CN101610770A

CN101610770A - 7,8-is saturated-4,5-epoxy-morphinanium analogs

Info

Publication number: CN101610770A
Application number: CNA2007800501446A
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: 2009-12-23
Also published as: CN101636160A

Abstract

Disclose newly 7,8-is saturated-4,5-epoxy-morphinanium analogs.Also disclose and contained 7,8-is saturated-4, the pharmaceutical composition of 5-epoxy-morphinanium analogs and their medicinal method.Disclosed chemical compound is useful, especially as the regulator of Opioid Receptors.

Description

7,8-is saturated-4,5-epoxy-morphinanium analogs

Background of invention

Invention field

The present invention relates generally to comprise 7,8-dihydro-4,5-epoxy-morphinanium (7,8-dihydro-4,5-epoxy-morphinanium) analog is interior new 7,8-singly-bound-4, the synthetic method of 5-epoxy-morphinanium analogs (hereinafter referred to as " 7; 8-is saturated-4,5-epoxy-morphinanium "), their preparations, comprise their pharmaceutical preparation and their using method.The sequence number that the application requires on November 22nd, 2006 to submit to is the rights and interests of 60/867,099 U.S. Provisional Application and the U.S. Provisional Application 60/867,390 submitted on November 27th, 2006, and it all incorporates this paper by reference in full into.

Description of Related Art

Opioid (opioid) is to be incorporated into some to be called Opioid Receptors, mainly to be present in the medicament of central nervous system and gastrointestinal receptor.They demonstrate the characteristic of similar Opium or morphine usually.Four big OPIOIDS sample materials are arranged: endogenous opioid peptide results from the body; Opium alkaloid, for example morphine (prototype opioid) and codeine; Semi-synthetic opioid, for example heroin and oxycodone; And structure and the irrelevant complete synthesis opioid of Opium alkaloid, for example Pethidine and methadone.Although use with term " opiate (opiate) " synonym, term " opiate " more properly is used to describe the semi-synthetic derivant derived from the alkaloidal opioid compounds of natural Opium or these derivative compounds.Having the active opioid chemical species of similar morphine has: the Opium alkaloid of the purification of being made up of luxuriant and rich with fragrance class (morphine and codeine all have phenanthrene ring or morphinan ring structure) and benzylisoquinoline class, semi-synthetic derivant, phenylpiperidine derivative, morphinan derivant, benzomorphans derivant, Diphenylheptane derivant and the N-propionanilide derivant of morphine.

The opioid compounds receptor has been divided at least four main kind: μ (μ-1, μ-2 and μ-3), κ and δ.Another Opioid Receptors is identified.This receptor is nociceptin receptor or ORL 1 receptor.In the receptor of these kinds each all is considered to spread all over CNS and periphery.All these receptors all are assumed that the G-G-protein linked receptor that GABA energy neurotransmission is worked.The exciting activation of these receptors has activated increase K ⁺The K of outflow ⁺Electric current, promptly hyperpolarization reduces voltage-gated Ca thus ²⁺Interior stream.Via K ⁺The hyperpolarization of the transmembrane potential of electric current and Ca ²⁺The block nerves transmission is plain in the different neuron paths discharges and the pain transmission interior being suppressed at of flowing.To opioid pharmacology response depend on it bonded receptor, it still is the mode combination of antagonism to the affinity and the described opioid compounds of receptor with excitement.The activation of relative another receptor of receptor can cause different pharmacodynamic profile.For example, activate μ-1 receptor by the opioid agonist morphine and can cause analgesia (supraspinal analgesia) on the sour jujube, and can mediate respiration inhibition and drug dependence, can mediate the spinal cord analgesia by activating κ-receptor by activating μ-2 receptor.

Opioid compounds can be divided into agonist and antagonist by broad sense.Term " agonist " is meant and receptors bind, thereby induces the signaling molecule that produces the conformation change that responds.Term " antagonist " broadly refers to reduce the medicine of agonist effect.

The effectiveness of opioid compounds is fallen on the slip scale (slidingscale) from the full agonist to the antagonist.For example, several morphinan derivants that have different substituents on the N atom have been found and have shown narcotic antagonist and narcotic analgesics activity.These chemical compounds are called as agonist-antagonist.The United States Patent (USP) of Pachter and Matossian discloses that the N-that comprises N-cyclobutylmethyl radical derivative replaces for the 3rd, 393, No. 197-14-hydroxyl dihydro normorphine, is commonly referred to nalbuphine.The United States Patent (USP) of Monkovik and Thomas discloses N-cyclobutylmethyl-3 the 3rd, 775, No. 414, and 14-dihydroxy morphinan is commonly referred to butorphanol.People's such as Bentley United States Patent (USP) discloses 17-(cyclopropyl methyl)-α-(1 for the 3rd, 433, No. 791, the 1-dimethyl ethyl)-4,5-epoxy-18,19-dihydro-3-hydroxyl-6-methoxyl group-Alpha-Methyl-6,14-ethylene morphinan-7-methanol is commonly called buprenorphine.

Opioid agonist is used for many indications by clinical, comprises producing analgesia and anesthesia, cough-relieving, alleviation diarrhoea, improving because breathing (breadth) very brief anxiety that causes (oxymorphone) and the excessive detoxifcation of opioid antagonists.Except their clinical useful effect, opioid agonist also is in the news and has many side effect, comprises constipation, dysphoria, respiration inhibition, dizziness, feels sick, dependence and pruritus.In these side effect some may be relevant with the activation of periphery rather than maincenter receptor.For example, because the receptor on the intestinal wall, using of [mu agonist can cause for example constipation of intestinal dysfunction.Concerning the patient who has accepted long-term opioid dosage, suffering from tedious especially disease (being known as intestinal obstruction) is common problem, and intestinal obstruction is to coordinate the caused intestinal of broken ring (bowel) of wriggling or the obstruction of intestinal (gut), especially colon normally by intestinal.

WO 2004/029059N-quaternary hydromorphone agonist, wherein nitrogen has methyl substituents and C ₁-C ₆Substituent group.These chemical compounds it is said provides effective μ-agonist activity, but does not pass blood brain barrier, thereby has reduced opioid agonist CNS side effect.Similarly, the N-methyl quaternary derivant (naltrexone and naloxone) of WO 2004/043964 open antagonism morphinane alkaloid is effective antagonist of μ receptor, this is not enter the central nervous system because their ionic charge can not be passed through blood brain barrier, thereby when both during by exogenous using simultaneously, the central pain that can not block the endogenous opioid compound of excitability opioid or natural generation is alleviated active.

Known some opioid analog plays Opioid Receptors in conjunction with antagonist, and in other words, analog is bonded to Opioid Receptors and disturbs the active expression of acceptor site place's opioid.Opioid antagonists has reversed the narcotic most of drug action of opioid, for example analgesia, calmness, respiration inhibition and contracted pupil.According to being emulative or noncompetitive, antagonist generally can be divided into two big classes, " surmountable (surmountable) " or " unsurmountable (insurmountable) " (or " unvanquishable (unsurmontable) ").

Be classified as the [mu of G-G-protein linked receptor (GPCR), shown to have available μ ^*The constitutively activate state of expression (referring to, for example the U.S. the 6th, 007, No. 986 patents).Since the contact of the medicine before not having (initial condition), μ ^*The activity of state is considered to minimum.Show the chemical compound of antagonist activities to having the active specific GPCR of baseband signal (for example μ-Opioid Receptors), the effect that is shown based on the baseband signal activity to special receptor has been classified as neutral antagonist or inverse agonist, and reactive compound is the part of described special receptor in interaction." reverse antagonists " is to block the effect of the agonist that is positioned at target recipient and suppress the active medicament of natural receptor." neutral antagonist " means and only is incorporated into receptor but do not change its active chemical compound.Invalid antagonist optionally is bonded to immobilized drug susceptibility μ receptor status or constitutively activate μ receptor status or this two states.

The morphinan derivant that also has other N-replacement is the pure narcotic antagonist that has seldom or do not have agonist activity.The United States Patent (USP) of Lewenstein discloses N-pi-allyl-7 the 3rd, 254, No. 088, and 8-dihydro-14-hydroxyl normorphine ketone is commonly called naloxone.The United States Patent (USP) of Pachter and Matossian discloses that the N-that comprises N-cyclopropyl methyl analogue replaces for the 3rd, 332, No. 950-14-hydroxyl-dihydro normorphine ketone, is commonly called naltrexone.The chemical compound of these two patents is narcotic antagonists.

Naloxone and naltrexone are actually does not have the pure opioid antagonists of analgesic activities (Bulberg, H.; Dayton, H.B.Narcotic Antagonists (narcotic antagonist), Braude, M.C., Harris, L.S.; May, E.L.; Smith, J.P.; Villarrela, J.E., Ed.; Raven:New York, 1974; The 33-43 page or leaf).Competitive antagonist, for example naloxone and naltrexone are bonded to Opioid Receptors but activated receptor not with the affinity that is higher than agonist.This has replaced agonist, weakens and/or reverses the agonist effect.This has blocked receptor effectively, avoids health to utilize opioid and endorphins (the natural protein that is incorporated into Opioid Receptors).On the other hand, nalorphine and nalbuphine, although their effective μ antagonistic activities described above, be in the news and had their analgesic activities (Casy, A.F., Parfitt by the excitement of opioid κ-receptor, R.T., Opioid Analgesics, Chemistry and Receptors (opioid analgesic, chemical property and receptor); Plenum:New York, 1986; Chapter 4,153-214 page or leaf).

For many years, drug dependence or the drug addiction that is caused by opioid treated by the drug withdrawal of using opioid agonist drug (for example naltrexone and naloxone).This therapeutic scheme may define another kind of medicine (for example methadone, buprenorphine or acemethadone (methadylacetate)) to opioid replacement.Opioid is excessive can also to be reversed rapidly by opioid antagonists.

Recently, carried out by using the optionally trial of the inductive side effect of antagonism opioid of receptor antagonist (for example naloxone or nalmefene).Yet owing to these chemical compounds also can reverse analgesia and cause opioid to be given up, so this successfully can be described as limited (Yuan, C.-S. etc., J.Pharm.Exp.Ther.300:118-123 (2002)).For example, naloxone and naltrexone pointed out in the treatment of gastrointestinal motility obstacle effectively (referring to, for example United States Patent (USP) the 4th, 987, No. 126 and Kreek, M.J.Schaefer, R.A., Hahn, E.F., Fishman, J.Lancet, 1983,1,8319,261, it discloses naloxone and other opioid antagonists based on morphinan (being naloxone, naltrexone) that are used for spontaneous gastrointestinal motility treating dysfunction).Naloxone also is in the news and can effectively treats the inductive intestinal obstruction of non-opioid, hint this medicine may be directly to the GI road or in brain, work (referring to, Schang for example, J.C., Devroede, G., Am.J.Gastroenerol., 1985,80,6,407), and point out treatment (Mack, D.J.Fulton as paralytic ileus, J.D., Br.J.Surg., 1989,76,10,1101).Yet well-known, the activity of naloxone and naltrexone is not limited to peripheral-system and can disturbs the narcotic analgesic activity of opioid.

Many side effect that opioid agonist produces are considered to the maincenter origin.For avoiding these side effect, proposed and developed and do not passed peripheral opioid sample material agonist and the antagonist that blood brain barrier enters the central nervous system.

Advised causing the constipation effect (referring to United States Patent (USP) the 4th with what quaternized opioid antagonists was used for the selective exclusion narcotic antagonist, 806, No. 556, second hurdle, 51-53 is capable), it comprises some peripheral mu-antagonisies derived from the naltrexone structure (people such as Botros, J.Med.Chem.1989,32,2068-2071).Tested the effectiveness of many peripheral opioid sample substance antagonists of having developed in the opioid gastrointestinal side effect of prevention.For example, at United States Patent (USP) the 5th, 250, No. 542, United States Patent (USP) the 5th, 434, No. 171, United States Patent (USP) the 5th, 159, No. 081 and United States Patent (USP) the 5th, 270, in No. 328, periphery optionally piperidines-N-alkyl carboxyl opioid antagonists (piperidine-N-alkylcarboxylate opioid antagonist) is described as be in the treatment of spontaneous constipation, irritable bowel syndrome and the constipation of opioid inductivity effectively.The WO2004/043964 that above discussed discloses the n-methyl quaternary derivant of naltrexone and naloxone, described derivant be positioned mainly that peripheral acceptor in the gastrointestinal tract combine and alleviate the adverse side effect of opiate treatment, for example constipation and nauseating by their antagonist activities thus.United States Patent (USP) the 4th, 176 has been described the quaternary derivant of nor-oxymorphone (being methyl naltrexone) No. 186, and described derivant is reported prevention or alleviated the intestinal immobility side effect of narcotic analgesics and reduce analgesia and render a service.United States Patent (USP) the 5th, opioid-and/or non-opioid is inductive uses purposes in the relevant side effect (comprising the reduction of using relevant intestinal mobility with opioid) with opioid preventing and/or treating for other quaternary derivants of having described methyl naltrexone, enteric-coated methyl naltrexone or nor-oxymorphone for 972, No. 954.

Need not have obvious maincenter activity but other opioid compounds of adjusting 10K receptor (especially μ-Opioid Receptors).Minimized while of periphery side effect that need opioid be used also, anti-peripheral opioid sample material is active and/or allow the opioid compounds of positive opioid effect (for example analgesia), or in the enteral effect so that opioid use the minimized opioid compounds of the harmful effect of enteral dynamic equilibrium.

Summary of the invention

This paper provides and has been incorporated into the new 7 of μ-Opioid Receptors, and 8-is saturated-4,5-epoxy-morphinanium chemical compound, particularly 7,8-dihydro-4,5-epoxy-morphinanium.In one embodiment, 7,8-is saturated-4, and 5-epoxy-morphinan compounds has limited or depletion of blood brain barrier, so can the central effect and cause significant maincenter side effect.

Chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I are disclosed in one embodiment of the invention:

Wherein:

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

(a) unsubstituted or non-halogen replaces: C4-C20 (cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl ((cycloheteryl) alkyl), (cyclophane base) alkyl; C4-C10 (cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl

(b) C1-C3 alkyl, C2-C3 thiazolinyl or C3 alkynyl that replace or unsubstituted straight or branched;

Wherein, if (b) be chosen as methyl, and following R6 is chosen as=O, and then (a) is not unsubstituted (cyclopropyl) methyl;

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

R ₇And R ₈Be H or alkyl;

R ₁₄Be OH, halogenide, acylamino-, amino or and R ₁₈Form ring-like ring, and if R ₆=ring-like ring or and R ₇When forming ring-like ring, R ₁₄Can also be alkoxyl or aryloxy group, and if R ₆Be not=during O, R ₁₄Can be alkoxyl or aryloxy group;

R ₁And R ₂Independent is H, halogenide, alkoxyl, alkyl or aryl

R ₃Be H, C1-C4 alkyl or C1-C3 acyl group ,-silicyl;

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

X ^-It is anion.

Chemical compound with formula I (a) is disclosed in another embodiment, or its pharmaceutically acceptable salt form, polymorphs body or prodrug:

Wherein:

R ₁And R ₂Independent is H, OH, OR ₂₉, halogenide, silicyl;

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;

Perhaps R ₁And R ₂In conjunction with forming C ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silicyl;

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 ₅Be H, OH, OR ₂₉,

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, N (CH ₃) ₂, or any ring-like ring;

R ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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;

Perhaps R ₆And R ₇In conjunction with forming O-condensed ring, C ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₈Be H, OH, OR ₂₉

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 ₁₄Be H, OH, halogenide,

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 group, acyloxy,

Perhaps with R ₁₈In conjunction with forming O-condensed ring or C ₃-C ₆If the carbocyclic ring condensed ring is perhaps R ₆=ring-like ring or and R ₇When forming ring-like ring, can also be alkoxyl or aryloxy group;

If R wherein ₆Be=during O, R ₁₄Be not:

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;

R ₁₇Be 0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

R ₁₉When occurring, independently be selected from 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 sulfur, wherein said 5 to 10 yuan of heterocycles are through 0-3 R ₂₁Replace;

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

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

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

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

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl, 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 (piperizinyl) and morpholinyl;

R ₂₂When occurring, independently be 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 ₂₃, when occurring, independently be 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 ₂₄, when occurring, independently be selected from H, phenyl, benzyl, (C at every turn ₁-C ₆) alkyl and (C ₂-C ₆) alkoxyalkyl;

R ₂₅, when occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

Contain 1 to 4 heteroatomic 5 to 10 yuan of heterocycle that are selected from nitrogen, oxygen, wherein said 5 to 10 yuan of heterocycles are through 0-3 R ₂₇Replace;

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, independently be selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, independently be selected from every turn:

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

R ₂₉When occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

Contain 1 to 4 heteroatomic 5 to 10 yuan of heterocycle that are selected from nitrogen, oxygen and sulfur, wherein said 5 to 10 yuan of heterocycles are through 0-3 R ₂₁Replace; Or 0-3 R ₂₀The aryl that replaces; And

X ^-It is anion.

Chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (b) are disclosed in another embodiment:

Wherein:

R ₁And R ₂Independent is H, OH, OR ₂₉, halogenide, silicyl;

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 ₃Be H, silicyl;

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 ₅Be H, OH, OR ₂₉,

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,

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, amide, sulfonamide, ester, heterocycle, ring-like hydrocarbons (cyclic carbohydride), aryl;

R ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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 ₈Be H, OH, OR ₂₉

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 ₁₄Be H, OH,

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 group, acyloxy,

Or R ₁₄With R ₁₈In conjunction with forming O-condensed ring or C ₃-C ₆The carbocyclic ring condensed ring;

If wherein during R6=O, R ₁₄Be not

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;

R ₁₇Be 0-3 R ₂₅(the C that replaces ₄-C ₁₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₁₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₁₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

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

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

0-3 R ₂₁The aryl that replaces; Or

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

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

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

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

C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl, 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 ₂₂, when occurring, independently be 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 ₂₃, when occurring, independently be 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 ₂₅, when occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, independently be selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, independently be selected from every turn:

R ₂₉When occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

X ^-It is anion.

Chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (c) are disclosed in another embodiment:

Wherein:

(a) unsubstituted or non-halogen replaces: C ₄-C ₂₀(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl; C ₄-C ₁₀(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;

Wherein, if (b) be chosen as methyl and following R ₆Be chosen as=O, then (a) is not unsubstituted (cyclopropyl) methyl;

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

R ₇And R ₈It is the part of H, alkyl, cyclic hydrocarbon radical, alkoxyl, amine, amide, hydroxyl or its replacement;

R ₁₄Be H, OH, halogenide, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkyl-alkyl, perhaps with R ₁₇Or R ₁₈Form ring-like ring; And if R ₆Be not=during O, R ₁₄Can be alkoxyl, aryloxy group or aryl-alkoxyl;

R ₁And R ₂Independent is H, halogenide, alkoxyl, alkyl or aryl;

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

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

X ^-It is anion.

In another embodiment of formula 1c, wherein R is disclosed ₇And R ₈Be chemical compound or its pharmaceutically acceptable salt form or the prodrug of H or alkyl.

Chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (d) are disclosed in another embodiment:

Wherein:

R ₁₇And R ₁₈Be that replace or unsubstituted alkyl, when R6 be=during O, R ₁₇And R ₁₈In at least one be not methyl at another when being unsubstituted cyclopropyl methyl;

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

R ₇And R ₈It is the part of H or alkyl, cyclic hydrocarbon radical, alkoxyl, amine, amide, hydroxyl or its replacement;

R ₁₄Be H, OH, halogenide, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkyl-alkyl, SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅, perhaps with R ₁₇Or R ₁₈Form ring-like ring; And if R ₆Be not=during O, R ₁₄Can be alkoxyl, aryloxy group or aryl-alkoxyl;

R ₁And R ₂Independent is H, halogenide, alkoxyl, alkyl or aryl;

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

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

R ₂₅Be alkyl, aryl, aryl alkyl; And

X ^-It is anion.

Chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (e) are also disclosed:

Wherein:

R ₁And R ₂Independent is H, OH, OR ₂₉, halogenide, silicyl;

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 ₃Be H, silicyl, CO ₂R ₁₉, SO ₂R ₁₉, B (OR ₁₉) 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;

R ₅Be H, OH, OR ₂₉,

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, N (CH ₃) ₂,=(R ₁₉) (R _{19 '}) ,=(0-3 R ₂₀The heterocycle that replaces) ,=(0-3 R ₂₀The C that replaces ₃-C ₇Encircle) or any ring-like ring;

R ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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;

Or R ₆And R ₇In conjunction with forming O-condensed ring, C ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring, have 0-3 R ₂₀5-, 6-or 5-6 unit's aryl or heteroaryl condensed ring;

R ₈Be H, OH, OR ₂₉, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Aryl alkyl,

Wherein, X be key ,=O, O, S, N (R ₂₉), SO, SO ₂, SO ₂N (R ₂₉), CON (R ₂₉), N (R ₂₉) CON (R _{29 '}), N (R ₂₉) C (=NR _{29 '}) N (R _{29 "}), COO,

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 ₁₄Be H, OH, halogenide, have a 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Aryl alkyl,

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 group, acyloxy,

If R wherein ₆Be=during O, R ₁₄Be not:

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;

R ₁₇Be to have 0-3 R ₂₀Heterocycle, have 0-3 R ₂₀Alkylaryl, have 0-3 R ₂₀Aryl alkyl,

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

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

H, a 0-3 R ₂₀The aryl, the C that replace 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

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

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

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

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

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

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

R ₂₂, when occurring, independently be selected from H, C at every turn ₁-C ₆Alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl, aryl alkyl,

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

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

H, (C ₁-C ₆) alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl, haloalkyl and aryl alkyl,

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

R wherein ₂₂And R ₂₃Can also have 0-3 R in conjunction with forming ₂₀5-, 6-, 5-6-unit ring;

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

R ₂₅, when occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, haloalkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, independently be selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, independently be selected from every turn:

R ₂₉When occurring, independently be selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

X ^-It is anion.

The prodrug, pharmaceutically acceptable salt, stereoisomer, polymorphs body, hydrate, solvate, acid hydrate and the N-oxide that also comprise the chemical compound of the effective formula I of disease, I (a), I (b), I (c), I (d) and I (e) that this paper is discussed.For example, known prodrug has strengthened many required pharmacy characteristics (for example, dissolubility, bioavailability, manufacturing etc.).The prodrug of the chemical compound of formula I, I (a), I (b), I (c), I (d) and I (e) can prepare by the functional group that exists in the modified compound as follows: modify body in routine operation or be cracked into parent compound in vivo.

This paper also provides one or more the compositions of material of salt, polymorphs body or prodrug that is selected from by the following group of forming:

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-methylene morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl-17-methyl-3-propoxyl group-6-oxo morphinanium;

17-pi-allyl-17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-6-oxo morphinanium;

17-cyclobutylmethyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-cyclopentyl-methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-methylene morphinanium;

17-(3,3 '-dimethyl-allyl)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-(3 '-phenyl fourth-2 '-alkynyl)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-(2 ', 2 '-difluoro cyclopropyl) methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3-benzyl Oxy-1 4-hydroxyl-17-methyl-6 α-methoxyl group-morphinanium; And

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 beta-hydroxies-8-propoxyl group-morphinanium;

17-(2 '-methyl cyclopropyl) methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 α-methoxyl group morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 'beta '-methoxy morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3-methoxyl group-14-hydroxyl-17-methyl-6-methylene morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methylmorphine alkane ion;

3-acetyl group-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl-17-methylmorphine alkane ion;

17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo-morphinanium (morphinaninium);

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-(3 '-phenyl propoxyl group) morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-propoxyl group morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-methoxyl group-morphinanium;

17-methyl-4,5 α-epoxy-3-hydroxyl-(17,14-N, O-ethylidene-6-oxo-morphinanium; And

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-(17,14-N, O-ethylidene)-6-oxo-morphinanium.

Detailed Description Of The Invention

Also need to be used to the method for excitement or antagonism Opioid Receptors, in particular for the chemical compound of prevention or the treatment adverse side effect relevant with the administration of exogenous opioid.Present disclosure relates to these required chemical compounds and other important aspect (end).

In embodiments of the invention, compounds effective in the method for excitement or antagonism Opioid Receptors, especially μ-Opioid Receptors is disclosed.Interested especially is the chemical compound that does not pass through blood brain barrier at peripheral action.

Opioid Receptors is judged in conjunction with the receptor binding assays of knowing in the available this area of activity.For example, can use diprenorphine as treating that metathetical medicament carries out radioligand dosage displacement test.Unlabelled opioid antagonists, for example naloxone can be used as positive control.Available quick filtration stops association reaction and uses the harvester collection, tests in hole array (well array).

Usually disclosed is formula I, I (a), I (b), the I (c) of proposition in above-mentioned " summary of the invention ", the chemical compound of I (d), I (e).

In specific embodiment, disclose one group in conjunction with 7 of μ-receptor, 8-is saturated-4,5-epoxy-morphinanium, it has following structure:

No matter term " acyl group " still for example uses in " acyl amino " at term separately, 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 (CH ₃C (=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 (hydrido) residue afterwards provides.

As used herein, " alkanoyl " be meant-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 (for example 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 cycloalkenyl groups that alkyl or alkenyl replaces and cycloalkyl or cycloalkenyl group replace.Term " low-grade alkylidene " this paper is meant 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 is meant and has substituent alkenyl part, and described substituent group has replaced the hydrogen on one or more carbon of hydrocarbon skeleton.These substituent 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 ester; 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); sulfonamides; sulfonamido; nitro; trifluoromethyl; cyano group; azido; heterocyclic radical; part alkylaryl or aromatics or heteroaromatic.

Alkenylene (alkenylene) generally is meant 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=CHCH ₂-).Preferred alkenylene group has 2 to about 4 carbon.

Term " alkoxyl " and " alkoxyalkyl " comprise the moieties that has one to about ten carbon atom separately 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.

" alkyl " is meant that generally all combination and subgroups are closed in have 1 aliphatic hydrocarbon groups to about 10 carbon atoms in chain (it can be straight chain, side chain or cyclic) 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 is meant to have substituent moieties, and described substituent group has replaced the hydrogen on one or more carbon of skeleton." low alkyl group " is meant 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 ester; 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 " positive alkyl " means straight chain (promptly unbranched) unsubstituted alkyl group." side chain " is meant 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 reagent " is the chemical compound that can with (generally covalently) alkyl group be connected to parent material with the parent material reaction.Alkylating reagent is usually included in when being connected to parent material from the isolating leaving group of alkyl group.Leaving group can be, for example, and halogen, halogenosulfonic acid ester, halogenated acetic acids ester.An example of alkylating reagent is 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-BuMe ₂

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 bivalence--S (=O)--atom.Term " aryl sulfinyl " comprises and is connected in bivalence--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 (CH ₃--(S)--).

Term " alkynyl " comprises 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 (for example 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 " amidoalkyl ", " 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)--NH ₂Atomic group.Term " cyano group amidino groups " means--C (=N--CN)--NH ₂Atomic 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 is meant the straight chained alkyl group that is replaced by the optional aromatic yl group that replaces (the preferred optional phenyl ring that replaces), preferred low-grade alkyl group on a carbon.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 bicyclo-, and perhaps 7-to 13-unit's bicyclo-or three encircles, and wherein any one can be saturated, and part is undersaturated or aromatics.These isocyclic examples comprise, 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, the 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 is meant by group of naphthene base (preferred C ₃-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 " is meant that generally having about 4 all combinations and subgroups to the unsaturated group of naphthene base of the olefinic of about 10 carbon and its scope closes.In certain embodiments, cycloalkenyl groups is C ₅-C ₈Cycloalkenyl groups promptly has from about 5 cycloalkenyl groups to about 8 carbon.

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

" 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-propanol, ethanol, methanol), carboxylic acid (for example formic acid, acetic acid and propanoic acid).

Phrase " does not pass " substantially, as used herein, mean the chemical 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 chemical 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 the combination of two or more same halogen atoms or 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 bicyclo-, 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 of being 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 the alkyl atomic group of any one straight or branched that is replaced by one or more hydroxyl atomic groups that has in one to about ten carbon atom and the described carbon atom.

Term " hydrogen base " means one 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 (--CH ₂--) 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 " is meant the chemical 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 extraction, methanol and toluene.Comprise anhydrous organic solvent.

As used herein, " patient " is meant and comprises mammal by animal, and be preferred human.

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

It should be further appreciated that, when mentioning chemical compound of the present invention, mean and comprise its hydrate, solvate and polymorphs body.Hydrate forms when water is bonded to the crystal structure of chemical compound with fixed stoichiometric proportion, although when generally this ratio will be in balance according to hydrate around humidity change.Hydration is the form more specifically of solvation.Solvate is the crystalline solid adduct, its contain Chemical Calculation or non-chemically amount of calculation be combined in solvent in the crystal structure.If bonded solvent is a water, the still common alleged hydrate of solvate.Hydrate and solvate are known the people or the those skilled in the art of this area.

The medicine polymorphism is characterized as the ability that medicine exists with two or more crystalline phases that have different molecules align and/or conformation in lattice.The molecule that amorphous solid is arranged by confusion constitutes and does not have the lattice that can distinguish.Polymorphism is meant the existence of the different crystal forms of identical medicine.Polymorphs body is that persons skilled in the art are known.

The polymorphs body of medical solid or solvate can have different chemistry and physical characteristic, for example fusing point, chemical reactivity, apparent solubility, dissolution rate, optics and electrology characteristic, vapour pressure and density.These characteristics have direct influence to the quality or the performance of medicine processing and medicine.In these characteristics some are chemistry and physical stability, dissolution and bioavailability.But metastable medical solid form response environment condition, processing or change in time and change crystalline texture or solvation or desolvation.New, Wei Zhi polymorphs body can be spontaneous in time and can not be expectedly produced before.

As used herein, " prodrug " is meant to making the specially designed chemical 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 biotransformation.

As used herein, " pharmaceutically acceptable " is meant in rational medical science and concludes in the scope, be suitable for contacting with human and animal's tissue, no excessive toxicity, stimulation, allergy or other problems complication also have those chemical compounds, material, compositions and/or the dosage form of rational benefit/risk ratio.As used herein, " pharmaceutically acceptable salt " is meant the derivant of disclosed chemical 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 the alkalescence or the organic salt of carboxylic acid for example; And analog.Pharmaceutically acceptable salt for example comprises the 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, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid and analog of mineral acid; And from organic acid for example acetic acid, propanoic acid, succinic 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 chemical compound comprises free acid, free alkali and amphion, all comprises within the scope of the invention.This area is well-known, the chemical compound that contains amino and carboxylic group usually with their zwitterionic form balance existence.Therefore, any chemical compound of describing everywhere in this paper for example amino and carboxylic group that contains also comprises their corresponding amphion of being mentioned.

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

" stereoisomer " is meant and has same chemical composition but atom or the different chemical compound of group spatial arrangements 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 (--SO ₂NH 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 bivalent group--SO respectively ₂--." 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 wherein ₁, R ₂And R ₃Be alkyl 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.According to the useful exemplary tertiary of the present invention is R wherein _1-3Be formula (C _nH _2n+1, alkyl group n=1-4) or formula (C ₆H 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).

The curee that can use The compounds of this invention is a vertebrates, especially mammal.In one embodiment, mammal is the mankind, non-human primate, dog, cat, sheep, goat, horse, cattle, pig and Rodents.In one embodiment, mammal is human.

Pharmaceutical preparation of the present invention when being used alone or as a mixture, is used with the effective dose in the treatment.Effective dose in the treatment will be determined by the parameter of hereinafter discussing; But all be to set up the amount that effectively treatment suffers from curee's (for example human subject) levels of drugs of one of disease described herein under any circumstance.Effective dose means separately or with multiple dose, to being postponed, reduce severity by treatment disease or relative symptom or suppressing, reduce progress fully or stop fully showing effect or developing necessary amount.

Effective dose with pharmaceutical preparation of the present invention of main opioid agonist activity (especially μ-opioid agonist activity) is prevention, treats or control acute or chronic pain, hyperpathia, diarrhoea or because the amount of at least one symptom in the anxiety that short of breath causes.Effective dose is the amount that reduces cough in an example.The effective dose of opioid agonist can cause calmness or anesthesia.

This area definition constipation in three days before, be less than a defecation for (i) or (ii) in it previous week, be less than three defecations (referring to, for example United States Patent (USP) 6,559,158).In the example of constipation, the effective dose of opioid antagonists for example, is the constipation relieving symptom, induces defecation, increases the amount in stool or minimizing mouth-caecum shipping time.Therefore effective dose can be the necessary amount of bowel movement of setting up or keep rule.

The opioid patient of life-time service comprises patient above middle age, methadone maintenance patient, neuropathic pain and the chronic back pain patient that patient with advanced cancer, osteoarthritis change.From view of life quality, and for reducing the complication that causes by prolonged constipation, for example hemorrhoid, appetite inhibiting, mucosa damage, sepsis, colon cancer risk and myocardial infarction, these patients' treatment is important.

The patient who accepts the treatment of use The compounds of this invention can simultaneously or in a sequence accept opioid.Chemical compound disclosed herein can mix with conventional opioid compounds.Conventional opioid comprises and being selected from by alfentanil, anileridine, Asimadoline, bremazocine; buprenorphine; butorphanol; codeine; dezocine; diacetylmorphine (heroin); paracodin; diphenoxylate; fedotozine; fentanyl; richness is received bent amine (funaltrexamine); hydrocodone; hydromorphone; levallorphan; levacetylmethadol; levorphanol; loperamide; dolantin (Pethidine); methadone; morphine; morphine-6-glucosiduronic acid (morphine-6-glucoronide); nalbuphine; nalorphine; Opium; oxycodone; oxymorphone; pentazocine; propiram; the third oxygen sweet smell; remifentanil (remifentanyl); sufentanil; tilidate; those chemical compounds of the group that trimebutine and tramadol are formed.Randomly, non-opium sample anesthetis/antipyretic for example acetaminophen can mix with opioid especially oxycodone.Opioid also can provide and provide with any form described herein with chemical compound disclosed herein.

Depend on method of application, can suitably regulate dosage to reach required part or system's levels of drugs.For example, the opioid Orally administered dosage of expection enteric coating preparation lacks than the oral formulations of instant-free.The patient responds under the insufficient 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 chemical 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 combinations of selected medicine, the seriousness of a disease for the treatment of or preventing, patient's health status and the required dosage of treatment effectiveness naturally.In general, can use medically acceptable any method of application to implement the inventive method, medically acceptable method of application means the effect level that produces reactive compound and can not cause any way of unacceptable detrimental effect clinically.That such method of application comprises is oral, rectum, part, percutaneous, Sublingual, intravenous infusion, in lung, intra-arterial, fatty tissue, in the lymph, intramuscular, intracavity, aerosol, send through ear (for example through ear drop), intranasal, suction, intraarticular, Needleless injection, subcutaneous or Intradermal (for example, percutaneous).For continuous infusion, can use patient-controlled analgesia (PCA) device or implantable drug delivery device.Oral, rectum or partial to use for preventative or long-term treatment be important.The preferred rectum mode of sending comprises with suppository or coloclysis lotion (enema wash) to be used.

Pharmaceutical preparation can unit dosage forms 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 constitutes one or more auxiliary agents.Usually, compositions is by being prepared as follows: The compounds of this invention is all closely combined with liquid carrier, solid-state carrier in small, broken bits or both in the lump, afterwards if desired, with product shaping.

When being applied, pharmaceutical preparation of the present invention uses with pharmaceutically acceptable compositions.These goods routines comprise salt, buffer agent, antiseptic, compatibility carrier, lubricant (lubricant) and other optional therapeutic component.When being used for medicine, 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.Those that these pharmacologys and pharmaceutically acceptable salt include but not limited to be equipped with by following processed with acid: hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-methyl benzenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, succinic acid, naphthalene-2-sulfonic acid, pounce on acid, 3-hydroxyl-2-naphthalene-carboxylic acid and benzenesulfonic acid.

What should know is when mentioning The compounds of this invention, means to comprise its salt.Such salt has the people or the known kind of those skilled in the art of this area.When being used for pharmaceutical preparation, it is pharmaceutically acceptable that salt is preferably when being used for the mankind.Bromide is an 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 compatibilitys solid-state or liquid fillers, diluent or encapsulating substance, and it is suitable for, and for example non-human primate, dog, cat, horse, cattle, sheep, pig or goat are used to human or other mammals.Term " carrier " means the organic or inorganic composition, and is natural or synthetic, and active component can use with convenient with its combination.Carrier can be significantly not damage the interactional mode and the goods of the present invention of required pharmaceutical efficacy or stability and to be mixed with each other.Being suitable for carrier formulation that Orally administered, suppository and parenteral use etc. can be at Remington ' s Pharmaceutical Sciences (Lei Mingdun pharmaceutical science), Mack PublishingCompany, and Easton, Pa finds.

Preparation can comprise chelating agen, buffer agent, antioxidant, and randomly comprises isotonic agent, preferably includes pH regulator agent and infiltration/penetration enhancers.It is 10/821,811 U. S. application that autoclaving and these stable examples of formulations of long preservation are described in sequence number co-pending simultaneously, and its name is called " Pharmaceutical Formulation (pharmaceutical formulations) ".

Chelating agen comprises, for example, and ethylenediaminetetraacetic acid (EDTA) and derivant, citric acid and derivant thereof, nicotiamide and derivant thereof, sodium deoxycholate and derivant thereof and L-glutamic acid, N, N-oxalic acid and derivant thereof.The EDTA derivant comprises ethylenediamine tetraacetic acid,dipotassium salt, disodiumedetate, calcium disodium chelate, sodium ethylene diamine tetracetate, sodium versenate and ethylenediaminetetraacetic acid potassium.

Buffer agent comprises and being selected from by citric acid, sodium citrate, sodium acetate, acetic acid, sodium phosphate and phosphoric acid, sodium ascorbate, tartaric acid, maleic acid, glycine, sodium lactate, lactic acid, ascorbic acid, imidazoles, sodium bicarbonate and carbonic acid, sodium succinate and succinic acid, histidine, sodium benzoate and benzoic acid, or combinations thereof those materials of group.

Antioxidant comprises those materials that are selected from the group of being made up of ascorbic acid derivates, butylated hydroxyanisol, Yoshinox BHT, alkyl gallates, sodium pyrosulfite, sodium sulfite, sodium dithionite, sodium thioglycolate, sodium formaldehyde sulphoxylate, tocopherol and derivant thereof, monothioglycerol and sodium sulfite.Preferred anti-oxidants is a monothioglycerol.

Isotonic agent comprises those materials that are selected from the group of being made up of sodium chloride, mannitol, lactose, dextrose, glycerol and sorbitol.

Can comprise benzyl alcohol, parabens, thimerosal, methaform and preferred benzalkonium chloride with the antiseptic that the present composition uses.Usually, antiseptic is present in the compositions with the concentration of maximum about 2% weight.And the definite concentration of antiseptic will depend on desired use and change and determined by those skilled in the art easily.

The compounds of this invention can freeze dried preparation of compositions, preferably cryoprotective agent is being arranged for example in the presence of mannitol, lactose, sucrose, Polyethylene Glycol and the polyvinylpyrrolidine.Produce 6.0 or the cryoprotective agent 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 cryoprotective agent, for example mannitol or lactose, it preferably is neutral or acid in water.

Oral, the parenteral of medicament or suppository formulations are well-known and can commercial acquisitions.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 at the suspension in these preparations in the granule that maybe can be contained 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 therapeutic agent of the present invention afterwards or simultaneously 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 intestinal, discharge, in intestinal, 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 intestinal 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 nuclear or the piller that is contained in the enteric coating bag quilt in pill or the capsule, and this pill or capsule at first discharge other medicaments and only pass stomach and enter release therapeutic agent of the present invention in back in the intestinal at therapeutic agent of the present invention.Therapeutic agent of the present invention also can be present in the material that continue to discharge, and therapeutic agent of the present invention whereby spreads all over that gastrointestinal tract discharges 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 with the bonded therapeutic agent of the present invention of therapeutic agent of the present invention of enteric coating bag quilt.In these examples, other medicaments can be under one's belt, spread all over gastrointestinal tract or only instant-free in intestinal.

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 binding agent that dissolves in the stomach, instant-free is getable.Dissolved coating will be realized same purpose during in dissolving under the pH of stomach or in intensification.Use conventional enteric coating for example under the pH environment of intestinal (rather than stomach) dissolved pH sensitivity coating or dissolved in time coating can realize the only release in intestinal.Can realize spreading all over gastrointestinal by the combination (for example, dissolved piller under different pH) of using the enteral delivery system that continues releasable material and/or instant-free system and lasting and/or delay discharges.

For improving the oral bioavailability rate of The compounds of this invention, can use to strengthen the infiltrative excipient of goldbeater's skin (Aungst, B.J. (2000) J.Pharm.Sci., the 89th volume, the 5th phase, 429-442 page or leaf).Penetration enhancers can comprise surfactant, fatty acid, medium chain triglycerides, steroid detergent, 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 polymer.Concrete example comprises: cholate (cholate), glycocholate (glycocholate), glycosursodeoxycholate, EDTA, HP-, hydroxypropyl-gamma-cyclodextrin, gamma-cyclodextrin, myristyl-β-D-maltose, Octyl glucoside, citric acid, enoxolone and Tween-80 (Shah, R.B. wait the people, J.Pharm Sci., 93 (4): 1070-82,2004).

At first discharge at needs under 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 coating, described preparation is being applicable to these coatings and is allowing in any pharmaceutically acceptable carrier of therapeutic agent release of the present invention that described carrier is for example conventional pharmaceutically acceptable carrier of temperature sensitivity that is used for controlled release.Dissolved coating 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 be free, 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 coating intersperses among in the material of preparation.The piller of coating 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 lasting release, described lasting delivery mode comprises the material that uses prior art also to know as persons skilled in the art, the mode that demonstrates one-level 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 nuclear, disperse to be dispersed throughout material by the material coating, coating is on material or absorption or spread all over material.

That should know is piller or endorses to be any kind in fact.They can be the medicines by the releasable material coating, intersperse among material medicine, be adsorbed to medicine in the material or the like.Material is corrodible or not corrodible.

Can provide therapeutic agent of the present invention by granule.Granule used herein means nanometer or the micron particle (or bigger in some instances) that can be made up of therapeutic agent of the present invention or other medicament described herein wholly or in part.Granule can contain therapeutic agent in the nuclear that is surrounded by coating (including but not limited to enteric coating).Therapeutic agent can also disperse to spread all in the granule.Therapeutic agent can also be absorbed in the granule.Granule can have the release dynamics of any grade, comprises that zero level discharges, one-level discharges, secondary discharges, postpones to discharge, continue release, instant-free and any combination thereof or the like.Except that therapeutic agent, granule can comprise that routine is used for those materials any of pharmacy and medical domain, described material includes but not limited to corrodible, not corrodible, biodegradable or non-biodegradable material or its combination.Granule can be the microcapsule that contains the antagonist of solution form or semi-solid state.Granule can have in fact Any shape.

Abiotic degradable and biodegradable polymer material can be used to make the granule 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-anhydride, polyacrylic acid, alginate, chitosan, poly-(methyl methacrylate), poly-(ethyl methacrylate), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(N-Hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), poly-(phenyl methacrylate), poly-(acrylic acid methyl ester .), poly-(isopropyl acrylate), poly-(Isobutyl 2-propenoate) 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 medicine is controlled from mode and the feature that preparation discharges.This is meant instant and non-IR formulation, and non-IR formulation includes but not limited to continue to discharge and delayed release preparation.Term " continues to discharge " (being also referred to as " prolong and discharge ") to be used with its conventional sense, finger provides the release gradually of medicine in the time of an elongated segment, and preferred, though be not essential, in the time of an elongated segment, produce the pharmaceutical preparation of constant haply medicine blood levels.Term " postpone discharge " uses with its conventional sense, refer to preparation use and the release of medicine between have time delay pharmaceutical preparation." postpone discharge " can comprise or can not comprise medicine in the gradually release of an elongated segment in the time, and therefore can be or can not be " continuing to discharge ".These preparations can be used for any type of using.

Specifically be used for the gastrointestinal delivery system and be divided into three types roughly: first kind is to be designed to respond for example pH variation and the delay delivery system of release medicine; Second kind is the timing delivery system that is designed to discharge afterwards at the fixed time medicine; With the third is the microbial enzyme system (for example preparation that discharges in the colon fixed point) that utilizes a large amount of enterobacterias in gastrointestinal tract the latter half.

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

Be used for determining that various experiment in vitro that whether coating classifies as enteric coating have been published in the pharmacopeia of country variant.Example is for being kept perfectly at least 2 hours when for example the HCl of pH 1 contacts with the artificial gastric juice at 36 ℃ to 38 ℃, and afterwards at the artificial intestinal juice KH of pH 6.8 for example ₂PO ₄In the buffer in 30 minutes the coating of disintegrate.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 regularly delivery system.According to these systems, the site of drug release is by the time decision of preparation transportation in the gastrointestinal tract.Because the transportation of preparation is subjected to the very big influence in gastric emptying time in the gastrointestinal tract, so some timing delivery system also is an enteric coating.

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

Enteric coating usually but must not be polymeric material.Preferred enteric-coating material comprises biodegradable, hydrolysis gradually and/or water-soluble gradually polymer.The relative quantity of " coat weight " or each capsular coating material generally determined to ingest and drug release between interval.Any coating 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 dependency 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 dissolving in the stomach and disintegrate; In the time of under one's belt to the impermeability of gastric juice and drug/vehicle/enzyme; The ability of rapid dissolving or disintegrate in target intestinal site; The physics of duration of storage and chemical stability; Avirulence is easy to use (friendly substrate) as coating; 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 carboxymethyl cellulose for example; Acrylate copolymer and copolymer, preferably by acrylic acid, methacrylic acid, acrylic acid methyl ester., methacrylate ammonium, ethyl acrylate, (for example those copolymers of selling with trade name EUDRAGIT) that methyl methacrylate and/or ethyl methacrylate form; Polyvinyl and copolymer, for example polyvinyl acetate, polyethylene acetic acid phthalate ester, vinyl acetate butenoic acid copolymer and vinyl-vinyl acetate copolymer; And Lac (lac of purification).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.EUDRAGIT series RL, NE and RS copolymer are soluble but permeable and be mainly used in the release of prolongation in gastrointestinal tract.EUDRAGIT series E copolymer dissolves in the stomach.EUDRAGIT series L, L-30D and S copolymer are soluble under one's belt but solvable in intestinal, are that this paper is most preferred therefore.

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 is approximately 1: 1.Known in addition copolymer is lower than 5.5 having, be generally the pH of 1.5-5.5, it is insoluble promptly 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 promptly generally being present in the pH in the gastrointestinal tract lower liquid or is partly dissolved.Another kind of specific methacrylate polymer is EUDRAGIT S, and it is approximately 1: 2 with the different ratios of its free carboxy group and ester group that are of EUDRAGIT L-30D.EUDRAGIT S is insoluble less than 5.5 o'clock at pH, but different with EUDRAGIT L-30D, and the gastro-intestinal Fluid of pH also dissolves badly in the time of for example in small intestinal in having 5.5 to 7.0 scopes.This copolymer dissolves when promptly being present in the pH in the colon usually more than pH7.0 reaches.EUDRAGIT S can be used as coating 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 dissolved EUDRAGITL-30D be used in combination, to be provided as the compositions that the delay bioactive agent delivery being delivered to the intestinal different parts and prepare discharges.The EUDRAGIT L-30D that uses is many more, discharge and to send the beginning approaching more, and the EUDRAGIT S that uses is many more, then discharge and send the beginning and 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.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, to such an extent as to drug release can be finished in some common expected position.Enteric coating prevents that also epithelium that therapeutic agent and carrier be exposed to oral cavity, pharynx, esophagus stomach function regulating is with mucosa and be exposed to the relevant enzyme of these tissues.Therefore the enteric coating intestinal tissue that helps protection activating agent, carrier and patient avoids any adverse events in required sending before the site discharges at medicine.In addition, the material of coating of the present invention provides the optimization of drug absorption, activating agent protection and safety.Being that the multiple enteric coating of purpose will provide even more effective and lasting spreads all over sending of gastrointestinal improvement at gastrointestinal tract zones of different release bioactive agent.

Coating 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, tributyl citrate, acetylated monoglyceride, glycerol, fatty acid ester, propylene glycol and Dibutyl phthalate.Especially, comprise that the coating 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.Coating also can contain other coating excipient, and for example antitack agent, defoamer, lubricant (for example magnesium stearate) and stabilizing agent (for example hydroxy propyl cellulose, bronsted lowry acids and bases bronsted lowry) be with dissolving with disperse coating material, and the product of improvement coating performance and coating.

Use conventional coating method and equipment, coating can be used for the treatment of the granule of agent, the tablet of therapeutic agent contains the 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), people such as Lieberman edit (New York: Marcel Dekker, Inc., 1989) and people such as Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems (pharmaceutical dosage form and drug delivery system), sixth version (Media, Pennsylvania: Williams﹠amp; Wilkins, 1995) find in.Coating thickness is annotated as mentioned, the required site of in the arriving lower intestine local delivery of must the sufficient to guarantee peroral dosage form being kept perfectly.

In another embodiment, provide and contained the enteric coating coating, 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 semipermeable membrane or barrier with aperture.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 of drug release will equal water multiply by drug level.Water flows into and the size in the hole that the effusive speed of medicine can be by compositions and device is controlled.The material that is applicable to semipermeable membrane includes but not limited to polyvinyl alcohol, polrvinyl chloride, semi permeability Polyethylene Glycol, semi permeability polyurethane, semi permeability polyamide, semi permeability sulfonated polystyrene and polystyrene derivative; Semi permeability is gathered (Sodium styrene sulfonate), 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 Palmic acid celluloses, three sad celluloses, three cellulose propionates, the disuccinic acid cellulose, two Palmic acid celluloses, cellulose dicylate, cellulose acetate succinate, propanoic acid succinic acid cellulose, the sad cellulose of acetic acid, valeric acid Palmic 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 and contained the pharmaceutical dosage form that continues to discharge coating device, this device is equipped with preparation of the present invention.In this embodiment, the preparation that contains medicine is packaged in and continues in release film or the thin film.As indicated above, film can be semipermeable.Semipermeable membrane allows the device internal water to pass through with dissolved substance.Dissolved drug solution diffuses out by semipermeable membrane.The speed of drug release depends on the thickness of the thin film of coating, 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 and contained the pharmaceutical dosage form that continues to discharge coating device, this device is equipped with preparation of the present invention.In this embodiment, the preparation that contains medicine mixes with lasting release polymers homogeneous.These lasting release polymers are molecular weight water-soluble polymers, and it is when contacting with water, and expansion also produces the passage of water to 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 lasting release matrix.The material that is applicable to such device comprises hydrogen propyl methocel (hydropropylmethylcellulose), 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, the product as described above that contains medicine is by enteric polymer coatings.This device will not discharge any medicine under one's belt, and when device arrives intestinal, enteric polymer begin dissolving and only after begin drug release.Drug release will carry out in the mode that continues to discharge.

Can use conventional material, method and apparatus to make the enteric coating coating, have the device of osmotically active.For example, have osmotically active device can by at first will before the The compounds of this invention described be encapsulated in pharmaceutically acceptable soft capsule, liquid or the semi-solid preparation and make.Then, for example use the air suspension machine, (comprise with the semipermeable membrane compositions, for example, in appropriate solvent cellulose acetate and the Macrogol 4000 in the methylene chloride-methanol mixture for example) this inner capsule of coating, up to the enough thick lamination (laminate) of formation, for example about 0.05mm.Use the dry semipermeable lamination capsule of routine techniques afterwards.Use for example erosion of gelatin plug of for example machine drilling, laser drill, mechanical disruption or erodable element afterwards, pass semipermeable layer moulding cyst wall and produce 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 include but not limited to be used to contain the enteric coating of liquid state or semisolid pharmaceutical preparation capsular those.

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 with for example ratio be about 1: 1 methacrylate and methyl or ethyl-methyl acrylate be the base molecule amount greater than 100000 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 (EastmanKodak, 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 mark HP50 also can be from Shin-EtsuChemical 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 trade mark is that HP55 also can be from the product sold of same supplier's acquisition.

Can be at coating or do not provide therapeutic agent in the capsule of coating.Capsule material can be hard or soft, and is to be understood that as those skilled in the art, contain usually tasteless, easily use and water miscible chemical 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 been described and has been used to prepare material and the method that encapsulates medicine.

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

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, inert on chemical inertness and the physiology.Manyly can contain oiliness or lipid substrate material by the commercial suppository that obtains, for example cupu oil, Oleum Cocois, palm-kernel oil and Petiolus Trachycarpi oil, they usually at room temperature melt or distortion and need cold preservation or other storage restriction is arranged.People's such as Tanaka United States Patent (USP) the 4th, 837, described the suppository base of being made up of the Laurel class of 80-99 percentage by weight fat for No. 214, described Laurel class fat has 20 or littler hydroxyl value and contain same bonded 8 to the 18 fat of carbon atom acid glycerides of 1 to 20 percentage by weight fatty acid (for example erucic acid) diglyceride.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 stimulation to local mucous membrane (referring to for example, people's such as Hartelendy United States Patent (USP) the 6th, 099, No. 853, people's such as Ahmad United States Patent (USP) the 4th, 999, No. the 4th, 765,978, people's such as No. 342 and Abidi United States Patent (USP)).

The substrate 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, Oleum Cocois, fractionated coconut oil, Adeps Sus domestica and

The wax class is lanoline and reductive lanoline for example; Hydrocarbon for example

Squalene, squalane and liquid paraffin; Grow to that medium-chain fatty acid is for example sad, lauric acid, stearic acid and oleic acid; Higher alcohol is lauryl 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 glycerol replaces is the glycerol acetoacetic acid for example; And Polyethylene Glycol and its derivant for example Polyethylene Glycol (macrogol) and cetomacrogol.They can be separately or two or more unite use.If desired, the present composition can further comprise the surfactant that is generally used for suppository, coloring agent etc.

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

According to all right nasal spray of compositions of the present invention, nose drop, suspension, gel, ointment, cream or powder are used.Using of compositions 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 agent of keeping pH, pharmaceutically acceptable thickening agent and wetting agent with delivery system.Can select the pH of buffer agent so that pass the absorption optimization of the therapeutic agent of nasal mucosa.

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

Use pharmaceutically acceptable thickening agent the viscosity of the present composition can be maintained required level.Comprise methylcellulose, Xanthan gum, carboxy methyl cellulose, hydroxy propyl cellulose, carbomer, polyvinyl alcohol, alginate, acacin, chitosan and combination thereof according to the available thickening agent of the present invention.The concentration of thickening agent will depend on selected dose and required viscosity.The powder formulation that these agent also can be used to above discuss.

Compositions of the present invention can comprise that also wetting agent is to reduce or to prevent that mucosa is dry and prevent stimulation to it.Can be used for suitable wetting agent of the present invention and comprise sorbitol, mineral oil, vegetable oil and glycerol; Soothing agent; The film regulator; Sweeting agent; And combination.The concentration of wetting agent will depend on selected dose and change in the present composition.

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

For the local application composition prepared can be that liquid state or semisolid (for example comprise, gel, washing liquid, Emulsion, cream, 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 binder) in conjunction with providing.It can be moisture or water-free; It can be configured to solution, Emulsion, dispersion, suspension or any other mixture.

The important way of using comprises the topical application to skin, eye or mucosa.Therefore, common vehicle is to be fit to those of the medicine of body surface or cosmetic applications.Compositions provided herein can local or zone (locally) application to the zones of different of patient body.Annotate as mentioned, topical application means for example can reaching body surface organization, such as the application of skin (outer cover or overcover) and mucosa (produce, secrete or contain mucous surface).Exemplary mucomembranous surface comprises the mucomembranous surface of eye, mouthful (for example top of lip, tongue, gingiva, cheek, Sublingual 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 is meant 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, ophthalmic or other meat interior zone) or health.Therefore, as used herein, area applications is meant the application to the health discontinuity zone.

For the part and/or the Zoned application of the present composition, the effectiveness of hope can comprise, therapeutic agent for example 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 analgesics reach much the same.But, go through 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 do not have the common ill effect relevant with the central opiate, it comprises for example respiration inhibition, calmness and addiction.

And in some embodiment that comprises the embodiment that relates to aqueous vehicle, compositions also can contain glycol,, contains the chemical compound of two or more oh groups that is.The glycol that can be used in particular for the compositions use is a propylene glycol.Gross weight with compositions is a benchmark, and compositions can contain glycol from the concentration greater than 0 to about 5wt.%.

Use for local interior, for example intraarticular is used, and compositions preferably is formulated as solution or the suspension (for example saline solution of isotonic buffer) in aqueous medium, perhaps combines with inner biocompatibility support or the bioadhesive polymer of using of expection.

Washing liquid, it for example can suspension, and the form of dispersion or Emulsion exists, and contains one or more chemical compounds of valid density.Valid density is preferably sent effective dose.For example, chemical compound of the present invention can be between about 0.1-50% of one or more chemical compounds provided herein (weight) or use is provided during higher concentration.Washing liquid can comprise, for example, and lubricant of from 1% to 50% (weight) (emollient) and equilibrium water, suitable buffer agent 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 solublity 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, Oleum Ricini, safflower oil, Oleum Gossypii semen, Semen Maydis oil, olive oil, cod-liver oil, almond oil, American Avocado Tree oil, Petiolus Trachycarpi oil, Oleum Sesami and Oleum Glycines.(d) aceto-glyceride, for example acetylated monoglyceride.(e) ethoxylated glycerol ester, for example ethoxylation glyceryl monostearate.(f) have the effective for treatment of premature ejaculation of 10 to 20 carbon atoms, the methyl of fatty acid, isopropyl and butyl ester are available at this paper.Example includes but not limited to, lauric acid hexyl ester, lauric acid dissident ester, Palmic acid dissident ester, isopropyl palmitate, isopropyl myristate, decyl oleate, Ceraphyl 140A, stearic acid hexadecyl ester, stearic acid ester in the last of the ten Heavenly stems, isostearic acid isopropyl ester, diisopropyl adipate, adipic acid two dissident's esters, adipic acid dihexyl ester in the last of the ten Heavenly stems, Dermol DIPS, Lauryl lactate, Tetradecyl lactate, cetyl lactate.(g) have the alkenyl esters of the fatty 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 fatty acid of 9 to 22 carbon atoms.The example that is fit to includes but not limited to n-nonanoic acid, lauric acid, myristic acid, Palmic 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 aliphatic alcohol of 10 to 22 carbon atoms, such as but not limited to lauryl 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 aliphatic 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 lauryl 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) lanoline and derivant; include but not limited to lanoline; lanolin oil; lanolin wax; lanolin alcohol; lanolin fatty acid; isopropyl lanolate; the ethoxylation lanoline; the ethoxylation lanolin alcohol; the ethoxylation cholesterol; the propoxylation lanolin alcohol; the acetyl group lanoline; the acetyl group lanolin alcohol; the lanolin alcohol linoleate; the lanolin alcohol ricinoleate; the acetas of lanolin alcohol ricinoleate; the acetas of ethoxylated alcohol-ester, the hydrogenolysis of lanoline; ethoxylation aquation lanoline; ethoxylated sorbitol lanoline and liquid and semisolid lanoline absorption base.(m) polyhydric alcohol and polyether derivative, include but not limited to propylene glycol, dipropylene glycol, polypropylene glycol [M.W.2000-4000], the polyoxyethylene polyoxypropylene glycol, the polyoxyethylene polyoxypropylene glycol, glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol, ethoxylated sorbitol, the hydroxypropyl sorbitol, Polyethylene Glycol [M.W.200-6000], methoxy poly (ethylene glycol) 350,550,750,2000,5000, poly-(oxirane) homopolymer [M.W.100,000-5,000,000], poly alkylene glycol and derivant, hexanediol (2-methyl-2, the 4-pentanediol), 1, the 3-butanediol, 1,2,6,-hexanetriol, Rutgers 612 USP (2-ethyl-1,3-hexanediol), C ₁₅-C ₁₈The polyoxypropylene derivant 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, propylene glycol list and di fatty acid ester, polypropylene glycol 2000 monoleates, polypropylene glycol 2000 monostearates, ethoxylated propylene glycol monostearate, glycerol list and double acid ester, polyglycereol polyglycerol fatty acid ester, the ethoxylated glycerol monostearate, 1,3-butanediol monostearate, the 1,3 butylene glycol distearate, the polyoxyethylene polyols fatty acid ester, sorbitan fatty ester and polyoxyethylene sorbitan fatty acid ester.(o) wax ester, include but not limited to Cera Flava, spermaceti, myristyl myristate and geoceric acid stearyl alcohol ester and mellisic derivant, this derivant includes but not limited to, forms the polyoxyethylene sorbitol Cera Flava of the product of ether-ester mixture as the ethoxylated sorbitol of Cera Flava and ethylene oxide content variation.(p) vegetable wax includes but not limited to Brazil wax and candelilla wax.(q) phospholipid, for example lecithin and derivant.(r) sterin includes but not limited to cholesterol and cholesterol fatty acid ester.(s) amide, for example fatty acid amide, ethoxylated fat amide and solid-state fatty acid alkanol amides.

Washing liquid 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 have the aliphatic alcohol of 10 to 20 carbon atoms, have 10 to 20 carbon atoms and aliphatic 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, the Polyethylene Glycol of molecular weight 200 to 6000, the propylene glycol of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic 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 compounds are gratifying cationic emulsifiers.Some lubricant of describing at leading portion also has emulsification property.When the washing liquid of preparation contains such lubricant, do not need other emulsifying agent, although it can add in the compositions.

The other parts of washing liquid are water or C ₂Or C ₃Alcohol, the perhaps mixture of water and alcohol.By all components is simply mixed the preparation washing liquid.Preferably chemical 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 liquid.A kind of such additive is at the thickening agent from composition weight 1% to 10% level.The example of the thickening agent that is fit to includes but not limited to: crosslinked carboxypolymethylene polymer (cross-linked carboxypolymethylene polymer), ethyl cellulose, Polyethylene Glycol, Tragacanth, karaya (gum kharaya), Xanthan gum and bentonite, hydroxy ethyl cellulose and hydroxy propyl cellulose.

Cream can be formulated as and contain effectively the therapeutic agent delivery of the present invention of 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.Cream 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 the lubricant that is used for washing liquid as mentioned and also can be used to the cream compositions.As indicated above, cream also can contain suitable emulsifying agent.Compositions contains from 3% to 50%, preferably the emulsifying agent of from 5% to 20% level.

These compositionss that are configured to solution or suspension can be used to skin, maybe can be configured to aerosol or foam and spray to be used for skin.Aerosol composition contains (weight) from 25% to 80% usually, preferably from 30% to 50% the propellant that is fit to.The example of this propellant is chlorating, fluorizated and the chlorating low molecular weight hydrocarbon of fluorine.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 inclusions understood as this area use these propellants.

Solution that is suitable for preparing and suspension also can be used for eye and mucosa by the part.Solution especially for eye uses those solution of preparing, can be configured to the isosmotic 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 chemical 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, its described eye with rinse solution and be 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 sodium citrate, 0.5-1.5mM magnesium chloride, 1.5-2.5mM calcium chloride, 15-25mM sodium acetate, 10-20mMD.L.-sodium. β .-hydroxybutyric acid (D.L.-sodium. β .-hydroxybutyrate) and the 5-5.5mM glucose.

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

Jelly composition contains the therapeutic agent of the present invention of effective dose, and usually concentration is about 0.1-50% weight or more one or more chemical compounds provided herein; From 5% to 75%, preferred 10% to 50% organic solvent as discussed previously; From 0.5% to 20%, preferred from 1% to 10% thickening agent; 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 medicine from speed that circulation is removed, 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 medicine often raises after using beginning immediately, and often when medicine by disperseing to advance cell and tissue, by metabolism, or when circulation is removed, descend in time by draining.When keeping constant in time, mean drug concentration obtains stable state.Under the situation of interrupted administration, drug level circulation mode repeats in each interval between administration in the same manner, and it is constant that mean concentration keeps.Under 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 medicine at least one administration cycle period, is multiple in the same manner between administration so that examine cycle period.Usually in interrupted dose regimen, keeping of stable state can be examined by measuring the successive just drug level 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 level.

Embodiment comprises test kit, and described test kit comprises container that contains the opioid preparation and the container that contains chemical compound of the present disclosure.This test kit can comprise pharmaceutical preparation bottle and pharmaceutical preparation diluent bottle.The diluent bottle can for example contain diluent (for example being used for the concentrated solution of diluted compounds or the normal saline of lyophilization powder).Operation instructions can comprise that the spissated pharmaceutical preparation with the diluent of specified quantitative and specified quantitative mixes, and preparation is used to inject or the operation instruction of the final preparation of infusion whereby.Operation instructions can comprise the operation instruction with the compounds for treating patient of effective dose.Also should be understood that, no matter container is bottle, is with membranous bottle, is with membranous ampoule bottle, transfusion bag or other analog, the container that contains goods can contain extra labelling, for example when goods can variable color during by high pressure steam sterilization or other sterilization the routine sign.

Embodiment 1

17-pi-allyl-17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-6-oxo morphinanium iodate Thing (D0001)

Naltrexone D0001

(2.0g 5.86mmol) is dissolved in DMF (10mL, anhydrous) under nitrogen with naltrexone.The adding allyl iodide (0.5mL, 5.18mmol).In stirring at room mixture 4 days.Remove DMF, residue and 50mL water stir 10min together.Aqueous solution is separated with solid precipitation and wash with dichloromethane (50mL).With the solid (1.2g) of its lyophilization with the generation moisture absorption.In 0.2g gained solid water-soluble (30mL).Use Na ₂CO ₃The pH of aqueous solution is transferred to 10.(2 * 20mL) washings and lyophilization are to produce yellow solid with dichloromethane with this solution.(4g is the 28mg solid that contains product D 0001 with gained solid purification C-18) with reversed-phase column.

Embodiment 2

17-isobutyl group-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium fluoroform sulphonate (D0002)

(i) 17-isobutyl group-4,5 α-epoxy-3,14-dihydroxy morphinan-6-ketone (2)

With nor-oxymorphone 1 (0.574g, 2mmol), isobutyl iodide (0.253ml, 2.2 mMs) and NaHCO ₃(0.184g, 2.2 mMs) mixture in DMF (6ml) is at N ₂Under be heated to 90 ℃, 8h.Solvent evaporation to drying is also passed through to use 4%NH ₄The OH+4%MeOH+ ethyl acetate as the column chromatography purification of eluant to obtain the product 2 of 0.505g (67%). ¹H NMR demonstrates complex spectrum (complex spectra), so identify { (APCI with mass spectrum ⁺): 344 (M+1) }, and enter next step.

(ii) 17-isobutyl group-4,5 α-epoxy-3-benzyloxy-14-hydroxyl morphinan-6-ketone (3)

In dry DMF (20mL) with chemical compound 2 (560mg, 1.63mmol) and K ₂CO ₃(562mg 4.08mmol) mixes.The adding benzyl bromide a-bromotoluene (0.21mL, 1.80mmol).With the mixture of gained in room temperature at N ₂Following stirring is spent the night.Mass spectral analysis shows 1 full consumption.Add EtOAc (100mL).With solution with water (3x60mL) and saline (60mL) washing, through Na ₂SO ₄Dry also filtration.The evaporation filter liquor.With the yellow colloidal solid residue of post (EtOAc of eluant: 5-50% is in hexane) purification to be produced as 3 (510mg, 72%) of white solid. ¹H?NMR(300MHz，CDCl ₃)δppm?7.43-7.50(m，2H)，7.29-7.41(m，3H)，6.72(d，J＝8.0Hz，1H)，6.58(d，J＝8.3Hz，1H)，5.22(s，1H)，5.18-5.34(m，2H)，4.70(s，1H)，2.88-3.17(m，3H)，2.09-2.66(m，7H)，1.59-1.95(m，4H)，0.95(t，J＝6.6Hz，6H).MS[M+H]：434.2.

(iii) 17-isobutyl group-4,5 α-epoxy-3-benzyloxy-14-hydroxyl morphinan-6-ketone dimethyl ketal (4)

In anhydrous MeOH (10mL) with chemical compound 3 (134mg, 0.31mmol) and HC (OMe) ₃(0.34mL 3.1mmol) mixes.(0.15mL is in the 4M Yu diox, 0.6mmol) to add HCl.With the mixture of gained in room temperature at N ₂Following stirring is spent the night.Mass spectral analysis shows that 3 all consume.Add Na ₂CO ₃(2M, 10mL).Remove MeOH, and with DCM (3X20mL) extraction water solution.Merge the DCM extract, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor.Yellow colloidal solid product 4 (126mg, 85%) need not purification and are used for next reaction.MS[M+H]：480.3.

(iv) 17-isobutyl group-4,5 α-epoxy-3-benzyloxy-14-hydroxyl-17-methyl-6 oxos-morphinanium fluoroform sulphonate (5)

Chemical compound 4 (126mg, 0.263mmol, the crude product that obtains from above-mentioned reaction) is dissolved in anhydrous 1,2-dichloroethanes (5mL).Add the trifluoromethanesulfonic acid methyl ester (0.78M in DCM, 1.68mL, 1.31mmol).With the mixture of gained in room temperature at N ₂Under stir 2d.Mass spectral analysis shows that＞60% transforms.Reaction solution is added to 20g silicagel column and purification (eluant: 5-10%MeOH is in DCM) to be produced as 5 (91.6mg, 60%) of white solid. ¹H NMR (300MHz, methanol-d ₃) δ ppm 7.26-7.48 (m, 5H), 6.90 (d, J=8.3Hz, 1H), 6.80 (d, J=8.3Hz, 1H), 5.25 (d, J=2.8Hz, 2H), 4.94 (s, 1H), 3.95 (d, J=5.0Hz, 1H), 3.71 (s, 3H), 3.60-3.69 (m, 1H), 3.34-3.55 (m, 3H), 2.91-3.24 (m, 5H), 2.34-2.47 (m, 1H), 2.18-2.29 (m, 1H), 2.00-2.10 (m, 1H), 1.64-1.82 (m, 2H), 1.22 (dd, J=12.4,6.6Hz, 6H) .MS[M+H]: 448.3.

(iv) 17-isobutyl group-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium fluoroform sulphonate (D0002)

(91.6mg 0.158mmol) is dissolved in MeOH (10mL) with chemical compound 5.Adding Pd/C (92mg, 10%, wet type (wet), 0.086mmol).With the mixture of gained in room temperature at H ₂Air bag (balloon) stirs down.Mass spectral analysis shows that parent material is converted into product fully behind the 35min.By Celite pad filtering reacting solution.With MeOH (2x10mL) washing Celite.The evaporation filter liquor.The D0002 (71.6mg, 92%) with residue water-soluble (3mL) and lyophilization to be produced as white solid. ¹H?NMR(300MHz，D ₂O)δppm?6.77(d，J＝8.3Hz，1H)，6.75(d，J＝8.5Hz，1H)，4.98(s，1H)，3.98(d，J＝5.0Hz，1H)，3.61(s，3H)，3.63(d，J＝4.1Hz，1H)，3.27-3.54(m，2H)，2.73-3.21(m，5H)，2.16-2.39(m，2H)，1.97-2.09(m，1H)，1.68-1.83(m，2H)，1.10(dd，J＝12.4，6.6Hz，6H)。HPLC purity: 100%.MS[M+H]：358.1.

Embodiment 3

17-(3,3 '-dimethyl-allyl)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium Iodide (D0003)

Nor-oxymorphone 1 D0003

(i) 17-(3,3 '-dimethyl-allyl)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium bromide (1)

In the 5mL DMF solution of nor-oxymorphone (498mg, 1 equivalent), add sodium bicarbonate (160mg, 1.1 equivalents) and allyl bromide, bromoallylene (222 μ L, 1.1 equivalents).At 90 ℃ the reactant mixture stirring is spent the night.Reactant mixture is cooled to room temperature also to be used chloroform (20mL) dilution and uses the salt water washing.With chloroform extraction (3x50mL) aqueous cleaning thing and concentrated Organic substance.With the anhydrous Mg of chloroform extraction liquid that merges ₂SO ₄Dry and concentrated.By using silicon dioxide column chromatography (the 10g SiO of methylene chloride-methanol (98: 2) as eluant ₂) purification crude product 1 to be to obtain 388mg (63%) intermediate compound 1.

(ii) 17-(3,3 '-dimethyl-allyl)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium iodide

In the 2mL DMF solution of chemical compound 1 (388mg, 1 equivalent), add methyl iodide (680 μ L, 10 equivalents) and descend stirring 5 days at 55 ℃.By the percentage ratio of HPLC analytic sample to determine to transform.Crude reaction mixture is distributed between dichloromethane and sodium bicarbonate solution (pH＞10).Come purification obtaining white solid to obtain solid, solid is passed to use the water-methanol solvent mixture as the anti-phase C-18 post of eluant (gradient elution) the water lyophilization, with white solid by partly prepare HPLC once more purification with acquisition product D 0003.

Embodiment 4 and 5

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 α-methoxyl group morphinanium trifluoro Acetate (D0004) and 17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 β-first Oxygen base morphinanium trifluoroacetate (D0005)

(i) 17-cyclopropyl methyl-4,5 α-epoxy-3-benzyloxy-6,14-dihydroxy morphinan (2)

(1.64g 3.8mmol) is dissolved in the mixture of THF (35mL) and MeOH (35mL), and stirs under 0 ℃ the chemical compound 1 that will prepare by the method that hereinafter is used for Compound D 0010-D0013.Add NaBH ₄(0.29g, 7.63mmol).The reaction solution of gained is stirred 1h.Add entry (110mL) and extract mixture with DCM (3X100mL).The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor and with post (eluant: 3-10%MeOH is in DCM) purification residue to be produced as 2 (1.39g, 84%) of white foam.Because this chemical compound is 6 α-and 6 beta-hydroxy mixture of isomers, therefore have compound ¹H NMR.MS shows correct molecular weight: [M+H]: 434.

(ii) 17-cyclopropyl methyl-4,5 α-epoxy-3-benzyloxy-14-hydroxyl-6-methoxyl group morphinan (3)

With chemical compound 2 (1.24g, 3.8mmol) be dissolved in anhydrous THF (50mL) and in room temperature at N ₂The following stirring.(0.66mL, 6.86mmol), (172mg, 60% in mineral oil, 4.29mmol) to add NaH subsequently to add MeI.The reaction solution of gained is stirred 17h.Water (1.0mL) cancellation reaction is also removed volatile matter.By post (eluant: 50-100%EtOAc is in hexane) purification residue to be produced as 3 (0.37g, 29%) of white foam.Because this chemical compound is 6 α-and 6 'beta '-methoxy mixture of isomers, therefore have compound ¹H NMR.MS shows correct molecular weight: [M+H]: 448.

(iii) 17-cyclopropyl methyl-4,5 α-epoxy-3-benzyloxy-14-hydroxyl-17-methyl-6-methoxyl group morphinanium fluoroform sulphonate (4)

With chemical compound 3 (0.37g, 0.83mmol) be dissolved in anhydrous DCM (10mL) and in room temperature at N ₂The following stirring.Add TfOMe (2.4mL, 0.69M in DCM, 1.66mmol) and with the solution stirring 22h of gained.Add moisture Na ₂CO ₃(5mL 2M) and with DCM (2X20mL) extracts mixture.The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor and with post (eluant: 3-10%MeOH is in DCM) purification residue to be produced as 4 (154mg, 30%) of white foam.Because this chemical compound is 6 α-and 6 'beta '-methoxy mixture of isomers, therefore have compound ¹H NMR.MS shows correct molecular weight: [M+H]: 462.

(iv) 17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 α-methoxyl group morphinanium trifluoroacetate (D0004) and (R)-17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6 'beta '-methoxy morphinanium trifluoroacetate (D0005)

(150mg 0.25mmol) is dissolved in MeOH (10mL) with chemical compound 4.Adding Pd/C (152mg, 10%, wet type, 0.141mmol).With the mixture of gained in room temperature at H ₂Air bag stirs down.2.5h mass spectral analysis afterwards shows that parent material all is converted into product.Filtering reacting solution.Evaporation filter liquor and with partly preparing HPLC purification residue with the D0004 (29mg, 21%) that is produced as white foam be the D0005 (45mg, 32%) of white foam.

D-0004: ¹H NMR (300MHz, D ₂O) δ ppm 6.78 (d, J=8.3Hz, 1H), 6.66 (d, J=8.3Hz, 1H), 4.91 (d, J=5.2Hz, 1H), and 3.81-4.00 (m, 3H), 3.57 (s, 3H), 3.59 (d, J=21.0Hz, 1H), 3.32 (s, 3H), 2.96-3.29 (m, 3H), 2.51-2.82 (m, 2H), 1.67-1.90 (m, 2H), 1.54-1.64 (m, 2H), 1.22-1.39 (m, 1H), and 1.05-1.21 (m, 1H), 0.64-0.92 (m, 2H), 0.45-0.59 (m, 1H), 0.26-0.42 (m, 1H) .HPLC purity: 100%.MS[M+H]: 372.2.

D-0005: ¹H NMR (300MHz, D ₂O) δ ppm 6.80 (d, J=8.3Hz, 1H), 6.73 (d, J=8.3Hz, 1H), 4.57 (d, J=6.3Hz, 1H), and 3.84-3.96 (m, 2H), 3.50-3.65 (m, 4H), 3.36 (s, 3H), 3.05-3.29 (m, 3H), 2.83-3.00 (m, 1H), and 2.48-2.74 (m, 2H), 1.40-1.91 (m, 5H), 1.05-1.20 (m, 1H), and 0.77-0.91 (m, 1H), 0.66-0.77 (m, 1H), 0.45-0.60 (m, 1H), 0.25-0.38 (m, 1H) .HPLC purity: 100%.MS[M+H]: 372.2.

Embodiment 6

17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3,14-dihydroxy-17-methyl-morphinanium-6-ketone Trifluoroacetate (D0006)

(i) methyl 17-[(2 '-tetrahydrofuran base)]-4,5 α-epoxy-3,14-dihydroxy morphinan-6-ketone (2)

With nor-oxymorphone 1 (1.0g, 3.48mmol), 2-chloromethyl oxolane (1.51mL, 13.9mmol), KI (1.16g, 7.0mmol) and NaHCO ₃(1.16g 13.9mmol) mixes in dry DMF (20mL) and is incorporated in 90-100 ℃ at N ₂The following stirring.Mass spectral analysis shows that most 1 has consumed after the 19h.Reaction solution is cooled to room temperature and adds entry (80mL).Extract this mixture with DCM (2x70mL).The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor.With the brown colloidal solid of column chromatography (eluant: 0-5%MeOH is in DCM) purification to be produced as yellow gelationus 2 (1.14,88%). ¹H?NMR(300MHz，CDCl ₃)δppm?6.72(d，J＝8.0Hz，1H)，6.60(d，J＝8.3Hz，1H)，4.67(s，1H)，3.61-4.34(m，5H)，2.99-3.18(m，2H)，2.51-2.78(m，4H)，2.22-2.50(m，3H)，1.73-2.14(m，7H)，1.46-1.71(m，3H).MS[M+H]：372.2

(ii) 17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3-isobutyl acyloxy (isobutryloxy)-14-hydroxyl morphinan-6-ketone (3)

With chemical compound 2 (1.14g, 3.08mmol) be dissolved in anhydrous DCM (60mL) and in 0 ℃ at N ₂The following stirring.Add EtN (iPr) ₂(2.13mL, 12.28mmol), drip subsequently isobutyryl chloride (0.65mL, 6.15mmol).With the mixture of gained in stirring at room 4h.Add moisture Na ₂CO ₃(60mL 0.5N) and with DCM (2x60mL) extracts mixture.The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor.(eluant: EtOAc) the brown colloidal solid of purification is to be produced as yellow foamy 7 (202mg, 15%) with post. ¹H?NMR(300MHz，CDCl ₃)δppm?6.84(d，J＝8.3Hz，1H)，6.69(d，J＝8.0Hz，1H)，5.12(s，1H)，4.69(s，1H)，3.97-4.09(m，1H)，3.85-3.95(m，1H)，3.72-3.82(m，1H)，2.21-3.20(m，10H)，1.81-2.12(m，4H)，1.51-1.69(m，6H)，1.33(d，J＝7.4Hz，6H).MS[M+H]：442.2.

(iii) 17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3-isobutyryl Oxy-1 4-hydroxyl-17-methyl-morphinanium-6-ketone fluoroform sulphonate (4)

With chemical compound 3 (202mg, 0.46mmol) be dissolved among the anhydrous DCM (10mL) and in room temperature at N ₂The following stirring.Add TfOMe (2.4mL, 0.69M in DCM, 1.66mmol) and with the solution stirring 22h of gained.Add moisture Na ₂CO ₃(5mL 2M) and with DCM (2X20mL) extracts mixture.The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor and with post (eluant: 2-10%MeOH is in DCM) purification residue to be produced as 8 (113mg, 41%) of white foam. ¹H?NMR(300MHz，CDCl ₃)δppm?6.96(d，J＝8.0Hz，1H)，6.82(d，J＝8.3Hz，1H)，5.66(s，1H)，4.78(s，1H)，4.64(d，J＝3.6Hz，1H)，4.35-4.48(m，1H)，3.99(s，3H)，3.80-3.96(m，2H)，2.79-3.71(m，10H)，2.39-2.51(m，1H)，2.18-2.36(m，2H)，1.92-2.06(m，2H)，1.84(d，J＝10.7Hz，1H)，1.52-1.73(m，3H)，1.34(d，J＝6.9Hz，6H).MS[M+H]：456.2.

(iv) 17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3,14-dihydroxy-17-methyl-morphinanium-6-ketone trifluoroacetate (D-0006)

(112mg 0.185mmol) is dissolved in MeOH (10mL) and add moisture HBr (0.4mL, 48%) with chemical compound 4.Gained solution stirs 2.5h in 70 ℃.Evaporating solvent is also with partly preparing the D-0006 (27mg, 26%) of HPLC purification residue to be produced as white foam. ¹H NMR (300MHz, D ₂O) δ ppm 6.77 (d, J=8.3Hz, 1H), 6.70 (d, J=8.3Hz, 1H), 4.97 (s, 1H), 4.44-4.56 (m, 1H), 4.01 (d, J=3.9Hz, 1H), 3.82 (d, J=7.2Hz, 3H), 3.68 (s, 3H), 3.28-3.45 (m, 3H), 2.74-3.19 (m, 4H), 2.14-2.28 (m, 2H), 1.98-2.08 (m, 1H), and 1.66-1.96 (m, 4H), 1.51-1.65 (m, 1H) .HPLC purity: 100%.MS[M+H]: 386.2.

Embodiment 7

4,5 α-epoxy-3-hydroxyl-(17,14-N, O-ethylidene) morphinanium-6-ketone trifluoroacetate (D-0007)

(i) nor-oxymorphone dimethyl ketal (2)

(3.0g 10.4mmol) is suspended in anhydrous MeOH (100mL) with nor-oxymorphone 1.(3.4mL, 31.2mmol), (2M is in Et to add HCl subsequently to add trimethyl orthoformate ₂Among the O, 15.6mL, 31.2mmol).With the mixture of gained in stirring at room 21h.Add Na ₂CO ₃(2M, 50mL, 100mmol).Remove MeOH by rotary evaporation after stirring 10min.Extract with moist residue water (50mL) dilution and with DCM (3x 60mL).The DCM extract is merged, use Na ₂SO ₄Dry also filtration.The evaporation filter liquor.White solid product (2.6g, 75%) is used to next reaction and need not purification.MS[M+H]：334.2

(ii) 3-benzyloxy-4,5 alpha-epoxy-17-(2 '-hydroxyethyl) morphinan-6-ketone dimethyl ketal (3)

With nor-oxymorphone dimethyl ketal 2 (2.4g, 7.2mmol), ethylene iodohydrin (0.67mL, 8.65mmol) and NaHCO ₃(0.79g 9.36mmol) mixes in dry DMF (50mL) and is incorporated in 80-90 ℃ at N ₂Under heat 1h.(0.97mL 8.65mmol), adds K subsequently to add benzyl bromide a-bromotoluene ₂CO ₃(1.98g, 14.4mmol).The mixture of gained is stirred 2h and is cooled to room temperature.Add more K ₂CO ₃(3.80g 27.5mmol) also continues to stir other 18h.(0.5mL 4.3mmol) also continues the other 24h of reaction to add more benzyl bromide a-bromotoluene.Reaction solution is diluted with EtOAc (150mL) and water (3x80mL) and saline (80mL) washing.Use Na ₂SO ₄Dry also filtration.The evaporation filter liquor also uses post (eluant: 30-100%EtOAc is in hexane, and 10%MeOH is in DCM afterwards) purification residue to be produced as yellow gelationus 3 (0.91g, 27%). ¹H?NMR(300MHz，CDCl ₃)δppm?7.28-7.49(m，5H)，6.75(d，J＝8.3Hz，1H)，6.53(d，J＝8.3Hz，1H)，5.16-5.34(m，2H)，4.59(s，1H)，3.63-3.72(m，2H)，3.38(s，3H)，3.27-3.46(m，1H)，3.17(s，3H)，2.86-3.11(m，4H)，2.52-2.78(m，4H)，2.28-2.42(m，2H)，1.84-1.98(m，1H)，1.36-1.68(m，3H).MS[M+H]：468.2.

(iii) 3-benzyloxy-4,5 alpha-epoxy-17-(2 '-chloroethyl) morphinan-6-ketone dimethyl ketal (4)

(0.91g 1.95mmol) is dissolved in anhydrous DCM (20mL) and at N with morphinan 3 ₂The following stirring.Add EtN (iPr) ₂(1.06ml, 5.85mmol), add subsequently mesyl chloride (0.17mL, 2.15mmol).With the mixture of gained in stirring at room 1h.Remove DCM and with post (eluant: 20-50%EtOAc is in hexane) purification residue to be produced as 4 (454mg, 48%) of white solid. ¹H?NMR(300MHz，CDCl ₃)δppm?7.29-7.50(m，5H)，6.75(d，J＝8.3Hz，1H)，6.53(d，J＝8.5Hz，1H)，5.15-5.35(m，2H)，5.01(s，1H)，4.62(s，1H)，3.59(br.s.，2H)，3.40(s，3H)，3.08(s，3H)，2.48-3.01(m，6H)，2.25-2.42(m，2H)，1.89-2.03(m，1H)，1.34-1.71(m，4H).MS[M+H]：486.2.

(iv) 3-benzyloxy-4,5 α-epoxy-(17,14-N, O-ethylidene) morphinan-6-ketone dimethyl ketal (5)

With chemical compound 4 (452mg, 0.932mmol) and KI (295mg 1.77mmol) mixes in anhydrous THF (50mL) and is incorporated in N ₂The following stirring.(123mg, 60% in mineral oil, 3.08mmol) and with the mixture of gained heats 7h under refluxing to add NaH.After being cooled to room temperature, it adds entry (0.5mL).Continue to stir 10min also except that desolvating.With post (eluant: 4-10%MeOH is in DCM) purification residue to be produced as 5 (399mg, 95%) of white solid. ¹HNMR(300MHz，CDCl ₃)δppm?7.28-7.49(m，5H)，6.77(d，J＝8.3Hz，1H)，6.56(d，J＝8.3Hz，1H)，5.31(s，1H)，5.16-5.34(m，2H)，4.61(s，1H)，3.83-3.92(m，2H)，3.49-3.65(m，2H)，3.39(s，3H)，3.01-3.03(m，3H)，2.93-3.19(m，3H)，2.50-2.70(m，2H)，1.86-2.00(m，1H)，1.58-1.70(m，1H)，1.37-1.57(m，2H)，1.15-1.28(m，1H).MS[M+H]：450.2.

(v) 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-(17,14-N, O-ethylidene) morphinanium-6-ketone dimethyl ketal (6)

(124mg 0.276mmol) is dissolved in dry DMF (5mL) and at N with chemical compound 5 ₂The following stirring.Add KI (137mg, 0.828mmol), add subsequently the cyclopropyl methyl bromide (0.134mL, 1.38mmol).The mixture of gained is heated 18h in 80-90 ℃.(0.10mL 1.03mmol) also continues the other 24h of reaction to add more cyclopropyl methyl bromide.Concentrated reaction solution and with post (eluant: 5-10%MeOH is in DCM) purification residue to be produced as 6 (123mg, 75%) of yellow solid. ¹H?NMR(300MHz，DMSO-d ₆)δppm?7.95(s，1H)，7.28-7.44(m，5H)，6.92(d，J＝8.5Hz，1H)，6.68(d，J＝8.5Hz，1H)，5.11(s，2H)，4.99(s，1H)，4.71(d，J＝5.0Hz，1H)，4.62(d，J＝6.6Hz，1H)，3.86-4.27(m，3H)，3.45(s，3H)，3.28-3.76(m，4H)，3.13-3.27(m，1H)，2.21-2.33(m，1H)，1.74-1.93(m，2H)，1.12-1.40(m，4H)，0.73(d，J＝8.0Hz，2H)，0.48(d，J＝2.2Hz，2H).MS[M+H]：504.3.

(vi) (S)-17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-(17,14-N, O-ethylidene) morphinanium-6-ketone trifluoroacetate (D0007)

With chemical compound 6 (121mg, 0.21mmol) be dissolved in TFA (5mL) and in 60-70 ℃ the heating 4.5h.Remove TFA.Brown solid residue and the crude product that originates from another reaction (67mg 2) mixed and with partly preparing the D0007 (71mg, tfa salt, 46%) of HPLC purification to be produced as white foam. ¹H NMR (300MHz, D ₂O) δ ppm 6.79 (d, J=8.3Hz, 1H), 6.72 (d, J=8.5Hz, 1H), 5.06 (s, 1H), 4.64 (d, J=5.5Hz, 1H), 4.27-4.41 (m, 1H), and 4.09-4.27 (m, 2H), 3.88-4.04 (m, 1H), and 3.45-3.75 (m, 3H), 3.12-3.29 (m, 2H), and 2.92-3.10 (m, 3H), 2.09-2.29 (m, 2H), 1.80 (d, J=9.6Hz, 1H), and 1.50-1.68 (m, 1H), 1.06-1.23 (m, 1H), 0.69-0.89 (m, 2H), 0.35-0.55 (m, 2H) .HPLC purity: 100%.MS[M+H]: 368.1.

Embodiment 8-11

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methylmorphine alkane ion fluoroform sulphonate (18) (D0008), 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-(3-phenyl third The oxygen base) morphinanium fluoroform sulphonate (21) (D0009), 17-cyclopropyl methyl-4,5 α-epoxy -3-hydroxyl-17-methyl isophthalic acid 4-propoxyl group morphinanium fluoroform sulphonate (20) (D0010), and 17- Cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-methoxyl group-17-methylmorphine alkane ion trifluoromethanesulfonic acid Salt (19) (D0011)

17-cyclopropyl methyl-4,5 α-epoxy-3, the 3-O-benzylization of 14-dihydroxy morphinan derivant general Program

At N ₂In the DMF solution (2mL/mmol) of 3-hydroxy compounds (1 equivalent), add K down ₂CO ₃(1.3 equivalent) adds benzyl bromide a-bromotoluene (1.1 equivalent) subsequently and the mixture of gained stirred 20h.With the reactant mixture dilute with water and use dichloromethane extraction.With the Organic substance MgSO that merges ₄Dry and concentrate producing rough 3-O-benzyl derivative, as this derivant of further processing described at instantiation.

The 14-O-alkylation of 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan derivant General procedure

At N ₂Down NaH (3 equivalents, 60% is suspended in mineral oil) is joined in the DMF solution of 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan derivant (1 equivalent).Add alkyl halide/alkyl sodium sulfate ester (1.3 equivalent) after 20 minutes and with the mixture of gained in stirring at room 2-5h.Destroy excessive N aH by adding ice.Add entry and use the dichloromethane extraction reactant mixture.Collect Organic substance and dry (MgSO ₄) and evaporate to produce rough material, this material is purified when needed or in statu quo further uses.

Hydrogenant general procedure

The palladium catalyst (10% carbon carries Pd, 50% wet type) of 10-50Mol% is joined chemical compound in the solution of methanol or methanol-THF mixture (1: 1) and in room temperature hydrogenation 2 to 3 hours under 1 atmospheric pressure.Catalyst filtered out and evaporate filter liquor to produce raw product, it in statu quo is used for next step and need not to be further purified.

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methylmorphine alkane ion fluoroform sulphonate (18) (D0008)

Described at general procedure, by handling from 3-benzyloxy-17-cyclopropyl methyl-4 with cinnamyl bromine and NaH, 5 α-epoxy-14-hydroxyl morphinan 3 synthetic 3-benzyloxy-14-cinnamoyloxy group (cinnamyloxy)-17-cyclopropyl methyl-4,5 α-epoxy morphinans 6 (productive rate=62%).

¹H NMR (301MHz, the δ ppm 7.38-7.46 of chloroform-d) (m, 5H), 6.73 (d, J=8.3Hz, 1H), 6.66 (d, J=16Hz, 1H), 6.54 (d, J=8.0Hz, 1H), and 6.29-6.47 (m, 1H), 5.16 (dd, J=15.7,12.1Hz, 2H), 4.78 (t, J=7.4Hz, 1H), 4.38 (dd, J=5.0,1.4Hz, 1H), 4.34 (dd, J=5.5,1.7Hz, 1H), 3.94-4.05 (m, 1H), 3.44 (d, J=5.0Hz, 1H), 3.11 (d, J=18.4Hz, 1H), and 2.63-2.77 (m, 1H), 2.47-2.62 (m, 1H), 2.43 (d, J=5.5Hz, 1H), 2.31-2.39 (m, 5H), 2.05-2.22 (m, 4H), 1.68-1.77 (m, 2H), 1.30-1.39 (m, 1H), and 0.99-1.17 (m, 1H), 0.76-0.91 (m, 1H), 0.34-0.59 (m, 2H), 0.13 (d, J=5.0Hz, 2H); APCI[M+H] 534.3.

(ii) 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan

With trifluoromethanesulfonic acid methyl ester (solution of 3 equivalent 0.69M in dichloromethane) in the dichloromethane solution 36h of room temperature treatment 3-benzyloxy-14-cinnamoyloxy group-17-cyclopropyl methyl-4,5 α-epoxy morphinan 6 (1 equivalent).Evaporating solvent also uses silicon dioxide column chromatography (methylene chloride) purification residue to obtain 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan 14 (MeOTf cracking 14-O-cinnamyl ether) (95%).

¹H NMR (301MHz, and the δ ppm 7.30-7.39 of chloroform-d) (m, 5H), 6.84 (d, J=8.25Hz, 1H), 6.67 (d, J=8.25.0Hz, 1H), 5.16 (s, 2H), 4.78 (t, J=7.4Hz, 1H), 4.69 (br.s.1H), 4.25 (d, J=3.3Hz, 1H), 4.79 (m, 4H), 3.36-3.47 (m, 2H), 3.10-3.22 (m, 2H), 2.59-2.88 (m, 3H), 2.11-2.16 (m, 1H), 1.64 (d, J=13.17Hz, 1H), 1.15-1.39 (m, 5H), and 0.82-0.877 (m, 2H), 0.59-0.62 (m, 1H), 0.36-0.41 (m, 1H) APCI[M+H] 432.3.

The hydrogenation of 14 described in the general procedure has produced title compound D0008 with 98% productive rate.

¹H NMR (301MHz, deuterium oxide) δ ppm 6.82 (d, J=8.3Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 4.85 (t, J=7.4Hz, 1H), 3.80-4.02 (m, 2H), 3.53-3.66 (m, 4H), 3.12-3.34 (m, 3H), 2.90-3.04 (m, 1H), 2.63-2.74 (m, 1H), 2.44-2.62 (m, 1H), 2.06-2.20 (m, 1H), 1.54-1.75 (m, 2H), 1.35-1.50 (m, 2H), and 1.07-1.25 (m, 2H), 0.68-0.93 (m, 2H), 0.49-0.61 (m, 1H), and 0.30-0.40 (m, 1H); APCI[M+H] 342.2; HPLC (the 85/15 water/methanol that contains 0.1%TFA) R _T=5.49min.

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-(3-phenyl propoxyl group) morphinanium Fluoroform sulphonate (21) (D0009)

(i) 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-(3-phenyl propoxyl group) morphinan

As described in the general procedure with 3-benzyloxy-14-cinnamoyloxy group-17-cyclopropyl methyl-4,5 α-epoxy morphinan (6) hydrogenation is so that produce 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-(3-phenyl propoxyl group) morphinan (9) with quantitative productive rate.

¹H NMR (301MHz, and the δ ppm 6.99-7.44 of chloroform-d) (m, 5H), 6.70 (d, J=8.0Hz, 1H), 6.55 (d, J=8.0Hz, 1H), 4.75 (t, J=7.4Hz, 1H), 3.59-3.70 (m, 2H), 3.22-3.45 (m, 2H), 3.09 (d, J=17.9Hz, 1H), 2.78 (t, J=8.0,7.4Hz, 2H), 2.47-2.73 (m, 4H), and 2.27-2.43 (m, 4H), 2.04-2.19 (m, 1H), and 1.89-2.02 (m, 2H), 1.69 (d, J=12.9Hz, 1H), 1.19-1.35 (m, 2H), 0.93-1.13 (m, 1H), 0.68-0.85 (m, 1H), 0.42-0.44 (m, 2H), 0.04-0.17 (m, 2H); APCI[M+H] 446.3.

(ii) 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-(3-phenyl propoxyl group) morphinan

In room temperature at N ₂Under use K ₂CO ₃Handle 9 DMF solution 20h with benzyl bromide a-bromotoluene.With the reactant mixture dilute with water and use dichloromethane extraction.With the Organic substance MgSO that merges ₄Dry also concentrated solvent is to produce 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-(3-phenyl propoxyl group) morphinan 13 by the productive rate with 68% after using hexane/ethyl acetate as the silicon dioxide column chromatography purification of eluant.

1H NMR (301MHz, and the δ ppm 7.11-7.55 of chloroform-d) (m, 10H), 6.72 (d, J=7.4Hz, 1H), 6.52 (d, J=8.0Hz, 1H), 5.15 (m, 2H), 4.72 (t, J=7.7Hz, 1H), 3.54-3.67 (m, 1H), 3.35 (d, J=4.7Hz, 1H), 3.23-3.31 (m, 1H), 3.07 (d, J=18.4Hz, 1H), 2.78 (t, J=7.7Hz, 2H), 2.65 (dd, J=11.6,4.7Hz, 1H), 2.44-2.59 (m, 1H), 2.25-2.41 (m, 2H), 2.00-2.20 (m, 2H), 1.82-1.98 (m, 2H), 1.61-1.74 (m, 2H), 1.15-1.45 (m, 4H), 0.93-1.11 (m, 0H), 0.63-0.80 (m, 1H), 0.39-0.52 (m, 2H), 0.02-0.10 (m, 2H); APCI[M+H] 536.2

(iii) 3-benzyloxy-17-cyclopropyl methyl-4,5 alpha-epoxy-17s-methyl isophthalic acid 4-(3-phenyl propoxyl group) morphinanium fluoroform sulphonate

In room temperature at N ₂Handle the dichloromethane solution 17h of 13 (1 equivalents) under the atmosphere with trifluoromethanesulfonic acid methyl ester (solution of 3 equivalent 0.69M in dichloromethane).Evaporating solvent is also used preparation type TLC (1000 μ plates, eluant MeOH/DCM, 5/95) the purification of crude material is 3-benzyloxy-17-cyclopropyl methyl-4,5 alpha-epoxy-17s-methyl isophthalic acid 4-(3-phenyl propoxyl group) morphinanium fluoroform sulphonate (17) of 55% of white solid with the acquisition.

¹H NMR (301MHz, and the δ ppm 7.16-7.48 of chloroform-d) (m, 10H), 6.84 (d, J=8.5Hz, 1H), 6.68 (d, J=8.0Hz, 1H), 5.16 (s, 2H), 4.66 (t, t, J=8.0,7.4Hz, 1H), 4.50 (s, 1H), 3.69-3.85 (m, 2H), 3.63 (s, 3H), 3.42-3.58 (m, 2H), 3.20-3.38 (m, 2H), 2.91-3.16 (m, 2H), 2.69-2.91 (m, 2H), 2.44-2.64 (m, 1H), 1.89-2.25 (m, 5H), 1.58-1.72 (m, 1H), 1.32 (m, 2H), 0.99-1.27 (m, 2H), 0.77-0.99 (m, 2H), 0.48-0.65 (m, 2H); APCI[M+H] 550.4.

(iv) 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-(3-phenyl propoxyl group) morphinanium fluoroform sulphonate

Methanol solution with 17 stands the hydrogenation described in general procedure so that produce title compound 21, D0009 with quantitative productive rate.

¹H NMR (301MHz, and the δ ppm 9.37 of chloroform-d) (s, 1H), 7.04-7.41 (m, 5H), and 6.42-6.92 (m, 2H), 4.66 (t, J=8.0,7.4Hz, 1H), 4.27-4.32 (m, 1H), and 3.70-3.84 (m, 1H), 3.51-3.65 (m, 2H), 3.46 (s, 3H), 3.39 (d, J=1.9Hz, 1H), 3.14-3.26 (m, 1H), 2.80-3.01 (m, 3H), 2.62-2.80 (m, 4H), 1.78-2.19 (m, 4H), 1.47 (d, J=14.0Hz, 1H), and 0.98-1.31 (m, 4H), 0.45-0.88 (m, 2H), and 0.14-0.42 (m, 1H); APCI[M+H] 460.3; HPLC (40/60 water/methanol contains 0.1%TFA) R _T=4.50min.

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-propoxyl group morphinanium fluoroform Sulfonate (20) (D0010)

(i) 14-allyloxy-3-benzyloxy-17-cyclopropyl methyl-4,5 alpha-epoxy-17s-methylmorphine alkane

With trifluoromethanesulfonic acid methyl ester (solution of 3 equivalent 0.69M in dichloromethane) in the dichloromethane solution 17h of room temperature treatment 14-allyloxy-3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy morphinan 5 (1 equivalent).Evaporating solvent and usefulness silicon dioxide column chromatography (methylene chloride) purification residue obtain 14-allyloxy-3-benzyloxy-17-cyclopropyl methyl-4 with 76% productive rate, 5 alpha-epoxy-17s-methylmorphine alkane 16, it shows a bit impure and in statu quo is used for next step through NMR.

¹H NMR (301MHz, and the δ ppm 7.26-7.46 of chloroform-d) (m, 5H), 6.84 (d, J=8.3Hz, 1H), 6.69 (d, J=8.3Hz, 1H), 5.82-6.03 (m, 1H), 5.38 (d, J=17.1Hz, 1H), 5.21 (d, J=10.5Hz, 1H), 5.11 (s, 2H), 4.78 (d, J=8.1Hz, 1H), 4.58 (br.s., 1H), 4.14-4.30 (m, 1H), 3.97-4.10 (m, 1H), 3.73 (dd, 1H), 3.59 (s, 3H), 3.55 (br.s., 1H), 3.47 (d, J=5.2Hz, 1H), 3.34 (d, J=10.7Hz, 1H), 3.10 (dd, J=20.4,3.6Hz, 1H), 2.61-2.99 (m, 2H), and 2.05-2.29 (m, 2H), 1.68 (d, J=13.5Hz, 1H), and 1.33-1.49 (m, 3H), 1.14-1.29 (m, 2H), 0.71-1.01 (m, 2H), 0.25-0.66 (m, 2H); APCI[M+H] 472.3.

(ii) 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-17-methyl isophthalic acid 4-propoxyl group morphinanium fluoroform sulphonate (20) (D0010)

Described in general procedure, carry out 16 hydrogenation.Use methanol (30/70) (containing 0.1%TFA) partly to prepare purification of crude material on the HPLC post and obtain be the title compound D0010 (32%) of white solid.

¹H NMR (301MHz, methanol-d ₃) δ ppm 6.63-6.82 (m, 2H), 4.74 (t, J=8.3,7.7Hz, 1H), 4.29 (d, J=3.6Hz, 1H), 3.88 (dd, J=14.0,3.9Hz, 1H), 3.64 (d, J=1.4Hz, 1H), 3.61 (s, 3H), 3.52-3.58 (m, 2H), and 3.40-3.48 (m, 1H), 3.04-3.12 (m, 3H), and 2.95-3.04 (m, 1H), 2.68-2.81 (m, 2H), and 2.12-2.25 (m, 1H), 2.02-2.11 (m, 1H), and 1.62-1.78 (m, 2H), 1.48-1.56 (m, 1H), and 1.41-1.47 (m, 1H), 1.20-1.34 (m, 2H), 1.03 (t, J=7.4Hz, 3H), 0.87-0.99 (m, 1H), 0.76-0.88 (m, 1H), 0.59-0.69 (m, 1H), 0.37-0.48 (m, 1H); APCI[M+H] 384.3; HPLC (50/50 water/methanol contains 0.1%TFA) R _T=4.30min.

17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-methoxyl group-17-methylmorphine alkane ion fluoroform sulphur Hydrochlorate (19) (D0011)

(i) 3-hydroxyl-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan (2)

In diethylene glycol (55mL) solution of Naltrexone Hydrochloride (1.HCl, 10g, 1 equivalent), add hydrazine hydrate (98%, 8mL) and potassium hydroxide (28g, 30 equivalents) and with mixture at 100 ℃ of heating 1h and 165 ℃ heating 3h.With reactant mixture cooling and water (150mL) dilution and be acidified to pH6 with dense HCl and use solid NaHCO then ₃Transfer to pH10 and use methanol: dichloromethane (1: 9) (2X200mL) extracts.With the Organic substance MgSO that merges ₄Dry and concentrated to obtain the brown residue.By using hexane/ethyl acetate/triethylamine; 50/45/5 column chromatography purification rough material is 17-cyclopropyl methyl-4, the 5 α-epoxy-3 of white solid with what obtain 4.5g (35%), 14-dihydroxy morphinan 2.

¹H NMR (301MHz, and the δ ppm 6.69 of chloroform-d) (d, J=8.0Hz, 1H), 6.51-6.62 (d, J=8.0Hz, 1H), 5.13 (br.s., 1H), 4.73 (t, J=8.22Hz, 1H), 2.95-3.08 (m, 2H), 2.54-2.70 (m, 2H), 2.31-2.41 (m, 2H), 2.06-2.27 (m, 2H), 1.77 (tt, J=12.9,3.0Hz, 1H), 1.35-1.57 (m, 2H), 1.13-1.35 (m, 2H), and 0.74-0.94 (m, 1H), 0.45-0.59 (m, 2H), 0.41-0.70 (m, 2H), and 0.07-0.23 (m, 2H); APCI[M+H] 328.2.

(ii) 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-hydroxyl morphinan (3):

Use K ₂CO ₃With described in benzyl bromide a-bromotoluene such as the general procedure at N ₂Under handle DMF (10mL) solution of 2 (0.991g, 1 equivalents).20h stirs the mixture.With the reactant mixture dilute with water and use dichloromethane extraction.With the Organic substance MgSO that merges ₄Dry also concentrated solvent is to produce the title compound 3 of 1.2g (95%), and it is used to next step and need not to be further purified.

¹H NMR (301MHz, and the δ ppm 7.29-7.47 of chloroform-d) (m, 5H), 6.75 (d, J=8.3Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.17 (dd, J=26.4,12.4Hz, 2H), 5.08 (s, 1H), 4.73 (t, J=8.0Hz, 1H), 2.94-3.12 (m, 2H), 2.51-2.73 (m, 2H), 2.36 (d, J=6.6Hz, 2H), and 2.03-2.28 (m, 3H), 1.67-1.99 (m, 1H), and 1.10-1.65 (m, 5H), 0.72-0.92 (m, 1H), 0.53 (d, J=7.7Hz, 2H), and 0.00-0.26 (m, 2H); APCI[M+H] 418.3.

(iii) 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-methoxyl group-17-methylmorphine alkane

With trifluoromethanesulfonic acid methyl ester (solution of 3 equivalent 0.69M in dichloromethane) in the dichloromethane solution 17h of room temperature treatment 3-benzyloxy-17-cyclopropyl methyl-4,5 α-epoxy-14-methoxyl group morphinan (4) (1 equivalent).Evaporating solvent and usefulness silicon dioxide column chromatography (methylene chloride) purification residue obtain 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-methoxyl group-17-methylmorphine alkane 15 with 90% productive rate.

¹H NMR (301MHz, and the δ ppm 7.21-7.42 of chloroform-d) (m, 5H), 6.83 (d, J=8.3Hz, 1H), 6.68 (d, J=8.3Hz, 1H), 5.14 (dd, J=14.0,12.1Hz, 2H), 4.72 (t, J=8.0Hz, 1H), 4.45 (d, J=2.5Hz, 1H), 3.72 (dd, J=13.5,4.1Hz, 1H), 3.60 (s, 3H), 3.49 (d, J=20.4Hz, 1H), 3.32-3.39 (m, 2H), 3.25 (s, 1H), 2.96-3.15 (m, 2H), 2.56-2.73 (m, 2H), 2.30-2.51 (m, 1H), 2.05-2.25 (m, 3H), 1.54-1.66 (m, 1H), 1.24-1.49 (m, 3H), 0.88-1.01 (m, 1H), 0.69-0.85 (m, 1H), 0.38-0.67 (m, 2H); APCI[M+H] 446.2

(iv) 17-cyclopropyl methyl-4,5 α-epoxy-3-hydroxyl-14-methoxyl group-17-methylmorphine alkane ion fluoroform sulphonate (19) (D0011)

Described in general procedure, carry out 15 hydrogenation.Partly prepare purification of crude material on the HPLC post to obtain title compound D0011 (77%) what use methanol (35/85) (containing 0.1%TFA) as white solid.

¹H NMR (301MHz, deuterium oxide) δ ppm 6.79 (d, J=8.3Hz, 1H), 6.71 (d, J=8.3Hz, 1H), 4.80 (t, J=8.3Hz, 1H), 4.24 (d, J=3.6Hz, 1H), 3.79-3.97 (m, 1H), 3.59 (d, J=19.8Hz, 1H), 3.49 (s, 3H), 3.26 (s, 3H), 3.12-3.22 (m, 1H), 2.82-3.09 (m, 2H), and 2.49-2.71 (m, 2H), 2.02-2.22 (m, 1H), 1.94 (d, J=14.0Hz, 1H), 1.59 (dd, J=14.9,3.3Hz, 1H), and 1.31-1.45 (m, 2H), 1.04-1.25 (m, 3H), 0.63-0.92 (m, 2H), 0.46-0.59 (m, 1H), 0.18-0.43 (m, 1H); APCI[M+H] 356.3; HPLC (75/25 water/methanol contains 0.1%TFA) R _T=5.20min.

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 improvement to the present invention.All documents that this paper mentions are incorporated herein the place that is fit to instruction extra or selectable details, feature and/or technical background by reference.

Claims

1. chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (e),

I(e)

Wherein:

R ₁And R ₂Be H, OH, OR independently ₂₉, halogenide, silicyl;

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;

Or R ₁And R ₂In conjunction with forming C ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring or 5-6 unit heteroaryl condensed ring;

R ₃Be H, silicyl, CO ₂R ₁₉, SO ₂R ₁₉, B (OR ₁₉) 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;

R ₅Be H, OH, OR ₂₉,

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 ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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;

Perhaps R ₆And R ₇In conjunction with forming O-condensed ring, C ₃-C ₆Carbocyclic ring condensed ring, fused benzo ring, have 0-3 R ₂₀5-, 6-or 5-6 unit aryl, or heteroaryl condensed ring;

With

Wherein X be key ,=O, O, S, N (R ₂₉), SO, SO ₂, SO ₂N (R ₂₉), CON (R ₂₉), N (R ₂₉) CON (R _{29 '}), N (R ₂₉) C (=NR _{29 '}) N (R _{29 "}), COO,

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;

With

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 group, acyloxy,

Or and R ₁₈In conjunction with forming O-condensed ring or C ₃-C ₆If the carbocyclic ring condensed ring is perhaps R ₆=ring-like ring or and R ₇When forming ring-like ring, also alkoxyl or aryloxy group;

If R wherein ₆Be=during O, R ₁₄Be not:

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;

With

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

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, acetyl group, OR ₂₅, XR ₂₅,

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

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

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

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

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

NR ₂₂R ₂₃Be selected from the heterocyclic type ring of group piperidyl, homopiperidinyl, thio-morpholinyl, piperazinyl and morpholinyl;

R ₂₂, when occurring, be independently selected from H, C at every turn ₁-C ₆Alkyl, C ₆-C ₁₀Aryl, heteroaryl, heterocycle, alkylaryl, aryl alkyl,

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

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

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

R wherein ₂₂And R ₂₃Also can have 0-3 R in conjunction with formation ₂₀5-, 6-, 5-6-unit ring;

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

R ₂₅, when occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, haloalkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, be independently selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, be independently selected from every turn:

R ₂₉When occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

X ^-It is anion.

2. chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I,

I

Wherein:

(a) unsubstituted or non-halogen replaces: C4-C20 (cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl; C4-C10 (cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl;

R ₆Be 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 ₁And R ₂Be H, halogenide, alkoxyl, alkyl or aryl independently;

R ₃Be H, C1-C4 alkyl or C1-C3 acyl group ,-silicyl;

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

X ^-It is anion.

3. chemical compound or its a pharmaceutically acceptable salt form or prodrug with formula I (a),

I(a)

Wherein:

R ₁And R ₂Be H, OH, OR independently ₂₉, halogenide, silicyl;

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 ₃Be H, silicyl;

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 ₅Be H, OH, OR ₂₉,

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, N (CH ₃) ₂Or any ring-like ring;

R ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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 ₈Be H, OH, OR ₂₉,

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 ₁₄Be H, OH, halogenide,

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 group, acyloxy,

If R wherein ₆Be=during O, R ₁₄Be not:

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;

R ₁₇Be 0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₂₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

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, acetyl group, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃,

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

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

R ₂₁, when occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, CF ₃, acetyl group, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃,

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

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

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

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

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

H, (C ₁-C ₆) alkyl, benzyl, phenethyl,

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

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

R ₂₅, when occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, be independently selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, be independently selected from every turn:

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

R ₂₉When occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

X ^-It is anion.

4. chemical compound or its pharmaceutically acceptable salt form, polymorphs body or prodrug with formula I (b),

I(b)

Wherein:

R ₁And R ₂Be H, OH, OR independently ₂₉, halogenide, silicyl;

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 ₃Be H, silicyl;

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 ₅Be H, OH, OR ₂₉,

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,

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, amide, sulfonamide, ester, heterocycle, ring-like hydrocarbons, aryl;

R ₇Be H, OH, OR ₂₉,

0-3 R ₁₉(the C that replaces ₁-C ₂₀) alkyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) thiazolinyl;

0-3 R ₁₉(the C that replaces ₂-C ₂₀) 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 ₈Be H, OH, OR ₂₉,

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 ₁₄Be H, OH,

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 group, acyloxy,

If R wherein ₆During=O, R ₁₄Be not

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;

R ₁₇Be 0-3 R ₂₅(the C that replaces ₄-C ₁₀) alkyl;

0-3 R ₂₅(the C that replaces ₄-C ₁₀) thiazolinyl;

0-3 R ₂₅(the C that replaces ₄-C ₁₀) alkynyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) cycloalkyl;

0-3 R ₂₆(the C that replaces ₃-C ₁₀) carbocyclic ring;

0-3 R ₂₆The aryl that replaces;

R ₁₈Be 0-3 R ₂₇(the C that replaces ₁-C ₃) alkyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) thiazolinyl;

0-3 R ₂₇(the C that replaces ₂-C ₄) alkynyl;

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 ₂₀, when occurring, be independently selected from H, OH, Cl, F, Br, I, CN, NO at every turn ₂, NR ₂₂R ₂₃, acetyl group, SCH ₃, S (=O) CH ₃, S (=O) ₂CH ₃,

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

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

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

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

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

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

H, (C ₁-C ₆) alkyl, benzyl, phenethyl,

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

R ₂₅, when occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, OR ₂₄,=O, CN, NO ₂, NR ₂₇R ₂₈

0-3 R ₂₇The C that replaces ₃-C ₁₀Carbocyclic ring;

0-3 R ₂₇The aryl that replaces; Or

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

H, (C ₁-C ₆) alkyl, benzyl, phenyl, phenethyl, (C ₁-C ₆Alkyl)-C (=O)-;

R ₂₇, when occurring, be independently selected from every turn:

-OH ,-OR ₂₈, C ₁-C ₆Alkyl, C ₁-C ₄Alkoxyl;

R ₂₈, when occurring, be independently selected from every turn:

R ₂₉When occurring, be independently selected from every turn:

H, C ₁-C ₆Alkyl, CF ₃, acyl group (C ₁-C ₆) alkyl;

0-3 R ₂₁The acyl group aryl that replaces;

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

0-3 R ₂₁The aralkyl that replaces;

X ^-It is anion.

5. compositions, it contains at least a chemical compound that is selected from by the following group of forming, its polymorphs body or salt:

17-cyclobutylmethyl-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinanium;

17-cyclopropyl methyl-4,5 α-epoxy-3-benzyloxy-14-hydroxyl-17-methyl-6 α-methoxyl group-morphinanium; And

17-cyclopropyl methyl-4,5 α-epoxy-3,14-dihydroxy-17-methylmorphine alkane ion;

17-[(2 '-tetrahydrofuran base) methyl]-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo-morphinanium;

6. pharmaceutical composition, it contains described chemical compound of claim 5 and pharmaceutically acceptable carrier.

7. pharmaceutical composition as claimed in claim 6, wherein said pharmaceutical composition comprise IR formulation, enteric coating, extended release preparation or cryodesiccated goods.

8. pharmaceutical composition as claimed in claim 7, wherein said pharmaceutical preparation are the unit dose of having packed.

9. pharmaceutical composition as claimed in claim 8, wherein said unit dose of having packed is a solution.

10. pharmaceutical composition as claimed in claim 6, it also contains opioid.

11. compositions as claimed in claim 10, wherein said opioid is selected from by alfentanil, anileridine, Asimadoline, bremazocine; buprenorphine; butorphanol; codeine; dezocine; diacetylmorphine (heroin); paracodin; diphenoxylate; fedotozine; fentanyl; richness is received bent amine; hydrocodone; hydromorphone; levallorphan; levacetylmethadol; levorphanol; loperamide; dolantin (Pethidine); methadone; morphine; morphine-6-glucosiduronic acid; nalbuphine; nalorphine; Opium; oxycodone; oxymorphone; pentazocine; propiram; the third oxygen sweet smell; remifentanil; sufentanil; tilidate; trimebutine; the group that tramadol and combination thereof are formed.

12. pharmaceutical composition as claimed in claim 6, it also contains at least a is not the medicament of opioid or opioid antagonists.

13. pharmaceutical composition as claimed in claim 12, wherein at least a medicament are non-opium sample analgesics/antipyretic, antiviral agent, infection medicament, anticancer agent, spasmolytic medicament, Antimuscarinic medicament, anti-inflammatory agents, short gastrointestinal prokinetic agent, 5HT ₁Agonist, 5HT ₃Antagonist, 5HT ₄Antagonist, 5HT ₄Agonist, cholate screening agent, volume medicament, α 2-2-adrenergic agonist components, mineral oil, antidepressant, medical herbs, antiemetic agents, antidiarrheal, laxative, manure bate, fiber or hemopoiesis stimulant.

14. compositions as claimed in claim 13, wherein said anti-inflammatory agents be selected from by nonsteroidal anti-inflammatory drug (NSAIDS), tumor necrosis factor inhibitors, basiliximab, daclizumab, infliximab, wheat examine phenol ethyl ester, azathioprine, tacrolimus, steroid, sulfasalazine, Olsalazine, U.S. salad is bright and the group formed.

15. pharmaceutical composition as claimed in claim 6, wherein said compositions are oral formulations.

16. pharmaceutical composition as claimed in claim 6, wherein said compositions are freeze-dried preparation or parenteral formulation.

17. pharmaceutical composition as claimed in claim 6, wherein said compositions are extended release preparation.

18. a method that is used to regulate μ-Opioid Receptors, it comprises that the patient to needing μ-opioid to regulate uses the described compositions of claim 6 to regulate effective dose.

19. method as claimed in claim 18, it is consistent that wherein said μ-Opioid Receptors is regulated with opioid agonist.

20. method as claimed in claim 18, it is consistent that wherein said μ-Opioid Receptors is regulated with opioid antagonists.

21. a method that is used to regulate κ or delta-opioid receptor, it comprises that the patient to this adjusting of needs uses the described compositions of claim 6 to regulate effective dose.

22. method as claimed in claim 21, it is consistent that wherein said κ regulates with kappa agonist.

23. method as claimed in claim 21, it is consistent that wherein said κ regulates with the κ antagonist.

24. method as claimed in claim 21, it is consistent that wherein said δ regulates with delta agonists.

25. method as claimed in claim 21, it is consistent that wherein said δ regulates with delta antagonist.

26. method as claimed in claim 18, wherein said compositions is by subcutaneous administration.

27. method as claimed in claim 18, wherein said compositions is used by intravenous.

28. method as claimed in claim 18, wherein said compositions is by Orally administered.

29. chemical compound or its pharmaceutically acceptable salt form, polymorphs body or the prodrug with formula I (c),

I(c)

Wherein:

(a) unsubstituted or non-halogen replaces: C ₄-C ₂₀(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl; C ₄-C ₁₀(cycloalkyl) alkyl or (cycloalkenyl group) alkyl, (the assorted base of ring) alkyl, (cyclophane base) alkyl;

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

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

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

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

X ^-It is anion.

30. chemical compound as claimed in claim 29, wherein R ₇And R ₈Be H or alkyl.

31. chemical compound or its pharmaceutically acceptable salt form, polymorphs body or the prodrug with formula I (d),

I(d)

Wherein:

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

R ₁₄Be H, OH, halogenide, N-alkyl, N-dialkyl group, N-aryl, N-alkylaryl, N-cycloalkyl-alkyl, SR ₂₅, S (=O) R ₂₅, SO ₂R ₂₅, perhaps with R ₁₇Or R ₁₈Form ring-like ring; And if R ₆Be not=during O, R ₁₄But alkoxyl, aryloxy group or aryl-alkoxyl;

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

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

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

R ₂₅Be alkyl, aryl, aryl alkyl; And

X ^-It is anion.

32. a compositions, described compositions comprise at least a chemical compound that is selected from by the following group of forming, its polymorphs body or salt: