CN101646676A

CN101646676A - 7,8-is saturated-4, (S)-N-steric isomer of 5-epoxy-morphinanium analogs

Info

Publication number: CN101646676A
Application number: CN200780050146A
Authority: CN
Inventors: J·佩雷斯; A·Q·韩; Y·罗特什泰恩
Original assignee: Progenics Pharmaceuticals Inc
Current assignee: Progenics Pharmaceuticals Inc
Priority date: 2006-11-22
Filing date: 2007-11-21
Publication date: 2010-02-10

Abstract

Disclose novelly 7,8-is saturated-4, (S)-N-steric isomer of 5-epoxy-morphinanium analogs.Also disclose and contained 7,8-is saturated-4, the pharmaceutical composition of (S)-N-steric isomer of 5-epoxy-morphinanium analogs and their medicinal method.Disclose this analogue and under different condition, be used for the treatment of GI supermotility.

Description

7,8-is saturated-4, (S)-N-steric isomer of 5-epoxy-morphinanium analogs

Background of invention

Invention field

The present invention relates generally to (S)-7,8-N-singly-bound-4,5-epoxy-morphinanium analogs (after this being called " 7; 8-saturated-4; 5-epoxy-morphinanium ") (comprises 7,8-is saturated-4,5-epoxy-morphinanium analogs), prepare they synthetic method, comprise their pharmaceutical preparation and use their method.The application requires the right of priority of U. S. application of submitting on November 22nd, 2,006 60/867,101 and the U. S. application of submitting on November 27th, 2,006 60/867,394, they each incorporate in this integral body.

Description of related art

The medical treatment and the mentation of opium have just been understood from ancient times.Yet up to about earlier 1800s, morphine just separates from opium, after this is morphine monomethyl ether and Papaverine.Arrived 19th-century mid-term, pure alkaloid rather than crude opium agent become perfect medical practice gradually.Since 19th-century, a large amount of these natural alkaloidal synthetic and semi-synthetic derivatives have been made.

About morphinan compounds, known that at present the substituting group replacement can produce remarkable influence on pharmacology.For example, existing people reports may be because significant first pass metabolism, and 3-hydroxyl morphinane is Orally administered to be compared effect with parenteral administration and significantly reduce.It is believed that morphine has stopped described activity in the glucoside acidifying of its 3-oh group.Yet, have 3-methoxy group that the people can see in for example oxycodone and morphine monomethyl ether to be associated with good oral effectiveness.

The opium sample activity of opioid (morphinoids) has been shown as the influence of the substituent character of nitrogen that is subject to them especially.For example replace morphine and produced potent antagonist, for example nalorphine, naloxone, TREXUPONT and nalbuphine with N-methyl group in the relevant opioid with the substituting group (for example allyl group, cyclobutylmethyl and propyl group methyl) that is rich in π-electronics.

Symbol " R " and " S " are normally used for the concrete configuration of organic chemistry with the indication chiral centre.Symbol " R " is meant " right side " and is meant when being the clockwise chiral centre configuration that concerns along group priority when the key of lowest priority group is observed (being up to inferior low).Term " S " or " left side " are meant the chiral centre configuration of edge towards the key of lowest priority group.

The group priority of R/S symbol is based on ordination number (the heaviest isotropic substance is preceding).The part tabulation and the stereochemical discussion of priority are included in books: The Vocabulary of OrganicChemistry (organic chemistry vocabulary), people such as Orchin, John Wiley and Sons, Inc., in the 126th page (1980), this book is incorporated this paper by reference in full into.When producing quaternary nitrogen morphinane structure, this structure can be characterized as being (R) or (S) steric isomer.

Prior art is pointed out the isolating steric isomer of compound, and whether no matter enantiomorph diastereomer (diastereomer) can have opposite physics and functional performance sometimes, be all to be this situation under any specified conditions although can not predict this.Dextromethorphane Hbr is an antitussive, yet its enantiomorph levomethorphan is potent narcotic.(R, R)-Methylphenidylacetate is to be used for the treatment of the medicine that attention deficit moves obstacle (ADHD) more, however its enantiomorph (S, S)-Methylphenidylacetate is an antidepressive.(S)-and fluoxetine has the anti-migraine activity, however its enantiomorph (R)-fluoxetine is used to the treatment depression.(the S)-enantiomorph of citalopram is to be used for activated isomer in the depressed treatment for the treatment of.(R)-the enantiomorph non-activity.For pyrotic treatment, (the S)-enantiomorph of omeprazole is more potent than (R)-enantiomorph.

The people such as Caldwell; Complete Proton and Carbon Nuclear MagneticResonance Spectral Assignments of Some Morphin-6-one Alkaloids byTwo-Dimensional NMR Techniques (measuring the alkaloidal full proton of some morphine-6-ketone and carbon atom Nmr Lines by two dimensional NMR techniques), described two-dimentional NMR conformational analysis (nuclear Ou Fuhaoze strengthen variance analysis (Nuclear Overhauser enhancement difference analysis)) select (select) season N-methyl Oxycodone analog with determine the N-methyl group be in equatorial position aspect purposes. They notice that the proton coupling constant of the compound that they tested shows, the chair conformation that the pimelinketone ring of morphinane skeleton and piperidine ring have slight deformation.

People such as Bianchetti, Quaternary Derivatives of Narcotic Antagonists:Stereochemical Requirements at the Chiral Nitrogen for In Vitro and In VivoActivity (the season derivative of narcotic antagonist: the chirality nitrogen stereochemistry that is used for external and activity in vivo requires), 1983 Life Science 33 (supplementary issue I): 415-418 studied three pairs season narcotic antagonist (levallorphan, nalorphine and naloxone) diastereomer (diastereoisomer) and their parent tertiary amine, how to influence external and activity in vivo with the configuration of observing chirality nitrogen.Find that activity change depends on considerably how the season derivative prepares.In each series, have only the diastereomer (being called " N-methyl diastereomer ") that obtains that methylates of the tertiary amine by N-allyl group-replacement replacing from the rat meninx ³H-TREXUPONT and to play aspect the morphine antagonist effect in guinea pig ileum be potent.On the contrary, the diastereomer (being called " N-allyl group diastereomer ") that is obtained by tertiary amine and allyl halide reaction with N-methyl-replacement can not replace the 3H-TREXUPONT and have insignificant antagonistic activity and slight agonist effect in guinea pig ileum.Find consistent with external discovery usually in the body.Therefore have only " N-methyl " rather than " N-allyl group diastereomer " in rat, to suppress the constipation that morphine causes and show as antagonist.The author claims ¹H and ¹³The material of C nucleus magnetic resonance (NMR) analysis revealed preparation is pure, but these methods are inaccurate.The author quotes and specifies " the N-methyl diastereomer " of nalorphine to be the reference of (R) configuration.There is not the appointment of proposition to levallorphan and naloxone diastereomer.The configuration of calculating these diastereomers is risky (people such as R.J.Kobylecki, J.Med.Chem.25,1278-1280,1982).

People such as Kobylecki, 1982, N-methylnalorphine:Definition of N-allylconformation for antagonism at the opiate receptor (N-methyl nalorphine: the N-allyl group conformation definition of opiate receptor antagonism), J.Med Chem.25:1278-1280 report, according to the X-ray diffraction data, has calm configuration derived near the allyl group the quaternary nitrogen of the active diastereomer (N-methyl diastereomer) of nalorphine.The Kobylecki report has the substituent isomer of upright N-and demonstrates some agonist activities (although very low) and relative (contrasting its agonist activity) considerable antagonistic activity, yet calm N-substituting group shows pure opium sample antagonistic activity.

People such as Iorio, Narcotic agonist/antagonist properties of quaternarydiasteromers derived from oxymorphone and naloxone (derived from the anesthesia agonist/antagonist characteristic of the season diastereomer (diasteromers) of oxymorphone and naloxone), 1984, Chim.Ther.19:301-303, the related Kobylecki of following that shows the direction that ratio between agonist and the antagonist and N-replace is about diastereoisomeric season same pattern of being found of morphinanium salt, that is to say that the compound with bigger calm group shows than the corresponding upright bigger antagonistic activity of diastereomer.These authors propose, activated type, and agonism, antagonistic action and mixed active all can be explained by the interactional not isomorphic map type of calm N-substituting group and acceptor sublocus.By direct external ileum contraction test and the activity by compound injection is come their prepared compound of comparison to the mouse brain in vivo.Funke and deGraaf, with reference to people such as Ioria, A ¹H and ¹³C nuclear magnetic resonance study of three quaternarysalts of naloxone and oxymorphone be (three kinds of quaternary salts of naloxone and oxymorphone ¹H and ¹³The C nuclear magnetic resonance research), 1986, J.Chem.Soc.Perkin Trans.II 735-738 has reported three kinds of N, N-dialkyl group-morphinanium chloride derivatives (a kind of N, N-diallyl and two kinds of N-allyl group-N-methyl diastereomers) ¹H and ¹³C n.m.r. data.

Cooper (United States Patent (USP) the 6th, 455, No. 537) suspects correlation of data in the Iorio body, thinks that using in brain is inappropriate, because known quaternised medicament can not enter in the brain.Cooper use intravenously is used the methyl nalorphine and has been carried out a large amount of in vivo test, find to compare with (the S)-isomer or the R/S mixture of N-methyl nalorphine, (the R)-isomer of N-methyl nalorphine is for example nauseating to the side effect that opposing or prevention opiate cause in Mammals, vomiting and ataxia provide better treatment.

People such as Feinberg, The opiate receptor:A model explaining structure-activityrelationships of opiate agonists and antagonists (opiate acceptor: a kind of model of explaining the structure-activity relation of opiate agonist and antagonist), 1976 Proc.Natl.Acad.Sci.USA 73:4215-4219 think that " antagonist substituting group " for example determined " purity " of the antagonism pharmacosexology character of opium sample medicine in the locus of N-allyl group and cyclopropyl methyl.People such as Feinberg infer that the structural 14-oh group of morphinane helps to have increased the antagonism substituent ratio in the equatorial conformation (with respect to the upright conformation relevant with piperidine ring), and this relevant with the cyclopropyl methyl with the N-allyl group at least equatorial conformation (confirmation) has increased " pure " antagonistic action.They further infer in antagonistic activity is regulated, the atomic configuration of allylic πDian Zi of N-that antagonist binding site that acceptor is specific and antagonism pharmacology are required or N-cyclopropyl methyl or N-cyclobutylmethyl group interacts, and has therefore stablized the antagonist receptor conformation.In order to ensure " pure " antagonist properties, they advise the antagonist substituting group to the antagonist binding site of acceptor near must by as 14-hydroxyl or 9-Beta-methyl substituting group seen in naloxone or benzomorphans antagonist promote.If there are not these substituting groups, they are agonist and the pharmacological variable mixing of antagonist at conjecture.

Although these reference may propose the antagonism activity of the raising of some functional group when this type of group is in equatorial position on the morphinane nitrogen, but they do not propose to have the morphinan compounds of different substituents simultaneously, especially about at the compound that provides different saturation to distribute aspect the ring of skeleton morphinane structure, have (the quaternary charged nitrogen) compound of quaternary nitrogen and have isolating (R) of the right compound of different substituents in 3 and 6 sites of morphinane skeleton, (S) agonist-antagonistic activity of conformer or upright-equatorial conformation isomer.

Summary of the invention

In embodiment described herein, highly purified (S)-7 that prepared are disclosed, 8-saturated-4,5-epoxy-morphinanium analogs, allow to identify that they in contrast to their corresponding (R)-saturated-4, the relative retention time of 5-epoxy-morphinanium analogs retention time in chromatogram.The diastereomer of having found this analogue has the activity that is different from their corresponding non-enantiomer mixtures.

In one embodiment of the invention, substantially pure or highly purified (S)-7 are provided, 8-saturated-4,5-epoxy-morphinanium, substantially pure or highly purified (S)-7,8-saturated-4, the crystal of 5-epoxy-morphinanium and its intermediate, prepare pure substantially or highly purified (S)-7,8-saturated-4, the novel method of 5-epoxy-morphinanium compound, containing counterpart (R)-7,8-saturated-4,5-epoxy-morphinanium steric isomer and specific (S)-7,8-saturated-4, analyze in the mixture of 5-epoxy-morphinanium, quantitatively and separate (S)-7,8-is saturated-4, the method for 5-epoxy-morphinanium compound, difference (R)-7,8-saturated-4,5-epoxy-morphinanium and its (S)-7,8-is saturated-4, the method for 5-epoxy-morphinanium steric isomer, contain the medicament production of this compound and the associated uses of these materials.

(S)-7 also are provided, and 8-is saturated-4, the salt of 5-epoxy-morphinanium.Acquisition (S)-7 also is provided, and 8-is saturated-4, the scheme of 5-epoxy-morphinanium.In addition, find (S)-7 surprisingly, 8-is saturated-4, and 5-epoxy-morphinanium has the opioid agonist activity.The invention provides (S)-7,8-saturated-4, the stereoselectivity synthetic synthetic route of 5-epoxy-morphinanium, pure substantially (S)-7,8-saturated-4,5-epoxy-morphinanium, pure substantially (S)-7,8-is saturated-4, the crystal of 5-epoxy-morphinanium, contains pure substantially (S)-7,8-is saturated-4, the pharmaceutical preparation of 5-epoxy-morphinanium and their using method.

According to one embodiment of the invention, provide comprise surpass 99.5% with (S) configuration (this is with regard to nitrogen) exist 7,8-is saturated-4, the composition of 5-epoxy-morphinanium.In other embodiment, be present in 7 of (S)-configuration (with regard to nitrogen) in the composition, 8-saturated-4, it is about 99.6% that 5-epoxy-morphinanium surpasses, or about 99.7%, or about 99.8%, about 99.9%, or about 99.95%, or even more preferably surpass 99.95%.In one embodiment, in the composition of being analyzed, use chromatographic procedure described herein, do not have detectable counterpart (R)-7,8-is saturated-4,5-epoxy-morphinanium compound.But preferred composition does not have corresponding (R)-7, and 8-is saturated-4,5-epoxy-morphinanium, such as on HPLC detection.In one embodiment, under detectability 0.02% and 0.05% the quantitative limit, do not have the detectable counterpart of HPLC (R)-7,8-is saturated-4,5-epoxy-morphinanium.In another embodiment, composition of the present invention comprise 99.85% with regard to nitrogen (S)-configuration 7,8-saturated-4,5-epoxy-morphinanium, and it contains stereomeric (R)-7 of counterpart, 8-is saturated-4,5-epoxy-morphinanium compound, and this compound is that HPLC is detectable under the quantitative limit of 0.02% detectability and 0.05%.

According to an aspect of the present invention, provide and comprised 7,8-saturated-4, the composition of 5-epoxy-morphinanium, wherein at least 99.6% in the composition, 99.7%, 99.8%, 99.85%, 99.9% and or even 99.95% 7,8-saturated-4,5-epoxy-morphinanium compound is (S)-configuration with regard to nitrogen, and said composition comprise following one or more: buffer reagent, sequestrant, sanitas (preservingagent), cryoprotector, penetration enhancer, lubricant, preservatives, antioxidant or tackiness agent.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium comprises the structure of formula Z:

Formula Z

((S)-7,8-is saturated-4,5-epoxy-morphinane)

Wherein X is a counter ion and according to Cahn, Ingold, and Prelog configuration specified rule, this compound is (S) configuration with regard to nitrogen, and R ₁₈And R ₁₇Be C ₁-C ₈Alkyl or C ₁-C ₆Alkyl.R ₃It can be hydroxyl protecting group.This molecule can exist with zwitter-ion.This counter ion can be any counter ion.Preferably, negatively charged ion is pharmaceutically acceptable.Negatively charged ion comprises halogenide, vitriol, phosphoric acid salt, nitrate and is with anionic (anionic-charged) organism class.Described halogenide can be iodide, bromide, muriate, fluorochemical or its combination.In one embodiment, described halogenide is iodide.In one embodiment, described halogenide is bromide.Being with anionic organism class can be sulfonate or carboxylate salt.

One aspect of the present invention relates to isolated compound or its pharmacy acceptable salt form or the prodrug forms of (S) configuration with regard to nitrogen of formula I:

Wherein:

R ₁And R ₂Independently be H, OH, OR ₂₆, halogenide, silyl; Alkyl, cyclic hydrocarbon radical or its replacement part; Or R ₁And R ₂Also can be in conjunction with can be according to R to form ₁₉The C that replaces ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silyl;

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

C ₁-C ₃Acyl group

R ₅Be H, OH, OR ₂₆,

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

R ₆Be H ,=O, OH, OR ₂₆

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

Amine, acid amides, sulphonamide or ester;

R ₇And R ₈Independently be H, alkyl, cyclic hydrocarbon radical or its replacement part; Or R ₇And R ₈In conjunction with can be according to R to form ₁₉The carbocyclic ring condensed ring that replaces, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₁₄Be H, OH, OR ₂₆, NR ₂₂R ₂₃SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces; Aryloxy, acyloxy,

Or R ₁₄Can be according to its configuration with regard to quaternary nitrogen and and R ₁₇Or R ₁₈In conjunction with to form O-condensed ring or C ₃-C ₆The carbocyclic ring condensed ring;

R ₁₇And R ₁₈Be commutable C ₁-C ₆If alkyl is R wherein ₁₈Be methyl, R then ₁₇It or not allyl group;

R ₁₉Independently be selected from when occurring at every turn:

H, C ₁-C ₆Alkyl, CF ₃, OR ₂₄, Cl, F, Br, I ,=O, CN, NO ₂, NR ₂₂R ₂₃

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

Contain 1 to 4 heteroatomic 5 to 10 yuan of heterocycle that are selected from nitrogen, oxygen and sulphur, wherein

Described 5 to 10 yuan of heterocycles are through 0-3 R ₂₁Replace;

R ₂₀Independently be selected from H, OH, Cl, F, Br, I, CN, NO when occurring at every turn ₂, NR ₂₂R ₂₃, ethanoyl,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-;

R ₂₁Independently be selected from H, OH, Cl, F, Br, I, CN, NO when occurring at every turn ₂, NR ₂₂R ₂₃, CF ₃, ethanoyl,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-; Or

NR ₂₂R ₂₃Can be the heterocyclic type ring that is selected from group piperidyl, homopiperidinyl, thio-morpholinyl, piperazinyl and morpholinyl,

R ₂₂Independently be selected from H, C when occurring at every turn ₁-C ₆Alkyl, (C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₃Independently be selected from when occurring at every turn:

H, (C ₁-C ₆) alkyl,

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₄Independently be selected from H, phenyl, benzyl, (C when occurring at every turn ₁-C ₆) alkyl and (C ₂-C ₆) alkoxyalkyl;

R ₂₅Be alkyl, aryl or arylalkyl;

R ₂₆Independently be selected from when occurring at every turn

H, C ₁-C ₆Alkyl, CF ₃

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

Contain 1 to 4 heteroatomic 5 to 10 yuan of heterocycle that are selected from nitrogen, oxygen and sulphur, wherein said 5 to 10 yuan of heterocycles are through 0-3 R ₂₁Replace; And

X ^-It is negatively charged ion.

The S-steric isomer with regard to nitrogen that comprises formula Ia in the embodiment of this paper:

Wherein

R ₁₇And R ₁₈Be selected from alternatively relative to each other (a) or (b):

(a) do not replace or non-halogen replaces: C ₄-C ₈(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring (cycloheteryl)) alkyl, (cyclophane base) alkyl; C ₄-C ₆(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl

(b) replacement or unsubstituted straight or branched C ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl or C ₃-alkynyl;

If wherein (b) elect methyl and R as ₆Be=O that then (a) is not unsubstituted (cyclopropyl) methyl;

R ₆Be H, OH ,=O ,=CH ₂,-N (CH ₃) ₂Or any ring-like ring, or and R ₇Form ring-like ring together;

R ₇And R ₈Be H or alkyl;

R ₁₄Be H, OH, halogenide, aryl amido, amino, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkylalkyl, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃, alkoxyl group, aryloxy or aryl-alkoxyl group, or and R ₁₇Or R ₁₈Form ring-like ring together;

R ₁And R ₂Independently be H, halogenide, alkoxyl group, alkyl or aryl;

R ₃Be H, C ₁-C ₄Alkyl or C ₁-C ₃Acyl group ,-silyl;

R ₅Be H, OH, alkyl, alkoxyl group or aryloxy; And

X ^-It is negatively charged ion.

(the S)-steric isomer with regard to nitrogen that comprises formula Ib in the embodiment of this paper:

Wherein

R ₁₇And R ₁₈Be to replace or unsubstituted C ₁-C ₆Alkyl is wherein worked as R ₆Elect as=during O, R ₁₇And R ₁₈In at least one is not methyl when another is the cyclopropyl methyl;

R ₆Be H, OH, OR ₂₅,=O ,=CH ₂,-N-alkyl, N-dialkyl group, acyloxy, alkoxyl group, alkyl ,=CR ' R ", wherein R ' and R " independently be H or C ₁-C ₁₀Alkyl or any ring, or R ₆With R ₇Form ring together;

R ₇And R ₈Be H or alkyl, cyclic hydrocarbon radical, alkoxyl group, amine, acid amides, hydroxyl or its replacement part;

R ₁₄Be H, OH, halogenide, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkylalkyl, SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅Alkoxyl group, aryloxy or alkoxy aryl, or and R ₁₇Or R ₁₈Form ring together;

R ₁And R ₂Independently be H, halogenide, alkoxyl group, alkyl or aryl;

R ₃Be H, alkyl, C ₁-C ₃Acyl group, silyl;

R ₅Be H, OH, alkyl, alkoxyl group or aryloxy;

R ₂₅Be alkyl, aryl, arylalkyl; And

X ^-It is negatively charged ion.

Some group can be preferentially selected.For example, in one embodiment, R ₁₄May be selected to be OH or O-alkyl.

Isolated compound or its pharmacy acceptable salt form or the prodrug forms of (S) configuration with regard to nitrogen of formula I (c):

Wherein:

R ₁And R ₂Independently be H, OH, OR ₂₆, halogenide, silyl; Alkyl, cyclic hydrocarbon radical or its replacement part;

Or R ₁And R ₂Also can be in conjunction with can be according to R to form ₁₉The C that replaces ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silyl, CO ₂R ₁₉, SO ₂R ₁₉, B (OR ₂₆) ₂

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

C ₁-C ₃Acyl group

R ₅Be H, OH, OR ₂₆,

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

R ₆Be H ,=O, OH, OR ₂₆,=(R ₁₉) (R _{19 '}) ,=(0-3 R ₂₀The heterocycle that replaces) ,=(0-3 R ₂₀The C that replaces ₃-C ₇Ring);

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

Amine, acid amides, sulphonamide or ester;

R ₇And R ₈Independently be H, alkyl, cyclic hydrocarbon radical, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Arylalkyl (arylakly) or its replace part, or

Wherein, X be key ,=O, O, S, N (R ₁₉), SO, SO ₂, SO ₂N (R ₁₉), CON (R ₁₉), N (R ₁₉) CON (R _{19 '}), N (R ₁₉) C (=NR _{19 '}) N (R _{19 "}), COO;

Or R ₇And R ₈In conjunction with can be according to R to form ₁₉Carbocyclic ring condensed ring, the fused benzo ring that replaces, have 0-3 R ₂₀5-, 6-or 5-6 unit aryl or heteroaryl;

R ₁₄Be H, OH, OR ₂₆, NR ₂₂R ₂₃SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Arylalkyl,

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces; Aryloxy, acyloxy,

Or R ₁₄Can be according to its configuration with regard to quaternary nitrogen and and R ₁₈In conjunction with to form O-condensed ring or C ₃-C ₆The carbocyclic ring condensed ring;

R ₁₇And R ₁₈Be commutable C ₁-C ₆If alkyl is R wherein ₁₈Be methyl, R then ₁₇Not allyl group, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Arylalkyl,

R ₁₉Independently be selected from when occurring: H, C at every turn ₁-C ₆Alkyl, CF ₃, OR ₂₄, Cl, F, Br, I ,=O, CN, NO ₂, NR ₂₂R ₂₃, a 0-3 R ₂₀The aryl that replaces;

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

Contain 1 to 4 heteroatomic 5 to 10 yuan of heterocycle that are selected from nitrogen, oxygen and sulphur, wherein said 5 to 10 yuan of heterocycles are through 0-3 R ₂₁Replace;

R ₂₀Independently be selected from H, OH, Cl, F, Br, I, CN, NO when occurring at every turn ₂, NR ₂₂R ₂₃, ethanoyl, OR ₂₅, XR ₂₅,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-;

R ₂₁Independently be selected from H, OH, Cl, F, Br, I, CN, NO when occurring at every turn ₂, NR ₂₂R ₂₃, CF ₃, ethanoyl, OR ₂₅, XR ₂₅,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-; Or

NR ₂₂R ₂₃It can be the heterocyclic type ring that is selected from group piperidyl, homopiperidinyl, thio-morpholinyl, piperazinyl and morpholinyl;

R ₂₂Independently be selected from H, C when occurring at every turn ₁-C ₆Alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl and arylalkyl;

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₃Independently be selected from when occurring: H, (C at every turn ₁-C ₆) alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl, haloalkyl, arylalkyl,

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₅Be alkyl, aryl or arylalkyl;

R ₂₆Independently be selected from when occurring at every turn:

H, C ₁-C ₆Alkyl, CF ₃

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

X ^-It is negatively charged ion.

As explain, (S)-7,8-is saturated-4,5-epoxy-morphinanium is a salt.Therefore, it will be a negatively charged ion, and for the application, it comprises halogenide, vitriol, phosphoric acid salt, nitrate or is with anionic organism class.Halogenide comprises fluorochemical, muriate, iodide and bromide.In some embodiments, described halogenide is iodide, and in other embodiment, described halogenide is bromide.It is in some embodiments, described that to be with anionic thing class be sulfonate or carboxylate salt.The example of sulfonate comprises mesylate, benzene sulfonate, tosylate and phenylfluoroform sulfonate (triflate).The example of carboxylate salt comprises formate, acetate, Citrate trianion and fumarate.

According to another aspect of the present invention, comprise in some embodiments that the foregoing of (S)-configuration is 7 with regard to nitrogen, 8-is saturated-4, the crystal of 5-epoxy-morphinanium, solution or bromine salt (bromidesalt).In other embodiment, above-mentioned composition is preferred with pharmaceutical preparation significant quantity and that contain pharmaceutically acceptable carrier.

According to an aspect of the present invention, provide certain 7,8-is saturated-4, the crystal of 5-epoxy-morphinanium, it is at least about 99.5%, about 99.6%, or about 99.7%, or about 99.8%, or about 99.9%, or most preferably surpass 99.95% with regard to nitrogen (S)-configuration 7,8-is saturated-4,5-epoxy-morphinanium.

According to another aspect of the present invention, provide (S)-7 of unpack format, 8-is saturated-4,5-epoxy-morphinanium compound.Separate and to refer to at least 50% pure.In embodiments, provide 75% purity, 90% purity, 95% purity, 98% purity and even 99% purity or above (S)-7,8-is saturated-4,5-epoxy-morphinanium.In one embodiment, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium is a crystalline form.

According to another aspect of the present invention, provide composition.Said composition comprises 7, and 8-is saturated-4, and 5-epoxy-morphinanium wherein is present in 7 in the composition, and 8-is saturated-4, and it is (S) configuration with regard to nitrogen that 5-epoxy-morphinanium surpasses 10%.More preferably, be present in 7 in the composition, 8-is saturated-4, and 5-epoxy-morphinanium surpasses 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.6%, 99.7%, 99.8% and even 99.9% be (S) configuration with regard to nitrogen.In some embodiments, as measured by high performance liquid chromatography (HPLC), do not have detectable counterpart (R)-7,8-is saturated-4,5-epoxy-morphinanium compound.

In some embodiments, composition is a solution, is oil in other embodiment, is emulsifiable paste in other embodiment, and is solid or semisolid in other embodiment.In one embodiment, said composition is a crystal.

According to another aspect of the present invention, provide pharmaceutical preparation.This pharmaceutical preparation is included in described above specific (S)-7 in the pharmaceutically acceptable carrier, and 8-is saturated-4, any one in the composition of 5-epoxy-morphinanium.This pharmaceutical preparation comprises significant quantity (S)-7, and 8-is saturated-4,5-epoxy-morphinanium.In some embodiments, have seldom or do not have detectable counterpart (R)-7 in composition, 8-is saturated-4,5-epoxy-morphinanium structure.If have, (R)-7,8-is saturated-4, and 5-epoxy-morphinanium compound is in (S)-7 that make significant quantity, and 8-is saturated-4, and 5-epoxy-morphinanium compound is applied to curee's level.In some embodiments, pharmaceutical preparation further comprises and removes 7, and 8-is saturated-4, the therapeutical agent outside 5-epoxy-morphinanium.In one embodiment, described therapeutical agent is opioid or opioid agonist.The example of opioid or opioid agonist is an alfentanil, anileridine, asimadoline, Bremazocine; buprenorphine (burprenorphine); butorphanol; morphine monomethyl ether; Wy-16225; diacetylmorphine (heroine); saturated morphine monomethyl ether; diphenoxylate; fedotozine; fentanyl; richness is received bent amine (funaltrexamine); hydrocodone; hydromorphone; levallorphan; Levomethadyl Acetate (levomethadyl acetate); levorphanol; Loperamide; dolantin (Pethidine); methadone; morphine; morphine-6-glucuronide; nalbuphine; nalorphine; opium; oxycodone; oxymorphone; pentazocine; propiram; the third oxygen sweet smell; remifentanil; sufentanil; Tilidine; trimebutine; U-26225A or its combination.Therefore in some embodiments, opioid or opioid agonist are not easy to pass hemato encephalic barrier, and when systemic administration, it does not have central nervous system (CNS) activity (being that it is the medicament class that is called as " peripheral action agent ") substantially.

In other embodiment, therapeutical agent is an opium sample antagonist.Opium sample antagonist comprises the peripheral mu opioid antagonist.The example of peripheral mu opioid antagonist comprise first oxymorphone (noroxymorphone) season derivative (referring to people such as Goldberg, United States Patent (USP) the 4th, 176, people WO 2004/043964 such as No. 186 and Cantrell), such as United States Patent (USP) 5,250,542; 5,434,171; 5,159,081; 5,270,328 and 6,469,030 described N-alkyl carboxylic acid piperidines ester, such as United States Patent (USP) 4,730,048; 4,806,556 and 6,469,030 described opium alcaloid-derivatives, such as United States Patent (USP) 3,723,440 and 6,469,030 described season the benzomorphans compound.In one embodiment, peripheral opioid sample antagonist is (S)-7, and 8-is saturated-4,5-epoxy-morphinanium.

In other embodiments, therapeutical agent is not opioid, opioid agonist or opium sample antagonist.For example, therapeutical agent can be antiviral agent, antibiotic agent, anti-mycotic agent, antiseptic-germicide, sanitas (antiseptic agent), antiprotozoan agent, antiparasitic, anti-inflammatory agent, vasoconstrictor, local anesthetic, diarrhea, anti-hyperalgesic agent or its combination.

In one embodiment of the invention; (S)-7; 8-saturated-4; 5-epoxy-morphinanium and diarrhea (anti-diarrhea agent) combination, described diarrhea is Loperamide; the Loperamide analogue; the N-oxide compound of Loperamide and its analogue; metabolite and prodrug; diphenoxylate; cisapride; antacid; aluminium hydroxide; neusilin; magnesiumcarbonate; magnesium hydroxide; lime carbonate; polycarbophil; dimethyl silicone oil; tropine; coromegine; Nifurazolidone; difenoxin; Sostatin; lansoprazole; kaolin; pectin; gac; sulfanilylguanidine; succinylsulfathiazole; phthalylsulfathiazole; Bismuth Aluminate; Bismuth Subcarbonate; bismuth sub citrate; bismuth citrate; Bismuth Potassium Citrate; Bismuth tartrate; bismuth subsalicylate; Vikaline and Bismuth Subgallate; laudanum (pain killer); herbal medicine; plant-sourced diarrhea or its combination.

In one aspect of the invention, (S)-7,8-saturated-4, the combination of 5-epoxy-morphinanium and anti-inflammatory agent, described anti-inflammatory agent are that NSAID (non-steroidal anti-inflammatory drug) (NSAID), tumor necrosis factor inhibitors, basiliximab, daclizumab, infliximab, wheat are examined phenol ethyl ester, azathioprine, tacrolimus, steroid, sulfasalazine, Olsalazine, U.S. salad is bright or its combination.

Pharmaceutical preparation of the present invention can be taken in a variety of forms, include but not limited to that it is the composition of enteric coating, it is the composition of quick releasing formulation, controlled release or sustained release preparation, it is the composition of solution, it is the composition of topical formulations, and it is the composition of suppository, cryodesiccated composition, composition in sucker, composition in the nose spraying plant and similar compositions.That said composition can be used for is Orally administered, parenteral administration, mucous membrane are used, nose is used, topical application, ocular administration, Zoned application or the like.If parenteral, using can be in subcutaneous, intravenously, intracutaneous, intraperitoneal, the sheath or the like.

According to another embodiment of the invention, synthetic (S)-7 are provided, 8-is saturated-4, the method for 5-epoxy-morphinanium analogs salt.This method (for example is included in first solvent chemical combination alkylogen, if desired methyl cyclopropane partly being added to and then being the iodomethyl cyclopropane on the nitrogen) structure is (for example, remove first oxymorphone derivative if desired then for removing the first oxymorphone) to produce (S)-7,8-is saturated-4, the halogen of 5-epoxy-morphinanium (halide salt).Counter ion can be substituted then, and randomly, for example, iodide can be by with (S)-7, and 8-is saturated-4, and the salt compounded of iodine of 5-epoxy-morphinanium is transferred in second solvent and the counter ion that iodide are exchanged for outside the iodide exchanges.For example can be with (S)-7,8-is saturated-4, the salt compounded of iodine of 5-epoxy-morphinanium is transferred to second solvent from first solvent, and in second solvent with bromide exchange iodide producing (S)-7,8-is saturated-4, the bromine salt of 5-epoxy-morphinanium.For example, first solvent can be a dipolar aprotic solvent.For example, first solvent can be N-Methyl pyrrolidone (NMP) or DMF.For example, second solvent can be methylene dichloride, Iso Butyl Acetate, dioxane.

Some embodiment need be passed through chromatography, recrystallization or its combination purifying (S)-7, and 8-is saturated-4, the salt of 5-epoxy-morphinanium.In one embodiment, purifying is by recrystallization repeatedly.

In some embodiments, reaction can be carried out under wide temperature range and atmospheric condition.In other embodiment, the reaction in first solvent may for example carried out between 65 ℃ to 75 ℃ or under about 70 ℃ in the temperature of reaction of control, and the reaction in second solvent may for example be carried out under the room temperature in another temperature.

This method can comprise generally by suitable derivative and suitable uncle's hydroxyl morphan (tertiaryoxymorphan) chemical combination in first solvent is added counter ion and synthesizes (S)-7 to produce (S)-analogue, 8-is saturated-4, and 5-epoxy-morphinanium analogs adds counter ion.Suitable derivative can comprise leavings group, for example halogenide or sulphonate.Halogenide can be, for example iodide.First solvent can be a dipolar aprotic solvent.The example of this solvent is N-Methyl pyrrolidone, dimethyl formamide, methylphosphine acid amides (methylphosphoramide), acetone, 1,4-dioxane and acetonitrile and its combination.Preferred N-Methyl pyrrolidone.First solvent can be a dipolar aprotic solvent alternatively.Example is 2-propyl alcohol, 1-propyl alcohol, ethanol, methyl alcohol.This method can further comprise (S)-7 that form with the exchange of another counter ion, and 8-is saturated-4, the counter ion of 5-epoxy-morphinanium.The example of counter ion is bromide, muriate, fluorochemical, nitrate, sulfonate or carboxylate salt.Sulfonate can be mesylate, benzene sulfonate, tosylate or phenylfluoroform sulfonate.Carboxylate salt can be formate, acetate, Citrate trianion and fumarate.This method can be included in (S)-7, and 8-is saturated-4, and before the counter ion of 5-epoxy-morphinanium and the exchange of another counter ion, with (S)-7,8-is saturated-4, and 5-epoxy-morphinanium counter ion is transferred in second solvent.This method can further comprise purifying (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium adds counter ion, for example by recrystallization, by chromatography or by the two.

According to another aspect of the present invention, be provided at the method that suppresses diarrhoea among the curee, its use by curee to the described treatment of needs effective treatment or prevention diarrhoea amount contain (S)-7,8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.This pharmaceutical preparation can be a type described above.Diarrhoea can be acute or chronic.Diarrhoea can cause alone or in combination by any various environment, such as by infectious agent, food intolerance, food anaphylaxis, malabsorption syndrome, the reaction or the non-specific nosetiology of medicine caused.In some embodiments, diarrhoea is relevant with easily sharp disease (irritable bowel disease) of intestines or inflammatory bowel.In one embodiment, inflammatory bowel is a celiac disease.In another embodiment, inflammatory bowel is the Crohn disease.In another embodiment, inflammatory bowel is a ulcerative colitis.In other embodiment, diarrhoea is caused by stomach or enterectomy, gallbladder removal or organic lesion.In other embodiment, diarrhoea is relevant with carcinoid tumor or vasoactive intestinal polypeptide secreting tumor.In other embodiment, diarrhoea is chronic functional (spontaneous) diarrhoea.

According to the present invention, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can be together with non-(S)-7, and 8-is saturated-4, and the diarrhea of 5-epoxy-morphinanium is used together.Together with being meant in identical time or enough approaching time, thereby two kinds of medicaments are treated illness at one time.In one embodiment, described medicament is opioid or opioid agonist.In another embodiment, described medicament is not opioid or opioid agonist.

According to another aspect of the present invention, provide the ileostomy of minimizing from the curee or the method for the excretion of colostomy.This method comprises that the curee to this minimizing of needs uses and contains (S)-7 of effective minimizing from the amount of the excretion of ileostomy or colostomy, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.

According to another aspect of the present invention, provide the ileostomy of minimizing from the curee or the method for the excretion rate of colostomy.This method comprises that the curee to this minimizing of needs uses and contains (S)-7 of effective minimizing from the amount of the excretion rate of ileostomy or colostomy, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.

The method of the gastrointestinal peristalsis that suppresses the curee is provided according to another aspect of the present invention.This method comprises that the curee to this inhibition of needs uses (S)-7 of the present disclosure of the amount of the gastrointestinal peristalsis that contains effective inhibition curee, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.According to the present invention, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can be together with non-(S)-7, and 8-is saturated-4, and the another kind wriggling inhibitor of 5-epoxy-morphinanium is used together.In one embodiment, described medicament is opioid or opioid agonist.Opioid and opioid agonist are as mentioned above.In another embodiment, described medicament is not opioid or opioid agonist.The example of this class gastrointestinal peristalsis inhibitor is described hereinafter, and they each just look like specific reference in the present invention's general introduction.

The method of treatment irritable bowel syndrome is provided according to another aspect of the present invention.This method comprises that the patient to this treatment of needs uses (S)-7 of the present disclosure of the amount that contains effective at least a symptom of improving irritable bowel syndrome, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.In one embodiment, described symptom is a diarrhoea.In another embodiment, described symptom is alternative constipation and diarrhoea.In another embodiment, described symptom is stomachache, abdominal bloating, unusual stool, unusual ight soil denseness or its combination.

The method of the pain that suppresses the curee is provided according to another aspect of the present invention.Described pain can be acute pain or chronic pain.This method comprises (S)-7 of using the amount that contains effective inhibition of pain to the patient of this treatment of needs, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.This method can further comprise to described curee uses (S)-7, and 8-is saturated-4, the therapeutical agent beyond 5-epoxy-morphinanium.In one embodiment, described (S)-7,8-is saturated-4, and the medicament beyond 5-epoxy-morphinanium is an opioid.In another embodiment, described (S)-7,8-is saturated-4, and the medicament beyond 5-epoxy-morphinanium is non-opium sample pain relief agents.Non-opium sample pain relief agents comprises corticosteroid and NSAID (non-steroidal anti-inflammatory drug).Pain relief agents is described in hereinafter in further detail, just as quoting in this general introduction.If pain is periphery hyperpathia, it may by for example sting, sting, calcination, virus or infectation of bacteria, oral surgery, exodontia, skin and flesh damage, wound, scratch, contusion, surgical incision, sunburn, fash, skin ulcer, mucositis, gingivitis, bronchitis, laryngitis, throat pain, zoster, fungi stimulate (fungal irritation), fever blster, furuncle, sole of the foot wart (plantar ' s warts), vaginal injury, anal lesions, corneal abrasion, radiation corneal ablation postoperative or inflammation are caused.It also can be relevant with postoperative recovery.Operation can be for example to radiate kerectomy, exodontia, lumpectomy, perineotomy, laparoscopy and arthroscopy.In another embodiment, (S)-7,8-is saturated-4, and the medicament beyond 5-epoxy-morphinanium is antiviral agent, antibiotic agent, anti-mycotic agent, antiseptic-germicide, sanitas, antiprotozoan agent, antiparasitic, anti-inflammatory agent, vasoconstrictor, local anesthetic, diarrhea or anti-hyperalgesic agent.

In some embodiments, with the pharmaceutical composition Zoned application in painful area.In some embodiments, it is IA using.In some embodiments, using is general.In some embodiments, it is partial using.In some embodiments, composition is applied to eye.

The method of the inflammation that suppresses the curee is provided according to another aspect of the present invention.This method comprises (S)-7 of using the amount that contains effective inflammation-inhibiting to the patient of this treatment of needs, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.This method also can comprise to described curee uses (S)-7, and 8-is saturated-4, the therapeutical agent beyond 5-epoxy-morphinanium.Described (S)-7,8-is saturated-4, and the therapeutical agent beyond 5-epoxy-morphinanium can be an anti-inflammatory agent.Use and to be, for example be locally applied to inflammation part, general is used or topical application.

In some embodiments, inflammation is that periodontitis, tooth are corrected inflammation (orthodonticinflammation), inflammatory conjunctivitis, hemorrhoid and venereal disease inflammation.In other embodiment, inflammation is a skin inflammatory illness.Example comprises the inflammation relevant with the illness that is selected from the group of being made up of following illness, atopic dermatitis and UV inductive inflammation: irritant contact dermatitis, psoriatic, eczema, pruritus, seborrheic dermatitis, nummular dermatitis, lichen planus, acne vulgaris, acne, leaflet nuclear neutrophil leucocyte (polymorphs), tubercle acne cystica (nodulokystic acne), acne conglobata, senile acne (senile acne), the Secondary cases acne, internal medicine acne (medical acne), keratinization illness and foaming corium (blistery derma).Skin inflammatory illness also can or stimulate relevantly with use cause that the allergic or makeup that stimulate or skin care product cause allergic, maybe can be non-allergic inflammatory dermatopathy.It can also be induced by alltrans (S) vitamin A acid.In other embodiment, inflammation can be a general inflammatory illness.Example comprises the illness that is selected from the group of being made up of following illness: inflammatory bowel, rheumatoid arthritis, emaciation, asthma, Crohn disease, endotoxin shock, adult respiratory distress syndrome, ischemia/reperfusion injury, graft-vs-host reaction, bone resorption, transplanting and lupus.Other embodiment can comprise be selected from by multiple sclerosis, diabetes and with acquired immune deficiency syndrome (AIDS) (AIDS) or cancer the relevant inflammation of illness of the relevant group formed of becoming thin.

According to another aspect of the present invention, provide the inhibition curee to produce the method for tumour necrosis factor.This method comprises that the patient to this treatment of needs uses (S)-7 of containing the amount that effective inhibition tumour necrosis factor produces, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium.Described pharmaceutical preparation can be a type described above.This method also can comprise to described curee uses (S)-7, and 8-is saturated-4, the therapeutical agent beyond 5-epoxy-morphinanium.

According to another embodiment of the invention, provide the method for the gastrointestinal function of regulating the curee.This method comprises that the patient to this treatment of needs uses and contains (S)-7, and 8-is saturated-4, and the pharmaceutical composition of 5-epoxy-morphinanium also is applied to the curee with the peripheral mu opioid antagonist, and wherein both all use with the amount of regulating functions of intestines and stomach.In one embodiment, the peripheral mu opioid antagonist is (R)-7, and 8-is saturated-4,5-epoxy-morphinanium.

According to another embodiment of the invention, provide a kind of method.This method relates to prevention or feed of treatment spirituality or digestive disorder, its composition described above by using effective prevention to the patient or treating the amount of spirituality feed or digestive disorder.

According to another embodiment of the invention, provide test kit.Described test kit comprises a packing that contains the sealed vessel of pharmaceutical composition, and described pharmaceutical composition contains (S)-7, and 8-is saturated-4,5-epoxy-morphinanium.Described test kit further can comprise (S)-7, and 8-is saturated-4, the therapeutical agent beyond 5-epoxy-morphinanium.In one embodiment, (S)-7,8-is saturated-4, and the therapeutical agent beyond 5-epoxy-morphinanium is opioid or opioid agonist.In one aspect, when systemic administration, opioid or opioid agonist do not have CNS activity (being " peripheral action ") substantially.In other embodiment, (S)-7,8-is saturated-4, and the therapeutical agent beyond 5-epoxy-morphinanium is an opium sample antagonist.Opium sample antagonist comprises the peripheral mu opioid antagonist.In one embodiment, peripheral opioid sample antagonist is (R)-7, and 8-is saturated-4,5-epoxy-morphinanium.In other embodiment, (S)-7,8-is saturated-4, and the medicament beyond 5-epoxy-morphinanium is antiviral agent, antibiotic agent, anti-mycotic agent, antiseptic-germicide, sanitas, antiprotozoan agent, antiparasitic, anti-inflammatory agent, vasoconstrictor, local anesthetic, diarrhea or anti-hyperalgesic agent or its combination.

According to one embodiment of the invention, be provided at (R)-7,8-is saturated-4, analyzes (S)-7 in the mixture of 5-epoxy-morphinanium and its stereoisomerism (isostereomeric) counterpart, and 8-is saturated-4, the method for 5-epoxy-morphinanium.This method comprises carries out high performance liquid chromatography (HPLC) and with (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium puts on chromatographic column as standard substance.This method preferably includes and applies (S)-7, and 8-is saturated-4,5-epoxy-morphinanium and its stereoisomerism counterpart (R)-7,8-is saturated-4,5-epoxy-morphinanium as standard substance to determine reservation/elution time relatively.Wherein (therein) discloses (R) and (S)-7, and 8-is saturated-4, the relative retention time of 5-epoxy-morphinanium.In one embodiment, use two kinds of solvents, solvent orange 2 A and solvent B, carry out chromatography, wherein for example solvent orange 2 A is that water solvent and solvent B are methanol solvates, and wherein for example A and B contain trifluoroacetic acid (TFA), and for example A is that 0.1% the TFA aqueous solution and B are 0.1% TFA methanol solutions.In embodiments, post comprises the end capped silicon-dioxide of bonding.In embodiments, the aperture of post gel is 5 microns.In one embodiment, post, flow velocity and gradient program are as follows:

Post: Luna C18 (2), 150 * 4.6mm, 5 μ

Flow velocity: 1mL/ minute

The gradient program:

Time (minute)	?％A	??％B
Time (minute)	?％A	??％B	??0:00	?95	??5
??8:00	?65	??35	??0:00	?95	??5
??8:00	?65	??35	??12:00	?35	??65
??15:00	?0	??100	??12:00	?35	??65
??15:00	?0	??100	??16:00	?95	??5
??18:00	?95	??5	??16:00	?95	??5

Detection can (UV) @230nm wavelength be carried out easily by ultraviolet.

Also can use previous described HPLC, by in the color atlas of determining to be produced separately (R) and (S) area under a curve determine (S)-7,8-is saturated-4,5-epoxy-morphinanium and its counterpart steric isomer (R)-7,8-is saturated-4, the relative quantity of 5-epoxy-morphinanium.

According to another embodiment of the invention, providing to guarantee to produce does not have (R)-7, and 8-is saturated-4, (S)-7 of 5-epoxy-morphinanium (it is an opium sample antagonist), and 8-is saturated-4, the method for 5-epoxy-morphinanium (it is an opioid agonist).This method allows to guarantee (S)-7 of the present disclosure for the first time, 8-saturated-4, the pharmaceutical preparation of 5-epoxy-morphinanium (it is contemplated to agonist activity) is not by antagonism (S)-7,8-saturated-4, the active compound of 5-epoxy-morphinanium (is its (R)-7,8-is saturated-4,5-epoxy-morphinanium steric isomer) pollute.Of the present invention this on the one hand in, preparation (S)-7 is provided, 8-is saturated-4, the method for 5-epoxy-morphinanium.This method comprises: (a) obtain to contain (S)-7 of paying close attention to some extent, 8-saturated-4, first composition of 5-epoxy-morphinanium (b) by chromatography, recrystallization or its combination purifying first composition, (c) is carried out HPLC to the first purified composition sample, use counterpart (R)-7,8-is saturated-4, and 5-epoxy-morphinanium is as standard substance, and (d) determines whether there is counterpart (R)-7 in the sample, 8-is saturated-4,5-epoxy-morphinanium.In some embodiments, (R)-7,8-is saturated-4,5-epoxy-morphinanium and its (S)-7, and 8-saturated-4,5-epoxy-morphinanium steric isomer is used as standard substance to determine, (R)-7 for example, 8-is saturated-4,5-epoxy-morphinanium and (S)-7,8-is saturated-4, the relative retention time of 5-epoxy-morphinanium.In one embodiment, purifying is repeatedly re-crystallization step or chromatographic step repeatedly.In another embodiment, carry out purifying up to as determine there are not (R)-7 in the sample by HPLC, 8-is saturated-4,5-epoxy-morphinanium steric isomer.Yet in should be understood that aspect more of the present invention, " first composition of purifying " must not have detectable (R)-7, and 8-is saturated-4,5-epoxy-morphinanium.Have described (R)-7,8-is saturated-4, and 5-epoxy-morphinanium for example can show pure if desired (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium then should carry out further purification step.This method can comprise further that packing does not have detectable (R)-7 of HPLC, and 8-is saturated-4, first composition of the purifying of 5-epoxy-morphinanium.This method can further be included on first composition of purifying of packing or in mark is provided, show that first composition of the purifying of this packing does not have detectable (R)-7 of HPLC, 8-is saturated-4,5-epoxy-morphinanium.This method can further comprise any one pharmaceutically effective amount in the packing treatment illness described herein.Contain (S)-7,8-is saturated-4, and first composition of 5-epoxy-morphinanium can obtain by method described herein.Pure (R)-7,8-is saturated-4, and 5-epoxy-morphinanium counterpart can obtain as described herein.

According to another embodiment of the invention, provide packaged products.This packing comprises and contains (S)-7,8-saturated-4, the composition of 5-epoxy-morphinanium, wherein said composition does not have detectable (R)-7 of HPLC, 8-is saturated-4,5-epoxy-morphinanium counterpart, and mark on the packing or that be included in wherein shows that said composition does not have detectable (R)-7,8-is saturated-4,5-epoxy-morphinanium steric isomer.Said composition can adopt various ways, includes but not limited to the standard substance that use in laboratory experiment, the standard substance that use in production decision or pharmaceutical composition.If said composition is a pharmaceutical composition, a kind of form of mark is to write exactly on the label of describing the pharmaceutical preparation feature or package insert so.This mark can show directly that said composition does not have (R)-7,8-is saturated-4,5-epoxy-morphinanium steric isomer, or it can be pure or 100% (S)-7 by stating composition for example, 8-is saturated-4,5-epoxy-morphinanium and show identical content indirectly.This pharmaceutical composition can be used for treating any illness described herein.This pharmaceutical composition can contain pure (S)-7 of significant quantity, 8-saturated-4,5-epoxy-morphinanium and can be adopted as (just as what specifically quote) described below any form in this general introduction includes but not limited to solution, solid, semisolid, enteric-coating material and similar type.

These and other aspect of the present invention is described hereinafter in further detail.

The accompanying drawing summary

It is of the present invention 7 that Fig. 1 a provides, and 8-is saturated-4, a potential structure of 5-epoxy-morphinanium embodiment.Fig. 1 b has set forth (R) of the present invention and (S) 7 in further detail, and 8-is saturated-4, the substituent upright/calm relation on the nitrogen of 5-epoxy-morphinanium embodiment.

Fig. 2 sets forth representative reactions scheme of the present invention.

Fig. 3 provides (S)-17-allyl group-17-cyclopropyl methyl-4,5 α-epoxy-3, the proton N MR spectrum of saturated (the saturatedxy)-6-of 14-oxo morphinanium iodide.

Fig. 4 provides (R)-17-allyl group-17 cyclopropyl methyl-4,5 α-epoxy-3, the NMR spectrum of saturated (the saturatedxy)-6-of 14-oxo morphinanium iodide.

Detailed Description Of The Invention

The invention provides (S)-7,8-saturated-4,5-epoxy-morphinanium compound, stereoselectivity is synthesized (S)-7,8-saturated-4, the synthetic route of 5-epoxy-morphinanium compound, substantially pure (S)-7,8-saturated-4,5-epoxy-morphinanium compound, substantially pure (S)-7,8-saturated-4, the crystal of 5-epoxy-morphinanium compound, analyze (S)-7,8-is saturated-4, the method for 5-epoxy-morphinanium compound, contain substantially pure (S)-7,8-is saturated-4, the pharmaceutical preparation of 5-epoxy-morphinanium compound and their using method.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium has following structure:

Wherein X is counter ion, and selects R₁₇And R₁₈Meet Cahn with generation, Ingold, (S) configuration with regard to nitrogen of Prelog configuration specified rule, and R₁₈And R₁₇C₁-C ₈Alkyl or C₁-C ₆Alkyl. R₃It can be hydroxyl protecting group. Counter ion can be any counter ion, comprises amphion. Preferably, counter ion is pharmaceutically acceptable. Counter ion comprises halide, sulfate, phosphate, nitrate and with the organic matter class of anion. Halide can be iodide, bromide, chloride, fluoride or its combination. In one embodiment, halide is iodide. In one embodiment, halide is bromide. Organic matter class with anion can be sulfonate or carboxylate.

It is of the present invention 7 that Fig. 1 provides, and 8-is saturated-4, a potential structure of 5-epoxy-morphinanium embodiment.

No matter term " acyl group " for example uses in " acyl amino " separately or at term, and the atomic group that is provided by the residue after organic acid is removed hydroxyl is provided. Term " acyl amino " comprises the amine atomic group that carboxyl groups replaces. An example of " acyl amino " atomic group is acetamide (CH₃C (=O)--NH--). Term " aryloxy group " means by the aryl moiety (for example, phenol) that replaces from hydroxyl and removes the atomic group that hydrogen base residue afterwards provides.

As used herein, " alkanoyl " refer to-C (=O)-alkyl group, wherein alkyl such as existing definition. Exemplary alkanoyl group comprises acetyl group (acetyl) (acetyl group (ethanoyl)), n-propiono, n-bytyry, 2-methylpropionyl, n-valeryl, 2-methylbutyryl base, 3-methylbutyryl base, 2,2-dimethyl propylene acyl group, heptanoyl group, capryl and palmityl.

Term " thiazolinyl " comprises the similar unsaturated aliphatic group of length and the possibility substituent of alkyl mentioned above, but comprises at least one two key and must comprise at least two carbon atoms. For example, term " thiazolinyl " comprises straight-chain alkenyl group (such as vinyl, acrylic, cyclobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base, decene base etc.), the branched-chain alkenyl group, cycloalkenyl group (alicyclic ring) group (cyclopropanyl, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base), the alkenyl group that the cycloalkenyl groups that alkyl or alkenyl replaces and cycloalkyl or cycloalkenyl group replace. Term " low-grade alkylidene " this paper refers to have from about 1 those alkylidene groups to about 6 carbon atoms. Term " thiazolinyl " comprises " unsubstituted thiazolinyl " and " thiazolinyl of replacement ", and wherein the latter refers to have substituent alkenyl part, and described substituting group has replaced the hydrogen on one or more carbon of hydrocarbon skeleton. These substituting groups can comprise; for example, alkyl group; alkynyl group; halogen; hydroxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl carbonyl oxygen base; aryloxy group carbonyl oxygen base; carboxylate; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl group; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; the alkylthio group carbonyl; alkoxyl; phosphate; phosphono (phosphonato); inferior phosphono (phosphinato); cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); amidino groups; imino group; sulfydryl; alkylthio group; arylthio; carbothioic acid ester; sulfuric ester; the alkyl sulfinyl; sulfonyl (sulfonato); sulfamoyl; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; part alkylaryl or aromatics or heteroaromatic.

" alkenylene (alkenylene) " generally refers to comprise at least one carbon--the alkylidene group of the two keys of carbon. Exemplary alkenylene group comprises, for example, ethenylidene (CH=CH-) and allylidene (CH=CHCH₂-). Preferred alkenylene group has 2 to about 4 carbon.

Term " alkoxyl " and " alkoxyalkyl " comprise the moieties that has separately one to about ten carbon atom straight or branched contain oxygen atomic group, for example methoxyl group atomic group. Term " alkoxyalkyl " also comprises the alkyl atomic group with two or more alkoxyl groups, and described alkoxyl group is connected in the alkyl atomic group, that is to say, forms monoalkoxy alkyl and dialkoxy alkyl atomic group. Described " alkoxyl " or " alkoxyalkyl " atomic group can further for example fluorine, chlorine or bromine replace formation " halogenated alkoxy " or " halogenated alkoxy alkyl " atomic group by one or more halogen atoms. The example of " alkoxyl " atomic group comprises methoxyl group, butoxy and trifluoromethoxy.

All combination and subgroups are closed in " alkyl " generally refer to have 1 aliphatic hydrocarbon groups to about 10 carbon atoms in chain (it can be straight chain, side chain or ring-type) and its scope, for example cycloalkyl, side chain cycloalkyl-alkyl, have the branched alkyl cycloalkyl of 4-10 carbon atom. Term " alkyl " comprises " unsubstituted alkyl " and " alkyl of replacement ", and the latter wherein refers to have substituent moieties, and described substituting group has replaced the hydrogen on one or more carbon of skeleton. " low alkyl group " refers to have 1 alkyl group to about 6 carbon atoms. Alkyl group includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, cyclopenta, isopentyl, neopentyl, n-hexyl, isohesyl, cyclohexyl, ring octyl group, adamantyl, 3-methyl amyl, 2-dimethylbutyl and 2,3-dimethylbutyl, cyclopropyl methyl and cyclobutylmethyl. Alkyl substituent can comprise; for example, thiazolinyl; alkynyl; halogen; hydroxyl; alkyl carbonyl oxy; aryl-carbonyl oxygen; alkoxyl carbonyl oxygen base; aryloxy group carbonyl oxygen base; carboxylate; alkyl-carbonyl; aryl carbonyl; alkoxy carbonyl; amino carbonyl; alkyl amino-carbonyl; dialkyl amino carbonyl; alkyl thiocarbonyl; alkoxyl; phosphate; phosphono; inferior phosphono; cyano group; amino (comprises alkyl amino; dialkyl amido; arylamino; ammonia diaryl base and alkyl aryl amino); acyl amino (comprises alkyl-carbonyl-amino; aryl-amino-carbonyl; carbamoyl and urea groups); amidino groups; imino group; sulfydryl; alkylthio group; arylthio; carbothioic acid ester; sulfuric ester; the alkyl sulfinyl; sulfonyl; sulfonamides; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; part alkylaryl or aromatics or heteroaromatic. Term " aralkyl " comprises alkyl atomic group that aryl replaces for example benzyl, benzhydryl, trityl, phenethyl, phenylpropyl and two phenethyls. Term benzyl and benzyl are interchangeable. Term " alkyl " means the unsubstituted alkyl group of straight chain (namely unbranched). " side chain " refers to a kind of alkyl group, and wherein for example methyl, ethyl or propyl group are connected on the linear alkyl chain low-grade alkyl group.

" alkylating agent " is the compound that can with (generally covalently) alkyl group be connected to the parent material reaction parent material. Alkylating agent is usually included in the leaving group that separates from alkyl group when being connected to parent material. Leaving group can be, for example, and halogen, halogenosulfonic acid ester, halogenated acetic acids ester. An example of alkylating agent is the cyclopropyl methyl iodide.

Term " alkyl silicyl " means the silicyl atomic group that alkyl group replaces. Term " alkyl silyloxy " mean the silyloxy atomic group that alkyl group replaces (--O--Si--). An example of " alkyl silyloxy " atomic group is--O--Si-t-BuMe₂。

Term " alkyl sulfinyl " comprises the atomic group of the alkyl atomic group that contains straight or branched, and described alkyl atomic group contains one to ten carbon atom, is connected in divalence--S (=O)--atom. Term " aryl sulfinyl " comprises and is connected in divalence--S (=O)--and the aryl atomic group of atom (for example--S=OAr).

Term " alkylthio group " comprises the atomic group of the alkyl atomic group that contains straight or branched, and described alkyl atomic group contains one to ten carbon atom, is connected in bivalent sulfur atom. Term " artyl sulfo (arylsulfenyl) " comprise the aryl atomic group that is connected in bivalent sulfur atom (--SAr). An example of " alkylthio group " is methyl mercapto (CH₃--(S)--)。

Term " alkynyl " comprises the similar undersaturated aliphatic group of the length of abovementioned alkyl and possible substituent, but it comprises at least one triple bond and two carbon atoms. For example, term " alkynyl " comprises straight-chain alkynyl group (such as acetenyl, propinyl, butynyl, pentynyl, hexin base, heptyne base, octyne base, n-heptylacetylene base, decynyl etc.), the alkynyl group that side chain alkynyl group and cycloalkyl or cycloalkenyl group replace.

Term " acylamino-", in that for example " amido alkyl ", " N-monoalkyl acylamino-", " N-single aryl acylamino-", " N; N-dialkyl group acylamino-", " N-alkyl-N-aryl acylamino-", " N-alkyl-N-alcohol amide base " and " N-alkyl-N-alcohol amide base alkyl " comprise the carbonyl atomic group of amino atomic group replacement when using together alone or with other terms. Term " N-alkyl amido " and " N, N-dialkyl group acylamino-" mean respectively by an alkyl atomic group and two acylamino-groups that the alkyl atomic group replaces. Term " the single aryl acylamino-of N-" and " N-alkyl-N-aryl acylamino-" mean respectively by an aryl atomic group and an alkyl and the acylamino-atomic group that the aryl atomic group replaces. Term " N-alkyl-N-alcohol amide base " comprises the acylamino-atomic group that hydroxyl atomic group replaces and the alkyl atomic group replaces. Term " N-alkyl-N-alcohol amide base alkyl " comprises the alkyl atomic group that N-alkyl-N-alcohol amide base atomic group replaces. Term " amidoalkyl " comprises the alkyl atomic group that the acylamino-atomic group replaces.

Term " aminoalkyl " comprises the alkyl atomic group that the amine atomic group replaces. Term " alkyl amino alkyl " comprises the aminoalkyl atomic group of the nitrogen-atoms with the replacement of alkyl atomic group. Term " amidino groups " means--C (=NH)--NH₂Atomic group. Term " cyano group amidino groups " means--C (=N--CN)--NH₂Atomic group.

Term " aryl " separately or in combination, means and contains one, the carbocyclic ring type aromatic systems of two or three rings, and wherein these rings can hanging type link together and maybe can condense. Term " aryl " comprises aromatics atomic group for example phenyl, naphthyl, tetralyl, indane and biphenyl.

" alkyl of aryl-replacement " generally refers to by the optional aromatic yl group that replaces (the preferred optional phenyl ring that replaces) at the straight chained alkyl group that a carbon replaces, preferred low-grade alkyl group. The alkyl group of exemplary aryl-replacement comprises, for example, and benzyl, phenethyl and 3-(4-aminomethyl phenyl) propyl group.

Term " carbocyclic ring " means any stable 3-to 7-unit's monocycle or two rings, and perhaps 7-to 13-unit two rings or three encircle, and wherein any one can be saturated, and part is undersaturated or aromatics. The example of these carbocyclic rings comprises, but be not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, adamantyl, ring octyl group, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] two cyclodecane (naphthalane), [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl or tetralyl (1,2,3,4-tetrahydronaphthalene). Preferably " carbocyclic ring " is cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.

Term " cycloalkyl " comprises the atomic group with three to ten carbon atoms, for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.

" alkyl of cycloalkyl-replacement " generally refers to by group of naphthene base (preferred C₃-C ₈Group of naphthene base) the straight chained alkyl group that replaces on the carbon endways, preferred low-grade alkyl group. The alkyl group of typical cycloalkyl-replacement comprises cyclohexyl methyl, cyclohexyl ethyl, cyclopenta ethyl, cyclopenta propyl group, cyclopropyl methyl and analog.

" cycloalkenyl group " generally refers to have about 4 to the unsaturated group of naphthene base of the olefinic of about 10 carbon and interior all of its scope make up and subgroup is closed. In certain embodiments, cycloalkenyl groups is C₅-C ₈Cycloalkenyl groups namely has from about 5 cycloalkenyl groups to about 8 carbon.

" dipolar aprotic " solvent is protophilic solvent, and it can not provide labile hydrogen atom and show permanent dipole moment. Example comprises acetone, ethyl acetate, dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF) and 1-METHYLPYRROLIDONE.

" dipole proton " solvent is those solvents that labile hydrogen atom can be provided and show permanent dipole moment. Example comprises water, alcohol (for example 2-propyl alcohol, ethanol, methyl alcohol), carboxylic acid (for example formic acid, acetic acid and propionic acid).

Phrase " does not pass " substantially, as used herein, mean the compound that is used for the inventive method that is less than about 20% weight and pass blood-brain barrier, preferably be less than about 15% weight, pass blood-brain barrier more preferably less than about 10% weight even more preferably less than about 5% weight and the compound that most preferably is 0% weight.

Term " halogen " means halogen for example fluorine, chlorine, bromine or iodine atom. The atomic group that any one or a plurality of carbon atom that term " haloalkyl " comprises alkyl wherein replaced by defined halogen above. Especially comprise single haloalkyl, two haloalkyl and multi-haloalkyl atomic group. Single haloalkyl atomic group for instance, can have bromine, chlorine or a fluorine atom in atomic group. Two halo atomic groups can have two or more same halogen atoms or the combination of different halogen atom group, and the multi-haloalkyl atomic group can have the combination more than two same halogen atoms or different halogen atom group.

As used herein, term " heterocycle " or " heterocyclic type ring " mean stable 5-to 7-unit's monocycle or two rings, or 7-to 14-unit bicyclic heterocycles type ring, its be saturated, part is undersaturated or undersaturated (aromatics) and its are made up of carbon atom and 1,2,3 or 4 hetero atom that independently is selected from the group that is made up of N, O and S, and comprises any any bicyclic groups that condenses in phenyl ring with the heterocyclic type ring of above-mentioned definition. The example of saturated heterocyclic atomic group comprises pyrrolidinyl and morpholinyl.

Term " hydroxyalkyl " comprises any one the alkyl atomic group through the straight or branched of one or more hydroxyl atomic groups replacements that has in one to about ten carbon atom and the described carbon atom.

Term " hydrogen base " means single hydrogen atom (H). This hydrogen base atomic group can quilt, for example, be connected in oxygen atom and form hydroxyl atomic group, perhaps two hydrogen base atomic groups can be connected to carbon atom and form methylene (--CH₂--) atomic group.

Term " N-alkyl amino " and " N, N-dialkyl amido " mean respectively by an alkyl atomic group and two amine groups that the alkyl atomic group replaces.

As used herein, " N-oxide " refers to the compound of the oxidized oxygen atom that adheres to quaternary nitrogen that the positive formal charge of load is provided and the negative formal charge of load of the basic nitrogen atom of heteroaromatic rings wherein or tertiary amine.

" organic solvent " has its common its ordinary meaning to one skilled in the art. Be used for exemplary organic solvent of the present invention and include but not limited to oxolane, acetone, hexane, ether, chloroform, acetic acid, acetonitrile, chloroform, cyclohexane, methyl alcohol and toluene. Comprise anhydrous organic solvent.

As used herein, " patient " refers to comprise mammal by animal, and be preferred human.

As used herein, " periphery " or " peripheral action " refers to the medicament that worked in the central nervous system outside. As used herein, " central action " refers to the medicament that works in central nervous system (CNS). Term " periphery " shows that compound mainly works to physiological system and the part of central nervous system outside. Phrase " essentially no CNS activity ", as used herein, mean less than pharmacological activity about 20%, that be used for the compound of the inventive method and find expression in CNS, preferably less than about 15%, more preferably less than about 10%, even more preferably find expression in CNS less than pharmacological activity about 5% and most preferably 0%, that be used for the compound of the inventive method.

As used herein, " prodrug " refers to making the specially designed compound of amount maximization of the active species that arrives the anticipation reaction position, itself is common non-activity or bottom line activity concerning required activity, but can change bioactive metabolites into by bio-transformation.

As used herein, " pharmaceutically acceptable " refers to conclude in the scope in rational medical science, be suitable for contacting with human and animal's tissue, no excessive toxicity, stimulation, allergy or other problems complication also have those compounds, material, composition and/or the formulation of rational benefit/risk ratio. As used herein, " pharmaceutically acceptable salt " refers to the derivative of disclosed compound, wherein modifies parent compound by making its acidity or basic salt. The example of pharmaceutically acceptable salt includes but not limited to for example inorganic or acylate of amine of alkaline residue; Acidic residues is alkalescence or the organic salt of carboxylic acid for example; And analog. Pharmaceutically acceptable salt for example comprises nontoxic salts or the quaternary ammonium salt of the routine of the parent compound that forms from nontoxic inorganic or organic acid. For example, these conventional nontoxic salts comprise and are derived from for example those salt of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and analog of inorganic acid; And from organic acid for example acetic acid, propionic acid, butanedioic acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pounce on the salt of acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-globentyl, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid and analog preparation. These physiologically acceptable salt are by methods known in the art, for example by free amine base and excessive acid are dissolved in aqueous alcohol, or with alkali metal base for example in hydroxide or the amine and the free carboxy acid prepare. Some acidity among the present invention or alkali compounds can exist by amphion. The form of ownership of compound comprises free acid, free alkali and amphion, all comprises within the scope of the invention. This area is well-known, the compound that contains amino and carboxylic group usually with their zwitterionic form balance existence. Therefore, any compound that for example contains amino and carboxylic group of describing everywhere in this paper also comprises their mentioned corresponding amphions.

As used herein, term " side effect " refers to the result outside medicament or the measure application target, produce for medicine, especially to using benefited tissue or the detrimental effect of the tissue the organ or tract except wanting by it.

" stereoisomer " refers to have same chemical composition but atom or the different compound of group space arrangement as used herein.

Term " sulfonamides " or " sulfoamido "; separately or with term for example " N-alkyl sulfonamides ", " N-aryl sulfonamide ", " N; N-dialkyl amino sulphonyl " and " N-alkyl-N-aryl sulfonamide " when using together; mean the sulfonyl atomic group that the amine atomic group replaces, the formation sulfonamide (--SO₂NH ₂). Term " N-alkyl sulfonamides " and " N, N-dialkyl amino sulphonyl " mean respectively by an alkyl atomic group, cycloalkyl ring, or two sulfonamides atomic groups that the alkyl atomic group replaces. Term " N-aryl sulfonamide " and " N-alkyl-N-aryl sulfonamide " mean respectively by an aryl atomic group, and an alkyl and the sulfonamides atomic group that the aryl atomic group replaces.

Term " sulfonyl ", separately or with other terms for example during the related use of alkyl sulphonyl, mean respectively bivalent group--SO₂--. " alkyl sulphonyl " comprises the alkyl atomic group that is connected in the sulfonyl atomic group, and wherein alkyl is above defined. Term " aryl sulfonyl " comprises the sulfonyl atomic group that the aryl atomic group replaces.

" tertiary amine " has its common its ordinary meaning. Usually, be used for tertiary amine of the present invention and have general formula:

R wherein₁、R ₂And R₃Alkyl group, alkenyl group, alkylidene group, alkenylene group, the group of naphthene base of identical or different straight or branched, alkyl group, cycloalkenyl groups, alkoxy base, alkoxyl-alkyl group, carboxyl groups, aromatic yl group, the alkyl group of aryl-replacement and the combination of heterocyclic group of cycloalkyl-replacement. R wherein according to the useful exemplary tertiary of the present invention_1-3Formula (C_nH _2n+1, alkyl group n=1-4) or formula (C₆H ₅(CH ₂) _n-, [n=1-2]) those tertiary amines of aromatic alkyl group. Also have cycloalkyl tertiary amine (for example N-methylmorpholine, N-crassitude, N-methyl piperidine), pyridine and Proton according to the useful exemplary tertiary of the present invention

(N, N, N ', N '-tetramethyl-1,8-naphthalene).

(S)-7,8-is saturated-4, and 5-epoxy-morphinanium shows (R)-7 corresponding with it, 8-is saturated-4, the character that 5-epoxy-morphinanium is different, and with specific 7,8-is saturated-4, (S) of 5-epoxy-morphinanium and the different character of (R) mixture. These character can comprise flowability, biology and functional activity and the crystal structure on the chromatographic column. It is believed that clearance rate in the body, side effect overview and similarity also can with single (R)-7,8-saturated-4,5-epoxy-morphinanium or (R)-7,8-saturated-4,5-epoxy-morphinanium and (S)-7,8-is saturated-4, the mixture difference of 5-epoxy-morphinanium. Gastrointestinal smoother is out-of-date for example suppressing, pure (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium can show as the activator of peripheral opioid sample acceptor. The result, (S)-7,8-saturated-4,5-epoxy-morphinanium activity can be contained (R)-7, and 8-is saturated-4,5-epoxy-morphinanium and (S)-7,8-saturated-4, (R)-7 in the mixture of 5-epoxy-morphinanium, 8-is saturated-4, and 5-epoxy-morphinanium is active to be disturbed or antagonism. Therefore, very need to obtain (S)-7 of the separative and substantially pure form of tool, 8-is saturated-4,5-epoxy-morphinanium.

In one aspect of the invention, provide synthetic (S)-7,8-is saturated-4, the method for 5-epoxy-morphinanium. According to chromatographic technique, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can prepare with the purity more than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99% and 99.5% TG-AUC (AUC). In one embodiment, (S)-7,8-is saturated-4, and the purity of 5-epoxy-morphinanium is 98% or higher. In pure (S)-7,8-saturated-4, corresponding (R)-7 in 5-epoxy-morphinanium, 8-is saturated-4, and the amount of 5-epoxy-morphinanium can be less than or equal about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 3%, 2%, 1%, 0.5%, 0.3%, 0.2%, 0.1% (AUC) or be undetectable by chromatographic technique described herein. Those of skill in the art it should be understood that the detection of method will depend on detectability and the quantitative limit of used technology. No matter quantitative limit is the variation of laboratory, analyst, instrument or reagent lot, (R)-7 that can as one man measure all the time and report, 8-is saturated-4, the minimum flow of 5-epoxy-morphinanium. Detectability can detect in sample but not need quantitatively to be exact value (R)-7, and 8-is saturated-4, the minimum flow of 5-epoxy-morphinanium. In one embodiment of the invention, detectability is 0.1% and quantitative limit is 0.2%. In another embodiment, detectability is 0.02% and quantitative limit is 0.05%.

Of the present invention many 7,8-is saturated-4, and the synthetic of 5-epoxy-morphinanium can be by uncle's morphinan direct alkylation of Oxymorphone for example. The phenol OH group of Oxymorphone is unprotected or protection. (S)-7,8-is saturated-4, and 5-epoxy-morphinanium salt can comprise then its available preferred counter ion (for example bromide) exchange of counter ion (for example iodide). Many (S)-7 herein, 8-is saturated-4, and useful parent material was disclosed as Oxymorphone during 5-epoxy-morphinanium was synthetic, and it can be by for example coming the productive rate with about 95% to obtain with Boron tribromide demethylation Oxycodone. Alternatively, Oxymorphone can obtain by commercial source.

Alkylated reaction can carry out in solvent or solvent system, and described solvent or solvent system can be anhydrous. But the solvent system single solvent maybe can comprise the combination of two or more solvents. Suitable solvent system can comprise dipolar aprotic solvent, such as 1-METHYLPYRROLIDONE (NMP), dimethyl formamide (DMF), hexamethyl phosphoramide (HMPA), acetone, 1,4-dioxane and acetonitrile, and dipolar aprotic solvent are such as the 2-propyl alcohol. Solvent system also can comprise the combination of dipolar aprotic solvent and aliphatic ether, described aliphatic ether such as oxolane (THF), 1,2-dimethoxy-ethane (glyme (glyme)), diethylene glycol dimethyl ether (diethylene glycol dimethyl ether (diglyme)), 1,4-dioxane, methyl tertiary butyl ether(MTBE) (methyl 1,1-dimethyl ethyl ether or 2-methyl-2-methoxy propane) Anaesthetie Ether, also can comprise other polar solvents in some embodiments. For example, solvent system can comprise acetone, methyl ethyl ketone, metacetone (propione) and tert-butyl group MIBK (3,3-dimethyl butyrate-2-ketone). The alkylation solvent system also can comprise above aliphatic series or the alicyclic congener of disclosed any compound. Solvent system can any ratio comprise two or more solvents, and the proper ratio of specific alkylated reaction can be determined by normal experiment.

Solvent can be less than, more than or equal about 1,2,3,4,5,10 or the ratio of more volume use. In some cases, for example when using liquid/liquid extraction that product is shifted from solvent, or when crystallized product, maybe when removing solvent from product, it may be preferred that the amount of solvent for use is minimized.

Can various mol ratios (for example whenever measuring the beginning material less than 8,12,16,20,24 or greater than 24 equivalents) alkylating agent be added parent material. In some cases, reaction efficiency (7,8-saturated-4, the generation of 5-epoxy-morphinanium) can be substantially irrelevant with the amount of used alkylating agent.

In one group of embodiment, can use the Finkelstein reaction to carry out alkylation. For example, alkyl halide (such as the cyclopropyl methyl chloride) can with halogen (such as sodium iodide) chemical combination so that active halogen substituted alkyl agent (such as the cyclopropyl methyl iodide) to be provided constantly, it replenishes when consuming.

Parent material can under the atmospheric pressure in open-top receptacle or the decompression under alkylation. Can with method/instrument as known in the art in the reaction time with temperature maintenance or be controlled at set point of temperature and react. A device keeping controlled temperature in whole alkylated reaction is heater/condenser unit. The control temperature suppresses or has reduced the fluctuation of temperature during whole alkylated reaction. Described reaction may need to continue a plurality of hours, for example to about 22 hours, or 15 to 22 hours, or 16 to 20 hours. In some cases, can Reaction time shorten by the use of microwave.

In some embodiments, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can separate from the solvent that it results from. For example, can be from containing (S)-7,8-is saturated-4, removes solvent in the residue of 5-epoxy-morphinanium, perhaps can be with any (S)-7,8-is saturated-4, and 5-epoxy-morphinanium is transferred to the transfer solvent from the alkylation solvent. Shifting solvent can be polarity or nonpolar, and can have and be lower than 100 ℃ boiling point. Shift solvent and can comprise ester, aldehyde, ether, alcohol, aliphatic hydrocarbon, aromatic hydrocarbon and halogenated hydrocarbons. Concrete transfer solvent comprises, for example dioxane, ethyl acetate, isopropyl acetate, methyl alcohol, ethanol, carrene, acetonitrile, water, the HBr aqueous solution, heptane and MTBE.

Any residue processing that obtains also can be separated (S) product with purifying from solvent. Can use method known to those skilled in the art, such as carrying out purification and separation by use as the isolation technics of the combination of chromatography, recrystallization or various isolation technics known in the art. In one embodiment, can use the flash chromatography that has utilized the C18 post. For example, use the CombiFlash from ISCO of anti-phase (C18) RediSep post^TMSq 16x can be used. For example, can analyze HPLC at Phenomenex Prodigy 5um OD53 100A post, and carry out purifying partly preparing Phenomenex Prodigy 5um OD53 100A post. Can use methanol content from for example about 2.5% to about 50% different solvents that changes, such as the methanol-water solvent of regulating with 0.2%HBr. But use recrystallization purifying (S)-7,8-is saturated-4,5-epoxy-morphinanium. Can repeat this process, until obtain the product of required purity. In one embodiment, (S)-7,8-is saturated-4,5-epoxy-morphinanium recrystallization at least 2 times, 3 times or 4 times or more times is to obtain purity of desired level. For example, can obtain to surpass or equal according to the purity of chromatographic technique (S)-7 of 50%, 80%, 85%, 90%, 95%, 97%, 98%, 98.5%, 99.8% (AUC), 8-is saturated-4,5-epoxy-morphinanium. Any impurity can comprise parent material, no detectable (R)-7, and 8-is saturated-4,5-epoxy-morphinanium. Can use the combination of single solvent or solvent to finish recrystallization. In one embodiment, by with (S)-7,8-is saturated-4, and 5-epoxy-morphinanium is dissolved in polar solvent, adds then a small amount of polar co-solvent and finishes recrystallization. In another recrystallization embodiment, by from solvent (for example methyl alcohol) and cosolvent (such as CH₂Cl ₂/ IPA (6: 1)) recrystallization comes purifying (S)-7 in, and 8-is saturated-4,5-epoxy-morphinanium. Repeated recrystallization is to reach required purity.

(S)-7,8-is saturated-4, the form production that 5-epoxy-morphinanium and its derivative can salt. Comprise derivative, such as (S)-7,8-is saturated-4, the amphion of 5-epoxy-morphinanium. (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can comprise the quaternary ammonium group of positively charged, and can be paired such as monovalence or multivalent anions with anion. These anion can comprise, for example halide, sulfate, phosphate, nitrate and charged organic matter class are such as sulfonate and carboxylate. Preferred anion comprises halide, such as bromide, chloride, iodide, fluoride and its combination. In some embodiments, bromide is most preferred. Concrete anion can be according to following selecting factors: for example reactivity, dissolubility, stability, activity, price, availability and toxicity.

(S)-7,8-is saturated-4, and the anion of 5-epoxy-morphinanium salt may be exchanged for optional anion. When the optional anion of needs, can be with (S)-7,8-saturated-4, the aqueous solution of 5-epoxy-morphinanium salt passes anion-exchange resin column with (S)-7,8-is saturated-4, and some or all of the counter ion of 5-epoxy-morphinanium salt are exchanged for preferred optional counter ion. The example of anion exchange resin comprises the AG 1-X8 of 100 to the 200 sieve aperture grades (mesh grade) that can obtain from Bio-Rad. In another embodiment, can be with (S)-7,8-saturated-4,5-epoxy-morphinanium cation is retained on the cationic ion-exchange resin, then can be by using the salting liquid that contains preferred anion (such as bromide or chloride) with (S)-7, and 8-saturated-4,5-epoxy-morphinanium removes to exchange from resin, form required (S)-7 in solution, 8-is saturated-4,5-epoxy-morphinanium salt.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium has multiple application. One aspect of the present invention is (S)-7,8-saturated-4, its homologue (R)-7 is identified and distinguished to 5-epoxy-morphinanium as other components from sample in chromatographic isolation, 8-is saturated-4, the chromatogram standard items of 5-epoxy-morphinanium. Another aspect of the present invention is to use (S)-7,8-saturated-4,5-epoxy-morphinanium is as containing (S)-7,8-saturated-4,5-epoxy-morphinanium and (R)-7,8-is saturated-4, identifies and distinguish (S)-7 in the mixture of 5-epoxy-morphinanium homologue, 8-is saturated-4, the chromatogram standard items of 5-epoxy-morphinanium. (S)-7 of separating, 8-is saturated-4, and 5-epoxy-morphinanium also is used for exploitation from (R)-7 of reactant mixture, 8-saturated-4,5-epoxy-morphinanium purifying is also distinguished (S)-7, and 8-is saturated-4, the scheme of 5-epoxy-morphinanium.

(S)-7,8-is saturated-4, and 5-epoxy-morphinanium can contain its kit form as the operation instructions of standard items to be provided. This kit can further comprise as reliable (authentic) of standard items (R)-7, and 8-is saturated-4,5-epoxy-morphinanium. As (S)-7 that standard items use, 8-is saturated-4, and 5-epoxy-morphinanium preferably has 99.8% or higher purity and do not have detectable stereomeric (R)-7, and 8-is saturated-4,5-epoxy-morphinanium.

One embodiment of the invention are saturated-4 at 7,8-, split and identify (S)-7 in the solution of 5-epoxy-morphinanium, 8-saturated-4,5-epoxy-morphinanium and homologue (R)-7,8-is saturated-4, the method for 5-epoxy-morphinanium. (S)-7,8-saturated-4,5-epoxy-morphinanium also is used for determining (S)-7 at composition or mixture, 8-saturated-4, the HPLC assay method of the amount of 5-epoxy-morphinanium, wherein the method comprises that the sample with composition or mixture puts on chromatographic column, split the component of composition or mixture, and by the percentage of the component that splits in the comparative sample and (S)-7,8-saturated-4, the percentage of the standard items concentration of 5-epoxy-morphinanium is (S)-7 in the calculation sample recently, and 8-is saturated-4, the amount of 5-epoxy-morphinanium. The method is particularly useful in reversed-phase HPLC chromatography. (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium is by its agonist activity to opioid receptor, and the agonist activity standard items in measuring as the opioid receptor in all as described herein external and bodies.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium can be used for preventative or exciting peripheral opioid sample acceptor, particularly peripheral mu opioid acceptor are regulated by the receptor-mediated illness of one or more peripheral opioid samples in therapeutic ground. Use (S)-7,8-is saturated-4, but curee's short-term of 5-epoxy-morphinanium, receives treatment chronically or as required.

Can use (S)-7,8-is saturated-4, and the curee of 5-epoxy-morphinanium is vertebrate, particularly mammal. In one embodiment, mammal is people, non-human primates, dog, cat, sheep, goat, horse, ox, pig and rodent. In one embodiment, mammal is the people.

μ and other opioid receptors are present in the intestines and stomach. In the main Types of intestines and stomach opioid receptor, the μ acceptor mainly participates in the adjusting of GI activity. Kappa opioid receptor also can work (the people Ann.Rev.Phamacol.Toxicol such as Manara L, 1985,25:249-73). In general, with (S)-7,8-is saturated-4, and 5-epoxy-morphinanium is used for prevention or the treatment illness relevant with the demand of activation or adjusting opioid receptor (particularly peripheral opioid sample acceptor). What pay close attention to is, (S)-7,8-is saturated-4, the purposes of the illness that 5-epoxy-morphinanium prevention or treatment are relevant with the demand of opioid receptor (particularly mu opioid acceptor) in activation or the adjusting intestines and stomach. This class illness that can prevent or treat comprises diarrhoea, and is used for preventing or suppressing the gastrointestinal dysfunction of some form, comprises inflammatory bowel syndrome and feed and the digestive disorder of some form.

In one embodiment, (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium can be used for treatment diarrhoea. Gastrointestinal function is regulated by one or more opioid receptors and endogenous opioid at least in part. Known opium sample antagonist increases gastrointestinal peristalsis, and therefore can effectively be used as the treatment of constipation. On the other hand, understand opioid agonist, particularly such as the peripheral opioid sample activator of Loperamide, reduced gastrointestinal peristalsis, and can be used for treating mammiferous diarrhoea. Activator of the present invention (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can be used to the patient of needs treatment diarrhoea as opioid agonist. Diarrhoea used herein is defined as following one or more situations: the 1) ight soil of low denseness; 2) surpass 3 defecations every day; And/or 3) feces volume 〉=200g of every day (150ml). Use (S)-7 of the amount of effective prolongation intestinal contents by the time, 8-is saturated-4, and 5-epoxy-morphinanium causes the ight soil amount to reduce the minimizing of the increase of ight soil viscosity and bulk density and fluid and electrolyte loss.

Because its opioid agonist activity, (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium is used for prevention and treatment has the diarrhoea that different pathogeny is learned, comprise acute and diarrhoea chronic form, comprise chronic functional (spontaneous) diarrhoea.

As used herein, acute diarrhea or short-term diarrhoea is the diarrhoea of duration (normally 1 to 3 day) of continuing to be less than 1 week. As used herein, chronic diarrhea, carrying out property or long-term diarrhea are to continue 1 week or the diarrhoea of long duration more. The sustainable several months of chronic diarrhea or or even the several years, and can be continuous or intermittently. Can (S)-7 of the present invention from using, 8-is saturated-4, those that the various forms of the diarrhoea that benefits in the treatment of 5-epoxy-morphinanium and reason include but not limited to hereinafter to describe.

The viral gastroenteritis or " the stomach and intestine flu (stomach flu) " that are caused by any virus are suitable for using (S)-7 of the present invention, 8-saturated-4, the treatment of 5-epoxy-morphinanium, described virus include but not limited to rotavirus, Norwalk virus, cytomegalovirus, herpes simplex virus, hepatitis viruse and adenovirus.

By edible or drink the food poisoning and the traveler's diarrhea that are caused by the food that pollutes such as bacterium and parasitic organism and water and be suitable for using (S)-7 of the present invention, 8-is saturated-4, the treatment of 5-epoxy-morphinanium. Usually the bacterium that causes diarrhoea comprises Escherichia coli (Escherichia coli), salmonella (Salmonella), Shigella (Shigella), clostridium (Clostridia), campylobacter (Campylobacter), Yersinia (Yersinia) and Listeria (Listeria). The parasite that causes diarrhoea comprises giardia lamblia (Giardia lamblia), Entamoeba histolytica (Entamaeba histolytica) and Cryptosporidium (Cryptosporidium). The fungi that can cause diarrhoea comprises Candida (Candida).

Some medical condition (medical conditions) also can cause diarrhoea, comprise malabsorption syndrome, such as lactose intolerance, chylous diarrhea (sprue or glutelin malabsorption), cystic fibrosis, the protein in milk or other the concrete food (for example beans or fruit) is not tolerated. Possible cause gastrointestinal irritation and/or the allergic another kind of situation of suffering from diarrhoea of causing to concrete food hypersenstivity. Typical food allergens comprises peanut, corn and shell class animal (shellfish). Be suitable for using (S)-7 of the present invention by these medical conditions diarrhoea that cause or associated, 8-is saturated-4, the treatment of 5-epoxy-morphinanium.

Cause suffering from diarrhoea, particularly other medical conditions of chronic diarrhea comprise inflammatory bowel disease (it comprises Crohn disease and ulcerative colitis), IBS (IBS) and immune deficiency also can be from (S)-7 of the present invention of prevention or treatment diarrhoea, 8-is saturated-4, is benefited in 5-epoxy-morphinanium.

(S)-7 of the present invention, 8-saturated-4,5-epoxy-morphinanium also can be used for preventing and treating the diarrhoea that is caused by medicine and/or treatment, described medicine and/or treatment such as antibiotic, the cathartic that contains magnesium, the chemotherapeutics that is used for treatment of cancer and high dose radiation treatment.

Diarrhoea also with following disease association: Zollinge (R)-Ellison syndrome, nervous disorders, carcinoid syndrome, vasoactive intestinal polypeptide secreting tumor and GI anatomy illness such as AN or diabetic neuropathy, comprise short bowel syndrome, gastrectomy, have or do not have intestines excision and the gall-bladder of ileostomy or colostomy to extract. These illness are suitable for using (S)-7 of the present invention, and 8-is saturated-4, the treatment of 5-epoxy-morphinanium.

(S)-7 of the present invention, 8-saturated-4,5-epoxy-morphinanium can use to prevent and treat diarrhoea by oral or parenteral any approach, and described approach comprises in the peritonaeum, intravenous, vagina, rectum, intramuscular, subcutaneous, aerosol, nasal spray, stride mucous membrane, transdermal, part, colon and similar approach.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium also can use in the method for the excretion of the ileostomy that reduces the curee or colostomy. With do not have (S)-7,8-is saturated-4, the excretion contrast of the neostomy of 5-epoxy-morphinanium can provide (S)-7 of amount of the excretion of effective minimizing neostomy, 8-is saturated-4,5-epoxy-morphinanium. (S)-7,8-is saturated-4, and 5-epoxy-morphinanium also can be used for controlling the excretion rate of neostomy, is used in particular for reducing the curee's who needs low excretion rate excretion rate.

The method of the gastrointestinal peristalsis that suppresses the curee is provided according to another aspect of the present invention. The method comprises the present invention (S)-7 who uses the amount of the gastrointestinal peristalsis that contains the establishment curee to the curee of this inhibition of needs, and 8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium. According to the present invention, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can be together with non-(S)-7, and 8-is saturated-4, and the another kind wriggling inhibitor of 5-epoxy-morphinanium is used together. In one embodiment, described medicament is opioid or opioid agonist. Opioid or opioid agonist are as mentioned above. In another embodiment, described medicament is not opioid or opioid agonist. The example of the non-opium sample of this class gastrointestinal peristalsis inhibitor comprises, for example Cisapride; antacids; aluminium hydroxide; aluminium-magnesium silicate; magnesium carbonate; magnesium hydroxide; calcium carbonate; polycarbophil; dimethicone; hyoscyamine; atropine; furazolidone; Difenoxin; Octreotide; Lansoprazole; kaolin; pectin; active carbon; sulphoamidine; succinylsulfathiazole; phthalylsulfathiazol; the bismuth-containing goods are (such as bismuth aluminate; basic bismuth carbonate; bismuth sub citrate; bismuth citrate; CBS; tartro-bismuthate; basic bismuth salicylate; basic bismuth nitrate and bismuth subgallate); laudanum (anodyne); herbal medicine and plant source antidiarrheal agent. In addition, this class medicament comprises the Benzodiazepine compound, antispasmodic, selective serotonin reuptake inhibithors (SSRI), cholecystokinin (CCK) receptor antagonist, NK (NK) receptor antagonist, cortico-trophin-releasing factor (CRF) (CRF) receptor stimulating agent, antacids, the GI relaxant, anti-gas (anti-gas) compound, pentosane polysulfate ester, antiemetic dopamine D 2 antagonist, Gonadorelin analogues (Leuprorelin), corticotropin-1 antagonist, neurokinin 2 receptor antagonists, cholecystokinin-1 antagonist, beta-Blocking agent, anti-esophageal reflux agent, antiinflammatory, 5HT₁Activator, 5HT₃Antagonist, 5HT₄Antagonist, bile salt chelating agent, volume medicament (bulk-forming agent), α₂-2-adrenergic agonist components, antidepressant are such as tricyclic antidepressants. Extra this medicament comprises muscarine antagonist, ganglionic block agents, hormone and hormone analogs and the motilin receptor antagonist. Muscarine antagonist comprises belladonna alkaloids, quaternary ammonium antimuscarinic compounds and tertiary amine antimuscarinic compounds. The example of belladonna alkaloids comprises belladonna leaf extract, belladonna tincture and belladonna extract. The example of quaternary ammonium muscarine antagonist comprises Anisotropine or octatropine methylbromide (Valpin), Clidinium (Clidinium) or clidinium bromide (Quarzan), GLYCOPYRRONIUM (Robinul), first sulphur Traline (Tral), homatropinum, ipratropium or Ipratropium Bromide, Isopropamide or Isopropamide Iodide (Darbid), Mepenzolate (Mepenzolate) or mepenzolate bromide (Cantil), methantheline or Methantheline Bromide (Banthine), epoxytropine tropate or Scopolamine Methobromide (Pamine), fragrant ammonium difficult to understand and propanthaline or propantheline bromide. The example of tertiary amine muscarine antagonist comprises atropine, bentyl or bentrl hydrothloride (Bentyl and other), flavoxate hydrochloride (Urispas), oxybutynin or ditropan XL (Ditropan), Oxyphencyclimine or oxyphencyclimine hydrochloride (Daricon), Propiverine, hyoscine, Tolterodine and bent ground ammonium or tridihexethyl chloride (Pathilon). Other muscarine antagonist comprises pirenzepine, Telenzepine, AF-DX116, Methoctramine (Methoctranine), himbacine and six hydrogen silicon difenidols (Hexahydrosiladifenidol). Ganglionic block agents comprises synthetic amine, such as hexamethylamine, mecamylamine, etamon and acetylcholine. That the hormone of anti-gastrointestinal peristalsis agent or the example of hormone analogs comprise: somatostatin and the somatostatin receptor activator. The example of somatostatin analogs comprises that Octreotide (for example

) and Vapreotide. The motilin antagonist comprises the motilin of (Phe3, Leu-13) pig, the 214th American Chemical Society (ACS) Meeting (American Chemical Society's meeting) (V part); Highlights from Medicinal Chemistry Poster Session (important news of pharmaceutical chemistry placard paper), September 10, Wednesday, Las Vegas, Nevada, (1997), Iddb Meeting Report (Iddb meeting report) 7-11 in September (1997); With the people such as ANQ-1 1 125, Peeters T.L., Biochern.Biophys.Res.Commun., the 198th volume (2), 411-416 page or leaf (1994).

In another embodiment, (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium can be used for treatment feed and digestive disorder. Be suitable for and use according to (S)-7 of the present invention, 8-saturated-4, feed imbalance and the digestive disorder of 5-epoxy-morphinanium treatment include but not limited to: regulate the unbalance appetite of pathology, loss of appetite or appetite reduce, and these are for example induced by following: gestation, cancer, infectious diseases is (such as influenza, HCV or HIV), the result of catabolism (catabolism), cachexia, apocleisis (particularly anorexia nervosa), dysorexia, body weight unusual (dysponderosis), fat, bulimia nerovsa, obesity, gastroparesis (neurogenicity gastroparesis particularly, diabetic gastroparesis, myogenicity gastroparesis or drug-induced gastroparesis), gastroatonia, gastroparalysis or enteroparesis and gastrointestinal stenosis (particularly pyloric stenosis).

Pain is in many ways definition. For example, pain may be defined as the curee to the perception of destructive stimulus, and it can make the curee produce withdrawing reaction (withdrawal reaction). Analgesia is the minimizing of pain perception. The selective exclusion animal is called as anesthetic to the response of intense stimulus and the medicament that do not suppress general behavior or motion function. Opiate and opioid agonist affect pain via the interaction with specific opioid receptor. (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium has agonist activity, can be used for treating pain.

The pain of controlling or treating can with various disease conditions, illness or disease in any relevant. As used herein, unless specifically note in addition, " pain " is intended to comprise the pain of any duration and frequency, includes but not limited to Acute Pain, chronic ache, intermittent pain and similar pain. The reason of pain can appraisablely maybe can not be identified. If can identify, the pain source can be, for example, and pernicious, non-pernicious, infection, non-infection or autoimmunity source. An embodiment is the control pain relevant with the disease that needs short, illness or illness, dental procedure (dental procedures), fracture, out-patient's operative treatment for example, for them, therapy comprises the treatment of a few hours to maximum 3 days cycles. Special concern be the control pain relevant with the illness that needs long-term treatment, disease or illness, for example chronic and/or continuation disease or illness, for them, therapy comprises a couple of days (for example about 3 days to 10 days) to several weeks (for example about 2 week or 4 thoughtful 6 weeks) to several months or several years, at the most to and comprise the treatment in cycle of curee's residue life. But the curee who does not suffer from present disease or illness easily suffer from them also can benefit from the preventative pain control (for example before trauma operation) of using the compositions and methods of the invention. Be fit to can comprise according to the pain for the treatment of of the present invention the outbreak of the prolongation that pain and painless interval replace, or the substantially continual pain of seriousness variation.

In general, pain can be nociception, physicogenic, neurogenous or psychogenic. Body originality pain can be (being Arteriosclerosis obliterans) of muscle or bone (being osteoarthritis, waist sacrum backache, post-traumatic, musculofascial), internal organ (being that pancreatitis, ulcer, intestines easily swash), ischemic or relevant with cancer (for example pernicious or nonmalignant) progress. Neurogenic pain may be owing to after the wound and postoperative neuralgia, can be relevant with neuropathy (being diabetes, toxicity etc.), and may with neurothlipsis, opalgia, perineal nerves pain, amputation after, thalamic pain, cusalgia be relevant with reflex sympathetic dystrophy.

The illness that is fit to the control according to the present invention, disease, the instantiation in illness and pain source comprises but must not be limited to cancer pain (for example transfer or not metastatic cancer), inflammatory disease pain, neuropathic pain, postoperative pain, iatrogenic pain (the pain after invasion property program or the high dose radiotherapy for example, for example relating to the weak sexual act of generation freely damages and the obviously scar tissue formation of pain), complex regional pain syndrome, back surgery failure pain (failed-back pain) (for example acute or chronic back pain), the soft tissue pain, joint and ostalgia, central pain, damage (for example weakness damage, paraplegia for example, quadriplegia etc., and non-weakness damage is (for example in the back of the body, neck, vertebra, the joint, leg, arm, hand, foot etc.)), arthritis pain (rheumatoid arthritis for example, osteoarthritis, arthritis symptom of unknown etiology etc.), genetic disease (for example sickle cell anemia), the syndrome of infectious diseases and generation (Lyme disease for example, AIDS etc.), headache (for example antimigraine), cusalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, denervate and similar pain. Pain can be relevant with any part of health, for example musculoskeletal system, internal organs, skin, nervous system etc.

Method of the present invention can be used for controlling to be used first opioid or no longer is the pain of using first opioid patient. It is exemplary that to use first opioid patient be the patient who does not also accept to be used for the long-term opioid treatment of pain control. Exemplaryly non-ly use first opioid patient to accept short-term or the treatment of long-term opioid and produced the patient of tolerance, dependence or other undesirable side effects. For example, have in oral, intravenous or the sheath and use morphine, the patient of the scabrous harmful side effect of Transdermal fentanyl paster or conventional subcutaneous administration fentanyl, morphine or the transfusion of other opioids, can be by administration (S)-7,8-is saturated-4,5-epoxy-morphinanium and its derivative and obtain good analgesia and keep favourable side effect feature.

As used herein, disappearing, suppress or alleviating of pain described usually in term " pain control or treatment ", thereby make the curee more comfortable, determines by subjective criterion, objective standard or both. In general, pain is by patient's report and healthy professional patient age, culture background, environment and known change patient subjectively to be estimated the consideration of other Psychology Background factors of the subjective response of pain.

As mentioned above, (S)-7,8-is saturated-4,5-epoxy-morphinanium can with non-(S)-7,8-is saturated-4, the therapeutic agent of 5-epoxy-morphinanium is used together, described therapeutic agent includes but not limited to it is the therapeutic agent of pain relief agents. In one embodiment, pain relief agents is opioid or opioid agonist. In another embodiment, pain relief agents is non-opium sample pain relief agents, such as corticosteroid or NSAIDs (NSAID) or paracetamol. Pain relief agents comprises: Fentanyl; Potassium p-aminobenzoate; Sodium aminobenzoate; Anidoxime; Anileridine; Anileridine hydrochloride; Anilopam hydrochloride; Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine hydrochloride; Bicifadine Hydrochloride; Brifentanil hydrochloride; The maleic acid bromadoline; Bromfenac sodium; Buprenorphin hydrochloride; Butacetin; Butixirate; Butorphanol; Butorphanol tartrate; Carbamazepine; Carbasalate calcium; Carbifene hydrochloride; The citric acid Carfentanil; Ciprefadol succinate; Ciramadol; Ciradol (Wyeth); Clonixeril; Clonixin; Codeine; Codeine phosphate; Codeine sulfate; Hydrochloric acid Conorphone; Cyclazocine; Dexoxadrol hydrochloride; Dexpemedolac; Dezocine; Diflunisal; The saturated codeine of acid tartaric acid (Saturatedcodeine Bitartrate); The dimefadane; Analgin; The hydrochloric acid doxpicomine; Drinidene (Drinidene); Enadoline hydrochloride; Epirizole; Gynergen; Ethoxazene hydrochloride; Etofenamate; Eugenol; Fenoprofen; Fenoprofen calcium; The citric acid fentanyl; Floctafenine; Flufenisal; Flunixin; Flunixin meglumine; Flupirtine maleate; Fluproquazone; The hydrochloric acid Fluradoline; Flurbiprofen; Dihydromorphinone hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol; Ketorolac tromethamine; Letimde hydrochloride; Levacetylmethadol; Levomethadyl acetate hydrochloride; The hydrochloric acid levonantradol; Levorphanol tartrate; Lofemizole hydrochloride; Lofentanil oxalate; Lorcinadol; Lornoxicam; Magnesium salicylate; Mefenamic acid; The hydrochloric acid menabitan; The hydrochloric acid Sauteralgyl; Meptazinol hydrochloride; Methadone hydrochloride; Acetylmethadol; Methopholine; Levomepromazine; Metkefamide Acetate; The hydrochloric acid mimbane; Mirfentanil hydrochloride; Molinazone; Morphine sulfate; Moxazocine; The hydrochloric acid nabitar; Nalbuphlne hydrochloride; Nalmexone hydrochloride; Namoxyrate; The hydrochloric acid nantradol; Naproxen; Naproxen sodium; Naproxol; Nefopam hydrochloride; Nexeridine hydrochloride; NIH-7667; Ocfentanil hydrochloride; Octazamide; Olvanil; Oxetorone fumarate; Oxycodone; Oxycodone hydrochloride; The terephthalic acids Oxycodone; Oxymorphone hydrochloride; Pemedolac; Pentamorphone; Pentazocine; Pentazocine hydrochloride; Pentazocine lactate; Phenazopyridine hydrochloride; Phenyramidol hydrochloride; The hydrochloric acid picenadol; Pinadoline; Pirfenidone; Piroxicam olamine; Pravadoline maleate; The hydrochloric acid prodilidine; Profadol hydrochloride; Propiram fumarate; Regretol; Propoxyphene napsylate; Proxazole; The citric acid proxazole; The tartaric acid proxorphan; Pyrrolidine hydrochloride is sharp fragrant; Remifentanil hydrochloride; Salcolex; Salethamide maleate (Salethamide Maleate); Salicylamide; Salicylate meglumine; Salsalate; Sodium salicylate; The methanesulfonic acid Spiradoline; Sufentanil; Sufentanil citrate; Talmetacin; Talniflumate; Talosalate; The butanedioic acid Tazadolene; Tebufelone; Tetrydamine (Tetrydamine); Tifurac sodium; Tilidine hydrochloride; Tiopinac; The methanesulfonic acid Tonazocine; Tramadol hydrochloride; Trefentanil hydrochloride; Triethanolamine; The hydrochloric acid veradoline; The hydrochloric acid verilopam; Volazocine; The methanesulfonic acid Xorphanol; Xylazine hydrochloride; Zenagocine Mesylate; Zomepirac sodium; Zucapsaicin and its combination.

Hyperalgia is the sensitiveness to pain that increases, or the intensity of the pain sensation that strengthens. When the curee to stimulating allergy can produce hyperalgia, cause the response of the undue pain of given stimulation. Hyperalgia is the result of local inflammation state normally, and can follow systemic wound or damage. Inflammation can be accompanied by following situation, or associated: local infection, blister, furuncle, skin injury such as cut wound, scratch, burn, sunburn, scratch, operative incision, the inflammatory dermatopathy such as the toxicodendron dermatitis, allergic rash, insect bite are hindered and are stung and hinder and arthritis. (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium can be used for prevention and the hyperalgia for the treatment of periphery, and is used for reducing pain and/or the symptom that is produced by inflammation. As used herein, hyperalgia comprises pruritus (pruritis) or itch (itching), and (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium can be used as the antipruritic treatment.

The composition of this paper is intended to for the prevention hyperalgia relevant with damage with treatment and multiple inflammatory illness with method. Composition provided herein can be used for treating multiple and following relevant hyperalgia illness with method: burn (includes but not limited to thermal burn, radiation burn, chemical burn, sunburn and windburn (wind burns)), scratch (comprising for example corneal abrasion), bruise, dampen, frostbite, rash (comprising for example irritated hot in nature and contact dermatitis (such as the toxicodendron dermatitis) and diaper rash), acne, wound is hindered/is stung in insect bite, skin ulcer (including but not limited to diabetic ulcer and bedsore), catarrh, inflammation (periodontitis for example, tooth is corrected inflammation, apply some make up or inflammation that skin care item cause/stimulation by making, the inflammatory conjunctivitis, hemorrhoid and venereal disease inflammation), gingivitis, bronchitis, laryngitis, sore-throat, herpes zoster (singles), fungi stimulates (for example ringworm of the foot and jock itch), fever blster, furuncle, sole of the foot wart or vaginal injury (comprising for example mycotic and the vaginal injury that spreads through sex intercourse).

The hyperalgia illness relevant with skin surface comprises that burn (including but not limited to thermal burn, radiation burn, chemical burn, sunburn and windburn), scratch (for example corneal abrasion), bruise, contusion, frostbite, rash (comprising for example anaphylaxis, thermo-contact dermatitis (such as the toxicodendron dermatitis) and diaper rash), acne, insect bite hinder/sting and hinder and skin ulcer (comprising diabetic ulcer and bedsore). Mouthful, larynx and bronchial hyperalgia illness comprise catarrh, exodontia after, periodontitis, gingivitis, tooth correct inflammation, bronchitis, laryngitis and sore-throat. The hyperalgia illness of eye comprises corneal abrasion, radiation corneal ablation postoperative and inflammatory conjunctivitis. The hyperalgia illness of rectum/anus comprises hemorrhoid and venereal disease inflammation. The hyperalgia illness relevant with the infection sources comprises that herpes zoster, fungi stimulate (comprising the ringworm of the foot and jock itch), fever blster, furuncle, sole of the foot wart and vaginal injury (comprising the damage relevant with sexually transmitted disease with mycotic). The hyperalgia illness also may be relevant with postoperative recovery, such as the recovery after lumpectomy, perineotomy, celioscopy, arthroscopy, radiation angle membranectomy and the exodontia.

As the hyperalgesic prevention of periphery or treatment, can use provides any approach that compound is delivered to ill district to use (S)-7, and 8-is saturated-4,5-epoxy-morphinanium. It can be oral or parenteral using. The method of using also comprises local application and Zoned application. (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium can be applicable to any body surface, comprises skin, joint, eye, lip and mucous membrane.

Stereoisomer (S)-7,8-saturated-4,5-epoxy-morphinanium can be sent with other compound combinations, other compounds include but not limited to anodyne (pain medication), antipruritic (itching medication), antiinflammatory and similar medicine such as those compounds that anti-hyperalgia effect is provided disclosed herein. It can use described compound such as antiviral agent, antimicrobial, antifungal and anti-infectious agent with other compounds that are used for the treatment of the illness that is caused by inflammation. These other compounds can the part or general work and use, and can be the part of same combination, maybe can use respectively. This compounds is described hereinafter in further detail.

Inflammation is usually relevant with the increase that TNF (TNF) produces, and thinks that the minimizing of TNF generation will cause the minimizing of inflammation. The opioid agonist of peripheral action has shown as the generation (United States Patent (USP) the 6th, 190, No. 691) that reduces TNF. The selective k-opioid of periphery, asimadoline has shown as effective Antiarthritic agent (Binder, W. and Walker, J.S.Br.J.Pharma 124:647-654) in the arthritis animal model that adjuvant is induced. Therefore (S)-7,8-is saturated-4, and the peripheral opioid sample agonist activity of 5-epoxy morphinanium and its derivative provides prevention and treatment inflammatory illness. Not bound by theory, (S)-7,8-is saturated-4, and the anti-inflammatory effect of 5-epoxy-morphinanium and its derivative may be the generation by direct or indirect inhibition TNF. (S)-7,8-is saturated-4, but 5-epoxy-morphinanium or derivatives thereof general ground or use partly. (S)-7,8-is saturated-4,5-epoxy-morphinanium can with another kind of tnf inhibitor (such as Loperamide and diphenoxylate) or with other antiinflammatory combined administrations described herein.

Another aspect of the present invention is to use (S)-7 of the present invention, 8-saturated-4,5-epoxy-morphinanium or derivatives thereof prevents and/or treats general inflammatory illness, preferred inflammatory bowel disease, rheumatoid arthritis, cachexia, asthma, Crohn disease, endotoxic shock, adult respiratory distress syndrome (ARDS), ischemia/reperfusion injury, anti-(S) host response of graft, bone absorption, transplanting or lupus.

In another group embodiment, be fit to use (S)-7 of the present invention, 8-is saturated-4, the inflammatory illness of 5-epoxy-morphinanium or derivatives thereof treatment and multiple sclerosis, diabetes or with acquired immunodeficiency syndrome (AIDS) or cancer relevant become thin relevant.

In one group of embodiment, be fit to use (S)-7 of the present invention, 8-saturated-4, what 5-epoxy-morphinanium or derivatives thereof was treated is skin inflammatory illness, inflammation, the contact dermatitis that preferred psoriasis, atopic dermatitis, UV induce or the inflammation of being induced by other drug, described medicine includes but not limited to RETIN-A (alltrans (S)-retinoic acid).

Another aspect of the present invention is the method for the treatment of nonallergic inflammatory dermatopathy, comprises (S)-7 of the present invention of the amount of using effective treatment inflammatory illness, and 8-is saturated-4,5-epoxy-morphinanium. Nonallergic inflammatory dermatopathy is with following relevant: irritant contact dermatitis, psoriasis, eczema, pruritus, seborrhea, nummular dermatitis, lichen planus, acne vulgaris, acne,, leaflet nuclear neutrophil leucocyte, tubercle cystic acne, acne conglobata, senile acne, Secondary cases acne, internal medicine acne, keratinization illness and foaming skin disease.

Some patient that may be particularly suitable for treating is the patient with symptom of any one illness described above. These patients use other treatment may can not obtain the alleviation of their symptom or stop to obtain the alleviation of their symptom, or their the alleviation degree of symptom is all the time consistent. These patients are called as conventional therapy are tolerated. This illness may be induced or its result by one or more different situations, described one or more different situations include but not limited to disease condition, health, drug-induced illness, physiology imbalance, stress, anxiety and similar state. These situations can be acute situation or chronic condition.

Available (S)-7,8-is saturated-4,5-epoxy-morphinanium and (S)-7,8-is saturated-4, and the curee is treated in the combination of the therapeutic agent beyond 5-epoxy-morphinanium. In these cases, (S)-7,8-is saturated-4, and 5-epoxy-morphinanium and other therapeutic agent were used with the enough approaching time, so that the curee experiences the effect of desired various medicaments usually simultaneously. In some embodiments, (S)-7,8-is saturated-4,5-epoxy-morphinanium in time with first by administration, be in time in some embodiments second, and be simultaneously in some embodiments. As hereinafter discussing in further detail, pharmaceutical preparation has been contained in the present invention, (S)-7 wherein, and 8-is saturated-4, and 5-epoxy-morphinanium is that the preparation that comprises another kind of medicament is used. Comprise solid, semisolid, liquid, controlled release and other such preparations.

Can with (S)-7,8-is saturated-4, the important therapeutic agent of a class that 5-epoxy-morphinanium becomes the part of prevention and therapeutic scheme together is opioid. Use (S)-7 of the present invention, 8-is saturated-4,5-epoxy-morphinanium and opioid combination can produce enhancing that gastrointestinal smoother is crossed and obviously collaborative inhibition. Therefore, the invention provides and contain (S)-7,8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium and one or more opioid combinations. This is with the change of acceptable dose. For example, if in the illness of some periphery for the treatment of mediation, need opioid than low dosage, then can by with (S)-7,8-is saturated-4, the incompatible realization of the treatment group of 5-epoxy-morphinanium.

Opioid can be any pharmaceutically acceptable opioid. Common opioid is the opioid that is selected from by the following group that forms: alfentanil, anileridine, asimadoline, bremazocine; buprenorphine; butorphanol; codeine; dezocine; diacetylmorphine (heroin); saturated codeine; diphenoxylate; Fedotozine; fentanyl; the bent amine of rich horse; hydrocodone; Hydromorphone; levallorphan; levacetylmethadol; levorphanol; Loperamide; Sauteralgyl (pethidine); methadone; morphine; M6G; Nalbuphine; nalorphine; opium; Oxycodone; Oxymorphone; pentazocine; propiram; the third oxygen sweet smell; Remifentanil; sufentanil; Tilidine; Trimebutine and C16H25NO2.

According to the intended effect that will reach, but opioid parenteral administration or other general approach use to affect central nervous system (CNS) and peripheral opioid sample acceptor. Opioid and (S)-7 of the present invention, 8-saturated-4, the intended effect of the combination of 5-epoxy-morphinanium can be prevention or treatment diarrhoea, and prevention or treatment comprise prevention or the hyperalgia for the treatment of periphery from the pain of any reason or the cause of disease. When indication is prevention or the hyperalgia for the treatment of periphery, the opioid of the CNS effect of not following need to be provided, or alternatively part or Zoned application opioid, so that opioid does not pass blood-brain barrier substantially, but provide the effect to the periphery opioid receptor.

With (S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium makes up to be used in particular for prevention or treatment diarrhoea or prevention or the hyperalgesic opioid for the treatment of periphery and includes but not limited to:

(i) Loperamide [hydrochloric acid 4-(rubigan)-4-hydroxy-n-N-dimethyl-α, α-diphenyl-1-piperidines butyramide]], Loperamide analog and related compound as defined herein are [referring to United States Patent (USP) the 3rd, 884, No. 916 and the 3rd, 714, No. 159; In addition referring to United States Patent (USP) the 4th, 194,045,4,116,963,4,072,686,4,069,223,4,066, No. 654], the N oxide of Loperamide and analog, metabolin and prodrug, and related compound as defined herein is [in addition referring to United States Patent (USP) the 4th, 824, No. 853], and relevant compound such as following (a), (b) and (c):

(a) as defined herein 4-(aroylamino) pyridine-butanamide derivatives and its N oxide [in addition referring to United States Patent (USP) the 4th, 990, No. 521];

(b) 5-(1,1-diphenyl-3-(5-or 6-hydroxyl-2-azabicyclic-(2.2.2) suffering-2-yl) propyl group)-2-alkyl-1,3,4-oxadiazole, 5-(1,1-diphenyl-4-(ring is amino) fourth-2-trans (S)-alkene-1-yl)-2-alkyl-1,3,4-oxadiazole, 2-[5-(ring is amino)-ethyl-10,11-is saturated-5H-dibenzo [a, d]-ring heptan-5-yl]-5-alkyl-1,3, the 4-oxadiazole] and related compound [referring to United States Patent (USP) the 4th, 013,668,3,996,214 and 4,012, No. 393]

(c) 2-replacement-1-azabicyclic [2,2,2] octane [referring to United States Patent (USP) the 4th, 125, No. 531];

(ii) 3-hydroxyl-7-oxo morphinan and 3-hydroxyl-different morphinan of 7-oxo [referring to No. the 4th, 277,605, United States Patent (USP) for example]

The amidinourea that (iii) provides such as this paper [in addition referring to United States Patent (USP) the 4th, 326,075,4,326,074,4203,920,4,060,635,4,115,564,4,025, No. 652] and 2-[(aminophenyl and amido phenyl) amino]-1-azacycloparaffin [referring to United States Patent (USP) the 4th, 533, No. 739];

(iv) metkefamide [H-L-Ty (R)-D-Ala-Bly-L-Phe-N (Me) Met-NH₂ Referring to No. the 4th, 430,327, United States Patent (USP) for example; The people such as Burkhart (1982) Peptides 3-869-871; The people such as Frederickson (1991) Science 211:603-605] and do not pass other synthetic opioid peptides of blood-brain barrier, such as H-Ty (R)-D-Nva-Phe-Orn-NH₂、H-Ty(R)-D-N1e-Phe-Orn-NH ₂、 H-Ty(R)-D-Arg-Phe-A ₂bu-NH ₂、H-Ty(R)-D-Arg-Phe-Ly(S)-NH ₂And H-Ly (S)-Ty (R)-D-Arg-Phe-Ly (S)-NH₂[referring to United States Patent (USP) the 5th, 312, No. 899; In addition referring to the people such as Gesellchen (1981) Pept.:Synth., Struct., Funct., Proc.Am.Pept.Symp., the 7th phase; The people such as Rich, (editor), Pierce Chem.Co., Rochford, Ill., 621-62 page or leaf]

(v) as at United States Patent (USP) the 5th, 236, defined propylamine and analog in No. 947.

(S)-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium also can be used for the treatment of diarrhoea with other antidiarrheal compounds and combination of compositions. For example, (S)-7,8-is saturated-4,5-epoxy-morphinanium can with known antidiarrheal agent combined administration in the curee. Two or more compounds can be used with the form of mixture, or use respectively administered compound of identical or different route of administration. Known antidiarrheal agent comprises, Loperamide for example, the Loperamide analog, N oxide and the analog thereof of Loperamide, metabolin and prodrug, diphenoxylate, Cisapride, antacids, aluminium hydroxide, aluminium-magnesium silicate, magnesium carbonate, magnesium hydroxide, calcium carbonate, polycarbophil, dimethicone, hyoscyamine, atropine, furazolidone, Difenoxin, Octreotide, Lansoprazole, kaolin, pectin, active carbon, sulphoamidine, succinylsulfathiazole, phthalylsulfathiazol, bismuth aluminate, basic bismuth carbonate, bismuth sub citrate, bismuth citrate, CBS, tartro-bismuthate, basic bismuth salicylate, basic bismuth nitrate and bismuth subgallate, laudanum (anodyne), herbal medicine and plant source antidiarrheal agent.

Can with (S)-7 of the present invention, 8-is saturated-4, and the other treatment agent that 5-epoxy-morphinanium becomes the part of therapeutic scheme together is irritable bowel syndrome (IBS) agent, antibiotic, antivirotic, antifungal agent, anti-infective, comprises antihistaminic antiinflammatory, vasoconstrictor, antidiarrheal agent and similar medicine.

Can with (S)-7,8-is saturated-4, and the IBS therapeutic agent that 5-epoxy-morphinanium is used in combination includes but not limited to the Benzodiazepine compounds, antispasmodic, selective serotonin reuptake inhibithors (SSRI), cholecystokinin (CCK) receptor antagonist, the motilin receptor activator or antagonist, NK (NK) receptor antagonist, cortico-trophin-releasing factor (CRF) (CRF) receptor stimulating agent or antagonist, the somatostatin receptor activator, antacids, the GI relaxant, anti-gasification compound, the bismuth-containing goods, pentosane polysulfate ester, antiemetic dopamine D 2 antagonist, prostaglandin E analogues, Gonadorelin analogues (Leuprorelin), corticotropin-1 antagonist, neurokinin 2 receptor antagonists, cholecystokinin-1 antagonist, beta blocker, anti-esophageal reflux agent, muscarine antagonist, antidiarrheal agent, antiinflammatory, anti-wriggling agent, 5HT₁Activator, 5HT₃Antagonist, 5HT₄Antagonist, 5HT₄Activator, bile salt chelating agent, volume medicament, α₂-2-adrenergic agonist components, mineral oil, antidepressant, herbal medicine.

The instantiation of IBS therapeutic agent includes but not limited to following:

Benzodiazepine compound and analog, for example

With

Its by with A type GABA (GABA) acceptor (GABA_A) interaction and work to suppress the outbreak.

SSRI, for example Fluvoxamine; Prozac; Paxil; Sertraline; Citalopram; Venlafaxine; Cericlnmine; Duloxetine; Milnacipran; Nefazodone; With cyano group dosulepin (cyanodothiepin) (referring to The Year Drugs News (annual medicine news), Prous J.R., nineteen ninety-five version, the 47-48 page or leaf) and WO 97/29739.

Cck receptor antagonist, for example Devazepide; Lorglumide; Dexloxiglumide (dexioxiglumide); Loxiglumide, D ' Amato, the people such as M., Br.J.Pharmacol. volume 102 (2), 391-395 page or leaf (1991); Cl 988; L364,718; L3637260; L740,093 and LY288,513; The cck receptor antagonist, be disclosed in United States Patent (USP) the 5th, 220, No. 017, Bruley-De (S)-Varannes, the people such as S, Gastroenterol.Clin.Biol. the 15th volume (10) 9,744-757 page or leaf (1991) and Worker C:EUPHAR ' 99-Second European Congress of Pharmacology (Part IV) Budapest, Hungary Iddb Meeting Report 3-7 day in July, 1999.

The motilin receptor activator or antagonist comprise for example motilin activator ABT-269 (erythromycin, 8,9-two dehydrogenations-N-dimethyl deoxidation generation-4 "; 6,12-, three deoxidations-6,9-epoxy-N-ethyl), take off (N methyl)-N-ethyl-8; the 9-Erythromycin A that dewater) and take off (N-methyl)-N-isopropyl-8; 9 Erythromycin As that dewater), the people such as Sunazika T., Chem.Pharm.Bull.; the 37th rolls up (10), 2687-2700 page or leaf (1989); A-173508 (Abbot Laboratories); Motilin antagonist (Phe3, Leu-13) pig motilin, the 214th American Chemical Society (ACS) meeting (V part); Highlights from Medicinal Chemistry Poster Session (important news of pharmaceutical chemistry placard paper), September 10, Wednesday, Las Vegas, Nevada, (1997), Iddb Meeting Report 7-11 in September (1997); With the people such as ANQ-1 1 125, Peeters T.L., Biochern.Biophys.Res.Commun., the 198th volume (2), 411-416 page or leaf (1994).

The NK receptor antagonist comprises for example FK 888 (Fujisawa); GR 205171 (Glaxo Wellcome); LY 303870 (Lilly); MK 869 (Merck); GR82334 (Glaxo Wellcome); L758298 (Merck); L 733060 (Merck); L 741671 (Merck); L 742694 (Merck); PD 154075 (Parke-Davis); S1 8523 (Servier); S1 9752 (Servier); OT 7100 (Otsuka); WIN 51708 (Sterling Winthrop); NKP-608A; TKA457; DNK333; CP-96345; CP-99994; CP122721; L-733060; L-741671; L742694; L-758298; L-754030; G (R)-203040; G (R)-205171; RP-67580; RP (R)-100893 (Dapitant); RP (R)-107880; RP (R)-111905; FK-888; SDZ-NKT-343; MEN-10930; MEN-11149; (S)-18523; (S)-19752; PD-154075 (CAM-4261); S (R)-140333; LY-303870 (lanepitant); EP-00652218; EP00585913; L-737488; CGP-49823; WIN-51708; S (R)-48968 (saredutant); S (R)-144190; YM383336; ZD-7944; MEN-10627; G (R)-159897; RP (R)-106145; PD-147714 (CAM-2291); ZM253270; FK-224; MDL-1 05212A; MDL-105172A; L-743986; The L-743986 analog; (S)-16474; S (R)-1 42801 (Osanetant); PD-161182; SB-223412; And SB-222200.

CRF receptor stimulating agent or antagonist, for example, such as WO 99/40089 disclosed AXC 2219, Antalarmin, NGD 1, CRA 0165, CRA 1000, CRA 1001.

The somatostatin receptor activator, for example Octreotide, Vapreotide, Lanreotide.

Anti-inflammatory compound, particularly immunity regulating type anti-inflammatory compound, for example NSAIDS; TNF (TNF, TNFa) inhibitor; Basiliximab (for example); Daclizumab (for example

); Infliximab (for example

); Etanercept (for example); Mycophenolate mofetil (for example

); Imuran (for example

); Tacrolimus (for example

); Steroids; Methotrexate (MTX) and GI antiinflammatory, for example, salicylazosulfapyridine (for example

); Olsalazine (for example

); And 5-ASA (for example

)。

Antacids is such as aluminium and magnesium antacids; And calcium hydroxide, such as

Anti-gasification compound is for example with trade name

With

Commercially available dimethicone; And enzyme preparation, comprise

With

The bismuth-containing goods, for example basic bismuth salicylate also is called

Pentosane polysulfate ester, the big molecular saccharides derivative of heparin sample, it is chemically being similar to GAG with structure, with trade name

Commercially available.

Antiemetic dopamine D 2 antagonist comprises for example domperidone.

Prostaglandin E analogues, Gonadorelin analogues (Leuprorelin), corticotropin-1 antagonist, neurokinin 2 receptor antagonists, cholecystokinin-1 antagonist, beta blocker.

Anti-esophageal reflux agent includes but not limited to

Antispasmodic and muscarine antagonist include but not limited to bentyl, oxybutynin (oxybutyin) (for example ditropan XL), Tolterodine (for example Tolterodine tartrate), alverine, Anisotropine, atropine (for example atropine sulfate), belladonna, homatropinum, Homatropine Methylbromide, hyoscyamine (for example hyoscyamine sulfate), epoxytropine tropate, hyoscine (for example Scopolamine Hydrochloride), Clidinium, west holder ammonium (cimetropium), hexocyclium, the dimension ammonium (pinaverium), difficult to understand for ammonium (otilonium), GLYCOPYRRONIUM and mebeverine.

Antidiarrheal agent includes but not limited to ipratropium, Isopropamide, Mepenzolate, propanthaline, Oxyphencyclimine, pirenzepine, diphenoxylate (for example diphenoxylate hydrochloride), atropine sulfate, alosetron hydrochloride, R-15403, basic bismuth salicylate, Lactobacillus acidophilus, Trimebutine, asimadoline and octreotide acetate.

Antiinflammatory also includes but not limited to 5-ASA, salicylazosulfapyridine, balsalazide disodium, hydrocortisone and olsalazine sodium.

5HT ₁Activator includes but not limited to buspirone.

5HT ₃Antagonist includes but not limited to Ondansetron, Cilansetron and Alosetron.

5HT ₄Antagonist includes but not limited to piboserod (piposcrod).

5HT ₄Activator includes but not limited to that tegaserod (for example Tijiaseluo maleate) and general Carlow must profits (povcalopride).

Antidepressant includes but not limited to desipramine (desiprimine), amitriptyline, imipramine (imiprimine), Prozac and Paxil.

Other IBS therapeutic agent comprises Dexloxiglumide, TAK-637, talnetant, SB 223412, AU 244, neurotrophic factor-3, GT 160-246, immunoglobulin (Ig) (IgG), Ramoplanin, rifaximin (risaxmin), dimethicone, darifenacin (darifenacine), Zamifenacin, Loxiglumide, Misoprostol (misoprostil), Leuprorelin, domperidone, somatostatin analogs, phenytoinum naticum, NBI-34041, saredutant and Dexloxiglumide.

Antibiotic includes but not limited to TCs, such as duomycin, terramycin, tetracycline, demethyl duomycin, metacycline, Doxycycline, minocycline and rolitetracycline; Such as kanamycins, amikacin, gentamicinC_1a、C ₂、C _2bOr C₁, SISO, Netilmicin, spectinomycin, streptomysin, TOB, actiline, dibekacin and kanamycin B sulfate; Macrolides is such as maridomycin and erythromycin; The lincomycin class is such as clindamycin and lincomycin; Has respectively 6 β-or the penicillanic acid (6-APA) of 7 β-acylamino--and cephalosporanic acid (7-ACA)-derivative, described 6 β-or 7 β-acylamino-be present in fermentation, in semi-synthetic or complete synthetic obtainable 6 β-acyl group aminopenicillanic acid or the 7 β-acyl group amino-cephalo-alkanoic acid derivative and/or at 7 β of 3 modifications-acyl group amino-cephalo-alkanoic acid derivative, such as with title benzyl penicillin or V and well-known penicillanic acid derivative, such as phenethicillin, propicillin, NAF, oxymycin (oxycillin), Cloxacillin, dicloxacillin, the flucloxacillin, cyclacillin, Epicillin, Mecillinam, the methicillin, the azlocillin, the sulbenicillin, Ticarcillin, the mezlocillin, Piperacillin, carindacillin, astracillin or ciclacillin, and with the well-known cephalosporins derivatives of following title: Cefaclor, cefuroxime, Cefazaflur (cefazlur), CEC, Cefazolin, cefalexin, cefadroxil, Cefaloglycine, Cefoxitin, cephaloridine, Cefsulodin, Cefotiam, ceftazidime (ceftazidine), cefonicid, CTX, Cefmenoxime, Ceftizoxime, cefoxitin, Cefradine, Cefamandole (cefamandol), Cephanone (cephanone), cefapirin, cefroxadine (cefroxadin), cefatrizine, Cefempidone, ceftriaxone (ceftrixon) and ceforanide (ceforanid); And other beta-Lactam antibiotics of carat dimension alkane, penem and carbapenem (carbapenen) type, such as latamoxef, clavulanic acid, nocardin (nocardicine A), Sulbactam, AZT and thienamycins; And other antibiotic comprise Bicozamycin, ovobiocin, chloramphenicol or Thiamphenicol, rifampin, phosphonomycin, colistin and vancomycin.

Antivirotic includes but not limited to nucleoside analog, non-nucleoside reverse transcriptase inhibitor, NRTI, protease inhibitors, integrase inhibitor, comprises following medicine: Acemannan; Acyclovir; Acyclovir Sodium; Adefovirdipivoxil; Aovudine; Alvircept Sudotox; Amantadine hydrochloride; Aranotin; Arildone; The methanesulfonic acid Atevirdine; Avridine; Cidofovir; Cipamfylline; Cytarabine hydrochloride; Delavirdine mesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime; FCV; Famotine hydrochloride; Fiacitabine; Fialuridine; Fosarilate; Foscarnet sodium; Fosfonet sodium; GCV; Cymevan (Syntex); Iodoxuridine; Receive Wei indenes; Ketoxal; Lamivudine; Lobucavir; Lopinovir; Memotine hydrochloride; Metisazone; Nelfinavir; NVP; Penciclovir; Pirodavir; Ribavirin; Rimantadine hydrochloride; Ritonavir; Saquinavir mesilate; Somantadine hydrochloride; Sorivudine; Statolon; Stavudine; Tenofovir; Tilorone hydrochloride; Trifluridine; Valaciclovir hydrochlordide; Arabinosy ladenosine; Vidarabine phosphate; Vidarabine phosphate sodium; Viroxime; Zalcitabine; Zerit; Zidovudine (AZT); And Zinviroxime.

Anti-infective includes but not limited to, Abbott 56619; Lauryl bromination isoquinolin nitrogen; Latamoxef disodium; Ornidazole; Pentisomicin; Sarafloxacin hydrochloride; HIV and other retroviral protease inhibitors; HIV and other retroviral integrase inhibitors; Cefaclor (Ceclor); Acyclovir (zovirax); Norfloxacin (noroxin); Cefoxitin (Cefoxitin); CEFUROXIME AXETIL (new bacterium spirit); Ciprofloxacin (cipro); Acramine; Benzethonium chloride: sodium bithionolate; Bromchlorenone; Urea peroxide; Cetalkonium chloride; Cetylpyridinium Chloride: chlorhexidine hydrochloride; Clioquinol; Domiphen bromide; Fenticlor; Fludazonium chloride (fludazonium chloride); Basic fuchsin; Furazolidone; Gentian violet; Halquinol; Hexachlorophene: hydrogen peroxide; Ammonium ichthosulfonate; Imidecyl iodine; Iodine; Isopropyl alcohol; Mafenide acetate; Meralein sodium; Mercufenol chloride; Ammoniated mercury; Methyl benzethonium chloride; Furacilin; Nitromersol metaphen; Octenidine dihydrochloride; Oxychlorosene; Oxychlorosene sodium; Camphorated parachlorophenol; Potassium permanganate; PVP-I; Sepazonium chloride (sepazonium chloride); Silver nitrate; Flamazine; Symclosene; Sodium timerfonate; Thimerosal: Troclosene Potassium.

Antifungal agent (antibiotic) comprising: polyenoid is (such as amphotericin B, candicidin, dermostatin, filipin, fungichromin, trichomycin, Hamycin, lucimycin, mepartricin, natamycin, nystatin, pecilocin, perimycin; With other antifungal agents, such as azaserine, griseofulvin, oligomycin, pyrrolnitrin, siccanin, tubercidin and viridin. Synthesis of antifungal agents comprises: allylamine, such as naftifine and Terbinafine; Imidazoles is such as bifonazole, butoconazole, clodantoin, Chlormidazole, croconazole, clotrimazole, econazole, enilconazole, Fenticonazole, Isoconazole, ketoconazole, Miconazole, Omoconazole, Oxiconazole Nitrate, sulconazole and tioconazole; Triazole is such as Fluconazole, Itraconazole, terconazole. Other antifungal agents comprise acrisorcin, Amorolfine, Biphenamine, Bromosalicylchloranilide, buclosamide, chlophenesin, ring pyrrole department, cloxiquine, Coparaffinate (coparaffinate), diamthazole, saturated chlorine (saturatedchloride), exalamide, Flucytosine, Haletazole, Hexetidine, loflucarban, nifuratel, KI, propionic ester, propionic acid, pyrrole sulphur father-in-law, salicylanilide, sulbentine, tenonitrozole, tolciclate, tolindate, Tolnaftate, 3 ', 4 ', 5 ', 5,7-quercetin, ujothion and undecenoic acid. Antifungal agent also comprises echinocandin-class or antifungal agent, comprises Caspofungin, MFG, anidulafungin, aminocandin and analog.

Vasoconstrictor includes but not limited to adrenaline, norepinephrine, pseudoephedrine, phyenlephrinium, oxymetazoline, propyl hexedrine, naphazoline, Tetryzoline (tetrahydrolozine), Xylometazoline (xylometazonline), ethylnorephinephrine, methoxamedrine, phenylhexedrine, mephentermine, aramine, dopamine, Dipivefrine, norphedrine and Cirazoline (ciraxzoline), and it can be advantageously used in composition and the method for this paper. Their use can be assisted the systemic delivery that reduces active anti-hyperalgesic agent.

Pharmaceutical preparation of the present invention when using separately or with mixture, is to treat effective amount to use. Effective amount will be determined by parameter discussed below in the treatment; But under any circumstance, it is to set up the amount of effectively treating the levels of drugs of the curee with one of illness described herein, and described curee is such as human subject. Effectively amount refers to the outbreak of the illness that postpones to treat or associated symptom, reduces its seriousness or fully suppresses them, reduces their progress or blocks their outbreak fully or make progress amount or the delivery rate of necessary single or multiple dose. In the case of diarrhoea, effectively amount can be, for example causes one or more the amount in the following situation: 1) reduce stool interval; 2) denseness of increase ight soil, and/or 3) feces volume is reduced to every day less than 200g. In one embodiment, effectively amount is to cause the every day of defecation 3 times or still less, preferred every day 2 times or still less, more preferably every day defecation 1 time amount. In some instances, according to mode of administration, described amount is enough to using (S)-7, and 8-is saturated-4, in 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour of 5-epoxy-morphinanium and even use after reduce immediately defecation. Intravenous is used and can be produced acute effect. In recovering gastrointestinal function, effectively amount can be, for example increases mouth-caecum by necessary amount of time. In order to control or treat pain, effectively amount can be, for example is enough to the amount that makes the curee more comfortable, describedly comfortablely determines by subjective criterion, objective standard or both. In the hyperalgesic case of periphery, effectively amount can be for example to alleviate the hyperalgesic symptom of the periphery amount of (such as to hyperalgesia or pruritus). In order to prevent or treat inflammation, effectively amount can be, for example be enough to reduce or rubescent (redness), swelling or tissue damage that reduction is relevant with inflammation, or the ambulant amount of increase involved area (such as the joint). When being applied to the curee, effectively amount will depend on the specific illness for the treatment of in the nature of things; The seriousness of illness; The individual patient parameter comprises age, health, size and body weight; The treatment of carrying out simultaneously; The frequency for the treatment of; And mode of administration. These factors are known to ordinary skill in the art, and only just can obtain (addressed) with normal experiment.

(S)-7 of the present invention, 8-is saturated-4, and the oral dose of 5-epoxy-morphinanium can be from every day about 0.05 to about 40mg/kg, from 0.05 to about 20mg/kg, from about 0.05 to about 10mg/kg or from about 0.05 to about 5mg/kg body weight. According to use the bullet formula or diffusion the using of (for example intravenous drip) in time, parenteral administration (comprising intravenous and subcutaneous administration) can be from about 0.001 to 1.0mg/kg, from about 0.01 to 1.0mg/kg or from about 0.1 to 1.0mg/kg body weight. Scope can produce required effect from the dosage of about 0.05 to 0.5mg/kg body weight. According to method of application, can suitably regulate dosage to reach required part or the levels of drugs of system. For example, (S)-7 of expection enteric coating preparation, 8-is saturated-4, and the oral formulations of the Orally administered dose ratio instant-free of 5-epoxy-morphinanium is few. The patient responds in the not enough situation when this dosage, and the degree that can patient's tolerance allows is used even high dose (or efficiently higher dosage of the route of delivery by different more localizations) more. Expection multiple dose every day is to reach the suitable system level of compound. Suitable system level can be determined by the measurement of the maximum or lasting medicine blood plasma level of for example patient. " consumption " and " dosage " this paper is used interchangeably.

Can use multiple route of administration. Selected ad hoc fashion will depend on the particular combination of selected medicine, the seriousness of an illness for the treatment of or preventing, patient's health status and the required dosage for the treatment of effectiveness naturally. In general, can use medically acceptable any method of application to implement the inventive method, medically acceptable method of application means the level of significance that produces reactive compound and can not cause clinically any mode of unacceptable detrimental effect. That such method of application comprises is oral, rectum, part, through skin, hypogloeeis, venoclysis, in lung, artery, in the adipose tissue, in the lymph, in the muscle, in the chamber, aerosol, through in ear (for example through [Dan), the nose, in the suction, joint, Needleless injection, subcutaneous or intracutaneous (for example, through skin) send. For continuous infusion, can use patient-controlled analgesia (PCA) device or implantable drug delivery device. Oral, rectum or local to use for preventative or long-term treatment be important. The preferred rectum mode of sending comprises with suppository or bowel lavage lotion (enema wash) to be used.

Pharmaceutical preparation can unit dosage form be given and and can be by any method preparation of knowing in the pharmaceutical field easily. All methods all comprise makes The compounds of this invention and the carrier-bound step that consists of one or more auxiliary agents. Usually, composition is prepared as follows: make compound all in the lump closely with liquid carrier, solid-state carrier or both combinations in small, broken bits, if need afterwards, with product shaping.

When being applied, pharmaceutical preparation of the present invention uses with pharmaceutically acceptable composition. These goods routines comprise salt, buffer, anticorrisive agent, compatibility carrier, lubricant (lubricant) and other optional therapeutic component. When being used for medical treatment, it is pharmaceutically acceptable that salt should be, but non-pharmaceutically acceptable salt also can be conveniently used for preparing its pharmaceutically acceptable salt thereby being not precluded within outside the scope of the present invention. These pharmacology and pharmaceutically acceptable salt include but not limited to by those of following acid preparation: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-methyl benzenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, butanedioic acid, naphthalene-2-sulfonic acid, pounce on acid, 3-hydroxyl-2-naphthalene-carboxylic acid and benzene sulfonic acid.

What should know is saturated-4 when mentioning 7,8-, 5-epoxy-morphinanium, and (R)-and (S)-7,8-is saturated-4, when 5-epoxy-morphinanium and therapeutic agent of the present invention, means and comprises its salt. Such salt has people or the known thing class of those skilled in the art of this area. When being used for pharmaceutical preparation, pharmaceutically acceptable when salt is preferably for the mankind. Bromide is the example of this salt.

Pharmaceutical preparation of the present invention can comprise or be diluted in pharmaceutically acceptable carrier. As used herein, term " pharmaceutically acceptable carrier " means one or more compatibilities solid-state or liquid fillers, diluent or encapsulating substance, and it is suitable for, and for example non-human primates, dog, cat, horse, ox, sheep, pig or goat are used to human or other mammals. Term " carrier " means the organic or inorganic component, natural or synthetic, active component can be used with convenient with its combination. Carrier can and be mixed with each other with the interactional mode and the goods of the present invention that do not have significantly to damage required pharmaceutical efficacy or stability. Being suitable for carrier formulation that Orally administered, suppository, stomach and intestine uses etc. outward can be at Remington ' s Pharmaceutical Sciences, Mack Publishing Company, and Easton, PA finds.

Preparation can comprise chelating agent, buffer, antioxidant, and randomly comprises isotonic agent, preferably includes pH adjusting agent or penetration enhancers.

Chelating agent comprises, for example, and ethylenediamine tetra-acetic acid (EDTA) and derivative, citric acid and derivative thereof, niacinamide and derivative thereof, deoxysodium cholate and derivative thereof and Pidolidone, N, N oxalic acid and derivative thereof. The EDTA derivative comprises EDTAP dipotassium ethylene diamine tetraacetate, disodium ethylene diamine tetraacetate, calcium disodium chelate, sodium ethylene diamine tetracetate, sodium versenate and ethylenediamine tetra-acetic acid potassium.

Buffer comprises and being selected from by citric acid, natrium citricum, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazoles, sodium acid carbonate and carbonic acid, sodium succinate and butanedioic acid, histidine, Sodium Benzoate and benzoic acid, or combinations thereof those materials of group.

Antioxidant comprises those materials that are selected from the group that is made up of ascorbic acid derivates, butylated hydroxyanisol, butylated hydroxytoluene, alkyl gallates, sodium pyrosulfite, sodium hydrogensulfite, sodium dithionite, sodium thioglycolate, sodium formaldehyde sulphoxylate, tocopherol and derivative thereof, monothioglycerol and sodium sulfite. Preferred antioxidant is monothioglycerol.

Isotonic agent comprises those materials that are selected from the group that is made up of sodium chloride, sweet mellow wine, lactose, dextrose, glycerine and sorbierite.

Can comprise with the anticorrisive agent that the present composition uses benzyl alcohol, p-hydroxybenzoate, thimerosal, methaform and preferred benzalkonium chloride. Usually, anticorrisive agent is present in the composition with the concentration of maximum about 2% weight. And the definite concentration of anticorrisive agent will change and determined by those skilled in the art easily according to desired use.

The compounds of this invention can freeze-drying the composition preparation, preferably cryoprotector is being arranged for example in the presence of sweet mellow wine, lactose, sucrose, polyethylene glycol and the polyvinylpyrrolidine. Produce 6.0 or the cryoprotector of lower reconstruct pH be preferred. Therefore the invention provides the freeze-dried products of therapeutic agent of the present invention. These goods can comprise cryoprotector, for example sweet mellow wine or lactose, it preferably is neutral or acid in water.

Outer or the suppository formulations of oral, the stomach and intestine of medicament is well-known and can commercial acquisition. Therapeutic agent of the present invention can be added to the preparation that these are known. Therapeutic agent can solution or semi-solid solution be mixed together in these preparations, can provide in the particle that maybe can be contained in these preparations by the suspension in these preparations.

The product that comprises therapeutic agent of the present invention and randomly comprise one or more other activating agents can be designed to oral dose. Oral dose can be liquid, semisolid or solid-state. Opioid randomly is contained in oral dose. Oral dose can be designed to discharge afterwards or simultaneously therapeutic agent of the present invention at other medicaments (and/or opioid) before. Oral dose can be designed to make therapeutic agent of the present invention and other medicaments to discharge fully under one's belt, partly in intestines, discharge, in intestines, discharge, in colon, discharge, partly discharge under one's belt or in colon, discharge fully with part under one's belt. Can design also that oral dose does not so limit the release of other activating agents whereby the release of therapeutic agent of the present invention is limited in stomach or the intestines or restriction that other activating agents discharge is different from therapeutic agent of the present invention. For example, therapeutic agent of the present invention can be coated nuclear or the piller of enteric coating that is contained in pill or the capsule, and this pill or capsule at first discharge other medicaments and only discharge therapeutic agent of the present invention after therapeutic agent of the present invention passes stomach and enters in the intestines. Therapeutic agent of the present invention also can be present in the material of sustained release, and therapeutic agent whereby of the present invention spreads all over that intestines and stomach discharge and other medicaments discharge with identical or different timetable. The same target that therapeutic agent of the present invention discharges can reach by the instant-free of the therapeutic agent of the present invention of being combined with the coated therapeutic agent of the present invention of enteric coating. In these examples, other medicaments can be under one's belt, spread all over intestines and stomach or only instant-free in intestines.

Can be used for realizing that the material of these different release characteristics is that those those skilled in the art are known in this area. By having the conventional tablet of the adhesive that dissolves in the stomach, instant-free is getable. Dressing in dissolving under the pH of stomach or dissolving when heating up will be realized same purpose. Use pH sensitiveness dressing that conventional enteric coating for example dissolves under the pH environment of intestines (rather than stomach) or the dressing of in time dissolving can realize the only release in intestines. Combination (piller that for example, dissolves under different pH) by delivery system in the intestines that use sustained release material and/or instant-free system and lasting and/or delay can realize spreading all over GI release.

At first discharge at needs in the situation of therapeutic agent of the present invention, therapeutic agent of the present invention can be on the surface of any suitable controlled release preparation dressing, described preparation is in being applicable to these dressings and allowing any pharmaceutically acceptable carrier that therapeutic agent of the present invention discharges, and described carrier be the conventional pharmaceutically acceptable carrier of temperature sensitivity for controlled release for example. The dressing of dissolving was that those general technical staff of this area are known when other placed in the body.

Therapeutic agent of the present invention also can mixedly be dispersed throughout controlled release preparation, and whereby, it discharged before other medicaments afterwards or simultaneously. Therapeutic agent of the present invention can dissociate, and that is to say, is dissolved in the material of preparation. The form of all right capsule of therapeutic agent of the present invention, for example the micropill of wax dressing intersperses among in the material of preparation. The piller of dressing can be made based on temperature, pH or other conditions of similarities and instant-free therapeutic agent of the present invention. Also piller can be designed to postpone the release of therapeutic agent of the present invention, to bring into play its effect at therapeutic agent of the present invention before, work for other medicament a period of time. Also therapeutic agent piller of the present invention can be designed to discharge therapeutic agent of the present invention in the mode of in fact any sustained release, described sustained release mode comprises the material that uses prior art also to know as those of ordinary skills, the mode that demonstrates first-order release dynamics or contrary flexure level (sigmoidal order) release dynamics.

Therapeutic agent of the present invention also can be contained in the nuclear in the controlled release preparation. Described nuclear has above any one or any combination of the character described with regard to piller. Therapeutic agent of the present invention can, for example, in the nuclear by the material dressing, disperse to be dispersed throughout material, dressing is on material or absorption or spread all over material.

What should know is piller or to endorse be in fact any type. They can be the medicines by the releasable material dressing, intersperse among material medicine, be adsorbed to medicine in the material etc. Material is corrodible or not corrodible.

Can provide therapeutic agent of the present invention by particle. Particle used herein means nanometer or the micron particles (or in some instances bigger) that can be made up of therapeutic agent of the present invention or other medicament described herein wholly or in part. Particle can contain therapeutic agent in the nuclear that is surrounded by dressing (including but not limited to enteric coating). Therapeutic agent can also disperse to spread all in the particle. Therapeutic agent can also be absorbed in the particle. Particle can have the release dynamics of any grade, comprises zero level release, first-order release, secondary release, delayed release, sustained release, instant-free and any combination thereof etc. Except therapeutic agent, particle can comprise any of conventional those materials that are used for pharmacy and medical domain, and described material includes but not limited to corrodible, and is not corrodible, biodegradable or non-biodegradable material or its combination. Particle can be the microcapsules that contain the antagonist of solution form or semi-solid state. Particle can have in fact any shape.

Abiotic degradable and biodegradable polymer material can be used to make the particle of delivering therapeutic agents. Such polymer can be natural or synthetic polymer. Based on discharging needed time period selective polymer. The bioadhesive polymer that cherishes a special interest comprises H.S.Sawhney, and C.P. Pathak and J.A.Hubell be in Macromolecules, (1993) but the hydrogel of the bioerodable described among the 26:581-587, this paper is incorporated in its instruction into. These comprise poly-hyaluronic acid, casein, gelatin, glutin, poly-acid anhydrides, polyacrylic acid, alginates, shitosan, poly-(methyl methacrylate), poly-(EMA), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), poly-(phenyl methacrylate), poly-(methyl acrylate), poly-(isopropyl acrylate), poly-(isobutyl acrylate) and poly-(octadecyl acrylate).

Therapeutic agent can be contained in the controlled release system. Term " controlled release " means any preparation that contains medicine, and its Chinese traditional medicine is controlled from mode and the feature that preparation discharges. This refers to instant and non-IR formulation, and non-IR formulation includes but not limited to sustained release and delayed release preparation. Term " sustained release " (being also referred to as " prolong and discharge ") uses with its conventional sense, finger provides the gradually release of medicine in the time of an elongated segment, and preferred, but not necessarily, in the time of an elongated segment, produce the haply pharmaceutical preparation of constant medicine blood level. Term " delayed release " uses with its conventional sense, refer to preparation use and the release of medicine between have time delay pharmaceutical preparation. Therefore " delayed release " can comprise or can not comprise medicine in the gradually release of an elongated segment in the time, and can be or can not be " sustained release ". These preparations can be used for any type of using.

Specifically be used for GI delivery system and be divided into roughly three types: first kind is to be designed to respond for example pH variation and the delayed release system of release medicine; Second is the time controlled released system that is designed to discharge medicine after the scheduled time; The microbial enzyme system (preparation that for example discharges in the colon fixed point) that utilizes in intestines and stomach the latter half a large amount of enterobacterias with the third.

An example of delayed release system is to use acrylic acid for example or coated cellulose material and change the delayed release system of dissolving with pH. Because preparation is easily, existing many reports about this " enteric coating ". Usually, enteric coating is to pass stomach and do not discharge under one's belt high amount of drug (namely under one's belt discharge be less than 10%, 5% even 1%) and fully disintegration in enteron aisle (by contact with neutral or alkaline intestinal juice roughly) is passed the dressing of intestinal walls transportation (active or passive) to allow activating agent.

Be used for to determine that various experiment in vitro that whether dressing classifies as enteric coating have been published in the pharmacopeia of country variant. Example is at least 2 hour in to keep complete with the artificial gastric juice when for example the HCl of pH 1 contacts at 36 ℃ to 38 ℃, and afterwards at the artificial intestinal juice KH of pH 6.8 for example₂PO ₄In the buffer solution in 30 minutes the dressing of disintegration. Such system of knowing can commercially obtain and by Behringer, Manchester University, the EUDRAGIT material of Saale Co. report, and analog. Hereinafter enteric coating can be discussed further.

Fujisawa Pharmaceutical Co., the Time Erosion System (TES) of Ltd. and the Pulsincap of R.P. Scherer. have represented the time controlled released system. According to these systems, the site that medicine discharges is by the Time dependent of preparation transportation in the intestines and stomach. Because the transportation of preparation is subjected to the very big impact in gastric emptying time in the intestines and stomach, so some time controlled released system also is enteric coating.

Utilize the system of enterobacteria can be divided into (the people such as M.Saffran of research group of Ohio University, Science, 1081 (1986)) and (people such as J. Kopecek of the research group of Utah University the 233rd volume:, Pharmaceutical Research, 9 (12), 1540-1545 (1992)) utilization of reporting the azo reductase that produces of enterobacteria those systems to the degraded of azo aromatic polymer; And (the people such as K.H.Bauer of the research group of the research group of Hebrew University (the unexamined Japanese patent application of having announced based on PCT application 5-50863 number) and Freiberg University, Pharmaceutical Research, 10 (10), S218 (1993)) utilization of reporting the beta galactosidase of enterobacteria to those systems of the degraded of polysaccharide. In addition, also having comprised utilization that Teikoku Seiyaku K. K (the unexamined Japanese patent application of having announced 4-217924 number and the unexamined Japanese patent application of having announced 4-225922 number) reports can be by the system of the shitosan of chitosan enzyme degraded.

Enteric coating usually but must not be polymeric material. Preferred enteric-coating material comprises biodegradable, gradually hydrolysis and/or water-soluble polymer gradually. The relative quantity of the coating material of " coat weight " or each capsule has generally determined to ingest and the time interval of medicine between discharging. Any dressing all should be used so that enteric coating can not dissolve in pH is lower than about 5 gastro-intestinal Fluid with enough thickness, and in pH about 5 and dissolving when above. Expect that any anionic polymer that shows pH dependence dissolving characteristic can be used as the enteric coating in the practice of the present invention. The selection of concrete enteric-coating material will be depended on following characteristic: to the resistance of the dissolving in the stomach and disintegration; In the time of under one's belt to the impermeability of gastric juice and drug/vehicle/enzyme; The ability of rapid dissolving or disintegration in target intestines site; The physics and chemistry stability of duration of storage; Avirulence is easy to use (friendly matrix) as dressing; And economic and practical.

The enteric-coating material that is fit to includes but not limited to: cellulosic polymer is acetic acid phthalandione cellulose, acetic acid trimellitic acid cellulose, HYDROXY PROPYL METHYLCELLULOSE phthalate ester, HYDROXY PROPYL METHYLCELLULOSE succinate and sodium carboxymethylcellulose for example; Acrylate copolymer and copolymer, preferably by acrylic acid, methacrylic acid, methyl acrylate, methacrylate ammonium, ethyl acrylate, (those copolymers of for example selling with trade name EUDRAGIT) that methyl methacrylate and/or EMA form; Polyvinyl and copolymer, for example polyvinyl acetate, polyethylene acetic acid phthalate ester, vinyl acetate butenoic acid copolymer and vinyl-vinyl acetate copolymer; And shellac (lac of purifying). Also can use the combination of different coating materials. Those acrylate copolymers and the copolymer of the spendable enteric coating of knowing of this paper for can trade name EUDRAGIT obtaining from Rohm Pharma (Germany). Solution, aqueous dispersion or dry powder that EUDRAGIT series E, L, S, RL, RS and NE copolymer can be dissolved in organic solvent obtain. Soluble but the permeable and release that be mainly used in prolonging in intestines and stomach of EUDRAGIT series RL, NE and RS copolymer. EUDRAGIT series E copolymer dissolves in the stomach. Therefore EUDRAGIT series L, L-30D and (S) copolymer is under one's belt soluble but solvable in intestines be that this paper is most preferred.

Specific methacrylic acid copolymer is EUDRAGIT L, especially L-30D and EUDRAGIT L 100-55. In EUDRAGIT L-30D, the ratio of free carboxy group and ester group group is approximately 1: 1. Known copolymer is lower than 5.5 having in addition, be generally the pH of 1.5-5.5, it is insoluble namely generally being present in the gastrointestinal fluid of pH of upper gastro-intestinal tract liquid, and is higher than 5.5 at pH, dissolves easily when namely generally being present in the pH in the intestines and stomach lower liquid or is partly dissolved. Another kind of specific methacrylate polymer is EUDRAGIT (S), and it is approximately 1: 2 from the different ratios of its free carboxy group and ester group group that are of EUDRAGIT L-30D. EUDRAGIT S is insoluble less than 5.5 o'clock at pH, but different from EUDRAGIT L-30D, and the gastro-intestinal Fluid of pH also dissolves badly in the time of for example in small intestine in having 5.5 to 7.0 scopes. This copolymer dissolves when namely usually being present in the pH in the colon more than pH7.0 reaches. EUDRAGIT (S) can be used as dressing and uses so that medicine sending in large intestine to be provided separately. Selectively, pH be lower than the bad EUDRAGIT (S) of dissolving in 7 the intestinal juice can be higher than 5.5 intestinal juice at pH in the EUDRAGIT L-30D that dissolves be used in combination, to be provided as the composition of the delayed release of bioactive agent delivery being delivered to the enteron aisle different parts and preparing. The EUDRAGIT L-30D that uses is more many, discharge and to send the beginning more approaching, more should be understood that away from, those skilled in the art other pharmaceutically acceptable polymer that EUDRAGIT L-30D and EUDRAGIT (S) can be had a similar pH dissolution characteristics replace and the EUDRAGIT S that uses discharges more at most and send the beginning. In certain embodiments of the invention, preferred enteric coating is ACRYL-EZE^TM(methacrylic acid copolymer C type; Colorcon, West Point, PA).

Enteric coating provides the controlled release of activating agent, can finish in some common expected position so that medicine discharges. Enteric coating also prevents epithelium that therapeutic agent and carrier be exposed to oral cavity, pharynx, esophagus and stomach with mucous membrane and is exposed to the relevant enzyme of these tissues. Therefore enteric coating helps prolection agent, carrier and patient's intestinal tissue to avoid any adverse events at medicine before site release is sent in expection. In addition, the material of dressing of the present invention provides the optimization of drug absorption, activating agent protection and safety. Will provide even more effective and lasting spread all over sending of GI improvement as the multiple enteric coating of purpose at intestines and stomach zones of different release bioactive agent.

Dressing can and usually contain plasticizer really with the hole avoiding gastric juice and can permeate and the formation in slit. The plasticizer that is fit to includes but not limited to triethyl citrate (Citroflex 2), glyceryl triacetate (glyceryl triacetate), acetyl triethyl citrate (Citroflex A2), Carbowax 400 (PEG400), ethyl phthalate, ATBC, acetylated monoglyceride, glycerine, fatty acid ester, propane diols and Dibutyl phthalate. Especially, comprise that the dressing of anionic carboxylic acid acrylate copolymer will contain plasticizer, particularly Dibutyl phthalate, polyethylene glycol, triethyl citrate and the glyceryl triacetate of 10% to 25% weight of having an appointment usually. Dressing also can contain other dressing excipient, antitack agent, defoamer, lubricant (for example dolomol) and stabilizing agent (hydroxy propyl cellulose for example for example, bronsted lowry acids and bases bronsted lowry) with dissolving and dispersion coating material, and the product of improvement dressing performance and dressing.

Use conventional coating method and equipment, dressing can be used for the treatment of the particle of agent, the tablet of therapeutic agent contains capsule and the analog of therapeutic agent. For example, use coating pan, airless spraying technology, fluidized bed coating equipment or analog enteric coating can be used for capsule. The details of material, equipment and method about the preparation coated dosage form can be at Pharmaceutical Dosage Forms:Tablets (pharmaceutical dosage form: tablet), the people such as Lieberman edit (New York: Marcel Dekker, Inc., 1989) and the people such as Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems (pharmaceutical dosage form and drug delivery system), sixth version (Media, Pennsylvania: Williams ﹠ Wilkins, 1995) finds in. Coating thickness is annotated as mentioned, and essential sufficient to guarantee peroral dosage form keeps complete until arrive the required site of local delivery in the lower intestine.

In another embodiment, provide and contained the enteric coating dressing, had the pharmaceutical dosage form of the device of osmotically active, this device is equipped with preparation of the present invention. In this embodiment, the preparation that contains medicine is packaged in the foraminate semipermeable membrane of tool or the barrier. As in this area about known to so-called " osmotic pumps " drug delivery device, semipermeable membrane allows water but does not allow medicine to pass through in either direction. Therefore, when device was exposed to water liquid, because the permeable pressure head of device between inside and outside, water was with inflow device. When water inflow device, the preparation that medicine is contained in inside will be gone out by " pump " by the hole. The inflow velocity that the speed that medicine discharges will equal water multiply by drug concentration. Water flows into and the size in the hole that the speed of medicine outflow can be by composition and device is controlled. The material that is applicable to pellicle includes but not limited to polyvinyl alcohol, polyvinyl chloride, semi permeability polyethylene glycol, semi permeability polyurethane, semi permeability polyamide, semi permeability sulfonated polystyrene and polystyrene derivative; The semi permeability PSS, semi permeability poly-(vinyl benzyl trimethyl ammonium chloride) and cellulosic polymer be cellulose acetate for example, cellulose diacetate, Triafol T, cellulose propionate, cellulose acetate propionate, acetylbutyrylcellulose, three cellulose valerates, cellulose trilmate, three palmitic acid celluloses, three sad celluloses, three cellulose propionates, the disuccinic acid cellulose, two palmitic acid celluloses, cellulose dicylate, cellulose acetate succinate, propionic acid butanedioic acid cellulose, the sad cellulose of acetic acid, valeric acid palmitic acid cellulose, acetic acid enanthic acid cellulose, acetaldehyde dimethyl-acetal cellulose, acetic acid urethanes cellulose, acetic acid methyl carbamate cellulose, dimethylamino cellulose acetate and ethyl cellulose.

In another embodiment, provide the pharmaceutical dosage form that contains the sustained release coating device, this device is equipped with preparation of the present invention. In this embodiment, the preparation that contains medicine is packaged in sustained release film or the film. As indicated above, film can be semipermeable. Pellicle allows the device internal water to pass through with dissolved substance. The drug solution that has dissolved diffuses out by pellicle. The speed that medicine discharges depends on the thickness of the film of dressing, and the release of medicine can begin in any part in GI road. The suitable membrane material of this film comprises ethyl cellulose.

In another embodiment, provide the pharmaceutical dosage form that contains the sustained release coating device, this device is equipped with preparation of the present invention. In this embodiment, the preparation that contains medicine mixes with sustained release polymer homogeneous. These sustained release polymer are molecular weight water-soluble polymers, and it is when contacting with water, and expansion also produces water to the passage of diffusion inside and dissolved substance. When polymer expanded in water and dissolves, more drug exposure was in water and stripping. Such system is commonly called sustained release matrix. The material that is applicable to such device comprises hydrogen propyl methocel (hydropropyl methylcellulose), hydroxy propyl cellulose, hydroxy ethyl cellulose and methylcellulose.

In another embodiment, provide the pharmaceutical dosage form that contains the enteric coating device, this device is equipped with extended release preparation of the present invention. In this embodiment, contain the product as described above of medicine by enteric polymer coatings. This device will not discharge any medicine under one's belt, and when device arrives intestines, enteric polymer begin dissolving and only after begin medicine release. Medicine discharges and will carry out in the mode of sustained release.

Can use conventional material, method and apparatus to make the enteric coating dressing, have the device of osmotically active. The device that for example has osmotically active can be encapsulated in pharmaceutically acceptable soft capsule, liquid or the semisolid preparation by the The compounds of this invention that at first will describe before and make. Then, for example use the air suspension machine, (comprise with the semipermeable membrane composition, for example, in appropriate solvent cellulose acetate and the Macrogol 4000 in the methylene chloride-methanol mixture for example) this inner capsule of dressing, until form enough thick lamination (laminate), for example about 0.05mm. Use afterwards the dry semipermeable lamination capsule of routine techniques. Use afterwards for example erosion of gelatin plug of for example machine drilling, laser drill, mechanical disruption or erodable element, pass semipermeable layer moulding cyst wall and produce the hole with required diameter (for example about 0.99mm). Enteric coating has the device of osmotically active as described above afterwards. For the device with osmotically active that contains solid-state carrier rather than liquid state or semisolid carrier, inner capsule is chosen wantonly; That is to say, can directly form semipermeable membrane around carrier-pharmaceutical composition. Yet the preferred carrier that uses in the preparation that contains medicine of the device with osmotically active is solution, suspension, liquid, immiscible liquid, emulsion, colloidal sol, colloid and oil. Especially preferred carrier includes but not limited to be used to those of the enteric coating capsule that contains liquid state or semisolid pharmaceutical preparation.

Coated cellulose comprises acetic acid phthalandione cellulose and acetic acid trimellitic acid cellulose; The methacrylic acid copolymer that contains at least 40% methacrylic acid for example derives from the copolymer of methacrylic acid and its ester; Especially HYDROXY PROPYL METHYLCELLULOSE phthalate ester. Methacrylate comprise take ratio for example as about 1: 1 methacrylate and methyl or ethyl-methyl acrylate as the base molecule amount greater than 100,000 daltonian those. Typical product comprises Rohm GmbH, Darmstadt, the Endragit L that Germany sells, for example L 100-55. General acetic acid phthalandione cellulose has the acetyl content of 17-26% and from the phthalandione content of 30-40% and the viscosity of about 45-90cP. General acetic acid trimellitic acid cellulose has the acetyl content of 17-26%, and the content of trimellitic acid base (trimellityl) is from 25-35%, and viscosity is about 15-20cS. The cellulosic example of acetic acid trimellitic acid is product sold CAT (Eastman Kodak Company, the U.S.). The HYDROXY PROPYL METHYLCELLULOSE phthalate ester has 20,000 to 130,000 daltonian molecular weight usually, from 5% to 10% hydroxypropyl content, from 28% to 24% methoxyl content and from 21% to 35% phthalyl content. The cellulosic example of acetic acid phthalandione is product sold CAP (Eastman Kodak, Rochester New York, the U.S.). The example of HYDROXY PROPYL METHYLCELLULOSE phthalate ester is the hydroxypropyl content that has from 6-10%, methoxyl content from 20-24%, phthalyl content from 21-27%, about 84,000 daltonian molecular weight, selling with trade name HP50 also can be from Shin-Etsu Chemical Co.Ltd, Tokyo, the product sold that Japan obtains and have the 5-9% of being respectively, the hydroxypropyl content of 18-22% and 27-35%, methoxyl content and phthalyl content, molecular weight are 78,000 dalton, known commodity HP55 by name also can be from the product sold of same supplier's acquisition.

Can be at dressing or do not provide therapeutic agent in the capsule of dressing. Capsule material can be hard or soft, and is to be understood that such as those skilled in the art, usually contain tasteless, easily use and water miscible compound for example: gelatin, starch or cellulosic material. Preferably use for example gelatin band or analog seal capsule. Referring to, for example, Remington:The Science and Practice of Pharmacy (pharmacy science and put into practice), the 19 edition (Easton, Pa.:Mack Publishing Co., 1995), it has described the materials and methods for the preparation of the encapsulation medicine.

Can be suppository with the product shaping that contains therapeutic agent of the present invention. Therapeutic agent of the present invention can be put in any position in the suppository or on it advantageously to affect the relative release of therapeutic agent. The character that discharges can be as required zero level, one-level or contrary flexure type.

Suppository is the solid dosage forms of the medicine used of expection per rectum. Preparation suppository discharges the medicine that wherein contains whereby so that (about 98.6 °F) melt in body cavity, softening or dissolving. That suppository base should be is stable, non-irritating, inertia on chemical inertness and the physiology. Manyly can contain oiliness or lipid substrate material by the commercial suppository that obtains, for example cupu oil, coconut oil, palm-kernel oil and palm oil, they usually at room temperature melt or distortion and need refrigeration or other storage restriction is arranged. The people's such as Tanaka United States Patent (USP) the 4th, 837, described the suppository base that is made up of the bay class of 80-99 percentage by weight fat for No. 214, described bay class fat has 20 or littler hydroxyl value and contain 8 to 18 fat of carbon atom acid glycerides of same 1 to 20 percentage by weight aliphatic acid (for example erucic acid) diglyceride combination. The pot-life of the suppository of these types is owing to degraded is restricted. Other suppository base comprises alcohols, surfactant and analog, they fusion temperature is raise but also caused the absorption variation of medicine and the side effect that produces owing to the stimulation to local mucous membrane (referring to for example, the people's such as Hartelendy United States Patent (USP) the 6th, 099, No. 853, the people's such as Ahmad United States Patent (USP) the 4th, 999, No. the 4th, 765,978, the people's such as No. 342 and Abidi United States Patent (USP)).

The matrix that is used for suppository composition pharmaceutically of the present invention generally comprises, and contains the oil ﹠ fat of main component triglyceride, for example cupu oil, palmin, palm-kernel oil, coconut oil, fractionated coconut oil, lard and

The wax class is the lanolin of lanolin and reduction for example; Hydrocarbon for example

Squalene, saualane and atoleine; Grow to medium chain fatty acid for example sad, laurate, stearic acid and oleic acid; Higher alcohol is laruyl alcohol, hexadecanol and stearyl alcohol for example; Fatty acid ester is butyl stearate and malonic acid two lauryls for example; In to long-chain carboxylic acid's glyceride for example triolein and tristearin; The carboxylate that glycerine replaces is the glycerine acetoacetate for example; And polyethylene glycol and its derivative for example polyethylene glycol (macrogol) and cetomacrogol. They can be separately or two or more unite use. If need, the present composition can further comprise the surfactant that is generally used for suppository, colouring agent etc.

Can by active component, absorption auxiliary agent and the optional preparation pharmaceutically acceptable compositions of the present invention such as matrix of homogeneous mix predetermined quantities in agitator or grinder, if need, then at high temperature carry out. Can be by molded mixture in mould for example, or with capsule filling machine it is formed gelatine capsule the composition of gained is configured as suppository with unit dosage form.

According to all right nasal spray of composition of the present invention, nose drops, suspension, gel, ointment, newborn frost or powder are used. Using of composition comprises that also using the nose that contains the present composition to use fills in or the nose silk floss.

Can various ways be can adopt with delivery system with the nose that the present invention uses, aqueous compositions, not aqueous compositions and combination thereof comprised. Aqueous compositions comprises, for example aqueous gel, aqueous suspension, moisture liposome dispersion, aqueous emulsions, moisture microemulsion and combination thereof. Aqueous compositions does not comprise, for example not aqueous gel, not aqueous suspension, not moisture liposome dispersion, non-aqueous emulsions, not moisture microemulsion and combination thereof. Multi-form nose can comprise the buffer of keeping pH, pharmaceutically acceptable thickener and NMF with delivery system. Can select the pH of buffer so that pass the absorption optimization of the therapeutic agent of schneiderian membrane.

For not moisture nasal formulations, can select the buffer of appropriate format so that when preparation is delivered in the mammiferous nasal cavity, in the pH scope that reaches selection when for example schneiderian membrane contacts. In the present invention, the pH of composition should maintain from about 2.0 to about 6.0. When using, need composition pH for can not be to the pH of the very big stimulation of generation of recipient's schneiderian membrane.

Use pharmaceutically acceptable thickener the viscosity of the present composition can be maintained required level. According to the present invention can with thickener comprise methylcellulose, xanthan gum, carboxy methyl cellulose, hydroxy propyl cellulose, carbomer, polyvinyl alcohol, alginates, acacin, shitosan and combination thereof. The concentration of thickener will depend on selected dose and required viscosity. The powder formulation that these agent also can be used to above discuss.

Composition of the present invention can comprise that also NMF is to reduce or to prevent that mucous membrane is dry and prevent stimulation to it. Can be used for suitable NMF of the present invention and comprise sorbierite, mineral oil, vegetable oil and glycerine; Soothing agent; The film conditioning agent; Sweetener; And combination. The concentration of NMF will change according to selected dose in the present composition.

Can comprise one or more therapeutic agents in delivery system or any other delivery system described herein at nose.

The composition of preparing for local application can be that liquid state or semisolid (for example comprise, gel, washing lotion, emulsion, breast frost, ointment, spray or aerosol) or can for example keep the non-material of sprawling of its shape (to comprise with " limited " carrier, paster for example, bioadhesive polymer, dressing or bandage) in conjunction with providing. It can be moisture or water-free; It can be configured to solution, emulsion, dispersion, suspension or any other mixture.

Some methods of application comprise the topical application to skin, eye or mucous membrane. Therefore, common medium is to be fit to those of the medicine of body surface or cosmetic applications. Composition provided herein can be to zones of different part or the area applications of patient body. Annotate as mentioned, topical application refers to for example reaching body surface organization, such as the application of skin (outer cover or overcover) and mucous membrane (producing, secrete or contain the surface of mucus). Exemplary mucomembranous surface comprises the mucomembranous surface of eye, mouthful (for example top of lip, tongue, gum, cheek, hypogloeeis and mouth), larynx, esophagus, bronchus, nasal meatus, vagina and rectum/anus; In certain embodiments, preferred port, larynx, esophagus, vagina and rectum/anus; In other embodiments, preferred eye, larynx, esophagus, bronchus, nasal meatus and vagina and rectum/anus. Annotate as mentioned, the area applications of this paper refers to the discontinuous interior zone of health, for example, and such as the application of other interior zones of joint, soft tissue area's (for example muscle, tendon, ligament, intraocular or other meat interior zone) or health. Therefore, as used herein, area applications refers to the application to the health discontinuity zone.

For part and/or the Zoned application of the present composition, the effectiveness of hope can comprise, for example therapeutic agent of the present invention infiltrate into skin and or tissue in the hyperalgesic position of basic arrival so that required anti-hyperalgesic pain relief to be provided. The effectiveness of the present composition can with for example, with central opium analgestic reach much the same. But, be discussed in detail such as this paper, because therapeutic agent of the present invention is considered to pass blood-brain barrier, therefore can preferably obtain the effectiveness that reaches with therapeutic agent of the present invention and not have the usually ill-effect relevant with the central opiate, it comprises for example respiration inhibition, calmness and habituation.

And in some embodiment that comprises the embodiment that relates to aqueous vehicle, composition also can contain glycol,, contains the compound of two or more oh groups that is. The glycol that is used in particular for composition is propane diols. In these embodiments, take the gross weight of composition as benchmark, composition is preferably to contain glycol from the concentration greater than 0 to about 5wt%. More preferably, composition contains from about 0.1 to the glycol that is less than about 5wt.%, and is preferred from about 0.5 to about 2wt.%. More preferably, composition contains the glycol of the 1wt.% that has an appointment.

Use for intra-zone, for example use in the joint, composition preferably is formulated as solution or the suspension (for example salting liquid of isotonic buffer) in aqueous medium, perhaps is combined with inner biocompatibility support or the bioadhesive polymer of using of expection.

Washing lotion, it for example can suspension, and the form of dispersion or emulsion exists, and contains one or more compounds of valid density. Usually between about 0.1-50% of one or more compounds provided herein (weight) or during higher concentration, valid density is preferably sent effective dose. Washing lotion also comprises lubricant and the equilibrium water of (weight) from 1% to 50%, suitable buffer and other agent described above. Any lubricant that can use being suitable for known to those skilled in the art that human skin is used. These lubricants include but not limited to, and are as follows: (a) hydrocarbon ils and wax comprise mineral oil, vaseline, paraffin, purification ceresine, ozocerite, microwax, polyethylene and perhydro squalene. (b) silicone oil comprises dimethyl polysiloxane, methyl phenyl silicone, water-soluble and pure dissolubility silicone-diol copolymer. (c) triglyceride fats and oil comprise from those of plant, animal and marine source. Example includes but not limited to, castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod-liver oil, apricot kernel oil, avocado oil, palm oil, sesame oil and soya-bean oil. (d) aceto-glyceride, for example acetylated monoglyceride. (e) ethoxylated glycerol ester, for example ethoxylation glycerin monostearate. (f) have the Arrcostab of the aliphatic acid of 10 to 20 carbon atoms, the methyl of aliphatic acid, isopropyl and butyl ester are available at this paper. Example includes but not limited to, lauric acid hexyl ester, laurate dissident ester, palmitic acid dissident ester, isopropyl palmitate, isopropyl myristate, decyl oleate, Isodecyl oleate, stearic acid hexadecyl ester, stearic acid ester in the last of the ten Heavenly stems, IPIS, diisopropyl adipate, adipic acid two dissident's esters, adipic acid dihexyl ester in the last of the ten Heavenly stems, diisopropyl sebacate, Lauryl lactate, Tetradecyl lactate, cetyl lactate. (g) have the alkenyl esters of the aliphatic acid of 10 to 20 carbon atoms, the example includes but not limited to myristic acid oleyl alcohol ester, stearic acid oleyl alcohol ester, oleic acid oleic alcohol ester. (h) has the aliphatic acid of 9 to 22 carbon atoms. The example that is fit to includes but not limited to n-nonanoic acid, laurate, myristic acid, palmitic acid, stearic acid, isostearic acid, hydroxy stearic acid, oleic acid, linoleic acid, castor oil acid, arachidonic acid, behenic acid and erucic acid. (i) has the fatty alcohol of 10 to 22 carbon atoms, such as but not limited to laruyl alcohol, myristyl alcohol, hexadecanol, hexadecene-1-alcohol, stearyl alcohol, isooctadecane alcohol, hydroxy stearic acid alcohol, oleyl alcohol, ricinoleyl alcohol, tadenan, erucyl alcohol and 2-octyldodecanol. (j) fatty alcohol ether, include but not limited to the fatty alcohol of 10 to 20 carbon atoms of ethoxylation, such as but not limited to, have from 1 to 50 ethylene oxide group or 1 to 50 propylene oxide group or its mixture and be connected in laruyl alcohol, hexadecanol, stearyl alcohol, isooctadecane alcohol, oleyl alcohol and cholesterol on the alcohol. (k) ether-ester, for example fatty acid ester of ethoxylized fatty alcohol. (l) lanolin and derivative; include but not limited to lanolin; lanolin oil; lanolin wax; lanolin alcohol; lanolin fatty acid; isopropyl lanolate; ethoxylation lanolin; the ethoxylation lanolin alcohol; the ethoxylation cholesterol; the propoxylation lanolin alcohol; acetyl group lanolin; the acetyl group lanolin alcohol; the lanolin alcohol linoleate; the lanolin alcohol ricinoleate; the acetic acid esters of lanolin alcohol ricinoleate; the acetic acid esters of ethoxylated alcohol (S)-ester, the hydrogenolysis of lanolin; ethoxylation aquation lanolin; ethoxylated sorbitol lanolin and liquid and semisolid lanolin absorption base. (m) polyalcohol and polyether derivative include but not limited to propane diols, dipropylene glycol, polypropylene glycol [M.W.2000-4000], polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene glycol, glycerine, ethoxylated glycerol, propoxylated glycerol, sorbierite, ethoxylated sorbitol, hydroxypropyl sorbierite, polyethylene glycol [M.W.200-6000], methoxy poly (ethylene glycol) 350,550,750,2000,5000, [M.W. 100 for poly-(oxirane) homopolymer, 000-5,000,000], PAG and derivative, hexylene glycol (2-methyl-2, the 4-pentanediol), 1,3-BDO, 1,2,6 ,-hexanetriol, Rutgers 612 USP (2-ethyl-1, the 3-hexylene glycol), C₁₅-C ₁₈The polyoxypropylene derivative of the pure and mild trimethylolpropane of vicinal. (n) polyol ester, include but not limited to, glycol monomethyl and di fatty acid ester, diethylene glycol list and di fatty acid ester, polyethylene glycol [M.W.200-6000], list and two fatty esters, propane diols list and di fatty acid ester, polypropylene glycol 2000 monoleates, polypropylene glycol 2000 monostearates, ethoxylated propylene glycol monostearate, glycerine list and double acid ester, polyglycereol polyglycerol fatty acid ester, the ethoxylated glycerol monostearate, 1,3-butanediol monostearate, the 1,3-BDO distearate, the polyoxyethylene polyols fatty acid ester, sorbitan fatty ester and polyoxyethylene sorbitan fatty acid ester. (o) wax ester, include but not limited to the derivative of beeswax, spermaceti, myristyl myristate and geoceric acid stearyl alcohol ester and beeswax, this derivative includes but not limited to, forms the polyoxyethylene sorbitol beeswax of the product of ether-ester mixture as the ethoxylated sorbitol of beeswax and ethylene oxide content variation. (p) vegetable wax includes but not limited to Brazil wax and candelila wax. (q) phosphatide, for example lecithin and derivative. (r) sterol includes but not limited to cholesterol and cholesterol fatty acid ester. (s) acid amides, for example fatty acid amide, ethoxylated fat acid amides and solid-state fatty acid alkanol amides.

Washing lotion also preferably includes (weight) from 1% to 10%, more preferably from 2% to 5% emulsifying agent. Emulsifying agent can be nonionic, anion or cationic. The example of gratifying nonionic emulsifier includes but not limited to, fatty alcohol with 10 to 20 carbon atoms, have 10 to 20 carbon atoms and fatty alcohol 2 to 20 moles of ethylene oxide or expoxy propane condensation, with the alkyl chain of 2 to 20 moles of ethylene oxide condensations in have the alkylphenol of 6 to 12 carbon atoms, the list of oxirane and di fatty acid ester, the list of ethylene glycol and di fatty acid ester (wherein fatty acid part contains from 10 to 20 carbon atoms), diethylene glycol (DEG), the polyethylene glycol of molecular weight 200 to 6000, the propane diols of molecular weight 200 to 3000, glycerine, sorbierite, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophily wax ester. The anion emulsifier that is fit to includes but not limited to, fatty acid soaps, and for example sodium, potassium and triethanolamine soap, wherein fatty acid part contains from 10 to 20 carbon atoms. Other anion emulsifiers that are fit to include but not limited to that alkylsurfuric acid ammonium, aryl sulfonic acid Arrcostab and the moieties of alkali metal, alkylsurfuric acid ammonium or replacement have the ethyoxyl ether sulfonic acid Arrcostab of 10 to 30 carbon atoms. Ethyoxyl ether sulfonic acid Arrcostab contains 1 to 50 ethylene oxide unit. Quaternary ammonium, morpholine and pyridine compound are gratifying cationic emulsifiers. Some lubricant of describing at leading portion also has emulsification property. When the washing lotion of preparation contains such lubricant, do not need other emulsifying agent, although it can add in the composition.

The other parts of washing lotion are water or C₂Or C₃Alcohol, perhaps water and alcohol mixture, by all components is simply mixed the preparation washing lotion. Preferably compound for example Loperamide be dissolved in, be suspended in or otherwise homogeneous be scattered in the mixture.

Other conventional components that can contain this washing lotion. A kind of such additive is at the thickener from composition weight 1% to 10% level. The example of the thickener that is fit to includes but not limited to: crosslinked carboxypolymethylene polymer (cross-linked carboxypolymethylene polymer), ethyl cellulose, polyethylene glycol, bassora gum, karaya (gum kharaya), xanthan gum and bentonite, hydroxy ethyl cellulose and hydroxy propyl cellulose.

Newborn frost can be formulated as and contain effectively the therapeutic agent delivery of the present invention of the effective dose therapeutic agent of the present invention to the concentration of treated tissue, be generally and contain concentration about 0.1%, preferably be higher than 1% to being higher than between 50%, preferably between about 3% to 50%, the therapeutic agent of the present invention between about 5% and 15% more preferably. The breast frost also contains from 5% to 50%, and preferably from 10% to 25% lubricant and remainder are water or other nontoxic carrier that is fit to, for example isotonic buffer solution. Describe as mentioned the lubricant that is used for washing lotion and also can be used to newborn cream composition. As indicated above, the breast frost also can contain suitable emulsifying agent. Composition contains from 3% to 50%, preferably the emulsifying agent of from 5% to 20% level.

These compositions that are configured to solution or suspension can be used to skin, maybe can be configured to aerosol or foam and spraying for skin. Aerosol combination contains (weight) from 25% to 80% usually, preferably from 30% to 50% the propellant that is fit to. The example of this propellant is chlorination, that fluoridize and the low molecular weight hydrocarbon fluorine chlorination. Nitrous oxide, carbon dioxide, butane and propane also can be used as propulsive gas. Amount and the pressure to be fit to the amount discharge container inclusion understood such as this area use these propellants.

The solution that is suitable for preparing and suspension also can be used for eye and mucous membrane by the part. Solution, especially those use the solution of preparing for eye, can be configured to the isotonic solution of 0.01%-10%, the about 5-7 of pH contains suitable salt, and preferably contains and have an appointment 0.1%, preferably be higher than 1%, until 50% or one or more compounds of this paper of higher concentration. The ophthalmic solution that is fit to be known [referring to, for example United States Patent (USP) the 5th, 116, No. 868, it has been described eye with rinse solution and has been used for the exemplary composition of the solution of topical application]. These pH are adjusted to about 7.4 solution and contain, for example, 90-100mM sodium chloride, 4-6mM dipotassium hydrogen phosphate, 4-6mM sodium hydrogen phosphate, 8-12mM natrium citricum, 0.5-1.5mM magnesium chloride, 1.5-2.5mM calcium chloride, 15-25mM sodium acetate, 10-20mM D.L.-sodium. β .-hydroxybutyric acid and 5-5.5mM glucose.

Can be by thickener and previously described solution or the suspension composition mixed preparing gel combination that will be fit to. The example of the thickener that is fit to is described when before speaking of washing lotion.

Jelly composition contains therapeutic agent of the present invention or one or more compounds provided herein of the effective dose of common about 0.1-50% weight; From 5% to 75%, preferred 10% to 50% organic solvent as discussed previously; From 0.5% to 20%, preferred from 1% to 10% thickener; All the other are the moisture or aqueous carrier not of water or other, for example, and such as organic liquid, or carrier mixture.

Can construct and arrange preparation to produce steady state blood plasma level. As is known to the person skilled in the art, Cpss can use the HPLC commercial measurement. When equaling speed that medicine removes from circulation, the speed of drug utilization reaches stable state. In common treatment was set, therapeutic agent of the present invention was applied to the patient with cyclical administration method or constant speed gasing injection method. The concentration of blood plasma Chinese traditional medicine often the time raises immediately using beginning, and often when medicine by disperseing to advance cell and tissue, by metabolism, or descend in time by draining when removing from circulation. When keeping constant in time, mean drug concentration obtains stable state. In the situation of interrupted administration, repeat in the same manner in mode each interval between administration of drug concentration circulation, it is constant that mean concentration keeps. In the situation of constant speed gasing injection, mean drug concentration will keep constant with minimum fluctuation. The realization of stable state is determined by the concentration of measuring the blood plasma Chinese traditional medicine at least one administration cycle period, so that the cycle of examining repeats between administration in the same manner. Usually in interrupted dose regimen, keeping of stable state can be examined by measuring the continuous just drug concentration of the circulation trough before another administration is used. In the low constant speed gasing injection method of fluctuation of concentration, stable state can be examined by any two continuous measurements of drug concentration.

For improving the oral bioavailability rate of The compounds of this invention, can use to strengthen the infiltrative vehicle of goldbeater's skin (Aungst, B.J.JPharmaceutical Science, the 89th volume, the 4th phase, 429-442 page or leaf, 2000).Penetration enhancers can comprise tensio-active agent, lipid acid, medium chain triglycerides, steroid stain remover, acylcarnitines and alkane phatidylcholine, the acetylizad alpha amino acid of N-and the acetylizad non-alpha amino acid of N-, and chitosan and other mucosa-adherent polymkeric substance.Concrete example comprises: cholate, glycocholate, glycosursodeoxycholate, ethylenediamine tetraacetic acid (EDTA), hydroxypropyl-beta-cyclodextrin, hydroxypropyl-γ-Huan Hujing, γ-Huan Hujing, tetradecyl-β-D-maltose, Octyl glucoside, citric acid, glycyrrhetinic acid and Tween-80 (Shah, R.B. wait the people, J.Pharm Sci., Apr.93 (4): 1070-82,2004).

(S)-7 of the present invention of kit form can be provided, and 8-is saturated-4, epoxy-morphinanium.Described test kit comprises and contains (S)-7, and 8-is saturated-4, the bottle of 5-epoxy-morphinanium compound tablet.Described test kit also comprises the specification sheets that tablet is applied to curee's (for example being applied to the patient who has diarrhoea or have symptom of diarrhea).This specification sheets comprises mark, and for example written mark shows (S)-7, and 8-is saturated-4, and 5-epoxy-morphinanium is not have its counterpart (R)-7, and 8-is saturated-4, pure (S)-7 of 5-epoxy-morphinanium, and 8-is saturated-4,5-epoxy-morphinanium.

In some embodiments of the present invention, described test kit can be randomly or is comprised pharmaceutical preparation bottle and pharmaceutical preparation thinner bottle alternatively.The bottle that contains the thinner of pharmaceutical preparation is chosen wantonly.The thinner bottle contains and is useful on dilution and may be (S)-7, and 8-is saturated-4, and the concentrated solution of 5-epoxy-morphinanium or the thinner of freeze-dried powder are such as physiological saline.Described specification sheets can comprise and be used to mix the thinner of specified quantitative and the concentrated pharmaceutical preparation of specified quantitative, thereby preparation is used to inject or the specification sheets of the final preparation of infusion.This specification sheets can comprise (S)-7 that are used for significant quantity, and 8-is saturated-4,5-epoxy-morphinanium treatment patient's specification sheets.Should also be understood that the container that contains goods, no matter this container is bottle, has membranous bottle, has membranous ampoule, infusion bag and similar containers, it can contain extra mark, such as conventional mark, when goods are sterilized through autoclaving or with method for distinguishing, its color change.

The structure of the integral part of example explanation and the details of layout in that the present invention is not limited to propose in the following description in it is used or the accompanying drawing.The present invention can have other embodiments and can be implemented in a different manner or be implemented.And employed term of this paper and term are should not be considered to restrictive to be described as purpose." comprise ", " comprising " or " having ", " containing ", " relating to " and the use in this article of its version, mean and comprise clauses and subclauses and its equivalent and the additional clauses and subclauses of after this listing.

Example I

(S)-and 17-(3 '-phenyl fourth-2 '-alkynyl)-4,5 α-epoxy-3,14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide synthetic and separating

(200mg .66mmol) (209mg 0.997mmol) is dissolved in the dimethyl formamide of 1mL with methylsulfonic acid 3-phenyl alkynes propyl ester with oxymorphone.Be reflected to stir in the steam bath and spend the night.The HPLC analysis revealed has 54% product, 13% oxymorphone and several unknown impuritie (adding up to 33%).Reaction is removed desolvate (stripped), and it is dissolved in the ethanol (1mL), be stored in and spend the night in the refrigerating chamber and elution once more.Residue is distributed between the chloroform of water and 20% Virahol.Separate each layer, and handle water layer with 10% IodineSodium Solution of 1ml.Water is with the chloroform extraction of 20% Virahol.Organic phase is filtered by 1PS paper, and solvent removed in vacuo, and residue is distributed between the chloroform of water and 20% Virahol, separates each layer then.Water is handled with the sodium iodide of 200mg, and extracts once more with the chloroform of 20% Virahol.Merge organic phase, filter, and on Rotary Evaporators, remove and desolvate to obtain the 100mg residue by 1PS paper.Described then residue is used the methylene dichloride wash-out of the 0-20% methyl alcohol of 650mL linear gradient by column chromatography (Biotage25M silicagel column) purifying.Merge the fraction (fraction) contain pure products, and remove and desolvate to obtain 50mg product (yield 18%).

¹H NMR (300MHz, CD ₃OD) δ 7.7-7.4 (m, 5H), 6.79 (s, 2H), 5.99 (d, J=15.9,1H), 4.93 (d, J=15.9,1H), 4.92 (s, 1H), 4.27 (d, J=4.2,1H), 3.7-3.6 (m, 2H), 3.45 (s, 3H), 3.4-3.1 (m, 2H), 3.1-2.9 (m, 2H), 2.25 (dt, J=15,3,1H), and 2.2-2.1 (m, 1H), 1.9-1.8 (m, 2H) .MS[M ⁺]: 417.2.HPLC purity: 95.9% (UV of 280nm place detection).

HPLC analyzes and shows purity＞95%.

The HPLC condition:Hewlett Packard 1100 series; Post: Phenomonex Synergi hydroRP post (C18,5 μ, 150 * 4.6mm); Flow velocity: 1.0mL/min; Column temperature: 40 ℃; Detector: the diode-array detector of monitoring @220 and 210nm; Wash-out: no gradient.60% water, 30% damping fluid ^*, 10% methyl alcohol; ^*700ml water, 300mL methyl alcohol, 3mL triethylamine and be enough to produce the phosphoric acid of pH3.4; Or alternatively: post: Phenomonex Synergihydro RP post (C18,5 μ, 150 * 4.6mm); Flow velocity: 1.5mL/min; Column temperature: 50 ℃; Detector: the diode-array detector of monitoring @220 and 280nm; Wash-out: gradient.

Time minute	Methyl alcohol	Water	Mix ^a	Curve
Time minute	Methyl alcohol	Water	Mix ^a	Curve	??0	??0％	??90％	??10％	Initial
??45	??30％	??60％	??10％	Linear	??0	??0％	??90％	??10％	Initial
??45	??30％	??60％	??10％	Linear	??45.1	??0％	??90％	??10％	Linear
??50	??0％	??90％	??10％	Stop	??45.1	??0％	??90％	??10％	Linear

^a(49.5% water, 49.5% methyl alcohol, 1% trifluoroacetic acid)

Example II

Summary.Anhydrous response carries out in the glass wares of oven drying and under nitrogen environment.The hydrochloride of TREXUPONT and Nalmefene is bought from Mallinkrodt, and before use by coming free alkalization (free based) with the sodium hydrogen carbonate solution washing.Methyl-iodide is bought from Alfa Aesar.All solvents are bought from Aldrich Co.Chemical preparations from commercial source directly uses.The purifying of quaternary compound is at the CombiFlash from ISCO Inc. ^TMOn the Sq16x, use 4.3g anti-phase (C18) RediSep post to carry out, described anti-phase (C18) RediSep post is reused.(150 * 4.6mm) go up execution analysis HPLC, and (carry out purifying on 250 * 21.2mm) partly preparing Phenomenex Prodigy 5 μ m ODS3 100A posts at Phenomenex Prodigy 5 μ mODS3 100A posts.NMR spectrum record on JEOL 300MHz spectrograph.In Agilent series 1100/1200LC/MSD system, obtain HPLC and MS data.

(S)-17-allyl group-17-cyclopropyl methyl-4,5 α-epoxy-3,14-two-hydroxyl-6-oxo morphinane from Sub-iodide

Synthesis program.(2.0g 5.86mmol) is dissolved in DMF (10mL, anhydrous) with TREXUPONT under nitrogen.The adding allyl iodide (0.5mL, 5.18mmol).With mixture in stirring at room 4 days.Remove DMF.Residue stirs 10min with 50mL water.The aqueous solution is separated with solid precipitation and wash with methylene dichloride (50mL).With its lyophilize to produce water absorbability solid (1.2g).With this solid of 0.2g water-soluble (30mL).Use Na ₂CO ₃The pH of the aqueous solution is transferred to 10.(2 * 20mL) washings and lyophilize are to produce yellow solid with methylene dichloride with this solution.With this solid with reversed-phase column (4g, C18) purifying is the 28mg solid, this solid is afterwards through being accredited as the mixture of F27-R and F27-S.With remaining above-mentioned water absorbability solid (～1.0g) stand same processing to be produced as the other 81mg solid of F27-R and F27-S mixture.With partly prepare HPLC with this 81mg solids constituent to produce (R) and the S of 9.5mg (0.3%) of 55mg (2%).

R: ¹H NMR (300MHz, D ₂O) δ 6.83 (d, J=8.4Hz, 1H), 6.77 (d, J=8.4Hz, 1H), 6.14-6.04 (m, 1H), 5.73-5.67 (m, 1H), 5.13-5.04 (m, 1H), 5.04 (s, 1H), 4.97-4.89 (m, 1H), 3.72-3.58 (m, 3H), and 3.17-2.83 (m, 5H), 2.30-2.25 (m, 1H), 2.16-2.09 (m, 1H), 1.88-1.78 (m, 1H), 1.24-1.14 (m, 1H), and 0.85-0.75 (m, 2H), 0.52-0.42 (m, 2H) .MS[M ⁺]: 382.2.HPLC purity: 99% (UV of 254nm place detection).

Fig. 4 is (R)-17-allyl group-17-cyclopropyl methyl-4,5 α-epoxy-3, the proton N MR spectrum of 14-dihydroxyl-6-oxo morphinanium iodide.

S: ¹H NMR (300MHz, D ₂O) δ 6.67 (d, J=8.4Hz, 1H), 6.39 (d, J=8.4Hz, 1H), 6.64 (m, 1H), 5.5.42 (m, 2H), 5.05 (s, 1H), 4.8 (m, 2H), 3.68 (m, 2H), 3.17 (m, 1H), 2.90 (m, 4H), 2.40 (m, 1H), 2.16 (m, 4H), 1.70 (m, 1H), 0.83 (m, 1H), 0.58 (m, 2H), 0.21 (m, 2H) .MS[M ⁺]: 382.2.HPLC purity: 99% (UV of 254nm place detection).

Fig. 3 is (S)-17-allyl group-17-cyclopropyl methyl-4,5 α-epoxy-3, the proton N MR spectrum of 14-dihydroxyl-6-oxo morphinanium iodide.

(S)-7,8-saturated-the opiate receptors bind of 4,5 α-epoxy-morphinanium.Science reference (Simonin, people such as F 1994, Mol.Pharmacol 46:1015-1021 are selected from use; Maguire, people such as P. 1992, Eur. J.Pharmacol.213:219-225; Simonin, people PNAS USA92 (15): 1431-1437 such as F.; Wang, JB 1994 .FEBS Lett 338:217-222) method, can carry out radioligand in conjunction with measuring to determine (S)-7,8-is saturated-4,5-epoxy-morphinanium to μ-, κ-and the binding specificity of δ-opiate acceptor.For example, film can be relevant with human opioid receptor material.Diprenorphine has the avidity to all four opioid receptors, and the competitiveness that can be used as test compounds is attacked thing (competitive challenge).Detachable film then, and can determine the combination of test compounds by scintillation counting to acceptor material.Can use such as the contrast of TREXUPONT to determine relative binding affinity.

Found to compare with the TREXUPONT contrast, (S)-17-allyl group-17-cyclopropyl methyl-4,5 α-epoxy-3,14-two-hydroxyl-6-oxo morphinanium iodide show 68% μ acceptor inhibition.(S)-and 17-(3 '-phenyl (phyenyl) fourth-2 '-alkynyl)-4,5 α-epoxy-3,14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide show for the contrast specificity and suppress in conjunction with 80% of μ acceptor.(S)-and 17-(3, the 3-dimethyl-allyl)-4,5 α-epoxy-3,14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide show contrast μ (TREXUPONT) specificity bonded 65% to be suppressed.

(S)-7,8-saturated-4,5 α-epoxy-morphinanium is to the external pharmacology of μ acceptor.Can determine M μ-receptor stimulant/antagonistic activity by (field-stimulated) guinea pig ileum that methods known in the art stimulate use.For example, the terminal ileum section of cavy can be suspended in (the 95%O that 20-ml has filled oxygenate ₂And 5%CO ₂) and the organ bath (organ bath) of the physiological salt solution of the following composition (mM) of (37 ℃) that heat up in advance in: NaCl 118.0, and KCl 4.7, MgSO ₄1.2, CaCl ₂2.5, KH ₂PO ₄1.2, NaHCO ₃25.0 and glucose 11.0 (pH 7.4).Other experiment conditions that can defer to are referring to people such as Hutchinson. (1975) Brit.J.Pharmacol., 55:541-546.

Indomethacin (1 μ M), nor-binaltorphimine (0.01 μ M), methysergide (1 μ M), ondansetron (10 μ M) and GR113808 (0.1 μ M) also can be present in the whole experiment to prevent prostanoid (prostanoid) release and to block k-opioid receptor, 5-HT2 acceptor, 5-HT3 acceptor and 5-HT4 acceptor respectively.In this test, organize to be connected in force transducer usually, be used for the equal tension record.For example, organize extending rest tension, made it balance then for example about 60 minutes to 1g, in the meantime, but repeated washing they and readjust tension force.The electricity irritation that triggers maximum collapse and the minimum strength pulse of short time length (for example 1ms time length) by constant current stimulator with the such Frequency Transfer of 0.1Hz.Can use the semi-automatic separation tract and the multi-channel data acquisition that have many organ baths to experimentize.

The example test of agonist activity.The reference agonist DAMGO (0.1 μ M) that tissue can be exposed to time peak concentration is with proof responsiveness and acquisition contrast response.Washing fully and recover the contraction suddenly of contrast after, tissue can be exposed to (S)-7 that increase concentration, 8-is saturated-4,5-epoxy-morphinanium or identical agonist.Can add different concentration cumulatively, and each keeps all contacting until obtaining stable response or continuing maximum 15 minutes with tissue.If obtain the response (suppressing to shrink suddenly) of agonist-like, can confirm that the μ acceptor participates in (S)-7 of the peak concentration of response at being used to so, 8-is saturated-4,5-epoxy-morphinanium test reference antagonist naloxone (0.1 μ M).

The example test of antagonistic activity.The reference agonist DAMGO (0.1 μ M) that tissue can be exposed to time peak concentration is to obtain the contrast response.After DAMGO inductive response is stable, can add (S)-7 that increase concentration cumulatively, 8-is saturated-4,5-epoxy-morphinanium or with reference to the antagonist naloxone.Every kind of concentration can keep contacting with tissue, up to obtaining stable response or continuing the longest time, such as 15 minutes.Can measure by each compound concentration inductive electricity and bring out the maximum variation of shrinkage amplitude suddenly.The result can be expressed as the per-cent (mean value) of contrast response to DAMGO.EC ₅₀Value (producing the concentration of half peak response) or IC ₅₀Value (causing the maximum concentration that suppresses of the half of DAMGO response) can be determined by the linear regression analysis of concentration-response curve.By (S)-7,8-is saturated-4, and 5-epoxy-morphinanium can show antagonistic activity to the μ acceptor to the inhibition of DAMGO inductive response.

In the guinea pig ileum of stimulation on the scene, μ receptor stimulant DAMGO has induced the concentration dependent minimizing of shrinkage amplitude suddenly, and it is reversed in the concentration dependent mode by the antagonist naloxone.In untreated tissue, agonist causes minimizing concentration dependent and the shrinkage amplitude suddenly naloxone sensitivity.Formerly in the tissue with the DAMGO inhibition, agonist does not produce any answer of shrinkage amplitude suddenly, but causes further minimizing.

EXAMPLE III

Estimate (S)-17-(3 '-phenyl fourth-2 ' alkynyl)-4.5 α-epoxy-3,14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide (" (S)-PM ") and (S)-17-(3, the 3-dimethyl-allyl)-4,5 α-epoxy-3,14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide (" (S)-DMAM ") is to the agonist and the antagonistic activity effect of the μ-opioid receptor in the guinea pig ileum

The evaluation of agonist activity

The evaluation of antagonistic activity

Results expression is per-cent (minimizing of the shrinkage amplitude suddenly) (mean value to DAMGO contrast response; N=2)

Determine (S)-17-(3 '-phenyl fourth-2 ' alkynyl)-4.5 α-epoxy-3, (3,3-dimethyl-allyl-dihydroxyl-17-methyl-6-oxo morphinanium oxide compound (" (S)-DMAM ") is to the EC of the μ-opioid receptor in the guinea pig ileum for 14-two-hydroxyl-17-methyl-6-oxo morphinanium iodide (" (S)-PM ") and (S)-17- ₅₀And IC ₅₀Value

Gastrointestinal smoother mistake in the rat test.Use methods known in the art, comprise A.F.Green, Br.J.Pharmacol.14:26-34,1959; L.B.Witkin, people J.Pharmacol.Exptl.Therap.133:400-408 such as C.F., 1961; People J.Pharmacol.Exptl.Ther.236:8-13 such as D.E.Gmerek, 1986; With people .Neurogastroenterol.Motil.10:523-532 such as O.Yamamoto, method described in 1998, can determine (S)-N-7 of the present invention, 8-is saturated-4, the influence of the inhibition of the morphine induction that 5-epoxy-morphinanium is crossed gastrointestinal smoother in the rat.This test can be used for the validity of proof (S)-agonist in excessive (intestinal hypermotility) problem of treatment bowel movement.

In this test, will increase the compound subcutaneous administration of concentration in rat.Behind subcutaneous administration contrast (for example morphine) and the test agonist compound, the suspension of Orally administered 10% gac in 0.25% methylcellulose gum.By euthanasia (euthanized), the taking-up intestines also are stretched in it along meter ruler on the paper of humidity rat lightly after accepting charcoal.The small intestine of measurement from the pyloric sphincter to the caecum, and assess the ratio that charcoal moves in every rat distance accounts for this length.The cms of the individual distance that the charcoal of every rat moves is divided by the cms of the total length (from the pyloric sphincter to the caecum) of intestines.

The anti-diarrhoea activity test.(S)-N-7 of the present invention, 8-is saturated-4, and 5-epoxy-morphinanium also can carry out the anti-diarrhoea activity test.For example, can use people such as Niemegeers. (1972) Arzneim Forsch22:516-518; United States Patent (USP) the 4th, 867,979; 4,990,521; The Viscotrol C test of describing in 4,824, No. 853.In this test, can be with rat or mouse overnight fasting.Every animal of compound intravenous therapy to be tested with projected dose.Period of time hereafter, the oral potion oil of accepting of animal is such as Viscotrol C or Viscotrol C (ricinio oil).Every animal is raised in independent cage.Viscotrol C treatment back for some time, estimate every animal and whether have diarrhoea.ED ₅₀Value is defined as the dosage (mg/kg body weight) that there is not diarrhoea in 50% test animal wherein.

Also can be by being evaluated in the mouse compound as PGE ₂The effect of the antagonist of inductive diarrhoea determines that anti-diarrhoea activity is [referring to people (1975) European Jour.Pharmacol.34:105-113 such as for example Dajani; With people (1977) J.Pharmacol.Exp.Ther.203:512-526 such as Dajani; Referring to No. the 4th, 870,084, United States Patent (USP) for example].This method causes diarrhoea in 15 minutes reliably in other untreated mouse.

The analgesic activity test.Following pain model is used to determine (S)-N-7, and 8-is saturated-4, the analgesic activity of 5-epoxy-morphinanium:

The acetic acid twisting of mouse is measured.Weigh mouse (CD-1, male) and be placed on single zone.Use test or contrast material, and behind the suitable soak time, intraperitoneal is used acetum.Behind the peritoneal injection acetic acid ten minutes, that writes down 5 minute period turned round the body number of times.

That writes down every mouse turns round the body total degree.Use ANOVA subsequently with relevant multinomial comparing check compare and each test substances group on average turn round the body number of times, and calculate and suppress per-cent.

Benzoquinones (PPQ) is turned round body measurement.Weigh mouse (CD-1, male) and be placed on single zone.Use test or contrast material, and behind the suitable soak time, intraperitoneal is used PPQ solution (0.02% aqueous solution).The body surface of turning round of every animal of close observation shows ten minutes.

Randall-Selitto in the rat measures.The purpose of this mensuration is to determine the influence of test substances to the rat threshold of pain.

After the overnight fast, rat is divided into ten one group.20 rats are as the vehicle contrast.Then, the 20%Brewer yeast suspension sequentially is injected into the sole of the foot face of the left back pawl of rat.After two hours, use test substances, reference drug or contrast vehicle to rat.Administration was used back one hour, measure inflammation by " pain threshold detector " and the threshold of pain of the pawl of inflammation not, described " pain threshold detector " applies the power that increases along linear graduation with constant rate of speed.

Calculate the pawl of the threshold values of control group and inflammation and the standard deviation of the pawl of inflammation not.If the individual threshold of pain surpasses two mean value standard deviations of average threshold values of control group, think that then the rat in test substances group and the reference group is shielded.

The painless mensuration of hot plate.In whole experiment, every mouse (CD-1, male) is as himself contrast.Mouse is placed on the hot plate pain threshold detector (being set to 55 ℃ ± 2 ℃) in order.Mouse to the characteristic reaction of thermal stimulus is:

1. lick fore paw

2. rear solid end agitates fast

3. jump out hot plate suddenly

In these three types of reactions any one is considered to the terminal point of thermal stimulus.When showing terminal point, immediately mouse is removed from hot plate.By being positioned over mouse on the hot plate and showing the second number that experiences between definite terminal point, measure the reaction times quantitatively.Measure the time of experiencing by the stopwatch that was accurate at least 1/5 second.Only using the own control reaction times is 10.0 seconds or mouse still less.15,30,60 and 120 minutes (± 1 to 5 minutes) after using in test or contrast material will obtain in order and write down the reaction times of each group.

Painless response is the increase of mouse to the reaction times of thermal stimulus.Under the concrete timed interval, calculate painless per-cent from the average response of the groups of ten mouse of every dosage level:

Carry out the ANOVA of suitable multinomial comparing check then.

The radiant heat test (whipping) of rat tails.In rat, produce potential ability in order to assess test substances to the painless response of thermal stimulus.

After the overnight fast, rat is weighed, and be divided into ten one group.Use test or vehicle contrast material.Use the whipping pain threshold detector.Orally administered (or recommend according to Sponsor) back 60 minutes the afterbody of every rat is exposed to the thermal stimulus of certain strength, and record causes response (distinctive whipping) the required time.

To use the average control response, contrast average test substance responds is calculated painless per-cent.

Be used as the evaluation of the compound of the anti-hyperalgesic agent of periphery.In general, method described above also is used to assess the anti-hyperpathia activity of periphery of test compounds.Be used for assessing the active method of anti-hyperpathia, most preferably those methods of describing among people (1974) the Drug Res.24:1633-1636 such as Niemegeers.

The test of assessment anti-diarrhoea activity is such as the ED in the Viscotrol C test ₅₀Value [A] and CNS effect test are such as ED in the tail test (Tail Withdrawal Test) of contracting ₅₀The ratio [C] of value [B].Being intended for use in medicament in this method and composition can lack the CNS effect as the active of diarrhea and they by them and identify.Especially, selected compound shows anti-hyperpathia activity in arbitrary standard model discussed above, and preferred (a) is as measured in standard test, these active ratios [B/A] substantially more than or equal to [equal at least, more preferably at least about 2 times greater than] the described active ratio of diphenoxylate; Perhaps (b) in measuring the active mensuration of CNS, the activity of compound basically than diphenoxylate little [at least 2 times, preferred 3 times or more].

The external pharmacology cAMP that expresses the Chinese hamster ovary celI of human μ (MOP) acceptor measures.The mu opioid acceptor is G _iLink coupled, it works by suppressing the cAMP increase.Therefore, the variation of cAMP can be used for definite agonist/antagonist activity to the μ acceptor.Cell cAMP can increase by adding forskolin.Preferential DAMGO or the similar agonist of adding, for example interior morphine peptide-1 (endomorphin-1), fentanyl or morphine, suppressing this forskolin inductive increases.Lack the agonist effect and produce the result who is equal to independent forskolin.Therefore, the concentration that increases agonist reduces the cAMP level.

Antagonist suppresses the inhibition of cAMP such as CTOP, naloxone and ciprodime.By adding test compounds, follow by DAMGO, be forskolin then, the technician can determine whether test compounds has antagonistic activity.The antagonist concentration that increases increases cAMP.

The cAMP level of extracting can be measured via competitive EIA, utilizes alkaline phosphatase to determine.Other experiment condition as, Toll L. for example, J Pharmacol Exp Ther. (1995) 273 (2): described in the 721-7.

Comprise the name of submitting on May 25th, 2006 be called " Synthesis of (R)-N-Methylnaltrexone ((R)-N-methyl naltrexone synthetic) " the 11/441st, No. 395 and name be called " (S)-N-Methylnaltrexone ((S)-N-methyl naltrexone) " the 11/441st, No. 452 U.S. Patent applications, this paper are quoted or the disclosure of all patents, patent application and the scientific publication thing of reference is all incorporated the place that this paper is fit to instruction additional or selectable details, feature and/or technical background by reference into.Exist when conflicting in the file of incorporating into by reference and the application, be as the criterion with the application.

So far described several embodiments of the present invention, should be understood that, those skilled in the art can expect various variations, modification and improvement easily.These change, modify and improve the part that is contemplated to present disclosure, and expection within the spirit and scope of the present invention.Correspondingly, explanation before and accompanying drawing are only as an example.

Statement about embodiment

Although described the present invention with regard to embodiment, the person skilled in the art will easily understand, under the situation of the spirit or scope of the present invention that do not deviate from the claims qualification, can make different variations and/or modification to the present invention.The All Files that this paper mentions is incorporated herein the place that is fit to instruction extra or selectable details, feature and/or technical background by reference.

Claims

1. the isolated compound of (S) configuration with regard to nitrogen of a formula I (c), perhaps its pharmacy acceptable salt form or prodrug forms:

Wherein:

R ₁And R ₂Be H, OH, OR independently ₂₆, halogenide, silyl; Alkyl, cyclic hydrocarbon radical or its replacement part;

Perhaps R ₁And R ₂Also can be according to R in conjunction with forming ₁₉The C that replaces ₃-C ₆Carbocyclic ring condensed ring, benzene

And condensed ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silyl, CO ₂R ₁₉, SO ₂R ₁₉, B (OR ₂₆) ₂

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

C ₁-C ₃Acyl group

R ₅Be H, OH, OR ₂₆,

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

Amine, acid amides, sulphonamide or ester;

R ₇And R ₈Be H, alkyl, cyclic hydrocarbon radical independently, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Arylalkyl or its replace part, perhaps

Wherein X be key ,=O, O, S, N (R ₁₉), SO, SO ₂, SO ₂N (R ₁₉), CON (R ₁₉), N (R ₁₉) CON (R _{19 '}), N (R ₁₉) C (=NR _{19 '}) N (R _{19 "}), COO;

Perhaps R ₇And R ₈Can be in conjunction with forming according to R ₁₉Carbocyclic ring condensed ring, the fused benzo ring that replaces, have 0-3 R ₂₀5-, 6-or 5-6 unit aryl or heteroaryl;

R ₁₄Be H, OH, OR ₂₆, NR ₂₂R ₂₃SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Arylalkyl;

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces; Aryloxy, acyloxy,

Or R ₁₄Can be according to its configuration with regard to quaternary nitrogen and and R ₁₈In conjunction with forming O-condensed ring or C ₃-C ₆The carbocyclic ring condensed ring;

R ₁₇And R ₁₈Be can substituted C ₁-C ₆If alkyl is R wherein ₁₈Be methyl, R then ₁₇Not allyl group, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 _R20Arylalkyl,

R ₁₉When occurring, be independently selected from: H, C at every turn ₁-C ₆Alkyl, CF ₃, OR ₂₄, Cl, F, Br, I ,=O, CN, NO ₂, NR ₂₂R ₂₃, a 0-3 R ₂₀The aryl that replaces;

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

R ₂₀When occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, ethanoyl, OR ₂₅, XR ₂₅,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-;

R ₂₁When occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, CF ₃, ethanoyl, OR ₂₅, XR ₂₅,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-; Perhaps

R ₂₂When occurring, be independently selected from H, C at every turn ₁-C ₆Alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl and arylalkyl;

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₃When occurring, be independently selected from: H, (C at every turn ₁-C ₆) alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl, haloalkyl, arylalkyl,

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₄When occurring, be independently selected from H, phenyl, benzyl, (C at every turn ₁-C ₆) alkyl and (C ₂-C ₆) alkoxyalkyl;

R ₂₅Be alkyl, aryl or arylalkyl;

R ₂₆When occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

X ^-It is negatively charged ion.

2. the isolated compound of (S) configuration with regard to nitrogen of a formula I, perhaps its pharmacy acceptable salt form or prodrug forms:

Wherein:

R ₁And R ₂Be H, OH, OR independently ₂₆, halogenide, silyl; Alkyl, cyclic hydrocarbon radical or its replacement part; Perhaps R ₁And R ₂Also can be according to R in conjunction with forming ₁₉The C that replaces ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silyl;

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

C ₁-C ₃Acyl group

R ₅Be H, OH, OR ₂₆,

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

R ₆Be H ,=O, OH, OR ₂₆

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces;

Amine, acid amides, sulphonamide or ester;

R ₇And R ₈Be H, alkyl, cyclic hydrocarbon radical or its replacement part independently; Perhaps R ₇And R ₈Can be in conjunction with forming according to R ₁₉The carbocyclic ring condensed ring that replaces, fused benzo ring or 5-6 unit heteroaryl condensed ring;

0-3 R ₁₉(the C that replaces ₁-C ₈) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₈) alkynyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₀(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₀The aryl that replaces; Aryloxy, acyloxy,

Or R ₁₄Can be according to its configuration with regard to quaternary nitrogen and and R ₁₇Or R ₁₈In conjunction with forming O-condensed ring or C ₃-C ₆The carbocyclic ring condensed ring;

R ₁₇And R ₁₈Be can substituted C ₁-C ₆If alkyl is R wherein ₁₈Be methyl, R then ₁₇It or not allyl group;

R ₁₉When occurring, be independently selected from every turn:

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

R ₂₀When occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, ethanoyl,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-;

R ₂₁When occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, CF ₃, ethanoyl,

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl group, C ₁-C ₄Haloalkyl,

C ₁-C ₄Halogenated alkoxy and C ₁-C ₄Haloalkyl-S-; Or

R ₂₂When occurring, be independently selected from H, C at every turn ₁-C ₆Alkyl,

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₃When occurring, be independently selected from every turn:

H, (C ₁-C ₆) alkyl,

(C ₁-C ₆Alkyl)-C (=O)-and (C ₁-C ₆Alkyl)-S (=O) ₂-;

R ₂₅Be alkyl, aryl or arylalkyl;

R ₂₆When occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃

0-3 R ₂₁The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₁The aryl that replaces; Or

X ^-It is negatively charged ion.

3. the compound of formula I as claimed in claim 2, perhaps its pharmacy acceptable salt form or prodrug forms, wherein said negatively charged ion is halogenide, vitriol, phosphoric acid salt, nitrate or is with anionic organism class.

4. the compound of formula as claimed in claim 3 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein said halogenide is bromide.

5. the compound of formula as claimed in claim 3 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein said halogenide is iodide.

6. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, it has at least 90% purity.

7. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, it has at least 95% purity.

8. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, it comprises crystalline form.

9. the compound of formula as claimed in claim 4 (I), perhaps its pharmacy acceptable salt form or prodrug forms, it comprises crystalline form.

10. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein the S-configuration with regard to quaternary nitrogen is 95% pure.

11. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein the S-configuration with regard to quaternary nitrogen is 98% pure.

12. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein the S-configuration with regard to quaternary nitrogen is 99.5% pure.

13. the compound of formula as claimed in claim 2 (I), perhaps its pharmacy acceptable salt form or prodrug forms, wherein the S-configuration with regard to quaternary nitrogen is 99.8% pure.

14. a composition, it contains the described compound of claim 2 or its pharmacy acceptable salt form or prodrug forms, and wherein the S-configuration with regard to quaternary nitrogen is 99.8% pure.

15. composition as claimed in claim 14, wherein said composition is a solution.

16. composition as claimed in claim 14, wherein said composition is a solid.

17. a pharmaceutical composition, it comprises described compound of the claim 2 for the treatment of significant quantity and pharmaceutically acceptable carrier.

18. pharmaceutical composition as claimed in claim 17, wherein said composition is an oral preparations.

19. pharmaceutical composition as claimed in claim 17, wherein said composition are controlled release or sustained release preparation.

20. pharmaceutical composition as claimed in claim 17, wherein said composition is a topical formulations.

21. pharmaceutical composition as claimed in claim 17, wherein said composition is cryodesiccated.

22. pharmaceutical composition as claimed in claim 17, wherein said composition is a suppository.

23. a sucker, it contains the described pharmaceutical composition of claim 17.

24. a nose spraying plant, it contains the described pharmaceutical composition of claim 17.

25. pharmaceutical composition as claimed in claim 17, it further comprises the therapeutical agent outside the described compound of claim 2.

26. pharmaceutical composition as claimed in claim 25, wherein said therapeutical agent is an opioid agonist.

27. pharmaceutical composition as claimed in claim 26, wherein said opioid is selected from by alfentanil, anileridine, asimadoline, Bremazocine; buprenorphine; butorphanol; morphine monomethyl ether; Wy-16225; diacetylmorphine (heroine); saturated morphine monomethyl ether; diphenoxylate; fedotozine; fentanyl; richness is received bent amine; hydrocodone; hydromorphone; levallorphan; Levomethadyl Acetate; levorphanol; Loperamide; dolantin (Pethidine); methadone; morphine; morphine-6-glucuronide; nalbuphine; nalorphine; opium; oxycodone; oxymorphone; pentazocine; propiram; the third oxygen sweet smell; remifentanil; sufentanil; Tilidine; trimebutine; the group that U-26225A and its combination are formed.

28. pharmaceutical composition as claimed in claim 26, wherein said opioid or opioid agonist do not have central nervous system (CNS) activity substantially.

29. pharmaceutical composition as claimed in claim 25, wherein said therapeutical agent are not opioid, opioid agonist or opium sample antagonist.

30. pharmaceutical composition as claimed in claim 29, wherein said therapeutical agent are non-opium sample pain killer/febrifuge, antiviral agent, antibiotic agent, anti-mycotic agent, antiseptic-germicide, sanitas, antiprotozoan agent, antiparasitic, anti-inflammatory agent, vasoconstrictor, local anesthetic, diarrhea, anti-hyperalgesic agent or its combination.

31. pharmaceutical composition as claimed in claim 29; wherein said therapeutical agent is a diarrhea, and it is a Loperamide; the Loperamide analogue; the N-oxide compound of Loperamide and its analogue; metabolite and prodrug; diphenoxylate; cisapride; antacid; aluminium hydroxide; neusilin; magnesiumcarbonate; magnesium hydroxide; lime carbonate; polycarbophil; dimethyl silicone oil; tropine; coromegine; Nifurazolidone; difenoxin; Sostatin; lansoprazole; kaolin; pectin; gac; sulfanilylguanidine; succinylsulfathiazole; phthalylsulfathiazole; Bismuth Aluminate; Bismuth Subcarbonate; bismuth sub citrate; bismuth citrate; Bismuth Potassium Citrate; Bismuth tartrate; bismuth subsalicylate; Vikaline and Bismuth Subgallate; laudanum (pain killer); herbal medicine; plant-sourced diarrhea or its combination.

32. pharmaceutical composition as claimed in claim 29, wherein said therapeutical agent is an anti-inflammatory agent, and it is that NSAID (non-steroidal anti-inflammatory drug) (NSAID), tumor necrosis factor inhibitors, basiliximab, daclizumab, infliximab, wheat are examined phenol ethyl ester, azathioprine, tacrolimus, steroid, sulfasalazine, Olsalazine, U.S. salad is bright or its combination.

33. pharmaceutical composition as claimed in claim 29, wherein said therapeutical agent is an antiviral agent.

34. pharmaceutical composition as claimed in claim 29, wherein said therapeutical agent is an antiseptic-germicide.

35. pharmaceutical composition as claimed in claim 29, wherein said therapeutical agent are anti-hyperalgesic agents.

36. a method that suppresses curee's diarrhoea, it comprises the described pharmaceutical composition of claim 17 from the amount of effective treatment or prevention diarrhoea to the curee of this treatment of needs that use.

37. method as claimed in claim 36, it further comprises diarrhea from the compound of described (the S)-N-of non-claim 2 steric isomer to described curee that use.

38. method as claimed in claim 37, the diarrhea of the compound of described (the S)-N-of wherein said non-claim 2 steric isomer is opioid or opioid agonist.

39. the method for the excretion of ileostomy that reduces the curee or colostomy, it comprises that curee to this minimizing of needs uses the described pharmaceutical composition of claim 17 of amount of the excretion of effective minimizing ileostomy or colostomy.

40. the method for the excretion rate of ileostomy that reduces the curee or colostomy, it comprises that curee to this minimizing of needs uses the described pharmaceutical composition of claim 17 of amount of the excretion rate of effective minimizing ileostomy or colostomy.

41. the method for a curee who suppresses this treatment of needs gastrointestinal peristalsis, it comprises the described pharmaceutical composition of claim 17 of amount from effective inhibition curee's gastrointestinal peristalsis to described curee that use.

42. method as claimed in claim 41, it further comprises to described curee uses opioid or opioid agonist.

43. a method for the treatment of irritable bowel syndrome, it comprises that patient to this treatment of needs uses the described pharmaceutical composition of claim 17 of the amount of effective at least a symptom of improving irritable bowel syndrome.

44. a method that suppresses curee's pain, it comprises the described pharmaceutical composition of claim 17 of the amount of using effective prevention or treatment pain.

45. method as claimed in claim 44, it further comprises the therapeutical agent outside described curee is applied in the compound of described (the S)-N-of claim 2 steric isomer in the described composition.

46. method as claimed in claim 45, the therapeutical agent outside the compound of described (the S)-N-of wherein said claim 2 in described composition steric isomer is an opioid.

47. method as claimed in claim 45, the therapeutical agent outside the compound of described (the S)-N-of wherein said claim 2 in described composition steric isomer is antiviral agent, antibiotic agent, anti-mycotic agent, antiseptic-germicide, sanitas, antiprotozoan agent, antiparasitic, anti-inflammatory agent, vasoconstrictor, local anesthetic, diarrhea or anti-hyperalgesic agent.

48. method as claimed in claim 44, wherein said pain are periphery hyperpathia.

49. method as claimed in claim 44, wherein said pharmaceutical composition is locally applied to the position of described pain.

50. method as claimed in claim 44, wherein said using is IA.

51. method as claimed in claim 44, wherein said using is general.

52. method as claimed in claim 44, wherein said using is partial.

53. method as claimed in claim 44 wherein is applied to eye with described composition.

54. a method that suppresses curee's inflammation, it comprise Xiang Youxiang in requisition for the curee use the described pharmaceutical composition of claim 17 of the amount of the described inflammation of effective inhibition.

55. method as claimed in claim 54, it further comprises the therapeutical agent outside described curee is applied in the compound of described (the S)-N-of claim 2 steric isomer in the described composition.

56. method as claimed in claim 55, the therapeutical agent outside the compound of described (the S)-N-of wherein said claim 2 steric isomer is an anti-inflammatory agent.

57. one kind is suppressed the method that the curee produces tumour necrosis factor (TNF), it comprises composition from the described pharmaceutical composition of claim 17 that contains TNF generation amount of suppression to described curee that use.

58. a test kit, it comprises the packing that contains sealed vessel and working instructions, and described sealed vessel contains the described pharmaceutical composition of claim 17.

59. test kit as claimed in claim 58, it further comprises the combination of consistency therapeutical agent, and one of wherein said therapeutical agent is a peripheral opioid sample antagonist.

60. method as claimed in claim 17, counterpart (R)-N-steric isomer that wherein said peripheral opioid sample antagonist is described compound.

61. a composition, it comprises claim 2 described (S) compound, and wherein said composition does not have the detectable counterpart of HPLC (R)-steric isomer under the quantitative limit of 0.02% detectability and 0.05%.

62. the isolated compound of (S) configuration with regard to nitrogen of a formula Ia:

Wherein:

(a) do not replace or non-halogen replaces: C ₄-C ₈(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl; C ₄-C ₆(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl

(b) C that replace or unsubstituted straight or branched ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl or C ₃-alkynyl;

If wherein (b) be chosen as methyl and R ₆Be=O that then (a) is not unsubstituted (cyclopropyl) methyl;

R ₆Be H, OH ,=O ,=CH ₂,-N (CH ₃) ₂Or any ring-like ring, perhaps with R ₇Form ring-like ring;

R ₇And R ₈Be H or alkyl;

R ₁₄Be H, OH, halogenide, aryl amido, amino, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkylalkyl, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃, alkoxyl group, aryloxy or aryl-alkoxyl group or and R ₁₇Or R ₁₈Form ring-like ring;

R ₁And R ₂Be H, halogenide, alkoxyl group, alkyl or aryl independently;

R ₃Be H, C ₁-C ₄Alkyl or C ₁-C ₃Acyl group ,-silyl;

R ₅Be H, OH, alkyl, alkoxyl group or aryloxy; And

X ^-It is negatively charged ion.

63. the isolated compound of (S) configuration with regard to nitrogen of a formula Ib:

Wherein

R ₁₇And R ₁₈Be that replace or unsubstituted C ₁-C ₆Alkyl is wherein worked as R ₆Be chosen as=during O,

R ₁₇And R ₁₈In at least one be not methyl when another is the cyclopropyl methyl;

R ₆Be H, OH, OR ₂₅,=O ,=CH ₂,-N-alkyl, N-dialkyl group, acyloxy, alkoxyl group, alkyl, R ' and R " be H or C independently ₁-C ₁₀Alkyl=CR ' R " or any ring, perhaps R ₆With R ₇Form ring;

R ₁₄Be H, OH, halogenide, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkylalkyl, SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅Alkoxyl group, aryloxy or alkoxy aryl are perhaps with R ₁₇Or R ₁₈Form ring;

R ₁And R ₂Be H, halogenide, alkoxyl group, alkyl or aryl independently;

R ₃Be H, alkyl, C ₁-C ₃Acyl group, silyl;

R ₅Be H, OH, alkyl, alkoxyl group or aryloxy;

R ₂₅Be alkyl, aryl, arylalkyl; And

X ^-It is negatively charged ion.