JP2000501709A - Composition for treating pain - Google Patents

Abstract

  (57) [Summary] The present invention provides a composition comprising a selected muscarinic compound and one or more compounds selected from the group consisting of non-steroidal anti-inflammatory drugs, acetaminophen, opioids and α-adrenergic compounds. Provided are a composition for treating pain using a substance and a method for treating pain.

Description

DETAILED DESCRIPTION OF THE INVENTION                             Composition for treating pain   The present invention relates to a method for treating pain using a compound in combination.   The present invention relates to therapeutic combinations of compounds for providing analgesic activity.   There is always a need for more active analgesic combined effects. Because they are Lower doses relieve pain, thereby causing side effects that may occur at higher doses. It has the attractive potential of reducing action and toxicity. Synergistic combination It is particularly desirable to have an effect. Such compositions are the subject of the present invention.   The compositions of the present invention each employ a compound individually known in the art. Thereby provide a surprisingly synergistically effective treatment for pain. Synergy of the composition The effect is that each compound in the composition can be used at lower doses to treat pain. Steps are provided, thus providing a therapy with more desirable side effect characteristics .   The present invention relates to a compound selected from the group consisting of the following compounds, Further synergistic analgesics, and the compound's Provided are compositions useful for treating pain, wherein the weight ratio is from about 1 to about 1000: (R^lIs hydrogen, C₁-C₆Alkyl or phenyl. C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the phenyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourWith alkoxy May be substituted))); (R^FiveIs a group of the following formula (R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Base (R^TenAnd R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Arche Nil or C_Two-C₈Alkynyl)) or   Or R^FiveIs R⁶'(R⁶'Is the above R⁶Nafu which may be substituted with Represents chill); (R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. A carbon-based heterocyclic group), or NO_TwoOr OR¹²'Group (R¹²′ Is water C, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or aryl containing up to 14 carbon atoms), Or SR¹⁶Or S (O) R¹⁷Group (R¹⁶And R¹⁷Is linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl) Is present)   Or R¹²Is R¹³'(R¹³'Is the above R¹³With the same meaning) Represents naphthyl);(R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal One of the elementary atoms is provided by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R represented^{twenty four}And other ring carbon atoms are each independently Lipophilic R^{twenty three}, R^{twenty one}Or R^{twenty two}Substituents or hydrocarbons with up to 20 carbon atoms Has been replaced by) (R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents aromaticity (two double bonds), so 1,3,4-oxadiazole Or, a 1,2,4-oxadiazole skeleton is formed. R³¹Is a non-aromatic '927 aza ring Represents a formula ring system or a non-aromatic '927 azabicyclic ring system. R³²Is an amino group in the living body Represents a substituent which can be converted to (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl, Br, -CF_Three, OR³⁸,- NR³⁸R³⁹, -NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰Or replacement or Represents an unsubstituted saturated or unsaturated hydrocarbon group (provided that R³⁵, R³⁶And R³⁷ At least one is other than hydrogen or a hydrocarbon group), or R³⁵And R³⁶Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. This Here R³⁸Is C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R^{Three 9} Is hydrogen, C_1-6Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NH R³⁹Or -NR³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, Fluorine, chlorine, bromine, hydroxy, alkyl of 1 to 3 carbon atoms, or 1 to 3 carbons An alkoxy of an elementary atom or an alkoxy of 1 to 4 carbon atoms) Or(R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached , (R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or 1 to 4 carbon atoms Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy 2-10 carbon atoms substituted with hydroxy, hydroxy or alkoxy of 1-4 carbon atoms Substituted with alkenyl, hydroxy or alkoxy of 1-4 carbon atoms of Represents an alkynyl of 10 carbon atoms, n is as defined above), (X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (R⁵¹Is selected from the group consisting of:  R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....  Represents a single bond or a double bond. However,...Is double When representing a bond, X 'is nitrogen;...  Is a single bond, X ′ is CH_Two);(R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n 'is an integer 1 or 2); (X is oxygen, sulfur or -NR⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms Is). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Will be: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Form the ring shown: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four)_Two, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five, NHOR_Four, NHNH_Two, NO_Two, COR_Four, COR_Five, Cyclopropyl, terminal O R_Four, N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three C optionally substituted with a halogen atom_1-5Linear alkyl, C_2-5Straight chain alkenyl Or C_2-5Selected from linear alkynyl. Where each R_FourIs independently hydrogen or C_1-3Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{Two -Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R⁷⁵Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 2, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR⁸¹, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is 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 of the above compound.   The present invention relates to a method for treating pain, and in a patient in need thereof, the following compounds: A compound selected from the group consisting of: and one or more “synergistic analgesics” Wherein the weight ratio of the compound to the "synergistic analgesic" is from about 1 to about 1000 There is provided a method comprising administering an analgesic composition:(R¹Is hydrogen, C₁-C₆Alkyl or phenyl. C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the phenyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourWith alkoxy May be substituted))); (R^FiveIs a group of the following formula (R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Group (R^TenAnd R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two- C₈Alkenyl or C_Two-C₈Alkynyl)) or   Or R^FiveIs R⁶'(R⁶'Is the above R⁶Nafu which may be substituted with Represents chill); (R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or Next formula Base (R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. A carbon-based heterocyclic group), or NO_TwoOr OR¹²'Group (R¹²′ Is water C, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or aryl containing up to 14 carbon atoms), Or SR¹⁶Or S (O) R¹⁷Group (R¹⁶And R¹⁷Is linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl) Is present)   Or R¹²Is R¹³'(R¹³'Is the above R¹³With the same meaning) Represents naphthyl); (R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal One of the elementary atoms is provided by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R represented^{twenty four}And other ring carbon atoms are each independently Lipophilic R^{twenty three}, R^{twenty one}Or R^{twenty two}Substituents or hydrocarbons with up to 20 carbon atoms Has been replaced by) (R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents aromaticity (two double bonds), so 1,3,4-oxadiazole Or, a 1,2,4-oxadiazole skeleton is formed. R³¹Is a non-aromatic '927 aza ring Represents a formula ring system or a non-aromatic '927 azabicyclic ring system. R³²Is an amino group in the living body Represents a substituent which can be converted to (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl, Br, -CF_Three, OR³⁸,- NR³⁸R³⁹, NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰Or replacement or Represents an unsubstituted saturated or unsaturated hydrocarbon group (provided that R³⁵, R³⁶And R³⁷ At least one is other than hydrogen or a hydrocarbon group), or R³⁵And R³⁶Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. This Here R³⁸Is C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R^{Three 9} Is hydrogen, C_1-6Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NH R³⁹Or -NR³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, Fluorine, chlorine, bromine, hydroxy, alkyl of 1 to 3 carbon atoms, or 1 to 3 carbons An alkoxy of an elementary atom or an alkoxy of 1 to 4 carbon atoms) Or (R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached , (R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or alkyl of 1 to 4 carbon atoms. Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy Of 2-10 carbon atoms substituted with hydroxy or alkoxy of 1-4 carbon atoms 2-10 substituted by alkenyl, hydroxy or alkoxy of 1-4 carbon atoms Represents an alkynyl of a carbon atom, and n is as defined above), (X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (R⁵¹Is selected from the group consisting of:  R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....  Represents a single bond or a double bond. However,...  But two Heavy bond Where X 'is nitrogen,...  Is a single bond, X 'is CH_Two );(R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n'1 or 2); (X is oxygen, sulfur or .N-R⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms ). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Will be: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Forming a ring represented by: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four)_Two, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five, NHOR_Four, NHNH_Two, NO_Two, COR_Four, COR_Five, Cyclopropyl, terminal O R_Four, N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three C optionally substituted with a halogen atom_1-5Linear alkyl, C_2-5Straight chain alkenyl Or C_2-5Selected from linear alkynyl. Where each R_FourIs independently hydrogen or C_1-3Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{2- Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R⁷⁵Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 2, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR⁸¹, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is 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 of the above compound.   As mentioned above, the compounds used in the method of the invention are known. Those compounds And methods for producing these compounds and pharmaceutical preparations containing these compounds are described in US Pat. Nos. 4,923,880, 5,110,828, 5,041,436, 5,278,170, No. 7,177,084, No. 4,992,436, No. 5,260,293, No. 4,996,201, No. 5,066,662, No. 5,066,665, No. 5,066,663, No. 4,988,688, No. 5,106,853, No. 5,192,765, No. 5,041,455, No. 5,043,345, No. 5,260,314, No. 5,310,911, No. 5,106,851, No. 5,068,237, No. 5,318,978, No. 5,242,927, No. 5,300,516, No. 5,089,505, No. 5,302,595, No. 5,219,871, No. 5,096,890, No. 5,164,386, No. 5,164,514, No. 5,157,160, No. 5,217,975 and No. 5,081,130 And these patents are incorporated herein by reference. .   The present invention is directed to the use of each stereoisomer of the compounds of the invention as well as the pureness of the specified compounds. Understand the use of pure diastereoisomers, pure enantiomers and racemates Should.   As used herein, “synergistic analgesic (group)” refers to a nonsteroidal anti-inflammatory drug (N SAIDS), acetaminophen, α-adrenergic compounds and opiates A group consisting of Oid.   As used herein, the “selected muscarinic compound (group)” includes the following: Refers to a compound selected from the group consisting of: (R¹Is hydrogen, C₁-C₆Alkyl or phenyl-C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the Fe Nyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourSubstituted with alkoxy Is also good)); (R^FiveIs a group of the following formula (R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Group (R^TenAnd R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two -C₈Alkenyl or C_Two-C₈Alkynyl)) or Kuha R^FiveIs R⁶'(R⁶'Is the above R⁶Naphthyl optionally substituted with Represents)(R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. A carbon-based heterocyclic group), or NO_TwoOr OR¹²'Group (R¹²′ Is water C, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or aryl containing up to 14 carbon atoms), Or SR¹⁶Or S (O) R¹⁷Group (R¹⁶And R¹⁷Is linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl) Is present)   Or R¹²Is R¹³'(R¹³'Is the above R¹³With the same meaning) Represents naphthyl);(R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal One of the elementary atoms is provided by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R represented^{twenty four}And other ring carbon atoms are each independently Lipophilic R^{twenty three}, R^{twenty one}Or R^{twenty two}Substituents or hydrocarbons with up to 20 carbon atoms Has been replaced by) (R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents aromaticity (two double bonds), so 1,3,4-oxadiazole Or, a 1,2,4-oxadiazole skeleton is formed. R³¹Is a non-aromatic '927 aza ring Represents a formula ring system or a non-aromatic '927 azabicyclic ring system. R³²Is an amino group in the living body Represents a substituent which can be converted to (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl, Br, -CF_Three, OR³⁸,- NR³⁸R³⁹,- NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰, Or substituted or unsubstituted saturation Or an unsaturated hydrocarbon group (provided that R³⁵, R³⁶And R³⁷At least One is other than hydrogen or a hydrocarbon radical) or R³⁵And R³⁶Ma Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. Where R³⁸Is C_{1 -6} Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R³⁹Is hydrogen, C_{1- 6} Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NHR³⁹Or -N R³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, H N, chlorine, bromine, hydroxy, alkyl of 1-3 carbon atoms, or 1-3 carbon Atom alkoxy, or alkoxy of 1 to 4 carbon atoms) Or (R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached , (R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or 1 to 4 carbon atoms Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy 2-10 carbon atoms substituted with hydroxy, hydroxy or alkoxy of 1-4 carbon atoms Substituted with alkenyl, hydroxy or alkoxy of 1-4 carbon atoms of Represents an alkynyl of 10 carbon atoms, n is as defined above),(X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (R⁵¹Is selected from the group consisting of:  R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....  Represents a single bond or a double bond. However,...  But two When representing a heavy bond, X 'is nitrogen;...  Represents a single bond, X ′ Is CH_Two);(R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n 'is an integer 1 or 2); (X is oxygen, sulfur or -NR⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms Is). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Will be: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Form the ring shown: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four)_Two, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five, NHOR_Four, NHNH_Two, NO_TwoCOR_Four, COR_Five, Cyclopropyl, terminal is OR_Four , N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three c C optionally substituted by a logen atom_1-5Linear alkyl, C_2-5Straight chain alkenyl Or C_2-5Selected from linear alkynyl. Where each R_FourIs independently hydrogen or C_1-3 Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{Two -Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R⁷⁵Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 1, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR⁸¹, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is 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 of the above compound.   The term "low lipophilicity" refers to hydrogen, halogen, -CF_Three, -OR^{twenty five}, -NR^{twenty five}R²⁶ , -NHOR^{twenty five}, -NHNH_Two, -CN, COR⁸, Or substituted or unsubstituted saturation Or an unsaturated hydrocarbon group (here, R^{twenty five}Is hydrogen, C₁-C₆Alkyl, C_2-6 Alkenyl or C_2-6Alkynyl, R²⁶Is hydrogen, alkyl or -COCH_Threeso Yes, R27 is -OR^{twenty five}Or -NR^{twenty five}R²⁶Represents).   An azacyclic or azabicyclic ring system is defined as one nitrogen as the only heteroatom A non-aromatic ring system containing atoms. Preferably, the ring system contains 4 to 10 ring atoms. And preferably contains 5 to 8 ring atoms. This ring system is a tertiary cage structure It preferably contains an amino nitrogen atom. Bicyclic systems can be fused, spiro or Any of a bridge type may be used. The nitrogen atom is preferably at the bridgehead of the bicyclic system No. Examples of such heteroatom compounds include U.S. Patent No. 5,260,293, cited above. Heteroatom compounds described in columns 2 to 3 of the item are included.   "'927 azacyclic or' 927 azabicyclic" means one heteroatom Refers to a non-aromatic ring system containing a nitrogen atom. Preferably, the ring has 4 to 10 ring atoms And preferably contains 5 to 8 ring atoms. Bicyclic systems are fused, spiro It may be either a mold or a bridge. Examples of such heteroatom compounds include: Bicyclic heteroatom compounds described in column 2 of U.S. Pat. No. 5,242,927, cited in U.S. Pat. Is included. The most preferred '927 azabicyclic or' 927 azacyclic systems include methyl Pyrrolidine, 1,2,5,6-tetra, optionally substituted with Hydropyridine, quinuclidine or 1-azabicyclo [2.2.1] heptane ring included. A particularly preferred '927 azabicyclic ring has water available on any available atom. Quinuclidine to which an element, methyl or hydroxy is bonded.   The group on the compound for pain treatment claimed by the present application is converted into an amino group in vivo. The compound is administered to a human or animal, and the compound containing the corresponding amino substituent is By detecting the presence of a substance in the urine of a human or animal using conventional analytical techniques, And you can be sure. Examples of such groups include hydrolyzable amino groups in vivo. Includes groups such as amide substituents and urethane substituents that can be understood. In particular, the formula:- NH.Q group (where Q is CHO, COR³³Or CO_TwoR³³And R³³Is Represents an optionally substituted hydrocarbon group). The term hydrocarbon group includes 20 Up to 10 carbon atoms, suitably up to 10 carbon atoms, preferably up to 8 carbon atoms. Includes groups that have children. Suitable hydrocarbon groups include C_1-8Alkyl, C_2-8Alkene Le, C_2-8Alkynyl, C_3-7Cycloalkyl, C_3-7Cycloalkyl C_1-6Archi , Aryl and aryl C_1-6And alkyl.   Suitable R³⁴The groups include the following groups:(Dashed lines represent optional chemical bonds. R⁴¹And R⁴²Includes the point of attachment to the benzene ring Hydrogen, C_1-4Alkyl, F, Br , Cl, C_1-4Alkoxy, hydroxy, carboxy or C_1-4Alkoxycal Represents bonyl, or R⁴¹And R⁴²Represents carbonyl as a whole). This nitrogen atom is hydrogen or C_1-4It may be substituted with alkyl.   "Phenyl-C₁-C_FourThe term "" refers to an alkyl group substituted with a phenyl group. You. Preferred phenyl-alkyl groups include benzyl, 1-phenylethyl, 2-phenyl Phenylethyl, 1-phenylpropyl, 2.phenylpropyl, 3.phenylpro Pill and 1-methyl-1-phenylethyl are included. This phenyl group is designated May be substituted with 1 to 3 substituents independently selected from the above substituents.   "They together with the nitrogen atom to which they are attached form a heterocyclic group," Is a heterocyclic group that may contain another heteroatom (eg, S or O) means. Such groups include piperidyl, biperazinyl, morpholinyl, and And pyrrolidinyl, but are not limited to.   The term "alkyl" refers to the stated number of carbon atoms, but the number is explicitly specified Otherwise, the term is C_1-6Refers to alkyl. Unless otherwise specified, this alkyl is It may be linear or branched.   The term "halogen" refers to chloro, bromo and fluoro substituents.   “Alkynyl” has its generally accepted meaning, but it has a specified carbon number. If not, C_2-10Refers to alkynyl. This alkynyl group is not specified As long as it is a straight chain or a branched chain.   The term “alkoxy” refers to a C_1-4Refers to alkoxy .   As used herein, the term “analgesic amount” refers to a person who easily feels pain or a person who suffers from pain. Indicates the amount of compound required to prevent or treat as a result of administration to the individual. I forgot. The active compounds are effective over a wide dosage range. For example, a daily dose usually is about 0 It will range from .005 to about 500 mg / kg-body weight. For adult treatment, about 0.05 to about It is preferable to use the 100 mg / kg range once or in divided doses. But actually The amount of compound administered to a patient depends on the condition to be treated, the choice of compound to be administered, and the individual Includes the patient's age, weight and response, the severity of the patient's symptoms, and the route of administration chosen. The physician will decide in light of the relevant circumstances and, therefore, It will be understood that the boxes do not limit the scope of the invention in any way. this These compounds may be given orally to people who are susceptible or anxious. Preferably, these compounds are used transdermally, parenterally, subcutaneously, intranasally. Can be administered via a variety of other routes, including intramuscular and intravenous routes. Wear. Using formulation techniques known to those skilled in the art, delayed or sustained release may occur. As such, the formulation may be designed.   As used herein, “NSAIDS” refers to a non-step that a skilled artisan can identify as such. Represents a Lloyd anti-inflammatory drug. For example, "Merck Manual" 16th edition (Merck Resear chLaboratories (1990)), pages 1308-1309, the well-known NSAIDS An example is provided. This term refers to salicylic acids such as aspirin, Tasin, ibuprofen, naproxen, fenoprofen, tolmetin, pickpocket Duck, meclofenamic acid, keoprofen, piroxicam, full Includes but is not limited to rubiprofen and diclofenac Not only. Particularly preferred NSAIDS include aspirin, ibuprofen And naproxen. A preferred alternative NSAIDS is India Methacin, ibuprofen, naproxen, fenoprofen, tolmetin, Lindac, meclofenamic acid, keoprofen, piroxicam, Lurubip Lofen and diclofenac. Aspires are particularly preferred NSAIDS. And ibuprofen. As salicylic acids, acetylsalicylic acid, Sodium acetylsalicylate, calcium acetylsalicylate, salicylic acid And sodium salicylate. Particularly preferred NSAIDS are IbuP Lofen.   As used herein, the term "acetaminophen" is commonly used in the art. N- (4-hydroxyphenyl) acetoa shall have its accepted meaning. Refers to mido and 4'-hydroxyacetanilide. This compound is disclosed in U.S. Pat. No., 998,450 and are known to those skilled in the art.   As used herein, the term “central α-adrenergic active compound” refers to central α-adrenergic compounds. Represents a compound that has a drenaline receptor activity. Most preferred central α-adrenal Active compounds are 2- (2,6-dichlorophenylamino) -2-imidazoline Or a pharmaceutically acceptable salt thereof having the chemical name   Clonidine is known to be useful in treating hypertension. "Physicians' Desk Reference, 45th edition (1991), p. 673.   As used herein, the term "opioid" refers to opioid analgesics and opioids. Opioid antagonists, natural opioid analgesics, synthetic opioid analgesics, opioid antagonists Includes anti-drug and opioid agonist-antagonists. Preferred opioid compounds are Luhine, codeine, meperidine, methadone, propoxyphene, levorphane , Hydromorphone, oxymorphone, oxycodone, brompton, naro Exon, naltrexone, pentazocine, butorphanol, nabphine (nabup hine) and buprenorphine. More preferred opio The id compounds include codeine, nabuphine and naltrexone. Group.   Preferred opioid compounds are morphine, codeine, meperidine, methadone, Propoxyphene, levorphanol, hydromorphone, oxymorphone, oki Chicodone, brompton, naloxone, naltrexone, pentazocine, Tolphanol, nabuphine, and buprenorphine.   Particularly preferred opioid compounds are hydromorphone, hydrocodone, mepe Lidone, buprenorphine, butorphenol, nalbuphine, Pentazocine, oxymorphine, oxycodone, levorfano Or fentanyl, and alphaprozin.   Particularly preferred opioid compounds are propoxyphene, methadone, morphine, From the group consisting of hydrocodone, hydromorhine and codeine Selected. Particularly preferred opioid compounds are morphine and codei Selected from   As used herein, "one or more" refers most preferably to one or more However, two, three or more kinds may be used.   We have identified a class of compounds with muscarinic cholinergic activity as non-steroidal anti-inflammatory That it can be particularly useful in treating pain when used in combination with drugs (NSAIDS) I saw. More specifically, the present invention relates to the known compounds identified herein (where Collectively refer to these as "selected muscarinic compounds"). To provide a method for treating human pain by providing a synergistic effect in combination with These "selections" Selected muscarinic compounds '' are based on activity at muscarinic choline receptors. It is believed that the present invention is limited by its mechanism of action. Not.   There are many NSAIDS known in the literature that are known to those skilled in the art.   We refer to a group of compounds with muscarinic cholinergic activity as acetaminophen. It has been discovered that the combination can be particularly useful for treating pain. More specific In particular, the present invention provides the "selected muscarinic compounds" identified herein. Provides a method for treating human pain by providing a synergistic effect in combination with cetaminophen I do.   In addition, we have identified a class of compounds with muscarinic cholinergic activity as central α-addresses. It may be particularly useful in treating pain when used in combination with a narinergic active compound. And discovered. More specifically, the present invention relates to "selected muscarinizing Compound in combination with a central α-adrenergic active compound to produce a synergistic effect. The present invention provides a method for treating human pain.   Oral combination of aspirin with codeine and other narcotic analgesics is additive to humans It is known to provide analgesic effects. "The Pharmacological Basis of Thera peutics, 5th edition (Macmillan Publishing, 1975), pages 325-358.   Further according to the present invention, one or more "selected muscarinic compounds" Can be used at once in the composition of the invention to provide the desired analgesic effect it is conceivable that.   In the composition of the present invention, the “selected muscarinic compound” and the NSAIDS compound The weight ratio of the compound to NSAIDS is from about 1 to about 1000. Mix.   Preferred compositions have a compound to NSAIDS weight ratio of about 1 to about 100. belongs to. Particularly preferred ratios are from about 1 to about 30. More preferred The ratio will be from about 1 to about 10. The most preferred ratio will be from about 1 to about 3.   In the composition of the present invention, the “selected muscarinic compound” and acetaminophen The weight ratio of "selected muscarinic compound" to acetaminophen To about 1 to about 1000.   A preferred composition is the "selected muscarinic compound for acetaminophen. The weight ratio of "things" is from about 1 to about 100. A particularly preferred ratio is about 1 Up to about 30. A more preferred ratio will be from about 1 to about 10. Most preferred The ratio will be from about 1 to about 3.   "Selected muscarinic compounds" are effective over a wide dosage range, but It is desirable to administer lower doses. Amount of NSAIDS present in the composition Is adjusted to achieve the above ratio for the dose of the `` selected muscarinic compound ''. It is set. The amount of acetaminophen present in the composition is determined by the formula The ratio is adjusted to the above-mentioned ratio with respect to the dose of the “kalinic compound”.   In the compositions of the present invention, one or more selected "muscarinic compounds selected" Or more opioid compounds, the selected The weight ratio of the "scalinic compound" is from about 1 to about 1000.   A preferred composition is a "selected muscarinic compound" for an opioid compound. " Is from about 1 to about 100 by weight. Particularly preferred ratios are from about 1 to about 3 Up to zero. A more preferred ratio will be from about 1 to about 10. The most preferred ratio is From about 1 to about 3.   The amount of the opioid compound present in the composition may vary depending on the selected muscarinizing compound. The ratio is adjusted to the above-mentioned ratio with respect to the dose of the “compound”.   However, for each of the compositions claimed by the present application, the "selection" actually administered is The amount of the selected muscarinic compound depends on the condition to be treated and the Of muscarinic compounds, the age, weight and response of individual patients, Determined by the physician, taking into account the severity of the condition and the relevant circumstances, including the route of administration chosen. Therefore, the above dose ranges in no way limit the scope of the invention. It will be understood that it is not. These compounds may be Although preferably administered orally to persons suffering from pain, these compounds may be administered via the transdermal route. , Parenteral, subcutaneous, intranasal, intramuscular and intravenous routes. It can also be administered by various other routes. Using formulation techniques known to those skilled in the art The formulation may be designed so that delayed or sustained release occurs.   Transdermal formulations containing the compositions claimed herein are most preferably in an effective amount. The active compound is delivered for about 3 days to about 7 days. But like arthritis and cancer pain For severe chronic pain, transdermal delivery for about 3 days to about 2 weeks is desirable. Or It is also preferred that the compositions be delivered transdermally in effective amounts for about 1 day to about 3 days.   As used herein, the term "treatment" refers to any physical and / or mental condition. Prevention, or, once it has been established, its body Elimination of the target and / or mental condition or relief of symptoms specific to that condition Include.   The “selected muscarinic compound” used in the present invention is a human GABA / vehicle. Not likely to act via the nzodiazepine, 5HT1A or D1 receptor system No. Rather, the activity of this "selected muscarinic compound" as an analgesic is It is thought to be based on the regulation of scalinic cholinergic receptors. But realization The mechanism by which the compound functions is not necessarily the mechanism described above, and the present invention Mode of action It is not limited by.   Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts, such as salts. Acid, hydrobromide, sulfate, phosphate, acetate, fumarate, maleate, Citrate, lactate, tartrate, oxalate, and other pharmaceutically acceptable inorganics Acid or organic acid addition salts,Journal of Pharmaceutical Science,66,2 (1977) include the pharmaceutically acceptable salts known to those skilled in the art. Of the present invention Compounds may be prepared using common solvents with common low molecular weight solvents using methods known to those skilled in the art. A hydrate may be formed.   The route of administration is such that the active compound can be efficiently transported to the appropriate or desired site of action. By road, oral or parenteral (eg rectal, transdermal, depot, subcutaneous, intravenous) , Intramuscular or intranasal), but the oral route is preferred. New   Naturally, the dose administered will depend on the pharmacodynamic characteristics of the drug, the mode of administration. And route of administration, age, health and weight of the recipient, nature and extent of its symptoms, concomitant treatment Fluctuates depending on known factors such as type of treatment, frequency of treatment, desired effect, etc. right. Typically, the active ingredient is selected from about 0.2 mg / kg to about 100 mg / kg-body weight Scalinic compound "and a daily dose of about 0.6 to about 200 mg / kg NSAIDS. Daily doses such as   A composition suitable for internal use is from about 0.5 milligram to about 600 milligrams per unit. Contains active ingredients. These pharmaceutical compositions usually contain a total weight of the composition. The active ingredient is present in an amount from about 0.5% to about 95% by weight.   In the case of acetaminophen-containing compositions, the active ingredient is usually present in an amount of about 0.2 mg / kg to about 0.2 mg / kg. 500 mg / kg body weight of the `` selected muscarinic compound '' and about 0.6 to about 200 mg / kg The daily dose can be such as to be administered as a daily dose of cetaminophen.   A typical composition is mixed with a pharmaceutically acceptable excipient, such as a carrier or diluent. Or in the form of capsules, sachets, paper, or other containers diluted with a carrier One and one "selected muscarinic compound" encapsulated in a carrier that can take Or more NSAIDS. The production of these compositions involves the use of conventional pharmaceutical Product Build technology can be used. For example, it is common to mix the active compound with a carrier, or Or in the form of ampoules, capsules, sachets, paper, or other containers. In a carrier. When the carrier acts as a diluent, it is a medium for the active compound, It can be a solid, semi-solid or liquid material that functions as an excipient or medium. Activity The compound can also be adsorbed on a granular solid container (eg, a sachet). Suitable charge Examples of bodies include water, salt solutions, alcohols, polyethylene glycol, polyhydro Xyethoxylated castor oil, gelatin, lactose, amylose, magne stearate Cium, talc, silicic acid, fatty acid monoglyceride, fatty acid diglyceride, penta Erythritol fatty acid ester, hydroxymethyl cellulose, polyvinyl pyro Ridon. These preparations may also contain wetting agents, emulsifying agents, suspending agents, preservatives, Flavors or flavors may be included. Using methods well known in the art, After administration, the active ingredient may be released quickly, slowly or slowly Thus, the formulations of the present invention may be formulated.   A typical composition is mixed with a pharmaceutically acceptable excipient, such as a carrier or diluent. Or in the form of capsules, sachets, paper, or other containers diluted with a carrier One of the “selected muscarinic compounds” encapsulated in a carrier Contains toaminophen. For the production of these compositions, conventional pharmaceutical composition production techniques are used. Can be used.   Preferred compositions are those that are "selected" for a central alpha-adrenergic active compound. The weight ratio of the "muscarinic compound" is from about 1 to about 100. Above all Preferred ratios are from about 1 to about 30. A more preferred ratio is from about 1 to about 10 Would. The most preferred ratio will be from about 1 to about 3.   "Selected muscarinic compounds" are effective over a wide dosage range, but It is desirable to administer lower doses. Central α-adrena present in the composition The amount of the phosphorus agonist active compound will depend on the dose of the "selected muscarinic compound". Is adjusted so that the above-mentioned ratio is obtained.   Typically, the active ingredient is selected from about 0.2 mg / kg to about 500 mg / kg-body weight of the selected muscarinic. Compound and about 0.6 to about 200 mg / kg of the central α-adrenergic active compound for The daily dose may be such that it is administered in a quantity.   A typical composition is mixed with a pharmaceutically acceptable excipient, such as a carrier or diluent. Or in the form of capsules, sachets, paper, or other containers diluted with a carrier One and one "selected muscarinic compound" encapsulated in a carrier that can take Or more central alpha-adrenergic active compounds. These compositions Conventional pharmaceutical composition manufacturing techniques can be used for the production of.   These pharmaceutical preparations are sterile and, if desired, do not cause adverse reactions to the active compound. Mix with auxiliary agents, emulsifiers, salts that affect osmotic pressure, buffers and / or colorants, etc. Can be combined.   For parenteral administration, injection solutions or suspensions (preferably polyhydroxylated Aqueous solutions containing the active compounds dissolved in castor oil) are particularly suitable.   Tablets, dragees or tablets containing talc and / or carbohydrate carriers, binders, etc. Pusers are particularly suitable for oral administration. For tablets, tongue tablets or capsules Suitable carriers include lactose, corn starch and / or potato starch. Addition If sugar excipients can be used, syrups and elixirs can be used.   Generally, the present invention provides a unit dosage form containing from about 0.1 to about 300 mg per unit dose. The compound is dispersed in a pharmaceutically acceptable carrier.   The compositions of the present invention may be suitable for administration to an animal. Such animals include livestock (e.g., Non-domestic animals such as livestock, research and household pets) and wildlife Is included. More preferably, the animal is a vertebrate. Most preferably, The composition of the present invention is administered to a mammal. That the animal is a mammal or human Is particularly preferred. The most preferred mammal is a human. For livestock animals The composition of the present invention can be provided as a feed additive.   The following models and assays are used to demonstrate the efficacy of the compositions claimed herein. Useful.Nociceptive pain model Acetic acid-induced writhing: One way to detect and compare the analgesic activity of different analgesics A common technique that has a good correlation with human analgesic activity is To prevent acetic acid-induced writhing. Subcutaneous administration of various doses of the present composition to mice Inject acetic acid (0.5% solution, 10 ml / kg) intraperitoneally 5 minutes before the specified observation period . For recording, whole body extension or during the observation period starting 5 minutes after administration of acetic acid "Writhing" is defined as contraction of the abdomen. Suppression of writhing behavior is evidence of analgesic activity. (Haubrich, DR, Ward, SJ, Baizman, E., Bell, MR, Bradford, J., Ferra ri, R., Miller, M., Perrone, M., Pierson, A.K., Saelens, JK and Lutting. er, D. "Pharmacology of pravadoline: a new analgesic agent" ravadoline), The Journal of Pharmacology and Experimental Therap eutics 255 (1990) 511-522)Neuropathic pain model Sciatic nerve ligation model: Rats are anesthetized and subjected to nerve ligation. Exposed common sciatic nerve And loosely tie four ligatures around it at intervals of about 1 mm. 1 day to 10 weeks after surgery , Conduct infringement tests. Rats are placed in a chamber with a clear glass floor and the floor Directs a radiant heat source from directly below to the plantar surface of the affected foot, The response to this is measured. If the time to retract the hind legs increases, Proof. The response to an otherwise non-noxious mechanical stimulus will cause the rat to And put the sole surface of the foot on the graded von Frey hair ( These are calibrated with the grams of force required to bend it) Measured by Rats with sciatic nerve ligation are better than rats without surgery Even in response to low gram mechanical stimuli, the feet are reflexively withdrawn. Normally non This response to a noxious stimulus is called allodynia. It creates a reaction to retract your feet An increase in the number of grams of mechanical force required for an animal is evidence of antiallodynic activity. (Bennett, GJ and Xie, Y.-K. "A peripheral mononeuropathy in rat t hatproduces disorders of pain sensation like those seen in man Peripheral neuropathy in rats with impaired pain sensation) "Pain 33 (198 8) See 87-107. Lee, Y.-W., Chaplan, S.R. and Yaksh, T.L. `` Systemic andsupraspinal, but not spinal, opiates suppress allodynia in a  rat neuropathicpain model (allodynia in rat neuropathic pain model Sexual and epispinal Suppressed by opiates but not by spinal opiates) See also Lett 186 (1995) 111-114. ) Formalin Paw Test: Anesthetize a rat and follow the rat in the absence of spontaneous movement The dorsal surface of the foot is injected subcutaneously with 50 μl of a 5% formalin solution using a 30 gauge needle. next The rats are individually placed in open plexiglass chambers for observation. Rat Recovers from anesthesia within 1-2 minutes, showing spontaneous activity and normal motor function . Pain by regularly counting the occurrence of spontaneous atrophy / tremor in the injected foot Quantify behavior. Awe is every 10 to 60 minutes, every 1 to 2 minutes, every 5 to 6 minutes And count for 1 minute at 5 minute intervals. Suppression of pain behavior is evidence of analgesic activity. (Malmberg, AB and Yaksh, TL "Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat ( Anti-nociception of spinal non-steroidal anti-inflammatory drugs against formalin test in rats Receptive effect) "The Journal of Pharmacology and Experimental Therapeutics 26 3 (1992) 136-146. )Inflammatory pain model Brewing yeast-induced hyperalgesia (Randall-Celite test): nociception in rats To assess the threshold of acceptance, the Ugo Basil Analgesie Meter (Ugo Ba With the electric weight of the sileAnalgesy Meter), gradually increase the pressure applied to the foot. Rats respond to this pressure by pulling, struggling, or vocalizing to escape the device. put out. Inject 0.1 ml of a 1% brewer's yeast suspension in 0.9% saline under the hindpaw Induces hyperalgesia. After injection of brewer's yeast, various time points (0-4 hours) )), The composition of the invention is administered and the pressure threshold is again varied for the inflamed paw Measure at the time. Increased pressure that produces a behavioral response is evidence of analgesic activity. (Haubrich, DR, Ward, SJ, Baizman, E., Bell, MR, Bradford, J., Ferra ri, R., MiUer, M., Perrone, M., Pierson, A.K., Saelens, J.K. and Luttinge r, D. "Pharmacology of pravadohne: a new analgesic agent avadoline pharmacology) "The Journal of Pharmacology and ExperimentalTherapeut See ics 255 (1990) 511-522. ) Effectiveness test method   The unexpectedly increased analgesic activity of the composition of the present invention was initially determined by tests performed in mice. Is proved. Male mice are fasted for 16-22 hours and weighed. At the time of the test Mice weighing about 18-22 grams are used for the following experiments. The invention for all mice The suspension of the composition is administered sequentially by the oral route. The dose is a code unknown to the observer. Number. By mixing about 40 mL of the system excipient and the active ingredient, an original suspension of the test composition is prepared. Prepare. Using a sonicator, the mixture is sonicated for about 10 to about 15 seconds. All dosing suspensions were prepared by diluting this stock suspension with Methocel / Tween80. To make. Use all suspensions within 2 hours after preparation.                             Mouse agony test   Generally accepted as a method to detect and compare the analgesic activity of different analgesic compounds A standard that has a good correlation with human analgesic activity is phenyl-p -Prevention of agony induced in mice by benzoquinone [H. Blumberg et al. Proc. Soc. Exp. Biol. Med., 118, 763-766 (1965)].   Treatment with various doses of the "selected muscarinic compound", composition or carrier Mice were given a general challenge dose of phenyl-p-benzoquinone for the specified observation period. Intraperitoneal injection 5 minutes before. Phenyl-p-benzoquinone is about 5% by volume ethanol Prepared as an approximately 0.1 mg / ml solution in aqueous solution. The amount of agony was 1.25 mg / kg, which was about Inject at a volume of 0.25 ml / 10 g. For the record, administration of phenyl-p-benzoquinone "Writhing" is defined as full-body extension or abdominal contraction during the observation period starting after 5 minutes. You.   All ED50 values and their 95% confidence limits using accepted statistical methods To determine. For example, WF Thompson,Bacteriological Rev., 11,115-145 (1947) checking ... Against agony induced in mice by phenyl-p-benzoquinone The interaction between the different doses is determined by the Loewe isobologram (S. Loe 9, Pharm. Rev. 9, 237-242 (1957)).   The "selected muscarinic compound" (alone) and the "synergistic analgesic" (single The solid line connecting the German ED50 doses describes their combined effects by simple addition. 'Selected muscarinic compounds' and classical analgesia when assumed to be The position of the ED50 for the combination of drugs is shown. 95% confidence on ED50 weighted line The limit is indicated by the area between the dashed lines above and below the ED50 weight line.   According to Leve's isobolic theory, the analgesic effect is simply In each case, only a fixed dose ratio of "selected The expected positions of the ED50 of the “muscarinic compound” and “synergistic analgesic” components are It will be contained within or overlap the area of the overlap line. More significant than ED50 weighted line The composite ED50 in the lower position shows unexpectedly increased analgesic activity, The composite ED50 located above the bary line indicates that analgesia is unexpectedly reduced. Will show.   One way to confirm such unexpectedly increased or decreased activity is to use the general Calculate the best fit polynomial regression curve for the observed ED50 using mathematical analysis That is.   Through such experiments, the “selected muscarinic compound” and one or more The composition consisting of the above “synergistic analgesics” gives a statistically significant synergistic analgesic effect. It is proven that   Compounds that are preferably used for the treatment of pain include (3R, 4R) -3- (3-cycl Loppyropyl-1,2,4-oxadiazol-5-yl) -1-azabicyclo [2.2.1] Heptane, a compound of formula IV, V, VIII, IX, XIII, XIV and XV, or pharmaceutically Acceptable salts are included.   Particularly preferred compounds include the following compounds: Formulas XIII, XIV and XV Compound.   Examples of preferred compounds include, but are not limited to: No: 3- [2- (6-hydroxypyrazin) yl] -1-azabicyclo [2.2.2] o 3- (2-pyrazinyl) -1-azabicyclo [2.2.1] heptane, 6- (2-pi Radinyl) -1-azabicyclo [3.2.1] octane, 6- (2-pyrazinyl) -1-aza Bicyclo [2.2.1] octan-6-ol, 3- Fluoro-3- (2-pyrazinyl) -1-azabicyclo [2.2.1] heptane, 1-methyl -3- (2. Pyrazinyl) pyrrolidine, 3- [2- (3-methylpyrazin) yl] -1-azabi Cyclo [2.2.2] octane-3-ol, 3- [2- (3,6-dimethylpyrazin) yl] -1-Azabicyclo [2.2.1] heptane, 3- [2- (6-allyloxypyrazin) yl ] -1-Azabicyclo [2.2.1] heptane, 3- [2- (6-methoxypyrazin) yl]- 1-azabicyclo [2.2.2] octane, 3- [2- (6-chloropyrazin) yl] -1,2 , 5,6-tetrahydropyridine, 3- [5- (3-octanyloxycarbonylamino) -1,2,4-oxadiazol) -yl] -1-azabicyclo [2.2.1] heptane, 3- [5- (3-cyclohexylcarbonylamino-1,2,3-oxadiazol) -yl] Quinuclidine, 3- [5- (3- (1- (3-n-pentyloxycarbonyl) -1-ethoxy) (Cyclocarbonylamino) -1,2,4-oxadiazol) -yl] quinuclidine, 3- [5 -(3-Octanoylamino-1,2,4-oxadiazol) -yl] quinuclidine, 3 -[(1-Methyl-1H-imidazol-5-yl) methyl] -1,2,4-oxadiazole -5 (4H) -one, 4-methyl-3-[(1-methyl-1H-imidazol-4-yl) -methyl L] -1,2,4-oxadiazol-5 (4H) -one, 4-ethyl-3-[(1-methyl- 1H-Imidazol-4-yl) -methyl] -1,2,4-oxadiazole-5 (4H) -o , N- [4- (hexahydro-1H-azaepin-1-yl) -2-butynyl] -N, N-di Methyl urea, N- [4- (1-pyrrolidinyl) -2-butynyl] urea, 5-acetyl-1-a Zabicyclo [3.1.1] heptane, 1-azabicyclo [3.3.1] heptane-5-yl Carboxaldehyde, 3- (2-methyltetrazol-5-yl) -1-azabicyclo [2.2.1] Heptane, 3- (2-methyl-1,2,3-triazol-4-yl) -1-aza Bicyclo [2.2.2] octane, 3- (3-cyclopropyl-1,2,4-oxadiazo Yl-5-yl) -1-azabicyclo [2.2.1] heptane, and pharmaceutically acceptable Salts or solvates thereof.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 45/00 A61K 45/00 // C07D 513/04 343 C07D 513/04 343 521/00 521/00 ( 81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MG, MK, MN, MW , MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ, VN

Claims (1)

[Claims]   1. One or more compounds selected from the group consisting of the following compounds Including the analgesic amount of the synergistic analgesic, wherein the weight ratio of the compound to the synergistic analgesic is about A composition for treating pain that is from 1 to about 1000: (R¹Is hydrogen, C₁-C₆Alkyl or phenyl-C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the phenyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourWith alkoxy May be substituted))); (R^FiveIs a group of the following formula(R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Group (R^TenAnd R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two -C₈Alkenyl or C_Two-C₈Alkynyl)) or   Or R^FiveIs R⁶′ (R⁶'Is the above R⁶Nafu which may be substituted with Represents chill); (R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. A carbon-based heterocyclic group), or NO_TwoOr OR¹²'Group (R¹²′ Is water C, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or aryl containing up to 14 carbon atoms), Or SR¹⁶Or S (O) R¹⁷Group (R¹⁶And R¹⁷Is linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl) Is present)   Or R¹²Is R¹³′ (R¹³'Is the above R¹³With the same meaning) Represents naphthyl); (R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal Elementary One of the atoms is represented by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R^{twenty four}And other ring carbon atoms are each independently Oiliness R^{twenty three}, R^{twenty one}Or R^{twenty two}A substituent or hydrocarbon with up to 20 carbon atoms Has been substituted);(R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents the aromaticity (two double bonds), so that 1,3,4-oxadiazole or Forms a 1,2,4-oxadiazole skeleton. R³¹Is a non-aromatic '927 azacyclic ring system Or a non-aromatic '927 azabicyclic ring system. R³²Is converted to amino group in vivo Represents a possible substituent); (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl Br, -CF_Three, OR³⁸, -NR³⁸ R³⁹, -NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰, Or substituted or unsubstituted Represents a saturated or unsaturated hydrocarbon group of³⁵, R³⁶And R³⁷Few At least one is other than hydrogen or a hydrocarbon radical) or R³⁵When R³⁶Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. Where R^{Three 8} Is C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R³⁹Is hydrogen , C_1-6Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NHR³⁹Also Is -NR³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, Fluorine, chlorine, bromine, hydroxy, alkyl of 1 to 3 carbon atoms, or 1 to 3 carbons An alkoxy of an elementary atom or an alkoxy of 1 to 4 carbon atoms) Or (R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached , (R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or 1 to 4 carbon atoms Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy 2-10 carbon atoms substituted with hydroxy, hydroxy or alkoxy of 1-4 carbon atoms Substituted with alkenyl, hydroxy or alkoxy of 1-4 carbon atoms of Represents an alkynyl of 10 carbon atoms, n is as defined above), (X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by)(R⁵¹Is selected from the group consisting of:   R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....  Represents a single bond or a double bond. However,...Is double When representing a bond, X 'is nitrogen;...Is a single bond, X 'is C H_Two); (R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n 'is an integer 1 or 2); (X is oxygen, sulfur or -NR⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms Is). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Will be: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Form the ring shown: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four)_Two, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five, NHOR_Four, NHNH_Two, NO_Two, COR_Four, COR_Five, Cyclopropyl, terminal O R_Four, N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three C optionally substituted with two halogen atoms_1-5Linear alkyl, C_2-5Straight-chain arche Nil or C_2-5Selected from linear alkynyl. Where each R_FourAre independently hydrogen Or C_1-3Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{Two -Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R₇₅Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 2, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR⁸¹, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is Alkyl)); (3R, 4R) -3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -1-azabicik B [2.2.1] heptane; Or a pharmaceutically acceptable salt or solvate of the above compound.   2. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV or Or a pharmaceutically acceptable salt or solvate thereof. The composition of claim 1.   3. The composition of claim 1, wherein the synergistic analgesic is a non-steroidal anti-inflammatory.   4. Non-steroidal anti-inflammatory drugs are indomethacin, ibuprofen, naproki Sen, fenoprofen, tolmetin, sulindac, meclofenamic acid, keop Lofen (keoprofen), piroxicam, flurbiprofen and diclofe 4. The composition of claim 3, wherein the composition is selected from the group consisting of nac.   5. 4. The composition of claim 3, wherein the non-steroidal anti-inflammatory drug is ibuprofen.   6. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV, Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 4. The composition of claim 3.   7. 2. The composition of claim 1, wherein the synergistic analgesic is an opioid.   8. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV, Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. The composition of claim 7.   9. The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1. Azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or the composition of claim 8, wherein the composition is selected from the group consisting of pharmaceutically acceptable salts thereof. object.   Ten. Opioids are morphine, codeine, meperidine, methadone, propoxy Phen, levorphanol, hydromorphone, oxymorphone, oxycodone, Brompton combination, naloxone, naltrexone, pentazocine, butorfano , Nabuphine and buprenorphine 9. The composition of claim 8, wherein   11． Opioids are hydromorphone, hydrocodone, meperidone, buprenor Fin, butorphenol, nalbuphine, pentazocine, e Xymorphine, oxycodone, levorphanol, fenta 9. The composition of claim 8, wherein the composition is selected from the group consisting of nil, and alphaprozin.   12． Opioids are propoxyphene, methadone, hydrocodone, hydromol 9. The method of claim 8, wherein the fin is selected from the group consisting of hydromorphine and codeine. Composition.   13. Wherein the compound is of the formula I, II and III or a pharmaceutically acceptable salt thereof Or the composition of claim 1 selected from the group consisting of solvates.   14. Wherein the compound is of the formula XIV and XV or a pharmaceutically acceptable salt thereof or The composition of claim 1 wherein is selected from the group consisting of solvates.   15． The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or the composition of claim 14, wherein the composition is selected from the group consisting of pharmaceutically acceptable salts thereof. object.   16． 2. The composition of claim 1, wherein the synergistic analgesic is acetaminophen.   17． The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 16. The composition of claim 15.   18． The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or the composition of claim 17, wherein the composition is selected from the group consisting of pharmaceutically acceptable salts thereof. object.   19. The composition of claim 1, wherein the synergistic analgesic is an α-adrenergic compound.   20. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 20. The composition of claim 19.   twenty one. The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or the composition of claim 20, which is selected from the group consisting of pharmaceutically acceptable salts thereof. object.   twenty two. One or more compounds selected from the group consisting of the following compounds: A synergistic analgesic, wherein the weight ratio of the compound to the synergistic analgesic is about 1; Pain treatment comprising administering an analgesic amount of the composition that is up to about 1000: (R¹Is hydrogen, C₁-C₆Alkyl or phenyl-C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the phenyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourWith alkoxy May be substituted))); (R^FiveIs a group of the following formula (R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Group (R^TenAnd R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two -C₈Alkenyl or C_Two-C₈Alkynyl)) or   Or R^FiveIs R⁶'(R⁶'Is the above R⁶Nafu which may be substituted with Represents chill); (R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula(R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. Forms a carbon-based heterocyclic group) Or NO_TwoOr OR¹²'Group (R¹²'Is hydrogen, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or 14 Represents an aryl containing up to carbon atoms), or SR¹⁶Or S (O) R¹⁷ Group (R¹⁶And R¹⁷Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Al Kenyl or C_Two-C₈Alkynyl)) or   Or R¹²Is R¹³'(R¹³'Is the above R¹³With the same meaning) Represents naphthyl); (R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal One of the elementary atoms is provided by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R represented^{twenty four}And other ring carbon atoms are each independently Lipophilic R^{twenty three}, R^{twenty one}Or R^{twenty two}Substituents or hydrocarbons with up to 20 carbon atoms Has been replaced by) (R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents the aromaticity (two double bonds), so that 1,3,4-oxadiazole or Forms a 1,2,4-oxadiazole skeleton. R³¹Is a non-aromatic '927 azacyclic ring system Or a non-aromatic '927 azabicyclic ring system. R³²Is converted to amino group in vivo Represents a possible substituent); (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl, Br, -CF_Three, OR³⁸,- NR³⁸R³⁹, -NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰Or replacement or Represents an unsubstituted saturated or unsaturated hydrocarbon group (provided that R³⁵, R³⁶And R³⁷ At least one is other than hydrogen or a hydrocarbon group), or R³⁵And R³⁶Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. This Here R³⁸Is C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R^{Three 9} Is hydrogen, C_1-6Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NH R³⁹Or -NR³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, Fluorine, chlorine, bromine, hydroxy, alkyl of 1 to 3 carbon atoms, or 1 to 3 carbons An alkoxy of an elementary atom or an alkoxy of 1 to 4 carbon atoms) Or (R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached ,(R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or 1 to 4 carbon atoms Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy 2-10 carbon atoms substituted with hydroxy, hydroxy or alkoxy of 1-4 carbon atoms Substituted with alkenyl, hydroxy or alkoxy of 1-4 carbon atoms of Represents an alkynyl of 10 carbon atoms, n is as defined above), (X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (R⁵¹Is selected from the group consisting of:  R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....Represents a single bond or a double bond. However,...Is double tied Join Where X 'is nitrogen,...Is a single bond, X 'is CH_Twoso To be):(R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n 'is an integer 1 or 2); (X is oxygen, sulfur or -NR⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms Is). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Done: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Form the ring shown: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four)_Two, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five, NHOR_Four, NHNH_Two, NO_Two, COR_Four, COR_Five, Cyclopropyl, terminal O R_Four, N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three C optionally substituted with a halogen atom_1-5Linear alkyl, C_2-5Straight chain alkenyl Or C_2-5Selected from linear alkynyl. Where each R_FourIs independently hydrogen or C_1-3Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{Two -Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R⁷⁵Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 2, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR⁸¹, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is Alkyl)); (3R, 4R) -3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -1-azabicik B [2.2.1] heptane; Or a pharmaceutically acceptable salt or solvate of the above compound.   twenty three. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 23. The method of claim 22.   twenty four. 23. The method of claim 22, wherein the synergistic analgesic is a non-steroidal anti-inflammatory.   twenty five. Non-steroidal anti-inflammatory drugs are indomethacin, ibuprofen, naproki Sen, fenoprofen, tolmetin, sulindac, meclofenamic acid, keop Lofen (keoprofen), piroxicam, flurbiprofen and diclofe 25. The method of claim 24, wherein the method is selected from the group consisting of nak.   26. 25. The method of claim 24, wherein the non-steroidal anti-inflammatory drug is ibuprofen.   27. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 25. The method of claim 24.   28. 23. The method of claim 22, wherein the synergistic analgesic is an opioid.   29. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV or Or a pharmaceutically acceptable salt or solvate thereof. The method of claim 28.   30. The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or a method selected from the group consisting of pharmaceutically acceptable salts thereof. .   31. Opioids are morphine, codeine, meperidine, methadone, propoxy Phen, levorphanol, hydromorphone, oxymorphone, oxycodone, Brompton combination, naloxone, naltrexone, pentazocine, butorfano , Nabuphine and buprenorphine 30. The method of claim 29, wherein   32. Opioids are hydromorphone, hydrocodone, meperidone, buprenor Fin, butorphenol, nalbuphine, pentazocine, e Xymorphine, oxycodone, levorphanol, fenta 30. The method of claim 29, wherein the method is selected from the group consisting of nil and alphaprozin.   33. Opioids are propoxyphene, methadone, hydrocodone, hydromol 30. The method of claim 29, wherein the fin is selected from the group consisting of hydromorphine and codeine. Method.   34. Wherein the compound is of the formula I, II and III or a pharmaceutically acceptable salt thereof 23. The method of claim 22, wherein the method is selected from the group consisting of a solvate.   35. Wherein the compound is of the formula XIV and XV or a pharmaceutically acceptable salt thereof or 23. The method of claim 22, wherein is selected from the group consisting of solvates.   36. The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycarboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or a method selected from the group consisting of pharmaceutically acceptable salts thereof. .   37. 23. The method of claim 22, wherein the synergistic analgesic is acetaminophen.   38. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 38. The method of claim 37.   39. 23. The method of claim 22, wherein the synergistic analgesic is an [alpha] -adrenergic compound.   40. The compound has the formula IV, V, VIII, IX, XIII, XIV and XV Or selected from the group consisting of pharmaceutically acceptable salts or solvates thereof. 40. The method of claim 39.   41. The compound is 1-azabicyclo [2.2.2] octan-3-ylcyclopropyl ketone, 1-azabicyclo [2.2.1] heptane-3-ylcyclopropyl ketone, 3-oxo-3- (1-azabicyclo [2.2.1] heptane-3-yl) propionitrile, 1-azabicyclo [2.2.2] octan-3-yl-N-methoxycarboxamide, 1-azabicyclo [3.2.1] octan-5-yl-N-methoxycanoleboxamide, 1-azabicyclo [2.2.1] heptane-3-yl-N-methoxycarboxamide, (Methoxyimino)-(1-azabicyclo [R2.2.2] octan-3-yl) acetonitrile, Oxyimino- (1-azabicyclo [2.2.2] octan-3-yl) acetonitrile, and And 1-azabicyclo [2.2.2] octane-3-yridcyanoacetic acid, Or the method of claim 40 selected from the group consisting of pharmaceutically acceptable salts thereof. .   42. Select from the group consisting of the following compounds for manufacturing a drug for treating pain The use of a first compound and one or more synergistic analgesics, provided that The weight ratio of the first compound to the analgesic should be from about 1 to about 1000) (R¹Is hydrogen, C₁-C₆Alkyl or phenyl-C₁-C_FourAlkyl (the phenyl The group is halogen, C₁-C_FourAlkyl or C₁-C_FourMay be substituted with alkoxy I).   R^TwoIs C₁-C₆Alkyl, C_Three-C₆Alkenyl or C_Three-C₆Alkynyl, 1 With or without branches of up to 6 carbon atoms, Is fluoro, hydroxy or phenyl (fluoro, trifluoromethyl, lower Substituted by alkyl, hydroxy or lower alkoxy) It may be.   R^ThreeAnd R^FourIs independently hydrogen, C₁-C₆Alkyl, C_Three-C₆Cycloalkyl , Phenyl (halogen, trifluoromethyl, C₁-C_FourAlkyl and hydroxy Or C₁-C_FourOptionally substituted with alkoxy) or phenyl-C₁-C_FourAl Kill (the phenyl group is halogen, C₁-C_FourAlkyl or C₁-C_FourWith alkoxy May be substituted))); (R^FiveIs a group of the following formula (R⁶May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, Or a group of the following formula (R⁷And R⁸May be the same or different and include hydrogen, linear C₁-C₈Alkyl , C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl, or May contain another heteroatom as a whole together with the joining nitrogen atom Or a carbon-based heterocyclic group) or OR⁹Group (R⁹Is hydrogen, straight-chain or branched Or annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, also Or an aryl containing up to 14 carbon atoms), or SR^TenOr S (O) R¹¹Group (R^Ten And R¹¹Is a linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl Or C_Two-C₈Alkynyl)) or   Or R^FiveIs R⁶′ (R⁶'Is the above R⁶Nafu which may be substituted with Represents chill); (R¹²Is a group of the following formula (R¹³May be at any position on the benzene ring, and may be linear, branched or Annular C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or The following formula (R¹⁴And R¹⁵May be the same or different and include hydrogen, linear C₁-C₈Archi Le, C_Two-C₈Alkenyl or C_Two-C₈Represents alkynyl or they are It may contain another heteroatom as a whole with the nitrogen atom to which it is attached. A carbon-based heterocyclic group), or NO_TwoOr OR¹²'Group (R¹²′ Is water C, linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl, or aryl containing up to 14 carbon atoms), Or SR¹⁶Or S (O) R¹⁷Group (R¹⁶And R¹⁷Is linear, branched or cyclic C₁-C₈Alkyl, C_Two-C₈Alkenyl or C_Two-C₈Alkynyl) Is present)   Or R¹²Is R¹³'(R¹³'Is the above R¹³With the same meaning) Represents naphthyl);(R¹⁸, R¹⁹And R²⁰One represents nitrogen and the other represents carbon atoms. Ring charcoal One of the elementary atoms is provided by a non-aromatic azacyclic or non-aromatic azabicyclic ring system. R represented^{twenty four}And other ring carbon atoms are each independently Lipophilic R^{twenty three}, R^{twenty one}Or R^{twenty two}Substituents or hydrocarbons with up to 20 carbon atoms Has been replaced by) (R²⁸, R²⁹Or R³⁰One is an oxygen atom and the other two are nitrogen atoms. Represents the aromaticity (two double bonds), so that 1,3,4-oxadiazole or Forms a 1,2,4-oxadiazole skeleton. R³¹Is a non-aromatic '927 azacyclic ring system Or a non-aromatic '927 azabicyclic ring system. R³²Is converted to amino group in vivo Represents a possible substituent); (R³⁴Represents a non-aromatic non-fused 1-azabicyclic ring system.   R³⁵, R³⁶And R³⁷Is independently hydrogen, F, Cl, Br, -CF_Three, OR³⁸,- NR³⁸R³⁹, -NHOR³⁸, -NHNH_Two, -CN, COR⁴⁰Or replacement or Represents an unsubstituted saturated or unsaturated hydrocarbon group (provided that R³⁵, R³⁶And R³⁷ At least one is other than hydrogen or a hydrocarbon group), or R³⁵And R³⁶Or R³⁷Is C as a whole_1-6Forms an alkylenedioxy ring. This Here R³⁸Is C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl, R^{Three 9} Is hydrogen, C_1-6Alkyl or -COCH_ThreeAnd R⁴⁰Is OH, -OR³⁸, NH R³⁹Or -NR³⁸R³⁹Represents) (R⁴³Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 2 to 6 carbon atoms,     2-6 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, (N is 0 or an integer from 1 to 8;⁴⁷And R⁴⁸Is independently hydrogen, Fluorine, chlorine, bromine, hydroxy, alkyl of 1 to 3 carbon atoms, or 1 to 3 carbons An alkoxy of an elementary atom or an alkoxy of 1 to 4 carbon atoms) Or(R⁴⁷And R⁴⁸Is as defined above) It is.   X is oxygen or sulfur.   R⁴⁴Is     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 6 carbon atoms, Or (N, R⁴⁷, R⁴⁸Is as defined above) It is.   R⁴⁵And R⁴⁶Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R⁴⁵And R⁴⁶Together with the nitrogen atom to which they are attached , (R⁴⁹Is hydrogen, alkyl of 1 to 10 carbon atoms, hydroxy or 1 to 4 carbon atoms A Alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms substituted with alkoxy Of 2-10 carbon atoms substituted with hydroxy or alkoxy of 1-4 carbon atoms 2-10 substituted by alkenyl, hydroxy or alkoxy of 1-4 carbon atoms Represents an alkynyl of a carbon atom, and n is as defined above),(X is as defined above) Or (R⁵⁰Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (R⁵¹Is selected from the group consisting of:  R⁵²Is hydrogen, alkyl of 1 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, or Is aryl. n 'is 0 or an integer 1 or 2. X 'is carbon or Nitrogen....Represents a single bond or a double bond. However,...Is double tied X 'is nitrogen,...Is a single bond, X 'is CH_Two ); (R⁵³Is selected from the group consisting of:   R⁵⁴, R⁵⁵, R⁵⁶And R⁵⁷Are each independently hydrogen, an alkyl of 1 to 10 carbon atoms Killed, alkynyl of 2 to 10 carbon atoms, or phenyl, or C₁-C_TenArchi Le, alkoxy, C₁-C_Ten1 selected from halogen or trifluoromethyl Phenyl substituted with up to 4 substituents. n 'is an integer 1 or 2); (X is oxygen, sulfur or -NR⁶²(R⁶²Is hydrogen or alkyl of 1 to 10 carbon atoms Is). R⁵⁸Is selected from the group consisting of:  R⁵⁹, R⁶⁰And R⁶¹Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl or aryl of 2 to 10 carbon atoms. --- is a single bond or double Represents a bond. Provided that when-represents a double bond, R⁵⁷And R⁶⁰Does not exist Shall)(R⁶³, R⁶⁴And R⁶⁵Are each independently hydrogen, alkyl of 1 to 10 carbon atoms, Alkynyl of 2 to 10 carbon atoms, or phenyl, or alkyl, alkoxy , Thioalkoxy, selected from the group consisting of halogen and trifluoromethyl Phenyl substituted with 1 to 4 substituents. R⁶⁶Is hydrogen, hydroxy, or Or alkoxy of 1 to 10 carbon atoms. R⁶⁷Is selected from the group consisting of the following groups Will be: Or(R⁶⁹Is hydrogen and R⁶⁷Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     Substituted with hydroxy or alkoxy of 1-4 carbon atoms and having 3-6 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     A cycloalkyl of 3 to 6 carbon atoms, Or R⁶⁸And R⁶⁹Together with the nitrogen atom to which they are attached Form the ring shown: (N 'is 0 or an integer from 1 to 8;⁷³Is hydrogen, an atom of 1 to 10 carbon atoms 1 to 10 carbon atoms substituted by alkyl, hydroxy or alkoxy of 1 to 4 carbon atoms Alkyl of atoms, alkenyl of 2 to 10 carbon atoms, hydroxy or 1-4 carbon atoms Alkenyl of 2 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms Substituted by ruquinyl, or hydroxy or alkoxy of 1 to 4 carbon atoms Represents an alkynyl of 2 to 10 carbon atoms).   R⁷⁰Is hydrogen,     Alkyl of 1 to 6 carbon atoms,     1 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms An alkyl,     Alkenyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkenyl,     Alkynyl of 3 to 6 carbon atoms,     3 to 6 carbon atoms substituted by hydroxy or alkoxy of 1 to 4 carbon atoms Alkynyl,     Represents cycloalkyl of 3 to 6 carbon atoms, Or R⁷⁰Is R⁶⁸And together form a ring of the formula: (N is an integer from 1 to 3;⁶⁸Is as defined above).   R⁷¹And R⁷²Are each independently hydrogen,     Alkyl of 1 to 20 carbon atoms,     1-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms An alkyl,     Alkenyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkenyl,     Alkynyl of 3 to 20 carbon atoms,     3-20 carbon atoms substituted by hydroxy or alkoxy of 1-4 carbon atoms Alkynyl,     Cycloalkyl of 3 to 8 carbon atoms,     Phenyl,     Alkyl of 1-4 carbon atoms, hydroxy or alkoxy of 1-4 carbon atoms Alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, chlorine, Phenyl substituted with bromine, hydroxy, nitro or trifluoromethyl Or R^ThreeAnd R^FourTogether with the nitrogen to which they are attached (N 'and R⁷³Is as defined above) (X is as defined above) Or (R⁷⁴Is hydrogen or alkyl of 1 to 6 carbon atoms) Forming a ring represented by) (Z is a heterocyclic group of the following formula:(Q is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and includes oxygen, nitrogen and Containing one or two heteroatoms or three nitrogen atoms selected from sulfur And amino nitrogen are all C_1-2Alkyl, cyclopropyl or propargyl groups And the ring carbon atom is R₁May be substituted with a group) Or a group of the formula: (A₁, A_TwoAnd A_ThreeForms part of an aromatic 5-membered ring, and A₁Is oxygen or sulfur, A_Two And A_ThreeOne of them is CR_Two, The other being nitrogen or CR_ThreeOr A_TwoIs oxygen Or sulfur, A₁And A_ThreeOne of them is CR_Two, The other is CR_ThreeIs) (Where R₁, R_TwoAnd R_ThreeIs independently hydrogen, halogen, CN, OR_Four, SR_Four, N (R_Four) 2, NHCOR_Four, NHCOOCH_Three, NHCOOC_TwoH_Five , NHOR_Four, NHNH_Two, NO_Two, COR_Four, COR_Five, Cyclopropyl, terminated OR_Four, N (R_Four)_Two, SR_Four, CO_TwoR_Four, CON (R_Four)_TwoOr one, two or three C optionally substituted with a halogen atom_1.5Linear alkyl, C_2-5Straight chain alkene Or C_2.5Selected from linear alkynyl. Where each R_FourIs independently hydrogen or Is C_1-3Alkyl, R_FiveIs OR_Four, NH_TwoOr NHR_Four) Or Or, Z is -C (R₇) = NR₆Group (R₆Is OR₈Group (R₈Is C_1-4Alkyl, C_{Two -Four} Alkenyl, C_2-4Alkynyl), OCOR₉Group (R₉Is hydrogen or R₈),Also Is NHR_TenOr NR₁₁R₁₂Group (R_Ten, R₁₁And R₁₂Is independently C_1-2Al Kill) and R₇Is water Elementary or C_1-4Alkyl. Where R₆Is OCOR₉Group or NHR_TenBased on In some cases, R₇Is C_1-4Alkyl)); (One of X and Y represents hydrogen, the other represents Z, and Z ′ is a group of the formula: (Q ′ is a three-membered divalent residue constituting a part of an aromatic five-membered ring, and two or three And the amino nitrogen is C_1-2Alkyl, cyclopropyl or Or substituted with a propargyl group. r represents an integer 2 or 3, and s is an integer Represents 1 or 2, and t represents 0. However, when Y is hydrogen, s is 1 There is) ); (R⁷⁵Is(P and q are each independently an integer from 2 to 4, r is an integer from 2 to 4, s represents 1 or 2, t represents 0 or 1.) Represents   R⁷⁶Is OR⁷⁸Group (R⁷⁸Is C_1-4Alkenyl, C_2-4Alkynyl), OCOR⁷⁹ Group (R⁷⁹Is hydrogen or R⁷⁸) Or NHR⁸⁰Or NR^8l, R⁸²Group (R⁸⁰, R⁸¹And R⁸²Is independently C_1-2Alkyl) and R⁷⁷Is hydrogen or C_1-4Al Kill. Where R⁷⁶Is OCOR⁷⁹Group or NHR⁸⁰If it is a group⁷⁷Is 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 of the above compound.   43. 43. Use according to claim 42, wherein the synergistic analgesic is an opioid.   44. 43. Use according to claim 42, wherein the synergistic analgesic is acetaminophen.   45. 43. Use according to claim 42, wherein the synergistic analgesic is a non-steroidal anti-inflammatory drug.   46. 43. Use according to claim 42, wherein the synergistic analgesic is an [alpha] -adrenergic compound.