms in the ring with the substituent R23, R21 or R22 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) thereby forming a 1,3,4-oxadiazole or 1 nucleus; 2,4-oxadiazole; R31 represents a non-aromatic ring system '927azacyclo or' azabicyclic; and R32. represents a substituent which is converted in vi to an amino group; wherein R34 represents a non-aromatic 1-azabicyclic ring system; not merged; Y 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, with the provided that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form an alkylenedioxy ring of C? _6, wherein R38 is an alkyl group of C? 6, C2.6 alkenyl of C2.6 alkynyl, R39 is hydrogen, C6-6 alkyl or -COCH3 and R40 represents OH, -OR38, NHR39 or -NR38R39 wherein R43 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to six carbon atoms, alkenyl of two to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalicylic acid from three to six carbon atoms, wherein n is zero or an integer from one to eight and R47 and R48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy from one to four carbon atoms, or wherein R47 and R48 are as defined in the foregoing; X is oxygen or sulfur; R44 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, cycloalkyl of three to six carbon atoms , or wherein n, R47 and R48 are as defined in the foregoing, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl , phenyl substituted with alkyl of one to four carbon atoms, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of one to four carbon atoms, chlorine, bromine, hydroxy, nitro or trifluorome i of R45 and R46 are taken together with the nitrogen atom to which they are attached to form a ring indicated by ) n wherein R49 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to ten carbon atoms, alkenyl of two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R50 is hydrogen or alkyl of one to six carbon atoms, where R 51 is selected from the group consisting of and? R52 is hydrogen, alkyl of one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n1 is zero or an integer of one or two; X 'is carbon or nitrogen; and ... represents a single or double bond with the condition that when ... represents a double bond X 'is nitrogen and when.;. represent a single bond X 'be CH2; where R is selected from the group consisting R54, R55, R56 and R57 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from Ci-Cio alkyl, alkoxy, Halogen of Ci-Cio or •: rifluoromethyl; n 'is a whole number of one or two; wherein X is oxygen, sulfur or -N-R62, wherein R62 is hydrogen or alkyl from one to ten atoms R59, R60 and R61 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that when it represents a double bond R57 and R60 are absent; wherein R, 6O3J, R, 65"41 and R, 6D5J are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms', phenyl or phenyl substituted by one to four selected substituents of the group consisting of alkyl, alkoxy, thioalkoxy, halogen and trifluoromethyl, R66 is hydrogen, hydroxy or alkoxy from one to ten carbon atoms, and R 67 is selected from the group consisting of wherein R69 is hydrogen and R67 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms , cycloalkyl 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 indicated by wherein n 'is zero or an integer from one to eight and R73 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon loops; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six atoms carbon, or R70 when taken together with R68 forms a ring indicated by where n is an integer from one to three and R68 are as defined in the above; R71 and R72 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of one to four carbon atoms, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of one to four carbon atoms, carbon, 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 indicated by where n 'and R73 are as defined in the above, where X is defined in the above or wherein R, 74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 is CR2 and the other one is CR3; and Ri, R2 and R3 are independently selected from hydrogen, halogen, CN, 0R4, SR, N (R4) 2, NHCOR, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, N02, COR4, COR5, cyclopropyl, straight chain alkenyl of C2 -5, straight chain alkynyl of C2-5 or straight chain alkyl of C1-5 optionally substituted terminally with OR4, N (R4) 2, SR4, C02R, CON (R4) 2 or one, two or three halogen atoms, wherein each R 4 is independently hydrogen or C 1-3 alkyl and R 5 is OR, NH 2 or NHR; or wherein Z is a group -C (R7) = NR6 in which R6 is an OR8 group, where R8 is C1-4 alkyl, C2.4 alkenyl, C2-4 alkynyl, an OCOR9 group where R9 is hydrogen or R8, or a group NHR10 or NRnR? 2 where Rio R11 and R12 are independently alkyl or C? -2 and R7 is hydrogen or C? -4 alkyl, subject to the condition that when Re is a group OCOR9 or NHR10, R7 is C? -4 alkyl in which one of X and Y represents hydrogen and the other represents Z, and Z 'is a group wherein Q 'represents a 3-membered divalent residue which completes a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, 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; where R 75 represents in which each of p and q independently represents an integer. 2 to 4, r represents an integer from 2 to 4, s represents 1 or 2 and t represents 0 or 1; R76 is an OR78 group, where R78 is C? - alkenyl, C2.4 alkynyl, an OCOR79 group where R79 is hydrogen or R78, or a group NHR80 or NR81, R82, where R80, R81 and R82 are independently C? -2; and R77 is hydrogen or C? -4 alkyl, subject to the proviso that when R76 is an OCOR79 group or an NHR80 group, R77 is alkyl; (3R, 4R) -3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -1-azabicyclo [2.2.1] heptane; 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, C? -C6 alkyl, C2.6 alkenyl or C2_6 alkynyl; R26 is hydrogen, alkyl or -COCH3, and R27 represents -OR25 or -NR 5R26. The term "azacyclic or azabicyclic ring system" is a non-aromatic ring system that contains a nitrogen atom as the single heteroatom. Suitably, the ring system contains 4-10 ring atoms, preferably 5-8 ring atoms. Preferably, the ring system contains a tertiary amino nitrogen atom in a caged structure. The systems Bicyclics can be fused, spiro or bridged. Preferably, the nitrogen atom is in 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 have been incorporated by reference. The term "927 azacyclic" or "927 azabicyclic" refers to a non-aromatic ring system that contains a nitrogen atom as the single heteroatom. Properly, the ring contains from 4 to 10 ring atoms. Preferably, 5-8 ring atoms. The bicyclic systems can be fused, spiro or bridged. Examples of such heteroatoms include the heteroatoms described in U.S. Patent 5,242,927, column 2, which have been incorporated by reference. The most preferred azabicyclic or 927azacyclic systems include pyrrolidine, 1, 2, 5, 6-tetrahydropyridine, quinuclidine or 1-azabicyclo [2.2.1] heptane ring, optionally substituted by methyl or hydroxy. An especially preferred azabicyclic ring 927 is quinuclidine, which is substituted by hydrogen, methyl or hydroxy at any available atom.

Groups which are converted to an amino group in the compounds claimed herein to treat pain can be determined by administering the compound to a human or animal and detect, by conventional analytical techniques, the presence of the corresponding compound which has an amino substituent in the urine of a human or animal. Examples of such groups include groups which are hydrolysable to an amino group, such as amido, urethane substituents. In particular, a group of the formula -NH.Q, wherein 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 C? _ _ Alkyl, C2_ alkenyl, C2-8 alqu alkynyl, C3- ciclo cycloalkyl, C3--cycloalkyl. -C1-6alkyl, aryl and aryl-C1-6alkyl. Suitable R34 groups include the following: wherein the dashed line represents an optional 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, C1-4 alkyloxy, F, Br, Cl, C4-4 alkoxy, hydroxy, carboxy or alkoxycarbonyl of C? - or R41 and R42 together represent carbonyl. The nitrogen atom can be substituted by hydrogen or C 1-4 alkyl. The term "phenyl-C 1 -C 4 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-phenylpropyl and 1-methyl-1-phenylethyl. The phenyl group can be optionally substituted with 1-3 independently named substituents selected.

The term "formed together with the nitrogen atom to which they are attached, a heterocyclic radical" means that a heterocyclic radical optionally containing another hetero atom, for example, S or 0. Such groups include, but are not limited to, piperidyl, piperazinyl , morpholinyl and pyrrolidinyl. The term "alkyl" refers to the number of carbon atoms indicated; however, when no number is specified, the term refers to Ci-β alkyl. The alkyl may be linear or branched unless it is specified. The term "halogen" refers to chlorine, bromine and fluoro substituents. The term "alkynyl" has its accepted meaning; however, if the number of carbon atoms is unspecified, it refers to C2-? o alkynyl. The alkynyl group can be linear or branched unless specified. The term "alkoxy" refers to C 4 -4 alkoxy unless specified. The term "analgesic dose" as used herein, represents an amount of the compound necessary to prevent or treat a human being susceptible to or suffering from pain by following the administration to such a human being. The active compounds are effective over a wide range of doses. For example, the doses per day will normally fall within the range of from 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 currently administered will be determined by a physician, in light of the relevant circumstances that include 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 symptoms of the patients and the chosen route of administration, and therefore the ranges of previous doses 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 different routes such as transdermal, parenteral, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations can be designed to provide delayed or controlled release using formulation techniques which are known in the art. The term "NSAIDS", as used herein, represents an anti-inflammatory drug without steroids which can be identified as such by the person skilled in the art. For example, the Merck Manual, 16 h Edition, Merck Research Laboratories (1990) pp 1308-1309 provides 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. Preferred alternative 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, acetylsalicylic acid sodium, acetylsalicylic acid calcium, salicylic acid and sodium salicylate. An especially preferred NSA1D is ibuprofen.

The term "acetaminophen", as used herein, will have the accepted technique which means 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 person skilled in the art. 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 in treating hypertension. See Physicians' Desk Reference, 45th Ed. (1-991) p. 673. The term "opioid", as used herein, represents opioid analgesics and antagonists that include natural opioid analgesics, synthetic opioid analgesics, opioid antagonists, and opioid agonist-antagonists. Preferred opioid compounds are selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabufine and buprenorphine. The most preferred opioid compounds are selected from the group consisting of codeine, nabufine, naloxone and naltrexone. Preferred opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabufine and buprenorphine. Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl and alphaprodine. Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine and codeine. Particularly preferred and particularly preferred opioid compounds are selected from morphine and codeine. As used herein, the phrase "one or more", of higher preference refers to one; however, two, three or more can be used.

It has been found that a group of compounds having muscarinic cholinergic activity may be particularly useful for treating pain when used in combination with anti-inflammatory agents without steroids (NSAIDS). More specifically, the invention provides a method for treating pain in humans using known known compounds (collectively referred to herein as "selected muscarinic compounds") in combination with NSAIDS to provide a synergistic effect. It is believed that Selected Muscarinic Compounds are active based on activity in 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 by the person skilled in the art. It has been found that a group of compounds having muscarinic cholinergic activity may be particularly useful in treating pain when used in combination with acetaminophen. More specifically, the invention provides a method for treating pain in humans using selected Muscarinic Compounds specified in combination with acetaminophen to provide a synergistic effect. In addition, it has been discovered that a group of compounds having muscarinic cholinergic activity may be particularly useful for treating pain when used in combination with central alpha-adrenergic active compounds. More specifically, the invention provides a method for treating pain in humans using Selected Muscarinic Compounds in combination with ul. 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, 5a. edition, Macmillan Publishing Co., 1975, pp 325-358. The present invention further provides that one or more Selected Muscarinic Compounds can be used once in the composition of this invention to provide the desired analgesic effect. In the composition of this invention a Selected Muscarinic compound and a compound of the NSAIDS are combined in a weight ratio of Compound for NSAIDS from about 1 to about 1000. A preferred composition is a weight ratio of the Compound for NSAIDS 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 the Selected Muscarinic Compound for acetaminophen from about 1 to about 1000. A preferred composition is a weight ratio of the selected Muscarinic Compound for acetaminophen from about 1 to about 100. An especially preferred ratio is from about 1 to about 30. A further preferred ratio can be about 1 to about 10. A final preferred ratio may be from about 1 to about 3.

Selected Muscarinic Compounds are effective over a wide range of doses; however, it is desirable to administer a dose that is as low as possible. The amount of the NSAIDS present in the composition is adjusted as described above in relation to the dose of the Selected Muscarinic Compound. The amount of the acetaminophen present in the composition is adjusted as described above in relation to the dose of the Selected Muscarinic Compound. In the composition of this invention a Selected Muscarinic Compound and one or more of the opioid compounds are combined in a weight ratio of the Selected Muscarinic Compound for the opioid compound from about 1 to about 1000. A preferred composition is a weight ratio of the Selected Muscarinic Compound for the opioid compound 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 about 1. to approximately 3.

The amount of the opioid compound present in the composition is adjusted as described above in relation to the dose of the Selected Muscarinic Compound. However, for each composition claimed herein, it will be understood that the amount of the selected Muscarinic Compound currently administered will be determined by a physician, in light of the relevant circumstances that include the condition to be treated, the choice of the 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 dose ranges are not intended for the scope of the invention in any form. While the present compounds are preferably orally administered to humans susceptible to or suffering from pain, the compounds can also be administered via a variety of other routes such as transdermal, parenterally, subcutaneously, intranasally, intramuscularly and the intravenous routes. Such formulations can be designed to provide delayed or controlled relief using formulation techniques, which are known in the art. Transdermal formulations containing the composition claimed herein, more preferably release the active substances in an effective amount from about three days to about seven days. However, for chronic pain such as arthritis pain or cancer, a transdermal release from about three days to about two weeks is desirable. Alternatively, it may be preferred to release the claimed compositions transdermally in an effective amount from about one day to about three days. As used herein, the term "treatment" includes the 'prophylaxis of a physical and / or mental condition or improvement or elimination of the physical and / or mental condition developed once the characteristic symptoms of such a condition have been established or alleviated. The Selected Muscarinic Compounds employed in the invention are not believed to act via the GABA / benzodiazepine, 5HT1A, or the DI receptor systems in humans. Rather, the activity of the Muscarinic Compounds Selected ones present as analgesic agents are believed to be based on the modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds work is not necessarily the mechanism established upra. , 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, sulfate, 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 the Journal of Pharmaceutical Science, 66, 2 (1977), which are known to the person skilled in the art. The compounds of this invention can form solvates with standard low molecular weight solvents using methods known to the person skilled in the art. The route of administration can be any route, which effectively transports the active compound to the appropriate or desired site of action, such as orally or parenterally, eg, rectally, transdermal, deposit, subcutaneous, intravenous, intramuscular or intranasal, being -preferred orally. The dose 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; the nature and degree of the symptoms, the type of simultaneous treatment, the frequency of the treatment and the desired effect. Usually, the daily dose may be such that the active ingredient is administered at a daily dose of from about 0.2 mg / kg to about 100 mg / kg of body weight of the selected Muscarinic Compound and from about 0.6 to about 200 mg / kg of the NSAIDS Compositions suitable for internal administration contain from about one-half (0.5) milligrams to about 600 milligrams of the active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount from about 0.5% to about 95% by weight based on the total weight of the composition.

For compositions containing acetaminophen, usually, the daily dose may be such that the active ingredient is administered in a daily dose of from about 0.2 mg / kg to about 500 mg / kg of body weight of the Selected Muscarinic Compound and from about 0.6 to about 200 mg / kg of acetaminophen. Typical compositions include a Compound of the Selected Muscarinic Compound and one or more NSAIDS, associated with a pharmaceutically acceptable excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. In the manufacture of the compositions, conventional techniques for the preparation of pharmaceutical compositions can 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 an ampule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it can be solid, semi-solid or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be absorbed in a solid granular container, for example in a sachet. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, monoglycerides and fatty acid diglycerides, fatty acid esters of pentaerythritol, hydroxymethylcellulose and polyvinylpyrrolidone. The formulations may also include wetting agents, emulsifying and suspending agents, preservatives, sweetening agents or flavoring agents. The formulations of the invention can be formulated in order to provide rapid, sustained or delayed relief of the active ingredient after administration to the patient employing procedures well known in the art. Typical compositions include a Muscarinic Compound. Selected and acetaminophen, associated with a pharmaceutically acceptable excipient, which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container. In the manufacture of the compositions, conventional techniques can be used for the preparation of pharmaceutical compositions, as described above. A preferred composition is a weight ratio of the Selected Muscarinic Compound for the central alpha-adrenergic active compound 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 range of doses; however, it is desirable to administer a dose that is as low as possible. The amount of the central alpha-adrenergic active compound present in the composition is adjusted as described above in relation to the dose of the Selected Muscarinic Compound. Usually, the daily dose may be such that the active ingredient is administered at a dose daily from about 0.2 mg / kg to about 500 mg / kg body weight of the selected Muscarinic Compound and from about 0.6 to about 200 mg / kg of the 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 may be in the form of a capsule, sachet, paper or other container. In the manufacture of the compositions, conventional techniques for the preparation of pharmaceutical compositions can be used. The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing the osmotic pressure, buffers and / or coloring substances and the like, which do not detrimentally react with the active compounds. For parenteral application, injectable solutions or suspensions, preferably aqueous solutions, are particularly suitable. with the active compound dissolved in polyhydroxylated castor oil. Tablets, dragees, or capsules having talc and / or a carbohydrate or binder carrier or the like are particularly suitable for oral application. Preferred 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 used. In general, the compositions of this invention are distributed in a unit form comprising from about 0.1 to about 300 mg in a pharmaceutically acceptable carrier per unit dose. The compositions of this invention may be suitable for administration to an animal. Such animals also include domestic animals, for example, livestock, laboratory animals, and domestic animals, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate. More preferably, a composition of this invention will be administered to a mammal. It is especially preferred that the animal be a domestic mammal or a human. The most preferred mammal is a human. For the purposes of such a pet, a composition of this invention can be administered as a food additive. The following models and assays are useful to illustrate the effectiveness of the compositions claimed herein.

Mod * lo d__ nocicaptive pain: Conversion induced by acetic acid: A standard procedure to detect and compare the analgesic activity of the different classes of analgesic drugs for which there is a good correlation with the analgesic activity of the human being is the prevention of contortion induced by acetic acid in mice. The mice are subcutaneously administered several doses of the claimed composition and are injected intraperitoneally with acetic acid (0.5% solution, 10 ml / kg) 5 minutes before the designated observation period. For scoring purposes a "contortion" is indicated by narrowing or contraction of the entire body abdomen during the observation period beginning 5 minutes after receiving the acetic acid. The inhibition The behavior of contortion is demonstrative of the 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.

Modalo gives nauropathic pain: Modalo gives ligation of the sciatic narva: The rats are anesthetized and a nerve ligation procedure is performed. The common sciatic nerve is exposed and 4 ligatures are tied loosely around it with approximately 1 mm of spacing. From one day to 10 weeks after surgery, the nociceptive test is performed. The responses to the noxious heat are determined by placing the rats in a chamber with a clean glass floor and pointing to the plantar surface of the affected paw, a source of radiant heat below the floor. The increased latency to remove the hind paw is demonstrative of the analgesic activity. The responses to normally innocuous mechanical stimuli are determined by placing the rats in a camera with a floor screen and stimulating the plantar surface of the hind paw with von Frey hair graded, which are calibrated by the grams of force required to bend them. The rats with sciatic nerve ligation respond to smaller grams of mechanical stimulation by reflexive withdrawal of the leg of the rats without surgery. This response to stimuli, which are normally harmless, is qualified allodynia. The increments in grams of the mechanical force required to produce the withdrawal of the paw is demonstrative of antialodynic activity. See Bennett, G.J. and Xie, Y.-K. A mononeuropathy in mouse 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 mouse neuropathic pain model. Neuroci Lett 186 (1995) 111-11-4.

Test gives the leg with formalin: The rats are anesthetized and when there is a loss of spontaneous movement, the rats are injected subcutaneously on the dorsal surface of the hind paw with 50 μl of 5% formalin solution using a 30 gauge needle. The rats are then placed individually in an open plexiglass chamber for observation and at a maximum interval of 1 to 2 minutes, the animal shows recovery from anesthesia with spontaneous activity and normal motor function. The pain behavior is quantified by periodic counting of the incidents of shuddering / spontaneous shaking of the injected paw. The shudders are counted for periods of 1 minute in intervals of 1 to 2, 5 to 6 and 5 minutes during the interval of 10 to 60 minutes. The inhibition of pain behavior is demonstrative of an analgesic activity. See Malmberg, A.B. and Yaksh, T.L .: Antinoniceptive 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.

Modalo dal inflammatory pain Hiparalgasia induced by Brawßr wash (Pruaba da Randall-Salitto): To assess the nociceptive threshold in rats, gradual pressure is applied to the paw with a driving weight of generator of movement of a Ugo Basile Analgesic Meter. Rats respond to pressure either by free device traction, resistance opposition or vocalization. Hyperalgesia is induced by a subplant injection of the hind foot of 0.1 ml of 1% suspension of brewer's yeast in 0.9% saline. The composition of this invention is administered in times of variation (0-4 hours) after the injection of the brewer's yeast and the pressure threshold for the inflamed leg again determined in the times of variation. Increases in 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 increased analgesic activity of the composition of the invention is evidenced by tests initially conducted in mice. The female mice are fasted for 16-22 hours and weighed. The weighing of the mice of approximately 18-22 grams, at the time of testing, is used for the following studies. All mice are sequentially dosed orally with suspensions of a composition of this invention. The doses are encoded using a code unknown to the observer. The suspension in the presence of the test composition is prepared by mixing the active ingredients with approximately 40 ml of an aqueous vehicle containing approximately 2% Tween 80 (R), a pharmacological dispersant and containing 100% polysorbate 80 and 1% by weight. MC powder weight of Methocel (R), and containing 100% methylcellulose in distilled water. The mixture can be sonicated for approximately 10 to 15 seconds using an ultrasound system. All dosing suspensions are prepared by diluting the suspension in stock with Methocel / Tween 80. All suspensions are used within two hours of preparation.

Mouse Contortion Test An accepted standard for detecting and comparing the analgesic activity of different classes of analgesic compounds for which there is a good correlation with analgesic activity in a human being is the prevention of contortion induced by phenyl-p-benzoquinone in mice. [H. Blumberg et al. Proc. Soc. Exp. Biol. Med., 118, 763,766 (1965)]. The 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 before a designated observation period. The phenyl-p-benzoquinone is prepared as a solution of about 0.1 mg / ml in about 5% by volume of ethanol in water. The dose for contortion is 1.25 mg / kg injected at a volume of approximately 0.25 ml / 10 g. For scoring purposes, a "contortion" is indicated by narrowing or contraction of the entire body abdomen during an observation period beginning approximately five minutes after administering the dose of phenyl-p-benzoquinone.

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 doses in the contortion induced by phenyl-p-benzoquinone in the mice is demonstrated by the isobologram of Loewe (S. Loewe, Pharm, Rev. 9, 237-242 (1957). The continuous line joining the ED50 doses of the Selected Muscarinic Compound (alone) and the Synergistic Analgesic as claimed herein (alone) represents the "ED50 addition line" which indicates the expected location of the ED50 for the Compound Selected Muscarinic and classical analgesic combinations if simple additivity was to describe their combined effects. The 95% confidence range for the ED50 addition line is shown by the area between the dashed lines above and below the ED50 addition line. According to Loewe's isobolic theory, if the analgesic effects are simply additive to each other, then the expected location of the ED50 of the Selected Muscarinic Compound and the Synergistic Analgesic component of each relationship of fixed dose would be contained within or in overlap with the region of the ED50 addition line. The combination of the ED50s located significantly below the ED50 addition line would represent unexpectedly increased analgesic activity and the combination of ED50s located above the line would represent unexpectedly decreased analgesic effect. One method to establish the significance of such unexpectedly increased or decreased activity is to calculate the best polynomial regression line of fit for the ED50 observed using standard mathematical techniques. Such experiments show that compositions comprised of a Compound Muscarinic Selected and one or more Analgesics Sinergistics provide a statistically significant synergistic analgesic effect. Preferred compounds for use in treating pain include: (3R, 4R) -3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -1-azabicyclo [2.2.1] heptane and the compounds of Formulas IV, V, VIII, IX, XIII, XIV and XV; or a pharmaceutically acceptable salt thereof.

Especially preferred compounds include the following: compounds of Formulas XIII, XIV and XV. Examples of the preferred compounds include, but are not limited to, 3- [2- (6-hydroxypyrazin) yl] -l-azabicyclo [2.2.2] octane, 3- (2-pyrazinyl) -l-azabicyclo [2.2. 1] heptane, 6- (2-pyrazinyl) -l-azabicyclo [3.2.1] octane, 6- (2-pyrazinyl) -l-azabicyclo [3.2.1] octan-6-ol, 3-fluoro-3- (2-pyrazinyl) -1-azabicyclo [2.2.1] heptane, l-methyl-3- (2-pyrazinyl) pyrrolidine, 3- (2- (3-methylpyrazin) il] -1-azabicyclo [2.2.2] octan-3-ol, 3- [2- (3,6-dimethylpyrazin) yl] -1-azabicyclo [2.2.1] heptane, 3- [2- (6-allyloxypyrazin) ilj-l-azabicyclo [2.2.1] ] heptane, 3- [2- (6-methoxypyrazin) il] -1-azabicyclo [2.2.2] octane, 3- [2- (6-chloropyrazin) yl] -1,2,5,6-tetrahydropyridine, 3 - [5- (3-octanyloxycarbonylamino-1,4,4-oxadiazole) -yl] -1-azabicyclo [2.2.1] heptane, 3- [5- (3-cyclohexylcarbonylamino-1,2,3-oxadiazole) - il] quinuclidine, 3- [5- (3- (1- (3-n-pentyloxycarbonyl) -1-ethoxycarbonylamino) -1,2,4-oxadiazole) -yl] quinuclidine, 3- [5- (3-octanoylamino -l, 2,4-oxadiazole) -yl] quinuclidine, 3- [(1-methyl-1H-imide zol-5-yl) methyl] -1,4-oxadiazol-5 (4H) -one, 4-met i1-3- [(1-methyl-1H-imidazole -4-yl) -methyl] 1,2,4-oxadiazole-5 (4H) - ona, 4-ethyl-3 [(1-methyl-1H-imidazol-4-yl) -methyl] -1,2,4-oxadiazol-5 (4H) -one, N- [4- (hexahydro-1H- azaepin-1-yl) -2-butynyl] -N, N-dimethylurea, N- [4-1-pyrrolidinyl) -2-butynyl] -urea, 5-acetyl-1-azabicyclo [3.1.1] heptane, 1 -azabicyclo [3.1.1] hept-5-ylcarboxaldehyde, 3- (2-methyltetrazol-5-yl) -l-azabicyclo [2.2.1] heptane, 3- (2-methyl-1,2,3-triazole- 4-yl) -l-azabicyclo- [2.2.2] octane, 3- (3-cyclopropyl-1, 2,4-oxadiazol-5-yl) -l-azabicyclo [2.2.1] heptane and a salt or solvent of the same pharmaceutically acceptable. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims

1. A composition for treating pain characterized in that it comprises an analgesic dose of a Compound selected from the group consisting of: wherein R 1 is hydrogen, C 1 -C 4 alkyl or phenyl C 1 -C 4 alkyl, in which the phenyl group can be substituted with halogen, C 1 -C 4 alkyl or C 1 -C alkoxy; R2 is an alkyl group of C6-C6, C3-C6 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group can be optionally substituted with fluoro, hydroxy or substituted phenyl optionally with fluoro, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C 1 -C 4 alkyl, hydroxy, or C 1 -C 4 alkoxy, or phenyl-alkyl of d- C4, in which the Phenyl group can be substituted with halogen, C? -C alkyl or C? -C4 alkoxy; wherein R6 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical wherein R7 and R8, which may be the same or different, represent hydrogen, C?-C8 alkyl, C2-C8 alkenyl or linear C2-C8 alkynyl or form, together with the nitrogen atom to which they are attached , a carbonaceous heterocyclic radical optionally containing another heteroatom, or the radical OR9, R9 representing hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR10 or SIOJR11, R10 and R11 represent an alkyl group of C? ~ C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, represents naphthyl optionally substituted with R6 ', R6 'being defined in the above by R 6. in which R, 12 represents the radical wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-Cß alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical R14 wherein R14 and R15, which may be the same or different, represent hydrogen, C?-C8 alkyl, C2-C8 alkenyl or linear C2-Cs alkynyl or form together with the nitrogen atom to which they are attached. carbonaceous heterocyclic radical optionally containing another heteroatom, or the radical or N02, or OR12 ', R12' representing hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR16 or S (0) R17, R16 and R17 represent an alkyl group of C? -C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or R12 represents naphthyl optionally substituted with R 13 ', R 13' being defined in the foregoing by R 13; wherein, one of R18, R19 and R20 represents nitrogen and the remainder represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic azacyclic or azabicyclic ring system and independently substituted at each of the other carbon atoms on the ring with the substituent R23, R21 or R22 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 nucleus; 2,4-oxadiazole; R31 represents a non-aromatic ring system 927azacyclo or 927azabicyclic; and R32 represents a substituent which is converted in vi to an amino group; wherein R34 represents a non-aromatic 1-azabicyclic ring system; not merged; and 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, with the condition that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form a ring alkylene dioxy of Ci-β, wherein R38 is an alkyl group of C6-6, C2-6 alkenyl or C2-6 alkynyl, R39 is hydrogen, C6-6 alkyl or -COCH3 and R40 represents OH, -OR 38 NH R 3 9 • NR3 8 R39 R 30 6 wherein R43 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to six carbon atoms, alkenyl of two to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six atoms carbon wherein n is zero or an integer from one to eight and R47 and R48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy from one to four carbon atoms, or where, 47 R, 4 < 8 are as defined in the above; X is oxygen or sulfur; R44 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms , cycloalkyl from three to six carbon atoms, or wherein n, R47 and R48 are as defined above, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms , cycloalkyl of three to eight carbon atoms, phenyl, phenyl substituted with alkyl of one to four carbon atoms, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of one to four carbon, chlorine, bromine, hydroxy, nitro or trifluoromethyl atoms of R45 and R46 are taken together with the nitrogen atom to which they are attached to form a ring indicated by wherein R49 is hydrogen, alkyl from one to ten carbon atoms, alkyl from one to ten carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten atoms of carbon substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R, 50 is hydrogen or alkyl of one to six carbon atoms, where R51 is selected from the group consisting of R, 52 is hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; n 'is zero or a whole number 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 L_1 _: _ represents a single bond X' is CH2; wherein R, 53 is selected from the group consisting R54, R55, R56 and R57 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from Ci-Cio alkyl, alkoxy, Ci-Cio halogen or trifluoromethyl; n1 is an integer of one or two; wherein X is oxygen, sulfur or -N-R, 62, wherein R 62 is hydrogen or alkyl of one to ten carbon atoms; R58 is selected from the group consisting of R, R and R are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that when it represents a double bond R57 and R60 are absent; where, 63 R, 6 < 4 R 65 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl 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 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 one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms , cycloalkyl 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 indicated by wherein n 'is zero or an integer from one to eight and R73 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six atoms carbon, or R70 when taken together with R68 forms a ring indicated by ) n where n is an integer from one to three and R68 are as defined in the above; R71 and R72 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of one to four carbon atoms, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of one to four carbon atoms, carbon, 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 indicated by where n 'and R73 are as defined in the above, where X is defined in the above or 74 wherein R74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 is CR2 and the other one 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, straight chain alkenyl of C2 -5, C2-5 straight chain alkynyl or chain alkyl linear C1-5 optionally substituted terminally with OR4, N (R4) 2, SR4, C02R4, CON (R4) 2 or one, two or three halogen atoms, in which each R4 is independently hydrogen or C1 alkyl -3 and R5 is 0R4, NH2 or NHR4; or wherein Z is a group -C (R7) = NR6 in which R6 is an OR8 group, where R8 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, an OCOR9 group where Rg is hydrogen or R8, or a group NHR10 or NRnR? 2 where Rio, R11 'and R? 2 are independently C? _2 alkyl and R7 is hydrogen or C? -4 alkyl, subject to the proviso that when R6 is an OCOR9 or NHR10 group, R7 is C? alkyl? in which one of X and Y represents hydrogen and the other represents Z, and Z 'is a group wherein Q 'represents a divalent 3-membered residue that completes an aromatic ring of 5 members and comprises two or three nitrogen atoms, any amino nitrogen being substituted by an alkyl group of C? -2, cyclopropyl or propargyl, 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; where R 75 represents in which each of p and q independently represents an integer from 2 to 4, r represents a integer from 2 to 4, s represents 1 or 2 and t represents 0 or 1; R76 is an OR78 group, wherein R78 is C? -4 alkenyl, C2_4 alkynyl, an OCOR79 group where R79 is hydrogen or R78, or a group NHR80 or NR81, R82, wherein R80, R81 and R82 are independently alkyl C? -2; and R77 is hydrogen or C? -4 alkyl, subject to the proviso that when R76 is an OCOR79 group or an NHR80 group, R77 is alkyl; (3R, 4R) -3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -1-azabicyclo [2.2.1] heptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of a Compound to a Synergistic Analgesic from about 1 to about 1000.

2. A composition according to claim 1, characterized in that 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 according to claim 1, characterized in that the Analgesic Sinergístico is an anti-inflammatory drug without steroids.

4. A composition according to claim 3, characterized in that the anti-inflammatory drug without steroids is selected from the group consisting of indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen and diclofenac.

5. A composition according to claim 3, characterized in that the anti-inflammatory drug without spheroids is ibuprofen.

6. A composition according to claim 3, characterized in that 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 according to claim 1, characterized in that the Synergistic Analgesic is an opioid.

8. A composition according to claim 7, characterized in that 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 according to claim 8, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, 1-azabicyclo [2.2. l] hept-3-yl-cyclopropyl ketone, 3-oxo-3- (l-azabicyclo [2.2.1] hept-3-yl) propionitrile, l-azabicyclo [2.2.2] oct-3-yl-N-methoxycarboxamide, l -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 1-azabicyclo [2.2.2] oct-3-ylidecyanoacetic acid; or a pharmaceutically acceptable salt thereof.

10. A composition according to claim 8, characterized in that the opioid is selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabufine and buprenorphine.

11. A composition according to claim 8, characterized in that 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 according to claim 8, characterized in that the opioid is selected from the group consisting of propoxyphene, methadone, hydrocodone, hydromorphine and codeine.

13. A composition according to claim 1, characterized in that the Compound is selected from the group consisting of Formula I, II and III; or a pharmaceutically acceptable salt or solvate thereof.

14. A composition according to claim 1, characterized in that the Compound is selected from the group consisting of the Formula XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

15. A composition according to claim 14, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct'-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylketone, 3-oxo-3- (l-azabicyclo [2.2.1] hept-3-yl) propionitrile, l-azabicyclo [2.2.2] oct-3-yl-N-methoxycarboxamide, l-azabicyclo [3.2.1] oct -5-yl-N-methoxycarboxamide, l-azabicyclo [2.2.1] hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (l-azab? Cyclo [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.

16. A composition according to claim 1, characterized in that the Analgesic Synergistic is acetaminophen.

17. A composition according to claim 15, characterized in that the Compound is selected from the group consisting of the Formula IV, V, VIII, IX, XIII, XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

18. A composition according to claim 17, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylacetone, 3-oxo-3- (1-azabicyclo [2.2.1] hept-3-yl) propionitrile, 1-azabicyclo [2.2.2] oct-3-yl-N-methoxycarboxamide, 1-aza-Di-cyclo [3.2. l] oct-5-yl-N-methoxycarboxamide, l-azabicyclo [2.2.1] hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (l-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.

19. A composition according to claim 1, characterized in that the Synergistic Analgesic is an alpha-adrenergic compound.

20. A composition according to claim 19, characterized in that the Compound is selected from the group consisting of the Formula IV, V, VIII, IX, XIII, XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

21. A composition according to claim 20, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylketone, 3 -oxo-3- (l-azabicyclo [2.2.1] hept-3-yl) propionitrile, l-azaiciclo [2.2.2] oct.- 3- i 1-N-methoxycarboxamide, l-azabicyclo [3.2.1 ] oct-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2. l] hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (l-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.

22. A method for treating pain characterized in that it comprises administering an analgesic dose of a composition comprising a Compound selected from the group consisting of: wherein R 1 is hydrogen, C 1 -C 6 alkyl or phenyl-C 1 -C 4 alkyl, in which the phenyl group can be substituted with halogen, C 1 -C alkyl or C 1 -C alkoxy; R2 is an alkyl group of C -Cβ, C3-C6 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group can be optionally substituted with fluoro, hydroxy or optionally substituted phenyl with fluoro, trifluoromethyl, lower alkyl, hydroxy or lower alkoxy; R3 and R4 are independently hydrogen, Ci-Cß alkyl, C3-C6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C?-C4 alkyl, hydroxy, or C?-C 4 alkoxy, or phenyl-C alquilo-alkyl C 4, in which the phenyl group can be substituted with halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; in which R represents the radical wherein R6 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or radical wherein R7 and R8 may be the same or different, represent hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear C2-C8 alkynyl or form together with the nitrogen atom-to which a heterocyclic radical is attached? carbonaceous optionally containing another heteroatom, or the radical OR 9, R 9 representing hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or linear, branched or cyclic C 2 -C 8 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR10 or S (0) Ru, R10 and R11 represent an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or R5 represents naphthyl optionally substituted with R6 ' , R6 'being defined in the above by R6; in which R represents the radical wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical R14 N! R1S wherein R 14 and R 15 may be the same or different, represent hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl or linear C 2 -C 8 alkynyl or form together with the nitrogen atom to which a carbonaceous heterocyclic radical is attached optionally containing another heteroatom, or the radical or N02, or OR12 ', R12' representing hydrogen, C? -C8 alkyl, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR16 or S (0) R17, R16 and R17 represent an alkyl group of C? -C8, alkenyl of C2 -Cf C2-C8 alkenyl, ineal, branched cyclic,, 12 represents naphthyl optionally substituted with R 13 'R 13 s as defined above by R 13; wherein, one of R18, R19 and R20 represents nitrogen and the remainder represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic azacyclic or azabicyclic ring system and independently substituted at each of the other carbon atoms on the ring with the substituent R23, R21 or R22 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 ring system 927azacyclo or 927azabicyclic; and R32 represents a substituent which is converted to an amino group; ; wherein R34 represents a non-aromatic 1-azabicyclic ring system; not merged; and 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, with the condition that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form an alkylenedioxy ring of C? -6, wherein R38 is an alkyl group of C? _6, C2_6 alkenyl or C2_6 alkynyl, R39 is hydrogen, C? _6 alkyl or -COCH3 and R40 represents OH, -OR38, NHR39 or -NR38R39 wherein R43 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to six carbon atoms, alkenyl of two to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six atoms carbon where n is zero or an integer from one to eight and R 47 R 48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy of one to four carbon atoms, or where, 47 R 48 are as defined in the above; X is oxygen or sulfur; R44 is alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkenyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or wherein n, R47 and R48 are as defined above, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four carbon atoms, alkyl from one to four atoms of carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkoxy from one * _. four carbon, chloro, bromo, hydroxy, nitro or trifluoromethyl atoms of R45 and R46 are taken together with the nitrogen atom to which they are attached to form a ring indicated by wherein R49 is hydrogen, alkyl of one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to ten carbon atoms, alkenyl of two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R50 is hydrogen or alkyl of one to six carbon atoms, where R51 is selected from the group consisting of R52 is hydrogen, alkyl of one to ten carbon atoms, alkynyl of from two to ten carbon atoms or aryl; n 'is zero or a whole number 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 R, 53 is selected from the group consisting R54, R5, R56 and R57 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from Ci-Cio alkyl, alkoxy, halogen of C? -C? o or trifluoromethyl; n 'is a whole number of one or two; wherein X is oxygen, sulfur or -N-R62, wherein R62 is hydrogen or alkyl of one to ten carbon atoms; R, 58 is selected from the group consisting of R59, R60 and R61 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that iand represents a double bond R57 and R60 are absent; wherein 63, 64, 65 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl 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 from one to ten carbon atoms; and R 67 is selected from the group consisting of wherein R69 is hydrogen and R67 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or R68 and R69 are turned together with the nitrogen atom to which they are attached to form a ring indicated by wherein n1 is zero or an integer from one to eight and R73 is hydrogen, alkyl from one to ten carbon atoms, alkyl from one to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or R70 when taken together with R68 forms a ring indicated by where n is an integer from one to three and R68 are as defined in the above; R71 and R72 are each independently hydrogen, alkyl. from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four atoms of carbon, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of 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 bound to form a ring indice-tdo by n ' where n 'and R73 are as defined in the above, where X is defined in the above or wherein R, 74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 ' is CR2 and the other is CR3; and Ri, R2 and R3 are independently selected from hydrogen, halogen, CN, 0R4, SR4, N (R4) 2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, N02, COR4, COR5, cyclopropyl, straight chain alkenyl of C2 -5, straight chain alkynyl of C2-5 or straight chain alkyl of C1-5 optionally substituted terminally with OR4, N (R4) 2, SR4, C02R4, CON (R4) 2 or one, two or three atoms of halogen, in which each R is independently hydrogen or C1-3 alkyl and R5 is OR4, NH2 or NHR4; or wherein Z is a group -C (R7) = NR6 in which Rβ is an O 8 group, where R8 is C1-4 alkyl, C2-4 alkenyl, C2_4 aikinyl, an OCOR9 group where R9 is hydrogen or R3, or a group NHRi0 or NR? R? 2 where Rio, R11 and ^ are independently C? -2 alkyl and R7 is hydrogen or C1-4 alkyl, subject to the condition that when Re is a group OCOR9 or NHR10, R7 is rent ie C1-4 in which one of X and Y represents hydrogen and the other represents Z, and Z 'is a group wherein Q 'represents a 3-membered divalent residue which completes a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? -2, cyclopropyl or propargyl, 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; where R, 75 represents wherein each of p and q independently represents an integer from 2 to 4, r represents an integer from 2 to 4, s represents 1 or 2 and t represents 0 or 1; , 76 is an OR group where R 78 is C1-4 alkenyl, C2-4 alkynyl, an OCOR79 group where R79 is hydrogen or R78, or a- group NHR80 or NR81, R82, where R80, R81 and R82 are independently C? -2 alkyl; and R77 is hydrogen or C? -4 alkyl, subject to the proviso that when R6 is an OCOR79 group or an NHR80 group, R77 is alkyl; i 3R, 4R) -3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -l-azao_c? clo [2.2.1] heptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Allergens in a weight ratio of a Compound to an Analgesic Synergistic from 'approximately 1 to approximately 1000.

23. A method according to claim 22, characterized in that the Compound is selected from the group consisting of the Formula IV, V, VIII, IX, XIII, XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

24. A method according to claim 22, characterized in that the Synergistic Analgesic is an anti-inflammatory drug without steroids.

25. A method according to claim 24, characterized in that the non-steroidal 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 according to claim 24, characterized in that the anti-inflammatory drug without steroids is ibuprofen.

27. A method according to claim 24, characterized in that 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.

28. A method according to claim 22, characterized in that the Synergistic Analgesic is an opioid.

29. A method according to claim 28, characterized in that 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 according to claim 29, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylketone, 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, l-azabicyclo [2.2.1] hept-3-ii-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 acid [2.2.2 ] oct-3-ylidecyanoacetic; or a pharmaceutically acceptable salt thereof.

31. . A method according to claim 29, characterized in that the opioid is selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabufina and buprenorphine.

32. A method according to claim 29, characterized in that 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 according to claim 29, characterized in that the opioid is selected from the group consisting of propoxyphene, methadone, hydrocodone, hydromorphine and codeine.

34. A method according to claim 22, characterized in that 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 according to claim 22, characterized in that the Compound is selected from the group consisting of Formula XIV and XV; or a pharmaceutically acceptable salt or solvate thereof.

36. A method according to claim 35, characterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylketone, 3 -oxo-3- (l-azabicyclo [2.2.1] hept-3-yl) propionitrile, l-azacyclo [2.2.2] oct-3-yl-N-methoxycarboxamide, l-azabicyclo [3.2.1] oct -5-yl-N-methoxycarboxamide, l-azabicyclo [2.2.1] hept-3-yl-N-methoxycarboxamide, (methoxyimino) - (l-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-i-leadcyanoacetic acid; or a pharmaceutically acceptable salt thereof.

37. A method according to claim 22, characterized in that the Synergistic Analgesic is acetaminophen.

38. A method according to claim 37, characterized in that 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 according to claim 22, characterized in that the Synergistic Analgesic is an alpha-adrenergic compound.

40. A method according to claim 39, acterized in that 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 according to claim 40, acterized in that the Compound is selected from the group consisting of: l-azabicyclo [2.2.2] oct-3-ylcyclopropylketone, l-azabicyclo [2.2.1] hept-3-ylcyclopropylketone, 3-oxo-3- (l-azabicyclo [2.2.1] hept-3-yl) propionitrile , l-azabicyclo [2.2.2] oct-3-yl-N-methoxycarboxamide, l-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 1-azabicyclo acid [2.2.2] ] oct-3-ylidecyanoacetic; or a pharmaceutically acceptable salt thereof.

42. The use of a First Compound selected from the group consisting of wherein R 1 is hydrogen, C 1 -C 4 alkyl or phenyl-C 1 -C 4 alkyl, in which the phenyl group can be substituted with halogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; R2 is an alkyl group of Ci-Cß. C3-C6 alkenyl, C3-C6 alkynyl, branched or unbranched with 1-6 carbon atoms inclusive, which group it 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-Cß alkyl, C 3 -C 6 cycloalkyl, phenyl optionally substituted with halogen, trifluoromethyl, C 1 -C 4 alkyl, hydroxy, or C?-C 4 alkoxy, or phenyl-C 1 -C 4 alkyl, in the which phenyl group can be substituted with halogen, C 1 -C 4 alkyl or C 1 -C alkoxy; in which R represents the radical wherein R6 at any position on the benzene ring represents an alkyl group of Ci-Cs, C2-Ca alkenyl or straight, branched or cyclic C2-C8 alkynyl or radical N-R > wherein R7 and R8 may be the same or different, represent hydrogen, C?-C8 alkyl, C2-C8 alkenyl or linear C2-Cs alkynyl or form together with the nitrogen atom to which a carbonyl heterocyclic radical is attached Ceo optionally containing another heteroatom, or the radical OR 9, R 9 representing hydrogen, C 1 -C 8 alkyl, C 2 -C 2 alkenyl or linear, branched or cyclic C 2 -C 8 alkynyl, or aryl containing up to 14 carbon atoms , or the radical SR10 or S (0) R1X, R10 and R represent an alkyl group of C? -C8, C2-C8 alkenyl or linear C2-C2 alkynyl, branched or cyclic, or R5 represents naphthyl optionally substituted with R6 ', R6' being defined in the above by R6; in which R, 12 represents the radical .OR wherein R13 at any position on the benzene ring represents an alkyl group of C?-C8, C2-C8 alkenyl or linear, branched or cyclic C2-C8 alkynyl or the radical wherein R14 and R15 may be the same or different, represent hydrogen, Ci-Cß alkyl, C.sub.2 -C.sub.2 alkenyl or linear C 2 -C.sub.w alkynyl or form together with the nitrogen atom to which they are attached, a heterocyclic radical carbonaceous optionally containing another heteroatom, or the radical or N02, or OR12 ', R12' representing hydrogen, Ci-Cß alkyl, C2-Cβ alkenyl or straight, branched or cyclic C2-C3 alkynyl, or aryl containing up to 14 carbon atoms, or the radical SR16 or S (0) R17, R16 and R17 represent an alkyl group of C? -C8, C2-Cs alkenyl or linear, branched or cyclic C2-8 alkynyl, or R12 represents naphthyl optionally substituted with R13 ', R13' being defined in the foregoing by R13; wherein, one of R18, R19 and R20 represents nitrogen and the remainder represents carbon atoms; substituted on one of the carbon atoms in the ring with a substituent R24 represented by a non-aromatic ring system. azacyclic or azabicyclic and independently substituted on each of the other carbon atoms in the ring with the substituent R23, R21 or R22 of low lipophilicity or a hydrocarbon having a maximum of 20 carbon atoms; where one of Ri8, Rí9 or R30 is an oxygen atom and the other two are nitrogen atoms, and the dotted circle represents aromaticity (two double bonds) in this way by taking a 1,3,4-oxadiazole nucleus or 1, 2, 4-oxad? A -.ol; R31 represents a ring system '927azac? Clo or' 927azabicyclic not aromatic; and R32 represents a substituent which is converted to an amino group; where R34 represents a ring system 1-non-aromatic azabicyclic; not merged; and 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, with the proviso that at least one of R35, R36 and R37 is different from hydrogen or a hydrocarbon group, or R35 and R36 or R37 taken together form an alkylenedioxy ring of C? -6, wherein R38 is an alkyl group of Ci -β, C2-6 alkenyl or C2-6 alkynyl »R39 is hydrogen, C6-6 alkyl or -COCH3 and R40 represents OH, -OR38, NHR39 or -NR38R39 wherein R43 is alkyl from one to six carbon atoms, alkyl from one to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from two to six carbon atoms, alkenyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms , alkynyl from two to six carbon atoms, alkynyl from two to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, wherein n is zero or an integer from one to eight and R47 and R48 are independently hydrogen, fluorine, chlorine, bromine, hydroxy, alkyl of one to three carbon atoms, or alkoxy of one to three carbon atoms, or alkoxy from one to four carbon atoms, or where R, 48 are as defined in the above; X is oxygen or sulfur; R44 is alkyl from one to six carbon atoms, alkyl from one to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from six to six carbon atoms, alkenyl from three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from six to six carbon atoms, alkynyl from: to six carbon atoms substituted with hyuroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six carbon atoms, or wherein n, R47 and R48 are as defined above, R45 and R46 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl of one to four carbon atoms, alkyl of one to four carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkoxy of 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 bound to form a ring indicated by wherein R49 is hydrogen, aikyl of from one to ten carbon atoms, alkyl of one to ten carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of two to ten carbon atoms, alkenyl of two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms and n is as defined above, where X is defined in the above or wherein R50 is hydrogen or alkyl of one to six carbon atoms, where R51 is selected from the group consisting of , 52 is hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; n 'is zero or a whole number 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 ... represents a single bond X' is CH2; wherein R, 53 is selected from the group consisting R54, R55, R56 and R57 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from Ci-Cio alkyl, alkoxy, halogen of Ci-Cio or rifluoromethyl; n 'is a whole number of one or two; wherein X is oxygen, sulfur or -N-R62, wherein R62 is hydrogen or alkyl der _~ one to ten carbon atoms; R58 is selected __-.! group consisting of R59, R60 and R61 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms or aryl; represents a single or double bond, with the proviso that when it represents a double bond R57 and R60 are absent; wherein R, 6β3, R, 6044 and R, 6053 are each independently hydrogen, alkyl from one to ten carbon atoms, alkynyl from two to ten carbon atoms, phenyl or phenyl substituted by one to four substituents selected from the group it consists of alkyl, alkoxy, thioalkoxy, halogen and trifluoromethyl; R66 is hydrogen, hydroxy or alkoxy from one to ten carbon atoms; and R 67 is selected from the group consisting of wherein R69 is hydrogen and R67 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkynyl of three to six carbon atoms, alkynyl of three to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms , cycloalkyl 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 indicated by wherein n 'is zero or an integer from one to eight and R73 is hydrogen, alkyl from one to ten carbon atoms, alkyl from one to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, a-nickyl from two to ten carbon atoms, alkenyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from two to ten carbon atoms or alkynyl from two to ten carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms; R70 is hydrogen, alkyl of one to six carbon atoms, alkyl of one to six carbon atoms substituted with hydroxy or alkoxy of one to four carbon atoms, alkenyl of three to six carbon atoms, alkenyl of three to six carbon atoms, carbon substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to six carbon atoms, alkynyl from three to six carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to six atoms carbon, or R70 when taken together with R68 forms a ring indicated by where n is an integer from one to three and R68 are as defined in the above; R71 and R72 are each independently hydrogen, alkyl from one to twenty carbon atoms, alkyl from one to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkenyl from three to twenty carbon atoms, alkenyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkynyl from three to twenty carbon atoms, alkynyl from three to twenty carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, cycloalkyl from three to eight carbon atoms, phenyl, phenyl substituted with alkyl from one to four carbon atoms, alkyl from one to four carbon atoms substituted with hydroxy or alkoxy from one to four carbon atoms, alkoxy 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 indicated by where n 'and R73 are as defined in the above, where X is defined in the above or wherein R74 is hydrogen or alkyl of one to six carbon atoms, in which Z is a heterocyclic group wherein Q represents a 3-membered divalent residue that completes a 5-membered aromatic ring and comprises one or two heteroatoms selected from oxygen, nitrogen and sulfur, or three nitrogen atoms, any amino nitrogen being replaced by an alkyl group of C? _2, cyclopropyl or propargyl, and any carbon atom in the ring 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 sulfur, one of A2 and A3 is CR2 and the other is nitrogen or CR3, or A2 is oxygen or sulfur, one of Ai and A3 is C_.2 and the other is CR3; and Ri, R2 and R3 are independently selected from hydrogen, halogen, CN, R4, SR4, N (R4) 2, NHCOR4, NHCOOCH3, NHCOOC2H5, NHOR4, NHNH2, N02, C0R4, COR5, cyclopropyl, chain alkenyl linear of C2-s, straight chain alkynyl of C2.5 or straight chain alkyl of C1-5 optionally substituted terminally with 0R4, N (R4) 2, SR4, C02R4, CON (R4) 2 or one, two or three halogen atoms, wherein each R 4 is independently hydrogen or C 1-3 alkyl and R 5 is OR 4, NH 2 or NHR 4; or wherein Z is a group -C (R7) = NR6 in which Re is an OR8 group, where R8 is C4 alkyl, C2.4 alkenyl, C2.4 alkynyl, an OCOR9 group where R9 is hydrogen or R8, or a group NHR10 or N uRi2 where Rio, R11 and R12 are independently C? -2 alkyl and R is hydrogen or C1-4 alkyl, subject to the proviso that when R? is an OCOR9 group 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 wherein Q 'represents a 3-membered divalent residue which completes a 5-membered aromatic ring and comprises two or three nitrogen atoms, any amino nitrogen being substituted by an alkyl group of C? _2, cyclopropyl or propargyl, 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; where R 75 represents in which each of p and q independently represents an enter number: from 2 to 4, r represents an integer from 2 to 4, 3 represents 1 or 2 and t represents 0 or 1; R76 is an OR78 group, wherein R78 is C1-4 alkenyl, C2_4 alkynyl, an OCOR79 group where R79 is hydrogen or R78, or a group NHR80 or NR81, R82, where R80, R81 and R82 are independently C? -2; and R77 is hydrogen or C1-4 alkyl, subject to the proviso that when R76 is an OCOR79 group or an NHR80 group, R77 is alkyl; (3R, 4R) -3- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) -l-azabicyclo [2.2.1] heptane; or a pharmaceutically acceptable salt or solvate thereof; and one or more Synergistic Analgesics in a weight ratio of a First Compound to a Synergistic Analgesic from about 1 to about 1000 for a manufacture of a medicament for therapeutic application in the treatment of pain.

43. A use according to claim 42, wherein the Synergistic Analgesic is an opioid.

44. A use according to claim 42, wherein the Synergistic Analgesic is acetaminophen.

45. A use according to claim 42, wherein the Synergistic Analgesic is an anti-inflammatory drug without steroids.

46. A use according to claim 42, wherein the Synergistic Analgesic is an alpha-adrenergic compound.