CN101351495A - Inhibitors of fatty acid amide hydrolase - Google Patents

Inhibitors of fatty acid amide hydrolase Download PDF

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CN101351495A
CN101351495A CNA2006800499583A CN200680049958A CN101351495A CN 101351495 A CN101351495 A CN 101351495A CN A2006800499583 A CNA2006800499583 A CN A2006800499583A CN 200680049958 A CN200680049958 A CN 200680049958A CN 101351495 A CN101351495 A CN 101351495A
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alkyl
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compound
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O·达斯
D·帕特曼
T·R·康普顿
J·帕罗特
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Organon NV
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Organon NV
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Abstract

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity leads to increased levels of fatty acid amides. Esters of alkylcarbamic acids are disclosed that are inhibitors of FAAH activity. Compounds disclosed herein inhibit FAAH activity. Described herein are processes for the preparation of esters of alkylcarbamic acid compounds, compositions that include them, and methods of use thereof.

Description

Inhibitors of fatty acid amide hydrolase
Related application
The right of the following application of the application's request: the U.S. Provisional Application US60/755 that on December 29th, 2005 submitted to, 035; The U.S. Provisional Application US60/828 that on October 9th, 2006 submitted to, 753; The U.S. Provisional Application US60/823 that on August 21st, 2006 submitted to, 076; The U.S. Provisional Application US 60/822,877 that on August 18th, 2006 submitted to; The U.S. Provisional Application US60/824 that on September 7th, 2006 submitted to, 887; The U.S. Provisional Application US60/827 that on October 2nd, 2006 submitted to, 861; With the U.S. Provisional Application US60/866 that submitted on November 20th, 2006,568; With the non--provisional application US11/561 that submitted on November 20th, 2006,774; The content of all these documents is incorporated herein by reference.
Technical field
This paper describes compound, prepares the method for this compounds, comprises pharmaceutical composition and medicament and this compounds of use and the active method of composition inhibition fatty acid amide hydrolase (FAAH) of this compounds.
Background technology
Fatty acid amide hydrolase (FAAH) is the enzyme of fatty acid amide (FAA) family of hydrolysis endogenous signal conduction lipid.The general type of FAA comprises N-acyl ethanol amine class (NAE) and lipid acid primary amide class (FAPA).The example of NAE comprises arachidonic acid thanomin (AEA), palmityl thanomin (PEA) and Oleoyl monoethanolamide (OEA).The active pharmacology of FAAH suppresses to cause the level of these fatty acid acyl amines to increase.
Summary of the invention
Provide and be used to suppress fatty acid amide hydrolase (FAAH) active compound, composition and method.In compound provided herein, the compound as fatty acid amide hydrolase (FAAH) inhibitor is arranged.Provide to prepare the method that suppresses the active compound of fatty acid amide hydrolase, comprised the composition of this compounds and the method for using this compounds.
Compound provided herein comprises those compounds and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound that has as shown in the formula the structure of (I):
Wherein, D is O or NR 11One of A or B are (CH 2) mC (O)-alkyl, (CH 2) mC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl, and wherein m is 0,1,2 or 3; Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together; Or A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group; Or A and B constitute optional non-aromatics or the aromatic carbocyclyl groups that replaces together; Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another; R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O); R 2Be selected from H or the optional alkyl that replaces independently of one another; R 11Be H or the optional alkyl that replaces.
With regard to any He all embodiments, substituting group can be selected from the group of listed alternatives.For example, in certain embodiments, one of A or B are (CH 2) nC (O)-alkyl, (CH 2) nC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl.In certain embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein n independently is 1,2 or 3 separately; And R wherein qBe selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement independently of one another; Or any two R qGroup can constitute carbocyclic ring or heterocycle.
In certain embodiments, A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, wherein n is 1,2,3 or 4.In other embodiments, A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group.In certain embodiments, R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O).In certain embodiments, R 2Be H or the optional alkyl that replaces.In another embodiment, D is O.In other embodiments, be pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In certain embodiments, R 2Be H.In another embodiment, R 11Be H.In certain embodiments, one of A or B are that C (O)-alkyl and another are H.In other embodiments, alkyl is a methyl.
In other embodiments, limiting examples is selected from: 3-formamyl benzyl ring hexyl carbamate; 3-formamyl benzyl ring hexyl methyl carbamate; 3-acetylphenyl cyclohexyl carbamate; 3-acetylphenyl cyclohexyl methyl carbamate; 3-acetylphenyl sec.-propyl carbamate; 3-acetylphenyl isobutylamino manthanoate; With 3-acetylphenyl styroyl carbamate.In certain embodiments, A and B constitute together optional replace comprise C (O)-(CH 2) nNon--aromatics the cyclic group of-part, wherein n is 1,2,3 or 4.In other embodiments, n is 2.In certain embodiments, R 2Be H.
In certain embodiments, limiting examples is selected from: 2, and 3-dihydro-1-oxo-1H-indenes-6-basic ring hexyl carbamate; 2,3-dihydro-1-oxo-1H-indenes-6-basic ring hexyl methyl carbamate; 2,3-dihydro-1-oxo-1H-indenes-5-basic ring hexyl carbamate; With 2,3-dihydro-1-oxo-1-H-indenes-5-basic ring hexyl methyl carbamate.
In another embodiment, A and B constitute together optional replace comprise at least one N, NR 2, the heteroaromatic group of S or O group.In certain embodiments, described heteroaromatic rings also comprise-(CH) n-part, wherein n is 1,2 or 3.In another embodiment, A and B constitute the optional heteroaromatic group that comprises single N on ring that replaces together.
In certain embodiments, limiting examples is selected from: quinoline-7-basic ring hexyl carbamate; Quinoline-7-basic ring hexyl methyl carbamate; Quinoline-7-basic ring heptyl carbamate; Quinoline-7-base (furans-2-yl) methyl carbamate; Quinoline-7-basic ring hexyl methyl carbamate; Quinoline-6-basic ring hexyl carbamate; Quinoline-6-basic ring hexyl methyl carbamate; Quinoline-6-base (furans-2-yl) methyl carbamate; Isoquinoline 99.9-7-basic ring hexyl carbamate; Isoquinoline 99.9-7-basic ring hexyl methyl carbamate; Isoquinoline 99.9-7-basic ring heptyl carbamate; And the acceptable N-oxide compound of pharmacy.
In certain embodiments, the optional heteroaromatic group that replaces comprises two heteroatomss that are selected from N, S and O.
In certain embodiments, limiting examples is selected from following group: 2-methyl benzo [d] thiazole-5-basic ring hexyl carbamate; 2-methyl benzo [d] thiazole-5-basic ring hexyl methyl carbamate; 2-methyl benzo [d] oxazole-5-basic ring hexyl carbamate; 2-methyl benzo [d] oxazole-5-basic ring hexyl methyl carbamate, 2-methyl benzo [d] oxazole-6-basic ring hexyl carbamate; 2-methyl benzo [d] oxazole-6-basic ring hexyl methyl carbamate, 2-methyl benzo [d] thiazole-6-basic ring hexyl carbamate; With 2-methyl benzo [d] thiazole-6-basic ring hexyl methyl carbamate.
In another embodiment, D is NR 11In certain embodiments; limiting examples is selected from following group: 1-(3-acetylphenyl)-3-cyclohexyl urea; 1-(3-acetylphenyl)-3-(cyclohexyl methyl) urea; 1-(3-acetylphenyl)-3-isobutyl-urea, 1-(3-acetylphenyl)-3-sec.-propyl urea and 1-(3-acetylphenyl)-3-phenthylcarbamide.In certain embodiments, limiting examples is selected from following group: 1-cyclohexyl-3-(2,3-dihydro-1-oxo-1H-indenes-6-yl) urea, 1-(cyclohexyl methyl)-3-(2,3-dihydro-1-oxo-1H-indenes-6-yl) urea, 1-cyclohexyl-3-(2,3-dihydro-1-oxo-1H-indenes-5-yl) urea and 1-(cyclohexyl methyl)-3-(2,3-dihydro-1-oxo-1H-indenes-5-yl) urea.
In another embodiment, limiting examples is selected from following group: 1-cyclohexyl-3-(quinoline-7-yl) urea, 1-(cyclohexyl methyl)-3-(quinoline-7-yl) urea, 1-suberyl-3-(quinoline-7-yl) urea, 1-((furans-2-yl) methyl)-3-(quinoline-7-yl) urea, 1-cyclohexyl-1-methyl-3-(quinoline-7-yl) urea, 1-cyclohexyl-3-(quinoline-6-yl) urea, 1-(cyclohexyl methyl)-3-(quinoline-6-yl) urea, 1-((furans-2-yl) methyl)-3-(quinoline-6-yl) urea, 1-cyclohexyl-3-(isoquinoline 99.9-7-yl) urea, 1-(cyclohexyl methyl)-3-(isoquinoline 99.9-7-yl) urea and 1-suberyl-3-(isoquinoline 99.9-7-yl) urea.
In another embodiment, limiting examples is selected from following group: 1-(cyclohexyl methyl)-3-(2-methyl benzo [d] thiazole-5-yl) urea, 1-cyclohexyl-3-(2-methyl benzo [d] thiazole-5-yl) urea, 1-cyclohexyl-3-(2-methyl benzo [d] oxazole-5-yl) urea and 1-(cyclohexyl methyl)-3-(2-methyl benzo [d] oxazole-5-yl) urea.
In another embodiment, limiting examples is selected from Fig. 1,2,3,4, any compound that exists in 5,6,7 and 8.
In certain aspects, be compound and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound of formula (II):
Figure A20068004995800141
Wherein D is O or NR 11X respectively do for oneself CH or N;
R 1Be selected from:
Figure A20068004995800151
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl (thiophenyl), thienyl (thiopheneyl), dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl;
R ' independence is the alkyl of H, alkyl or replacement separately;
R separately 5Independent is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Constitute together:
Figure A20068004995800161
N is 1,2,3 or 4; M is 1,2,3 or 4;
A and B constitute together and comprise C (O)-(CH 2) qNon--aromatics the cyclic group of the optional replacement of-part, wherein q is 1,2,3 or 4;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B constitute together and comprise at least one N, NR 2, the aromatics of the optional replacement of S or O group or non--aromatics cyclic group;
Or one of A or B are-L-G and another C that is selected from H and chooses replacement wantonly 1-C 6Alkyl;
Or A and B constitute the optional aromatic carbocyclyl groups that replaces together;
Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces, the optional acid amides that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
L is key or the optional group that replaces, and described group is selected from C 1-C 6Alkylidene group, C 1-C 6Inferior assorted alkyl, C 1-C 6The ketone group alkylidene group ,-C (O) NR 9-(CH 2) j-,-NR 9-C (O)-(CH 2) j-,-OC (O) O-(CH 2) j-,-NHC (O) O-(CH 2) j-,-O (O) CNH-(CH 2) j-,-C (O) O-(CH 2) j-,-OC (O)-(CH 2) j-,-NR 9C (O) N (R 9)-(CH 2) j-,-S (O)-(CH 2) j-,-S (O) 2-(CH 2) j-,-C (=NR 10) N (R 9)-(CH 2) j-and-NR 9C (=NR 10) N (R 9)-(CH 2) j-;
G be tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2NHR 8,-S (=O) 2The NH-phenyl ,-OH ,-SH ,-OC (O) NHR 8,-NHC (O) OR 8,-C (O) NHC (O) R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8,-S (=O) 2NHC (O) NHR 8,-NHC (O) R 8,-NHC (O) N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) NHC (=NR 10) N (R 9) 2,-NR 9C (=CHR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CHR 10) N (R 9) 2,-CO 2H ,-(OP (=O) OH) xOH ,-OP (=O) OR 8OH ,-OP (=O) R 8OH ,-NR 9P (=O) OR 8OH ,-NR 9P (=O) R 8OH ,-P (=O) OR 8OH;-P (=O) R 8OH ,-S (O) yOH;-OS (O) yOH;-NR 9S (O) yOH;
R 8Independent of separately replacing or unsubstituted C 1-C 6Alkyl;
R 9Independent separately is the C of H, replacement 1-C 6Alkyl or unsubstituted C 1-C 6Alkyl;
R 10Be selected from independently of one another H ,-S (=O) 2R 8,-S (=O) 2NH 2,-C (O) R 8,-CN and-NO 2
J is 0,1,2,3 or 4; X is 1,2 or 3; Y is 0,1 or 2;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
In certain embodiments, R 1Be selected from:
Figure A20068004995800171
In certain embodiments, M is a key, optional C 1-C 4Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 4Alkenylene or the optional C that replaces 2-C 4Alkynylene.In another embodiment, J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH.In another embodiment, R 3Be selected from the optional C that replaces 1-C 6Alkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl, they are optional by one or more following group replacement: C that are selected from 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2In another embodiment, R ' is independent separately is the alkyl of H, alkyl or replacement.In certain embodiments, R 5Independent separately is H, C 1-C 3Alkyl or halogen.In another embodiment, R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl.In some embodiments, R 2And R 11Be H or the optional alkyl that replaces.In another embodiment, R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl.In certain embodiments, n is 1,2,3 or 4.In another embodiment, m is 1,2,3 or 4.In another embodiment, A and B constitute together and comprise C (O)-(CH 2) qNon--aromatics the cyclic group of the optional replacement of-part, wherein q is 1,2,3 or 4.In another embodiment, A and B constitute together and comprise at least one N, NR 2, the aromatics of the optional replacement of S or O group or non--aromatics cyclic group.In certain embodiments, one of A or B are-L-G and another C that is selected from H and chooses replacement wantonly 1-C 6Alkyl.In another embodiment, A and B constitute the optional aromatic carbocyclyl groups that replaces together.In some embodiments, A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another. in certain embodiments, L is key or the optional group that replaces, and described group is selected from C 1-C 6Alkylidene group, C 1-C 6Inferior assorted alkyl, C 1-C 6The ketone group alkylidene group ,-C (O) NR 9-(CH 2) j-,-NR 9-C (O)-(CH 2) j-,-OC (O) O-(CH 2) j-,-NHC (O) O-(CH 2) j-,-O (O) CNH-(CH 2) j-,-C (O) O-(CH 2) j-,-OC (O)-(CH 2) j-,-NR 9C (O) N (R 9)-(CH 2) j-,-S (O)-(CH 2) j-,-S (O) 2-(CH 2) j-,-C (=NR 10) N (R 9)-(CH 2) j-and-NR 9C (=NR 10) N (R 9)-(CH 2) j-.In another embodiment, G be tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2NHR 8,-S (=O) 2The NH-phenyl ,-OH ,-SH ,-OC (O) NHR 8,-NHC (O) OR 8,-C (O) NHC (O) R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8,-S (=O) 2NHC (O) NHR 8,-NHC (O) R 8,-NHC (O) N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) NHC (=NR 10) N (R 9) 2,-NR 9C (=CHR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CHR 10) N (R 9) 2,-CO 2H ,-(OP (=O) OH) xOH ,-OP (=O) OR 8OH ,-OP (=O) R 8OH ,-NR 9P (=O) OR 8OH ,-NR 9P (=O) R 8OH ,-P (=O) OR 8OH ,-P (=O) R 8OH ,-S (O) yOH ,-OS (O) yOH ,-NR 9S (O) yOH.R in certain embodiments, 8Independent of separately replacing or unsubstituted C 1-C 6Alkyl.In another embodiment, R 9Independent separately is H, the C of replacement 1-C 6Alkyl or unsubstituted C 1-C 6Alkyl.In another embodiment, R 10Be selected from H independently of one another ,-S (=O) 2R 8,-S (=O) 2NH 2,-C (O) R 8,-CN and-NO 2In another embodiment, j is 0,1,2,3 or 4.In another embodiment, x is 1,2 or 3.In another embodiment, y is 0,1 or 2.In another embodiment, be pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In certain embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein n independently is 1,2 or 3 separately; And R wherein qBe selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement independently of one another.
In certain embodiments, be compound and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound of formula (III):
Figure A20068004995800201
Wherein D is O or NR 11X respectively do for oneself CH or N;
R 1Be selected from:
R 1Be selected from:
Figure A20068004995800202
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Constitute together:
N is 1,2,3 or 4; M is 1,2,3 or 4;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
In another embodiment, compound and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound for having following structure:
Figure A20068004995800221
R wherein 1Be selected from:
R 1Be selected from:
Figure A20068004995800222
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Constitute together:
Figure A20068004995800231
N is 1,2,3 or 4; M is 1,2,3 or 4;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
Compound provided herein comprises any above-mentioned amino formate and ureas, wherein with one of two " N " part of " N " of carbamate part or urea covalently bound group at least a be (CH 2) z(C 3-C 8Cycloalkyl), (CH 2) z(C 3-C 8Heterocyclylalkyl) or (CH 2) z(C 7-C 12Multi-ring alkyl) group, wherein z be 0 or 1 and wherein on the cycloalkyl ring at least one in the carbon atom or the optional polynaphthene basic ring at least one coverlet in the carbon atom replace or two replacements, and wherein every kind of replacement is independently selected from methyl, halogen, trifluoromethyl or C 3-C 6Cycloalkyl; Or wherein a carbon atom on the cycloalkyl ring is replaced by oxo group; Or wherein a carbon atom on the cycloalkyl ring is replaced to 3-, 4-or 5-unit carbocylic radical by two; Or wherein two adjacent atoms on the cycloalkyl ring are configured 3-, 4-separately, and the group of 5-or 6-unit carbocylic radical replaces; Or wherein with one of two " N " part of " N " of carbamate part or urea covalently bound group at least aly be the optional (CH that replaces 2) z(bridging carbocylic radical), z are 0 or 1, wherein optional methyl, halogen or the trifluoromethyl of being substituted by.
Compound provided herein comprises any above-mentioned amino formate and ureas, wherein with one of two " N " part of " N " of carbamate part or urea covalently bound group at least a being selected from:
Figure A20068004995800251
Neo-pentyl, new hexyl, methylene radical cyclopropyl, methylene radical cyclobutyl and methylene radical cyclopentyl; P independently can constitute 3-, 4-or 5-unit carbocylic radical for halogen, methyl, trifluoromethyl or each P separately each other; Q independently is H separately, and halogen, methyl, trifluoromethyl or each Q can constitute 3-, 4-or 5-unit carbocylic radical each other; And T is O, N-(C 1-C 6Alkyl) or SO 2
Compound provided herein comprises that those have the compound and the pharmacologically acceptable salts thereof of formula (I) structure, N-oxide compound, solvate, ester, acid and prodrug.The isomer and the chemical protected form of the compound of the structure with formula (I) expression also are provided in certain embodiments.
In another embodiment, for having the compound of formula (I), wherein R 1Be selected from:
Figure A20068004995800252
Neo-pentyl, new hexyl, methylene radical cyclopropyl, methylene radical cyclobutyl and methylene radical cyclopentyl; P independently can constitute 3-, 4-or 5-unit carbocylic radical for halogen, methyl, trifluoromethyl or each P separately each other; Q independently is H separately, and halogen, methyl, trifluoromethyl or each Q can constitute 3-, 4-or 5-unit carbocylic radical each other; T is O, N-(C 1-C 6Alkyl) or SO 2
In an alternate embodiment, R 1Be (CH 2) z(C 3-C 8Cycloalkyl) group, wherein z be 0 or 1 and wherein at least one the carbon atom coverlet on the cycloalkyl ring replace or two replacements, and wherein every kind of replacement is independently selected from methyl, halogen, trifluoromethyl or C 3-C 6Cycloalkyl; Or wherein a carbon atom on the cycloalkyl ring is replaced by oxo group; Or wherein a carbon atom on the cycloalkyl ring is replaced to 3-, 4-or 5-unit carbocylic radical by two; Or wherein two adjacent atoms on the cycloalkyl ring are configured 3-, 4-separately, and the group of 5-or 6-unit carbocylic radical replaces.In an alternate embodiment, R 1Be the optional (CH that replaces 2) z(bridging carbocylic radical), z are 0 or 1, wherein optional methyl, halogen or the trifluoromethyl of being substituted by.
In certain embodiments, the FAAH inhibitor can have the U.S. Provisional Patent Application US60/755 that submitted on December 29th, 2005, the formula (1) that discloses in 035, formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula (8), formula (9), formula (10), formula (11), formula (12), formula (13), formula (14), formula (15), formula (16), formula (17), formula (18), formula (19), formula (20), formula (21), formula (22), formula (23), formula (24), formula (25), formula (26), formula (27), the structure and the pharmacologically acceptable salts of formula (28) or formula (29), the acceptable N-oxide compound of pharmacy, the pharmaceutical activity metabolite, acceptable prodrug of pharmacy or pharmacy acceptable solvent compound are incorporated herein by reference the document; As long as R 1Group has following structure:
M is a key, optional C 1-C 4Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 4Alkenylene or the optional C that replaces 2-C 4Alkynylene; J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH; R 3Be selected from the optional C that replaces 1-C 6Alkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl, they are chosen wantonly and are replaced by one or more groups, and described group is selected from C 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) O R ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2R ' is independent separately to be the alkyl of H, alkyl or replacement; R 5Independent separately is H, C 1-C 3Alkyl or halogen; R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl; R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl; N is 1,2,3 or 4; M is 1,2,3 or 4;
Or R 1And R 2Constitute together:
N is 1,2,3 or 4; M is 1,2,3 or 4.
This paper is the arbitrary combination of the group of the above-mentioned various variablees of concern.Be appreciated that substituting group on the compound provided herein and substitute mode can be selected so that provide chemically stable and can be by technology synthetic compound well known in the art and those listed compounds of this paper by those skilled in the art.
In another embodiment, be pharmaceutical composition, it comprises formula (I), (II), (III) or the compound in any compound (IIIa), pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound (compound that provides in the compound of any name or the accompanying drawing is provided) and pharmacy acceptable diluent, vehicle or tackiness agent.
Be to suppress patient's fatty acid amide hydrolase or treat the method that can have benefited from suppressing the active disease of fatty acid amide hydrolase, illness or illness in a certain embodiment, comprise formula (I) to this patient's drug treatment significant quantity, (II), (III) or the compound in any compound (IIIa), pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound (compound that provides in the compound of any name or the accompanying drawing is provided).
In another embodiment, for suppressing fatty acid amide hydrolase or treatment disease, the method of illness or illness, comprise formula (I) to patient's drug treatment significant quantity, (II), (III) or the compound in any compound (IIIa), pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, the pharmaceutical activity metabolite, acceptable prodrug of pharmacy or pharmacy acceptable solvent compound (compound that provides in the compound of any name or the accompanying drawing is provided), wherein said disease, illness or illness are selected from acute or chronic pain, eating disorder, cardiovascular disorder, metabolic trouble, illness or illness, kidney local asphyxia, cancer, the immunity system obstacle, anaphylactic disease, metabolic trouble, illness or illness, the kidney local asphyxia, cancer, the immunity system obstacle, anaphylactic disease, parasite, virus or bacterial infection disease, inflammatory diseases, osteoporosis, ophthalmic, lung disease, gastrointestinal tract disease and the urinary incontinence.
In certain embodiments, be formula (I), (II), (III) or any compound (IIIa) (compound that provides in the compound of any name or the accompanying drawing is provided) maybe can have benefited from suppressing application in the active treatment disease of fatty acid amide hydrolase, illness or the illness suppressing the fatty acid amide hydrolase activity.In other embodiments, be formula (I), (II), (III) or any compound (IIIa) (compound that provides in the compound of any name or the accompanying drawing is provided) be used for suppressing the application of the medicament of fatty acid amide hydrolase in preparation.In another embodiment, be goods, it comprises wrapping material, the active formula of effective inhibition fatty acid amide hydrolase (I) in these wrapping material, (II), (III) or any compound (IIIa) (compound that provides in the compound of any name or the accompanying drawing is provided) and show that described compound or composition or pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound are used to suppress the active label of fatty acid amide hydrolase.
Be treatment releasing agent in one aspect of the method with following structure:
R wherein 1And R 2Structure with formula (I) or formula (II), Y 1For O or S and HO-TA are the hydroxy derivatives of therapeutical agent and therapeutical agent.The compound of formula (XX) can discharge HO-TA when interacting with hydroamidase (such as FAAH).Therefore, only as an example, the compound of formula (XX) can take place to interact to patient's administration the time and discharge HO-TA with FAAH.HO-TA can provide the further treatment helpfulness to the patient then.
Only as an example, HO-TA can for:
Figure A20068004995800292
It is an antihypertensive drug.
As another example, HO-TA can for:
Figure A20068004995800293
It is a serotonin, promptly is used for the treatment of the supplement of dysthymia disorders.
As another example, HO-TA can for:
Figure A20068004995800294
It is a synephrine, is decongestant.
As another example, HO-TA can for:
It is a tyrosine, i.e. amino acid and dietary supplements.
As another example, HO-TA is the NSAID of hydroxyl, and it is selected from Whitfield's ointment, salicylic amide, salsalate, diflunisal, gentisinic acid, piroxicam and meloxicam; The NSAID metabolite, it is selected from acetylsalicylic acid, Whitfield's ointment, salicylic amide, salsalate, diflunisal, gentisinic acid, indomethacin, sulindac, tolmetin, diclofenac, R-ETODOLAC, nabumetone, Ibuprofen BP/EP, fenoprofen, Ketoprofen, flurbiprofen, sutoprofen, carprofen, Naproxen Base, ketorolac, Taisho), vialidon, meclofenamate sodium, piroxicam, meloxicam, DuP 697, celecoxib, rofecoxib, valdecoxib, nimesulide, ns-398, parecoxib and L-791456; Or paracetamol.
As another example, HO-TA is a dietary supplements, such as tyrosol, and the peppery element of sweet oil (oleocanthal), P-coumaric acid, trans-resveratrol or umbelliferone.
As another example, HO-TA can be for the promoting agent (or hydroxyl homologue of promoting agent) of treatment digestion illness, such as cisapride and metoclopramide; Diet pill (or hydroxyl homologue of diet pill) are such as Mazindol; The compound of controlling blood pressure (or hydroxyl homologue of compound) is such as beta blocker; Or the promoting agent (or hydroxyl homologue of promoting agent) of treatment type ii diabetes, such as the compound in the glitazone.
For example, some HO-TA (hereinafter " therapeutical agent of release ") can have known anti-inflammatory or analgesic effect.The therapeutical agent of some release can have therapeutic action to metabolic disease.The administration of formula (XX) compound can have additional or synergy.In addition, FAAH inhibitor potential detrimental action can be offset or regulate to the activity of the therapeutical agent of release.In an example, the decreasing cholesterol effect of the therapeutical agent that discharges of statin (or statin-class) can reduce or prevent FAAH inhibitor temporary transient under certain conditions or in some individuality to rise the cholesterol effect.The additional advantage of formula (XX) compound comprises that the promoting agent that will discharge is delivered to blood plasma or target tissue better, comprise the release pharmaceutically active agents, the bioactive ingredients of diagnostic reagent and food or supplement (comprising dietetic product, dietary supplements, nutritious supplementary etc.).
In one aspect of the method, pharmaceutical composition is provided, and they comprise the acceptable N-oxide compound of at least a or its pharmacologically acceptable salts, pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound in any compound of this paper that treats significant quantity.In certain embodiments, composition provided herein further comprises pharmacy acceptable diluent, vehicle and/or tackiness agent.
The pharmaceutical composition of preparing for by suitable approach and mode administration is provided, it comprises a kind of in the compound provided herein of effective concentration or it is multiple or its effective derivative pharmaceutically, these pharmaceutical compositions can be carried effective treatment, prevention or improve the consumption of one or more symptoms of disease, illness or illness, one or more symptoms of described disease, illness or illness are regulated by FAAH is active, otherwise influenced by it, or wherein relate to the FAAH activity.Significant quantity and concentration are effectively improved any in the symptom of any disease, illness or illness that this paper discloses.
In certain embodiments, this is for providing pharmaceutical composition, and it comprises: i) physiology acceptable carrier, thinner and/or vehicle; One or more compounds ii) provided herein.
In one aspect, this paper provides the method by administration compounds for treating patient provided herein.In certain embodiments, this paper provides and has suppressed patient's fatty acid amide hydrolase activity or treat the method that can have benefited from suppressing the active disease of fatty acid amide hydrolase, illness or illness, comprises at least a or pharmacologically acceptable salts in any compound of this paper of this patient's drug treatment significant quantity, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In certain embodiments, compound provided herein and composition are effectively treated, are prevented or improve acute or chronic pain, eating disorder, cardiovascular disorder, metabolic trouble, illness or illness, kidney local asphyxia, cancer, immunity system obstacle, anaphylactic disease, parasite, virus or bacterial infection disease, inflammatory diseases, osteoporosis, ophthalmic, lung disease, one or more symptoms of the gastrointestinal tract disease and the urinary incontinence.
In other embodiments, compound provided herein is effectively treated, prevention or improve disease, one or more symptoms of illness or illness, described disease, illness or illness are selected from pain, nociception pain, neuropathic pain, inflammatory pain, non--inflammatory pain, pain property hemorrhagic cystitis, the pain relevant with simplexvirus, the pain relevant with diabetes, peripheral nerve pain, central pain, deafferentation pain, chronic injury susceptibility pain, nociception receptor for stimulating, phantom limb pain and one is crossed impatient property pain, Parkinson's disease, muscle spasm, epilepsy, obesity, hyperlipidaemia, insulin resistance syndrome, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, metabolic disease, feed and fasting, appetite changes, hypertension, septic shock, heart shock, enteritis and intestinal motility, irritable bowel syndrome, colitis, diarrhoea, ileitis, local asphyxia, cerebral ischemia, the liver ischemic, myocardial infarction, sacroiliitis, rheumatoid arthritis, back of the body vertebra inflammation, shoulder slip or bursitis, urarthritis, polymyalgia rheumatica, thyroiditis, hepatitis, inflammatory bowel, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disorder.
Some compound provided herein is the irreversible inhibitor of fatty acid amide hydrolase (FAAH); Other compound provided herein is the reversible inhibitor of FAAH.Compound provided herein increases the level of some endogenous fatty acid acyl amine.Compound increase provided herein is selected from AEA, the level of the endogenous fatty acid acyl amine of OEA and PEA.
Fatty acid amide hydrolase (FAAH) omnipresence is in body.In some cases, preferably make the FAAH inhibitor be limited to peripheral tissues, so that any short mentation is reduced to bottom line or eliminates them.In certain embodiments, compound provided herein preferably suppresses the FAAH activity in peripheral tissues and the fluid, and potential unwanted central nervous system side effect is reduced to bottom line.
In certain embodiments, to people's administration compound provided herein.
In certain embodiments, oral administration compound provided herein.
In certain embodiments, compound provided herein is used to suppress fatty acid amide hydrolase (FAAH) activity.In certain embodiments, compound provided herein is used to suppress the fatty acid amide hydrolase activity or is used for the treatment of to have benefited from suppressing active disease of fatty acid amide hydrolase or illness.
In other embodiments, compound provided herein is used for the medicament that preparation suppresses fatty acid amide hydrolase (FAAH).
In certain embodiments, one or more symptoms of disease, illness or illness are effectively treated, prevent or improved to compound provided herein and composition, and described disease, illness or illness are selected from acute or chronic pain, dizziness, vomiting is felt sick, eating disorder, nerve and psychosis, acute or chronic neurodegenerative disease, epilepsy, somnopathy, cardiovascular disorder, kidney local asphyxia, cancer, the immunity system obstacle, anaphylactic disease, parasite, virus or bacterial infection disease, inflammatory diseases, osteoporosis, ophthalmic, lung disease, gastrointestinal tract disease and the urinary incontinence.
In certain embodiments, compound provided herein and composition are effectively treated, prevention or improve disease, one or more symptoms of illness or illness, described disease, illness or illness are selected from pain, nociception pain, neuropathic pain, inflammatory pain, non--inflammatory pain, pain property hemorrhagic cystitis, the pain relevant with simplexvirus, the pain relevant with diabetes, peripheral nerve pain, central pain, deafferentation pain, chronic injury susceptibility pain, nociception receptor for stimulating, phantom limb pain and one is crossed impatient property pain, dysthymia disorders, anxiety, generalized anxiety disorder (GAD), obsession, anxiety, stress urinary incontinence, attention deficit Attention Deficit Hyperactivity Disorder, schizophrenia, psychosis, Parkinson's disease, muscle spasm, epilepsy, obesity, hyperlipidaemia, insulin resistance syndrome, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, metabolic disease, feed and fasting, appetite changes, hypomnesis, aging, hypertension, septic shock, heart shock, enteritis and intestinal motility, irritable bowel syndrome, colitis, diarrhoea, ileitis, local asphyxia, cerebral ischemia, the liver ischemic, myocardial infarction, brain excitatory toxicity, epileptic seizures, febrile seizure, neurotoxicity, neuropathy, sleep, bring out sleep, prolong sleep, insomnia, sacroiliitis, rheumatoid arthritis, back of the body vertebra inflammation, shoulder slip or bursitis, urarthritis, polymyalgia rheumatica, thyroiditis, hepatitis, inflammatory bowel, asthma, multiple sclerosis, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disorder.
In some extra embodiment, one or more symptoms of pain and/or inflammation are effectively treated, prevent or improved to compound provided herein and composition.
In one aspect, this paper provides inhibition Mammals fatty acid amide hydrolase active method, comprises compound provided herein or composition to this Mammals drug treatment significant quantity.In certain embodiments, described Mammals is behaved.In other embodiments, by oral administration compound or composition.
In one aspect of the method, compound provided herein is used for the medicament that preparation suppresses fatty acid amide hydrolase (FAAH).
Goods are provided, it comprises wrapping material, active compound of provided herein effective inhibition fatty acid amide hydrolase (FAAH) in these wrapping material or composition or its pharmacy acceptable derivates and show described compound or composition or pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound are used to suppress the active label of fatty acid amide hydrolase (FAAH).
This paper pays close attention to the arbitrary combination of the group of above-mentioned different variablees.
Other purpose of methods described herein and composition, feature and advantage can be apparent from the following detailed description.Yet, should understand detailed description and specific embodiment only provides as illustration, represent specific embodiment simultaneously, because apparent to those skilled in the art from this detailed description to various changes in the spirit and scope that belong to disclosure content of the present invention and modification.All reference with this paper citation comprise patent, and patent application and open source literature intactly are incorporated herein by reference.
Be incorporated herein by reference
All open source literatures and the patent application mentioned in this specification sheets are incorporated herein by reference, its degree with as with each open source literature or patent application as directed separately be incorporated herein by reference identical.
Description of drawings
Can obtain feature and advantage of the present invention are better understood with reference to the detailed description that illustrative embodiment and accompanying drawing are listed, wherein used method of the present invention, composition, the principle of device and equipment:
Fig. 1-8 illustration the limiting examples of formula described herein (I) type of compounds.Can use this compounds or incorporate it method of preparation, purifying, sign and use formula described herein (I) compound into, composition is in any in technology and the strategy.
Embodiment
In the claim that awaits the reply, listed new feature with singularity.By obtaining feature and advantage of the present invention are better understood, wherein used principle described herein with reference to relating to the following detailed description of listing illustrative embodiment.
This paper has disclosed the active compound of inhibition fatty acid amide hydrolase (FAAH), comprises these compound compositions and using method thereof.The compound that this paper discloses is fatty acid amide hydrolase (FAAH) inhibitor and is used for the treatment of disease, illness or the illness that can have benefited from fatty acid amide hydrolase inhibition and the increase of endogenous fatty acid acyl amine.
The Endocannabinoids type systematic
The Endocannabinoids signal transducting system by three kinds of elements form (J.Med.Chem.2005 such as Lambert, vol.48, no.16,5059-5087).First kind by forming in conjunction with the g protein coupled receptor of endogenous and exogenous cannaboid part.Identified two kinds of these receptoroids, promptly almost in vivo omnipresence but in central nervous system (CNS) the abundantest CB 1Acceptor (Freund etc., Physiol.Rev.2003; 83:1017-1066); With main expression in immunocyte and hematopoietic cell but also with the low-level CB that is present in the brain 2Acceptor (Munro etc., Nature, 1993; 365:61-65; Van Sickle etc., Science 2005; 310:329-332; Hanus etc., Proc.Nat.Acad.Sci., U.S.A., 1999; 96:14228-14233).
Second kind of element represented by Endocannabinoids, its be naturally occurring, in conjunction with and the lipid molecule of activation Cannabined receptor (Devane etc., Science 1992; 258:1946-1949; Mechoulam etc., Biochem.Pharmacol.1995; 50:83-90; Sugria etc., Biochem.Biophys.Res.Commun.1995; 215:89-97), they as required by neurone and other cell produce (Di Marzo etc., Nature 1994; 372:686-691; Nat.Neurosci.1999 such as Giuffrida; 2:358-363; Nature such as Stella 2001; 388:773-778) and can be eliminated fast (Beltramo etc., FEBS Lett.1997; 403:263-267; Nature2001 such as Stella; 388:773-778).
The third element by relate to various Endocannabinoids parts form and the protein of elimination is represented (Piomelli, D.Nat Rev.Neurosci.2003; 4:873-884).
Cannabined receptor can be by Endocannabinoids and synthetic ligands activation.
Arachidonic acid thanomin (arachidonic acyl glycollic amide) for first kind of Endocannabinoids material finding (Devane etc., Science 1992; 258:1946-1949; Piomelli, D.Nat Rev.Neurosci.2003; 4:873-884).Present evidence shows that this lipid deutero-amboceptor discharges (Nature such as Di Marzo, 1994 by the neurone that is upset as required; 372:686-691; Giuffrida etc., Nat.Neurosci.1999,2:358-363); Efficient activation Cannabined receptor (Devane etc., Science 1992; 258:1946-1949) and by by carrier mediated absorption and the two step processes that hydrolysis (metabolism) is formed in the cell subsequently eliminate fast (Beltramo etc., Science 1997; 277:1094-1097; Di Marzo etc., Nature 1994; 372:686-691; Hillard etc., J.Lipid Res.1997; 38:2383-2398).
Having confirmed that Endocannabinoids arachidonic acid thanomin and 2-arachidonic acyl glycerine (2-arachidonylglycerol, (2-AG)) demonstrate discharge to strengthen and can control basic nociception threshold, and these two kinds of materials are all by in conjunction with CB 1Acceptor produce its most of effect (Meng etc., Nature 1998; Sep 24; 395 (6700): 381-3).Especially, the arachidonic acid thanomin is as CB 1Agonist works and show the pharmacological activity very nearly the same with other synthetic cannaboid in mouse.
Fatty acid amide hydrolase (FAAH)
Fatty acid amide hydrolase (FAAH) is the enzyme of hydrolysed fat acid acid amides (FAA) family endogenous signal conduction lipid.The fatty acid acyl amine of general type comprises N-acyl ethanol amine class (NAE) and lipid acid primary amide class (FAPA).The example of NAE comprises arachidonic acid thanomin (AEA), palmityl thanomin (PEA) and Oleoyl monoethanolamide (OEA).The example of FAPA comprises 9-Z-octadecylene acid amides or oleylamide (McKinney MK, Cravatt BF.2005.Annu Rev Biochem74:411-32)].FAAH not only works to fatty acid ethanol amide class and primary amide class as lytic enzyme, and to ester, such as, for example, 2-arachidonic acyl glycerine (2-AG) work (Mechoulam etc., Biochem.Pharmacol.1995; 50:83-90; Stella etc., Nature, 1997; 388:773-778; Biochem.Biophys.Res.Commun.1995 such as Suguria; 215:89-97).
FAAH omnipresence CNS (Freund etc., Physiol.Rev.2003; 83:1017-1066) and peripheral tissues, such as, pancreas for example, brain, kidney, skeletal muscle, placenta and liver (Giang, D.K. etc., Molecular Characterization of Human and Mouse Fatty AcidAmide Hydrolases.Proc.Natl.Acad.Sci.U.S.A.1997,94,2238-2242; Cravatt etc., PNAS, 2004, vol.101, no.29,10821-10826) middle wide expression.
Arachidonic acid thanomin or Arachidonyl ethanolamide are to cannaboid 1 type (CB 1) NAE (Devane WA etc., 1992.Science 258:1946-49) that works of the endogenic ligand of acceptor.The arachidonic acid thanomin is by being eliminated fast by carrier mediated transhipment and the two step processes be made up of hydrolysis in the born of the same parents of FAAH subsequently.FAAH hydrolysis arachidonic acid thanomin causes forming arachidonic acid and thanomin.The catalyst mechanism of inferring at present of FAAH hydrolysis arachidonic acid thanomin relates to the nucleophillic attack of the 241 amino acids residue Serines of the FAAH on the amide moieties of arachidonic acid thanomin, cause forming arachidonic acid and thanomin (Deutsch etc., The Fatty Acid Amide Hydrolase (FAAH) Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66 (2﹠amp; 3), 201-210; Alexander etc., Chemistry ﹠amp; Biology, vol.12,1179-1187; 2005).
The mutant mice that lacks the gene of coding FAAH is showing obvious decline and Cannabined receptor is being shown the active sign of enhanced arachidonic acid thanomin aspect the hydrolytic activity of arachidonic acid thanomin and other fatty acid acyl amine, thereby produce noticeable physiology phenomenon, such as pain decline (Cravatt BF etc., 2001.Proc Nat Acad Sci USA 98:9371-9376).The therapeutical agent that this prompting changes the FAAH enzymic activity can increase the effect of the interior arachidonic acid thanomin of body and other fatty acid acyl amine.This class promoting agent can also be avoided because of directly effect cannaboid multiple common effect of not expecting of causing the indiscriminate activatable of Cannabined receptor to produce of administration Δ 9-THC (active ingredient in the hemp) and other.
The non-fatty acid acyl amine of the endogenous of many non-arachidonic acid thanomins debond CB 1Acceptor.Several in verified these lipids can produce specific cell and behavior effect and can represent big nation endogenous signal conduction lipid, and they are in vivo to being different from CB 1Receptor system work.They comprise palmityl thanomin (PEA) (Calignano A etc., 1998.Nature 394:277-81; Jaggar SI etc., 1998.Pain 76:189-99; FranklinA, Parmentier-Batteur etc., 2003.J Neurosci 23:7767-75), stearyl glycollic amide (SEA) (Terrazino etc., 2004 FASEB J:18:1580-82; Maccarrone M etc., 2002.Biochem J 366:137-44) and Oleoyl monoethanolamide (OEA) (deFonseca FR etc., 2001.Nature 414:209-12; Fu J etc., 2003.Nature 425:90-93; Fu J etc., 2005.Neuropharmacology 48 (8): 1147-53).Confirmed that OEA and PEA all can activate peroxisome Proliferator-activated receptor α (PPAR-α) (Fu J etc., 2003.Nature 425:90-93; Guzman M etc., 2004, J Biol Chem 279 (27): 27849-54; Lo Verme J etc., 2005.Cell Mol LifeSci 62 (6): 708-16; LoVerme J etc., 2005.Life Sci 77 (14): 1685-98; Lo Verme J etc., 2005.Mol Pharmacol 67 (1): 15-9).By these effects, OEA and PEA can regulate several biological approaches, include, but are not limited to carry metabolism, pain and inflammation.Therefore, change the promoting agent of FAAH enzymic activity can control agent in the level of various fatty acid acyl amines, have therapeutic action by various targets thus.
Because bound by theory not, thus think some fatty acid acyl amine, such as, for example, OEA works by peroxisome Proliferator-activated receptor α (PPAR-α), so that regulate different physiological processes, comprise, for example, conveying and steatolysis.Consistent therewith is that confirmer's fatty tissue combination and metabolism Endocannabinoids are such as arachidonic acid thanomin and 2-arachidonic acyl glycerine.Referring to Spoto etc., on August 22nd, 2006, Biochimie (the E-class document before publishing); With (2006) such as Matias, J.Clin.Endocrin. ﹠amp; Met., 91 (8): 3171-3180.Therefore, suppress the reduction that the interior FAAH activity of body causes body fat, body weight, calorie picked-up and liver triglyceride levels.Yet, be different from other lipid lowerers (anti-lipidemic agents) that works by PPAR-α, for example, the special class of shellfish, the FAAH inhibitor can not have side effects such as fash, fatigue, headache, erective dysfunction, more rare anaemia, oligoleukocythemia, angioedema and hepatitis.For example, referring to Muscari etc., (2002), Cardiology, 97:115-121.The additional procedures characteristic of FAAH inhibitor produces because of the ability of its rising arachidonic acid thanomin level, and their effective alleviate depression disease and anxieties are usually with the relevant illness of energy metabolism disorder (EMD), such as obesity.Referring to Simon etc., (2006), Archives of Gen.Psychiatry, 63 (7): 824-830.In certain embodiments, FAAH inhibitor compound periphery can be limited, and the obstacle that can not affect the nerves basically is such as for example dysthymia disorders and anxiety.Finally, the agonism that also confirms Cannabined receptor has been alleviated the atherosis progress of animal model medium sized artery.Referring to Steffens etc., (2005), Nature, 434:782-786; With Steffens etc., (2006), Curr.Opin.Lipid., 17:519-526.Therefore, estimating to increase Endocannabinoids (cannabinergic) fatty acid acyl amine (for example arachidonic acid thanomin) level effectively treats pulse atherosclerosis or alleviates the risk of its generation.
Many fatty acid acyl amines produce as required and are degraded fast by FAAH.As a result of, think that the FAAH hydrolysis is to regulate central nervous system one of the essential approach of fatty acid amide level in peripheral tissues and the fluid of unifying.The extensive distribution prompting of the FAAH of associating one group of fatty acid acyl amine biological action widely (mechanism of Endocannabinoids and non--Endocannabinoids) suppresses FAAH and can cause many tissues to change with fatty acid acyl amine level in the fluid and can be used for the treatment of many different illness.The FAAH inhibitor increases the level of endogenous fatty acid acyl amine.The FAAH inhibitor is blocked the Endocannabinoids degraded and is increased the level of organizing of these endogenous material.The FAAH inhibitor can be used in this respect prevent and treat Endocannabinoids and/or any other the pathology situation by the material of FAAH enzymes metabolism of relating to.
Estimating to suppress FAAH causes the level of arachidonic acid thanomin and other fatty acid acyl amine to increase.The increase of this fatty acid acyl amine can cause the nociception territory to increase.Therefore, in one embodiment, the FAAH inhibitor is used for the treatment of pain.This class inhibitor evil also can be used for the treatment of other illness that can use fatty acid acyl amine or Cannibinoid receptor modulators treatment, such as, for example, anxiety, eating disorder, metabolism disorder, cardiovascular disease and inflammation.
Various fatty acid ethanol amide classes have important with different physiologic functions.As a result of, the inhibitor molecules of selectivity inhibition FAAH enzymic activity can be carried out correspondingly selectivity adjusting with the outer FAAH concentration of substrate of born of the same parents in the pair cell.Biocompatibility FAAH inhibitor can be effective medical compounds when being used for any therapeutical agent that wherein needs the clinical indication that the FAAH enzyme suppresses being mixed with.In certain embodiments, the FAAH activity in the peripheral tissues preferentially is inhibited.In certain embodiments, mainly can be used for preferentially suppressing the FAAH activity of peripheral tissues through the FAAH inhibitor of hemato encephalic barrier.In certain embodiments, the active FAAH inhibitor of FAAH that preferentially suppresses in the peripheral tissues can be minimized the FAAH restraining effect in the central nervous system.In certain embodiments, it is active and the FAAH in the central nervous system suppressed to be reduced to bottom line preferentially to suppress FAAH in the peripheral tissues.
Can have benefited from disease, illness that the FAAH enzymic activity suppresses, syndrome and/or illness comprise, for example, alzheimer's disease, schizophrenia, dysthymia disorders, alcoholism, habituation, suicide, Parkinson's disease, Huntington Chorea, apoplexy, vomiting, miscarriage, embryo's implantation, endotoxin shock, liver cirrhosis, atherosclerosis, cancer, traumatic brain injury, glaucoma and bone cement are implanted syndrome.
Other can have benefited from the active disease that suppresses of FAAH, illness, syndrome and/or illness comprise, for example, and multiple sclerosis, the retinitis, amyotrophic lateral sclerosis, the encephalitis that immunodeficiency virus brings out, attention deficit Attention Deficit Hyperactivity Disorder, pain, nociceptive pain, neuropathic pain, inflammatory pain, non--inflammatory pain, pain property hemorrhagic cystitis, obesity, hyperlipidemia, metabolism disorder is fed and fasting, and appetite changes, anxiety, memory, aging, hypertension, septic shock, heart shock, enteritis and intestinal motility, irritable bowel syndrome, colitis, diarrhoea, ileitis, local asphyxia, cerebral ischemia, liver ischemic, myocardial infarction, the brain excitatory toxicity, epilepsy, febrile seizure, neurotoxicity, neuropathy, sleep, sleep derivation, sleep prolongs, insomnia and inflammatory diseases.
Can have benefited from active nerve and the mental disorder that suppresses of FAAH and comprise, for example, pain, dysthymia disorders, anxiety, generalized anxiety disorder (GAD), obsession, anxiety, stress urinary incontinence, the attention deficit Attention Deficit Hyperactivity Disorder, schizophrenia, psychosis, Parkinson's disease, muscle spasm, epilepsy, dyskinesia, epileptic seizures, trouble with jet lag and insomnia.
The FAAH inhibitor can also be used for the treatment of various metabolism syndromes, disease, and disorder and/or illness include, but are not limited to insulin resistance syndrome, diabetes, hyperlipidaemia, fatty liver disease, obesity, atherosclerosis and arteriosclerosis.
The FAAH inhibitor is used for the treatment of various pain syndromes, disease, illness and/or illness, include, but are not limited to be characterised in that with non--inflammatory pain, inflammatory pain, peripheral nerve pain, central pain, deafferentation pain, chronic injury susceptibility pain, the nociception receptor for stimulating, those diseases that it is feature that phantom limb pain and is crossed impatient property pain.
Suppress the FAAH activity and can also be used for the treatment of the various illness that relate to inflammation.These illness comprise, but be not limited to sacroiliitis (such as rheumatoid arthritis, shoulder slip or bursitis, urarthritis and polymyalgia rheumatica), the organ specificity inflammatory diseases is (such as thyroiditis, hepatitis, inflammatory bowel), asthma, other autoimmune disease (such as multiple sclerosis), chronic obstructive pulmonary disease (COPD), allergic rhinitis and cardiovascular disorder.
In some cases, the FAAH inhibitor is used to prevent neurodegeneration or neuroprotective.
In addition, verified when the FAAH activity descends or do not exist, one of its substrate arachidonic acid thanomin works as the substrate of COX-2, and the arachidonic acid thanomin is changed into prostamides (Weber etc., J.Lipid.Res.2004; 45:757).The concentration of some prostamides can raise in the presence of the FAAH inhibitor.Some prostamides reduces with intraocular pressure and borehole pressure is crossed low relevant.Therefore, in one embodiment, the FAAH inhibitor can be used for the treatment of glaucoma.
In certain embodiments, the FAAH inhibitor can be used for the treatment of EMD or reduce its risk, and it includes, but are not limited to obesity, limited appetite, overweight, honeycomb tissue, I type and type ii diabetes, hyperglycemia, hyperlipemia, fat hepatitis, fatty liver, nonalcoholic fatty liver disease, X syndrome, insulin resistant, diabetic hyperlipemia, appetite stimulator, easy hungry disease, anorexia nervosa, hyperlipidaemia, hypertriglyceridemia, atherosclerosis, arteriosclerosis, inflammatory conditions or illness, alzheimer's disease, Crohn's disease, vascular inflammation, inflammatory bowel, rheumatoid arthritis, asthma, thrombus or emaciation.
In other embodiments, the FAAH inhibitor can be used for the treatment of insulin resistance syndrome or reduce its risk, i.e. primary basic model diabetes are such as type i diabetes or type ii diabetes; With the non-basic model diabetes of Secondary cases.The composition that vivo medicine-feeding comprises the FAAH inhibitor for the treatment of significant quantity has alleviated the seriousness of diabetic symptom or the risk of generation diabetic symptom, such as atherosclerosis, and hypertension, hyperlipidaemia, fatty liver, ephrosis, neuropathy, retinopathy, ulcer of foot or cataract.
In another embodiment, the FAAH inhibitor can be used for the treatment of the food abuse, especially easily causes overweight those, and bulimia for example is to sugar or fatty appetite and non-insulin-dependent diabetes mellitus (NIDDM).
In certain embodiments, the FAAH inhibitor can be used for the treatment of and suffers from EMD and suffer from dysthymia disorders or the patient of anxiety disorder.Preferably the diagnosis experimenter suffers from dysthymia disorders or psychosis before administration FAAH inhibitor combination.Therefore, will to EMD and dysthymia disorders or anxiety disorder for the effective FAAH inhibitor dosage of treatment to experimenter's administration.The method that suppresses to treat anxiety disorder and dysthymia disorders by FAAH is described in for example Application No. US10/681, in 858 and 60/755,035.
The preferred experimenter who is treated behaves.Yet these methods can also be used for the treatment of inhuman Mammals.The animal model of EMD is such as for example U.S. Pat 6,946, and those are particularly useful described in 491.
Above-mentioned illness symptom separately, diagnostic test and prognostic assay are known in the art.For example, referring to " Harrison ' s Principles of Internal Medicine , " 16th ed., 2004, McGraw-Hill Companies, Inc. and " Diagnostic and Statistical Manual of Mental
Figure A20068004995800422
, " 4th ed., 1994, American Psychiatric Association.
The FAAH inhibitor combination can also be used to alleviate those not necessarily wish the individuality of reduction body weight for the medical treatment consideration for beauty treatment body weight.
Can be with FAAH inhibitor combination and the medication combined administration that reduces the circulation cholesterol levels (for example statins, nicotinic acid, fiber acid derivative or bile acide binding resin).The FAAH inhibitor combination can also with the weight reduction medicine, for example orlistat or appetite-inhibiting agent, such as Diethylpropion, Mazindol, orlistat, phendimetrazine, phentermine or sibutramine coupling.
Methods described herein can also comprise to be provided workout scheme or calorie restricted diet (for example limiting the triglyceride level diet) is provided the experimenter.
Alkyl carbamate class and alkylthio amino formate shown hope as selectivity FAAH inhibitor (Kathuria etc., Nat.Med.2003,9:76-81).A series of alkylamino formic acid aryl ester classes; such as; for example; confirmed cyclohexyl carboxylamine 3 '-formamyl biphenyl-3-base ester (be also referred to as 5 '-formamyl biphenyl-3-basic ring hexyl carbamate; UCM597, URB597 and KDS-4103 (URB-597)) be FAAH activity inhibitor effectively and optionally.Alkylamino formic acid aryl ester class, such as, for example, confirmed cyclohexyl carboxylamine 3 '-formamyl biphenyl-3-base ester is FAAH activity inhibitor effectively and optionally, they can be not obviously with the serine hydrolase of selecting or with the Cannabined receptor (Mor etc. that interact, J.Med.Chem.2004,47:4998-5008; People's such as Piomelli International Patent Publication No. WO 2004/033422; Be incorporated herein by reference).
Alkylamino formic acid aryl ester class suppresses the FAAH activity by the irreversible interaction with FAAH, this may be (Kathuria etc. due to the nucleophillic attack of the active ser residue (Serine 241) because of the FAAH on the carbamate moiety of alkylamino formic acid aryl ester compound, Nature Medicine, vol.9, no.1,76-81,2003; Deutsch etc., Prostaglandins, Leukotrienes and Essential Fatty Acids (2002) 66 (2﹠amp; 3), 201-210; Alexander etc., Chemistry ﹠amp; Biology, vol.12,1179-1187; 2005.).The FAAH enzyme causes the aryloxy of carbamate compounds hydrolysis and alkylamino formic acid aryl ester inhibitor partly to discharge to the metabolism of alkylamino formic acid aryl ester inhibitor.
This paper provides the compound of alkyl carbamate class, comprises their compoistion and method of use.Compound provided herein has and is selected from following structure:
Figure A20068004995800431
Wherein D is O or NR 11X respectively do for oneself CH or N; One of A or B are (CH 2) nC (O)-alkyl, (CH 2) nC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl, and wherein n is 0,1,2,3 or 4 and R 2Respectively do for oneself H or the optional alkyl that replaces; Or A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, wherein n is 1,2,3 or 4; Or A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group; Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together; R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O); R 2And R 11Be H or the optional alkyl that replaces;
And pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In other embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
In addition, compound provided herein has and is selected from following structure:
Wherein D is O or NR 11
R 1Be selected from:
R 1Be selected from:
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12, aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, imidazopyrimidine base, Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine Ji ， oxazole and pyridyl ， isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Common formation:
Figure A20068004995800451
N is 1,2,3 or 4; M is 1,2,3 or 4;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k is 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-and C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ', (alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
With pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In certain embodiments, the compound of formula (IIIa) has following structure:
Figure A20068004995800461
Compound described herein also is:
Figure A20068004995800462
Wherein D is O or NR 11
R 1Be selected from:
R 1Be selected from:
Figure A20068004995800463
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12, aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, imidazopyrimidine base, Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine Ji ， oxazole and pyridyl ， isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Common formation:
Figure A20068004995800471
N is 1,2,3 or 4; M is 1,2,3 or 4;
A and B constitute together and comprise C (O)-(CH 2) qNon--aromatics the cyclic group of the optional replacement of-part, wherein q is 1,2,3 or 4;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B constitute together and comprise at least one N, NR 2, the aromatics of the optional replacement of S or O group or non--aromatics cyclic group;
Or one of A or B are-L-G and another C that is selected from H and chooses replacement wantonly 1-C 6Alkyl;
Or A and B constitute the optional aromatic carbocyclyl groups that replaces together;
Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces, the optional acid amides that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
L is key or the optional group that replaces, and described group is selected from C 1-C 6Alkylidene group, C 1-C 6Inferior assorted alkyl, C 1-C 6The ketone group alkylidene group ,-C (O) NR 9-(CH 2) j-,-NR 9-C (O)-(CH 2) j-,-OC (O) O-(CH 2) j-,-NHC (O) O-(CH 2) j-,-O (O) CNH-(CH 2) j-,-C (O) O-(CH 2) j-,-OC (O)-(CH 2) j-, NR 9C (O) N (R 9)-(CH 2) j-,-S (O)-(CH 2) j-,-S (O) 2-(CH 2) j-,-C (=NR 10) N (R 9)-(CH 2) j-and-NR 9C (=NR 10) N (R 9)-(CH 2) j-;
G be tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2NHR 8,-S (=O) 2The NH-phenyl ,-OH ,-SH ,-OC (O) NHR 8,-NHC (O) OR 8,-C (O) NHC (O) R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8,-S (=O) 2NHC (O) NHR 8,-NHC (O) R 8,-NHC (O) N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) NHC (=NR 10) N (R 9) 2,-NR 9C (=CHR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CHR 10) N (R 9) 2,-CO 2H ,-(OP (=O) OH) xOH ,-OP (=O) OR 8OH ,-OP (=O) R 8OH ,-NR 9P (=O) OR 8OH ,-NR 9P (=O) R 8OH ,-P (=O) OR 8OH;-P (=O) R 8OH ,-S (O) yOH;-OS (O) yOH;-NR 9S (O) yOH;
R 8Independent of separately replacing or unsubstituted C 1-C 6Alkyl;
R 9Independent separately is H, the C of replacement 1-C 6Alkyl or unsubstituted C 1-C 6Alkyl;
R 10Be selected from H independently of one another ,-S (=O) 2R 8,-S (=O) 2NH 2,-C (O) R 8,-CN and-NO 2
J is 0,1,2,3 or 4; X is 1,2 or 3; Y is 0,1 or 2;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k is 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-and C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
With pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In other embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
Further compound described herein has the formula (1) that discloses among the U.S. Provisional Patent Application US 60/755,035 that submitted on December 29th, 2005, formula (2), formula (3), formula (4), formula (5), formula (6), formula (7), formula (8), formula (9), formula (10), formula (11), formula (12), formula (13), formula (14), formula (15), formula (16), formula (17), formula (18), formula (19), formula (20), formula (21), formula (22), formula (23), formula (24), formula (25), formula (26), formula (27), the structure of formula (28) or formula (29) is incorporated herein by reference the document; As long as R 1Group has and is selected from following structure:
Figure A20068004995800501
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12, aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, imidazopyrimidine base, Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine Ji ， oxazole and pyridyl ， isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl.
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Common formation:
N is 1,2,3 or 4; M is 1,2,3 or 4;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k is 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-and C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
Some technical term of chemistry
Unless otherwise defined, otherwise all technology used herein have and the identical implication of asking for protection theme person of an ordinary skill in the technical field common sense with scientific terminology.Unless otherwise stated, otherwise will be through all related patents in the complete disclosure content of this paper, patent application, open material intactly is incorporated herein by reference.In the situation of the various definitions that has this paper term, be defined as the master with in this part those.If relate to URL or other this class identifier or address, should understand so that this class identifier can change and the internet on specifying information can not be changeless, but the information that is equal to can find by the retrieval internet.Their reference has been confirmed the utilizability and the public popularization of this category information.
Should understand above-mentioned general description and following detailed description only for typical and indicative, but any theme of asking for protection not had the qualification effect.In this application, unless do concrete statement in addition, the application of odd number also comprises plural number.Must be noted that, describe, otherwise as the singulative " a kind of (a) " that uses in this specification sheets and the claim that awaits the reply, " a kind of (an) " and " described (the) " comprises plural indicator unless have in addition in the context clearly.In this application, unless otherwise stated, otherwise " or " the application intention " and/or ".In addition, term " comprises (including) " and other form, and such as " comprising (include) ", the application of " comprising (includes) " and " comprising (included) " is nonrestrictive.
Sub-section titles used herein only is used for organizational goal, but is not to be used for limiting described theme.For any purpose especially with the All Files quoted among the application or the part of file, include, but are not limited to patent, patent application, article, books, handbook and paper intactly are incorporated herein by reference.
The definition of standard chemical term can be found in book of reference, comprises Carey and Sundberg " ADVANCED ORGANIC CHEMISTRY 4 THED. " Vols.A (2000) and B (2001), Plenum Press, New York.Unless otherwise stated, otherwise the conventional mass spectrum of use, NMR, HPLC, protein chemistry, biological chemistry, recombinant DNA technology and pharmacological method.Unless provide concrete definition, otherwise analytical chemistry as herein described, synthetic organic chemistry and medical science and pharmaceutical chemical laboratory method and technology term related and that be used for them be as known in the art those.Standard technique can be used for chemosynthesis, chemical analysis, medication preparation, preparation and conveying and treatment patient.Standard technique can be used for recombinant DNA, synthetic and tissue culture of oligonucleotide and conversion (for example electroporation, fat transfection).Can use the test kit that for example has manufacturer specification react with purification technique or as this area usually as described in or as described herein carrying out.Above-mentioned technology and method generally as known in the art ordinary method or as citation in this context and discuss various generally with carry out described in the reference more specifically.
" alkoxyl group " intention (alkyl) O-group, wherein alkyl as defined herein.
" alkyl " intention aliphatic hydrocarbyl.Moieties can be " saturated alkyl ", this means that it does not contain any alkene or alkynyl moiety.Moieties can also be " unsaturated alkyl " part, this means that it comprises at least one alkene or alkynyl moiety." alkene " part intention has the group of at least one carbon-to-carbon double bond, and " alkynes " part intention has the group of at least one carbon-to-carbon triple bond.No matter moieties is saturated or undersaturatedly all can be side chain, straight chain or cyclic.According to the difference of structure, alkyl can be monoradical or divalent group (being alkylidene group).
C used herein 1-C xComprise C 1-C 2, C 1-C 3... C 1-C x
" alkyl " part can have 1-10 carbon atom, and (no matter whether it occurs each integer in numerical range such as this stated limit of " 1-10 " intention in this article; For example " 1-10 carbon atom " intention alkyl can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., up to and comprise 10 carbon atoms, but, this definition also covers the term of not specifying numerical range " alkyl " that occurs).Can be with the alkyl name " C of compound described herein 1-C 4Alkyl " or similar title.Only as an example, " C 1-C 4Alkyl " be illustrated in and have 1-4 carbon atom on the alkyl chain, promptly alkyl chain is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Therefore, C 1-C 4Alkyl comprises C 1-C 2Alkyl and C 1-C 3Alkyl.Alkyl can be substituted or not be substituted.Typical alkyl includes, but are not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
The acyclic alkyl of term used herein " non--cycloalkyl " intention (straight or branched that promptly comprises at least one carbon atom).Non--cyclic alkyl can be fully saturated non--cyclenes class and/or the alkynes class of maybe can comprising.Non--cycloalkyl can be chosen wantonly and be substituted.
Term " alkylamine " intention-N (alkyl) xH yGroup, wherein x and y are selected from x=1, y=1 and x=2, y=0.When x=2, alkyl can be chosen the formation ring system wantonly jointly with the N atom that is connected them.
The alkyl type of two keys of the integral part that preceding two atomic buildings of term " thiazolinyl " intention alkyl are not aromatic group.Be that thiazolinyl begins with atom-C (R)=C (R)-R, the remainder of R intention thiazolinyl wherein, it can be identical or different.The limiting examples of thiazolinyl comprises-CH=CH 2,-C (CH 3)=CH 2,-CH=CHCH 3With-C (CH 3)=CHCH 3Alkenyl part can be side chain, straight chain or cyclic (in this case, it can also be called " cycloalkenyl group ").According to the difference of structure, thiazolinyl can be monoradical or divalent group (being alkenylene).Thiazolinyl can be chosen wantonly and be substituted.
Preceding two atomic building triple-linked alkyl types of term " alkynyl " intention alkyl.Be that alkynyl begins with atom-C ≡ C-R, the remainder of R intention alkynyl wherein, it can be identical or different.The limiting examples of alkynyl comprises-C ≡ CH ,-C ≡ CCH 3With-C ≡ CCH 2CH 3" R " part of alkynyl can be side chain, straight chain or cyclic.According to the difference of structure, alkynyl can be monoradical or divalent group (being alkynylene).Alkynyl can be chosen wantonly and be substituted.
" acid amides " for have formula-C (O) NHR or-chemical part of NHC (O) R, wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (by the ring bond with carbon) and heterolipid cyclic group (by encircling bond with carbon).Amide moieties can form key between amino acid or peptide molecule and compound described herein, form prodrug thus.Any amine on the compound described herein or carboxylic side-chain all can be by amidations.The method and the concrete group that prepare this class acid amides find in reference for well known to a person skilled in the art and being easy to, such as Greene and Wuts, and Protective Groupsin Organic Synthesis, 3 RdEd., John Wiley ﹠amp; Sons, New York, NY, 1999, the document intactly is incorporated herein by reference.
Term " aromatics " intention has the planar rings of the not localization π-electronic system that comprises the 4n+2 πDian Zi, and wherein n is an integer.Aromatics contains can be by 5,6,7,8,9 or 9 above atomic buildings.Aromatic substance can be chosen wantonly and be substituted.Term " aromatics " comprises isocyclic aryl (for example phenyl) and heterocyclic aryl (or " heteroaryl " or " heteroaromatic ") (for example pyridine).This term comprises that monocycle or fused rings encircle (promptly total the right ring of adjacent carbons) group more.
Term used herein " aryl " intention aromatic ring, each atom that wherein constitutes this ring is carbon atom.Aryl rings can be by 5,6, and 7,8,9 or 9 above carbon atoms constitute.Aryl can be chosen wantonly and be substituted.The example of aryl includes, but are not limited to phenyl, naphthyl, phenanthryl, anthryl, fluorenyl and indenyl.According to the difference of structure, aryl can be monoradical or divalent group (being arylidene).
" aryloxy " intention (aryl) O-group, wherein aryl as defined herein.
Chemical bond between term " key " or two atoms of " singly-bound " intention or two parts is thought the atom that connects by this key integral part for big substructure this moment.
The atom that term " carbocyclic ring " intention comprises the compound of one or more covalently closed circle structures and constitutes this ring skeleton is carbon atom.This term thus with carbocyclic ring with wherein encircle skeleton and comprise at least one heterocycle that is different from the atom of carbon and make a distinction.
Term " cycloalkyl " intention is carbon containing and hydrogen and can be for saturated only, the unsaturated or complete undersaturated monocycle of part or many cyclic groups.Cycloalkyl comprises the group with 3-10 annular atoms.The illustrative example of cycloalkyl comprises as the lower section:
Figure A20068004995800551
Figure A20068004995800552
Deng.According to the difference of structure, cycloalkyl can be monoradical or divalent group (for example encircling alkylidene group).
Term used herein " carbocyclic ring " intention ring, each atom that wherein constitutes this ring is carbon atom.Carbocyclic ring can be by 3,4, and 5,6,7,8,9 or 9 above carbon atoms constitute.Carbocyclic ring can be chosen wantonly and be substituted.
Term " ester " intention has the chemical part of formula-COOR, and wherein R is selected from alkyl, cycloalkyl, aryl, heteroaryl (by the combination of ring carbon) and heterolipid cyclic group (by the combination of ring carbon).Any hydroxyl on the compound described herein or carboxylic side-chain all can be esterified.The method and the concrete group that prepare this class ester find in reference for well known to a person skilled in the art and being easy to, such as Greene and Wuts, and Protective Groups in Organic Synthesis, 3 RdEd., John Wiley ﹠amp; Sons, New York, NY, 1999, the document is intactly introduced this for as a reference.
Term " halogen (halo) " or alternately " halogen (halogen) " or " halogenide " intention fluorine, chlorine, bromine or iodine.
Term " haloalkyl, " " haloalkenyl group ", " halo alkynyl " and " halogenated alkoxy " comprise the alkyl that at least one hydrogen is replaced by halogen atom, thiazolinyl, alkynyl and alkoxyl group.In the embodiment that some two or more hydrogen atom is replaced by halogen atom, halogen atom is all identical each other.In other embodiment that two or more hydrogen atoms are replaced by halogen atom, halogen atom is not identical entirely each other.Term " fluoroalkyl " and " Fluoroalkyloxy " comprise haloalkyl and halogenated alkoxy respectively, and wherein halogen is a fluorine.In certain embodiments, haloalkyl is optional is substituted.
Term used herein " assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " comprises the optional alkyl that replaces, thiazolinyl and alkynyl, wherein one or more skeletal chain atoms are selected from the atom of non-carbon, for example oxygen, nitrogen, sulphur, silicon, phosphorus or its combination.
The atom of non-carbon of term " heteroatoms " intention or hydrogen.Heteroatoms generally is independently selected from oxygen, sulphur, and nitrogen, silicon and phosphorus, but be not limited to these atoms.In having two or more heteroatomic embodiments, two or more heteroatomss all can be mutually the same or two or more heteroatomss in some or all can be differing from each other.
Any covalently closed circle structure of term used herein " ring " intention.Ring comprises, for example, and carbocyclic ring (for example aryl and cycloalkyl), heterocycle (for example heteroaryl and non--aromatic heterocycle), aromatic substance (for example aryl and heteroaryl) and non--aromatic substance (for example cycloalkyl and non--aromatic heterocycle).Ring can be chosen wantonly and be substituted.Ring can constitute the integral part of ring system.
The two or more rings of term used herein " ring system " intention, wherein Huan two or more condensing.Term " condenses " intention, and two or more encircle the structure of shared one or more keys.
Term " heteroaryl " or selectively " heteroaromatic " intention comprise one or more nitrogen that are selected from, the aryl of the ring hetero atom of oxygen and sulphur.At least one skeletal atom that contains " heteroaromatic " or " heteroaryl " part intention ring of N is the aromatic group of nitrogen-atoms.Polyheteroaromatic can be for condensing or non--condensed.The illustrative example of heteroaryl comprises as the lower section:
Figure A20068004995800561
Deng.According to the difference of structure, heteroaryl can be monoradical or divalent group (being heteroarylidene).
Term used herein " non--aromatic heterocycle ", " Heterocyclylalkyl " or " heterolipid cyclic group " intention is non--aromatic ring, the one or more atoms that wherein constitute this ring are heteroatoms." non--aromatic heterocycle " or " Heterocyclylalkyl " intention comprise that at least one is selected from nitrogen, the heteroatomic cycloalkyl of oxygen and sulphur.These groups can with aryl or heteroaryl-condensed.Heterocycloalkyl ring can be by 3,4, and 5,6,7,8,9 or 9 above atomic buildings.Heterocycloalkyl ring can be chosen wantonly and be substituted.In certain embodiments, non--aromatic heterocycle comprises one or more carbonyls or thiocarbonyl group, such as, for example, contain the group of oxo and sulfo-.The example of Heterocyclylalkyl includes, but are not limited to lactams, lactone, and the cyclin imide class, epithio is for acid imide, the cyclic carbramates class, tetrahydrochysene sulfo-pyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxin, 1,3-diox, 1, the 4-dioxin, 1,4-diox, piperazine, 1, the 3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydrochysene-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacid, dioxo piperazine, glycolylurea, dihydrouracil, morpholine ， trioxane, six hydrogen-1,3, the 5-triazine, tetramethylene sulfide, tetrahydrofuran (THF), pyrroline, tetramethyleneimine, tetramethyleneimine, pyrrolidone, pyrazoline, pyrazolidine, tetrahydroglyoxaline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane isoxazoline ， isoxazole alkyl ， oxazoline ， oxazolidine oxazolidone, thiazoline, thiazolidine and 1,3-oxathiolane.The illustrative example that is also referred to as the Heterocyclylalkyl of non--aromatic heterocycle comprises:
Figure A20068004995800571
Figure A20068004995800572
Deng.Term heterolipid cyclic group also comprises all loop types of carbohydrate, includes, but are not limited to monose, disaccharides and oligosaccharides class.
Term " heterocycle " intention comprises 1-4 and is selected from O separately, the heteroatomic heteroaromatic of S and N and heterolipid cyclic group, and wherein each heterocyclic radical has 4-10 atom on its ring system, and wherein the ring of this group does not contain two adjacent O or S atom.No matter whether show carbonatoms on the heterocycle (C for example herein, 1-C 6Heterocycle), another atom (heteroatoms) must be present on this ring at least.Title is such as " C 1-C 6Heterocycle " carbonatoms on the finger ring only, and the sum of atom on the finger ring not.Should understand heterocycle and on its ring, can have extra heteroatoms.Title, and the total atom number that on ring, comprises such as " 4-6 unit heterocycle " intention (i.e. 4,5 or 6 yuan of rings, wherein at least one atom is a carbon atom, at least one atom is that a heteroatoms and a remaining 2-4 atom are carbon atom or heteroatoms).In having two or more heteroatomic heterocycles, these two or more heteroatomss each other can be identical or different.Heterocycle can be chosen wantonly and be substituted.Can combine with heterocycle by heteroatoms or carbon atom.Non--aromatic heterocyclic radical is included in the group that only has 4 atoms on its ring system, but aromatic heterocyclic radical must have at least 5 atoms on its ring system.Heterocyclic radical comprises benzo-fused ring system.The example of 4-unit heterocyclic radical is azetidinyl (derived from an azetidine).The example of 5-unit heterocyclic radical is a thiazolyl.The example of 6-unit heterocyclic radical is a pyridyl, and the example of 10-unit heterocyclic radical is a quinolyl.The example of non--aromatic heterocyclic radical is a pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydrochysene sulfo-pyranyl, piperidino-(1-position only), morpholino, thiomorpholine is for thioxane base, piperazinyl, azetidinyl, the propylene oxide base, Thietane base, homopiperidinyl, the oxepane alkyl, thia suberane base, oxygen azepine
Figure A20068004995800581
Base, diaza
Figure A20068004995800582
Base, the sulphur azepine
Figure A20068004995800583
Base, 1,2,3, the 6-tetrahydro pyridyl, the 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl ， alkyl dioxin, 1, the 3-alkyl dioxin, pyrazolinyl, dithiane base, dithia cyclopentyl, dihydro pyranyl, the dihydro-thiophene base, dihydrofuran base, pyrazolidyl, imidazolinyl, imidazolidyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptane base, 3H-indyl and quinolizinyl.The example of aromatic heterocyclic radical is a pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl ， isoxazolyl, thiazolyl ， oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, cinnolines base, indazolyl, the indolizine base, phthalazinyl, pyridazinyl, triazinyl, pseudoindoyl, pteridyl, purine radicals ， oxadiazole base, thiadiazolyl group, the furazan base, benzo furazan base, benzothienyl, benzothiazolyl benzoxazolyl, quinazolyl, quinoxalinyl, naphthyridinyl and furo pyridyl.As the above-mentioned group derived from above-mentioned group (if this class being arranged if possible) that can connect for C-or that N-connects.For example, the group derived from the pyrroles can be pyrroles-1-base (N-connects) or pyrroles-3-base (C-connects).In addition, can be imidazoles-1-base or imidazo-3-yl (N-connects) or imidazoles-2-base derived from the group of imidazoles, imidazol-4 yl or imidazoles-5-base (be C-connect).Heterocyclic radical comprises benzo-fused ring system and (=O) the ring system that replaces of part is such as pyrrolidin-2-one by one or two oxo.According to the difference of structure, heterocyclic radical can be monoradical or divalent group (being heterocycloalkenyl).
Term " unit's ring " can comprise any ring structure.Term " unit " is intended to represent to constitute the skeletal atom number of this ring.Therefore, for example, cyclohexyl, pyridine, pyrans and sulfo-pyrans are 6-unit ring; Cyclopentyl, the pyrroles, pyrans and thiophene are 5-unit ring.
" isocyanato " intention-NCO group.
" isothiocyanic acid base " intention-NCS group.
The alkyl that term " ketone group alkyl " intention is replaced by oxo group.
The assorted alkyl that one of term " assorted ketone group alkyl " intention carbon atom is replaced by oxo group.
The specific fragment or the functional group of term " part " intention molecule.Chemical part is generally the chemical entity that is contained in or is attached in generally acknowledged on the molecule.
Term " multi-ring alkyl " intention comprises the alkyl of dicyclo or tricyclic hydrocarbon ring structure, comprises the bridging cycloalkyl ring, spirocyclane basic ring or condense cycloalkyl ring.Example comprises norcamphyl, adamantyl, dicyclo [x.y.z] alkyl (wherein x, y and z independently are 1,2,3 or 4 separately) or tricyclic alkyl.
" sulfinyl " intention-S (=O)-R.
" alkylsulfonyl " intention-S (=O) 2-R.
" thio alkoxy " intention-S-alkyl.
Term used herein " O-carboxyl " the intention formula RC (=O) group of O-.
Term used herein " C-carboxyl " intention formula-C (=O) group of OR.
Term used herein " ethanoyl " intention formula-C (=O) CH 3Group.
Term used herein " three halo methylsulfonyls " intention formula X 3CS (=O) 2-group, wherein X is a halogen.
The group of term used herein " cyano group " intention formula-CN.
Term used herein " S-sulfonamido " intention formula-S (=O) 2NR 2Group.
Term used herein " N-sulfonamido " intention formula RS (=O) 2The group of NH-.
Term used herein " O-formamyl " intention formula-OC (=O) NR 2Group.
Term used herein " N-formamyl " the intention formula ROC (=O) group of NH-.
Term used herein " O thiocarbamoyl " intention formula-OC (=S) NR 2Group.
Term used herein " N thiocarbamoyl " the intention formula ROC (=S) group of NH-.
Term used herein " C-amido " intention formula-C (=O) NR 2Group.
Term used herein " N-amido " the intention formula RC (=O) group of NH-.
Used herein as himself and substituting group " R " intention that occurs of band numeral name be selected from alkyl, cycloalkyl, aryl, heteroaryl (by ring carbon in conjunction with) and the substituting group of non--aromatic heterocycle (by the combination of ring carbon).
The group that term " the optional replacement " or " replacement " intention relate to can be replaced by one or more extra groups, and these groups separately and be independently selected from alkyl, cycloalkyl; aryl; heteroaryl; the heterolipid cyclic group; hydroxyl, alkoxyl group; aryloxy, sulfydryl; alkylthio; arylthio, alkyl sulfoxide, aryl sulfoxide; the alkyl sulfone; aryl sulfone, cyano group, halogen; carbonyl; thiocarbonyl group, isocyanato, thiocyano; the isothiocyanic acid base; nitro, whole haloalkyl, perfluoroalkyl; silyl and amino comprise one-and two-the amino and protected derivative that replaces.As an example, Ren Xuan substituting group can be L sR s, each L wherein sBe independently selected from key ,-O-,-C (=O)-,-S-,-S (=O)-,-S (=O) 2-,-NH-,-NHC (O)-,-C (O) NH-, S (=O) 2NH-,-NHS (=O) 2,-OC (O) NH-,-NHC (O) O-,-(replace or unsubstituted C 1-C 6Alkyl) or-(replace or unsubstituted C 2-C 6Thiazolinyl); R separately sBe independently selected from H, (replacing or unsubstituted low alkyl group), (replacing or unsubstituted low-grade cycloalkyl), heteroaryl or assorted alkyl.The protecting group that can constitute above-mentioned substituent protection derivative is to well known to a person skilled in the art and can find in the reference such as above-mentioned Greene and Wuts.
The compound that this paper occurs can have one or more three-dimensional centers and each center can exist with R or S configuration.The compound that this paper occurs comprises all diastereomers, enantiomorph and epimer form and suitable mixture thereof.If desired, can obtain steric isomer by means commonly known in the art, for example, by the chiral chromatographic column separation of stereoisomers.
Methods described herein and preparation comprise the N-oxide compound that uses compound described herein, crystal formation (being also referred to as polymorphic form) or pharmacologically acceptable salts and the active metabolite with active these compounds of same type.In some cases, compound can be used as the tautomer existence.All tautomers include in the compound scope that this paper occurs.In addition, compound described herein can with non-solventization and with the pharmacy acceptable solvent, such as water, the solvation form of ethanol etc. exists.The solvation form of the compound that this paper is occurred is considered as also that this paper discloses.
In this context, can select group and substituting group thereof so that stable part and compound is provided by those skilled in the art.
Compound
Suppressing active some compound of fatty acid amide hydrolase (FAAH) works in health.In certain embodiments, the FAAH inhibitor compound is used for the treatment of any different disease, illness or illness.In certain embodiments, compound provided herein is FAAH inhibitor compound optionally.
The FAAH inhibitor combination is described in the following document: Application No. US 10/681,858, and 60/755,035; U.S. Pat 6,462,054,6,949,574 and 6,891,043; International publication number WO 04020430, WO 04067498, and WO 04099176, and WO 05033066, and WO 02087569, and WO 03065989, and WO 9749667, WO9926584, WO 04033652 and WO 06044617; Cravatt etc., Current Opinionin Chemical Biology, 2003,7:469-475.; Kathuria etc., NatureMedicine, vol.9, no.1, pp76-81,2003.; J.Med.Chem.2003 such as Tarzia, 46,2352-2360.; With Drysdale etc., Current MedicinalChemistry, 2003,10,2719-2732.
This paper has also described the pharmacologically acceptable salts of this compounds, the acceptable prodrug of pharmaceutical activity metabolite and pharmacy.Provide the pharmacologically acceptable salts that comprises at least a this compounds or this compounds, the pharmaceutical composition of pharmaceutical activity metabolite and the acceptable prodrug of pharmacy.
In certain embodiments, compound provided herein is ionogenic and can pass through hemato encephalic barrier basically.In certain embodiments, this paper provides carbamate FAAH inhibitor, and they can be in ionization under the physiological pH and so lower by the possibility of hemato encephalic barrier.In certain embodiments, compound provided herein has ionogenic part under physiological pH.In other embodiments, compound provided herein has electric charge under pH.In some other embodiment, compound provided herein is protonated under physiological pH.In other embodiments, compound provided herein deprotonation under physiological pH.When needs will be in central nervous system the FAAH close mentation that suppresses to cause when being reduced to bottom line and/or avoiding them, this class FAAH inhibitor is particularly useful.
In certain embodiments, compound provided herein has and is selected from following structure:
Wherein D is O or NR 11
One of A or B are (CH 2) nC (O)-alkyl, (CH 2) nC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl, and n is 0,1,2,3 or 4;
Or A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, wherein n is 1,2,3 or 4;
Or A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group;
Or A and B constitute optional non-aromatics or the aromatic carbocyclyl groups that replaces together;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl),
R wherein 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O);
R separately 2And R 11Independent is H or the optional alkyl that replaces;
And
Pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In other embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
In certain embodiments, compound provided herein has the structure of formula (II):
Figure A20068004995800631
Wherein D is O or NR 11
R 1Be selected from:
R 1Be selected from:
Figure A20068004995800641
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12, aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, imidazopyrimidine base, Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine Ji ， oxazole and pyridyl ， isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Common formation:
N is 1,2,3 or 4; M is 1,2,3 or 4;
A and B constitute together and comprise C (O)-(CH 2) qNon--aromatics the cyclic group of the optional replacement of-part, wherein q is 1,2,3 or 4;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B constitute together and comprise at least one N, NR 2, the aromatics of the optional replacement of S or O group or non--aromatics cyclic group;
Or one of A or B be-L-G, and another is selected from H and optional C that replaces 1-C 6Alkyl;
Or A and B constitute the optional aromatic carbocyclic group that replaces together;
Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces, the optional acid amides that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
L is key or the optional group that replaces, and described group is selected from C 1-C 6Alkylidene group, C 1-C 6Inferior assorted alkyl, C 1-C 6The ketone group alkylidene group ,-C (O) NR 9-(CH 2) j-,-NR 9-C (O)-(CH 2) j-,-OC (O) O-(CH 2) j-,-NHC (O) O-(CH 2) j-,-O (O) CNH-(CH 2) j-,-C (O) O-(CH 2) j-,-OC (O)-(CH 2) j-,-NR 9C (O) N (R 9)-(CH 2) j-,-S (O)-(CH 2) j-,-S (O) 2-(CH 2) j-,-C (=NR 10) N (R 9)-(CH 2) j-and-NR 9C (=NR 10) N (R 9)-(CH 2) j-;
G be tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2NHR 8,-S (=O) 2The NH-phenyl ,-OH ,-SH ,-OC (O) NHR 8,-NHC (O) OR 8,-C (O) NHC (O) R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8,-S (=O) 2NHC (O) NHR 8,-NHC (O) R 8,-NHC (O) N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) NHC (=NR 10) N (R 9) 2,-NR 9C (=CHR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CHR 10) N (R 9) 2,-CO 2H ,-(OP (=O) OH) xOH ,-OP (=O) OR 8OH ,-OP (=O) R 8OH ,-NR 9P (=O) OR 8OH ,-NR 9P (=O) R 8OH ,-P (=O) OR 8OH;-P (=O) R 8OH ,-S (O) yOH;-OS (O) yOH;-NR 9S (O) yOH;
R 8Independent of separately replacing or unsubstituted C 1-C 6Alkyl;
R 9Independent separately is H, the C of replacement 1-C 6Alkyl or unsubstituted C 1-C 6Alkyl;
R 10Be selected from H independently of one another ,-S (=O) 2R 8,-S (=O) 2NH 2,-C (O) R 8,-CN and-NO 2
J is 0,1,2,3 or 4; X is 1,2 or 3; Y is 0,1 or 2;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k is 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-and C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
With pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In other embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
In certain embodiments, compound provided herein has the structure of formula (IIa):
Figure A20068004995800671
Formula (IIa).
In other embodiments, compound provided herein has the structure of formula (IIb): Formula (IIb).
In some other embodiment, compound provided herein has the structure of formula (IIc):
Figure A20068004995800673
Formula (IIc).
In another embodiment, compound provided herein has the structure of formula (IId):
Figure A20068004995800674
Formula (IId).
In some other embodiment, compound provided herein has the structure of formula (IIe):
Figure A20068004995800675
Formula (IIe).
In certain embodiments, A and B are H, as long as have at least one X and be N.In having the embodiment of X, at least one X is N.
In certain embodiments, this paper provides compound and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound with formula (I) structure:
Figure A20068004995800681
Formula (I)
Figure A20068004995800682
Wherein D is O or NR 11One of A or B are (CH 2) mC (O)-alkyl, (CH 2) mC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl, and wherein m is 0,1,2 or 3; Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together; Or A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group; Or A and B constitute optional non-aromatics or the aromatic carbocyclyl groups that replaces together; Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another; R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O); R 2Be selected from H or the optional alkyl that replaces independently of one another; R 11Be H or the optional alkyl that replaces.
With regard to any He all embodiments, but substituting group can be selected from the subgroup of listed selection scheme.For example, in certain embodiments, one of A or B are that C (O)-alkyl and another are H or alkyl or assorted alkyl.In certain embodiments, A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, wherein n is 1,2,3 or 4.In other embodiments, A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group.In certain embodiments, R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, wherein each Y and each Z be independently selected from halogen, methyl or trifluoromethyl or Y and Z can constitute each other 3-, 4-or 5-unit's carbocylic radical or oxo (=O).In certain embodiments, R 2Be H or the optional alkyl that replaces.In certain embodiments, R 11Be H.In other embodiments, be pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In other embodiments, A and B constitute the heterocycle of the optional oxo-replacement that replaces together, and it is selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
In certain embodiments, R 2Be H.In certain embodiments, one of A or B are C (O)-CH 3And another is CH 3
In other embodiments, non--limitative examples is selected from: 3-formamyl benzyl ring hexyl carbamate; 3-formamyl benzyl ring hexyl methyl carbamate; 3-acetylphenyl cyclohexyl carbamate; 3-acetylphenyl cyclohexyl methyl carbamate; 3-acetylphenyl sec.-propyl carbamate; 3-acetylphenyl isobutylamino manthanoate; With 3-acetylphenyl styroyl carbamate.In certain embodiments, A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, wherein n is 1,2,3 or 4.In other embodiments, n is 2.In certain embodiments, R 2Be H.In other embodiments, A or B are C (O)-CH 2CH 3
In certain embodiments, non--limitative examples is selected from: 2, and 3-dihydro-1-oxo-1H-indenes-6-basic ring hexyl carbamate; 2,3-dihydro-1-oxo-1H-indenes-6-basic ring hexyl methyl carbamate; 2,3-dihydro-1-oxo-1H-indenes-5-basic ring hexyl carbamate; With 2,3-dihydro-1-oxo-1-H-indenes-5-basic ring hexyl methyl carbamate.
A and B constitute together and comprise at least one N, NR in another embodiment 2, the heteroaromatic group of the optional replacement of S or O group.In certain embodiments, also comprise (CH) n-part, wherein n is 1,2 or 3.In another embodiment, on ring, comprising the heteroaromatic group of the optional replacement of single N.
In certain embodiments, non--limitative examples is selected from: quinoline-7-basic ring hexyl carbamate; Quinoline-7-basic ring hexyl methyl carbamate; Quinoline-7-basic ring heptyl carbamate; Quinoline-7-base (furans-2-yl) methyl carbamate; Quinoline-7-basic ring hexyl methyl carbamate; Quinoline-6-basic ring hexyl carbamate; Quinoline-6-basic ring hexyl methyl carbamate; Quinoline-6-base (furans-2-yl) methyl carbamate; Isoquinoline 99.9-7-basic ring hexyl carbamate; Isoquinoline 99.9-7-basic ring hexyl methyl carbamate; Isoquinoline 99.9-7-basic ring heptyl carbamate; And the acceptable N-oxide compound of pharmacy.
In certain embodiments, the optional heteroaromatic group that replaces comprises two heteroatomss that are selected from N, S and O.
In certain embodiments, non--limitative examples is selected from following group: 2-methyl benzo [d] thiazole-5-basic ring hexyl carbamate; 2-methyl benzo [d] thiazole-5-basic ring hexyl methyl carbamate; 2-methyl benzo [d] oxazole-5-basic ring hexyl carbamate; With 2-methyl benzo [d] oxazole-5-basic ring hexyl methyl carbamate.
In addition, compound provided herein has and is selected from following structure:
Figure A20068004995800701
Wherein D is O or NR 11
R 1Be selected from:
R 1Be selected from:
Figure A20068004995800711
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12, aryl, heteroaryl, Heterocyclylalkyl, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl ， oxazolyl ， isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, imidazopyrimidine base, Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine Ji ， oxazole and pyridyl ， isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Common formation:
Figure A20068004995800721
N is 1,2,3 or 4; M is 1,2,3 or 4;
Wherein Ren Xuan substituting group is selected from C independently of one another 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR ', wherein k is 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-and C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
With
Pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
In certain embodiments, the compound of formula (IIIa) has following structure:
Figure A20068004995800722
The preparation of compound
Can use the combination that well known to a person skilled in the art the standard synthetic technology or use method well known in the art and methods described herein and synthesize the active compound provided herein of inhibition FAAH.As further guidance, can also use following synthetic method.
Can use linear precedence to react, connect by method described herein and/or well known in the art subsequently so that provide compound described herein maybe they can be used for synthetic fragment.
The application of protecting group
Term " protecting group " intention blocking-up (block) some or all is partly reactive and prevent that this class group from participating in the chemical part that chemical reaction is removed until protecting group.Preferably can remove each protecting group by different modes.The protecting group that can rupture under complete differential responses condition satisfies the requirement that difference is removed.Can be by acid, alkali and hydrogenolysis are removed protecting group.Such as trityl; dimethoxytrityl; the such group of acetal and t-butyldimethylsilyl is unstable to acid, and can be used to protect and having by the Cbz group that can remove by hydrogenolysis and carboxyl and hydroxyl reaction part in the presence of to the amino of alkali labile Fmoc radical protection.Carboxylic acid and hydroxyl reaction part can be in the presence of by the amine of unsettled group such as tertiary butyl carbamate or but the carbamate blocking-up that can by hydrolysis method remove all stable to bronsted lowry acids and bases bronsted lowry to acid; quilt is to the unstable group of alkali; such as, but not limited to methyl, ethyl and ethanoyl blocking-up.
Carboxylic acid and hydroxyl reaction part can also be blocked such as benzyl by the protecting group that can remove by hydrolysis method, and can be blocked such as Fmoc by to alkali labile group with the amido that acid forms hydrogen bond.Carboxylic acid and hydroxyl reaction part can be protected by changing into the illustrative simple ester derivative of this paper; or they can be by oxidable protecting group of removing such as 2; the 4-dimethoxy-benzyl is blocked, and the common amino that exists can be blocked the unsettled silyl amino formate of fluorochemical.In one embodiment, the compound that contains carboxylic acid reaction part and hydroxyl reaction part can have one of reactive moieties that is blocked, and another reactive moieties is not blocked.
The allyl group blocking group have subsequently acid-and alkali-protecting group in the presence of be useful because the former is stable and can be removed by metal or π acid catalyst subsequently.For example, can use Pd 0-catalytic being reflected to the unsettled tertiary butyl carbamate of acid or to making the carboxylic acid deprotection of allyl group-blocking-up under the alkali labile amine acetate protecting group existence.The resin that the another kind of form of protecting group can be connected with compound or intermediate.As long as residue is connected with this resin, functional group can not react with regard to being blocked so.In case discharge from resin, functional group just can be utilized and participate in reaction.
Typical blocking group/protecting group can be selected from:
Figure A20068004995800741
Other protecting group is for example at Greene and Wuts, Protective Groups inOrganic Synthesis, 3rd Ed., John Wiley ﹠amp; Sons, New York, NY in 1999, intactly is incorporated herein by reference the document.
The preparation method of alkyl carbamate class
In certain embodiments, this paper provides the preparation method and the using method thereof of FAAH inhibitor compound provided herein.In certain embodiments, can use following synthetic schemes to synthesize compound provided herein.Can use and those similar methods as described below, by using suitable selectable raw material synthetic compound.
This paper has described active compound of inhibition fatty acid amide hydrolase (FAAH) and preparation method thereof.This paper has also described the pharmacologically acceptable salts of this compounds, the acceptable N-oxide compound of pharmacy, the acceptable prodrug of pharmaceutical activity metabolite and pharmacy.Provide the pharmacologically acceptable salts that comprises at least a this compounds or this compounds, the acceptable N-oxide compound of pharmacy, the pharmaceutical composition of pharmaceutical activity metabolite and the acceptable prodrug of pharmacy.
Prepare the alkyl carbamate class that this paper discloses by the general method shown in the scheme 1.The compound of Ar-OH (2) expression hydroxyl, the heteroaryl compound that it is selected from the phenol of replacement and comprises hydroxylic moiety.R 1And R 2As defined herein.
Synthesizing of scheme 1. alkyl carbamate classes
Figure A20068004995800751
Handle Ar-OH (2) with isocyanic ester or lsothiocyanates (3) in the organic solvent in the presence of alkali is arranged, wherein said alkali such as, triethylamine for example, described organic solvent such as, for example ethanol or acetonitrile, the result forms the alkyl carbamate class of structure 1 (for example, referring to U.S. Pat 5,112,859; WO 2004/033422; US 2006/0014830; J.Med.Chem.2004,47 (21); 4998-5008; Tarzia etc., J.Med.Chem.46:2352-2360 (2003); Kathuria etc., Nature Medicine 9 (1): 76 (2003)).Isocyanates or isosulfocyanate are what be purchased.The method for preparing isocyanates or isosulfocyanate (3) is well-known in the art.For example, isocyanates (3, Q=O) can pass through to use the trinitride source, such as, for example, sodiumazide or diphenyl phosphoryl azide are handled, and carry out curtius' rearrangement subsequently, (are R by corresponding carboxylic acid 1-COOH) or acid derivative (R for example 1Preparation-C (O) Cl) (for example, referring to Synth.Commun.1993,23,335; Heterocycles 1993,36, and 1305).
Selectively, can alkali arranged, such as, for example, triethylamine exists down, prepares alkyl carbamate class (1) by handling Ar-OH (2) with the alkylamino carboxylic acid derivatives of structure (4), wherein G is a 4-nitrophenoxy, and chlorine or imidazoles-1-base obtains required compound (1).Can use method well-known in the art to prepare the compound of structure (4), such as, Greene, T.W. and Wuts, P.G.M " Protective Groups in Organic Synthesis ", 3rd Edition, p.549, New York:Wiley, method described in 1999.In brief, with phosgene or phosgene equivalent, such as, for example, superpalite or carbonyl dimidazoles are handled alkyl amine (R for example 1-NH 2), obtain the compound of structure (4).
Can also be by generalized method synthesis of alkyl (sulfo-) amino formate in the scheme 2.
Synthesizing of scheme 2. alkyl (sulfo-) amino formate
Figure A20068004995800761
Can prepare alkyl (sulfo-) amino formate by two-step approach.At first handle thiophosgene with Ar-OH (2) in the suitable organic solvent in the presence of alkali is arranged, phosgene or its equivalent are used alkylamine subsequently, such as, R 1R 2NH handles.Can put upside down the order of this reaction, promptly can handle thiophosgene with alkylamine, phosgene or its equivalent use Ar-OH (2) to handle subsequently.The equivalent of thiophosgene photoreactive gas includes, but are not limited to 1,1 '-thio-carbonyldiimidazole, 1,1 '-carbonyl dimidazoles and superpalite.
Contain must hydroxyl compd A r-OH (2) can or use known in this field or the generalized method preparation of this paper available from merchandise resources.
Use reaction conditions described herein, obtain the alkyl carbamate class of this paper disclosure of good yield and purity.By usual manner well known in the art, such as, recrystallization, chromatogram, the compound of the method preparation that distillation and combination purifying this paper thereof disclose for example filtered.
This paper pays close attention to the arbitrary combination of the group of above-mentioned different variablees.
Pharmaceutical composition/preparation
Can use one or more physiology acceptable carriers in a conventional manner, include and be beneficial to that active compound is processed into can be at the vehicle and the auxiliary agent of the preparation that pharmaceutically uses, compounding pharmaceutical composition.Appropriate formulation depends on the route of administration of selection.Any well-known technology, carrier and vehicle all can be used as suitable used and is understood by this area.The general introduction of pharmaceutical composition described herein can be found in following document, for example Remington:The Science and and Practice of Pharmacy, NineteenthEd (Easton, Pa.:Mack Publishing Company, 1995); Hoover, JohnE., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; With Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams ﹠amp; Wilkins 1999), these documents intactly are incorporated herein by reference.
This paper provides the pharmaceutical composition that comprises compound described herein and pharmacy acceptable diluent, vehicle or carrier.In addition, can as in conjoint therapy, compound described herein be mixed with other active ingredient with compound described herein as the pharmaceutical composition administration.In certain embodiments, pharmaceutical composition can comprise other material or pharmaceutical agent, carrier, and adjuvant, such as sanitas, stablizer, wetting agent or emulsifying agent, dissolution accelerator is used to regulate the salt and/or the buffer reagent of osmotic pressure.In addition, pharmaceutical composition can also comprise upward valuable material of other treatment.
In certain embodiments, composition can also comprise one or more pH regulator agent or buffer reagents, comprises acid, such as acetate, and boric acid, citric acid, lactic acid, phosphoric acid and hydrochloric acid; Alkali, such as sodium hydroxide, sodium phosphate, Sodium Tetraborate, Trisodium Citrate, sodium acetate, Sodium.alpha.-hydroxypropionate and three-hydroxymethyl aminomethane; And buffer reagent, such as Citrate trianion/dextrose, sodium bicarbonate and ammonium chloride.Comprise this class acid, alkali and buffer reagent to keep composition pH at the required consumption of tolerance interval.
In other embodiments, composition can also comprise that one or more make osmolarity reach the salt of tolerance interval institute expense.This class salt comprises having sodium, potassium or ammonium cation and muriate, Citrate trianion, ascorbate salt, borate, phosphoric acid salt, supercarbonate, vitriol, anionic those salt of thiosulphate or hydrosulphite; Suitable salt comprises sodium-chlor, Repone K, Sulfothiorine, sodium bisulfite and ammonium sulfate.
Term used herein " drug combination " intention obtains and comprises the fixing of active ingredient and the product of fixed combination not by mixing or merge more than one active ingredients.Term " fixed combination " intention is active ingredient, compound for example described herein and common reagent with single body or dosage simultaneously to patient's administration.Term " no-fixed combination " intention is with active ingredient, compound for example described herein and common reagent are as independent body simultaneously, parallel or do not have the concrete timed interval restrictedly successively to patient's administration, wherein this class administration provides the level of significance of two kinds of compounds in patient's body.The latter also is applied to drug cocktail therapy (treatment), for example administration active ingredient more than three kinds or three kinds.
The compound that pharmaceutical composition intention this paper used herein discloses and other chemical ingredients be such as carrier, stablizer, thinner, dispersion agent, suspensoid, the mixture of thickening material and/or vehicle.Pharmaceutical composition helps giving drug compound to organism.In the process of implementing treatment provided herein or using method, to the compound described herein of the Mammals drug treatment significant quantity of the disease, illness or the illness that have the desire treatment.Preferred described Mammals is behaved.The treatment significant quantity can be according to severity of disease, experimenter's age and relative healthy state, the effect of compound used therefor and other factors different and extensive change.Can be separately or use described compound with uniting as one or more therapeutical agent of mix ingredients.
Can be by multiple route of administration to experimenter's administration pharmaceutical preparation described herein, include, but are not limited to orally, parenteral route (for example intravenously is subcutaneous, intramuscular) in the nose, is sucked, part, rectum or transdermal administration approach.Pharmaceutical preparation described herein includes, but are not limited to liquid, aqueous dispersion, self-emulsifying dispersion, sosoloid, the liposome dispersion, aerosol, solid preparation, powder, quick releasing formulation, controlled release preparation, the fast thawing preparation, tablet, capsule, pill, delayed release preparation prolongs delivery formulations, the pulsed delivery formulations, many granular preparations and quick-release and controlled release slurriable combination.
Can only as an example,, dissolve in a conventional manner, granulate such as by conventional mixing, system ingot (dragee-making), levigate, emulsification, the glue capsule, embedding or drawing method preparation comprise the pharmaceutical composition of compound described herein.
Described pharmaceutical composition comprises that the compound described herein of at least a free acid or free alkali form or pharmacologically acceptable salts form is as active ingredient.In addition, methods described herein and pharmaceutical composition comprise that use has the N-oxide compound of active these compounds of same type, crystal formation (being also referred to as polymorphic form) or pharmacologically acceptable salts and active metabolite.In some cases, compound can be used as the tautomer existence.All tautomers include in the compound scope that this paper occurs.In addition, compound described herein can exist with non-solventization with the solvation form of pharmacy acceptable solvent such as water, ethanol etc.The solvation form of the compound that this paper is occurred is considered as also that this paper discloses.
The some drugs term
Term used herein " treatment (treat) ", " treatment (treating) " or " treatment (treatment) " comprises alleviation, reduce or improve disease or illness symptom, prevent extra symptom, improve or prevention potential symptom metabolism reason, suppress disease or illness, for example stop the development of disease or illness, alleviate disease or illness, cause making disease or illness to disappear, or disease or illness symptom are stopped to prevent and/or treat mode.
Term used herein " acceptable " is at preparation, and composition or component aspect intention do not have persistent deleterious effect to the experimenter's that treated general health situation.
Term used herein " selective depressant compound " intention energy selectivity suppresses the specific function/active compound of one or more target proteins.
Term used herein " selectivity inhibition " thus intention selective depressant compound suppresses the specific function/activity of target protein, such as, the active ability of the fatty acid amide hydrolase of fatty acid amide hydrolase for example, its effect is greater than the activity to non--target protein.In certain embodiments, selectivity suppresses intention use selective depressant and suppresses target protein activity, the IC that it has 50At least be lower than the active IC of non--target protein 5010,50,100,250, more than 500,1000 or 1000 times.
The symptom intention of improving specified disease, illness or illness by administration specific compound or pharmaceutical composition used herein alleviates any of seriousness, postpone outbreak, slow down development or shorten the time limit, no matter be lastingly or of short duration, can be owing to giving drug compound or composition or associated lasting or temporary transient.
Term used herein " targeted activity " intention can be by the biological activity of selective modulator adjusting.Some typical target activity includes, but are not limited to binding affinity, signal transduction, enzymic activity, tumor growth, inflammation or process and improvement and disease or illness relevant one or more symptoms relevant with inflammation.
IC used herein 50Intention is reflected at maximum and realizes in the assay method of measuring this class reaction that 50% suppresses, such as consumption, concentration or the dosage of the fc-specific test FC compound that suppresses FAAH.
EC used herein 50Intention causes dosage, concentration or the consumption of the fc-specific test FC compound of dose-dependently response under 50% maximum expression of the specific reaction of being induced, causing or strengthened by the fc-specific test FC compound.
Term used herein " carrier " intention helps making compound to mix the relative nontoxicity chemical compound or the reagent of cell or tissue.
Term used herein intentions such as " co-administereds " comprises that therapeutical agent and appointment to single patient's administering selected comprise treatment plan, wherein by identical or different route of administration or at the described promoting agent of identical or different time administration.
Term used herein " significant quantity " or " treatment significant quantity " intention with one or more remissions of the disease of being treated or illness to the to a certain degree used promoting agent or the q.s of compound.The result can be for reducing and/or alleviate the sign of disease, symptom or reason, or any other required change of biosystem.For example, " significant quantity " that is used for the treatment of application is meant disease symptoms provided significantly to alleviate clinically and do not have the required this paper that comprises of excessive adverse side effect and discloses the consumption of compound compositions.Can use progressively increases technology such as research and determines suitable " significant quantity " in any individual case such as dosage.Term " treatment significant quantity " comprises, for example prevents significant quantity." significant quantity " of the compound that this paper discloses improved the consumption that does not have excessive undesirable action for effectively realizing required pharmacotoxicological effect or treatment.Should understand " significant quantity " or " treatment significant quantity " can change with the different of experimenter according to the experimenter, this is because of giving the metabolism of drug compound, experimenter's age, body weight, generalized case, the treatment condition, the seriousness of the illness for the treatment of and opening according to due to the clinicist's of prescription the variation of judgement.
Term used herein " strengthens (enhance) " or " strengthening (enhancing) " intention increases or prolong the effect or the time limit of required effect.Therefore, with regard to the effect that strengthens therapeutical agent, term " enhancings " intention is in effect or increase or prolong the ability of the effect of other therapeutical agent in system on the time limit." reinforcement significant quantity " used herein intention is enough to strengthen the consumption of the effect of another kind of therapeutical agent in required system.
Term " test kit " and " goods " use as synonym.
The compound derivatives that " metabolite " of the compound that this paper discloses forms during by metabolism for this compound.The bioactive metabolites of the compound that term " active metabolite " intention forms during by metabolism at this compound.Term used herein " metabolism " intention predetermined substance is by the summation of the process of organism transform (including, but are not limited to hydrolysis reaction and enzymatic reaction, such as oxidizing reaction).Therefore, enzyme can produce the specificity structure change to compound.For example, various oxidations of Cytochrome P450 catalysis and reduction reaction, and the glucuronic acid molecular transfer of UDP glucuronic acid based transferase catalytic activation is to aromatic alcohols, and aliphatic alcohol class, carboxylic acid is on amine and the free sulfhydryl groups.Relevant metabolic extraneous information can be available from The PharmacologicalBasis of Therapeutics, 9th Edition, McGraw-Hill (1996).Can identify the metabolite of the compound that this paper discloses by the host being given drug compound and analyzing from host's tissue sample or by at incubated in vitro compound and liver cell and analysis gained compound.Two kinds of methods are well-known in the art.In certain embodiments, the metabolite of compound forms and is equivalent to the compound of corresponding hydroxyl by oxidising process.In certain embodiments, compound is metabolised to the pharmacological activity metabolite.
" prodrug " intention is converted to the reagent of parent drug in vivo.Prodrug is normally useful, because in certain embodiments, they are easier to administration than parent drug.For example, they can be biological utilisation by oral administration, improve and parent drug can not.Prodrug also has the good solubleness in pharmaceutical composition above parent drug.The example of prodrug can be compound described herein, but be not limited to it, compound described herein is carried by cytolemma helping as ester administration (" prodrug "), water-soluble unfavorable in cytolemma to flowability, and then in case at cell interior, just be hydrolyzed into carboxylic acid with metabolic way, water-soluble in the promptly active body, cell is useful.Another example of prodrug can for the small peptide (polyamino acid) of acidic-group bonding, wherein peptide is exposed active part by metabolism.In certain embodiments, during administration, prodrug is converted to biology by chemical mode in vivo, has more active compound form in pharmacy or the treatment.In certain embodiments, make prodrug be metabolized to biology in the enzymatic mode, have more active compound form in pharmacy or the treatment by a step or multistep or process.In order to produce prodrug, the modified medicaments active compound makes this active compound regenerate during administration in vivo.The design prodrug so that shelter side effect or toxicity, improves the further feature or the characteristic of the taste or the change medicine of medicine to change the metabolic stability or the transport features of medicine.By means of pharmacodynamics process and the metabolic knowledge of drug disposition, in case pharmaceutical active compounds is known, the prodrug that those skilled in the art just can design this compound (for example, referring to Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York, the 388-392 page or leaf; Silverman (1992), The Organic Chemistry ofDrug Design and Drug Action, Academic Press, Inc., San Diego, 352-401 page or leaf).
What is called used herein " pharmacy is acceptable " intention can not eliminated biological activity or the characteristic and the avirulent relatively material of compound, such as carrier or thinner, promptly, can be to this material of individual administration, but do not produce unwanted biological action or can not interact with harmful mode and any composition in the composition that comprises it.
Term " pharmacologically acceptable salts " intention can be to administration its organism produce obvious stimulation and can not eliminate the compound goods of the biological activity and the characteristic of compound.Can be by making compound described herein and acid, all example hydrochloric acids, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc. reaction and obtain pharmacologically acceptable salts.Can also obtain pharmacologically acceptable salts by making compound described herein and alkali reaction generate salt, such as ammonium salt, an alkali metal salt is such as sodium or sylvite, alkaline earth salt, such as calcium or magnesium salts, organic bases is such as dicyclohexyl amine, N-methyl D-glycosamine, the salt of trihydroxymethylaminomethane, with with amino acid such as arginine, the salt of Methionin etc.; Or the salt that obtains by other method well known in the art.
In the film that " defoamer " reduce the foaming that may cause aqueous dispersion to solidify in the course of processing, make or the bubble of general influence processing.Typical defoamer comprises silicon emulsion or Span-83.
" antioxidant " comprise, for example, and Butylated Hydroxytoluene (BHT), sodium ascorbate, xitix, Sodium Pyrosulfite and tocopherol.In certain embodiments, if desired, the antioxidant enhancement chemical stability.
In certain embodiments, composition provided herein can also comprise the sanitas of one or more microbiostatic activity.Suitable sanitas comprises mercurous material, such as Phenylmercurinitrate and Thiomersalate; Stabilized chlorine dioxide; And quaternary ammonium compound, such as benzalkonium chloride, hexadecyl front three brometo de amonio and cetylpyridinium chloride.
Preparation described herein can have benefited from antioxidant, and metal chelator contains the compound of sulfydryl and other general stablizer.The example of this class stablizer comprises, but be not limited to: (a) the about 2%w/v glycerine of about 0.5%-, (b) the about 1%w/v methionine(Met) of about 0.1%-, (c) the about 2%w/v monothioglycerol of about 0.1%-, (d) the about 10mM EDTA of about 1mM-, (e) the about 2%w/v xitix of about 0.01%-, (f) the about 0.02%w/v Polysorbate 80 of 0.003%-, (g) the about 0.05%w/v Polysorbate 20 of 0.001%-, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) xylan polysulfate and other heparitin, (m) divalent cation is such as magnesium and zinc; Or (n) its combination.
" tackiness agent " given viscosity and comprised, for example alginic acid and salt thereof; Derivatived cellulose, such as carboxy methyl cellulose, methylcellulose gum (methyl fiber for example
Figure A20068004995800821
), HPMC, Natvosol, hydroxypropylcellulose are (for example
Figure A20068004995800831
), ethyl cellulose is (for example
Figure A20068004995800832
) and Microcrystalline Cellulose (for example
Figure A20068004995800833
); Microcrystalline Cellulose glucose; Amylose starch; Neusilin; Polysaccharide acid; Wilkinite; Gelatin; Polyvinylpyrrolidone//vinyl acetate copolymers; Polyvinylpolypyrrolidone; Polyvidone; Starch; Pregelatinized Starch; Tragacanth gum, sugar, such as sucrose (for example
Figure A20068004995800834
), glucose, dextrose, molasses, N.F,USP MANNITOL, sorbyl alcohol, Xylitol are (for example
Figure A20068004995800835
) and lactose; Natural or synthetic gum, such as gum arabic, tragacanth gum, ghatti gum, Semen Plantaginis glue, polyvinylpyrrolidone are (for example
Figure A20068004995800836
CL,
Figure A20068004995800837
CL,
Figure A20068004995800838
XL-10), the tamarack arabogalactan,
Figure A20068004995800839
, polyoxyethylene glycol, wax, sodiun alginate etc.
" bioavailability " intention is the weight percent that is conveyed into the compound that this paper of administration of the animal or human's who is studied systemic circulation discloses.Usually will be at the overall contact (AUC of medicine when the intravenous administration (0-∞)) be defined as 100% bioavailability (F%)." oral administration biaavailability " intention is compared with intravenous injection in the degree that is absorbed into systemic circulation by the oral compound that this paper discloses when taking pharmaceutical composition.
The concentration of " plasma concentration " intention compound provided herein in the plasma component of experimenter's blood.The plasma concentration that should understand compound provided herein can be between the experimenter significantly changes, and this is because of metabolism and/or with due to the possible interaction of other therapeutical agent.According to the embodiment that this paper discloses, the plasma concentration of compound provided herein can change between experimenter and experimenter.Equally, such as maximal plasma concentration (C Max) or reach the time (T of maximal plasma concentration Max) or the plasma concentration time curve under the total area (AUC (0-∞)) this class value can change between experimenter and experimenter.Because this variability can change between experimenter and experimenter so constitute " treatment significant quantity " necessary amount of compound provided herein.
" carrier substance " comprises any vehicle commonly used in the pharmaceutics, and should select based on the consistency of the compound that discloses with this paper and the release profile characteristic of required formulation.Typical carrier substance comprises, tackiness agent for example, suspensoid, disintegrating agent, weighting agent, tensio-active agent, solubilizing agent, stablizer, lubricant, wetting agent, thinner etc." pharmacy consistency carrier substance " can include, but are not limited to gum arabic, gelatin, colloid silica, neurosin; calcium lactate, Star Dri 5, glycerine, Magnesium Silicate q-agent; polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium-caseinate; soybean lecithin, taurocholate, phosphatidylcholine, sodium-chlor; tricalcium phosphate, dipotassium hydrogen phosphate, Mierocrystalline cellulose and Mierocrystalline cellulose conjugate, stearoyl lactate sugar; carrageenin, monoglyceride, triglyceride, pregelatinized Starch etc.For example, referring to Remington:The Science and Practice of Pharmacy, NineteenthEd (Easton, Pa.:Mack Publishing Company, 1995); Hoover, JohnE., Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; With Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams ﹠amp; Wilkins 1999).
" dispersion agent " and/or " viscosity modifier " comprises by liquid medium or granulation or fusion method control drug diffusion and inhomogeneity material.In certain embodiments, these reagent also help the maybe validity of erosion property skeleton of dressing.Typical diffusion promotor/dispersion agent comprises, hydrophilic polymer for example, and ionogen,
Figure A20068004995800841
60 or 80, PEG, polyvinylpyrrolidone (PVP; Be called on the commodity
Figure A20068004995800842
) and the carbohydrate dispersion agent, such as, for example, hydroxypropylcellulose (HPC for example, HPC-SL and HPC-L), HPMC (for example HPMCK100, HPMC K4M, HPMC K15M and HPMC K100M), Xylo-Mucine, methylcellulose gum, Natvosol, hydroxypropylcellulose, the phthalic acid HPMC, acetate stearic acid HPMC (HPMCAS), amorphous cellulose element, magnesium aluminum silicate, trolamine, polyvinyl alcohol (PVA), V-Pyrol RC/vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethyl butyl)-and the polymkeric substance (being also referred to as tyloxapol) of phenol and oxyethane and formaldehyde, poloxamer (Pluronics for example
Figure A20068004995800843
With
Figure A20068004995800844
Segmented copolymer for oxyethane and propylene oxide); With the husky amine (Poloxamine) in pool Lip river (Tetronic for example
Figure A20068004995800845
, be also referred to as Poloxamine
Figure A20068004995800846
, for add to four functional blocks multipolymer (BASF Corporation, Parsippany on the quadrol successively derived from propylene oxide and oxyethane, N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone//vinyl acetate copolymers (S-630), polyoxyethylene glycol, for example polyoxyethylene glycol can have the molecular weight of about 300-about 6000 or about 3350-about 4000 or about 7000-about 5400, Xylo-Mucine, methylcellulose gum, Tween-80, sodiun alginate, natural gum, such as, for example tragacanth gum and gum arabic, guar gum, xanthan gum comprises xanthan gum, carbohydrate, cellulose family, such as, Xylo-Mucine for example, methylcellulose gum, Xylo-Mucine, Tween-80, sodiun alginate, polyethoxylated sorbitan laurate, the polyethoxylated sorbitan laurate, polyvidone, carbomer, polyvinyl alcohol (PVA), alginate, chitosan and combination thereof.Softening agent can also be used as dispersion agent such as Mierocrystalline cellulose or triethyl Mierocrystalline cellulose.The dispersion agent that is used in particular for liposome dispersion and self-emulsifying dispersion is a dimyristoyl phosphatidyl choline, from the natural phosphatldylcholine of egg, from natural phospholipid acyl glycerine, cholesterol and the Isopropyl myristate of egg.
The combination of one or more corrosion promotor and one or more diffusion promotor also can be used for composition of the present invention.
Term " thinner " intention is used for the chemical compound of dilution target compound before conveying.Thinner can also be used for stable compound, because they can provide more stable environment.The salt (can also provide pH control or keep) that is dissolved in buffered soln in the art includes, but are not limited to phosphate buffered saline(PBS) as thinner.In certain embodiments, thinner increases the loose density of composition so that compacting or generation are used for enough spaces of the even fusion of capsule filling.This compounds comprises, lactose for example, and starch, N.F,USP MANNITOL, sorbyl alcohol, dextrose, Microcrystalline Cellulose, such as
Figure A20068004995800851
Lin Suanergai, dicalcium phosphate dihydrate; Tricalcium phosphate, calcium phosphate; Lactose hydrous, spray-dired lactose; Pregelatinized Starch, compression sugars, such as
Figure A20068004995800852
(Amstar); N.F,USP MANNITOL, HPMC, acetate stearic acid HPMC, sucrose thinner, Icing Sugar; The calcium bisulfate monohydrate, calcium sulfate dihydrate; The calcium lactate trihydrate, dextrates; Hydrolysed cereal solid, amylose starch; Solka-floc, lime carbonate; Glycine, kaolin; N.F,USP MANNITOL, sodium-chlor; Inositol, wilkinite etc.
The stripping and the dispersion of preparation when term " disintegration " comprises the contact gastrointestinal fluid." disintegrating agent (Disintegration agents) or disintegrating agent (disintegrants) " helps material and pulverizes or disintegration.The example of disintegrating agent comprises starch, and native starch for example is such as W-Gum or yam starch; Pregelatinized Starch, such as National 1551 or
Figure A20068004995800853
Or sodium starch glycollate, such as
Figure A20068004995800854
Or
Figure A20068004995800855
, Mierocrystalline cellulose, such as timber products, the methyl crystalline cellulose, for example
Figure A20068004995800856
PH101, PH102, PH105,
Figure A20068004995800859
P100,
Figure A200680049958008510
Ming
Figure A200680049958008511
With
Figure A200680049958008512
, methylcellulose gum, croscarmellose or cross-linked cellulose, such as croscarmellose sodium (
Figure A20068004995800861
), cross-linked carboxymethyl cellulose or croscarmellose, cross-linking starch, such as sodium starch glycollate, cross-linked polymer, such as polyvinylpolypyrrolidone, cross-linked polyvinylpyrrolidone, alginate, such as alginic acid or alginate, such as sodiun alginate, clay, such as
Figure A20068004995800862
HV (magnesium aluminum silicate), natural gum is such as agar, guar gum, Viscogum BE, perverse karaya, pectin or tragacanth gum, sodium starch glycollate, wilkinite, natural sponge, tensio-active agent, resin, such as Zeo-karb, citrus pulp, sodium lauryl sulphate, the combination of sodium lauryl sulphate and starch etc.
" drug absorption " or " absorption " general intention medicine moves into blood vessel or site of action by barrier from medicine-feeding part, and for example medicine moves into portal vein or lymphoid process from gi tract.
" enteric coating " contacts stomach basically for keeping, and stripping and the material that discharges medicine in small intestine or colon.Generally speaking, enteric coating comprises a kind of polymer materials, and it prevents to discharge under the low pH environment of stomach, and at higher pH, be generally under the pH 6-7 ionization and thus in small intestine or colon fully stripping to discharge promoting agent wherein.
" corrosion promotor " comprises the material of control predetermined substance corrosion in gastrointestinal fluid.General known corrosion promotor is for well known to a person skilled in the art those.Typically corrosion promotor comprises, for example hydrophilic polymer, ionogen, protein, peptide and amino acid.
" weighting agent " comprises compound, such as lactose, and lime carbonate, Lin Suanergai, calcium sulfate, Microcrystalline Cellulose, cellulose powder, glucose, dextrates, starch, pregelatinized Starch, sucrose, Xylitol, Saccharum lactis, N.F,USP MANNITOL, sorbyl alcohol, sodium-chlor, polyoxyethylene glycol etc.
" correctives " and/or " sweeting agent " that be used for preparation described herein comprise,
Syrup acacia for example, acesulfame K, alitame, star anise, apple, aspartame, banana, bavarian cream, berry, black gooseberry, butterscotch, citrate of lime, camphor, caramel, cherry, the cherry breast, chocolate, Chinese cassia tree, bubble gum, oranges and tangerines, orange juice mixing drink (citrus punch), oranges and tangerines cream, marsh-mallow, cocoa, cola, cold cherry, cold oranges and tangerines, cyclohexyl-n-sulfonate, cyclohexyl-n-sulfonate (cylamate), glucose, volatile oil extracted from eucalyptus' leaves or twigs, Eugenol, fructose, the fruit juice mixing drink, ginger, glycyrrhetate, Radix Glycyrrhizae (G1ycyrrhiza glabra) syrup, grape, shaddock, honey, isomaltose, lemon, bitter orange, the lemon breast, Potenlini one ammonium (
Figure A20068004995800863
), maltol, N.F,USP MANNITOL, maple syrup, Althaea officinalis, menthol, peppermint cream, the blended berry, neohesperidin DC, knob sweet (neotame), orange, pears, peach, peppermint, the peppermint breast, Powder, blackberry, blueberry, root beer, Rum, asccharin, safrol, sorbyl alcohol, spearmint, spearmint breast, strawberry, strawberry breast, sweet Stevia, Sucralose, sucrose, soluble saccharin, asccharin, aspartame, Sunnett, N.F,USP MANNITOL, talin, syllitol (sylitol), Sucralose, sorbyl alcohol, Switzerland's cream, tagatose, red tangerine, thaumati, assorted candied fruits, vanilla, English walnut, watermelon, wild cherry, wintergreen oil, the arbitrary combination of Xylitol or these correctives components, star anise-menthol for example, cherry-star anise, Chinese cassia tree-orange, cherry-Chinese cassia tree, chocolate-peppermint, honey-lemon, lemon-bitter orange, lemon-peppermint, menthol-volatile oil extracted from eucalyptus' leaves or twigs, orange-cream, vanilla-peppermint and composition thereof.
" lubricant " and " glidant " is for preventing the compound that minimizing or inhibitory substance adhere to or rub.Typical lubricants comprises, stearic acid for example, calcium hydroxide, talcum powder, sodium stearyl fumarate, hydrocarbon, such as mineral oil or hydrogenated vegetable oil, such as hydrogenated soybean oil (
Figure A20068004995800872
), higher fatty acid and basic metal thereof and alkaline earth salt, such as aluminium, calcium, magnesium, zinc, stearic acid, sodium stearate, glycerine, talcum powder, wax,
Figure A20068004995800873
, boric acid, Sodium Benzoate, sodium acetate, sodium-chlor, leucine, polyoxyethylene glycol (for example PEG-4000) or methoxy poly (ethylene glycol) are such as Carbowax TM, sodium oleate, Sodium Benzoate ， docosoic glyceryl ester, polyoxyethylene glycol, Stepanol MG or dodecyl sulphate sodium sulfate, colloid silica is such as Syloid TM,
Figure A20068004995800874
, starch, such as W-Gum, silicone oil, tensio-active agent etc.
" serum-concentration that can measure " or " plasma concentration that can measure " described generally with mg, μ g or ng therapeutical agent/ml, and the administration post-absorption of dl or l determination of serum is gone into the serum or the plasma concentration of blood flow.The plasma concentration of measuring used herein is generally measured with ng/ml or μ g/ml.
" pharmacodynamics " intention is determined the factor of observed biologically for the drug level on the site of action.
" pharmacokinetics " intention determines to obtain and keep the factor of suitable drug level on the site of action.
" softening agent " is for being used for softening microencapsulated material or thin film coating material so that the compound that its fragility reduces.Suitable manufacturing methods comprises, polyethylene glycols for example, and such as PEG 300, PEG400, PEG 600, and PEG 1450, PEG 3350 and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl Mierocrystalline cellulose and triactin.In certain embodiments, softening agent can also play dispersion agent or wetting agent.
" solubilizing agent " comprises compound, such as triactin, and triethyl citrate, ethyl oleate, ethyl octylate, sodium lauryl sulphate, Docusate Sodium, vitamin-E TPGS, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, N-hydroxyethyl-pyrrolidone, polyvinylpyrrolidone, HPMC, hydroxypropyl cyclodextrin, ethanol, propyl carbinol, Virahol, cholesterol, biliary salts, Macrogol 200-600, Tetrahydrofurfuryl polyethylene glycol ether, Trivalin SF, propylene glycol and Isosorbide dimethyl ether etc.
" stablizer " comprises compound, such as any antioxidant, buffer reagent, acid, sanitas etc.
" stable state " used herein reaches maintenance level when dosage equals dose that single administration eliminates at interval or the constant drug plasma contacts.
" suspensoid " comprises compound, such as polyvinylpyrrolidone, and polyvinylpyrrolidone K12 for example, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, V-Pyrol RC/vinyl acetate copolymer (S630), polyoxyethylene glycol, for example polyoxyethylene glycol can have the molecular weight of about 300-about 6000 or about 3350-about 4000 or about 7000-about 5400, Xylo-Mucine, methylcellulose gum, HPMC, acetate stearic acid Walocel MT 20.000PV, Tween-80, Natvosol, sodiun alginate, natural gum, such as, for example tragacanth gum and gum arabic, guar gum, xanthan gum comprises xanthan gum, carbohydrate, cellulose family, such as, Xylo-Mucine for example, methylcellulose gum, Xylo-Mucine, HPMC, Natvosol, Tween-80, sodiun alginate, the polyethoxylated sorbitan laurate, polyethoxylated sorbitan laurate, polyvidone etc.
" tensio-active agent " comprises compound, such as sodium lauryl sulphate, and Docusate Sodium, Tween 60 or 80, triactin, vitamin-E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, poly yamanashi esters, poloxamer, biliary salts, glyceryl monostearate, the multipolymer of oxyethane and propylene oxide, for example
Figure A20068004995800881
(BASF) etc.Some other tensio-active agent comprises polyoxyethylene fatty acid glyceride type and vegetables oil, for example polyoxyethylene (60) hydrogenated castor oil; With Voranol EP 2001 class and alkyl phenyl ethers, for example octoxinol 10, octoxinol 40.In certain embodiments, tensio-active agent can be comprised so that strengthen physical stability or other purpose.
" tackifier " comprise, methylcellulose gum for example, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, HPMC, acetate stearic acid HPMC, the phthalic acid HPMC, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan and combination thereof.
" wetting agent " comprises compound, such as oleic acid, and glyceryl monostearate, sorbitan monooleate, Span-20, Emulphor FM, polyoxyethylene sorbitan monooleate, Tween-20, Docusate Sodium, sodium oleate, sodium lauryl sulphate, Docusate Sodium, triactin, Tween 80, vitamin-E TPGS, ammonium salt etc.
Formulation
Composition described herein can be mixed with can be by any usual manner to experimenter's administration, includes, but are not limited to orally, and parenteral (for example intravenously, subcutaneous or intramuscular) is sucked, in the nose, and rectum or transdermal administration approach.Term used herein " experimenter " is used in reference to animal, and preferred mammal comprises people or non--people.Term patient and experimenter can exchange use.
In addition, can will comprise that this paper provides the pharmaceutical composition described herein of compound to be mixed with any suitable formulation, includes, but are not limited to: moisture oral dispersant, liquid, gel, syrup, elixir, slurry, suspension etc., they are by the oral absorption of the patient who is treated; Solid oral dosage form, aerosol, controlled release preparation, the fast thawing preparation, effervescent formulation, freeze-dried preparation, tablet, powder, pill, lozenge, capsule, delayed release preparation prolongs delivery formulations, pulsed delivery formulations, many granular preparations, quick-release and controlled release slurriable combination.
Can obtain the pharmaceutical preparation of oral application through the following steps: mix one or more solid excipients and one or more compounds described herein; the optional gained mixture and if desired of grinding is processed into label or ingot core with granular mixture after adding proper auxiliary agent.Suitable vehicle comprises that for example, weighting agent such as carbohydrate, comprises lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulosics, such as, for example, W-Gum, wheat starch, rice starch, yam starch, gelatin, tragacanth gum, methylcellulose gum, Microcrystalline Cellulose, HPMC, Xylo-Mucine; Or other material, such as: polyvinylpyrrolidone (PVP or polyvidone) or calcium phosphate.If desired, can add disintegrating agent, such as croscarmellose sodium, polyvinylpyrrolidone, agar or alginic acid or its salt are such as sodiun alginate.
Suitable coatings is provided for the ingot core.For this purpose, can use priming, it can be chosen wantonly and comprise gum arabic, talcum powder, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Can in tablet or lozenge coatings, add dyestuff or pigment to differentiate or to characterize the various combination of active compound doses.
The pharmaceutical preparation that can orally use comprises by pushing-the formula capsule that gelatin is made, and by gelatin and softening agent, the sealing soft capsule of making such as glycerine or sorbyl alcohol.Push-the formula capsule can comprise the mixture of active ingredient and following component: weighting agent, such as lactose; Tackiness agent is such as starch; And/or lubricant, such as talcum powder or Magnesium Stearate; With optional stablizer.In soft capsule, active compound can be dissolved in or be suspended in suitable liquid, such as fatty oil, in whiteruss or the liquid macrogol.In addition, can add stablizer.All oral Preparations all should be in the dosage that is suitable for this class administration.
In certain embodiments; the solid dosage that this paper discloses can (comprise the suspendible sheet for tablet; fast melting tablets is chewed disintegrating tablet, fast disintegrating tablet; effervescent tablet or Caplet); pill, powder (comprising aseptic packaging powder, adjustable powder or effervesce powder); capsule (comprises soft capsule or hard capsule; for example origin comes from the gelatin of animal or derives from capsule or " Sprinkle Caps " that the HPMC of plant makes), solid dispersion, sosoloid; the bioerodable formulation; controlled release preparation, pulsed release dosage form, many particles formulation; pill, particle or aerosol form.In other embodiments, described pharmaceutical preparation is a powder type.In other embodiments, described pharmaceutical preparation is a tablet form, includes, but are not limited to fast melting tablets.In addition, can be with pharmaceutical preparation of the present invention as single capsule or with many capsule formulations form administration.In certain embodiments, with the form administration of described pharmaceutical preparation with 2 or 3 or 4 capsules or sheet.
In certain embodiments, by being mixed into loose blend composition, compound particle provided herein and one or more drug excipients prepare tablet, effervescent tablet, capsule.When relating to these for uniform loose blend composition, the compound particle that provides is provided in the whole composition intention this paper, makes the unit dosage that is easy to said composition is divided into again equivalence, such as tablet, and pill and capsule.The constituent parts formulation can also comprise the film coating layer, and they are when oral absorption or contact disintegration during thinner.Can prepare these preparations by conventional pharmaceutical technology.
Conventional pharmaceutical technology comprises that for example one of following method or its combination: (1) dry mixed, (2) are directly suppressed, and grind (3), and (4) drying or non--water are granulated (5) wet granulation; Or merge (6).For example, referring to Lachman etc., The Theory and Practiceof Industrial Pharmacy (1986).Other method comprises, spraying drying for example, and pan coating, melt granulation is granulated, bed spray drying or dressing (for example Butterworth spy (wurster) coating method), tangential dressing, the cat head spraying, compressing tablet is extruded etc.
Pharmaceutical dosage form described herein can comprise compound provided herein and one or more pharmacy acceptable additive, such as consistency carrier, tackiness agent, weighting agent, suspensoid, correctives, sweeting agent, disintegrating agent, dispersion agent, tensio-active agent, lubricant, tinting material, thinner, solubilizing agent, wetting agent, softening agent, stablizer, penetration enhancer, wetting agent, defoamer, antioxidant, the combination of one or more of sanitas or they.In others, use the standard coating method, such as Remington ' s Pharmaceutical Sciences, those methods described in the 20th Edition (2000) provide the film coating layer for compound formulation periphery provided herein.In one embodiment, give certain part or all of dressing of compound particle provided herein.In another embodiment, give certain part or all of bag micro-capsule of compound particle provided herein.In another embodiment, not to compound particle bag micro-capsule provided herein and dressing not.
The suitable carriers that is used for solid dosage described herein includes, but are not limited to gum arabic, gelatin, colloid silica, neurosin, calcium lactate, Star Dri 5, glycerine, Magnesium Silicate q-agent, sodium-caseinate, soybean lecithin, sodium-chlor, tricalcium phosphate, Rhodiaphos DKP, stearoyl lactate, carrageenin, glyceryl monoacetate, diglyceride, pregelatinized Starch, HPMC, acetate stearic acid HPMC, sucrose, Microcrystalline Cellulose, lactose, N.F,USP MANNITOL etc.
The suitable weighting agent that is used for solid dosage described herein includes, but are not limited to lactose, lime carbonate, calcium phosphate, Lin Suanergai, calcium sulfate, Microcrystalline Cellulose, cellulose powder, glucose, dextrates, dextran, starch, pregelatinized Starch, HPMC (HPMC), phthalic acid HPMC, acetate stearic acid HPMC (HPMCAS), sucrose, Xylitol, Saccharum lactis, N.F,USP MANNITOL, sorbyl alcohol, sodium-chlor, polyoxyethylene glycol etc.
In order from solid dosage matrix, to discharge the compound that this paper discloses as far as possible effectively, usually disintegrating agent is used for preparation, especially when using the compressed with adhesive formulation.When moisture content was absorbed into formulation, disintegrating agent helped by swelling or the broken formulation matrix of capillary action.The suitable disintegrants that is used for solid dosage described herein includes, but are not limited to: native starch, such as W-Gum or yam starch; Pregelatinized Starch, such as National 1551 or Or sodium starch glycollate, such as
Figure A20068004995800922
Or
Figure A20068004995800923
Mierocrystalline cellulose, such as timber products, the methyl crystalline cellulose, for example PH101, PH102,
Figure A20068004995800926
PH105,
Figure A20068004995800927
P100,
Figure A20068004995800928
Ming
Figure A20068004995800929
With , methylcellulose gum, croscarmellose or cross-linked cellulose, such as croscarmellose sodium (
Figure A200680049958009211
), crosslinked carboxy methylcellulose or croscarmellose; Cross-linking starch is such as sodium starch glycollate; Cross-linked polymer, such as polyvinylpolypyrrolidone, cross-linked polyvinylpyrrolidone, alginate are such as alginic acid or alginate, such as sodiun alginate; Clay, such as HV (magnesium aluminum silicate); Natural gum, such as agar, guar gum, Viscogum BE, karaya, pectin or tragacanth gum; Sodium starch glycollate; Wilkinite; Natural sponge; Tensio-active agent; Resin is such as Zeo-karb; Citrus pulp; Sodium lauryl sulphate; The combination of sodium lauryl sulphate and starch etc.
Tackiness agent is given the solid oral dosage form tackiness: with regard to the capsule that powder is filled, the filler that they help to be packed into soft or hard-shell capsule forms; And with regard to tablet, they guarantee that tablet is being kept perfectly after the compacting and is helping to guarantee the homogeneity of adulterant before compacting or filling step.Be suitable for including, but are not limited to carboxymethyl cellulose methylcellulose gum (methyl fiber for example as the material of the tackiness agent in the solid dosage described herein
Figure A200680049958009213
), HPMC (for example hypromellose USP Pharmacoat-603), acetate stearic acid HPMC (Aqoate HS-LF and HS), Natvosol, hydroxypropylcellulose are (for example
Figure A200680049958009214
), ethyl cellulose is (for example
Figure A200680049958009215
) and Microcrystalline Cellulose (for example
Figure A200680049958009216
), Microcrystalline Cellulose, glucose, amylose starch, magnesium aluminum silicate, polysaccharide acid, wilkinite, gelatin, polyvinylpyrrolidone//vinyl acetate copolymers, polyvinylpolypyrrolidone, polyvidone, starch, pregelatinized Starch, tragacanth gum, dextrin, sugar, such as sucrose (for example
Figure A200680049958009217
), glucose, dextrose, molasses, N.F,USP MANNITOL, sorbyl alcohol, Xylitol are (for example
Figure A200680049958009218
), lactose, natural or synthetic gum, such as gum arabic, tragacanth gum, ghatti gum, Semen Plantaginis glue, starch, polyvinylpyrrolidone are (for example
Figure A200680049958009219
CL,
Figure A200680049958009220
CL,
Figure A200680049958009221
XL-10 and
Figure A20068004995800931
K-12), the tamarack arabogalactan,
Figure A20068004995800932
, polyoxyethylene glycol, wax, sodiun alginate etc.
Generally speaking, being used for powder, to fill the binder levels of gelatine capsule agent be 20-70%.The application level of tackiness agent is variable in the tablet, no matter is direct compacting, wet granulation, and roll extrusion also is to use other vehicle, such as self can be used as the weighting agent that appropriate tackiness agent works.The common formulator in this area can be identified for the binder levels of preparation, but the adhesive application horizontal summation in tablet is 70% usually.
The examples of suitable lubricants or the glidant that are used for solid dosage described herein include, but are not limited to stearic acid, calcium hydroxide, talcum powder, W-Gum, sodium stearyl fumarate, basic metal and alkaline earth salt, such as aluminium, calcium, magnesium, zinc, stearic acid, sodium stearate, Magnesium Stearate, Zinic stearas, wax
Figure A20068004995800933
, boric acid, Sodium Benzoate, sodium acetate, sodium-chlor, leucine, polyoxyethylene glycol or methoxy poly (ethylene glycol) are such as Carbowax TM, PEG 4000, PEG5000, and PEG 6000, sodium oleate ， docosoic glyceryl ester, palmitinic acid stearin, phenylformic acid glyceryl ester, Stepanol MG or dodecyl sulphate sodium sulfate etc.
The suitable diluent that is used for solid dosage described herein includes, but are not limited to sugar (comprising lactose, sucrose and glucose), polysaccharide (comprising dextrates and Star Dri 5), polyvalent alcohol (comprising N.F,USP MANNITOL, Xylitol and sorbyl alcohol), cyclodextrin etc.
Term " water-insoluble thinner " expression generally is used for the compound of pharmaceutical preparation, such as calcium phosphate, and calcium sulfate, starch, treated starch and Microcrystalline Cellulose and Microcrystalline Cellulose (for example have about 0.45g/cm 3Density, Avicel for example, Solka-floc) and talcum powder.
The examples of suitable lubricants that is used for solid dosage described herein comprises, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, Span-20, Emulphor FM, polyoxyethylene sorbitan monooleate, Tween-20, quaternary ammonium compound (Polyquat for example
Figure A20068004995800934
), sodium oleate, sodium lauryl sulphate, Magnesium Stearate, Docusate Sodium, triactin, vitamin-E TPGS etc.
The suitable tensio-active agent that is used for solid dosage described herein comprises, for example, sodium lauryl sulphate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, biliary salts, glyceryl monostearate, the multipolymer of oxyethane and propylene oxide, for example
Figure A20068004995800935
(BASF) etc.
The suitable suspensoid that is used for solid dosage described herein comprises, but be not limited to polyvinylpyrrolidone, polyvinylpyrrolidone K12 for example, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyoxyethylene glycol, for example polyoxyethylene glycol can have the molecular weight of about 300-about 6000 or about 3350-about 4000 or about 7000-about 5400, V-Pyrol RC/vinyl acetate copolymer (S630), Xylo-Mucine, methylcellulose gum, HPMC, Tween-80, Natvosol Xylo-Mucine, methylcellulose gum, HPMC, acetate stearic acid Walocel MT 20.000PV, Tween-80, Natvosol, sodiun alginate, natural gum, such as, for example tragacanth gum and gum arabic, guar gum, xanthan gum comprises xanthan gum, carbohydrate, cellulose family, such as, Xylo-Mucine for example, methylcellulose gum, Xylo-Mucine, HPMC, Natvosol, Tween-80, sodiun alginate, the polyethoxylated sorbitan laurate, polyethoxylated sorbitan laurate, polyvidone etc.
The suitable antioxidant that is used for solid dosage described herein comprises, for example, and Butylated Hydroxytoluene (BHT), sodium ascorbate and tocopherol.
Should understand between the additive that in solid dosage described herein, uses exist obviously overlapping.Therefore, typical and nonrestrictive in the additive types that only above-mentioned additive should be considered as can comprising in the preparation described herein.The consumption of this class additive is easy to be determined according to required particular characteristics by those skilled in the art.
In other embodiments, give one or more layers plasticising of medicine preparation.As illustration, softening agent is generally high boiling point solid or liquid.Can add the suitable manufacturing methods that accounts for the about 0.01%-of coated composition weight (w/w) about 50%.Softening agent includes, but are not limited to diethyl phthalate, citric acid ester type, polyoxyethylene glycol, glycerine, acetylize glyceride type, triactin, polypropylene glycol, polyoxyethylene glycol, triethyl citrate, Uniflex DBS, stearic acid, Hydrogenated Polyisobutene, stearate and Viscotrol C.
The solid dosage that compressed tablet prepares for the loose adulterant by the above-mentioned preparation of compacting.In different embodiments, the compressed tablet that designs for dissolving in the oral cavity comprises one or more correctivess.In other embodiments, compressed tablet comprises final compressed tablet film on every side.In certain embodiments, this film coating layer can provide the delay release of compound from preparation that this paper discloses.In other embodiments, the film coating layer help the patient compliance (for example
Figure A20068004995800951
Coatings or sugarcoating layer).Comprise
Figure A20068004995800952
The film coating layer generally account for the heavy about 1%-of sheet about 3%.In other embodiments, compressed tablet comprises one or more vehicle.
For example, can place capsule to prepare capsule by loose adulterant with the above-claimed cpd preparation.In certain embodiments, preparation (non--aqueous suspension and solution) is put into soft gelatin capsule.In other embodiments, preparation is put into standard gelatin capsule or non--gelatine capsule, such as the capsule that comprises HPMC.In other embodiments, preparation is put into Sprinkle Caps, wherein this capsule can be swallowed or make this capsule to open and its content before is dispersed on the food on the feed by complete.In certain embodiments, therapeutic dose is divided into many (for example 2,3 or 4) capsules.In certain embodiments, the complete dosage of preparation is carried with a capsules form.
In different embodiments, the compound particle that this paper is disclosed and the dry fusion of one or more vehicle and suppress agglomerating, such as tablet, the hardness that it has is enough to provide makes pharmaceutical composition be less than about 30 minutes basically behind oral administration, is less than about 35 minutes, is less than about 40 minutes, be less than about 45 minutes, be less than about 50 minutes, be less than about 55 minutes or be less than about 60 minutes, make preparation discharge into gastrointestinal fluid thus with interior disintegration.
In one aspect of the method, formulation can comprise the microencapsulation preparation.In certain embodiments, one or more other compatible materials may reside in the microencapsulation material.Typical material includes, but are not limited to the pH regulator agent, corrosion promotor, and defoamer, antioxidant, correctives and carrier substance, such as tackiness agent, suspensoid, disintegrating agent, weighting agent, tensio-active agent, solubilizing agent, stablizer, lubricant, wetting agent and thinner.
The material that is used for microencapsulation described herein comprises the compatible material of compound that discloses with this paper, and the compound that they are enough to this paper is disclosed separates from other uncompatibility vehicle.The material that the material compatible with the compound of this paper disclosure discharges in vivo for those compounds that postpone this paper disclosure.
The typical microencapsulation material that the preparation of the compound that is used to postpone to comprise that this paper discloses discharges includes, but are not limited to hydroxypropylcelluloether ether class (HPC), such as
Figure A20068004995800953
Or Nisso HPC, the hydroxypropylcelluloether ether class (L-HPC) of low-replacement, HPMC ethers (HPMC), such as Seppifilm-LC,
Figure A20068004995800954
, Metolose SR, methyl fiber
Figure A20068004995800955
Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843, the methylcellulose gum polymkeric substance is such as the methyl fiber
Figure A20068004995800956
Acetate stearic acid HPMC Aqoat (HF-LS, HF-LG, HF-MS) and
Figure A20068004995800961
, ethyl cellulose (EC) and composition thereof, such as E461,
Figure A20068004995800962
Polyvinyl alcohol (PVA), such as Opadry AMB, Natvosol, such as
Figure A20068004995800963
, the salt of carboxymethyl cellulose and carboxy methyl cellulose (CMC), such as
Figure A20068004995800964
, polyvinyl alcohol and ethylene glycol copolymer are such as Kollicoat
Figure A20068004995800965
, glyceryl monoacetate class (Myverol), triglyceride (KLX), polyethylene glycols, modified food starch, the mixture of acrylate copolymer and acrylate copolymer and cellulose ethers, such as
Figure A20068004995800966
EPO, L30D-55,
Figure A20068004995800968
FS 30D
Figure A20068004995800969
L100-55,
Figure A200680049958009610
L100,
Figure A200680049958009611
S100,
Figure A200680049958009612
RD100,
Figure A200680049958009613
E100,
Figure A200680049958009614
L12.5,
Figure A200680049958009615
S12.5,
Figure A200680049958009616
NE 30D and
Figure A200680049958009617
NE 40D, Cellacefate, Sepifilms, such as HPMC and stearic mixture, cyclodextrin and these mixtures of material.
In other embodiments, with softening agent, such as polyethylene glycols, for example PEG 300, and PEG 400, and PEG 600, and PEG 1450, PEG 3350 and PEG 800, and stearic acid, propylene glycol, oleic acid and triactin mix the microencapsulation material.In other embodiments, be used to postpone microencapsulation material that pharmaceutical composition discharges from USP or National Formulary (NF, NF).In other embodiments, the microencapsulation material is Klucel.In other embodiments, the microencapsulation material is a methylcellulose gum.
Can be by the microencapsulation compound that well known to a person skilled in the art that method preparation this paper discloses.This class known method comprises, spray-drying process for example, and rotating disk-solvent method, hot melt process, the spray chilling method, fluidized-bed, electrostatic precipitation, centrifugal extruding, the rotation suspendible separates, liquid-gas or solid-air interface polymerization, pressure is extruded or the solvent extraction of spraying is bathed.Except that these, can also use several chemical technologies, for example complex coacervation, solvent evaporation, polymkeric substance-polymkeric substance uncompatibility, the interfacial polymerization in the liquid medium, in-situ polymerization, the desolvation in intra-liquid desiccation method and the liquid medium.In addition, also can use other method, such as roll extrusion, extruding/round as a ball, cohesion or nanoparticle dressing.
In one embodiment, after this compound particle microencapsulation with this paper discloses is mixed with one of above-mentioned formulation.In another embodiment, give some or most of dressing in the described particle, after this by use standard coating method, such as Remington ' sPharmaceutical Sciences, those methods are further prepared described in the 20th version (2000).
In other embodiments, the solid dosage plasticising (dressing) of the compound that discloses to this paper one or more layers.As illustration, softening agent is generally high boiling point solid or liquid.Can add the suitable manufacturing methods that accounts for the about 0.01%-of coated composition weight (w/w) about 50%.Softening agent includes, but are not limited to diethyl phthalate, citric acid ester type, polyoxyethylene glycol, glycerine, acetylize glyceride type, triactin, polypropylene glycol, polyoxyethylene glycol, triethyl citrate, Uniflex DBS, stearic acid, Hydrogenated Polyisobutene, stearate and Viscotrol C.
In other embodiments, can prepare the powder that comprises one or more drug excipients and correctives, it comprises the preparation of the compound that contains this paper disclosure.For example, can prepare this class powder by preparation and optional drug excipient are mixed into loose adulterant composition.Extra embodiment also comprises suspensoid and/or wetting agent.This loose adulterant is divided into unit dose packaging or multiple-unit container unit equably again.
In other embodiments, can also prepare the effervesce powder according to the content that the present invention discloses.Effervescent salt is used for medicine is scattered in water so that oral administration.Effervescent salt is for being included in usually by sodium bicarbonate the particle or the meal of the medicament in the drying composite that citric acid and/or tartrate are formed.When salt of the present invention was added to the water, bronsted lowry acids and bases bronsted lowry reacted and carbon dioxide gas, produced thus " effervesce ".The example of effervescent salt comprises, for example following component: the mixture of sodium bicarbonate or sodium bicarbonate and yellow soda ash, citric acid and/or tartrate.Any acid-alkali combination that causes carbonic acid gas to discharge all can be used to replace sodium bicarbonate and citric acid and tartaric combination, as long as described component is suitable for medicinal application and produces pH more than about 6.0 or 6.0.
In other embodiments, the preparation described herein that comprises the compound that this paper discloses is a solid dispersion.The method of producing this class solid dispersion is as known in the art, and includes, but not limited to for example U.S. Pat 4,343,789,5,340,591,5,456,923,5,700,485,5,723,269 and the U.S. openly apply for US2004/0013734, especially these documents are incorporated herein by reference separately.In other embodiments, preparation described herein is a sosoloid.Sosoloid has mixed a kind of material and promoting agent and other vehicle, and feasible this mixture of heating causes the medicine stripping and then resulting composition cooled off so that the solid adulterant that can further prepare or directly join capsule or be pressed into tablet is provided.The method of producing this class sosoloid is as known in the art, and includes, but not limited to for example U.S. Pat 4,151,273,5,281,420 and 6,083,518, especially these documents is incorporated herein by reference separately.
Can will comprise the oral administration solid pharmaceutical dosage form of the compound that this paper discloses, comprise the controlled release that preparation described herein further is mixed with can provide the compound that this paper discloses.The compound that controlled release intention this paper discloses discharges according to required characteristic in time limit time expand from the formulation of mixing it.Controlled release characteristics comprises that for example slowly-releasing prolongs release, and pulsed discharges and the delay release characteristics.Opposite with immediate release composition, controlled release composition makes promoting agent be delivered to the experimenter according to predetermined properties in time limit time expand.This class rate of release can provide the treatment level of significance of promoting agent in time limit time expand, and the long pharmacological reaction time limit is provided thus, compares with the fast dissolving dosage form of routine simultaneously side effect is minimized.The reaction time limit that this class is long provides many inherent helpfulnesses of using corresponding fugitive quick releasing formulation to realize.
In certain embodiments, solid dosage described herein can be mixed with enteric coating and postpone the liberation port oral dosage form, use enteric layer promptly as described herein is so that influence the oral dosage form of the pharmaceutical composition of the small intestine release in the gi tract.The enteric coating formulation can be for containing self dressing or the not active ingredient of dressing and/or the particle of other composition components, powder, pill, being pressed or the sheet/mould of molded or extruding (dressing or not dressing) of pearl or particle.The enteric coating oral dosage form can also be for containing self dressing or the not solid carrier of dressing or the pill of composition, pearl or particulate capsule (dressing or not dressing).
Term used herein " postpones to discharge " intention to be carried, and makes release generally to carry out on some predictable position in enteron aisle, if this position does not postpone to discharge the position that change institute the subject of knowledge and the object of knowledge reaches further from those.In certain embodiments, the method for delay release is a dressing.Any coatings should be applied to enough thickness, makes whole coatings can not dissolve in the gastrointestinal fluid under being lower than about 5 pH, and at pH about 5 and 5 with dissolving up and down.Estimating to show the deliquescent any anionic polymer of pH-dependency all can be as implementing enteric coat layer of the present invention, so that realize reaching the conveying of lower gastrointestinal tract.In certain embodiments, being used for polymkeric substance of the present invention is the anionic carboxylic acid polyalcohol.In other embodiments, some in polymkeric substance and compatibility mixture thereof and the characteristic thereof includes, but are not limited to:
Shellac is also referred to as pure shellac (lac), promptly available from insect resin excretory purified product.This coatings is dissolved in the medium of pH＞7;
Acrylate copolymer.The performance of acrylate copolymer (mainly being its solubleness in biological fluid) can change with the different of substituting group type based on substitution value.The example of suitable acrylate copolymer comprises Sipacril 2739OF and ammonio methacrylate copolymer.Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) buy as solubilising in organic solvent, aqueous dispersion or dried powder.Eudragit series RL, NE and RS are insoluble to gi tract, but permeable and be mainly used in segmented intestine targeted.Eudragit series E is dissolved in stomach.Eudragit series L, L-30D and S are insoluble to stomach, but are dissolved in intestines;
Derivatived cellulose.The example of suitable derivatived cellulose is: ethyl cellulose; The reaction mixture of cellulosic inclined to one side acetate esters and Tetra hydro Phthalic anhydride.Its performance can change with replacing the different of type based on substitution value.Cellacefate (CAP) is time dissolving in pH＞6.Aquateric (FMC) is for having＜the false latex of 1 μ m particulate CAP based on the system of water and for spray-dired.Other composition among the Aquateric can comprise the poloxamer class, Tweens (Tweens) and acetylated monoglyceride class.Other suitable derivatived cellulose comprises: Cellulose acetotrimellitate (Eastman); Methylcellulose gum (Pharmacoat, methylcellulose gum); Phthalic acid HPMC (HPMCP); Succsinic acid HPMC (HPMCS); With acetate succsinic acid HPMC (for example AQOAT (ShinEtsu)).Its performance can change based on the different of substitution value and type.For example, HPMCP such as, HP-50, HP-55, HP-55S, the HP-55F grade is suitable.Its performance can change based on the different of substitution value and type.For example, suitably the acetate succsinic acid HPMC of grade includes, but are not limited to: AS-LG (LF), and it is in pH 5 dissolvings; AS-MG (MF), it is in pH 5.5 dissolvings; And AS-HG (HF), it dissolves under higher pH.These polymkeric substance are provided as particle that is used for aqueous dispersion or fine powder;
Polyvinyl acetate phthalic ester (PVAP).PVAP dissolving and almost can not permeate water steam and gastric juice in pH＞5 time.
In certain embodiments, coatings can and comprise softening agent and other possible dressing vehicle usually, such as tinting material, and talcum powder and/or Magnesium Stearate, they are well-known in the art.Suitable manufacturing methods comprises triethyl citrate (Citroflex 2); triactin (vanay); Triethyl citrate acetate (Citroflec A2); Carbowax 400 (poly(oxyethylene glycol) 400), diethyl phthalate, tributyl citrate; acetylated monoglyceride; glycerine, fatty acid ester, propylene glycol and adjacent benzene first two dibutyl phthalates.Especially, anionic carboxylic acid acrylate copolymer comprises the softening agent of 10-25% weight usually, especially adjacent benzene first two dibutyl phthalates, polyoxyethylene glycol, triethyl citrate and triactin.Conventional packaging technique is applied to dressing such as spraying or pan coating.The thickness of coatings must be kept perfectly by the sufficient to guarantee oral dosage form, required local delivery site in reaching enteron aisle.
Except that softening agent, can also be with tinting material, release agent, tensio-active agent, defoamer, lubricant (for example carnauba wax or PEG) joins in the coatings, so that solubilising or disperse coating material and improve the performance of coatings and the product of dressing.
In other embodiments, use the pulsed formulation to carry the preparation described herein that comprises the compound that this paper discloses.Provide one or more quick-release pulses on predetermined point of time that the pulsed formulation can lag behind or the concrete position when controlled.Can use various pulsed preparation as known in the art administration to comprise the pulsed formulation of the compound that this paper discloses, comprise preparation described herein.For example, this class preparation includes, but are not limited to U.S. Pat 5,011, and those that disclose in 692,5,017,381,5,229,135 and 5,840,329 are incorporated herein by reference these documents especially separately.Other is applicable to that the pulsed release dosage form of preparation of the present invention includes, but not limited to for example U.S. Pat 4,871,549,5,260,068,5,260,069,5,508,040,5,567,441 and 5,837,284, is incorporated herein by reference all these documents especially.In one embodiment, controlled release form is that pulsed discharges solid oral dosage form, and it comprises at least two group particles (being many particles), their each self-contained preparations described herein.First group of particle provides the compound dosage of this paper disclosure of quick-release basically when Mammals is taken in.First group of particle not dressing or it comprises coatings and/or sealer coat.Second group of particle comprises coated granule, and it comprises that about 2%-is about 75%, preferably about 2.5%-about 70% and the total dose of the compound that more preferably from about this paper discloses in the preparation of about 70% weight of 40%-and the mixture of one or more tackiness agents.This coatings comprises the acceptable component of pharmacy, and its consumption is enough to discharge about 2 hours-Yue 7 hours delay of dosage prerequisite confession for the second time after absorption.Suitable coatings comprises: but the coatings of one or more difference degraded, only as an example, such as pH susceptibility coatings (enteric layer), such as separately or with derivatived cellulose for example the ethyl cellulose fusion acrylic resin (for example
Figure A20068004995801001
EPO,
Figure A20068004995801002
L30D-55,
Figure A20068004995801003
FS 30D
Figure A20068004995801004
L100-55, L100,
Figure A20068004995801006
S100,
Figure A20068004995801007
RD100,
Figure A20068004995801011
E100,
Figure A20068004995801012
L12.5,
Figure A20068004995801013
S12.5 and
Figure A20068004995801014
NE30D,
Figure A20068004995801015
NE ); Or non--enteric layer, they have the variable thickness of the difference release of the preparation that the compound that comprises that this paper discloses is provided.
The controlled release system of many other types is for well known to a person skilled in the art and be applicable to preparation described herein.The example of this class delivery system comprises that for example anhydrides and polycaprolactone such as poly(lactic acid) and polyglycolic acid, gather in the polymer class system; Porous matrix, the non-polymer type systematic is lipid, comprises steroid, such as cholesterol, cholesterol esters; Lipid acid or neutral fat, such as the glyceryl monoacetate class, di-glycerides and triglyceride; The hydrogel release system; The silicon rubber system; The peptide type systematic; The wax coatings, the bioerodable formulation is used the compressing tablet of typical binders etc.For example, referring to Liberman etc., Pharmaceutical Dosage Forms, 2 Ed., Vol.1, pp.209-214 (1990); Singh etc., Encyclopedia ofPharmaceutical Technology, 2 NdEd., pp.751-753 (2002); U.S. Pat 4,327,725,4,624,848,4,968,509,5,461,140,5,456,923,5,516,527,5,622,721,5,686,105,5,700,410,5,977,175,6,465,014 and 6,932,983, especially these documents are incorporated herein by reference separately.
The pharmaceutical preparation to experimenter's oral administration of being used for of the particle of the compound that comprises that this paper discloses and at least a dispersion agent or suspensoid is provided in certain embodiments.Said preparation can be powder and/or the particle that is used for suspendible, and obtains uniform basically suspension when mixing with water.
The liquid dosage form that is used for oral administration can be aqueous suspension, and it is selected from, and includes, but are not limited to pharmacy acceptable moisture oral dispersion liquid, emulsion, solution, elixir, gel and syrup.For example, referring to Singh etc., Encyclopedia of PharmaceuticalTechnology, 2 NdEd., pp.754-757 (2002).Except that the compound particle that this paper discloses, liquid dosage form can also comprise additive, such as: (a) disintegrating agent; (b) dispersion agent; (c) wetting agent; (d) at least a sanitas, (e) tackifier, (f) at least a sweeting agent; (g) at least a correctives.In certain embodiments, suitable dispersion liquid may further include crystallization inhibitor.
Aqueous suspension described herein and dispersion liquid can keep as the uniform state of definition among The USP Pharmacists ' Pharmacopeia (2005 edition, chapter 905) 4 hours at least.This homogeneity should be measured by the sampling system consistent with measuring integrally combined thing homogeneity.In one embodiment, the physical agitation that can continue to be less than 1 minute becomes even suspension with aqueous suspension suspendible again.In another embodiment, the physical agitation that can continue to be less than 45 seconds becomes even suspension with aqueous suspension suspendible again.In another embodiment, the physical agitation that can continue to be less than 30 seconds becomes even suspension with aqueous suspension suspendible again.In another embodiment, needn't stir and keep even aqueous dispersion.
The example that is used for the disintegrating agent of aqueous suspension and dispersion liquid includes, but are not limited to starch, native starch for example, such as W-Gum or yam starch, pregelatinized Starch, such as National 1551 or
Figure A20068004995801021
Or sodium starch glycollate, such as Or Mierocrystalline cellulose, such as timber products, the methyl crystalline cellulose, for example
Figure A20068004995801024
Figure A20068004995801025
PH101,
Figure A20068004995801026
PH102,
Figure A20068004995801027
PH105,
Figure A20068004995801028
P100,
Figure A20068004995801029
Ming
Figure A200680049958010210
With
Figure A200680049958010211
, methylcellulose gum, croscarmellose or cross-linked cellulose, such as croscarmellose sodium ( ), crosslinked carboxy methylcellulose or croscarmellose; Cross-linking starch is such as sodium starch glycollate; Cross-linked polymer is such as polyvinylpolypyrrolidone; Cross-linked polyvinylpyrrolidone; Alginate are such as alginic acid or alginate, such as sodiun alginate; Clay, such as
Figure A200680049958010213
HV (magnesium aluminum silicate); Natural gum, such as agar, guar gum, Viscogum BE, POLY-karaya, pectin or tragacanth gum, sodium starch glycollate; Wilkinite; Natural sponge; Tensio-active agent; Resin is such as Zeo-karb; Citrus pulp, sodium lauryl sulphate, the combination of sodium lauryl sulphate and starch etc.
In certain embodiments, the dispersion agent that is suitable for aqueous suspension described herein and dispersion liquid is as known in the art and comprises, for example, and hydrophilic polymer, ionogen, Tween
Figure A200680049958010214
Or 80, PEG, polyvinylpyrrolidone (PVP; Trade(brand)name is called
Figure A200680049958010215
) and the carbohydrate dispersion agent, such as, for example, hydroxypropylcellulose and hydroxypropylcelluloether ether class (for example HPC, HPC-SL and HPC-L), HPMC and HPMC ethers (HPMC K100 for example, HPMC K4M, HPMC K15M and HPMC K100M), Xylo-Mucine, methylcellulose gum, Natvosol, phthalic acid hydroxypropylmethyl-Mierocrystalline cellulose, acetate stearic acid hydroxypropylmethyl-Mierocrystalline cellulose, noncrystalline cellulose, magnesium aluminum silicate, trolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone//vinyl acetate copolymers (
Figure A200680049958010216
, S-630 for example), with 4-(1,1,3, the 3-the tetramethyl butyl)-cascophen (being also referred to as tyloxapol) of oxyethane and formaldehyde, poloxamer (Pluronics for example
Figure A20068004995801031
With
Figure A20068004995801032
Segmented copolymer for oxyethane and propylene oxide); With the husky amine (poloxamine) in pool Lip river (Tetronic for example , be also referred to as Poloxamine
Figure A20068004995801034
, for add to four functional blocks multipolymers on the quadrol (BASF Corporation, Parsippany, N.J.)) successively derived from propylene oxide and oxyethane.In other embodiments, dispersion agent is selected from the group that does not comprise one of following reagent: hydrophilic polymer; Ionogen;
Figure A20068004995801035
60 or 80; PEG; Polyvinylpyrrolidone (PVP); Hydroxypropylcellulose and hydroxypropylcelluloether ether class (for example HPC, HPC-SL and HPC-L); HPMC and HPMC ethers (HPMCK100 for example, HPMC K4M, HPMC K15M, HPMC K100M and
Figure A20068004995801036
USP2910 (Shin-Etsu)); Xylo-Mucine; Methylcellulose gum; Natvosol; The phthalic acid HPMC; Acetate stearic acid HPMC; Noncrystalline cellulose; Magnesium aluminum silicate; Trolamine; Polyvinyl alcohol (PVA); 4-(1,1,3, the 3-tetramethyl butyl)-cascophen with oxyethane and formaldehyde; Poloxamer (Pluronics for example
Figure A20068004995801037
With
Figure A20068004995801038
, be the segmented copolymer of oxyethane and propylene oxide); Or the husky amine (poloxamine) in pool Lip river (Tetronic for example
Figure A20068004995801039
, be also referred to as Poloxamine
Figure A200680049958010310
).
The wetting agent that is suitable for aqueous suspension described herein and dispersion liquid is as known in the art and includes, but are not limited to hexadecanol, glyceryl monostearate, and the polyoxyethylene sorbitan fatty acid ester class (for example is purchased
Figure A200680049958010311
, such as, Tween for example
Figure A200680049958010312
And Tween
Figure A200680049958010313
(ICI Specialty Chemicals)) and polyethylene glycols (Carbowaxs for example
Figure A200680049958010314
With And Carbopol
Figure A200680049958010316
(Union Carbide)), oleic acid, glyceryl monostearate; Sorbitan Oleate, sorbitan laurate, Emulphor FM; polyoxyethylene sorbitan monooleate, Tween-20, sodium oleate; sodium lauryl sulphate, Docusate Sodium, triactin; vitamin-E TPGS; Taurocholic acid sodium salt, Simethicone, phosphatidylcholine etc.
The suitable sanitas that is used for aqueous suspension described herein or dispersion liquid comprises, for example, and potassium sorbate, parabens (for example methyl p-hydroxybenzoate and propylparaben), phenylformic acid and salt thereof, other ester class of P-hydroxybenzoic acid is such as butyl p-hydroxybenzoate, alcohols, such as ethanol or benzylalcohol, phenolic compound is such as phenol, or quaternary ammonium compound, such as benzalkonium chloride.Sanitas used herein is mixed formulation with the concentration that is enough to suppress microorganism growth.
The suitable tackifier that are used for aqueous suspension described herein or dispersion liquid include, but are not limited to methylcellulose gum, xanthan gum, and carboxy methyl cellulose, hydroxypropylcellulose, HPMC,
Figure A20068004995801041
S-630, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan and combination thereof.The concentration of tackifier depends on the reagent of selection and required viscosity.
The example that is applicable to the sweeting agent of aqueous suspension described herein or dispersion liquid comprises, syrup acacia for example, acesulfame K, alitame, star anise, apple, aspartame, banana, bavarian cream, berry, black gooseberry, butterscotch, citrate of lime, camphor, caramel, cherry, the cherry breast, chocolate, Chinese cassia tree, bubble gum, oranges and tangerines, orange juice mixing drink (citrus punch), oranges and tangerines cream, marsh-mallow, cocoa, cola, cold cherry, cold oranges and tangerines, cyclohexyl-n-sulfonate, cyclohexyl-n-sulfonate (cylamate), glucose, volatile oil extracted from eucalyptus' leaves or twigs, Eugenol, fructose, fruit juice mixing drink, ginger, glycyrrhetate, Radix Glycyrrhizae (G1ycyrrhiza glabra) syrup, grape, shaddock, honey, isomaltose, lemon, bitter orange, the lemon breast, Potenlini one ammonium (
Figure A20068004995801042
), maltol, N.F,USP MANNITOL, maple syrup, Althaea officinalis, menthol, peppermint cream, the blended berry, neohesperidin DC, knob sweet (neotame), orange, pears, peach, peppermint, the peppermint breast,
Figure A20068004995801043
Powder, blackberry, blueberry, root beer, Rum, asccharin, safrol, sorbyl alcohol, spearmint, spearmint breast, strawberry, strawberry breast, sweet Stevia, Sucralose, sucrose, soluble saccharin, asccharin, aspartame, Sunnett, N.F,USP MANNITOL, talin, syllitol (sylitol), Sucralose, sorbyl alcohol, Switzerland's cream, tagatose, red tangerine, thaumati, assorted candied fruits, vanilla, English walnut, watermelon, wild cherry, wintergreen oil, the arbitrary combination of Xylitol or these correctives components, star anise-menthol for example, cherry-star anise, Chinese cassia tree-orange, cherry-Chinese cassia tree, chocolate-peppermint, honey-lemon, lemon-bitter orange, lemon-peppermint, menthol-volatile oil extracted from eucalyptus' leaves or twigs, orange-cream, vanilla-peppermint and composition thereof.In one embodiment, liquid, aqueous dispersion liquid can comprise sweeting agent or the correctives that concentration range accounts for the about 0.001%-of this aqueous dispersion volume about 1.0%.In another embodiment, liquid, aqueous dispersion liquid can comprise sweeting agent or the correctives that concentration range accounts for the about 0.005%-of this aqueous dispersion volume about 0.5%.In another embodiment, liquid, aqueous dispersion liquid can comprise sweeting agent or the correctives that concentration range accounts for the about 0.01%-of this aqueous dispersion volume about 1.0%.
Except that above-mentioned additive, liquid preparation can also comprise inert diluent commonly used in this area, such as water or other solvent, solubilizing agent and emulsifying agent.Typical emulsifying agent is an ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol; peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide; sodium lauryl sulphate, Docusate Sodium, cholesterol, cholesterol esters; taurocholate, phosphatidylcholine, oil is such as oleum gossypii seminis; peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil; glycerine, tetrahydrofurfuryl alcohol, polyethylene glycols, the mixture of sorbitan-fatty acid ester class or these materials etc.
In certain embodiments, pharmaceutical preparation described herein can be self-emulsified drug delivery system (SEDDS).Emulsion is the dispersion that each each other can not be miscible between mutually, is generally the drop form.Generally speaking, generate emulsion by violent mechanical dispersion.Spontaneous formation emulsion when the SEDDS opposite with emulsion or micro emulsion joins in the excessive water under no any exterior mechanical disperses or stirs.The advantage of SEDDS only need to be slowly to mix just can be with droplet distribution in whole solution.In addition, can before facing administration, add entry or water, thereby guarantee the stability of instability or hydrophobic active component.Therefore, SEDDS carries for the oral and parenteral of hydrophobic active component effective delivery system is provided.SEDDS can provide improvement aspect the bioavailability of hydrophobic active component.The method of producing the self-emulsifying formulation is as known in the art and for example includes, but are not limited to, U.S. Pat 5,858, and 401,6,667,048 and 6,960,563, especially these documents are incorporated herein by reference separately.
Should understand be used for existing between the above-mentioned additive of aqueous dispersion described herein or suspension overlapping because specified additive is classified by different way by different practitioners in the art usually or is usually used in any several different function.Therefore, typical case and nonrestrictive in the additive types that only above-mentioned additive should be considered as can comprising in the preparation described herein.The amount of this class additive is easy to be determined according to required particular characteristics by those skilled in the art.
Preparation in the nose
Preparation is as known in the art and is described in that for example U.S. Pat 4,476 in the nose, in 116,5,116,817 and 6,391,452, especially these documents is incorporated herein by reference separately.To become the solution in salt solution according to the formulation preparation that comprises compound provided herein of these and other technology preparation well-known in the art, wherein use benzylalcohol well known in the art or other aqueous sanitas, fluorocarbon and/or other solubilizing agent or dispersion agent.For example, referring to Ansel, H.C. etc., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Ed. (1995).The suitable acceptable component of nontoxicity pharmacy of preferred use prepares these compositions and preparation.Known these components of art technology person are used to prepare the nose formulation, and the canonical reference book REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY that in them some can be in the art, and 21st edition finds in 2005.The selection of suitable carriers is highly depended on the definite character of required asal agent type, for example solution, suspension, ointment or gel.The asal agent type generally comprises big water gaging and active ingredient.Can also there be a small amount of other component, such as the pH regulator agent, emulsifying agent or dispersion agent, sanitas, tensio-active agent, jelling agent or buffer reagent and other stablizer and solubilizing agent.Preferred this asal agent type should ooze with nasal discharge etc.
In order to pass through inhalation, the compound that this paper discloses can be aerosol, sprays or powder type.Since the aerosol form of self-pressurization packing or atomizer carry pharmaceutical composition described herein expediently, wherein use suitable propellent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.With regard to pressurised aerosol, can measure dose unit by the valve that the conveying and metering consumption is installed.Such as, only as an example, can prepare the gelatine capsule and the cartridge case that are used for sucker or insufflator, it comprises the powdered mixture of compound described herein and suitable powder matrix such as lactose or starch.
Buccal lozenge
Can use various preparation administration as known in the art to comprise the buccal lozenge of the compound that this paper discloses.For example, this class preparation includes, but are not limited to U.S. Pat 4,229, and 447,4,596,795,4,755,386 and 5,739,136, especially these documents are incorporated herein by reference separately.In addition, the formulation of sucking described herein may further include bioerodable (hydrolyzable) polymer support, and it also is used to make described formulation and oral mucosa adhesion.Formulation is sucked in preparation, so that progressively corrosion in the time limit at the fixed time, the compound that wherein provides basically this paper from start to finish to disclose is carried.Just as will be understood by the skilled person in the art, suck the shortcoming that administration has avoided oral administration to run into, for example absorb slowly, the fluid that is present in the gi tract is crossed inactivation to the degraded of promoting agent and/or the head in the liver.With regard to bioerodable (hydrolyzable) polymer support, be appreciated that and in fact can use any this class carrier, as long as the compound that required drug release characteristics is without prejudice and this carrier and this paper disclose is with to be present in any other composition of sucking in the dose unit compatible.Generally speaking, polymer support comprise can with wetting ability (the water-soluble and water-swellable) polymkeric substance of the wetted surface of oral mucosa adhesion.The example of polymer support used herein comprises acrylate copolymer and multipolymer, for example be called " carbomer " ( , can be a kind of this base polymer available from B.F.Goodrich).Other composition can also be mixed the formulation of sucking described herein, include, but are not limited to disintegrating agent, thinner, tackiness agent, lubricant, correctives, tinting material, sanitas etc.In order to suck or sublingual administration, composition can adopt tablet, lozenge or the gel form of preparation in a conventional manner.
Preparation capable of permeating skin
Can use the various device administrations preparation capable of permeating skin of putting down in writing in this area described herein.For example, this class device includes, but are not limited to U.S. Pat 3,598, and 122,3,598,123,3,710,795,3,731,683,3,742,951,3,814,097,3,921,636,3,972,995,3,993,072,3,993,073,3,996,934,4,031,894,4,060,084,4,069,307,4,077,407,4,201,211,4,230,105,4,292,299,4,292,303,5,336,168,5,665,378,5,837,280,5,869,090,6,923,983,6,929,801 and 6,946,144, especially these documents intactly are incorporated herein by reference separately.
Transdermal formulation described herein can be mixed vehicle commonly used in the acceptable this area of some pharmacy.In one embodiment, preparation capable of permeating skin described herein comprises at least three kinds of compositions: (1) this paper discloses the preparation of compound; (2) penetration enhancer; (3) moisture adjuvant.In addition, preparation capable of permeating skin can comprise extra composition, such as, but be not limited to jelling agent, emulsion and ointment base etc.In certain embodiments, preparation capable of permeating skin may further include and spins cloth or nonwoven interlining backing material and absorb and prevent that preparation capable of permeating skin breaks away from from skin so that promote.In other embodiments, preparation capable of permeating skin described herein can keep saturated or hypersaturated state so that promote to diffuse into skin.
The preparation that is suitable for compound transdermal administration described herein can use the transdermal delivery device or and transdermal delivery patch and can be lipotropy emulsion, or be dissolved in and/or be scattered in the buffered aqueous solution of polymkeric substance or tackiness agent.For continuously, pulsed or make up this class patch according to the requirement of carrying pharmaceutically active agents.In addition, can carry out the transdermal delivery of compound described herein by iontophoresis patch etc.In addition, transdermal patch can provide the controlled delivery of the compound that this paper discloses.Can be by using rate controlling membranes or slowing down uptake rate by compound is trapped in polymeric matrix or the gel.On the contrary, absorption enhancer can be used for increasing absorption.Absorption enhancer or carrier can comprise absorbable pharmacy acceptable solvent, so that help to pass through skin.For example, transdermal device is a form of bandage, it comprises the backing layer, comprise described compound randomly with the storage layer of carrier, choose wantonly and in time limit time expand, compound be delivered to the rate-controlling barrier of host's skin and will install and skin fixed apparatus with controlled and set rate.
Injectable formulation
Be suitable for intramuscular, the preparation that comprises the compound that this paper discloses subcutaneous or intravenous injection can comprise physiology acceptable aseptic moisture or non--aqueous solution, dispersion liquid, suspension or emulsion and the sterilized powder that reconstitutes sterile injectable solution or dispersion liquid.Suitable moisture and non--water carrier, thinner, the example of solvent or vehicle comprises water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine, breast is floating etc.), its suitable mixture, vegetables oil (such as sweet oil) and injectable organosilane ester are such as ethyl oleate.For example, can be with regard to dispersion by using coatings, such as Yelkin TTS, by keeping desired particle size and keeping suitable flowability by the use tensio-active agent.Be suitable for hypodermic preparation and can also comprise additive, such as sanitas, wetting agent, emulsifying agent and dispersion agent.Can be with various antiseptic-germicides and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. guarantee to prevent microorganism growth.Also may need to comprise isotonic agent, such as carbohydrate, sodium-chlor etc.Can make the prolongation of injectable drug absorb such as aluminum monostearate and gelatin by using the reagent that postpones absorption.
For intravenous injection, compound described herein can be mixed with preferred at physiology consistency buffer reagent such as the aqueous solution in Hank solution, Ringer's solution or the normal saline buffer solution.In order to stride mucosa delivery, will be suitable for being used for preparation through the permeate agent of barrier.This class permeate agent is generally well known in the art.With regard to other parenteral injection, appropriate formulation can comprise moisture or non-aqueous solution, preferably contains physiology consistency buffer reagent or vehicle.This class vehicle is generally as known in the art.
The parenteral injection can comprise bolus injection or continuous infusion.The preparation that is used to inject can exist with unit dosage, for example in ampoule that has added sanitas or multi-dose container.Pharmaceutical composition described herein can be for being suitable for the sterile suspension in oil or water vehicle of parenteral injection, the form of solution or emulsion and can comprise reagent preparation, and such as suspensoid, stablizer and/or dispersion agent.The pharmaceutical preparation that is used for parenteral admin comprises the aqueous solution of the active compound of water-soluble form.In addition, the suspension of active compound can be prepared into suitable oily injection suspension.Suitable lipophilic solvent or vehicle comprise fatty oil, such as sesame oil; Or the Acrawax class, such as ethyl oleate or triglyceride or liposome.Moisture injection suspension can comprise the material that increases this suspension viscosity, such as Xylo-Mucine, and sorbyl alcohol or dextran.Optional this suspension can also comprise suitable stabilizers or increase the reagent of compound dissolution degree, so that prepare highly enriched solution.Selectively, active ingredient can be for using appropriate excipients, for example aseptic pyrogen-free water-soluble powder type before use.
Other preparation
In certain embodiments, can use the delivery system that is used for medical compounds, such as, for example liposome and emulsion.In certain embodiments, composition provided herein can also comprise the mucoadhesive polymkeric substance, it is selected from, for example, and carboxymethyl cellulose, carbomer (acrylate copolymer), poly-(methyl methacrylate), polyacrylamide, polycarbophil (polycarbophil), vinylformic acid/butyl acrylate copolymer, sodiun alginate and dextran.
In certain embodiments, can and they can be mixed with the various topical drug delivery composition of passing through by topical compound described herein, such as solution, suspension, lotion, gel, paste, the rod of pastille, balm (balm), emulsion or ointment.This medicinal compound can comprise solubilizing agent, and stablizer is opened degree promotor, buffer reagent and sanitas.
Compound described herein can also be mixed with the rectum composition, such as enema, rectal gel, rectum foam, rectum aerosol, suppository, gel suppository or retention enema, they comprise suppository base commonly used, such as theobroma oil or other glyceride type and synthetic polymer, such as polyvinylpyrrolidone, PEG etc.In the composition of suppository form, at first melt low melt wax, such as, but be not limited to the optional mixture with theobroma oil of glycerin fatty acid ester class.
Medication and treatment plan
Compound described herein can be used to prepare and suppress fatty acid amide hydrolase or be used for the treatment of the medicament that can have benefited from suppressing the disease or the illness of fatty acid amide hydrolase to small part.In addition, the method that the experimenter of this class of needs treatment is treated any disease described herein or illness comprise to this experimenter with the administration of treatment significant quantity comprise compound or its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite that at least a this paper discloses, pharmacy is acceptable or the pharmaceutical composition of pharmacy acceptable solvent compound.
Can comprise compound compositions as herein described for preventing and/or treating administration.In treatment is used, patient's administration of suffering from disease or illness is enough to cure or suppress to small part the composition of the consumption of described disease or illness symptom.The significant quantity that is used for this application depends on the seriousness and the process of disease or illness, therapy in advance, patient's state of health, body weight and to the clinicist's of the reaction of medicine and treatment judgement.Those skilled in the art fully think and determine this class treatment significant quantity by normal experiment (including, but are not limited to the clinical trial that dosage rises gradually).
In prophylactic applications,, otherwise be exactly that the patient's administration that is in its risk comprises compound compositions described herein to susceptible specified disease, illness or illness.This class consumption is defined as " prevention significant quantity or dosage ".In this case, definite amount also depends on patient's state of health, body weight etc.Those skilled in the art fully think and determine this class prevention significant quantity by normal experiment (including, but are not limited to the clinical trial that dosage rises gradually).When being used for the patient, the significant quantity that is used for this application depends on the seriousness and the process of disease or illness, therapy in advance, patient's state of health, body weight and to the clinicist's of the reaction of medicine and treatment judgement.
In this case, if patient's the state of an illness is not improved according to doctor's judgement, so can the described compound of long term administration, i.e. time limit time expand, be included in administration in patient's the whole vital process, so that improve or the symptom of control or restriction patient disease or illness.
In this case, if patient's the state of an illness improves really according to doctor's judgement, so can the described compound of specified successive administration; Selectively, dosage can temporarily reduce or temporarily stop the certain hour time limit (i.e. " off-drug period ").The time span of off-drug period can change between 2 days-1 year, only comprised 2 days as an example, and 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days.Dosage in the off-drug period process reduces can only comprise 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% as an example at 10%-100%.
In case improving, patient's the state of an illness takes place, if necessary, and with regard to the administration maintenance dose.Can make subsequently that both reduce to the improvement level of disease, illness or illness as the dosage of symptom function or frequency or they.Yet the patient may be based on secular intermittent treatment when any symptomatic recurrence.
The specified activity agent consumption basis that is equivalent to this class consumption is such as specific compound, disease or illness and seriousness thereof, need the experimenter of treatment or host this class factor of characteristic (for example body weight) difference and change, however, but usually can be according to mode well known in the art, determine according to particular case around this case, comprise, the concrete promoting agent of administration for example, route of administration, the illness of treatment and experimenter or the host who is treated.But, generally speaking, be used for adult therapeutic dose, preferred 1-1500mg/ days scope generally at 0.02-5000mg/ days.Required dosage can be made expediently single dose or simultaneously (or in time limit short period of time) or in appropriate intervals, for example as the fractionated dose of the every day of sub-doses administration more than 2,3,4 or 4 times.
Pharmaceutical composition described herein can be the unit dosage of the single-dose that is suitable for exact dosage desired.In unit dosage, preparation is divided into the unitary dose that comprises one or more an amount of compounds.This unitary dose can be the packaged form of the preparation of the amount that comprises separation.Limiting examples is wrapping sheet or capsule and the powder in bottle or ampoule.The aqueous suspension composition can be packaged in single dose can not the secondary packaging container in.Selectively, can use multiple doses packaging container again, in this case, generally comprise sanitas in the composition.Only as an example, the preparation that is used for the parenteral injection can be made unit dosage, include, but are not limited to add the ampoule or the multi-dose container form of sanitas.
Be suitable for compound described herein every day dosage in about 0.01-2.5mg/kg body weight.Than large mammals, include, but are not limited to shown in the philtrum every day dosage at the about 100mg of about 0.5mg-, expediently with the fractionated dose administration, include, but are not limited to reach every day 4 times or to prolong the releasing pattern administration.The suitable unit dosage that is used for oral administration comprises about 1-50mg active ingredient.Above-mentioned scope only is suggestive, because the variable quantity of relevant individual treatment scheme is big and to recommend the obvious deviation of numerical value from it be not uncommon.This class dosage can change according to the difference of many variablees, and is not limited to the activity of compound used therefor, disease of being treated or illness, administering mode, the demand of individual subjects, the disease for the treatment of or the seriousness of illness and practitioner's judgement.
Can measure the toxicity and the therapeutic efficiency of this class treatment plan by the standard drug method in cell culture or the laboratory animal, include, but not limited to measure LD 50(making the lethal dosage of 50% colony) and ED 50(the effective dosage of treatment in 50% colony).Be therapeutic index and it can be expressed as LD with the ratio of the dosage between toxicity and the therapeutic action 50With ED 50The ratio.Preferably show the compound of high therapeutic index.Data available from cell culture test and zooscopy can be used to prepare the dosage range that is applied to the people.The dosage of this compounds preferably includes has minimum toxic ED 50The circulation composition scope.This dosage can change in this scope that do not coexist according to used formulation and used route of administration.
Conjoint therapy
Composition described herein and method can also with because of the treatment illness being had other well-known treatment reagent coupling that specific availability is selected.Generally speaking, in using the embodiment of conjoint therapy, composition described herein and other promoting agent be not necessarily with the form administration in same pharmaceutical composition, and their may be because different physics and chemical feature and must be by the different approaches administration.If possible, the ken that the administering mode in same pharmaceutical composition and administration appropriateness is fully belonged to clinical those of ordinary skill.Can carry out initial administration according to the scheme of foundation well known in the art, and, can change dosage, administering mode and administration number of times by clinical those of ordinary skill then based on observed effect.
In some cases, suitable administration at least a compound described herein and another kind of therapeutical agent.Only as an example, if one of side effect of patient's experience when accepting one of compound described herein for feeling sick, so suitably administration prevents the medicine of feeling sick and initial therapeutical agent.Or only as an example, can strengthen the treatment validity (be that adjuvant itself may have minimum treatment helpfulness, then can strengthen overall treatment helpfulness) of one of compound described herein by the administration adjuvant to the patient with another kind of therapeutical agent coupling.Or only as an example, can increase the helpfulness of patient experience by one of administration compound described herein and the another kind of therapeutical agent (also comprising treatment plan) that also has the treatment helpfulness.Under any circumstance, the overall helpfulness of patient experience can be that adding up merely of two kinds of therapeutical agents or patient can experience collaborative helpfulness, and is irrelevant with the disease of being treated, illness or illness.
The concrete selection of compound used therefor is depended on attending doctor's diagnosis and to the judgement of conditions of patients and suitable treatment plan.Can be simultaneously (for example simultaneously, basically simultaneously or in the identical treatment scheme) or give drug compound successively, this depends on the character of disease, illness or illness, patient's the state of an illness and to the actual selection of compound used therefor.To the administration order of every kind of therapeutical agent in the treatment plan process and repeat administration number of times determine fully belong to the ken of common clinicist after the state of an illness of estimating the disease of being treated and patient.
Those skilled in the art's known treatment effective dose can change when medicine is used for conjoint therapy.Measuring the method for the treatment effective dose of the medicine be used for combined treatment and other promoting agent by experiment describes in the literature.For example, extensively described the application of metronome (metronomic) formula administration in the document, promptly provide upper frequency, than low dosage, so that toxic side effect is reduced to bottom line.Conjoint therapy further comprises with different number of times and begins regularly to treat with terminated, so that help the Clinical Processing to the patient.
With regard to conjoint therapy described herein, the dosage of the compound of co-administered certainly can be according to the medicine of common use, used concrete medicine, the difference of the disease of being treated or the state of an illness etc. and changing.In addition, when with one or more biologically active agent co-administereds, can be with compound provided herein and described biologically active agent while or administration successively.If administration successively, the attending doctor can determine the suitable order of protein with described biologically active agent administration so.
Under any circumstance, can be according to any order or the multiple therapeutical agent of administration (for one of compound of this paper disclosure) simultaneously.If administration simultaneously can be made multiple therapeutical agent single unified standard formulation or a plurality of formulation (only as an example, being single pill or two kinds of different pills) so.One of therapeutical agent can be given with a plurality of dosage, or all give with a plurality of dosage.If not administration simultaneously, the timed interval between so a plurality of dosage can change to being less than 4 weeks more than 0 week.In addition, integrated processes, composition and preparation are not limited to only use two kinds of promoting agents; Also pay close attention to the application of multiple therapeutic combination.
The dosage that should understand treatment, prevent or improve the state of an illness of seeking to alleviate can change according to the difference of various factors.These factors comprise illness and this experimenter's age, body weight, sex, meals and the medical condition that the experimenter suffers from.Therefore, the dosage of practical application can extensively change based on dosage described herein.
The pharmaceutically active agents that constitutes the conjoint therapy of this paper disclosure can be for the coupling formulation or for being used for the multiple independently formulation of administration simultaneously basically.Successively administration constitute conjoint therapy pharmaceutically active agents, wherein by being called the arbitrary treatment compound of scheme administration of two step administrations.Two step dosage regimens can be called the administration successively of promoting agent or the interval administration of multiple independent promoting agent.Time bar between a plurality of dosing step can be at several minutes by several hours, and this depends on the characteristic of every kind of pharmaceutically active agents, such as the effect of pharmaceutically active agents, and solubleness, bioavailability, plasma half-life and dynamics.The circadian rhythm of concentration of target molecules changes also can determine the optimal dose interval.
In addition, compound described herein can also with the method coupling that extra additional or collaborative helpfulness can be provided the patient.Only as an example, estimate that the patient can feel the helpfulness that treats and/or prevents of methods described herein, wherein the pharmaceutical composition of the compound that this paper can be disclosed and/or with the combination of other therapeutical agent again with heredity test coupling so that determine whether this individuality is the known mutator gene carrier relevant with some disease or illness.
Can be before disease or illness take place, in the generation or give compound described herein and conjoint therapy afterwards, and the time of the composition of administration inclusion compound can change.Therefore, for example, compound can be used as preventive and can be with it continuously to having experimenter's administration of easy generation illness or disease tendency, so that prevent the generation of described disease or illness.Behind paresthesia epilepsy, give drug compound and composition to the experimenter as quickly as possible.Begin to drug compound in rise at paresthesia epilepsy 48 hours, in preferably rise at paresthesia epilepsy 48 hours, in more preferably rise at paresthesia epilepsy 6 hours, and in most preferably rise at paresthesia epilepsy 3 hours.Initial administration can be undertaken by any actual approach, such as, for example, intravenous injection, bolus injection, infusion in 5 minutes-Yue 5 hours, pill, capsule, transdermal patch is sucked to carry and is waited or its combination.Preferred in case detect or suspect that disease or illness outbreak back just give drug compound, and must be to this disease treatment certain hour time limit, such as, for example, about 1 month-Yue 3 months.The treatment time limit can change because of each experimenter's difference and use known standard to measure this time limit.For example, can with described compound or comprise at least 2 weeks of preparation administration of this compound, preferred about 1 month-Yue 5 years and more preferably 1 month-Yue 3 years.
Test kit/goods
With regard to regard to the application during treatment described herein is used, this paper has also described test kit and goods.This class test kit can comprise the carrier that is divided into the chamber, and packing or container, are managed etc. such as bottle so that hold one or more containers, and described container comprises independently one of the composition that is used for methods described herein separately.Suitable containers comprises, for example, and bottle, bottle, syringe and test tube.These containers can be made of such as glass or plastics various materials.
Goods provided herein comprise wrapping material.The wrapping material that are used for the packaged pharmaceuticals product are well-known for those skilled in the art.For example, referring to U.S. Pat 5,323,907,5,052,558 and 5,033,252.The example of drug packages material includes, but are not limited to blister pack, bottle, pipe, sucker, pump, bag, bottle, container, syringe, bottle and any preparation that is suitable for selecting and the wrapping material of specifying administration and therapeutic modality.Studied the preparation of one group of compound provided herein widely and composition because they be can have benefited from by suppress fatty acid amide hydrolase (FAAH) wherein or FAAH be the various methods of treatment of symptom or cause of disease amboceptor or contributor's any disease, illness or illness.
For example, can comprise one or more compounds described herein of choosing another kind of therapeutical agent coupling in composition or that disclose with this paper wantonly in the container.These containers are optional to have aseptic inlet (for example this container can for having the intravenous solution bag or the bottle of the plug that hypodermic needle can thrust).The optional inclusion compound of this class test kit and the sign description or mark or the specification sheets that relate to its application in methods described herein.
Test kit generally can comprise the container that one or more are extra, and they have separately from commodity and user's one or more different materials of use viewpoint ideal (such as reagent, optional conc forms, and/or device) from compound described herein.The non-limiting instance of this class material includes, but are not limited to buffer reagent, thinner, weighting agent, syringe needle, syringe; Carrier, packing, container, bottle and/or list inclusion and/or the label of operation instruction and package insert with operation instruction.Generally also comprise a group profile book.
Label can be positioned on the container or and container combination.When the letter that constitutes label, numeral or other character are pasted, molding or be etched in container oneself on one's body the time, label can be positioned on the container; When being present in container or also accommodate in the carrier of container, for example as package insert, label and container combination.Label can be used to represent to be used for the inclusion that concrete treatment is used.Label can also be represented the use of inclusion, such as the guidance of using in methods described herein.
In certain embodiments, pharmaceutical composition can be made cartridge bag or dispensation apparatus, it can comprise one or more unit dosage that contain compound provided herein.For example, cartridge bag can comprise metal or plastic foil, such as blister pack.Cartridge bag or dispensation apparatus can attach the administration specification sheets.Cartridge bag or dispenser can also be attached the regulation drug manufacture with container combination, and use or the government administration section of selling are opened the precaution according to form, and these precaution reflect that pharmaceutical dosage form can be applicable to people or beastly administration through approved by management.For example, these class precaution can for FDA (Food and Drug Adminstration) to the sign of prescription drugs approval or the product inset of approval.Can also prepare and be included in this paper for preparing in the consistency pharmaceutical carrier compound compositions is provided, be placed in the proper container and the illness of mark shown in can be used for treating.
The application of treatment and/or FAAH inhibitor compound
The endogenous acid amides of the various lipid acid of enzyme FAAH catalysis and the hydrolysis of ester derivative, such as, but be not limited to N-arachidonic acyl ethanol amine (arachidonic acid thanomin), N-palmityl thanomin, N-Oleoyl monoethanolamide, oleylamide and 2-arachidonic acyl glycerine.These derivatives are brought into play different pharmacological activities by especially taking place to interact with cannaboid and novel vanilloid receptor.This degradation pathway of compounds block provided herein and increase the tissue content of these endogenous material.In this respect, they can be used to prevent and treat Endocannabinoids and/or any other the pathology situation by the metabolic material of enzyme FAAH of relating to.
In certain embodiments, compound provided herein can be used for the treatment of and/or prevent the vomiting after the chemotherapy especially, dizziness, vomiting and feeling sick.
In certain embodiments, can administration compound provided herein so that alleviate experimenter's pain.This treatment can be for preventative or curative.Can give this treatment to the human body experimenter.Can be with the conjoint therapy of another kind of pain relief agents or antiphlogiston or do not use this conjoint therapy to carry out this treatment.
In certain embodiments, compound provided herein can be used for the treatment of various pain, comprises the pain relevant with status of cough, pain before the pain relevant, art with cancer, the chronic pain of arthritis pain and other form, such as postoperative pain, waist and sacrum pain, musculoskeletal pain, headache, migraine, myalgia, following waist and cervical pain, toothache etc.In certain embodiments, compound provided herein is used for the treatment of neuropathic pain.Neuropathic pain syndrome can take place behind neuronal damage, and the pain that produces even still may continue some months or several years after the initial damage recovery from illness.Neuronal damage may occur in peripheral nerve, and the Dorsal root nerve is in some zone in spinal cord or the brain.Traditionally according to disease or facilitate their consequence classification neuropathic pain syndrome.Neuropathic pain syndrome comprises: diabetic neuropathy; Sciatica; Non--the specificity low back pain; Multiple sclerosis pain; Fibromyalgia; HIV-related neural disease; Neurodynia is such as postherpetic neuralgia and trigeminal neuralgia; With because of the health wound, carry limb art, cancer, the pain that toxin or chronic inflammatory diseases situation cause.The symptom of neuropathic pain is different and is described as spontaneous outbreak usually and lancinating pain or burning property of carrying out property pain.In addition, exist and the relevant pain of the sexy feel of general non-pain, such as " pin and the sense of syringe needle thorn " (paresthesia and insensitive), tactile susceptibility is increased (oxypathy), the post-stimulatory pain perception of innocuousness (dynamic, the allodynia of fixed or heat), the susceptibility that hazardous property is stimulated increases (heat, cold, mechanical hyperalgesia), remove post-stimulatory lasting pain (hyperpathia) or selectivity sensory pathway through lacking or defective (hypoalgesia).
In certain embodiments, compound provided herein is used to prevent and/or treat pain, particularly acute or chronic neuropathic pains, migraine, neuropathic pain comprises the form relevant with simplexvirus and diabetes, acute or the chronic pain relevant: sacroiliitis with inflammatory diseases, rheumatoid arthritis, osteoarthritis, back of the body vertebra inflammation, gout, vasculitis, Crohn's disease, irritable bowel syndrome and on every side acute (acute)/acute (sharp) or chronic pain.
In certain embodiments, compound provided herein and composition can be used for the treatment of non--inflammatory pain and/or inflammatory pain.Can with compound as therapeutical agent be used for various types of non--inflammatory pain, include, but are not limited to:
-peripheral nerve pain, the pain that causes for the infringement in the peripheral nervous system or dysfunction, for example, the pain neuropathy that tissue injury's healing back pain continues for a long time;
-central pain for the pain that central nervous system damage or dysfunction cause, for example, is followed thalamus (thalmic) infringement of the serious pain in the uninfluenced part of health;
-deafferentation pain is the pain that causes because of the sensation transmission disappearance that enters central nervous system, for example, and because of the neural pain that causes away from the damage of spinal cord rapidly of Dorsal root;
-chronic injury pain, for example, the cancer pain of some type;
The noxious stimulation of-nociception acceptor, such as, for example, feel pain to the reaction of tissue injury or upcoming tissue injury;
-phantom limb pain is the pain of feeling that the part of health no longer exists;
The pain of-mental patient sensation is the pain of no physics cause of disease existence;
-wandering pain, wherein pain position in vivo changes repeatedly.
Compound provided herein can be used for the treatment of non--inflammatory pain and inflammatory pain.
In another embodiment, composition provided herein comprise compound provided herein and compatible with compound provided herein and preferred in oral dosage form effectively at least a generally acknowledged pain relieving or anti-inflammatory substance.The pain relieving of generally acknowledging or the example of anti-inflammatory compound include, but are not limited to: acetylsalicylic acid, Carbaspirin, choline salicylate ester, diflunisal, magnesium salicylate, salicylic amide, Whitfield's ointment, salsalate, Thiosalicylic acid,sodiumsalt, paracetamol, phenacetin, pyramidon, mefenamic acid, Levopromazine, Tacote, Phenylbutazone, indomethacin, Ibuprofen BP/EP, sulindac, piroxicam, meclofenamic acid, zomepirac, morphine monomethyl ether, morphine, Pethidine, Pethidine (pethinine), alphaprodine, fentanyl, levorphanol, methadone, phenazocine, butorphanol, ethoheptazine (ethobeptozine), nalbuphine, pentazocine, the third oxygen sweet smell, fenoprofen, Naproxen Base, tolmetin etc.In a preferred embodiment, with compound provided herein and generally acknowledged pain relieving or the anti-inflammatory compound co-administered of this class, thereby produce collaborative anti-inflammatory and/or analgesic effect.
In another embodiment, compound provided herein and composition can be used to alleviate neuropathic pain.
The pain that term used herein " neuropathic pain " intention causes because of injured nerve.Neuropathic pain is different from nociceptive pain, its pain for causing because of the acute tissue injury that relates to little cutaneous nerve in muscle or the reticular tissue or nervelet.The pain that relates to nociception mechanism is limited to during the tissue repair usually and generally passes through available anodyne or opioid alleviates (Myers, Regional Anesthesia 20:173-184 (1995) is incorporated herein by reference the document).
Neuropathic pain is generally long-term continuing or chronic and common several days or some months generation after initial acute tissue injury.Neuropathic pain can comprise persistent spontaneous pain and allodynia, and it is the pain reaction to general painless stimulation.The feature of neuropathic pain also is hyperpathia, wherein exists to being generally slight painful stimuli, such as the severe reaction of acupuncture.Compound provided herein can be used to alleviate and the irrelevant neuropathic pain of the cause of disease of pain.In certain embodiments, compound provided herein and composition can be used to alleviate the neuropathic pain that causes because of peripheral neuropathy, and described peripheral neuropathy is such as neuroma; Nerve compression; Nerve weighs wounded, and neural prolongation or incomplete nerve block; Mononeuropathy or polyneuropathy.
Neuroma is easy to take place after to nerve generation traumatic damage, especially when neural integral body is subjected to seriously weighing wounded or blocking.In neuroma, the perineural spinous process of generally regenerating is considered to unusual or misguided to outgrowth, and for example, this is because of due to physical blockage such as the scar tissue.Therefore, the regenerated nerve fiber is facilitated snarling in the environment of abnormal electrical physiological activity and pain (Myers, above, 1995) in machinery and physical factor.For example, the deformed limb neuroma can cause phantom limb pain maybe can produce the pain that causes because of the use artificial limb.This class neuropathic pain that discloses as this paper can be by administration FAAH inhibitor, is eased such as, compound for example provided herein.
Nerve compression also causes neuropathic pain.With regard to traumatic nerve weighed wounded, nerve compression can be unexpected, maybe can for prolong with appropriateness, in secondary tumor growth of main nerve tract vicinity or cicatrization.Repressive neurological disorder can be used as and arrives the result that neural blood flow changes and take place, thereby causes serious ischemic and nerve injury subsequently (Myers, above, 1995).
In other embodiments, compound provided herein and composition can be used to alleviate the neuropathic pain that disease due to illness causes, and described illness is such as the dorsal root ganglion pressurized; The spinal cord inflammation; Dampen, tumor of spinal cord or hemisection remove; Brain stem, thalamus or cortex tumour; Or brain stem, thalamus or cortex wound.
In certain embodiments, the administration of compound provided herein can be alleviated the neuropathic pain that causes because of mononeuropathy or polyneuropathy.Neuropathy used herein is that dysfunction in the peripheral nervous system or pathologic change, and is characterised in that clinically sensation or motor neuron are unusual.The term mononeuropathy represents that single peripheral nerve is encroached on, and the term polyneuropathy represents that several peripheral nerves are encroached on.The neuropathic cause of disease can be known or unknown (for example, referring to Myers, supra, 1995; Galer, Neurology 45 (suppl9): S17-S25 (1995); Stevens and Lowe, Pathology, Times MirrorInternational Publishers Limited, London (1995)).The known cause of disease comprises the complication of disease or toxicity state; For example, diabetes are for causing neuropathic modal metabolic disease.In certain embodiments, compound provided herein is alleviated for example because of diabetes, radiation, the neuropathic pain of the mononeuropathy that ischemic or vasculitis cause.In other embodiments, compound provided herein is alleviated for example because of poliomyelitis later stage syndrome, diabetes, alcohol, amyloid, toxin, HIV, hypothyroidism, uremia, vitamin deficiency, chemotherapy, the neuropathic pain of the polyneuropathy that ddC or Fa Bulishi disease cause.In some other embodiment, compound provided herein can also be alleviated the neuropathic pain of unknown etiology.
In certain embodiments, compound provided herein can be used for the treatment of inflammatory conditions, such as, for example, autoimmune disease.
Those are characterised in that pain (because of producing the pain that objectionable impurities and nerve stimulation cause) term " inflammatory conditions " intention, heat (because of vasodilation cause scorching hot), rubescent (because of vasodilation and blood flow increase cause rubescent), swelling (because of fluid excessively flows into or flows out the limited tumour that produces) and afunction (defunctionalization, can be part or completely, temporary transient or permanent) one or more disease or illness in the sign.Can there be many forms in inflammation and include, but are not limited to one or more inflammation in following: acute, and adhesive, atrophic, Catarrhal, chronic, cirrhosis, dispersivity, diffusive, exudative, fibering, fibrosis, focus, granulomatous, hyperplasia, hypertrophy, between matter, transitivity, gangrenosum acne, occlusive, substance, shaping, generation property, proliferative, pseudomembrane, purulence, cause hardening, pulp fibers albumen, serum, simple property, specificity, subacute, suppurative, toxicity, traumatic and/or ulcer.Inflammatory conditions further includes, but are not limited to encroach on blood vessel (polyarteritis, temporal arteritis); Joint (sacroiliitis: crystallographic, bone, psoriasis, reactivity, rheumatoid, Lai Teershi disease); Gi tract (Crohn's disease, ulcerative colitis); Skin (dermatitis); Or many organs and tissue (systemic lupus erythematous) [Harrison ' s Principles ofInternal Medicine, 16th Edition, Kasper DL etc., Editors; McGraw-Hill, publisher].
Can use compound provided herein or comprise the immune disorders that compound compositions provided herein is treated, comprise such as autoimmune disease: sacroiliitis (comprises rheumatoid arthritis, spondyloarthropathy, urarthritis, degenerative joint disease (being osteoarthritis), systemic lupus erythematous, this Jaeger logical sequence syndrome, tetanic property back of the body vertebra inflammation, poorly differentiated type back of the body vertebra inflammation, behcet's disease, hemolytic autoimmunity anaemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, acute painful shoulder, psoriasis and adolescent arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, the skin inflammatory conditions (is a psoriatic, eczema, burn, dermatitis), enuresis disease, the eosinophilic granulocyte disease, disorder of gastrointestinal tract (comprises inflammatory bowel, stomach ulcer, regional enteritis, diverticulitis, gastrointestinal hemorrhage, Crohn's disease, gastritis, diarrhoea, irritable bowel syndrome and ulcerative colitis) and the illness improved by short stomach motion medicine (be intestinal obstruction, the intestinal obstruction in postoperative ileus and the Sepsis process for example; Stomach oesophagus adverse current (GORD or and synonym GERD); The eosinophilic granulocyte esophagitis, gastroparesis is such as diabetic gastroparesis; Food intolerance and food anaphylaxis and other functional bowel disorder are such as non--ulcer maldigestion (NUD) and non--cardiac chest pain (NCCP)).
Comprise that compound compositions provided herein can also be used for the treatment of for example relevant with following situation inflammation: vascular disease, migraine, tension headache, arteritis nodosa, thyroiditis, aplastic anemia, Hodgkin, scleroderma (scierodoma), rheumatic fever, type i diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, behcet's syndrome, polymyositis, gingivitis, allergy, conjunctivitis, multiple sclerosis and local asphyxia (for example myocardial ischemia) etc.Described compound can be used for the treatment of neural inflammation relevant with disordered brain function (for example Parkinson's disease and alzheimer's disease) and the chronic inflammatory diseases relevant with the cranium radiation injury.This paper compound can be used for the treatment of acute inflammation illness (such as those acute inflammations that causes because of infection) and chronic inflammatory diseases illness (such as those because of asthma, the chronic inflammatory diseases that sacroiliitis and inflammatory bowel cause).The inflammation that these compounds can also be used for the treatment of with wound and non--the inflammatory myalgia is relevant.These compounds of administration before can also or taking anticoagulant in operation.Compound provided herein can reduce the thrombotic cardiovascular disease risk, it is defined as because of platelet aggregation, the anything unexpected situation of the known type that thrombosis and ischemia clinical consequences subsequently cause, comprise thrombosis or thromboembolic stroke, myocardial ischemia, myocardial infarction, stenocardia, transient ischemic attack (TIA; Amaurosis fagax), any similar thrombosis situation in reversible ischemic neurologic deficit and any vescular bed (internal organ, kidney, aorta, periphery etc.).
Compound provided herein can be used for the treatment of and influenza or the relevant symptom of other virus infection, and common cold is sprained and anxiety, myositis, neurodynia, synovitis, damage, such as those damages after sports damage and operation and the dental procedure, coagulation disorder, kidney disease (for example impaired renal function), ophthalmic (comprises glaucoma, the retinitis, retinopathy, uveitis, the acute injury of wet spot sex change and ocular tissue), hepatopathy (is the inflammatory hepatopathy, comprise chronic type B viral hepatitis, chronic viral hepatitis C, alcoholic liver injury, primary liver/bile cirrhosis, autoimmune hepatitis, nonalcoholic fatty liver disease and liver transplantation are repelled) and pulmonary inflammation disease (for example comprise asthma, allergic rhinitis, respiratory distress syndrome, chronic bronchitis and pulmonary emphysema).
Compound provided herein can be used to suppress because of hormone and uterine contraction that prostanoid-the inductive smooth muscle contraction causes.Compound provided herein can be used for the treatment of premature labor, menstruation cramp, menoxenia and dysmenorrhoea.
In certain embodiments, compound provided herein can suppress cell neoplastic transformation and metastatic tumo(u)r growth.These compounds are relevant with minimizing adenoma colorectal polyp quantity.Therefore, compound provided herein can be used to reduce the risk of some cancer, and the cancer of solid tumor for example is such as colon or colorectal carcinoma.In certain embodiments, compound provided herein can be used for the treatment of or preventing cancer, such as, but be not limited to the bladder cancer, with HER-2/neu uterine neck, skin, esophagus, head and neck, the cancer that the lung overexpression is relevant, comprise non-little-cell lung cancer, kidney, pancreas, prostate gland, gall-bladder and bile duct and uterine endometrium cancer, cancer of the stomach, neurospongioma, hepatocellular carcinoma, adenoma of colon, mammary cancer, ovarian cancer and salivary-gland carcinoma.In addition, compound provided herein can be used for the treatment of large bowel cancer and prostate cancer.These compounds can also use in the patient is in case in the risk of cancer, damage before comprising the oral cavity canceration, cervical intraepithelial neoplasia forms, chronic hepatitis, bile duct proliferation, the lung atypical adenomatous hyperplasia, prostatic intraepithelial neoplasm forms, bladder dysplasia, actinic keratosis, colorectal adenomas, gastric metaplasia and Barrett esophagus.
In certain embodiments, compound provided herein can be used for the treatment of cancer, such as, but be not limited to benign tumour of skin, papilloma and brain tumor, tumor of prostate, brain tumor, glioblastoma multiforme, marrow epithelioma, marrow sexual cell knurl, neuroblastoma derives from embryo's tumour, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, papilloma, neuroepithelioma, pinealoma, ependymoblastoma (ependyblastomas), malignant meningioma, sarcosis, malignant melanoma and schwannoma (schwennomas).
In certain embodiments, compound provided herein can also be used for the treatment of and/or prevent the proliferative disorders of cyclooxygenase-mediation, may occur in diabetic retinopathy and tumor vessel generation such as them.In certain embodiments, compound provided herein can be used for suppressing taking place such as the blood vessel that occurs in wet spot sex change.
The FAAH inhibitor, such as, compound for example provided herein is used for the treatment of, identification is sick, and such as dementia, particularly the sex change dementia (comprises senile dementia, alzheimer's disease (and omen), Pick's disease, Huntington Chorea, Parkinson's disease and Creutzfeldt-Jakob disease) and vascular dementia (comprising the multiple cerebral dementia), and with encephalic chamber occupying lesion, wound, infect and related disorders (comprising that HIV infects), metabolism, toxin, the dementia that anoxic is relevant with vitamin deficiency; With the mild cognitive impairment relevant with aging, particularly relevant memory impairment with aging.
The FAAH inhibitor, such as, compound for example provided herein can prevent neuronal damage by suppressing neurone free-radical generating (with oxidative stress thus), and is used for the treatment of apoplexy thus; Epilepsy and epileptic seizures (comprising grand mal, petit mal, myoclonic epilepsy and limitation outbreak).The FAAH inhibitor can be used for control or suppress epilepsy (be included as chemical induction those) such as compound provided herein.
In certain embodiments, the FAAH inhibitor compound, such as, compound for example provided herein can be used for acute and chronic neurodegenerative disease, such as, Parkinson's disease for example, alzheimer's disease, senile dementia, Huntington Chorea, the infringement relevant with cranium with the marrow wound with cerebrum ischemia.
In certain embodiments, FAAH inhibition compound is such as, compound for example provided herein with comprise that their composition can be used for the treatment of dysthymia disorders and depressibility illness or illness.For example, these compounds and composition can be used for the treatment of major depression obstacle (unipolar depression), dysthymic disorder (chronic mild dysthymia disorders) and bipolar disorder (manic-melancholy).Dysthymia disorders can be clinical or subclinical depression of sex.
FAAH inhibition compound is such as, compound for example provided herein with comprise that these compound compositions can be used for the treatment of anxiety and anxiety disorder or situation.For example, these compounds and composition are used for the treatment of anxiety, clinical property anxiety, and panic disorder, agoraphobia, generalized anxiety disorder, special phobia, social phobia, obsession, acute stress disorder and post-traumatic stress disorder; With the adjustment disorder relevant, the anxiety disorder that the general medicine situation causes, the sequela type of the anxiety disorder of material inductive anxiety disorder and NOS with the anxiety feature.Treatment can be for preventative or curative.These compounds can be used for the treatment of anxiety and anxiety disorder or situation separately and/or can also be used for treating simultaneously another kind of illness or illness, such as, for example, pain, obesity, dysthymia disorders or other illness.
In certain embodiments, suppress the active compound of FAAH, such as, compound for example provided herein with comprise that these compound compositions are used for the treatment of epilepsy and convulsive disorder or epileptic seizures.Can faint from fear or the seriousness of epileptic seizures or the individually dosed compound of the present invention of purpose and the composition of frequency for reducing.
In certain embodiments, suppress FAAH induced hypnotic (U.S. Pat 6,096,784; 6,096,784; 6,271,015; WO 98/24396).In one embodiment, can and can increase consumption subsequently to Mammals administration compound provided herein in the time (for example beginning process) of sleep in (for example close one's eyes, it is static to move).
In certain embodiments, the FAAH inhibitor compound can be used for the treatment of schizophrenia and Dopamine HCL associated conditions.In certain embodiments, compound provided herein and composition are used for the treatment of schizophrenia, paranoea, Paranoia's sample ideation, emotional poverty or other associated conditions or other Dopamine HCL conductive obstruction.
In certain embodiments, can administration compound provided herein and comprise compound compositions provided herein so that induce or promote the Mammals sleep.Treatment can for preventative or curative and can be only for the purpose that alleviates insomnia seriousness or frequency or degree individually dosed to healthy people patient.In other embodiments, compound provided herein and composition can be used for the treatment of somnopathy, such as, but be not limited to insomnia and sleep apnea.
In certain embodiments, suppress the active compound of FAAH, such as, compound for example provided herein and comprise that these compound compositions can be used to reduce Mammals appetite, fall its body fat and treatment or prevent it fat or overweight, and be used to prevent or treat the disease relevant with these health problems.In one embodiment, the FAAH inhibitor, such as, for example, the administration of compound provided herein can be used to reduce Mammals appetite, falls its body fat or body weight or is used for the treatment of or prevents it fat or overweight or be used to reduce its ingestion of food or treat its desire obstacle.
In one embodiment, compound provided herein and composition can be used to reduce human patient appetite, body fat or body weight or be used for the treatment of or prevent it fat or overweight or be used to reduce ingestion of food or treatment desire obstacle, comprise that changing body fat forms, such as percent fat or change thin muscle quality.
In another embodiment, administration FAAH inhibitor in conjoint therapy, such as, the combination therapy of compound for example provided herein and Oleoyl monoethanolamide (OEA) or another kind of fatty acid alkyl amide compound, homologue or analogue, can a) reduce appetite, reduce food consumption, subtract body fat or weight reduction; And b) carries out the hydrolysis of FAAH.
In certain embodiments, experimenter's administration is enough to subtract body fat, body weight or prevent body fat or weight increase or reduce the FAAH inhibitor of the consumption of appetite, such as, compound for example provided herein.In another embodiment, composition provided herein comprises the FAAH inhibitor, such as, compound for example provided herein and Oleoyl monoethanolamide or fatty acid amide compound, its homologue or analogue.
In certain embodiments, the FAAH inhibitor can be used for the treatment of various metabolic diseases such as compound provided herein, such as insulin resistant, diabetes, fat hepatitis, hyperlipidaemia, fatty liver disease, non--alcoholic fatty liver inflammation, atherosclerosis and arteriosclerosis.Measure compound provided herein the method for the influence of this class illness is disclosed in U.S. Pat 6,946, in 491, the document is incorporated herein by reference.
In one embodiment, compound provided herein and comprise that compound compositions provided herein can be used for the treatment of the illness that is selected from insulin resistance syndrome and diabetes (primary basic model diabetes are such as type i diabetes or type ii diabetes and the non-basic model diabetes of Secondary cases).The administration of compound provided herein and composition has reduced diabetic symptom or the chance of diabetic symptom has taken place, such as atherosclerosis, and hypertension, hyperlipidaemia, fatty liver disease, ephrosis, neuropathy, retinopathy, ulcer of foot and cataract, this class symptom is relevant with diabetes separately.
In one embodiment, compound provided herein and comprise that described compound compositions can be used for the treatment of hyperlipidaemia.The administration of compound provided herein or composition can reduce hyperlipidaemia experimenter's serum triglyceride and free fatty acids.In one embodiment, compound provided herein and pharmaceutical composition can be used for the treatment of fatty liver disease.In another embodiment, compound provided herein and pharmaceutical composition can be used for the treatment of atherosclerosis or arteriosclerosis.
In other embodiments, it (is eating disorder that compound provided herein and composition can be used for the treatment of and/or prevent food behavioral problem/disturbance of food intake, the emaciation of appetite stimulator and various character particularly, relevant with cancer loses weight and other expendable illness).
In certain embodiments, can administration FAAH inhibitor, such as compound provided herein so that treatment or prevention glaucoma or reduce intraocular pressure.In certain embodiments, can pass through this compound of whole body administration.In other embodiments, the FAAH inhibitor directly is applied to eye surface (for example passing through eye drop).The eye that is used for this class ocular administration is taught in Remington ' s Pharmaceutical Sciences, Gennaro A R ed.20thedition, 2000:Williams ﹠amp with carrier formulation; Wilkins Pa. is among the USA.
In certain embodiments, can administration compound provided herein and comprise described compound compositions so that treatment or prevention glaucoma or reduce intraocular pressure.In certain embodiments, can pass through this compound of whole body administration.In other embodiments, this compound directly is applied to eye surface (for example passing through eye drop).
Can use other disease, illness and/or the illness of compounds for treating provided herein and/or prevention to comprise: lung disease (being respiratory tract disease, bronchospasm, cough, asthma, chronic bronchitis, respiratory tract chronic obstruction, pulmonary emphysema); The urinary incontinence, bladder inflammation, the urinary incontinence, urocystitis, dyskinesia, psychomotor disturbance, hypertension; Cardiovascular disorder, particularly hypertension, irregular pulse, arteriosclerosis, heart attack, heart ischemia, renal ischaemia; Nervous system disease, psychotic disease trembles, ataxia, dystonia, spasticity, obsession, tourette's syndrome, emotional turmoil, mental disease.
Can use the listed illness of compounds for treating this paper provided herein, the combination arbitrarily of disease and/or illness.
Embodiment
Those skilled in the art can further understand the different aspect and the advantage of disclosure content of the present invention when the following illustrative and non-limiting example of summary:
The preparation of embodiment 1.FAAH inhibitor
Synthesizing of 3-acetylphenyl cyclohexyl carbamate: with the 3-hydroxy acetophenone (1mmol, 136mg), triethylamine (1.1mmol, 0.19mL) and cyclohexyl isocyanate (1.1mmol, solution 0.14mL) at room temperature stirred 3 hours.The solid of filtering-depositing and dry in a vacuum and obtain product is white solid then.
Embodiment 2. SCREENED COMPOUND FAAH suppress active method
Generally speaking, be accredited as the FAAH inhibitor at the external FAAH inhibitor that will be used for methods described herein.The hydrolysis that preferred external test method mediates according to the FAAH-such as AEA or this class substrate of OEA detects (for example arachidonic acid thanomin, level increase OEA) or the minimizing (for example fatty acid amide or thanomin) of reaction product release of unaltered FAAH substrate.Can labeled substrate to help detecting the reaction product of release.Be used for specific reaction product and exist, do not exist or quantitative high throughput assay method well-known for those skilled in the art.In addition, the high throughput screening system be purchased (for example, referring to Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc.Fullerton, CA; Precision Systems, Inc., Natick, MA etc.).The whole process of these system's general-auto-actions comprises that the suction of all samples and reagent moves, and dosing is regularly hatched and is suitable for finally reading of microtest plate in the detector of this assay method.Automation system can need not overlabor and thus at external evaluation lot of F AAH inhibitor.
FAAH inhibitor material standed for can be identified according to its ability that increases one or more FAA whole body levels in the body.Suitable FAA comprises the fatty acid ethanol amide class with the fatty acid part that comprises 14-28 carbon and 0-6 two keys, such as, for example, OEA, PEA, AEA and stearyl glycollic amide (SEA).Other suitable FAA comprises the primary fatty acids amides with the fatty acid part that comprises 14-28 carbon and 0-6 two keys, such as oleylamide.The biological sample that can measure the FAA level includes, but are not limited to blood plasma, serum, blood, celiolymph, saliva or urine.
For example, by the FAA level in liquid phase chromatography series connection-mass spectroscopy (LC-MS/MS) the mensuration biological sample.The biological sample realization as measuring the isotope-labeled FAA of target in the FAA that has known quantity by spike improves the circulation ratio of measuring.Can also use spectrophotometry technology (for example fluorescent method) to measure the level of FAA.Selectively, can use bioassay method to measure the FAA level.In certain embodiments, use the combine measured FAA level of above-mentioned technology.Can make any above-mentioned partially or completely automatization of assay method for high throughput to the FAA level.Of the present invention and other the FAA assay method and to analyze being specifically described as of method that the FAA level changes as known in the art.For example, referring to (2002) such as Quistad, Toxicology and Applied Pharmacology 179:57-63; Quistad etc. (2001), Toxicology and Applied Pharmacology 173,48-55; Boger etc. (2000), Proc.Natl.Acad.Sci.U.S.A.97,5044-49; Proc.Natl.Acad.Sci.U.S.A.98 such as Cravatt, 9371-9376 (2001); Ramarao etc. (2005) Anal.Biochem.343:143-51.Referring to U.S. Pat 6,096,784, U.S. Patent Publication No. US 2004/0127518 in addition, Application No. US10/681,858, international patent application no WO98/24396 and WO 04/033422.
The carbamate compounds of listing among the test pattern 1-8 compares the restraining effect of FAAH external with reference compound KDS-4103, and finds that they have certain inhibition activity.
Embodiment 3. screenings suppress the active method of FAAH-FAAH LC-MS/MS screening assay method:
In one embodiment, use LC-MS/MS to measure the active inhibition of FAAH.Following composition is incorporated in the 5-mL Glass tubing: arachidonic acid thanomin (200ug/mL, 5 μ L), comprise 0.125%BSA (w/v), 10 μ L DMSO not with (control group) or with the 960 μ L 50mM ammonium phosphate damping fluids (pH 7.4) and the 25 μ L people hepatomicrosomes (31.3 μ g) of FAAH inhibitor (1 μ g/mL).Before hatching, 100 μ L aliquots are changed over to comprise 0.25mL acetonitrile and D 4The 96-orifice plate of (deuterate) arachidonic acid thanomin (0.2 μ M).The jolting water-bath that every 5-mL of capping pipe and putting into maintains under 37 ℃ 60 minutes.After hatching in 60 minutes, change second 100 μ L aliquot over to the 96-orifice plate as mentioned above.Capping 96-orifice plate then, vortex mixed and place HPLC to go up to carry out liquid chromatography/tandem mass spectrum (LC/MS/MS) analysis.(Milford MA) carries out HPLC to use Waters 2790 Alliance systems.Use Phenomenex Polar RP post (2 mm * 150 mm, 4 μ; Torrance CA) separates, and wherein uses acetonitrile: water: and formic acid (75: 25: 0.1, moving phase such as degree such as grade v/v/v), flow velocity is that 0.3mL/ minute and column temperature are 45 ℃.The HPLC system connects with Micromass QuattroUltima, and (Beverly MA) forms the interface to MS.Use electrospray probe, with cation electrodeposition from pattern and be set in the taper voltage of 40V and the capillary action analytic sample under the 3.2kV.Source and desolvation desired temperature are respectively 130 ℃ and 500 ℃.The voltage of CID chamber is set in-20eV.The multiple reaction monitoring is used for the arachidonic acid thanomin is detected for [M+H] (m/z 348＞62) and with D 4Arachidonic acid thanomin (interior mark) detects and is [M+H] (m/z 352＞66).Ratio (arachidonic acid thanomin area response value/D to each sample determination area response value 4Arachidonic acid thanomin area response value).Measure the arachidonic acid thanomin percent hydrolysis of each sample by following equation: [(T=0 response value)-(T=60 response value)/T=0 response value] * 100.By determining percent hydrolysis divided by the hydrolysis % of control sample to the control group calibration with the hydrolysis % of specimen.
In order to measure the IC of FAAH inhibitor compound material standed for 50Value is used aforesaid method with the FAAH inhibitor concentration of adjustment.At IC 50In the mensuration, add the FAAH inhibitor of concentration range at about 3 μ M-0.03nM.By at first using " X=log (X) " to transform concentration and using S shape dose response curve (no constraints) then, use 4.00 editions (GraphPad Software of Windows GraphPadPrism, San Diego California USA, www.graphpad.com) analytical data is determined IC 50Final calculated value.
Embodiment 4. screenings suppress the active compound of FAAH-FAAH fluorescent screening assay method:
To black 96-orifice plate (Nunc; cat#267342) add 180 μ L arachidonic acyl group 7-amino, 4-methylcoumarin acid amides (AAMCA, 3 μ M) in; 20 μ L FAAH inhibitor (in DMSO, 0.05 μ g/mL) and 50 μ L people hepatomicrosomes (0.25mg/mL).Be used for the BSA (1.4mg/mL) of the thinner of AAMCA and people's hepatomicrosome for the not fatty acids of the HEPES/EDTA (50mM/1mM) under pH 7.4.When the 355nm on the fluorescent plate reader (SpectraMaxGeminiXS, Molecular Devices) excites with 460nm emission place and T=0, read plate and under 37 ℃, hatched 30 minutes.After hatching in 30 minutes, read the final time of plate and measure hydrolysis % (to the control group calibration).To being calculated as of hydrolysis % [(T=0)-(T=30)/T=0] * 100.By determining percent hydrolysis divided by the hydrolysis % of control sample (DMSO) to the control group calibration with the hydrolysis % of specimen.
Embodiment 5. screenings suppress the screening that FAAH suppresses in the active compound of FAAH-rat body:
Preparation is used for oral (p.o.), and abdominal cavity (i.p.) or intravenously (i.v.) are delivered to the possible FAAH inhibitor of rat.The compound of administration preparation and after administration execution animal during preset time point.When putting to death, the edta plasma test tube is gone in blood specimen collection and whole brain is chilled in the liquid nitrogen suddenly.From blood sample, separate edta plasma in centrifugal back.Brain and plasma sample are stored under-80 ℃, after this analyze.By test compounds (FAAH inhibitor) concentration of LC-MS/MS analysis all samples (brain and blood plasma), the metabolite of test compounds and endogenous fatty acid ethanol amide level (comprising the arachidonic acid thanomin, Oleoyl monoethanolamide and palmityl thanomin).Relatively through the time these compound levels so that determine the pharmacokinetic properties of test compounds and suppress the active part pharmacotoxicological effect of FAAH (comprising that the fatty acid ethanol amide level changes).
In one embodiment, can when putting to death, gather extra tissue and fluid sample.In one embodiment, can also be according to the FAAH activity in the method that discloses or method well known in the art mensuration fluid and the tissue.In one embodiment, can measure the metabolite of the test compounds in fluid and the tissue sample.
Embodiment 6: pharmacokinetics is measured
After with solution form oral administration, estimate the pharmacokinetic properties of compound provided herein in rat.In order to test the oral administration biaavailability of compound provided herein, the test compounds formulations prepared from solutions that will be used for oral administration becomes at 80% breast floating (cremephor) and the 10mg/mL solution of 20% ethanol (w/w) or the 10mg/mL solution of 90%PEG-400 and 10%Tween 80 (w/w).With test compounds solution with the dosage through port lumen feeding of 10mg/kg to the rat administration.
Animal model
Any different animals model can be used for testing compound that this paper discloses and reduce inflammation and treating the validity of pain.Useful compound can show in one or more animal models and reduce inflammation or the validity of pain.
Be used to estimate the animal model of anti-inflammatory activity
Embodiment 7. carrageenins-inductive foot pad (Foot Pad) edema model
For example, Winter etc. have described this model (1962, Proc Soc Exp Biol Med111:544).In brief, make the rat fasting but can freely drink water 17-19 hour, after this use the test compounds that reaches three kinds of dosage, indomethacin or celecoxib or control group vehicle (1% in deionized water methylcellulose gum) oral administration.Back 1 hour of final treatment is brought out the pawl oedema by 0.05ml 2% carrageenin solution is injected left back pawl.It is long-pending to use the plethysmometer to measure the left back corpus unguis of every rat, after this when carrageenin inject and injected behind the carrageenin 1.5 hours, and 3 hours, oral administration in the time of 4.5 hours.The change of volume when the oedema volume of every rat is expressed as from oral administration during with each time point, and the anti-inflammatory action in the treatment group is expressed as with carrageenin injected back 1.5 hours, 3 hours, only give the inhibition % that vehicle group is compared in the time of 4.5 hours.(ANOVA) estimates by a kind of variance analysis, subsequently by the non-matching Dunnett-t test evaluation significance of difference between the oedema on the same group not.In this model, hyperpathia reaction and PGE have also been measured 2Output (Zhang etc., 1997 JPharmacol and Exp Therap 283:1069).
The arthritis model that embodiment 8. complete Freund's adjuvants (CFA) bring out
In this model, in the time of the 1st day, by the Mycobacterium tuberculosis suspension (0.3mg in the 0.1mL light mineral oil with the deactivation of abundant suspendible; Complete Freund's adjuvant, CFA) plantar region of the right back pawl of injection brings out sacroiliitis in 8 Lewis deutero-male rat groups that are weighed as 160 ± 10g.Water displacement mensuration rear solid end volume by the water displacement the 0th, 1 and 5 day time the (right back pawl uses CFA) and the 0th, 14 and 18 day (left back pawl does not use CFA); The rat of in the time of the 0th and 18 day, weighing.Prepare every day and fresh be dissolved in or be suspended in test compounds among the 2%Tween 80, and be administered twice by oral every day, began to continue 5 days (the 1st day the-the 5th day) in preceding 1 hour from injection CFA.With regard to the vehicle control rats of CFA-injection, compared the long-pending increase (inflammation acute phase) of corpus unguis generally at 0.7-0.9 mL during with the 1st day on the 5th day; And compared (inflammation lag period) generally at 0.2-0.4mL during with the 14th day on the 18th day.Therefore, with the anti-inflammatory activity in this model of value representation that calculates in the process acute phase and lag period.The animal of also when the 0th day and the 18th day, weighing; The vehicle control animals of CFA-injection generally obtains the 40-60g body weight in this time bar.To for the control group of vehicle treatment, be considered as having remarkable anti-inflammatory activity more than 30% or 30% by long-pending minimizing of corpus unguis.Measure the mean value ± SEM of each treatment group and Dunnett check is applied to comparison between vehicle and the treatment group.Difference is considered as having significance in P＜0.05.Can be by the visual fore paw of giving, tail, the polyarthritis scoring of nose and ear and when the 1st day and last 1 day record, wherein positive (+) sign is that swelling reaction, negative (-) sign are for normal.Also rear solid end is carried out the X ray photography, measure so that further arthritic symptom is carried out radioactive index.Also in this model, measure hyperpathia, thereby can measure the analgesic effect (1999 Brit J.Pharmacol 128:1252 such as Bertorelli) of test compounds.
Embodiment 9. air bag models
Masferrer etc. have described this model (1994, Proc Natl Acad Sci USA91:3228).In brief, the 20mL sterile air is takeed on the territory inner compartment through the male Lewis rat of subcutaneous injection (175-200g, Harlan Sprague-Dawley) back so that generate air cavity.The 10mL air was injected this chamber opened to keep the space every 3 days again.Injected back 7 days at initial air, the solution that the carrageenin of 2mL 1% is dissolved in Sterile Saline directly injects capsule so that produce inflammatory reaction.In treatment and untreated animal, measure the volume of exudate and measure the quantity of leucocyte that exists in the exudate by Wright-Giemsa dyeing.In addition, (Cayman Chemicals, Ann Arbor Mich.) measure from the PGE in the capsule exudate for the treatment of and not treating animal by specific ELISA 2With 6-ketone group-PGF 1 α
Be used to estimate the animal model of analgesic activity
The thermal hyperalgesia of embodiment 10. carrageenins-bring out
Hargreaves etc. have described this model (1988, Pain 32:77).In brief, by being injected right back pawl, 2% carrageenin suspension (0.1mL) foot brings out inflammation.After 3 hours, use the sexy irriate of heat injury (vola test) to estimate the nociception threshold.Light beam (maximum strength 44%) is focused under the rear solid end and flick the response latency (dead line: 30 seconds) by pawl and estimate the heat injury sensitivity threshold.Behind use test compound or reference substance oral administration 1 hour, measure the threshold of pain in homonymy (inflammation) and offside (control group) rear solid end.The result is expressed as in the nociception threshold of every rear solid end of second (sec) with from the nociception threshold of every rat of the mean value of vehicle group (the variation per-cent of mean value ± SEM).Use student t check that the nociception threshold between the contrast pawl of inflammation pawl and vehicle-treated groups is compared, P＜0.05 is considered as having statistical significant difference.By Dunnett check, use the residual variance after a kind of variance analysis (P＜0.05), use SigmaStat software and measure significance,statistical between treatment group and the vehicle group.
The phantom type of turning round of embodiment 11. phenyl benzoquinones-bring out
Siegmund etc. have described this model (1957 Proc Soc Exp Bio Med 95:729).In brief, the use test compound behind morphine or the vehicle oral administration 1 hour, injects mouse by the intraperitoneal administration approach with 0.02% phenyl benzoquinones (PBQ) solution (12.5mL/kg).Record PBQ injection back the 5th minute to the 10th minute tetanic and turn round the body number of times, and counted at the 35th minute to the 40th minute and the 60th minute to the 65th minute, so that the kinetics evaluation is provided.Be expressed as the result tetanic and turn round body number of times (mean value ± SEM) and according to the variation per-cent of the nociception threshold of the mean value calculation of vehicle-treated groups.By the Dunnett check, the residual variance behind the use one-way analysis of variances (P＜0.05) is used the significance,statistical that SigmaStat software is measured any difference between treatment group and the control group.
The arthritis model of embodiment 12. kaolin-bring out
Hertz etc. have described this model (1980, Arzneim Forsch 30:1549).In brief, bring out sacroiliitis by the knee joint that 0.1mL kaolin suspension is injected the rat right rear leg.After 15 minutes and again through 2 hours through the subcutaneous administration test compounds.Reference compound is by oral or subcutaneous administration.Between treatment back 1.5 hours-5.5 hours, estimated gait and following score every 1 hour: normal gait (0), slightly unable (1), pawl intermittently lifts (2) and pawl lifts (3).The average gait score that individual values when being expressed as the result according to each time point is calculated (mean value ± SEM) and according to the variation per-cent of the average of the mean value calculation of back 4.5 hours of treatment and 5.5 hours vehicle-treated groups.When each time point, by the Dunnett check, the residual variance behind the use one-way analysis of variances (P＜0.05) is measured the significance,statistical of difference between treatment group and the vehicle-treated groups.
Mononeuropathy model around the embodiment 13.
Bennett etc. have described the test compounds anti-hyperpathia effect of mononeuropathy model around that this model (1988, Pain 33:87) and this model can be used for estimating oral administration.Can be with the effect of test substances and the reference substance or for example morphine comparison of reference material of non-treatment.Bring out mononeuropathy (Sodital on every side by loosening sciatic ligation in the male Sprague Dawley rat of anesthesia; 45mg/kg by abdominal channels).After 14 days, use the mechanical wounding impression to stimulate and estimate nociception threshold (analgesimeter pawl pressure test; UgoBasile, Italy).Oral administration test and reference compound and vehicle (1% methylcellulose gum that 10mL/kg carries).The pressure that increases is put on the animal rear solid end, up to reaching nociception reaction (sounding or pawl are shunk back).In treatment back 60 minutes, measure the threshold of pain (contact pressure gram number) in homonymy (impaired) and offside (not impaired) rear solid end.The result is expressed as: in the nociception threshold of the contact pressure of impaired pawl and not impaired pawl (vehicle-treated groups) gram number (mean value ± SEM) and according to the variation per-cent of the nociception threshold of the mean value calculation of vehicle-treated groups.Use student t check that the nociception threshold between the impaired pawl of not impaired pawl and vehicle-treated groups is compared.Check by Dunnett, residual variance behind the use one-way analysis of variances (P＜0.05), use SigmaStat software (SigmaStat.RTM.v.2.0.3 (SPSS Science Software, Erkrath GmbH)) and measure the significance,statistical of difference between treatment group and the vehicle group.
The Chung rat model of embodiment 14. peripheral neuropathys
In one embodiment, use the Chung rat model of the peripheral neurophaty of generally acknowledging to confirm the validity of compound provided herein in alleviating neuropathic pain.In the Chung rat model, the spinal nerves part ligation of left side spinal nerves L-5 and L-6 is continued allergy to produce to light pressure long-term on the foot of an affected left side.This allergy and pain similar (Kim and Chung, Pain 50:355-363 (1992) is incorporated herein by reference the document) with the neuropathic people's experience of bright property.
Embodiment 15. diabetic neuropathy pawl pressure tests
In (1963 Cancer Chemother Rep 29:91) such as Rakieten, can find the detailed description of complete scheme.In brief, bring out diabetes by abdominal injection U-9889 in rat.After 3 weeks, use the pawl pressure test to measure the nociception threshold so that estimate hyperpathia.Passed through intraperitoneal administration test compounds or reference substance in preceding 30 minutes at pain measurement.
Embodiment 16. acetate writhing tests
In brief, give rats by intraperitoneal injection acetate (0.5%, 10ml/kg) preceding 1 hour oral administration test compounds.The body number of times of observing in the process in 5-11 minute after the acetate administration in every treated animal of turning round has reduced (〉=50) more than 50% or 50% than the control group of vehicle treatment, has confirmed to have analgesic activity.This assay method is based on Inoue, K. etc. described (1991 Arzneim.Forsch./Drug Res.41:235).
Embodiment 17. gate-Papacostas' testses
In (1985 Neurosci.Meth.14:69) such as Hunskaar, can find the detailed description of complete scheme.In brief, after test compounds or the administration of reference substance pneumoretroperitoneum 30 minutes, 20 μ L, 5% formalin solution is injected rat right side rear solid end by the vola approach.Early stage and write down the time of licking rear solid end in the process late period after formalin injection.
Embodiment 18. tail-flick tests
Can in D ' Amour and Smith (1941 J Pharmacol.Exp Ther.72:74), find the detailed description of complete scheme.In brief, behind test compounds or reference substance intraperitoneal administration 30 minutes, light beam is focused on the rat tails.Recording feature be to contract nociception response latency of tail.To be set to dead line 15 seconds.
Embodiment 19. tail dip tests
In this test, the rat tail is immersed 50-60 ℃ of water-bath.Mensuration is characterised in that the nociception response latency (2004 Pain 109:319 such as 1990 J Pharmacol Exp Ther255:511 such as Haubrich and Lichtman) of the tail that contracts.
The test of embodiment 20. hot-plates
Can in (1950 J.Pharmacol.Exp.Ther.98:121) such as Eddy, find the detailed description of complete scheme.In brief, behind test compounds or reference substance intraperitoneal administration 30 minutes, mouse is placed on the metal heater plate that maintains 52 ℃.The nociception response latency that recording feature is to lick the fore paw reflection or jumps out of hot-plate.To be set to dead line 30 seconds.
Be used to estimate the active test of anxiety
Suppress the active and compound provided herein that regulate the fatty acid amide level thus of FAAH and also have the anxiety activity.Being used to estimate the active animal model of anxiety comprises:
Embodiment 21. overhead cross labyrinths
Overhead cross labyrinth origin comes from 4 labyrinth arms of central platform to be formed, and they have constituted effectively as Gaalen and the described cross shape of Steckler (2000 Behavioural Brain Research115:95).The labyrinth can be made and be generally overhead by resin glass.In the arm of labyrinth 2 is (sealing) that wall is arranged for (open) of no wall and 2.The arm of 2 openings is light and the arm of 2 sealings be (the crawley 2000 Wha t ' sWrong With My Mouse of dark fully?: Behavioral Phenotyping of Transgenic andKnockout Mice.Wiley-Liss, New York).Natural conflict the (1985 J.Neuroscience Methods.14:149 such as Pellow) between harmful characteristic of new environment is detected in this test based on animal trend and the open base area of light.
Can in (2001 J.Pharm.Exp.Ther.299:332) such as Fedorova, find the detailed description of complete scheme.In brief, behind test compounds or reference substance intraperitoneal administration 15 minutes, separately on the centre platform, one of open arms was towards the viewer with animal.Animal is entered the number of times of open and closure arm and marks (as (above) as described in the Gaalen etc.) in the time of labyrinth different compartments internal consumption (central platform, opening and closure arm).As (1998 EMBO J.17:886) as described in Simonin etc., when all four pawls of animal advance arm, be recorded as visiting to arm.In 5-minute testing period by the viewer and/or by video recorder to behavior scoring.Animal demonstrates the anxiety activity in the open arms internal ratio at most at the time of closure arm internal consumption number of times long or that enter.
Embodiment 22. overhead annular labyrinths
Overhead annular labyrinth is the improvement in overhead cross labyrinth.Overhead annular labyrinth is formed (circular passage that is 46cm diameter and 5.5cm passage width) by the circular resin glass device of the sector of 2 openings with equivalent size and 2 sealings and is formed.It is increased to the rice number that is above the ground level.This unit describe is in (above) such as Simonin and Crawley (above).
The detailed description of complete scheme can find in (2003 Nature Medicine9:76) such as Kathuria.In brief, behind test compounds or reference substance intraperitoneal administration 30 minutes, animal is placed on 1 open sector before 1 closed sectors.When all 4 pawls enter, be recorded in the time in the new sector.In 5-minute testing period by the viewer and/or by video recorder to behavior scoring.Animal shows the anxiety activity at most at open sector internal ratio number of times long in the time that wall fan district internal consumption is arranged or that enter.
Embodiment 23. isolates the test of inductive ultrasound emission
In another kind of animal model, promptly isolate in the test of inductive ultrasound emission, test the angst resistance effect of compound provided herein.Sounding number of times (Insel, T.R. etc., Pharmacol.Biochem.Behav., 24, the 1263-1267 (1986) of the stress-induced that the rat pup that the test determination of isolation inductive ultrasound emission is taken out from nest is sent; Miczek, K.A. etc., Psychopharmacology, 121,38-56 (1995); Winslow, J.T. etc., Biol.Psychiatry, 15,745-757 (1991); U.S.6,326,156).
Be used to estimate the test of anti-pain mechanism of action
Whether test compounds influences the related approach of the pain sensation so that measure them.This class test-results can be used to study the mechanism that test compounds mediates its analgesic activity.
Embodiment 24.3 α, 5 α-THP raises
3 Alpha-hydroxies-5 α-pregnant-20-ketone (3 α, 5 α-THP or allopregnenolone) is as inhibition GABA AThe pregnane steroids that the receptor subtype agonist works and known it in various animal models, have anxiety and analgesic effect, and be the supportive evidence that the similar effect in the people is arranged.Therefore, 3 α that raise, the compound of 5 α-THP can have analgesic activity.Can measure 3 α as (1982 J Neuroscience 20:200) as described in the VanDoren etc., 5 α-THP is with the level in the animal brain of test compounds treatment.In brief, after euthanasia, from the individual pallium hemisphere of ice-cold salt solution, dissecting, extract steroid.Cortex is chilled in-80 ℃ till use.Handle in 0.3N NaOH sample digestion and with the ethyl acetate extraction of 10% (v/v) in heptane of 3mL five equilibrium 3 times by ultrasonic degradation.Merge aliquot and dilute with 4 mL heptane.Make solid phase silica column (Burdick ﹠amp on the extract; Jackson, Muskegon, Mich.), with pentane washing and by in pentane, add 25% (v/v) acetone from the post wash-out down and 3 α, the similar polar steroid of 5 α-THP.Then at N 2Dry elutriant and steroid is dissolved in 20% (v/v) Virahol RIA damping fluid (0.1MNaH again in the environment 2PO 4, 0.9M NaCl, 0.1%w/v BSA, pH 7.0).Being determined at 50 μ L by the liquid scintillation spectrometry method dissolves the extraction efficiency in the extract again and remaining sample is used for measuring 3 α by radioimmunoassay 5 α-THP.By adding 725 μ L RIA damping fluids, 100 μ L[ 3H] 3 α, 5 α-THP (20,000dpm) with anti--3 α of 100 μ L, 5 α-THP antibody is according to duplicate mensuration regenerated sample extraction thing (75 μ L) and 3 α, 5 α-THP standard substance (at 6.25%v/v ethanol, 5-40 in the Virahol of 31%v/v in the RIA damping fluid, 000pg).Do not having unmarked 3 α, measuring total binding and do not having to measure non-specific binding in the presence of the antibody under 5 α-THP exists.Make antibodies reaction proceed at room temperature balance 120 minutes and by this mixture being cooled to 4 ℃ of terminations.By the gac (DCC that coats with the cold dextran of 300 μ L; 0.04% dextran, 0.4% at second distillation H 2Powdered carbon among the O) hatch 20 minutes together, from unconjugated 3 α, 3 α of separation and combination among 5 α-THP, 5 α-THP.By removing DCC in centrifugal 10 minutes with 2000 * g.Measure bonded radiant in the supernatant liquor by the liquid scintillation spectrometry method.With sample numerical value and 3 α that occur simultaneously, 5 α-THP typical curve compares and the calibration extraction efficiency.
The evaluation of embodiment 25. depression effects
In one embodiment, in animal model, estimate the depression effect of compound provided herein.The anhedonia model of chronic mild stress-induced is based on following observations: chronic mild stress cause the susceptibility to for example sugar consumption progressively to reduce and this be reduced to dose-dependently and by reversing with anti-depressant therapy for a long time.Formerly by Willner, Paul, Psychopharmacology, 1997,134,319-329 has described this method.
The active test of another kind of depression is forced swimming test (Nature 266,730-732,1977).In this test, before test, preferably passed through abdominal channels or by oral route to the animals administer compound in 30 or 60 minutes.Animal put into water-filled crystallizing dish and to keeping motionless time timing this process animal.Then dead time and the control group for the treatment of with distilled water are compared.Can be with imipramine (25mg/kg) as positive control.The depression compound has reduced mouse dead time, submergence thus.
Another kind is used for the tail trapeze test (Psychopharmacology, 85,367-370,1985) of the active test of depression for mouse is carried out.In this test, test preceding 30 minutes-6 hours preferred by abdominal channels or oral route with compounds for treating animal provided herein.Suspend the afterbody of animal then in midair and write down its dead time automatically with computer system.Then dead time and the control group that uses the vehicle treatment are compared.Can be with imipramine (25mg/kg) as positive control.The depression compound has reduced the mouse dead time.
The depression effect of test compound provided herein in DRL-72 TEST test.According to " Effects of imipramine and mirtazapine on operantperformance in rats " Drug Development Research 32 such as Andrews, this test that the scheme of 58-66 (1994) is carried out has obtained the active indication of depression sample.All right as US 6,403,573 and 5,952, the effect of check compound provided herein described in 315 in serotonin illness and bipolar disorder is incorporated herein by reference the document.
The evaluation of embodiment 26. anticonvulsant actions
In another embodiment, as US6, checked the anti-convulsant activity of compound provided herein in 309,406 and 6,326, the 156 described animal models.
Embodiment 27. compounds are to the effect of appetitive behavior
In one embodiment, to rat administration compound provided herein, so that mensuration is to the effect of appetitive behavior.Estimate effect by check rat picked-up sucrose solution to drug compound.This method is at W.C.Lynch etc., Physiol.Behav., and 1993,54, instruct among the 877-880.The male Sprague-Dawley rat that making weighs is about the about 210g of 190g-is in the normal illumination circulation (7am-7pm) and arbitrarily accepts water and food.Since 6 days,, extracted food and water bottle and given rat 5% sucrose solution and drunk at 11am-3pm.Get rid of and drink the rat that is less than 3g sucrose.In the time of the 7th day, test according to following method: 9am: extract food, 10am: test animal administration compound provided herein or vehicle; 11am=T0: import the bottle that contains the sucrose solution of weighing; T0+1 hour, T0+2 hour, T0+3 hour, T0+4 hour: bottle was measured sugar consumption by weighing.The sucrose solution picked-up of comparative experiments group subsequently (administration compound provided herein) and control group.For example, animal can be obesity or normal guinea pig, rat, mouse or rabbit.Suitable rat comprises, for example, and the Zucker rat.Suitable mouse comprises, for example, and normal mouse, ALS/LtJ, the C3.5W-H-2b/SnJ, (F1 of NON/LtJ * NZO/H1J), NZO/H1J, ALR/LtJ, NON/LtJ, KK.Cg-AALR/LtJ, NON/LtJ, KK.CgAy/J, B6.HRS (BKS)-Cpefat/+, B6.129P2-GcktmlEfr, B6.V-Lepob, BKS.Cg-m+1+Leprdb and C57BL/6J with obesity of diet induced.
In the another kind test, can in mouse, confirm the effect that The compounds of this invention consumes alcoholic solution.For example, in reversible cycle (10am-10pm at night), used water-filled 2 bottles to isolate male C 57 BL 6 mouse on the same day that reaches animal housing.After 1 week, replace one of water bottle, continue this test in 6 hours with the bottle that is full of 10% alcoholic solution.Every day is importing the alcohol bottle preceding 30 minutes, with compounds for treating mouse of the present invention.After 6 hours, measure the pure and mild water yield that consumes.This test is repeated 4 days.The result of comparative experiments group and control group or vehicle group.
Embodiment 28. body weight, the alleviating of body fat and hepatic steatosis venereal disease
Can promptly measure in the hyperlipemia animal model and suppress the FAAH activity to body weight, body fat, triglyceride levels, the effect of cholesterol levels APOE*3-Leiden transgenosis (E3L) mouse.The E3L mouse is expressed infringement apoE and ldl receptor bonded people apoE mutation variants apoE*3-Leiden.Therefore, the E3L mouse shows decline of lipoprotein clearance rate and the rising of serum lipid level that contains apoB.Referring to van Vlijmen etc., (1994), J.Clin Invest., 93:1403-1410.Feed down in higher fatty acid and cholesterol, the atherosclerotic lesion of different steps similarly takes place according to the different of total plasma cholesterol level and with situation about finding in these mouse in the people.Referring to (1996) such as Groot, Arterioscler.Thromb.Vasc.Biol., 16:926-933; Verschuren etc. (2005), Arterioscler.Thromb.Vasc Biol., 25:161-167; With (1999) such as Lutgens, Circulation; 99 (2): 276-283).Therefore, the E3L mouse is the proper model that is used to study the effect of antiatherosclerotic.
Give so-called hypercholesterolemia (1%w/w) meals of E3L mouse (HC meals) 4 time limits in week.Then based on its blood plasma cholesterol level pairing animal and be divided into 5 groups, and keep the HC meals separately to them.In this research (4 week) remaining every day, " control group " accepts not contain the food of additive, " fenofibrate " winding is contained the food (0.04%w/w) of fenofibrate, " oral vehicle " winding is subjected to the oral administration mixed suspension of vehicle, " oral OEA " winding is subjected to the OEA oral administration mixed suspension of 500mg/kg dosage, and " oral carbamate " winding is subjected to the oral administration mixed suspension of the compound provided herein of 10mg/kg dosage.
The the 0th, 14 and 28 day blood sample collection in the treatment phase.When the treatment phase finishes, put to death animal and analyze different tissues and organ.
Embodiment 29. Cannabined receptor combinations
Compound passes through in conjunction with Cannabined receptor CB 1And CB 2In any or they both bring into play analgesic activity.CB 1In brain, express (1990 Nature 346:561 such as Matsuda) and CB 2Express by scavenger cell and in spleen (1993 Nature 365:61 such as Munro).These acceptors all relate to by mediating analgesic effect (for example, referring to 2002Pain 96:253 such as Clayton) in conjunction with agonist.Therefore, test compounds can be measured so that whether measure them in conjunction with one or both people's Cannabined receptors.Be used for CB 1The bonded assay method is by descriptions (above) such as Matsuda.This assay method is used and is expressed CB 1Reconstitution cell.Can use and express CB according to same way as 2Reconstitution cell measure and CB 2Combination.In brief, in order to measure test compounds in conjunction with CB 1Ability, at the CB that has and do not have in the presence of the compound to measure mark 1Part, for example [ 3H] WIN 55212-2 (CB 1: 2nM; CB 2: 0.8nM) with separate from express recombinant CB 1The combination of film of HEK-293 cell.Several times of excessive unlabelled WIN 55212-2 (CB are being arranged 1: 5 μ M and CB 2: 10 μ M) non--specificity combination is measured in existence down respectively.To combine with the ligands specific of acceptor and be defined as total binding with poor what have in the presence of the excessive unlabelled WIN 55212-2 non--specificity of measuring combine.By using the Hill's equation fitting of a curve that competition curve is carried out non--linear regression analysis, determine IC 50Value and hill coefficient (n H).According to Cheng Prusoff equation (K i=IC 50/ (1+ (L/K D)) calculate and suppress constant (K i), the concentration of radioligand during wherein L=measures, and K D=radioligand is to the avidity of acceptor.
Embodiment 30: pharmaceutical composition
Embodiment 30a: parenteral composition
In order to prepare the parenteral pharmaceutical composition that is adapted to pass through drug administration by injection, 100 mg compounds provided herein are dissolved in DMSO and mix with 10mL 0.9% Sterile Saline then.This mixture is mixed in the unit dosage that is adapted to pass through drug administration by injection.
Embodiment 30b: oral compositions
In order to prepare the pharmaceutical composition that is suitable for oral delivery, 100mg compound provided herein is mixed with 750mg starch.This mixture is mixed the oral unit dosage form that is suitable for oral administration, such as hard gelatin capsule.
Embodiment 30c: hypogloeeis (hard lozenge) composition
In order to prepare the pharmaceutical composition that is suitable for sucking conveying,, mix 100mg compound provided herein and 420mg blended Icing Sugar, the light maize treacle of 1.6mL, 2.4mL distilled water and 0.42mL Folium Menthae extract such as hard lozenge.Slowly this mixture of fusion and impouring mold and form the lozenge that is suitable for sucking administration.
Embodiment 30d: composition for inhalation
In order to prepare the pharmaceutical composition that is used to suck conveying, 20mg compound provided herein is mixed with 50mg Citric Acid, usp, Anhydrous Powder and 100mL 0.9% sodium chloride solution.This mixture is mixed the suction e Foerderanlage that is suitable for inhalation, such as atomizer.
Embodiment 30e: rectal gel composition
Be used for the pharmaceutical composition that rectum is carried in order to prepare, with 100mg compound described herein and 2.5g methylcellulose gum (1500mPa), the 100mg methyl hydroxybenzoate, 5 g glycerine and 100mL purified water are mixed.Then the gained gel mixture is mixed the rectum e Foerderanlage that is suitable for rectal administration, such as syringe.
Embodiment 30f: topical gel composition
In order to prepare the topical gel composition, with 100mg compound described herein and 1.75g hydroxypropylcellulose, the 10mL propylene glycol, the pure USP of 10mL Isopropyl myristate and 100mL purifying mixes.Then the gained gel mixture is mixed the container that is suitable for topical, such as pipe.
Embodiment 30g: ophthalmic solution composition
In order to prepare the eye medicinal liquid composite, 100mg compound as herein described mixed in the 100mL purified water with 0.9g NaCl and use 0.2 micron membrane filtration.Then the gained isotonic solution is mixed and be suitable for the eye e Foerderanlage, all eye drop containers that eye is carried.
Embodiment as herein described and embodiment only are used for purpose of illustration, and the various modification or the change of those skilled in the art's prompting included in the scope of the application's the spirit and scope and the claim that awaits the reply.Be the whole open source literatures of all purposes with this paper citation, patent and patent application are incorporated herein by reference.

Claims (24)

1. the compound of formula (I) and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound:
Formula (I)
Figure A2006800499580002C2
Formula (I)
Wherein D is O or NR 11
One of A or B are (CH 2) mC (O)-alkyl, (CH 2) mC (O)-N (R 2) 2And another is H, alkyl or assorted alkyl, and wherein m is 0,1,2 or 3;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group;
Or A and B constitute optional non-aromatics or the aromatic carbocyclyl groups that replaces together; Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
R 1The C that is selected from for optional replacement 3-C 9Cycloalkyl, C 1-C 4Alkyl (C 3-C 9Cycloalkyl), C 1-C 4Alkyl (aryl) and C 1-C 4The group of alkyl (heteroaryl), wherein R 1Any carbon of cycloalkyl ring can be chosen wantonly by Y and Z and replace, and wherein each Y and each Z are independently selected from halogen, methyl or trifluoromethyl, or Y and Z can constitute together 3-, 4-or 5-unit's carbocylic radical or oxo (=O);
R 2Be selected from H or the optional alkyl that replaces independently of one another;
R 11Be H or the optional alkyl that replaces.
2. the described compound of claim 1, wherein A and B constitute the optional heterocycle that is selected from following oxo-replacement that replaces together, promptly are selected from-C (O)-(CR qR q) n-,-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-(CR qR q) n-,-C (O)-NR 2-NR 2-(CR qR q) n-,-C (O)-NR 2-N=(CR q)-,-O-C (O)-O-, O-C (O)-NR 2-,-NR 2-C (O)-NR 2-,-O-C (O)-O-(CR qR q) n-,-O-C (O)-(CR qR q) n-O-,-N-C (O)-(CR qR q) n-N-,-O-C (O)-(CR qR q) n-N-,-N-C (O)-(CR qR q) n-O-,-O-C (O)-NR 2-(CR qR q) n-,-NR 2-C (O)-O-(CR qR q) n-,-NR 2-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-O-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-(CR qR q) n-,-(CR qR q) n-C (O)-NR 2-NR 2-,-(CR qR q) n-C (O)-(CR qR q) n-,-C (O)-O-(CR qR q) n-O-,-C (O)-O-(CR qR q) n-NR 2-,-C (O)-NR 2-(CR qR q) n-NR 2,-C (O)-NR 2-(CR qR q) n-O-,-C (O)-NR 2-CR q=CR q-, C (O)-CR q=CR q-NR 2-,-C (O)-CR q=CR q-O-,-C (O)-CR q=CR q-S-; Wherein each n independently is 1,2 or 3; And each R wherein qBe independently selected from the heterocycle of assorted alkyl, heterocycle or the replacement of aryl, ketone group alkyl, the ketone group alkyl of replacement, the assorted alkyl of ketone group of alkyl, aryl, the replacement of H, alkyl, replacement, the assorted alkyl of ketone group of replacement, assorted alkyl, replacement.
3. the described compound of claim 1, wherein R 2For H and D are O.
4. the described compound of claim 1, wherein one of A or B are that C (O)-alkyl and another are H; Or one of A or B are C (O)-N (R 2) 2And another is H.
5. the described compound of claim 1, wherein A and B constitute together and comprise C (O)-(CH 2) nNon--aromatics the cyclic group of the optional replacement of-part, and wherein n is 1,2,3 or 4.
6. the described compound of claim 5, wherein n is 2; R 2Be H; And D is O.
7. the described compound of claim 1, wherein A and B constitute together and comprise at least one N, NR 2, the heteroaromatic group of the optional replacement of S or O group.
8. the described compound of claim 7, also comprise-(CH) n-part, wherein n is 1,2 or 3.
9. the described compound of claim 7 is wherein chosen the heteroaromatic group that replaces wantonly and comprise single N on ring.
10. the described compound of claim 7, wherein R 2For H and D are O.
11. the described compound of claim 7, the wherein optional heteroaromatic group that replaces comprises two heteroatomss that are selected from N, S and O.
12. the described compound of claim 11, the wherein optional heteroaromatic group that replaces is selected from optional benzoxazolyl that replaces or the optional benzothiazolyl that replaces.
13. pharmaceutical composition comprises the acceptable N-oxide compound of compound, pharmacologically acceptable salts, pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound and pharmacy acceptable diluent, vehicle or the tackiness agent of claim 1.
14. suppress the method that fatty acid amide hydrolase or treatment can have benefited from suppressing the active disease of patient's fatty acid amide hydrolase, illness or illness, comprise the acceptable N-oxide compound of compound, pharmacologically acceptable salts, pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound of described patient being treated the claim 1 of significant quantity.
15. the described method of claim 14, wherein said disease, illness or illness are selected from acute or chronic pain, eating disorder, cardiovascular disorder, metabolic trouble, illness or illness, kidney local asphyxia, cancer, the immunity system obstacle, anaphylactic disease, metabolic trouble, illness or illness, the kidney local asphyxia, cancer, immunity system obstacle, anaphylactic disease, parasite, virus or bacterial infection disease, inflammatory diseases, osteoporosis, ophthalmic, lung disease, gastrointestinal tract disease and the urinary incontinence.
16. goods comprise wrapping material; The compound of the active claim 1 of effective inhibition fatty acid amide hydrolase (FAAH) in these wrapping material; Be used to suppress the active label of fatty acid amide hydrolase (FAAH) with expression described compound or composition or its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
17. the compound of formula (II) and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound:
Figure A2006800499580005C1
Formula (II)
Wherein D is O or NR 11X respectively do for oneself CH or N;
R 1Be selected from:
R 1Be selected from:
Figure A2006800499580005C2
Wherein M is key, the optional C that replaces 1-C 8Alkylidene group, the inferior assorted alkyl of the optional 4-atom that replaces, the optional C that replaces 2-C 8Alkenylene, the optional C that replaces 3-C 8Cycloalkyl or the optional C that replaces 2-C 8Alkynylene;
J is CH or N; K is CH or N; Condition is when K is CH, and J can not be CH;
R 3Be selected from the optional group that replaces independently of one another, described group is selected from C 1-C 6Alkyl-(aryl), C 1-C 6Alkyl-(heteroaryl), C 1-C 6Alkoxyl group, C 1-C 6Alkylamine, C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 3-C 8Cycloalkyl, C 1-C 6Assorted alkyl ,-C (O)-R 12Aryl, aryloxy, heteroaryl, heteroaryloxy, Heterocyclylalkyl, the heterocycle alkoxyl group, phenyl, pyridyl, pyridazinyl, piperazinyl, piperidyl, morpholinyl, furyl, thiophenyl, thienyl, dibenzofuran group, the dibenzothiophene base, indyl, fluorenyl, carbazyl, pyrimidyl, pyrazinyl, triazinyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl oxadiazole base, thiadiazolyl group, triazolyl, naphthyl, quinolyl, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, the cinnolines base, the imidazopyrimidine base, the Thienopyrimidine base, benzofuryl, benzothienyl, benzimidazolyl-benzoxazolyl, the benzoisoxazole base, benzothiazolyl, the benzisothiazole base, indazolyl, pyrrolopyridinyl, the furo pyridyl, dihydrofuran and pyridyl, the thienopyridine base, dihydro-thiophene and pyridyl, imidazopyridyl, Pyrazolopyridine base oxazole and pyridyl isoxazole and pyridyl or thiazole and pyridyl;
R ' is independent separately to be the alkyl of H, alkyl or replacement;
R 5Independent separately is H, C 1-C 3Alkyl or halogen;
R 6Be C 1-C 3Alkyl or C 3-C 7Cycloalkyl;
R 2And R 11Be H or the optional alkyl that replaces;
R 12Be selected from C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 3-C 7Cycloalkyl, C 1-C 6Assorted alkyl, aryloxy, aryl, heteroaryl, Heterocyclylalkyl, benzyloxy, furyl, phenyl, benzyl or pyridyl;
Or R 1And R 2Constitute together:
Figure A2006800499580006C1
N is 1,2,3 or 4; M is 1,2,3 or 4;
A and B constitute together and comprise C (O)-(CH 2) qNon--aromatics the cyclic group of the optional replacement of-part, wherein q is 1,2,3 or 4;
Or A and B constitute together and comprise at least one N, NR 2, the aromatics of the optional replacement of S or O group or non--aromatics cyclic group;
Or one of A or B are-L-G and another C that is selected from H and chooses replacement wantonly 1-C 6Alkyl;
Or A and B constitute the optional aromatic carbocyclyl groups that replaces together;
Or A and B constitute the heterocycle of the optional oxo-replacement that replaces together;
Or A and B are selected from H, the optional alkyl that replaces, the optional assorted alkyl that replaces, the optional heterocyclic radical that replaces, the optional aryl that replaces, the optional heteroaryl that replaces, the optional ketone group alkyl that replaces, the optional acid amides that replaces and the assorted alkyl of the optional ketone group that replaces independently of one another;
L is key or the optional group that replaces, and described group is selected from C 1-C 6Alkylidene group, C 1-C 6Inferior assorted alkyl, C 1-C 6The ketone group alkylidene group ,-C (O) NR 9-(CH 2) j-,-NR 9-C (O)-(CH 2) j-,-OC (O) O-(CH 2) j-,-NHC (O) O-(CH 2) j-,-O (O) CNH-(CH 2) j-,-C (O) O-(CH 2) j-,-OC (O)-(CH 2) j-,-NR 9C (O) N (R 9)-(CH 2) j-,-S (O)-(CH 2) j-,-S (O) 2-(CH 2) j-,-C (=NR 10) N (R 9)-(CH 2) j-and-NR 9C (=NR 10) N (R 9)-(CH 2) j-;
G be tetrazyl ,-NHS (=O) 2R 8,-S (=O) 2NHR 8,-S (=O) 2The NH-phenyl ,-OH ,-SH ,-OC (O) NHR 8,-NHC (O) OR 8,-C (O) NHC (O) R 8,-C (O) NHS (=O) 2R 8,-S (=O) 2NHC (O) R 8,-S (=O) 2NHC (O) NHR 8,-NHC (O) R 8,-NHC (O) N (R 9) 2,-C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) N (R 9) 2,-NR 9C (=NR 10) NHC (=NR 10) N (R 9) 2,-NR 9C (=CHR 10) N (R 9) 2,-C (O) NR 9C (=NR 10) N (R 9) 2,-C (O) NR 9C (=CHR 10) N (R 9) 2,-CO 2H ,-(OP (=O) OH) xOH ,-OP (=O) OR 8OH ,-OP (=O) R 8OH ,-NR 9P (=O) OR 8OH ,-NR 9P (=O) R 8OH ,-P (=O) OR 8OH;-P (=O) R 8OH ,-S (O) yOH;-OS (O) yOH;-NR 9S (O) yOH;
R 8Independent of separately replacing or unsubstituted C 1-C 6Alkyl;
R 9Independent separately is the C of H, replacement 1-C 6Alkyl or unsubstituted C 1-C 6Alkyl;
R 10Be selected from independently of one another H ,-S (=O) 2R 8,-S (=O) 2NH 2,-C (O) R 8,-CN and-NO 2
J is 0,1,2,3 or 4; X is 1,2 or 3; Y is 0,1 or 2;
Wherein each optional substituting group is independently selected from C 1-C 3Alkyl, C 1-C 3Alkoxyl group, benzyl, halogen, nitro, cyano group or benzyloxy-C (O) R ' ,-C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) R ' ,-C (O) N (R ') 2,-C (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-C (O) N (R ') 2,-OC (O) N (R ') 2,-OC (O) N (R ')-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-OC (O) N (R ') 2,-N (R ') C (O) R ' ,-NR ' C (O)-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)--NR ' C (O) R ' ,-SR ' ,-S-(alkyl of alkyl or replacement) ,-S (O) kR '; Wherein k be 1 or 2 ,-S (O) k(alkyl of alkyl or replacement) ,-C (S)-(alkyl of alkyl or replacement) ,-CSN (R ') 2,-CSN (R ')-(alkyl of alkyl or replacement) ,-N (R ') CO-(alkyl of alkyl or replacement) ,-N (R ') C (O) OR ' ,-(alkyl of alkyl or replacement)-O-N=C (R ') 2The alkyl of ,-(alkyl or replacement)-C (O) NR '-(alkyl of alkyl or replacement) ,-(alkyl of alkyl or replacement)-S (O) k-(alkyl of alkyl or replacement)-SR ' ,-(alkyl of alkyl or replacement)-S-SR ' ,-S (O) kN (R ') 2,-N (R ') C (O) N (R ') 2,-N (R ') C (S) N (R ') 2,-N (R ') S (O) kN (R ') 2,-C (R ')=NR '-C (R ')=N-N (R ') 2With-C (R ') 2-N (R ')-N (R ') 2
18. the compound with formula (III) structure of claim 17 and pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound:
Figure A2006800499580008C1
Wherein p is 0,1 or 2; Q is 0,1 or 2;
R 13And R 14Be selected from H, C independently of one another 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl, C 3-C 6Cycloalkyl, C 1-C 4Alkyl-(C 3-C 6Cycloalkyl), the aryl of aryl, replacement, arylalkyl ,-C (O) R A, hydroxyl-(C 1-C 6Alkyl), amino-(C 1-C 6Alkyl) ,-CH 2-NR AR B,-O-(C 1-C 4), aryloxy, halogen, C 1-C 6-haloalkyl, cyano group, hydroxyl, nitro, amino ,-C (O) NR AR B,-ONR AR B,-O-C (O) NR AR B,-SO 2NR AR B
R AAnd R BBe selected from hydrogen independently of one another, C 1-C 6Alkyl and C 3-C 6Cycloalkyl.
19. the compound of claim 18 has following structure:
Figure A2006800499580008C2
20. the described compound of claim 19, wherein R 2Be H.
21. pharmaceutical composition comprises the acceptable N-oxide compound of compound, pharmacologically acceptable salts, pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound and pharmacy acceptable diluent, vehicle or the tackiness agent of claim 17.
22. suppress the method that fatty acid amide hydrolase or treatment can have benefited from suppressing the active disease of patient's fatty acid amide hydrolase, illness or illness, comprise the acceptable N-oxide compound of compound, pharmacologically acceptable salts, pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or the pharmacy acceptable solvent compound of described patient being treated the claim 17 of significant quantity.
23. the described method of claim 30, wherein said disease, illness or illness are selected from acute or chronic pain, eating disorder, cardiovascular disorder, metabolic trouble, illness or illness, kidney local asphyxia, cancer, immunity system obstacle, anaphylactic disease, metabolic trouble, illness or illness, kidney local asphyxia, cancer, immunity system obstacle, anaphylactic disease, parasite, virus or bacterial infection disease, inflammatory diseases, osteoporosis, ophthalmic, lung disease, gastrointestinal tract disease and the urinary incontinence.
24. goods comprise wrapping material; The compound of the active claim 17 of effective inhibition fatty acid amide hydrolase (FAAH) in these wrapping material; Be used to suppress the active label of fatty acid amide hydrolase (FAAH) with expression described compound or composition or its pharmacologically acceptable salts, the acceptable N-oxide compound of pharmacy, pharmaceutical activity metabolite, the acceptable prodrug of pharmacy or pharmacy acceptable solvent compound.
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CN105008323A (en) * 2012-10-31 2015-10-28 密执安大学评议会 Plasminogen activator-1 inhibitors and methods of use thereof
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PL424191A1 (en) * 2018-01-04 2019-07-15 Pozlab Spółka Z Ograniczoną Odpowiedzialnością Mucoadhesive oral preparation with the extract from Cannabis (Cannabis sativa) and method for producing it
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CN103917230A (en) * 2011-08-15 2014-07-09 雀巢产品技术援助有限公司 Methods for ameliorating symptoms or conditions caused by stress
CN105008323A (en) * 2012-10-31 2015-10-28 密执安大学评议会 Plasminogen activator-1 inhibitors and methods of use thereof
US9718760B2 (en) 2012-10-31 2017-08-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
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US11426368B2 (en) 2017-07-27 2022-08-30 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use
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CN112703003A (en) * 2018-08-02 2021-04-23 纯技术Lyt股份有限公司 Lipid prodrugs of pregnane neurosteroids and uses thereof
CN108912107A (en) * 2018-08-14 2018-11-30 李敬敬 There is the compound of selective inhibitory activity to people's fatty amide hydrolase and its treat the purposes of pain
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CN113773221B (en) * 2021-10-08 2023-09-29 湖北工业大学 P-benzoquinone compound and preparation method thereof

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