CN1208349A - Composition for treating pain - Google Patents

Composition for treating pain Download PDF

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CN1208349A
CN1208349A CN96199837A CN96199837A CN1208349A CN 1208349 A CN1208349 A CN 1208349A CN 96199837 A CN96199837 A CN 96199837A CN 96199837 A CN96199837 A CN 96199837A CN 1208349 A CN1208349 A CN 1208349A
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carbon atom
alkyl
alkoxyl
hydroxyl
hydrogen
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C·H·米奇
H·E·香农
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Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

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

Description

The compositions of treatment pain
The present invention relates to use the method for several compound compositions treatment pain.
The present invention relates to provide the therapeutic combination of several chemical compounds of analgesic activities.
Always require active higher analgesic composition effect, alleviate the attractive probability in analgesic, reduce the side effect and the toxicity of the expection that causes by higher dosage thus because they provide with less dosage.Special hope obtains the synergistic combination effect.A kind of like this compositions is a theme of the present invention.
Compositions of the present invention is used the independent known several chemical compounds in this area, provides surprising collaborative effectively to treatment of pain.The synergism of this compositions provides a method of using every kind of compounds for treating pain of the smaller dose in the said composition, and the treatment with the side effect that more meets the requirements is provided thus.
The invention provides a kind of composition that can be used for treating pain, it comprises and is selected from following compound:
Figure A9619983700611
R wherein1For hydrogen, C1-C 6Alkyl or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces; R2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, comprise side chain or non-side chain with 1-6 carbon atom, this group optionally replaces with fluorine, hydroxyl or phenyl, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700621
R wherein5Expression following formula groupAny locational R of this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700623
R wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11,R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R5R is optionally used in expression6’The naphthyl that replaces, R6’The same R of definition6Definition;
Figure A9619983700631
R wherein12Expression following formula groupAny locational R of this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700633
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or this group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17,R 16And R17Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’The same R of definition13；
Figure A9619983700641
Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on one of them carbon atom on this ring24Substituting group replaces, and on each carbon atom on another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or have maximum 20 carbon atom hydro carbons and replace;R wherein28、R 29Or R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;
Figure A9619983700643
R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39 R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom,
Figure A9619983700652
Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or Wherein
R 47And R 48As above definition;
X is oxygen or sulfur;
R 44For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 45The trifluoromethyl phenyl and the R that replace 46Form a ring with the nitrogen-atoms that connects them by the following formula definition
Figure A9619983700672
R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines
Figure A9619983700681
Wherein X as above define or R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700683
R wherein 51Be selected from
Figure A9619983700691
R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkynyl group or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983700701
R wherein 53Be selected from
Figure A9619983700702
R 54, R 55, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer;
Figure A9619983700703
Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist;
Figure A9619983700721
R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from
Figure A9619983700722
Wherein
R 69Be hydrogen, and R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Wherein n ' is the integer of zero or 1-8, and R 73The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
The phenyl that replaces by following groups: the phenyl or the R of the alkyl of 1-4 carbon atom, alkoxyl, chlorine, bromine, hydroxyl, nitro replacement with the alkyl of 1-4 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 1-4 carbon atom 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700751
Wherein n ' and R 73As above definition, Wherein X as above define or
Figure A9619983700753
R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom, Wherein Z is a heterocyclic radical Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983700762
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHNH 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983700771
Wherein among X and the Y represents hydrogen, and another expression Z, and Z ' is the group of following formula
Figure A9619983700772
Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1;
Figure A9619983700773
R wherein 75Expression Wherein each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, and s represents 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be group OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane; Or its pharmaceutically acceptable salt or solvate; And be one or more synergic antalgic agent of about 1-1000 with the weight ratio of described chemical compound and synergic antalgic agent.
The invention provides the method for the treatment of pain, comprise to a kind of analgesia composition of needed patient, said composition comprises and is selected from following a kind of compound:
Figure A9619983700791
R wherein1For hydrogen, C1-C 6Alkyl or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces; R2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, include only side chain or non-side chain with 1-6 carbon atom, this group optionally replaces with fluorine, hydroxyl or phenyl, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700792
R wherein5Expression following formula group
Figure A9619983700801
Any locational R on this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700802
R wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11,R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group; Or R5R is optionally used in expression6’The naphthyl that replaces, R6’The same R of definition6Definition;R wherein12Expression following formula group
Figure A9619983700804
Any locational R of this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700811
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or described group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17,R 16And R17Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’The same R of definition13；
Figure A9619983700812
Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on one of them carbon atom on this ring24Substituting group replaces, and on each carbon atom on another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or have maximum 20 carbon atom hydro carbons and replace;R wherein28、R 29Or R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;
Figure A9619983700822
R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39
Figure A9619983700823
R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom,
Figure A9619983700831
Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or
Figure A9619983700832
Wherein
R 47And R 48As above definition;
X is oxygen or sulfur; R 44For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or
Figure A9619983700841
Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 45The trifluoromethyl phenyl and the R that replace 46Form a ring with the nitrogen-atoms that connects them by the following formula definition R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines
Figure A9619983700852
Wherein X as above define or
Figure A9619983700853
R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700861
R wherein 51Be selected from R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkenyl or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983700871
R wherein 53Be selected from
Figure A9619983700872
R 54, R 53, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer;
Figure A9619983700881
Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from
Figure A9619983700891
R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist;
Figure A9619983700901
R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from Wherein
R 69Be hydrogen, and R 67Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700911
Wherein n ' is the integer of zero or 1-8, and R 73The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700931
Wherein n ' and R 73As above definition,
Figure A9619983700932
Wherein X as above define or
Figure A9619983700933
R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700934
Wherein Z is a heterocyclic radical
Figure A9619983700941
Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983700942
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHN 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983700951
Wherein among X and the Y represents hydrogen, and another expression Z, Z ' is the group of following formula
Figure A9619983700952
Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1; R wherein 75Expression
Figure A9619983700961
Wherein
Each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, and s represents 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane; Or its pharmaceutically acceptable salt or solvate; And be one or more synergic antalgic agent of about 1-1000 with the weight ratio of described chemical compound and synergic antalgic agent.
As mentioned above, it is known being used for chemical compound of the present invention.In United States Patent (USP) 4,923,880,5,110,828,5,041,436,5,278,170,7,177,084,4,992,436,5,260,293,4,996,201,5,066,662,5,066,665,5,066,663,4,988,688,5,106,853,5,192,765,5,041,455,5,043,345,5,260,314,5,310,911,5,106,851,5,068,237,5,318,978,5,242,927,5,300,516,5,089,505,5,302,595,5,219,871,5,096,890,5,164,386,5,164,514,5,157,160,5, these chemical compounds have been introduced in 217,975 and 5,081,130, the pharmaceutical formulation for preparing the method for these chemical compounds and contain these chemical compounds, these patents are attached to herein by reference.
Should be appreciated that the present invention comprises the purposes of the racemic form of every kind of stereoisomeric forms in any ratio of The compounds of this invention and pure diastereomer, pure enantiomer and described chemical compound.
Term used herein " a kind of synergic antalgic agent " and " multiple synergic antalgic agent " are meant a class analgesics of being made up of non-steroidal anti-inflammatory drugs (NSAIDS), acetaminophen, alpha-adrenergic chemical compound and opioid.
" a kind of selected muscarine compound " used herein and " multiple selected muscarine compound " refer to be selected from following a kind of compound
Figure A9619983700971
R wherein1For hydrogen, C1-C 6Alkyl or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces; R2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, include only side chain or non-side chain with 1-6 carbon atom, this group optionally replaces with fluorine, hydroxyl or phenyl, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700981
R wherein5Expression following formula group
Figure A9619983700982
Any locational R of this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700983
R wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11,R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group; Or R5R is optionally used in expression6’The naphthyl that replaces, R6’Definition with above R6Definition;
Figure A9619983700991
R wherein12Expression following formula group
Figure A9619983700992
Any locational R on this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700993
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or described group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17,R 16And R17Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’Definition with above R13； Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on a carbon atom on this ring24Substituting group replaces, and on each carbon atom on another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or the hydro carbons with maximum 20 carbon atoms replace;
Figure A9619983701002
R wherein28、R 29Or R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;
Figure A9619983701003
R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39 R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom,
Figure A9619983701012
Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or
Figure A9619983701021
Wherein
R 47And R 48As above definition;
X is oxygen or sulfur;
R 44For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or
Figure A9619983701031
Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 45The trifluoromethyl phenyl and the R that replace 46Form a ring with the nitrogen-atoms that connects them by the following formula definition
Figure A9619983701032
R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines
Figure A9619983701041
Wherein X as above define or
Figure A9619983701042
R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom, R wherein 51Be selected from
Figure A9619983701051
R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkenyl or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983701061
R wherein 53Be selected from
Figure A9619983701062
R 54, R 55, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer;
Figure A9619983701063
Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from
Figure A9619983701071
R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist;
Figure A9619983701081
R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from
Figure A9619983701082
Wherein
R 69Be hydrogen, and R 67Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983701091
Wherein n ' is the integer of zero or 1-8, and R 73The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next
Figure A9619983701101
Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983701111
Wherein n ' and R 73As above definition,
Figure A9619983701112
Wherein X as above define or
Figure A9619983701113
R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom, Wherein Z is a heterocyclic radical
Figure A9619983701121
Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983701122
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHNH 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983701131
Wherein among X and the Y represents hydrogen, and another expression Z, and Z ' is the group of following formula
Figure A9619983701132
Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1; R wherein 75Expression
Figure A9619983701141
Wherein
Each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, and s represents 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane; Or its pharmaceutically acceptable salt or solvate.
" low lipotropy " speech be meant hydrogen, halogen ,-CF 3,-OR 25,-NR 25R 26,-NHOR 25,-NHNH 2,-CN ,-COR 8Or replace or do not replace, saturated or unsaturated alkyl, wherein R 25Be hydrogen, C 1-6Alkyl, C 2-6Alkenyl or C 2-6Alkynyl group, R 26For hydrogen, alkyl or-COCH 3, and R 27Expression-OR 25Or-NR 25R 26
Term azacyclo-or azabicyclo system are meant and contain a nitrogen as unique heteroatomic non-aromatic ring system.This loop systems contains 4-10 annular atoms suitably, preferably contains 5-8 annular atoms.This loop systems preferably contains uncle's amino nitrogen atom in cage structure.Bicyclic system can be condensed, volution or bridge connected.This nitrogen-atoms is preferably in the end of the bridge in the bicyclic system.The heteroatomic example of this class comprises United States Patent (USP) 5,260, the hetero atom of describing in the 293 2-3 hurdles, and this patent is attached to herein by reference.
Term " ' 927 azacyclo-s or ' 927 azabicyclos " be meant and contain a nitrogen-atoms as unique heteroatomic non-aromatic ring system.This ring suitably contains 4-10 annular atoms, preferably contains 5-8 annular atoms.These bicyclic systems can be condensed, volution or bridge connected.The heteroatomic example of this class comprises United States Patent (USP) 5,242, the hetero atom of describing in 927 the 2nd hurdles, and this patent is attached to herein by reference.Most preferred ' 927 azacyclo-system or ' 927 azabicyclo system comprise pyrrolidine, 1,2,5, and 6-tetrahydropyridine, quinuclidine or 1-azabicyclo [2.2.1] heptane ring can randomly replace with methyl or hydroxyl.Particularly preferred ' 927 azacyclo-system is the quinuclidine that is replaced by hydrogen, methyl or hydroxyl on any available atom.
The group that is converted into amino in vivo on the chemical compound that is used for the treatment of pain that this paper is claimed; can be by this chemical compound to be given and the mankind or animal, the existence that has amino substituent respective compound by the conventional analysis technology for detection in human or animal's urine is determined.This class examples of groups comprises that hydrolyzable is for amino group, such as acylamino-, urethane substituent group in the body.Specifically, wherein Q represents CHO, COR 33Or CO 2R 33Formula-NHQ group and R 33Expression can be chosen the alkyl of replacement wantonly.Alkyl one speech comprise have 20 carbon atoms of as many as, the group of 10 carbon atoms of as many as, 8 carbon atoms of conventional as many as suitably.Suitable alkyl comprises C 1-8Alkyl, C 2-8Alkenyl, C 2-8Alkynyl group, C 3-7Cycloalkyl, C 3-7Cycloalkyl-C 1-6Alkyl, aryl and aryl-C 1-6Alkyl.
Suitable R 34Group comprises following group:
Figure A9619983701161
Its line that breaks is represented optional chemical bond; R 41And R 42May reside in any position, comprise the point that is connected with phenyl ring, and be hydrogen, C independently 1-4Alkyl, F, Br, Cl, C 1-4Alkoxyl, hydroxyl, carboxyl or C 1-4Carbalkoxy, or R 41And R 42Represent carbonyl together.This nitrogen-atoms can be by hydrogen or C 1-4Alkyl replaces.
Term " phenyl-C 1-4Alkyl " be appointed as the alkyl that replaces with phenyl.Preferred phenyl-alkyl comprises benzyl, 1-and 2-phenethyl, 1-, 2-, 3-phenylpropyl and 1-methyl isophthalic acid-phenethyl.This phenyl can randomly replace with 1-3 independent selected described substituent group.
Term " forms a heterocyclic radical with the nitrogen-atoms that connects them " and is meant the heterocyclic radical that can randomly contain another hetero atom (for example S or O).This class group includes but not limited to piperidyl, piperazinyl, morpholinyl and pyrrolidinyl.
Term " alkyl " is meant the carbon atom of designation number; Yet when unqualified numerical value, this term is meant C 1-6Alkyl.This alkyl can be linearity or side chain, unless specify.
" halogen " speech is meant chlorine, bromine and fluoro substituents.
Term " alkynyl group " has its acceptable implication; Yet if there is not the particular carbon atomic number, it is meant C so 2-10Alkynyl group.This alkynyl group can be linearity or side chain, unless concrete the appointment.
The term alkoxyl is meant C 1-4Unless alkoxyl is concrete the appointment.
Term used herein " analgesic dose " is illustrated in after being subject to pain or suffering people's administration of pain prevention or treats the amount of essential chemical compound.Reactive compound is effective in very wide dosage range.For example, the dosage of every day is generally in the scope of about 0.005-500mg/kg body weight.In adult's treatment, be preferably the scope of about 0.05-100mg/kg body weight in single dose or the fractionated dose.Yet, should be appreciated that, the actual dosage of this chemical compound will be determined according to correlation circumstance by the attending doctor, these situations comprise the state of an illness to be treated, treat to the selection of chemical compound, each patient's age, body weight and reaction, the seriousness of patient symptom and the selection of route of administration, therefore above-mentioned dosage range never limits the scope of the invention.Although The compounds of this invention is preferably given people with easy anxiety or anxiety attack with oral form, these chemical compounds also can pass through multiple other administration, such as percutaneous, parenteral, subcutaneous, intranasal, intramuscular and intravenous route administration.Can design this class preparation, postpone to discharge or controlled release to adopt preparation technique known in the art to provide.
The non-steroidal anti-inflammatory drugs that term used herein " NSAIDS " expression can be identified by the technical staff.For example, MerckManual, the 16th edition, Merck research laboratory (1990) 1308-1309 pages or leaves provide the example of the NSAIDS that knows.This term will include but not limited to Salicylate, such as aspirin, indometacin, ibuprofen, naproxen, fenoprofen, TOL, sulindac, Meclofenamate, keoprofen, piroxicam, flurbiprofen and diclofenac.There is preferred NSAIDS to comprise aspirin, ibuprofen and naproxen especially.It is optional that to select preferred NSAIDS be indometacin, ibuprofen, naproxen, fenoprofen, TOL, sulindac, Meclofenamate, keoprofen, piroxicam, flurbiprofen and diclofenac.Particularly preferred NSAIDS comprises aspirin and ibuprofen.Salicylate can comprise aspirin, Aspirin sodium, tylcalsin, salicylic acid and sodium salicylate.Particularly preferred NSAIDS is an ibuprofen.
Term used herein " acetaminophen " has the implication that this area is accepted, and is meant N-(4-hydroxyphenyl) acetamide and 4 '-hydroxy-n-acetanilide.This chemical compound is at United States Patent (USP) 2,998, and is claimed in 450, is known to the skilled.
Term used herein " maincenter alpha-adrenergic reactive compound " expression has the active chemical compound of maincenter alpha-adrenergic receptor.Most preferred maincenter alpha-adrenergic reactive compound is that chemical name is clonidine or its pharmaceutically acceptable salt of 2-(2,6-dichloro-benzenes amino)-2-imidazoline.
Clonidine is known to can be used for treating hypertension.Referring to Physician ' Desk Reference, the 45th edition, (1991) the 673rd pages.
Term used herein " opioid " expression opioid analgesics and antagonist comprise natural opioid analgesics, synthetic opioid analgesics, opioid antagonists and opioid agonist-antagonist.Preferred opioid chemical compound is selected from morphine, codeine, pethidine, methadone, the third oxygen sweet smell, levorphan, Dilauid, Numorphan, dihydrohydroxycodeinone, bromptonShi mixture, naloxone, naltrexone, pentazocine, butorphanol, nalbuphine (nabuphine) and uncle's fourth coffee.Preferred opioid chemical compound is selected from codeine, nalbuphine, naloxone and naltrexone.
Preferred opioid chemical compound is morphine, codeine, pethidine, methadone, the third oxygen sweet smell, levorphanol, hydromorphone, Numorphan, dihydrohydroxycodeinone, bromptonShi mixture, naloxone, naltrexone, pentazocine, butorphanol, nalbuphine and uncle's fourth coffee.
Especially preferred opioid chemical compound is selected from hydromorphone, hydrocodone, pethidine, buprenorphine, butorphanol, nalbuphine, pentazocine, Numorphan, dihydrohydroxycodeinone, levorphan, fentanyl and anadol.
Particularly preferred opioid chemical compound is selected from the third oxygen sweet smell, methadone, morphine, dihydrocodeinone, paramorphane and codeine.Especially particularly preferred opioid chemical compound is selected from morphine and codeine.
Phrase used herein " one or more " most preferably is meant a kind of; Yet can use two kinds, three kinds or multiple.
We have found that one group of chemical compound with muscarine cholinergic activity is when being used in particular for treating pain when being used in combination with non-steroidal anti-inflammatory agents (NSAIDS).More particularly, the invention provides and adopt specific known compound (this paper is referred to as " selected muscarine chemical compound ") to combine, treat the method for human pain with synergistic NSAIDS is provided.Selected muscarine chemical compound it is believed that on mAChR it is activated; Yet the present invention is never by the restriction of this mechanism of action.
Known in the literature have many NSAIDS, and be known to the technical staff.
We have found that one group of chemical compound with muscarine cholinergic activity can be used in particular for treating pain when being used in combination with acetaminophen.More particularly, the invention provides the selected especially muscarine chemical compound of employing and combine, treat the method for human pain with synergistic acetaminophen is provided.
In addition, we have found that one group of chemical compound with muscarine cholinergic activity can be used in particular for treating pain when being used in combination with some maincenter alpha-adrenergic reactive compound.More particularly, the invention provides the selected especially muscarine chemical compound of employing provides synergistic maincenter alpha-adrenergic reactive compound to combine with a kind of, treats the method for human pain.
The known analgesic activity that increase is provided in the mankind of the Orally administered composition of aspirin and codeine or other narcotic analgesics.The Parmaco1ogical Basis of Therpeutics, the 5th edition, Macmillan publishing company, 1975, the 325-358 pages or leaves.
The present invention also provides anticipation, and one or more selected muscarine chemical compounds can use for 1 time in the present composition, so that required analgesic activity to be provided.
In compositions of the present invention, selected muscarine chemical compound and NSAIDS chemical compound mix with the weight ratio of NSAIDS with the described chemical compound of 1-1000.
The described chemical compound of preferred composition and the weight ratio of NSAIDS are about 1-100.Particularly preferred ratio can be about 1-30.Preferred ratio can be about 1-10.Final preferred ratio can be about 1-3.
In compositions of the present invention, selected muscarine chemical compound and acetaminophen mix with the weight ratio of acetaminophen with the chemical compound of 1-1000.
The selected muscarine chemical compound of preferred composition and the weight ratio of acetaminophen are about 1-100.Particularly preferred ratio can be about 1-30.Preferred ratio can be about 1-10.Final preferred ratio can be about 1-3.
Selected muscarine chemical compound is effective in very wide dosage range; Yet, preferably give and alap dosage.Amount by NSAIDS in the rate regulation said composition of above-mentioned and selected muscarine chemical compound dosage.Amount by acetaminophen in the rate regulation said composition of above-mentioned and selected muscarine chemical compound dosage.
In compositions of the present invention, selected muscarine chemical compound and one or more opioid chemical compounds mix with the weight ratio of opioid chemical compound with the chemical compound of about 1-1000.
The described chemical compound of preferred composition and the weight ratio of opioid chemical compound are about 1-100.Particularly preferred ratio can be about 1-30.Preferred ratio can be about 1-10.Final preferred ratio can be about 1-3.
Amount by opioid chemical compound in the rate regulation said composition of above-mentioned and selected muscarine chemical compound dosage.
Yet; for the claimed every kind of compositions of this paper; should be appreciated that; the actual dosage of selected muscarine chemical compound can will be determined according to correlation circumstance by the attending doctor; these situations comprise the state of an illness to be treated, treat to the selection of selected muscarine chemical compound, each patient's age, body weight and reaction, the seriousness of patient symptom and the selection of route of administration, therefore above-mentioned dosage range never limits the scope of the invention.Although it is responsive or stand the human oral of pain with pain that The compounds of this invention is preferably given with oral form, these chemical compounds also can pass through multiple other administration, such as percutaneous, parenteral, subcutaneous, intranasal, intramuscular and intravenous route administration.Can design this class preparation, postpone to discharge or controlled release to adopt preparation technique known in the art to provide.
The percutaneous preparation that contains the claimed compositions of this paper most preferably discharges the active substance of about 3-7 days effective dose.Yet,, wish that percutaneous discharges about 3 days about at the most 2 weeks about the chronic pain of arthritis or cancer pain and so on.Perhaps, preferably percutaneous discharges the claimed compositions of about 1-3 days effective dose.
Term used herein " treatment " comprises prevention body illness and/or mental sickness, in case or this disease established the development that alleviates or eliminate body illness and/or mental sickness, or alleviate the characteristic symptom of this class disease.
The selected muscarine chemical compound that is used for the present invention is believed what the GABA/ benzazepines, 5HT1A or the D1 receptor system that are not by human body worked.But, believe that the selected muscarine chemical compound of the present invention is as the adjusting based on mAChR of the activity of analgesics.Yet the mechanism that this chemical compound works needs not to be above-mentioned mechanism, and the present invention is not subjected to the restriction of any binding mode.
The example of pharmaceutically acceptable salt comprises inorganic and organic addition salts, such as hydrochlorate.Hydrobromate, sulfate, phosphate, acetate, fumarate, maleate, citrate, lactate, food and drink hydrochlorate, oxalates or similar pharmaceutically acceptable inorganic or organic acid addition salt, comprise Journal of Pharnaceutical Science, 66, listed pharmaceutically acceptable salt in 2 (1977), these are known to the skilled.The compounds of this invention can adopt method known to the skilled, forms solvate with the standard low molecular weight solvent.
Route of administration can be any approach, it is transported to this reactive compound suitable or required site of action effectively, these approach are such as oral or parenteral, for example rectum, percutaneous, storage (depot), subcutaneous, intravenous, intramuscular or intranasal administration, preferably oral route.
Certainly, dosage is with known factors vary, the pharmacodynamic profile of these factors such as particular agent and mode of administration and route of administration; The age of receptor, health and body weight; The nature and extent of symptom, the type of simultaneous treatment, therapeutic frequency and required effect.Daily dose usually can be so that the administration daily dose of this active component be the selected muscarine chemical compound of about 0.2-100mg/kg body weight and the NSAIDS of about 0.6-200mg/kg body weight.
The compositions per unit that is applicable to inner administration contains about half (0.5) milligram to 600 milligrams of active components.In these pharmaceutical compositions, the common amount of this active component is about 0.5-95% (weight) of said composition total amount.
About containing the compositions of acetaminophen, this daily dose usually can be so that the administration daily dose of this active component be the selected muscarine chemical compound of about 0.2-500mg/kg body weight and the acetaminophen of about 0.6-200mg/kg body weight.
Typical compositions comprises a kind of chemical compound and one or more NSAIDS and the pharmaceutically acceptable excipient of selected muscarine chemical compound, the latter can be a kind of carrier or diluent or with the carrier dilution, or to be encapsulated in can be in the carrier of capsule, sachet, paper or other container.In these preparation of compositions, can use the routine techniques of pharmaceutical compositions.For example, this reactive compound mixes with a kind of carrier usually, or by the dilution of a kind of carrier, or to be encapsulated in can be in the carrier of ampoule, capsule, sachet, paper or other container.When this carrier was used as diluent, it can be solid, semisolid or liquid substance as carrier, excipient or this reactive compound medium.This reactive compound can be adsorbed on the granular solids container of sachet for example.Some examples of suitable carrier are water, saline solution, alcohol, Polyethylene Glycol, polyhydroxy ethoxylation Semen Ricini oil, gelatin, lactose, amylopectin, magnesium stearate, Talcum, silicic acid, glycerine monofatty ester and diglyceride, pentaerythritol fatty ester, hydroxy methocel and polyvinylpyrrolidone.These preparations also can comprise wetting agent, emulsifying agent and suspending agent, antiseptic, correctives or flavoring agent.Can prepare preparation of the present invention, so as to be provided at by adopt method well known in the art give with patient after, the rapid release of this active component, discharge or slow release lastingly.
Typical compositions comprises selected muscarine chemical compound and acetaminophen and pharmaceutically acceptable excipient, the latter can be a kind of carrier or diluent or with the carrier dilution, or to be encapsulated in can be in the carrier of capsule, sachet, paper or other container.In these preparation of compositions, can use the routine techniques of above-mentioned pharmaceutical compositions.
The selected muscarine chemical compound of preferred composition and the weight ratio of maincenter alpha-adrenergic reactive compound are about 1-100.Particularly preferred ratio is 1-30 approximately.Preferred ratio can be about 1-10.Final preferred ratio can be about 1-3.
Selected muscarine chemical compound is effective in very wide dosage range; Yet, preferably give and alap dosage.Amount by maincenter alpha-adrenergic reactive compound in the rate regulation said composition of above-mentioned and selected muscarine chemical compound dosage.
This daily dose usually can be so that the administration daily dose of this active component be the selected muscarine chemical compound of about 0.2-500mg/kg body weight and the maincenter alpha-adrenergic reactive compound of about 0.6-200mg/kg body weight.
Typical compositions comprises a kind of chemical compound and one or more maincenter alpha-adrenergic chemical compounds and the pharmaceutically acceptable excipient of selected muscarine chemical compound, the latter can be a kind of carrier or diluent or with the carrier dilution, or to be encapsulated in can be in the carrier of capsule, sachet, paper or other container.In these preparation of compositions, can use the routine techniques of pharmaceutical compositions.
Pharmaceutical preparation can be sterilized, when needing can with can not mix with adjuvant, emulsifying agent, the salt that influences osmotic pressure, buffer and/or the coloring material etc. that reaction nocuously takes place reactive compound.
About parenteral application, particularly suitable is injection or suspension, preferably has the aqueous solution that is dissolved in this reactive compound in the polyhydroxylated Semen Ricini oil.
Tablet, dragee or capsule with Talcum and/or carbohydrate carrier or binding agent etc. are particularly suitable for oral.Be preferred for tablet, dragee or capsular carrier comprise lactose, corn starch and/potato starch.Syrup or elixir can be used, the flavoring carrier can be used in these cases.
Put it briefly, the present composition is made into the unit form that per unit dosage in pharmaceutically acceptable carrier comprises about 0.1-300mg.
The present composition go for to animal.This class animal comprises performing animal, for example domestic animal, laboratory animal and house pet; With non-performing animal, such as wild animal.This animal is vertebrates more preferably.The present composition is most preferably given and mammal.Preferred especially this animal is for taming the mammal or the mankind.Most preferred mammal is human.For this class performing animal, the present composition can be used as feed additive give with.
With drag with analyze the effectiveness of the compositions can be used to illustrate that this paper is claimed.The neuralgia model:
The inductive body of turning round of acetic acid: be used to detect and more dissimilar analgesic analgesic activities and with human analgesic activities the standard method of fine dependency to be arranged be to prevent the inductive body of turning round of mice acetic acid.Give the claimed compositions of mouse subcutaneous injection various dose, peritoneal injection acetic acid of preceding 5 minutes of specified observation period (0.5% solution, 10ml/kg).In order to score, " turning round body " is appointed as whole body distortion or abdominal part contraction in the observation period that 5 minutes begin after accepting acetic acid.Turn round the inhibition proof analgesic activities of body behavior.
Referring to Haubrich, D.R., Ward, S.J., Baizman., E., Bell., M.R., Bradford, J., Ferrari., R., Miller, M., Perrone, M., Pierson, A.K., Saelens, J.K. and Luttinger, the pharmacology of D.:pravadoline: a kind of new analgesics.The?Journal?ofPharmaco1ogy?and?Experinental?Therapeutics?255(1990)511-522。The neuralgia model:
Sciatic nerve ligation model:, carry out neural ligation step with rat anesthesia.Expose the sciatic nerve trunk, 4 root knot binding looselys tie up to around it, at interval 1mm.In operation back 1-10 week, carry out the nociception test.Have the indoor of clear glass floor by rat is placed, and this underfloor radiant heat source is aimed at influenced sufficient plantar surface, measure reaction harmful heat.The preclinical increase proof analgesic activities of withdrawal rear solid end.Have the indoor of screen cloth floor by rat is placed, and use by the gram number that makes the crooked required power of hair and calibrate of the stimulation of the vonFrey hair of generation, measure reaction harmless usually mechanical stimulus to the plantar surface of rear solid end.Rat with sciatic nerve ligation is by the reflexive ground foot that contracts, and the gram number of mechanical stimulus reaction is lower than the rat of being performed the operation.This reaction to harmless usually stimulation is called allodynia.Generation is contracted enough, and the increase of the gram number of required power proves anti-allodynic activity.Referring to Bennett, G.J. and Xie, Y.-K.A peripheral mononeuropathy in rat thatproduces disorders of pain sensation like those seen in man.Pain 33 (1988) 87-107.Also referring to Lee, Y.-W., Chaplan, S.R. and Yaksh, T.L.:Systemic andsupraspinal, but not spinal, opiates suppress allodynia in a rat neuopathicpain mode.Neuroci Lett 186 (1995) 111-114.
Formalin paw test:, when the forfeiture autonomic movement, carry on the back surperficial subcutaneous injection 50 μ l 5% formalin solution at rat hind paw with 30 label syringe needles with rat anesthesia.Then rat being placed respectively that open Plexiglas is indoor to be observed, is in 1-2 minute at largest interval, and this animal shows spontaneous activity and normal motor function, recovery from anesthesia.By the occurrence number of spontaneous shrinking back/shake injection pawl is periodically counted the behavior of quantitative assay pain.10-60 minute interim, with the interval of 1-2 minute, 5-6 minute and 5 minutes, to the counting of shrinking back and carrying out 1 minute.The inhibition proof analgesic activities of pain behavior.
Referring to Malmberg, A.B. and Yaksh, T.L.: non-steroidal anti-inflammatory agents is to the spinal column antinociceptive activity of rat gate-Papacostas' tests.The?Journal?of?Pharmacology?andExperimental?Therapeutics?263(1992)136-146。The inflammatory pain model:
The inductive hyperpathia of BrewerShi yeast (Randall-Selitto test):, gradually this pawl is applied the pressure of increase with the weight of Ugo Basile analgesia meter motor driving in order to estimate the nociception threshold of rat.Rat by or be pulled away from a device, struggle or sound, as reaction to this pressure.By at 1% suspension of rear solid end foot injection 0.1ml brewer yeast in 0.9% saline, induce hyperpathia.Behind injection brewerShi yeast, give and the present composition, again with the pressure threshold of the timing inflammation pawl that changes with the time (0-4 hour) that changes.Produce the increase proof analgesic activities of the pressure of behavior reaction.
Referring to Haubrich, D.R., Ward, S.J., Baizman, E., Bell, M.R., Bradford, J., Ferrari, R., Miller, M., Perrone, M., Pierson, A.K., Saelens, J.K. and Luttinger, the pharmacology of D.:pravadoline: a kind of new analgesics.The?Journal?ofPharmacology?and?Experimental?Therapeutics?255(1990)511-522。
The practicality test method
Analgesic activities by the initial evidence present composition that carries out on mice unexpectedly increases.With male mice fasting 16-22 hour, weigh then.The mice of heavy 18-22 gram is used for following research during test.All mice by oral route are taken a kind of suspension of the present composition continuously.Adopt the coding of observer's the unknown, dosage is encoded.
By this active component is mixed with the water-soluble matchmaker of 40ml of containing about 2%Tween 80 (R), pharmacology's dispersant and contain 100% PS and 1% (weight) Methocel (R) MC powder and contain 100% methylcellulose in distilled water, prepare the suspension of stocking of subject composition.This mixture can be used the about 10-15 of ultrasonic system supersound process second.By this stocks suspension with Methocel/Tween 80 dilutions, prepare all administration suspensions.All suspensions are preparing use in 2 hours.
The mouse writhing test
Be used to detect and more dissimilar analgesic analgesic activities and with human analgesic activities the acceptable standard method of fine dependency to be arranged be to prevent the inductive body of turning round of mice phenyl-1,4-benzoquinone.[H.Blumberg etc., Proc.Soc.Exp.Biol.Med., 118,763-766 (1965)].
With the selected muscarine compound treatment mice of various dosage, specifying preceding 5 minutes of observation period, peritoneal injection has the compositions or the solvent of the phenyl-1,4-benzoquinone of standard-required dosage.Preparation about 0.1mg/ml phenyl-1,4-benzoquinone solution in containing the alcoholic acid water of about 5% (volume).Turn round body dosage and be 1.25mg/kg with about 0.25ml/10g volume injection.In order to score, " turning round body " is appointed as whole body distortion or abdominal part contraction in the observation period that 5 minutes begin after accepting phenyl-1,4-benzoquinone.
Adopt acceptable digital method, determine all ED 50Value and 95% confidence limit thereof.For example referring to W.F.Thompson, Bacteriological Rev., 11,115-145 (1947).Confirm of the interaction of these dosage by Loewe isobologram (S.Loewe, Pharm.Rev.9,237-242 (1957)) to the inductive mouse writhing of phenyl-1,4-benzoquinone.
The solid line of the synergic antalgic agent (separately) that the ED50 dosage of the selected muscarine chemical compound (separately) of connection and this paper are claimed is represented " ED 50The phase ledger line ", if simple addition will be described their compound action, it shows the ED of selected muscarine chemical compound and traditional analgesic composition so 50Desired location.This ED 5095% confidence limit of phase ledger line is by on the dotted line and the cartographic represenation of area between under the ED50 phase ledger line.
According to the isobolic theory of Loewed, if analgesic activity is addition each other simply, the so selected muscarine chemical compound of every kind of fixed dosage ratio and the ED of synergic antalgic component 50Desired location will be included in this ED 50Phase ledger line scope is interior or overlapping with it.Obviously be positioned at this ED 50The ED of the compositions under the phase ledger line 50To represent unexpected enhanced analgesic activities, and be positioned at the compositions ED on this line 50The unexpected analgesic activities that reduces of expression.
Establishing this unexpected method that strengthens the active significance that reduces with accident is employing standard mathematical method, calculates the ED to observing 50The best fit of polynomial regression line.
This class experiment showed, that these compositionss of being made up of selected muscarine chemical compound and one or more synergic antalgic agent provide statistics significant synergic antalgic effect.
The chemical compound that is preferred for treating pain comprises:
(3R, 4R)-chemical compound or their pharmaceutically acceptable salt or the solvate of 3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane and formula IV, V, VIII, IX, X III, X IV and X V.
Particularly preferred chemical compound comprises following chemical compound:
The chemical compound of formula X III, X IV and X V.
The example of preferred compound includes, but is not limited to 3-[2-(6-hydroxyl pyrazine) base]-1-azabicyclo [2.2.2] octane; 3-(2-pyrazinyl)-1-azabicyclo [2.2.1] heptane; 6-(2-pyrazinyl)-1-azabicyclo [3.2.1] octane; 6-(2-pyrazinyl)-1-azabicyclo [3.2.1] suffering-6-alcohol; 3-fluoro-3-(2-pyrazinyl)-1-azabicyclo [2.2.1] heptane; 1-methyl-3-(2-pyrazinyl) pyrrolidine; 3-[2-(3-methylpyrazine)-yl]-1-azabicyclo [2.2.2] suffering-3-alcohol; 3-[2-(3; the 6-dimethyl pyrazine) base]-1-azabicyclo [2.2.1] heptane; 3-[2-(6-allyloxy pyrazine)-yl]-1-azabicyclo [2.2.1] heptane; 3-[2-(6-methoxypyrazine)-yl]-1-azabicyclo [2.2.2] octane; 3-[2-(6-chloropyrazine)-yl]-1; 2; 5; the 6-tetrahydropyridine; 3-[5-(3-monooctyl ester base amino-1; 2; the 4-oxadiazole)-yl]-1-azabicyclo [2.2.1] heptane; 3-[5-(3-cyclohexyl-carbonyl amino-1; 2; the 3-oxadiazole)-and yl] quinuclidine; 3-[5-(3-(1-(3-n-pentyl ester base)-1-ethoxycarbonyl amino)-1; 2; the 4-oxadiazole)-and yl] quinuclidine; 3-[5-(3-caprylyl amino-1; 2; the 4-oxadiazole)-and yl] quinuclidine; 3-[(1-methyl isophthalic acid H-imidazoles-5-yl)-and methyl]-1; 2; 4-oxadiazole-5 (4H)-ketone; 4-methyl-3-[(1-methyl isophthalic acid H-imidazol-4 yl)-and methyl]-1; 2; 4-oxadiazole-5 (4H)-ketone; 4-ethyl-3-[(1-methyl isophthalic acid H-imidazol-4 yl)-and methyl]-1; 2; 4-oxadiazole-5 (4H)-ketone; N-[4-(hexahydro-1 H-azepines (azaepiny)-1-yl)-2-butyne base]-N; the N-dimethyl urea; the N-[4-pyrrolidinyl)-the 2-butyne base]-urea; 5-acetyl group-1-azabicyclo [3.1.1] heptane; 1-azabicyclo [3.1.1] heptane-5-formaldehyde; 3-(2-methyl tetrazolium-5-yl)-1-azabicyclo [2.2.1] heptane; 3-(2-methyl isophthalic acid; 2; 3-triazole-4-yl)-1-azabicyclo [2.2.2] octane; 3-(3-cyclopropyl-1; 2,3-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane and their pharmaceutically acceptable salts or solvate

Claims (46)

1. compositions for the treatment of pain, what comprise the analgesic dose a kind ofly is selected from following chemical compound:
Figure A9619983700021
R wherein 1Be hydrogen, C 1-C 6Alkyl or phenyl-C 1-C 4Alkyl, wherein this phenyl can be used halogen, C 1-C 4Alkyl or C 1-C 4Alkoxyl replaces;
R 2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, comprise side chain or non-side chain with 1-6 carbon atom, this group optionally replaces with fluorine, hydroxyl or phenyl, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700022
R wherein5Represent following groupAny locational R of this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following groupR wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11,R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group; Or R5R is optionally used in expression6’The naphthyl that replaces, R6’Definition with above R6Definition;
Figure A9619983700033
R wherein12Represent following group
Figure A9619983700034
Any locational R of this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700041
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or described group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17，R 16And R17Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’Definition with above R13； Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on a carbon atom on this ring24Substituting group replaces, and on each carbon atom on another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or have maximum 20 carbon atom hydro carbons and replace;R wherein28、R 29And R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39
Figure A9619983700053
R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom,
Figure A9619983700061
Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or Wherein
R 47And R 48As above definition;
X is oxygen or sulfur; R 44For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or
Figure A9619983700071
Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 45The trifluoromethyl phenyl and the R that replace 46Form the ring that a following formula defines with the nitrogen-atoms that connects them
Figure A9619983700081
R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines
Figure A9619983700082
Wherein X as above define or
Figure A9619983700083
R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700091
R wherein 51Be selected from
Figure A9619983700092
R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkynyl group or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983700101
R wherein 53Be selected from
Figure A9619983700102
R 54, R 55, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer; Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from
Figure A9619983700121
R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist; R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from
Figure A9619983700132
Wherein
R 69Be hydrogen, and R 67Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700141
Wherein n ' is the integer of zero or 1-8, and R 73The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next
Figure A9619983700151
Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
The phenyl or the R of the alkyl of 1-4 the carbon atom that replaces with the alkyl of 1-4 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkoxyl of a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700161
Wherein n ' and R 73As above definition,
Figure A9619983700162
Wherein X as above define or R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700164
Wherein Z is a heterocyclic radical
Figure A9619983700171
Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983700172
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHNH 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983700181
Wherein among X and the Y represents hydrogen, and another expression Z, and Z ' is the group of following formula Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1; R wherein 75Expression
Figure A9619983700191
Wherein
Each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, and s represents 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane; Or its pharmaceutically acceptable salt or solvate; And be one or more synergic antalgic agent of about 1-1000 with the weight ratio of described chemical compound and synergic antalgic agent.
2. the compositions claimed as claim 1, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
3. the compositions claimed as claim 1, wherein this synergic antalgic agent is a non-steroidal anti-inflammatory drugs.
4. the compositions claimed as claim 3, wherein this non-steroidal anti-inflammatory drugs is selected from indometacin, ibuprofen, naproxen, fenoprofen, TOL, sulindac, Meclofenamate, keoprofen, piroxicam, flurbiprofen and diclofenac.
5. the compositions claimed as claim 3, wherein this non-steroidal anti-inflammatory drugs is an ibuprofen.
6. the compositions claimed as claim 3, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
7. the compositions claimed as claim 1, wherein this synergic antalgic agent is an opioid.
8. the compositions claimed as claim 7, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
9. the compositions claimed as claim 8, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
10. the compositions claimed as claim 8, wherein this opioid is selected from morphine, codeine, pethidine, methadone, the third oxygen sweet smell, levorphan, Dilauid, Numorphan, dihydrohydroxycodeinone, bromptonShi mixture, naloxone, naltrexone, pentazocine, butorphanol, nalbuphine and uncle's fourth coffee.
11. the compositions claimed as claim 8, wherein this opioid is selected from Dilauid, dihydrocodeinone, pethidine, uncle's fourth coffee, butorphanol, nalbuphine, pentazocine, Numorphan Oral, dihydrohydroxycodeinone, levorphan, fentanyl and anadol.
12. the compositions claimed as claim 8, wherein this opioid is selected from the third oxygen sweet smell, methadone, dihydrocodeinone, paramorphane and codeine.
13. the compositions claimed as claim 1, wherein this chemical compound is selected from formula I, II and III chemical compound or their pharmaceutically acceptable salt or solvate.
14. the compositions claimed as claim 1, wherein this chemical compound is selected from formula X IV and X V chemical compound or their pharmaceutically acceptable salt or solvate.
15. the compositions claimed as claim 14, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
16. the compositions claimed as claim 1, wherein this synergic antalgic agent is an acetaminophen.
17. the compositions claimed as claim 15, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
18. the compositions claimed as claim 17, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
19. the compositions claimed as claim 1, wherein this synergic antalgic agent is the alpha-adrenergic chemical compound.
20. the compositions claimed as claim 19, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
21. the compositions claimed as claim 20, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2 2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
22. the method for the treatment of pain, comprise to a kind of composition with analgesic dose, said composition comprises and is selected from following a kind of compound:
Figure A9619983700231
R wherein1For hydrogen, C1-C 6Alkyl or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces; R2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, include only side chain or non-side chain with 1-6 carbon atom, this group optionally replaces with fluorine, hydroxyl or phenyl, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700232
R wherein5Expression following formula group
Figure A9619983700241
Any locational R of this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700242
R wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11，R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group; Or R5R is optionally used in expression6’The naphthyl that replaces, R6’Definition with above R6Definition;
Figure A9619983700243
R wherein12Expression following formula groupAny locational R of this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700251
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or described group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17,R 16And R17Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’Definition with above R13；
Figure A9619983700252
Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on a carbon atom on this ring24Substituting group replaces, and on each carbon atom on another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or have maximum 20 carbon atom hydro carbons and replace;R wherein28、R 29Or R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;
Figure A9619983700262
R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39
Figure A9619983700263
R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom, Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or
Figure A9619983700272
Wherein
R 47And R 48As above definition;
X is oxygen or sulfur; R 44For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or
Figure A9619983700281
Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl replacement or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro 45The trifluoromethyl phenyl and the R that replace 46Form a ring with the nitrogen-atoms that connects them by the following formula definition R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines
Figure A9619983700292
Wherein X as above define or
Figure A9619983700293
R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700301
R wherein 51Be selected from
Figure A9619983700302
R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkynyl group or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983700311
R wherein 53Be selected from
Figure A9619983700312
R 54, R 55, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer;
Figure A9619983700321
Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from
Figure A9619983700331
R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist; R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from Wherein
R 69Be hydrogen, and R 67Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them Wherein n ' is the integer of zero or 1-8, and R 73The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them Wherein n ' and R 73As above definition,
Figure A9619983700372
Wherein X as above define or
Figure A9619983700373
R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom, Wherein Z is a heterocyclic radical
Figure A9619983700381
Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983700382
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHNH 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983700391
Wherein among X and the Y represents hydrogen, and another expression Z, Z ' is the group of following formula
Figure A9619983700392
Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1;
Figure A9619983700393
R wherein 75Expression
Figure A9619983700401
Wherein
Each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, and s represents 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane; Or its pharmaceutically acceptable salt or solvate; And be one or more synergic antalgic agent of about 1-1000 with the weight ratio of described chemical compound and synergic antalgic agent.
23. the method claimed as claim 22, wherein chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
24. the method claimed as claim 22, wherein this synergic antalgic agent is a non-steroidal anti-inflammatory drugs.
25. the method claimed as claim 24, wherein this non-steroidal anti-inflammatory drugs is selected from indometacin, ibuprofen, naproxen, fenoprofen, TOL, sulindac, Meclofenamate, keoprofen, piroxicam, flurbiprofen and diclofenac.
26. the method claimed as claim 24, wherein this non-steroidal anti-inflammatory drugs is an ibuprofen.
27. the method claimed as claim 24, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
28. the method claimed as claim 22, wherein this synergic antalgic agent is an opioid.
29. the method claimed as claim 28, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
30. the method claimed as claim 29, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
31. the method claimed as claim 29, wherein this opioid is selected from morphine, codeine, pethidine, methadone, the third oxygen sweet smell, levorphan, Dilauid, Numorphan, dihydrohydroxycodeinone, bromptonShi mixture, naloxone, naltrexone, pentazocine, butorphanol, nalbuphine and uncle's fourth coffee.
32. the method claimed as claim 29, wherein this opioid is selected from Dilauid, dihydrocodeinone, pethidine, uncle's fourth coffee, butorphanol, nalbuphine, pentazocine, Numorphan Oral, dihydrohydroxycodeinone, levorphan, fentanyl and anadol.
33. the method claimed as claim 29, wherein this opioid is selected from the third oxygen sweet smell, methadone, dihydrocodeinone, paramorphane and codeine.
34. the method claimed as claim 22, wherein this chemical compound is selected from formula I, II and III chemical compound or their pharmaceutically acceptable salt or solvate.
35. the method claimed as claim 22, wherein this chemical compound is selected from formula X IV and X V chemical compound or their pharmaceutically acceptable salt or solvate.
36. the method claimed as claim 35, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
37. the method claimed as claim 22, wherein this synergic antalgic agent is an acetaminophen.
38. the method claimed as claim 37, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
39. the method claimed as claim 22, wherein this synergic antalgic agent is the alpha-adrenergic chemical compound.
41. the method claimed as claim 39, wherein this chemical compound is selected from chemical compound or their pharmaceutically acceptable salt or the solvate of formula IV, V, VIII, IX, X III, X IV and X V.
41. the method claimed as claim 40, wherein this chemical compound is selected from 1-azabicyclo [2.2.2] oct-3-yl cyclopropyl ketone; 1-azabicyclo [2.2.1] heptan-3-basic ring propyl group ketone; 3-oxygen-3-(1-azabicyclo [2.2.1] heptan-3-yl) propionitrile; 1-azabicyclo [2.2.2] oct-3-yl-N-methoxymethylamide; 1-azabicyclo [3.2.1] suffering-5-base-N-methoxymethylamide; 1-azabicyclo [2.2.1] heptan-3-base-N-methoxymethylamide; (methoxyimino)-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile; oximido-(1-azabicyclo [2.2.2] oct-3-yl) acetonitrile and 1-azabicyclo [2.2.2] suffering-3-ylide cyanoacetic acid or their pharmaceutically acceptable salt.
42. be selected from the first following compound or its pharmaceutically acceptable salt or solvate and the purposes take the weight ratio of described compound and collaborative analgestic as one or more collaborative analgestics of about 1-1000R wherein1For hydrogen, C1-C 6Alkyl or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces; R2For C1-C 6Alkyl, C3-C 6Alkenyl, C3-C 6Alkynyl group, include only side chain or non-side chain with 1-6 carbon atom, this group can optionally use fluorine, hydroxyl or phenyl to replace, and this phenyl is optionally replaced by fluorine, trifluoromethyl, low alkyl group, hydroxyl or rudimentary alkoxyl; R3And R4Be hydrogen, C independently1-C 6Alkyl, C3-C 6Cycloalkyl, phenyl (are optionally used halogen, trifluoromethyl, C1-C 4Alkyl, hydroxyl or C1-C 4Alkoxyl replaces) or phenyl-C1-C 4Alkyl, wherein this phenyl can be used halogen, C1-C 4Alkyl or C1-C 4Alkoxyl replaces;
Figure A9619983700441
R wherein5Expression following formula group
Figure A9619983700442
Any locational R of this phenyl ring wherein6All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700443
R wherein7And R8Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or form one optionally contain another heteroatomic carbon containing heterocyclic radical or OR together with the nitrogen-atoms that connects them9Group (R9Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR10Or S (O) R11，R 10And R11Expression linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group; Or R5R is optionally used in expression6’The naphthyl that replaces, R6’Definition with above R6Definition;
Figure A9619983700451
R wherein12Expression following formula group
Figure A9619983700452
Any locational R of this phenyl ring wherein13All represent linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or following formula group
Figure A9619983700453
R wherein14And R15Can be identical or different, expression hydrogen, linear C1-C 8Alkyl, C2- C 8Alkenyl or C2-C 8Alkynyl group, or form one optionally contain another heteroatomic carbon containing heterocyclic radical or described group or NO together with the nitrogen-atoms that connects them2Or OR12’(R 12’Expression hydrogen, linearity, side chain or ring-type C1-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group or contain the aryl of 14 carbon atoms of as many as) or group SR16Or S (O) R17,R 16And R17Expression linearity, side chain or ring-type Cl-C 8Alkyl, C2-C 8Alkenyl or C2-C 8Alkynyl group, or R12R is optionally used in expression13’The naphthyl that replaces, R13’Definition with above R13；
Figure A9619983700461
Wherein, R18、R 19And R20In one the expression nitrogen, remaining represents carbon atom; The R that represents with non-aromatic azacyclo-system or azabicyclo system on a carbon atom of this ring24Substituting group replaces, and on each carbon atom of another ring independently with the low R of lipophilicity23、R 21Or R22Substituting group or the hydro carbons with maximum 20 carbon atoms replace;R wherein28、R 29Or R30In one be oxygen atom, and other two be nitrogen-atoms, the dotted line ring represents armaticity (two two keys) to form thus 1,3,4-oxadiazole core or 1,2,4-oxadiazole core; R31Represent non-aromatic ' 927 azacyclo-or ' 927 azabicyclo system; And R32Can be converted into amino substituting group in expression one is individual;
Figure A9619983700463
R wherein34Represent one non-aromatic; Non-condensed 1-azabicyclo system; And R35、 R 36And R37Represent independently hydrogen, F, Cl, Br ,-CF3、-OR 38、 -NR 38R 39、-NHOR 38、-NHNH 2、-CN、-COR 40Or replace or do not replace, saturated or unsaturated alkyl, as long as R35、R 36And R37In at least one be not hydrogen or alkyl, or R35And R36Or R37Form a C together1-6Alkylene dioxo base ring, wherein R38For C1-6Alkyl, C2-6Alkenyl or C2-6Alkynyl group, R39For hydrogen, C1-6Alkyl or-COCH3, and R40Expression OH ,-OR38、NHR 39Or-NR38R 39 R wherein43For
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 2-6 carbon atom,
The alkenyl of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 2-6 carbon atom,
The alkynyl group of 2-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom, the cycloalkyl of 3-6 carbon atom, Wherein n is the integer of zero or 1-8, and R 47And R 48Be independently the alkoxyl of the alkyl of hydrogen, fluorine, chlorine, bromine, hydroxyl, a 1-3 carbon atom or 1-3 carbon atom or 1-4 carbon atom alkoxyl or
Figure A9619983700481
Wherein
R 47And R 48As above definition;
X is oxygen or sulfur;
R 44For
The alkyl of 1-6 carbon atom,
1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom
Alkyl,
The alkenyl of 3-6 carbon atom,
3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom
Alkenyl,
The alkynyl group of 3-6 carbon atom,
3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom
Alkynyl group,
The cycloalkyl of 3-6 carbon atom, or
Figure A9619983700491
Wherein n, R 47And R 48As above definition, R 45And R 46Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom,
Phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 45The trifluoromethyl phenyl and the R that replace 46Form a ring with the nitrogen-atoms that connects them by the following formula definition
Figure A9619983700492
R wherein 49For the alkyl of hydrogen, a 1-10 carbon atom, by the alkenyl of the alkyl of 1-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 2-10 carbon atom, by the alkenyl of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, by the alkynyl group of 2-10 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, and n as above defines Wherein X as above define or R wherein 50Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700503
R wherein 51Be selected from
Figure A9619983700511
R 52Be the alkyl of the carbon atom of hydrogen, 1-10, the alkynyl group or the aryl of a 2-10 carbon atom; N ' is zero or 1 or 2 integer; X ' is carbon or nitrogen; And ... expression singly-bound or two key are as long as work as ... during the two key of expression, X ' is a nitrogen, and works as ... during the expression singly-bound, X ' is CH 2
Figure A9619983700521
R wherein 53Be selected from
Figure A9619983700522
R 54, R 55, R 56And R 57Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: C 1-C 10Alkyl, alkoxyl, C 1-C 10Halogen or trifluoromethyl; N ' is 1 or 2 integer;
Figure A9619983700523
Wherein X be oxygen, sulfur or-N-R 62, R wherein 62Alkyl for hydrogen or 1-10 carbon atom; R 58Be selected from
Figure A9619983700531
R 59, R 60And R 61Each is the alkyl of hydrogen, a 1-10 carbon atom, the alkynyl group or the aryl of a 2-10 carbon atom independently;---expression singly-bound or two key, as long as work as--during-expression pair key, R 57And R 60Do not exist;
Figure A9619983700541
R wherein 63, R 64And R 65Each is independently for the alkynyl group of the alkyl of hydrogen, a 1-10 carbon atom, a 2-10 carbon atom, phenyl or with the individual phenyl that is selected from following substituent group replacement of 1-4: alkyl, alkoxyl, thio alkoxy, halogen and trifluoromethyl; R 66Alkoxyl for hydrogen, a hydroxyl or 1-10 carbon atom; And R 67Be selected from Wherein
R 69Be hydrogen, and R 67Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 68And R 69Form a ring that is expressed from the next with the nitrogen-atoms that connects them
Figure A9619983700551
Wherein n ' is the integer of zero or 1-8, and R 63The alkyl of 1-10 the carbon atom that replaces for the alkyl of hydrogen, a 1-10 carbon atom, with the alkoxyl of hydroxyl or 1-4 carbon atom, the alkenyl of a 2-10 carbon atom, with the alkynyl group of the alkenyl of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom, a 2-10 carbon atom or with the alkynyl group of 2-10 carbon atom of the alkoxyl replacement of hydroxyl or 1-4 carbon atom;
R 70Be hydrogen,
The alkyl of 1-6 carbon atom,
The alkyl of 1-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-6 carbon atom,
The alkenyl of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-6 carbon atom,
The alkynyl group of 3-6 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-6 carbon atom, or R 70When with R 68One time-out forms a ring that is expressed from the next
Figure A9619983700561
Wherein n is the integer of 1-3, and R 68As above definition;
R 71And R 72Each is hydrogen independently,
The alkyl of 1-20 carbon atom,
The alkyl of 1-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkenyl of 3-20 carbon atom,
The alkenyl of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The alkynyl group of 3-20 carbon atom,
The alkynyl group of 3-20 the carbon atom that replaces with the alkoxyl of hydroxyl or 1-4 carbon atom,
The cycloalkyl of 3-8 carbon atom, phenyl,
With the alkyl of 1-4 carbon atom, by the phenyl or the R of the alkoxyl of the alkyl of 1-4 carbon atom of the alkoxyl of hydroxyl or 1-4 carbon atom replacement, a 1-4 carbon atom, chlorine, bromine, hydroxyl, nitro replacement 3The trifluoromethyl phenyl and the R that replace 4Form a ring that is expressed from the next with the nitrogen-atoms that connects them Wherein n ' and R 73As above definition,
Figure A9619983700572
Wherein X as above define or
Figure A9619983700573
R wherein 74Be the alkyl of hydrogen or 1-6 carbon atom,
Figure A9619983700574
Wherein Z is a heterocyclic radical Wherein Q represents 3 Yuans residue of divalent finishing 5 Yuans aromatic rings, comprises one or two hetero atom that is selected from oxygen, nitrogen and sulfur or 3 nitrogen-atoms, and any amino nitrogen is by a C 1-2Alkyl, cyclopropyl or propargyl replace, and any available ring carbon atom is randomly by R 1Group replaces; Or following formula group
Figure A9619983700582
A wherein 1, A 2And A 3Finish 5 Yuans aromatic rings, and A 1Be oxygen or sulfur, A 2And A 3In one be CR 2, and another is CR 3, or A 2Be oxygen or sulfur, A 1And A 3In one be CR 2, and another is nitrogen or CR 3R 1, R 2And R 3Be independently selected from hydrogen, halogen, CN, OR 4, SR 4, N (R 4) 2, NHCOR 4, NHCOOCH 3, NHCOOC 2H 5, NHOR 4, NHNH 2, NO 2, COR 4, COR 5, cyclopropyl, C 2-5Straight alkenyl, C 2-5Straight-chain alkynyl groups or C 1-5Straight chained alkyl, the latter can randomly use OR 4, N (R 4) 2, SR 4, CO 2R 4, CON (R 4) 2Or one, two or three halogen atoms carries out end and replaces, wherein each R 4Be hydrogen or C independently 1-3Alkyl, and R 5Be OR 4, NH 2Or NHR 4Or wherein Z is group-C (R 7)=NR 6, R wherein 6Be OR 8, R here 8Be C 1-4Alkyl, C 2-4Alkenyl, C 2-4Alkynyl group, group OCOR 9(R here 9Be hydrogen or R 8), or group NHR 10Or NR 11R 12, R here 10, R 11And R 12Be C independently 1-2Alkyl, and R 7Be hydrogen or C 1-4Alkyl is as long as work as R 6Be OCOR 9Or NHR 10The time, and R 7Be C 1-4Alkyl,
Figure A9619983700591
Wherein among X and the Y represents hydrogen, and another expression Z, and Z ' is the group of following formula
Figure A9619983700592
Wherein 3 Yuans residue of divalent of 5 Yuans aromatic rings are finished in Q ' expression, comprise two or three nitrogen-atoms, any amino nitrogen C 1-2Alkyl, cyclopropyl or propargyl replace, and r represents 2 or 3 integer, and s represents 1 or 2 integer, and t represents 0, as long as when Y is hydrogen, s is 1;
Figure A9619983700593
R wherein 75Expression
Figure A9619983700601
Wherein
Each of p and q represented the integer of 2-4 independently, and r represents the integer of 2-4, s
Expression 1 or 2, and t represents 0 or 1;
R 76Be group OR 78, R here 78Be C 1-4Alkenyl, C 2-4Alkynyl group, group OCOR 79(R here 79Be hydrogen or R 78) or group NHR 80Or NR 81, R 82, R here 80, R 81And R 82Be C independently 1-2Alkyl; R 77Be hydrogen or C 1-4Alkyl is as long as work as R 76Be OCOR 79Or group NHR 80The time, R 77Be alkyl; (3R, 4R)-3-(3-cyclopropyl-1,2,4-oxadiazole-5-yl)-1-azabicyclo [2.2.1] heptane.
43. the purposes claimed as claim 42, wherein this synergic antalgic agent is an opioid.
44. the purposes claimed as claim 42, wherein this synergic antalgic agent is an acetaminophen.
45. the purposes claimed as claim 42, wherein this synergic antalgic agent is a non-steroidal anti-inflammatory drugs.
46. the purposes claimed as claim 42, wherein this synergic antalgic agent is the alpha-adrenergic chemical compound.
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