HK1139951B - Orally bioavailable prodrugs of (+)-3-hydroxymorphinan for parkinson's disease prevention or treatment - Google Patents

Description

Orally bioavailable prodrugs of (+) -3-hydroxymorphinan for use in the prevention or treatment of parkinson's disease

Technical Field

The present invention relates to novel orally bioavailable prodrugs of (+) -3-hydroxymorphinan that are useful as neuroprotective agents in Parkinson's disease.

Background

Approximately 1 million people in the world suffer from Parkinson's Disease (PD), and 80 million people in a single United states.

Parkinson's disease is the result of chronic progressive degeneration of neurons, the cause of which has not been fully elucidated. Although the main cause of parkinson's disease is not known, it is characterized by degeneration of dopaminergic neurons of the Substantia Nigra (SN). The substantia nigra is a portion of the lower brain or brainstem that helps control voluntary movements. It is believed that the deficiency of dopamine in the brain caused by the loss of these neurons causes observable disease symptoms. Clinically, its major symptoms are manifested in the form of resting tremor, rigidity, bradykinesia, and postural instability.

Levodopa, dopamine agonists (such as rotigotine), pramipexole, bromocriptine, ropinirole, cabergoline, pergolide, apomorphine and lisuride, anticholinergics, NMDA antagonists, beta-blockers and the MAO-B inhibitor selegiline and the COMT inhibitor entacapone are used as agents for alleviating motor symptoms. Most of these agents intervene in dopamine and/or choline signal cascades and thus affect parkinsonian dyskinesia symptomatically.

In current parkinson's disease therapies, treatment begins after the onset of the primary symptoms. Generally, parkinson's disease is considered clinically significant if at least two of the four major symptoms (bradykinesia, resting tremor, rigidity, and postural instability) are detected and responsive to L-dopa (Hughes, JNeurol Neurosurg Psychiatry 55, 1992, 181). Unfortunately, motor dysfunction in Parkinson's patients only becomes apparent after an unrecoverable destruction of approximately 70-80% of dopaminergic neurons in the Substantia Nigra (SN) (Becker et al, J Neurol 249, 2002, Suppl 3: III, 40; Hornykiewicz, Encyclopaedia of Life Science 2001, 1). At that time, the possibility of treatment with sustained effect is very small. Therefore, it is desirable to initiate treatment as early as possible.

Current clinical observations and anatomical and genetic studies indicate that early diagnosis of parkinson patients and identification of high risk patients is possible. In view of this, there is an opportunity to influence the course of the disease when more neurons are still present, rather than when several of the major motor symptoms of parkinson's disease occur, and thus to protect a greater number of neurons. It is expected that the early administration of an effective neuroprotective agent will significantly delay the progression of the disease: the earlier treatment begins, the higher the chance of preventing the onset of quality of life-reducing symptoms for a long duration.

Thus, there is a need for therapeutic approaches that not only affect dopaminergic transmission and alleviate symptoms of parkinson's disease in the advanced stages, but also reverse, prevent or at least significantly delay dopaminergic neuron destruction in the early stages of parkinson's disease (largely without motor symptoms) (Dawson, nature neuroscience Supplement 5, 2002, 1058).

(+) -3-hydroxymorphinans ((+) -3-HM) and derivatives thereof have shown neuroprotective properties in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model of Parkinson's disease. In this animal model, daily injections of (+) -3-HM or an analog thereof showed that Dopamine (DA) neurons in the compact part of the substantia nigra were protected and DA levels in the striatum were restored (U.S. Pat. Pub. No. 2005-0256147A 1; International patent publication WO 2005/110412; Zhang et al, FASEB J.2006Dec.20 (14): 2496-2511; Zhang et al, FASEB J.2005Mar.19 (3): 395-397; and Kim et al, Life Science 72(2003) 1883-1895). However, (+) -3-HM and its derivatives are effective only when administered intraperitoneally or intravenously.

The present invention relates to the provision of novel prodrugs of (+) -3-hydroxymorphinans which are effective as neuroprotective agents in Parkinson's disease when they are delivered orally.

Summary of The Invention

It is a primary object of the present invention to provide novel prodrugs of (+) -3-hydroxymorphinan compounds of formula (I) or pharmaceutically acceptable salts thereof, which are useful as neuroprotective agents in Parkinson's disease.

It is another object of the present invention to provide a process for preparing the compounds of the present invention.

It is another object of the present invention to provide a pharmaceutical composition for treating or preventing parkinson's disease, which comprises the compound of the present invention as an active ingredient.

Brief description of the drawings

The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the accompanying drawings which respectively show:

FIG. 1 illustrates the drug metabolism profile of the compound of example 2 in mice; and

FIG. 2 illustrates the efficacy of intraperitoneal injection of (+) -3-HM and oral administration of the compound of example 2 on an MPTP-induced animal model of Parkinson's disease.

Detailed Description

According to one aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof and a process for their preparation:

wherein the content of the first and second substances,

a is a direct bond or oxygen;

R₁selected from hydrogen, -C (O) OC_1-10Alkyl, substituted-C (O) OC_1-10Alkyl, -C (O) OC_1-4alkyl-Ar and substituted-C (O) OC_1-4alkyl-Ar, wherein Ar is selected from the group consisting of phenyl, naphthyl, furyl, pyridyl, thienyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, benzofuryl, indolyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl and pyrimidinyl, all of which are optionally substituted with one or more Z groups, wherein Z is independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_mC(O)OR₃、C(O)NR₃R₄、-CN、-(CH₂)_nOH、-NO₂、F、Cl、Br、I、-NR₃R₄And NHC (O) R₃Wherein m is 0-4, n is 0-4, R₃Is hydrogen, C_1-6Alkyl or substituted C_1-6Alkyl radical, R₄Is selected from C_1-6Alkyl, substituted C_1-6Alkyl, -CH₂Ar and Ar, wherein Ar is as defined above; and is

R₂Is selected from C_1-10Alkyl, substituted C_1-10Alkyl radical, C_3-10Carbocyclic ring, substituted C_3-10Carbocycle, (CH)₂)_n-phenyl and substituted (CH)₂)_n-phenyl, wherein n is 0-4.

One embodiment of the present invention is to provide a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

wherein R is₁And R₂The meaning of (a) is the same as defined above.

Another embodiment of the present invention is to provide a compound of formula (Ib):

wherein R is₁And R₂The meaning of (a) is the same as defined above.

Preferred compounds of formula (I) are those wherein R is₁Is hydrogen, -C (O) OC_1-4alkyl-Ar or substituted-C (O) OC_1-4alkyl-Ar, wherein Ar is phenyl or naphthyl, both of which are optionally substituted with one or more Z groups, wherein Z is independently selected from C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_mC(O)OR₃、C(O)NR₃R₄、-CN、-(CH₂)_nOH、-NO₂、F、Cl、Br、I、-NR₃R₄And NHC (O) R₃Wherein m is 0-4, n is 0-4, R₃Is hydrogen, C_1-6Alkyl or substituted C_1-6Alkyl radical, R₄Is selected from C_1-6Alkyl, substituted C_1-6Alkyl, -CH₂Ar and Ar, wherein Ar is as defined above; and R is₂Is selected from C_1-10Alkyl, substituted C_1-10Alkyl radical, C_3-10Carbocyclic ring, substituted C_3-10Carbocycle, (CH)₂)_n-phenyl and substituted (CH)₂)_n-phenyl, wherein n is 0-4.

As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.

As used herein, the term "substituted alkyl" refers to a straight or branched chain saturated hydrocarbon radical, optionally substituted with one or more C groups selected from C optionally having 1-3 fluoro substituents_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, C optionally having 1-3 fluoro substituents_1-2Substituent of alkoxy.

As used herein, the term "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group consisting of 3 to 7 carbon atoms or a fused bicyclic hydrocarbon group, each ring in the fused bicyclic ring referring to a non-aromatic cyclic hydrocarbon group consisting of 3 to 7 carbon atoms. The 5-7 membered ring may contain a double bond in the ring structure. Exemplary "carbocyclic" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cycloheptyl. Exemplary "fused bicyclic" groups include, but are not limited to, decahydronaphthyl.

As used herein, the term "substituted carbocyclic ring" refers to a non-aromatic cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, optionally substituted with one or more C groups selected from C optionally having 1 to 3 fluoro substituents_1-3Alkyl radical, C_2-3Alkenyl radical, C_2-3Alkynyl, C optionally having 1-3 fluoro substituents_1-2Alkoxy, aryl and arylSubstituted by an oxy group.

As used herein, the term "aryl" refers to an optionally substituted benzene ring or to a ring system that may be obtained by the fusion of one or more optional substituents. Examples of optional substituents include substituted C_1-3Alkyl, substituted C_2-3Alkenyl, substituted C_2-3Alkynyl, heteroaryl, heterocyclyl, aryl, alkoxy optionally having 1-3 fluoro substituents, aryloxy, aralkoxy, acyl, aroyl, heteroaroyl, acyloxy and aroyloxy. The ring or ring system may be optionally fused with an aromatic ring (including a benzene ring), carbocyclic ring or heterocyclic ring optionally having one or more substituents. Examples of "aryl" include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, biphenyl, indanyl, anthracenyl, and phenanthrenyl, and substituted derivatives thereof.

As used herein, the term "alkoxy" refers to the group-OR_aWherein R is_aIs an alkyl group as defined above. Examples of alkoxy groups useful in the present invention include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy.

As used herein, the term "aralkoxy" refers to the group-OR_aR_bWherein R is_aIs alkyl as defined above, R_bIs an aryl group as defined above.

As used herein, the term "aryloxy" refers to the group-OR_bWherein R is_bIs an aryl group as defined above.

It is to be understood that the invention also includes pharmaceutically acceptable salts and acid addition salts of the compounds of the invention, such as the hydrochloride, trifluoroacetic acid, formic acid, citric acid, fumaric acid, monosodium fumarate, p-toluenesulfonic acid, stearic acid, disodium citrate, tartaric acid, malic acid, lactic acid, succinic acid or salicylic acid addition salts. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the invention.

Compounds particularly useful in the present invention are selected from:

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate;

(+) - (morphinan-3-yloxy) methylpropyl carbonate;

(+) -cyclopropylmethyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclopentyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclohexyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclohexylmethyl (morphinan-3-yloxy) methyl carbonate;

(+) -hept-4-yl (morphinan-3-yloxy) methyl carbonate;

(+) -decahydronaphthalen-2-yl (morphinan-3-yloxy) methyl carbonate;

(+) -decahydronaphthalen-1-yl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclopentylmethyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -cyclobutylmethyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -2-ethylhexyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -butyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -isobutyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -sec-butyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -cycloheptyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) - (morphinan-3-yloxy) methylphenethylcarbonate TFA;

(+) - (morphinan-3-yloxy) methyl 1-phenylprop-2-yl carbonate TFA;

(+) -ethyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -methyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -cyclobutyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -hexyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) - (morphinan-3-yloxy) methylpent-2-yl carbonate TFA;

(+) -decyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -methyl isobutyrate (morphinan-3-yloxy) methyl ester;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester, TFA;

(+) -3, 3-dimethylbutyric acid (morphinan-3-yloxy) methyl ester TFA;

(+) -hexanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -2-propylpentanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -2-ethylbutanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -cyclohexanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -cyclopentanecarboxylic acid (morphinan-3-yloxy) methyl ester, TFA;

(+) -2-ethylhexanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -butyric acid (morphinan-3-yloxy) methyl ester TFA;

(+) -pentanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -2-methylbutanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -cyclopropanecarboxylic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -3-methylbutanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -2-phenylbutyric acid (morphinan-3-yloxy) methyl ester TFA;

(+) -1-adamantanecarboxylic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -acetic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -3-Cyclohexylpropionic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -3, 5, 5-trimethylhexanoic acid (morphinan-3-yloxy) methyl ester TFA;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate TFA;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -tartaric acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate HCl;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate carboxylic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate citric acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate fumarate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate monosodium fumarate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate 4-methylbenzenesulfonic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate stearic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate disodium citrate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (-) -malic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -lactic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate succinic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate salicylic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester succinic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester HCl;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester carboxylic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester citric acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester fumarate;

monosodium (+) -pivalic acid (morphinan-3-yloxy) methyl ester fumarate;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester 4-methylbenzenesulfonic acid;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester stearic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester disodium citrate;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (+) -tartaric acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (-) -malic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (+) -lactic acid;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester salicylic acid;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylisopropyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclopentyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclohexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyldecalin-1-yl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclopentylmethyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 2-ethylhexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylbutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl isobutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl sec-butyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcycloheptylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylphenethylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 1-phenylprop-2-yl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ethyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl hexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylpent-2-yl carbonate;

(+) -isobutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -hexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-propylpentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-ethylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclohexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-ethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -butyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -pentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-methylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclopropanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -3-methylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-phenylbutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -1-adamantanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester; and

(+) -3, 5, 5-trimethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester.

General Synthesis of Compounds of formula (I)

The compounds of formula (Ia) can be prepared, for example, by the following steps: (i) reacting (+) -3-hydroxymorphinan ((+) -3-HM) hydrobromide (1) with CbzCl in aqueous NaOH to provide (+) -N-17-Cbz-3-hydroxymorphinan of formula (2); (ii) alkylating the resulting product with iodomethyl alkyl carbonate (3) in the presence of a suitable base such as cesium carbonate, or sodium hydride, or DBU, to obtain an alkylphenoxymethyl carbonate of formula (4); finally (iii) deprotection of the N-17-Cbz group of the resulting product to obtain the compound of formula (Ia), as shown in scheme 1.

Reaction scheme 1

Wherein R is₂The meaning of (a) is the same as defined above.

The iodomethyl alkyl carbonate derivative (3) used as a starting material in the preparation of the compound of formula (Ia) can be prepared by a conventional method, for example, by treating chloromethyl chloroformate (5) with an alcohol in anhydrous diethyl ether containing an organic base such as pyridine or DMAP to provide the corresponding chloromethyl alkyl carbonate (6), and reacting the resulting product with sodium iodide in an appropriate solvent such as acetone or acetonitrile to provide the corresponding iodomethyl alkyl carbonate (3) (see Rigel Pharmaceuticals, inc., US2006/247287a1), as shown in reaction scheme 2.

Reaction scheme 2

Reaction scheme 3

Wherein R is₂The meaning of (a) is the same as defined above.

The compound of formula (Ib) may be prepared by the following steps: (i) reacting (+) -3-hydroxymorphinan hydrobromide (1) with CbzCl in aqueous NaOH to provide (+) -N-17-Cbz-3-hydroxymorphinan of formula (2); (ii) alkylating the resulting product with iodomethyl ester (7) in the presence of a suitable base such as cesium carbonate, or sodium hydride, or DBU to obtain a phenoxymethyl ester of formula (8); finally (iii) deprotection of the N-17-Cbz group of the resulting product to obtain the compound of formula (Ib), as shown in scheme 3.

Reaction scheme 4

Wherein R is₂The meaning of (a) is the same as defined above.

The iodomethyl ester derivative (7) used as a starting material in the preparation of the compound of formula (Ib) may be prepared by treating chloromethyl ester (9) with sodium iodide in a suitable solvent such as acetone or acetonitrile to provide the corresponding iodomethyl ester (7), as shown in scheme 4 (see Bristol-Myers Squibb Company, US5470845a 1).

Alternatively, the preparation of compounds of formula (Ib) can be illustrated by scheme 5, wherein R₂The meaning of (a) is the same as defined above. Deprotonating the compound of formula (2) with a base such as sodium hydride in a suitable solvent such as HMPA and then alkylating with chloromethyl methyl sulfide toTo provide methylthiomethyl ether (9). Treatment of a compound of formula (9) with a chlorinating agent such as sulfonyl chloride provides a chloromethyl ether of formula (10), which is then treated with a carboxylic acid in the presence of a suitable base such as cesium carbonate to provide a phenoxymethyl ester of formula (8). Finally, deprotection of the N-17-Cbz group of the resulting product using palladium on carbon under hydrogen atmosphere gives the compound of formula (Ib).

Reaction scheme 5

The formation of salt forms of these compounds can be achieved as shown in scheme 6. Thus, the Cbz-protected compound of structure (4) can be hydrogenated over Pd/C in IPA. The reaction mixture may be filtered through celite. A specific acid, such as L- (+) -tartaric acid (11), may be added to the IPA solution. After thoroughly mixing the ingredients (e.g., by stirring at 40 ℃ for 30 minutes), IPA can be replaced with EtOAc in order to get better solid state behavior. The solid can then be filtered and washed with EtOAc to give the drug substance such as (1 a') with minimal impurities.

Reaction scheme 6

The compounds of formula (I) may contain basic functional groups and therefore, by treatment with a suitable acid, pharmaceutically acceptable acid addition salts can be formed. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include the hydrochloride, hydrobromide, nitrate, methyl nitrate, sulphate, bisulphate, sulphamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, orthoacetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, methylnicotinate, dimethylolbenzoate, dimethylol, Pamoate, malonate, laurate, glutarate, glutamate, propionate dodecylsulfate (estolate), methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, sulfanilate, p-toluenesulfonate (toluenesulfonate), and naphthalene-2-sulfonate.

The compounds of the invention may be present in solid or liquid form. In the solid state, the compounds of the invention may be present in crystalline form or in amorphous form or as a mixture thereof. For compounds of the invention in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed, wherein solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may comprise non-aqueous solvents such as acetone, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may comprise water as the solvent contained in the crystal lattice. Solvates in which water is the solvent contained in the crystal lattice are generally referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing varying amounts of water. The present invention includes all such solvates.

The skilled artisan will also appreciate that certain compounds of the invention, including their various solvates, in crystalline form may exhibit polymorphism (i.e., the ability to occur in different crystal structures). These different crystalline forms are commonly referred to as "polymorphs". The present invention includes all such polymorphs. Polymorphs have the same chemical composition, but differ in packing, geometric arrangement and other descriptive properties of the crystalline solid. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra and X-ray powder diffraction patterns, which can be used for identification. The skilled artisan will appreciate that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or reagents used in preparing the compounds. For example, a change in temperature, pressure or solvent may produce a polymorph. Moreover, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compounds of formula (I) undergo hydrolysis in vivo and are then converted to their parent compounds, namely (+) -3-HM, which is effective as a neuroprotective agent in Parkinson's disease. Accordingly, the compounds of formula (I) are useful in the treatment or prevention of parkinson's disease.

The pharmaceutical composition of the present invention may be administered orally, intramuscularly or subcutaneously. Formulations for oral administration may take a variety of forms such as syrups, tablets, capsules, creams and lozenges. Syrups typically contain a suspension or solution of the compound or salt in a liquid carrier such as ethanol, peanut oil, olive oil, glycerol or water, optionally with a flavoring or coloring agent. When the composition is in the form of a tablet, any one of pharmaceutical carriers conventionally used for preparing solid preparations may be used. Examples of such carriers include magnesium stearate, kaolin, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any conventional encapsulation method may be employed, for example using the above-mentioned carriers in a hard capsule shell. When the composition is prepared in the form of soft gelatin shell capsules, any pharmaceutical carrier conventionally used for the preparation of dispersions or suspensions may be prepared using aqueous gums, celluloses, silicates or oils. Formulations for intramuscular or subcutaneous administration may take liquid forms such as solutions, suspensions, and emulsions comprising aqueous solvents such as water, physiological saline, and ringer's solution, or lipophilic solvents such as fatty oil, sesame oil, corn oil, and synthetic fatty acid esters.

Preferably, the composition is formulated into a specific dosage form for a particular patient.

Each dosage unit for oral administration suitably contains from 0.1mg to 500mg/kg, preferably from 1mg to 100mg/kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Suitable daily dosages for oral administration are from about 0.1mg/kg to 3g/kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which may be administered 1 to 3 times per day or every other day, depending on the patient's condition.

The following examples are provided to further describe and illustrate the present invention, but are not intended to limit the scope of the present invention.

Examples

All starting materials were obtained from commercial suppliers and used without further purification unless otherwise indicated.

As used herein, the symbols and conventions used to describe the methods, schemes and examples of the present invention are consistent with those used in contemporary scientific literature, e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry. The following abbreviations are used in the examples:

hz (Hertz)

TLC (thin layer chromatography)

T_r(Retention time)

RP (inverse)

MeOH (methanol)

i-PrOH (isopropanol)

TFA (trifluoroacetic acid)

TEA (triethylamine)

EtOH (ethanol)

THF (tetrahydrofuran)

DMSO (dimethyl sulfoxide)

EtOAc (ethyl acetate)

DCM (dichloromethane)

HOAc (acetic acid)

DMF (N, N-dimethylformamide)

Ac (acetyl)

CDI (1, 1-carbonyldiimidazole)

Bn (benzyl)

HOSu (N-hydroxysuccinimide)

HOBT (1-hydroxybenzotriazole)

Boc (tert-butyloxycarbonyl)

mCPBA (m-chloroperbenzoic acid)

FMOC (9-fluorenylmethoxycarbonyl)

DCC (dicyclohexylcarbodiimide)

Cbz (benzyloxycarbonyl)

NMM (N-methylmorpholine)

HOAt (1-hydroxy-7-azabenzotriazole)

TBAF (tetra-n-butylammonium fluoride)

THP (tetrahydro-2H-pyran-2-yl)

DMAP (4-dimethylaminopyridine)

HPLC (high pressure liquid chromatography)

BOP (bis (2-oxo-3-oxazolidinyl) phosphinic chloride);

EDCI (1-ethyl-3- [ 3-dimethylaminopropyl ] carbodiimide hydrochloride)

HBTU (O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate)

DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene)

IPA (2-propanol)

All the ethers mentioned are diethyl ether; brine refers to a saturated aqueous solution of NaCl. All temperatures are expressed in degrees celsius (degrees celsius) unless otherwise indicated. All reactions were carried out at room temperature under an inert atmosphere unless otherwise indicated, and all solvents were of the highest attainable purity unless otherwise indicated.

The microwave reaction was carried out using a Biotage microwave reactor.

Recording with Jeol ECX-400 or Jeol JNM-LA300 spectrometer¹H NMR spectrum. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in hertz (Hz). The split-map describes the apparent multiplicities, denoted as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad).

Mass spectra were obtained using a Micromass, Quattro LC Triple Quadrupolole Tandem Mass spectrometer, ESI or Agilent, 6110 Quadrupolole LC/MS, ESI.

For preparative HPLC, approximately 100mg of product in 1mL DMSO was injected into a SunAirTMPrep C18 OBD 5um 19X 100mm column using 10min, 10% CH₃CN-90％CH₃CN (in water) gradient elution. Flash chromatography was performed using Merck silica gel 60(230- & 400 mesh). Most reactions were monitored by thin layer chromatography on 0.25mm e.merck silica gel plates (60F-254) developed under uv light using 5% phosphomolybdic acid in alcohol or p-methoxybenzaldehyde in alcohol.

Experiment 1 measurement of permeability by drug transport assay with MDCK monolayer cells

(+) -3-HM was dissolved in DMSO at a concentration of 10mM and stored at 4 ℃. MDCK cells were obtained from ATCC (American type culture Collection, CCL-34). MDCK cells were maintained in DMEM (Dulbecco's MEM with high glucose) containing 1XNEAA (non-essential amino acids), 10mM HEPES, 100 units penicillin, 0.1mg/ml streptomycin and 8% FBS. Cells were cultured in T-75 flasks at 37 ℃ in a cell incubator. MDCK cells were passaged twice weekly. When cells were 90% confluent, at 1X 10⁵Cells/well cells were plated into transwells. Cells were given fresh medium every other day. Over a period of 5 days, cells grew on Transwell to confluence. When the cells reach fusion and differentiate, they are ready for transport studies. TEER (trans-epithelial electrical resistance) was measured with a Millicell-ERS system ohmmeter. The electrodes were immersed in 70% ethanol and PBS for 15 minutes. The system was then adjusted with a screwdriver at the potentiometer until the potentiometer displayed a voltage reading of 0.0, and the resistance of each well was recorded. MDCK monolayers with TEER values greater than 400 Ω were used. Wells were washed with sterile HBSS (Hank's buffer) and (+) -3-HM was diluted 100-fold in HBSS, after which the top wells were filled with 200ul of test compound. The wells on the outside of the bottom were filled with 1ml of HBSS buffer. Wells treated with only 0.1% DMSO were prepared to adjust the assay. Cells were cultured at 37 ℃ for 1 hour. At the end of the run period, the final samples were removed from the top wells (150ul) and the bottom outside wells (900 ul). Representative compounds of the examples were operated under the same conditions.

Experiment 2HPLC analysis and P_appIs calculated by

HPLC analysis was performed using WATERS HPLC system. ZORBAX eclipse XDB-C18 (4.6X 250mm, 5 μm particle size) was used. The optimum operating conditions were as follows: mobile phase a consisted of distilled water-acetonitrile (CAN) (9: 1, v/v) with 0.1% trifluoroacetic acid (TFA) and mobile phase B was 90% acetonitrile with 0.1% TFA. All buffers were used after 0.45 μm filtration.

UV detection at 280nm or fluorescence detection at 228nm excitation and 330nm emission.

The concentration of the A and B buffers was manipulated by gradient method, and the total assay time was 38 min. The optimal operating conditions are as follows: the elution gradient is 0-10min (10-50%), 10-20min (50-90%), 20-25min (90%), 25-27min (90-10%), and 27-38min (10%). After HPLC analysis, the area percentage of (+) -3-HM and the compound of example 2 was calculated from the remaining concentration (. mu.g/ml).

The apparent permeability coefficient (P) was calculated by the following equation_app) (in nm/sec):

permeability (P)_app) (acceptor volume x acceptor concentration)/(filter surface area x reaction time x donor concentration) × 10⁷。

When MDCK P_appAn approximately sigmoidal relationship was observed when values were plotted against percent human absorption (JENNIFER D. IRVINE et al, Journal of Pharmaceutical Sciences, Vol.88, No.1, January 1999).

Well absorbed prodrug compounds generally exhibit high P_appValue, poorly absorbed Compounds generally show Low P_appThe value is obtained.

Given the permeability values of drugs such as acetaminophen, dexamethasone and ketoprofen which are 350, 200 and 200nm/s, respectively, it is clear that their human absorption values are very high for good oral bioavailability of 94, 98 and 100%, respectively.

The results are shown in table 1. Table 1 shows that the permeability values for all tested compounds are increased by a factor of 2 or more compared to the parent molecule (+) -3-HM. Since all tested compounds, except the compounds of examples 56 and 58, had permeability values above 100nm/s, they are expected to have good oral bioavailability.

TABLE 1 apparent permeation coefficients (P) of (+) -3-HM and of the compounds of the invention_app)

Example numbering	Papp(nm/sec)
		HM	33.3
80	185.7
		105	202.9
15	337.0
		54	288.7
58	60.5
		17	227.3
60	202.3
		56	94.3

Experiment 3 pharmacokinetic study

Male Sprague-Dawley rats (200-230 g) were purchased from Charles River Laboratory. The animals were kept under standard temperature, humidity and light conditions. Food and water were provided ad libitum. One day prior to administration, jugular vein cannulae were inserted for blood collection under anesthesia with intraperitoneal injection of 1mL/kgg ketamine vs. xylazine (90: 10, v/v) solution. Oral administration at a dose of 60mg/10ml/kg by oral gavage and/or intravenous administration at a dose of 10mg/1 ml/kg. After oral and/or intravenous administration of the compounds of the invention, blood (. about.0.3 ml/sample) was collected at various time intervals into heparinized tubes and centrifuged. Each plasma sample (-0.2 ml) was immediately frozen until analysis. The concentration of the parent molecule (+) -3-HM in plasma after administration of (+) -3-HM or the compound of example 2 is determined by HPLC (Waters 2487). The results are summarized in tables 2.1 and 2.2. Maximum plasma concentration (C)_max) Time to maximum plasma concentration (T)_max) Eliminating half-decay device (t)_1/2) And area under the plasma concentration-time curve (AUC) over an infinite range of zero to time_0-∞) Is the main parameter. Overall, the oral bioavailability (92.4%) of the compound of example 2 was significantly higher than the HM (17.85%) at the same dose. These results indicate that the compound of example 2 has a favorable drug metabolism profile as a prodrug. Such a metabolic profile of the drug indicates a 4-fold or greater increase in oral availability of the compound of example 2 (table 2.2).

Table 2.1 pharmacokinetic parameters for HM and example 2 compounds in intravenous experiments. Plasma concentrations of (+) -3-HM were measured after intravenous administration of (+) -3-HM or the compound of example 2 to rats.

CL: clearance (in units of flow/weight; mL/hr/kg) is the volume of blood or plasma per unit weight of an individual that must be cleared of a drug per unit time.

MRT: the mean residence time is the arithmetic mean of the time durations that the respective drug molecules are retained in the body (MRT ═ AUMC/AUC).

Table 2.2 pharmacokinetic parameters of HM and example 2 compounds in oral dosing experiments. Plasma concentrations of (+) -3-HM or the compound of example 2 were measured after oral delivery of the HM to rats.

In vivo potency measurements of the compounds of experiment 4(+) -3-HM and example 2.

To test the efficacy of (+) -3-HM and the compound of example 2 on an MPTP-induced animal model of Parkinson, C57BL6/J was injected daily with MPTP for 7 days. On the last 3 days, (+) -3-HM (25mg/kg, i.p.) and the compound of example 2 (25mg/kg, p.o.) were administered 30min before the MPTP injection, and the animals were sacrificed 3 days after the last MPTP injection. The brain was sectioned on a microtome, and SNpc TH immunoreactivity was performed by the ABC method. These results, shown in figure 2 for TH-immunoreactive neurons throughout SNpc, indicate that oral administration of the compound of example 2 has more protective effect against MPTP-induced dopamine neuron loss than intraperitoneal injection of the same dose of HM.

Example 1

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylisopropyl carbonate

Step 1: (+) -3-hydroxy-N- (benzyloxycarbonyl) morphinan

(+) -3-Hydroxymorphine to a mixture of 1, 4-dioxane (200mL) and water (200mL) at room temperatureTo furan (HM) hydrobromide (50.0g, 154.2mmol), sodium hydroxide (12.3g, 308.4mmol) was added Cbz-Cl (24.2mL, 169.6mmol) dropwise. The reaction mixture was stirred vigorously at room temperature overnight. After completion of the reaction, water (200mL) was added. The mixture was extracted with diethyl ether (500 mL. times.2). The combined organics were over MgSO₄Dried, filtered and concentrated in vacuo. Standing under high vacuum gave the title compound as a pale yellow solid (57.7g, 99%). The compound was used in the next step without further purification.

¹H NMR(400MHz，CDCl₃)δ7.39-7.31(m，5H)、6.70-6.91(m，1H)、6.77(d，J＝2.4Hz，1H)、6.65-6.61(m，1H)、5.18-5.13(m，2H)、4.36(br d，J＝42.0Hz，1H)、3.94-3.83(m，1H)、3.12-3.03(m，1H)、2.72-2.57(m，2H)、2.32(d，J＝11.2Hz，1H)、1.71-1.24(m，9H)、1.11-1.02(m，1H)。

MH+378。

Step 2: (+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylisopropyl carbonate

To (+) -3-hydroxy-N- (benzyloxycarbonyl) morphinan (33.0g, 87.4mmol) and cesium carbonate (28.5g, 87.4mmol) in acetone (450mL) was added iodomethyl isopropyl carbonate (21.3g, 87.4mmol) at room temperature (see Rigel Pharmaceuticals, Inc. US2006/247287A1, appl.; US2006-381215 (2006/05/02)). The reaction mixture was stirred vigorously at room temperature overnight. Acetone was then removed by vacuum rotary evaporation. To the residue was added saturated NaHCO₃And (3) solution. The mixture was extracted with EtOAc (300 mL. times.2). The combined organics were washed with 1N HCl solution (300mL) over MgSO₄Dry, filter and concentrate under vacuum to provide the title compound as a yellow gum (42.0g, 97%).

[α]_D ²⁷+112.0°(c＝1.0，MeOH)；IR(KBr)v_max 2931，1754，1695，1496，1422，1270，1234，1218，1185，1044cm^-1；¹H NMR(400MHz，CDCl₃) δ 7.39-7.32(m, 5H), 7.03(t, J ═ 8.4Hz, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.70(AB q, J ═ 6.8Hz, 2H), 5.21-5.09(m, 2H), 4.93(m, 1H), 4.37(br d, J ═ 43.2Hz, 1H), 3.96-3.84(m, 1H), 3.17-3.05(m, 1H), 2.76-2.56(m, 2H), 2.34(d, J ═ 10.8Hz, 1H), 1.72-1.43(m, 6H), 1.43-1.26(m, 9H), 1.08-0.08 (m, 99H);¹³C NMR(400MHz，CDCl₃)δ155.8，155.4，153.7，140.8，136.9，130.9，130.7，129.3，129.2，128.4，127.9，127.8，114.0，113.4，88.6，72.9，66.9，49.8，43.7，41.5，38.3，37.6，36.4，31.3，26.4，26.3，22.3，22.0，21.7。

MH+494。

example 2

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate

(+) -isopropyl [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate from example 1 (42.0g, 84.1mmol) was hydrogenated in EtOH (250mL) over 10% Pd/C (6.3g) at room temperature (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with EtOH (400 mL). The combined EtOH solution was concentrated in vacuo. The residue was further purified by preparative reverse phase HPLC to provide the title compound as a yellow solid (5.82g, 19%).

[α]_D ²⁷+27.9°(c＝1.0，MeOH)；IR(KBr)v_max 2980，2929，2856，1753，1610，1496，1271，1218，1112，1045cm^-1；¹H NMR(400MHz，CDCl₃)δ7.06(d，J＝8.4Hz，1H)，6.94(d，J2.6Hz, 1H), 6.87(dd, J8.4, 2.6Hz, 1H), 5.77 and 5.71(AB q, J6.4 Hz, 2H), 4.93(m, 1H), 3.16-3.05(m, 2H), 2.94-2.54(m, 4H), 2.29(d, J11.9 Hz, 1H), 1.78-1.74(m, 1H), 1.66-1.50(m, 3H), 1.41-1.20(m, 10H), 1.07-0.99(m, 1H);¹³C NMR(400MHz，CDCl₃)δ155.6，153.7，141.8，132.2，128.8，113.9，113.1，88.7，72.6，65.9，50.9，46.8，42.2，38.9，38.2，36.8，33.1，26.7，26.6，22.0，21.7。

MH+360。

the following compounds of examples 3-42 were obtained by repeating the methods of example 1 and example 2.

Example 3

(+) - (morphinan-3-yloxy) methylpropyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.0Hz, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.72(AB q, J ═ 6.4Hz, 2H), 4.14(t, 6.6Hz, 2H), 3.14-3.04(m, 2H), 2.84-2.57(m, 4H), 2.36-2.22(m, 2H), 1.82-1.61(m, 5H), 1.51-1.49(m, 2H), 1.40-1.30(m, 2H), 1.05-0.90(m, 4H).

MH+360。

Example 4

(+) -Cyclopropylmethyl (morphinan-3-yloxy) methyl carbonate

¹HNMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.78, and 5.73(AB q, J ═ 6.4Hz, 2H), 4.01(d, J ═ 9.2Hz, 2H), 3.16-3.08(m, 2H), 2.80-2.54(m, 4H), 2.28(d, J ═ 13.2Hz, 1H), 1.81-1.76(m, 1H), 1.66-1.50(m, 3H), 1.42-1.26(m, 4H), 1.20-1.10(m, 1H), 1.09-1.00(m, 1H), 0.60(m, 2H), 0.32(m, 2H).

MH+372。

Example 5

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl cyclopentyl carbonate

¹H NMR(300MHz，CDCl₃) δ 7.39-7.32(m, 5H), 7.03(t, J ═ 8.4Hz, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.70(AB q, J ═ 6.4Hz, 2H), 5.16-5.05(m, 3H), 4.37(br d, J ═ 43.2Hz, 1H), 3.96-3.84(m, 1H), 3.17-3.05(m, 1H), 2.76-2.56(m, 2H), 2.32(d, J ═ 10.8Hz, 1H), 1.98-1.51(m, 13H), 1.50-1.25(m, 4H), 1.08-0.99(m, 1H).

MH+520。

Example 6

(+) -cyclopentyl (morphinan-3-yloxy) methyl carbonate

¹H NMR(400MHz，CDCl₃)δ7.05(d，J＝8.4Hz，1H)，6.94(d，J＝2.4Hz，1H)，6.83(dd，J＝8.4，2.4Hz，1H)，5.76 and 5.71(AB q, J ═ 6.4Hz, 2H), 5.15-5.09(m, 1H), 3.14-3.09(m, 2H), 2.81-2.60(m, 4H), 2.30-2.27(m, 1H), 1.89-1.49(m, 11H), 1.49-1.26(m, 5H), 1.09-1.01(m, 1H).

MH+386。

Example 7

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclohexyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.32(m, 5H), 7.03(t, J ═ 8.4Hz, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.72(AB q, J ═ 6.4Hz, 2H), 5.18-5.13(m, 2H), 4.70-4.63(m, 1H), 4.37(br d, J ═ 43.2Hz, 1H), 3.96-3.84(m, 1H), 3.15-3.05(m, 1H), 2.76-2.56(m, 2H), 2.34(d, J ═ 10.8Hz, 1H), 1.94-1.91(m, 2H), 1.77-10H), 1.35-1.35 (m, 1.35-1.20H), 1.09-1H).

MH+534。

Example 8

(+) -cyclohexyl (morphinan-3-yloxy) methyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.72(AB q, J ═ 6.4Hz, 2H), 4.70 to 4.64(m, 1H), 3.16 to 3.10(m, 2H), 2.81 to 2.58(m, 4H), 2.30 to 2.28(m, 1H), 1.92 to 1.24(m, 18H), 1.09 to 1.01(m, 1H).

MH+400。

Example 9

(+) -Cyclohexylmethyl (morphinan-3-yloxy) methyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.72(AB q, J ═ 6.4Hz, 2H), 3.99(d, J ═ 6.4Hz), 3.16-3.08(m, 2H), 2.80-2.54(m, 4H), 2.30(d, J ═ 12.8Hz, 1H), 1.75-1.64(m, 8H), 1.51-1.13(m, 9H), 1.11-0.93(m, 3H).

MH+414。

Example 10

(+) -hept-4-yl (morphinan-3-yloxy) methyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.8Hz, 1H), 6.86(dd, J ═ 8.4, 2.8Hz, 1H), 5.75 and 5.72(AB q, J ═ 7.6Hz, 2H), 4.80-4.76(m, 1H), 3.16-3.04(m, 2H), 2.78-2.52(m, 4H), 2.28(d, J ═ 12.0Hz, 1H), 1.82-1.72(m, 1H), 1.70-1.46(m, 8H), 1.44-1.24(m, 7H), 1.12-0.98(m, 2H), 0.91(t, J ═ 7.2, 6H).

MH+416。

Example 11

(+) -decahydronaphthalen-2-yl (morphinan-3-yloxy) methyl carbonate

¹H NMR(300MHz，CDCl₃)δ7.04(d，J＝8.4Hz，1H)，6.93(s，1H)，6.86(d，J＝8.4Hz，1H)，5.76-5.69(m，2H)，4.65-4.61(m，1H)，3.19-3.07(m，2H)，2.76-2.65(m，4H)，2.28(d，J＝12.9Hz，1H)，1.75-1.64(m，8H)，1.51-1.13(m，15H)，1.11-0.93(m，2H)。

MH+454。

Example 12

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyldecalin-1-yl carbonate

¹H NMR(300MHz，CDCl₃)δ7.36-7.32(m，，5H)，7.07-6.98(m，1H)，6.95(s，1H)，6.87(dd，J＝8.3Hz，2.4Hz，1H)，5.73-5.71(m，2H)，5.15-5.12(m，2H)，4.71(m，1H)，4.40-4.30(d，J＝29.4Hz，1H)，3.92-3.82(m，1H)，3.11-3.03(m，1H)，2.72-2.56(m，2H)，2.31-2.28(m，1H)，2.18-2.01(m，1H)，1.98-1.26(m，24H)，1.11-1.00(m，1H)。

MH+588。

Example 13

(+) -decahydronaphthalen-1-yl (morphinan-3-yloxy) methyl carbonate

¹H NMR(300MHz，CDCl₃)δ7.05(d，J＝8.4Hz，1H)，6.93(d，J＝2.7Hz，1H)，6.87(dd，J＝8.4，2.7Hz，1H)，5.77-5.70(m，2H)，4.71-4.68(m，1H)，3.09-3.08(m，2H)，2.77-2.59(m，4H)，2.01-2.17(m，1H)，1.82-1.64(m，8H)，1.64-1.18(m，15H)，1.11-0.93(m，2H)。

MH+454。

Example 14

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclopentyl methyl carbonate

¹H NMR(400MHz，CDCl₃)δ7.40-7.30(m，5H)，7.03-6.99(m，1H)，6.96(d，J＝2.4Hz，1H)，6.87(dd，J＝8.4，2.4Hz，1H)，5.73(m，2H)，5.16-5.11(m，2H)，4.41-4.31(m，1H)，4.06(d，J＝7.2Hz，2H)，3.98-3.82(m，1H)，3.16-3.03(m，1H)，2.71-2.58(m，2H)，2.38-2.31(m，1H)，2.27-2.20(m，1H)，1.80-1.42(m，11H)，1.38-1.21(m，6H)，1.05-0.98(m，1H)。

MH+534。

Example 15

(+) -Cyclopentylmethyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.08(br s, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.96-6.92(m, 2H), 5.76 and 5.71(AB q, J ═ 6.8Hz, 2H))，4.06(d，J＝7.2Hz，2H)，3.68(m，1H)，3.22-3.09(m，3H)，2.85-2.70(m，1H)，2.39-2.30(m，1H)，2.28-2.21(m，1H)，2.11-2.05(m，1H)，1.96-1.89(m，1H)，1.79-1.39(m，12H)，1.30-1.20(m，3H)，1.07-0.98(m，1H)。

MH+400。

Example 16

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutylmethyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.40-7.28(m, 5H), 7.03-6.99(m, 1H), 6.95(d, J ═ 2.8Hz, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.71(AB q, J ═ 6.4Hz, 2H), 5.18-5.08(m, 2H), 4.44-4.28(m, 1H), 4.14(d, J ═ 6.8Hz, 2H), 3.88-3.81(m, 1H), 3.15-3.03(m, 1H), 2.72-2.58(m, 2H), 2.37-2.29(m, 1H), 2.10-2.02(m, 2H), 1.93-1.76(m, 4H), 1.74-1.42(m, 1H), 1.38-1H, 1H), 1.0-1H (m, 1H), 1.0.05-1H).

MH+520。

Example 17

(+) -cyclobutylmethyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.00(br s, 1H), 7.12(d, J ═ 8.0Hz, 1H), 6.95-6.92(m, 2H), 5.76 and 5.71(AB q, J ═ 6.8Hz, 2H), 4.15(d, J ═ 6.8Hz, 2H), 3.70(m, 1H), 3.23-3.09(m, 3H), 2.82-2.61(m, 2H), 2.37-2.37 (m, 2H).32(m，1H)，2.12-2.02(m，1H)，1.97-1.76(m，5H)，1.68-1.62(m，1H)，1.57-1.34(m，5H)，1.31-1.20(m，1H)，1.09-1.01(m，1H)。

MH+386。

Example 18

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 2-ethylhexyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.40 to 7.29(m, 5H), 7.02(d, J ═ 8.0Hz, 1H), 6.95(d, J ═ 2.0Hz, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.71(AB q, J ═ 6.4Hz, 2H), 5.18 to 5.07(m, 2H), 4.44 to 4.28(m, 1H), 4.13 to 4.05(m, 2H), 3.98 to 84(m, 1H), 3.14 to 3.03(m, 1H), 2.74 to 2.56(m, 2H), 2.35 to 2.31(m, 1H), 1.71 to 1.41(m, 7H), 1.39 to 1.21(m, 11H), 1.07 to 0.98(m, 0.89H), 0.85H, 6 to 1H).

MH+564。

Example 19

(+) -2-ethylhexyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.03(br s, 1H), 7.12(d, J ═ 8.0Hz, 1H), 6.99 to 6.92(m, 2H), 5.76 and 5.71(AB q, J ═ 6.8Hz, 2H), 4.13 to 4.05(m, 2H), 3.71(m, 1H), 3.24 to 3.11(m, 3H), 2.76(m, 1H), 2.35(d, J ═ 14.0Hz, 1H), 2.08(d, J ═ 12.4Hz, 1H), 2.00 to 1.92(m, 1H), 1.68 to 1.26(m, 16H), 1.09 to 1.00(m, 1H), 0.89 to 0.84(m, 6H)。

MH+430。

Example 20

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylbutyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.40-7.28(m, 5H), 7.04-6.98(m, 1H), 6.95(d, J ═ 2.0Hz, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.71(AB q, J ═ 6.4Hz, 2H), 5.18-5.08(m, 2H), 4.41-4.28(m, 1H), 4.17(t, J ═ 6.4Hz, 2H), 3.96-3.76(m, 1H), 3.15-3.03(m, 1H), 2.72-2.55(m, 2H), 2.35-2.30(m, 1H), 1.72-1.44(m, 7H), 1.41-1.19(m, 6H), 1.92-0.08 (m, 0.08, 1H), 1.7H (m, 3H).

MH+508。

Example 21

(+) -butyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 8.84(br s, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.99 to 6.93(m, 2H), 5.76 and 5.71(AB q, J ═ 6.4Hz, 2H), 4.19(t, J ═ 6.4Hz, 2H), 3.76(m, 1H), 3.24 to 3.08(m, 3H), 2.77(m, 1H), 2.35(d, J ═ 13.6Hz, 1H), 2.06(d, J ═ 12.0Hz, 1H), 1.96 to 1.90(m, 1H), 1.69 to 1.51(m, 3H), 1.49 to 1.34(m, 7H), 1.26 to 1.20(m, 1H), 1.10 to 1.00(m, 1H), 0.92(t, 1H), 0.7, 3H).

MH+374。

Example 22

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl isobutyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.29(m, 5H), 7.08-6.98(m, 1H), 6.96(s, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.4Hz, 2H), 5.16-5.11(m, 2H), 4.41-4.31(m, 1H), 3.95(d, J ═ 6.4Hz, 2H), 3.86-3.77(m, 1H), 3.13-3.03(m, 1H), 2.75-2.55(m, 2H), 2.36-2.30(m, 1H), 2.04-1.92(m, 1H), 1.72-1.45(m, 5H), 1.39-1.21(m, 4H), 1.10-0.99(m, 0.93, 6H), 6.93(d, 6H).

MH+508。

Example 23

(+) -isobutyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.03(br s, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.99 to 6.93(m, 2H), 5.76 and 5.72(AB q, J ═ 6.8Hz, 2H), 3.96(d, J ═ 6.4Hz, 2H), 3.71(m, 1H), 3.24 to 3.10(m, 3H), 2.76(m, 1H), 2.35(d, J ═ 13.6Hz, 1H), 2.08(d, J ═ 13.2Hz, 1H), 2.04 to 1.90(m, 1H), 1.68 to 1.65(m, 1H), 1.58 to 1.36(m, 6H), 1.29 to 1.23(m, 1H), 1.09 to 1.03(m, 1H), 0.93(d, 6H), 2H).

MH+374。

Example 24

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl sec-butyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.38-7.27(m, 5H), 7.02(t, J ═ 8.4Hz, 1H), 6.95(s, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.71(AB q, J ═ 6.8Hz, 2H), 5.14-5.08(m, 1H), 4.79-4.71(m, 1H), 4.41-4.30(m, 1H), 3.93-3.72(m, 1H), 3.14-3.04(m, 1H), 2.72-2.55(m, 2H), 2.36-2.30(m, 1H), 1.74-1.44(m, 8H), 1.40-1.28(m, 4H), 1.27(d, J ═ 6.4H), 1.91.95 (t, 0.08 Hz), 1.7H, 3.7H, 3H, 1H).

MH+508。

Example 25

(+) -sec-butyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 8.83(br s, 1H), 7.12(d, J ═ 8.0Hz, 1H), 6.99-6.93(m, 2H), 5.76 and 5.71(AB q, J ═ 6.4Hz, 2H), 4.75(m, 1H), 3.71(m, 1H), 3.24-3.08(m, 3H), 2.78(m, 1H), 2.35(d, J ═ 14.0Hz, 1H), 2.06(d, J ═ 12.0Hz, 1H), 1.96-1.90(m, 1H), 1.70-1.33(m, 8H), 1.27(d, J ═ 6.4Hz, 3H), 1.25-1.23(m, 1H), 1.10-0.96(m, 1H), 0.91(t, 7, 3H).

MH+374。

Example 26

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcycloheptyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.38-7.28(m, 5H), 7.02(t, J ═ 8.8Hz, 1H), 6.95(s, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.74 and 5.70(AB q, J ═ 6.8Hz, 2H), 5.20-5.11(m, 2H), 4.86-4.80(m, 1H), 4.41-4.30(m, 1H), 3.95-3.82(m, 1H), 3.13-3.03(m, 1H), 2.71-2.58(m, 2H), 2.35-2.31(m, 1H), 2.00-1.92(m, 2H), 1.76-1.60(m, 6H), 1.57-1.34(m, 9H), 1.32-1.01 (m, 1H), 1.07-1H).

MH+548。

Example 27

(+) -cycloheptyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR (400MHz，CDCl₃) δ 9.30(br s, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.96-6.93(m, 2H), 5.76 and 5.71(AB q, J ═ 6.8Hz, 2H), 4.88-4.81(m, 1H), 3.62(m, 1H), 3.17-3.06(m, 3H), 2.85-2.72(m, 2H), 2.35(d, J ═ 13.6Hz, 1H), 2.08(d, J ═ 12.0Hz, 1H), 2.01-1.88(m, 3H), 1.77-1.65(m, 5H), 1.58-1.36(m, 10H), 1.35-1.21(m, 1H), 1.07-1.03(m, 1H).

MH+414。

Example 28

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylphenylethyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.38-7.19(m, 10H), 7.09-7.00(m, 1H), 6.94(s, 1H), 6.86(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.71(AB q, J ═ 6.8Hz, 2H), 5.17-5.12(m, 2H), 4.46-4.31(m, 3H), 3.92-3.84(m, 1H), 3.29-3.05(m, 1H), 2.99(t, J ═ 7.2Hz, 2H), 2.74-2.60(m, 2H), 2.35-2.29(m, 1H), 1.74-1.43(m, 5H), 1.40-1.22(m, 4H), 1.10-0.98(m, 1H).

MH+556。

Example 29

(+) - (morphinan-3-yloxy) methylphenethylcarbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.11(br s, 1H), 7.36 to 7.18(m, 5H), 7.13(d, J ═ 8.4Hz, 1H), 6.98 to 6.92(m, 2H), 5.76 and 5.71(AB q, J ═ 6.8Hz, 2H), 4.39(t, J ═ 7.2Hz, 2H), 3.65(m, 1H), 3.29 to 3.05(m, 3H), 2.99(t, J ═ 7.2Hz, 2H), 2.84 to 2.73(m, 1H), 2.35(d, J ═ 13.2Hz, 1H), 2.03(d, J ═ 13.2Hz, 1H), 1.95 to 1.87(m, 1H), 1.69 to 1.36(m, 6H), 1.30 to 1.21(m, 1H), 1.01 to 1H).

MH+422。

Example 30

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 1-phenylprop-2-yl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.33(m, 6H), 7.25-7.17(m, 4H), 7.03(t, J ═ 8.8Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.86(dd, J ═ 8.4, 2.4Hz, 1H), 5.72 and 5.68(AB q, J ═ 6.8Hz, 2H), 5.16-5.11(m, 2H), 5.04-4.97(m, 1H), 4.43-4.31(m, 1H), 3.96-3.84(m, 1H), 3.15-2.98(m, 2H), 2.81-2.76(m, 1H), 2.73-2.56(m, 2H), 2.35-2.32(m, 1H), 1.73-1.45(m, 1H), 6.01-4H, 1H), 1H (d, 1H), 6.6.15-4.31 (m, 1H).

MH+570。

Example 31

(+) - (morphinan-3-yloxy) methyl 1-phenylprop-2-yl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.33(br s, 1H), 7.28 to 7.16(m, 5H), 7.12(d, J ═ 8.2Hz, 1H), 7.08 to 7.01(m, 1H), 6.96 to 6.90(m, 2H), 5.73 and 5.68(AB q, J ═ 6.4Hz, 2H), 5.08 to 4.98(m, 1H), 3.63(m, 1H), 3.20 to 2.98(m, 4H), 2.82 to 2.73(m, 1H), 2.34(d, J ═ 13.6Hz, 1H), 2.09(d, J ═ 12.8Hz, 1H), 1.95 to 1.88(m, 1H), 1.69 to 1.36(m, 7H), 1.29(d, J ═ 5.6, 3H), 1.28 to 1.01(m, 1H).

MH+436。

Example 32

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ethyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.32(m, 5H), 7.05-7.01(m, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.72(AB q, J ═ 6.4Hz, 2H), 5.17-5.12(m, 2H), 4.44-4.32(m, 1H), 4.24(q, J ═ 6.8Hz, 2H), 3.96-3.83(m, 1H), 3.16-3.04(m, 1H), 2.76-2.56(m, 3H), 2.38-2.31(m, 1H), 1.73-1.49(m, 5H), 1.44-1.33(m, 3H), 1.32(t, J ═ 6.8, 3H), 1.29.09-1H, 1.09 (m, 1H), 1.32(t, J ═ 6.8, 1H), 1.23.00 (m, 1H).

MH+480。

Example 33

(+) -Ethyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 8.93(br s, 1H), 7.13(d, J ═ 8.4Hz, 1H), 6.98-6.94(m, 2H), 5.78 and 5.73(AB q, J ═ 6.8Hz, 2H), 4.25(q, J ═ 7.2Hz, 2H), 3.67(m, 1H), 3.23-3.06(m, 3H), 2.78(m, 1H), 2.36(d, J ═ 13.6Hz, 1H), 2.05(d, J ═ 12.4Hz, 1H), 1.95-1.86(m, 1H), 1.70-1.36(m, 6H), 1.32(t, J ═ 7.2Hz, 3H), 1.29-1.23(m, 1H), 1.11-1.00(m, 1H).

MH+346。

Example 34

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.31(m, 5H), 7.05-7.01(m, 1H), 6.96(s, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.78 and 5.73(AB q, J ═ 6.4Hz, 2H), 5.17-5.12(m, 1H), 4.42-4.31(m, 1H), 3.96-3.84(m, 1H), 3.83(s, 3H), 3.14-3.05(m, 1H), 2.77-2.56(m, 1H), 2.35-2.32(m, 1H), 1.72-1.46(m, 6H), 1.42-1.21(m, 5H), 1.09-0.90(m, 1H).

MH+466。

Example 35

(+) -methyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 8.92(br s, 1H), 7.13(d, J ═ 8.4Hz, 1H), 6.97 to 6.94(m, 2H), 5.78 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.83(s, 3H), 3.67(m, 1H), 3.24 to 3.06(m, 3H), 2.78(m, 1H), 2.36(d, J ═ 13.2Hz, 1H), 2.04(d, J ═ 12.0Hz, 1H), 1.95 to 1.86(m, 1H), 1.70 to 1.36(m, 6H), 1.32 to 1.20(m, 1H), 1.11 to 1.00(m, 1H).

MH+332。

Example 36

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.40-7.29(m, 5H), 7.05-7.00(m, 1H), 6.96(s, 1H), 6.87(dd, J ═ 8.4, 2.8Hz, 1H), 5.75 and 5.70(AB q, J ═ 6).4Hz，2H)，5.17-5.12(m，2H)，5.00-4.92(m，1H)，4.42-4.31(m，1H)，3.96-3.82(m，1H)，3.16-3.03(m，1H)，2.76-2.56(m，2H)，2.45-2.31(m，3H)，2.25-2.08(m，2H)，1.88-1.76(m，1H)，1.73-1.45(m，6H)，1.42-1.22(m，4H)，1.08-1.00(m，1H)。

MH+506。

Example 37

(+) -cyclobutyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.38(br s, 1H), 7.12(d, J ═ 8.2Hz, 1H), 6.97 to 6.93(m, 2H), 5.76 and 5.71(AB q, J ═ 6.4Hz, 2H), 5.00 to 4.92(m, 1H), 3.62(m, 1H), 3.21 to 3.04(m, 3H), 2.74(m, 1H), 2.46 to 2.31(m, 4H), 2.25 to 2.07(m, 4H), 1.99 to 1.77(m, 2H), 1.71 to 1.35(m, 5H), 1.32 to 1.21(m, 1H), 1.10 to 1.00(m, 1H).

MH+372。

Example 38

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl hexyl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.28(m, 5H), 7.03(t, J ═ 8.8Hz, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.72(AB q, J ═ 6.8Hz, 2H), 5.21-5.12(m, 1H), 4.42-4.31(m, 1H), 4.17(t, J ═ 7.2Hz, 2H), 3.96-3.84(m, 1H), 3.14-3.05(m, 1H), 2.72-2.57(m, 2H), 2.36-2.32(m,1H)，1.72-1.43(m，7H)，1.43-1.23(m，11H)，1.05-0.96(m，1H)，0.88(t，J＝6.8Hz，3H)。

MH+536。

example 39

(+) -hexyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.28(br s, 1H), 7.12(d, J ═ 8.4Hz, 1H), 7.00-6.93(m, 2H), 5.78 and 5.74(AB q, J ═ 6.8Hz, 2H), 4.20(t, J ═ 6.4Hz, 2H), 3.65(m, 1H), 3.25-2.70(m, 5H), 2.36(d, J ═ 13.6Hz, 1H), 2.11(d, J ═ 12.0Hz, 1H), 1.98-1.88(m, 1H), 1.78-1.22(m, 14H), 1.16-1.01(m, 1H), 0.88(t, J ═ 7.2Hz, 3H).

MH+402。

Example 40

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylpent-2-yl carbonate

¹H NMR(400MHz，CDCl₃) δ 7.39-7.31(m, 5H), 7.03(t, J ═ 8.4Hz, 1H), 6.96(s, 1H), 6.88(dd, J ═ 8.4, 2.4Hz, 1H), 5.76 and 5.72(AB q, J ═ 6.4Hz, 2H), 5.17-5.12(m, 2H), 4.86-4.78(m, 1H), 4.43-4.31(m, 1H), 3.95-3.82(m, 1H), 3.14-3.04(m, 1H), 2.72-2.56(m, 2H), 2.38-2.32(m, 1H), 2.20-2.06(m, 3H), 1.73-1.59(m, 3H), 1.56-1.43(m, 3H), 1.42-1.42 (m, 1H), 1.42-1H), 1.7.01 (m, 3H), 1.7, 1H), 1.7.26 (t, J ═ 6, 1H), 1H.2Hz，3H)。

MH+522。

EXAMPLE 41

(+) - (morphinan-3-yloxy) methylpent-2-yl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.33(br s, 1H), 7.12(d, J ═ 8.0Hz, 1H), 6.89-6.89(m, 2H), 5.77 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.86-4.78(m, 1H), 3.61(m, 1H), 3.22-3.02(m, 3H), 2.75(m, 1H), 2.35(d, J ═ 14.0Hz, 1H), 2.20-2.06(m, 3H), 1.98-1.87(m, 1H), 1.70-1.33(m, 8H), 1.27(d, J ═ 6.4Hz, 3H), 1.25-1.23(m, 1H), 1.11-0.95(m, 1H), 0.91(t, 7.7, 3H).

MH+388。

Example 42

(+) -decyl (morphinan-3-yloxy) methyl carbonate TFA

¹H NMR(400MHz，CDCl₃) δ 9.09(br s, 1H), 7.13(d, J ═ 8.0Hz, 1H), 6.97 to 6.93(m, 2H), 5.78 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.18(t, J ═ 6.8Hz, 2H), 3.65(m, 1H), 3.22 to 3.07(m, 3H), 2.80 to 2.72(m, 1H), 2.36(d, J ═ 13.6Hz, 1H), 2.06(d, J ═ 12.4Hz, 1H), 1.96 to 1.88(m, 1H), 1.71 to 1.63(m, 4H), 1.59 to 1.21(m, 19H), 1.10 to 1.01(m, 1H), 0.88(t, J ═ 6.4H, 3H).

MH+458。

Example 43

(+) -isobutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

Step 1: (+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl sulfide

To sodium hydride (763mg of a 60% dispersion in mineral oil, 19.1mmol) in HMPA (15mL) at room temperature was added the solution of (+) -3-hydroxy-N- (benzyloxycarbonyl) morphinan (6.00g, 15.9mmol) from example 1 in HMPA (50 mL). The reaction mixture was stirred for 30min, then chloromethyl methyl sulfide (1.60mL, 19.1mmol) was added dropwise. The reaction mixture was stirred vigorously at room temperature overnight. The product was extracted with EtOAc (500 mL). The EtOAc layer was washed with saturated NaHCO₃The solution is washed over MgSO₄Dried, filtered and concentrated in vacuo to afford the crude product which was further purified by preparative reverse phase HPLC to afford the title compound as a yellow gum (1.78g, 26%).

MH+438。

Step 2: (+) -isobutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

To (+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl sulfide (1.78g, 4.07mmol) in DCM (40mL) was added sulfuryl chloride (6.1mL, 6.11mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of excess reagent and DCM by rotary evaporation, the product was dried under vacuum to afford (+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl chloride as a yellow gum. The product was then added to a stirred suspension of cesium carbonate (1.59g, 4.88mmol) and isobutyric acid (0.45mL, 4.88mmol) in acetone (20mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was filtered and concentrated in vacuo to afford the crude product, which was further purified by preparative reverse phase HPLC to afford the title compound as a yellow solid (0.844g, 43%).

¹H NMR(400MHz，CDCl₃)δ7.38-7.33(m，5H)，7.02-6.93(m，3H)，5.75(s，2H)，5.17-5.12(m，2H)，4.36(d，J＝43.6Hz，1H)，3.94-3.84(m，1H)， 3.14-3.04(m，1H)，2.72-2.56(m，3H)，2.33(d，J＝12.0Hz，1H)，1.73-1.42(m，6H)，1.39-1.25(m，3H)，1.20(d，J＝7.2Hz，6H)，1.11-1.00(m，1H)。

MH+478。

Example 44

(+) -isobutyric acid (morphinan-3-yloxy) methyl ester

(+) -isobutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester from example 44 (4.12g, 8.63mmol) was hydrogenated over 10% Pd/C (600mg) in EtOH (100mL) at room temperature (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with EtOH (300 mL). The combined EtOH solution was concentrated in vacuo. The residue was further purified by reverse phase preparative HPLC to provide the title compound as a pale yellow gum (1.11g, 37%).

¹H NMR(400MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.93(d, J ═ 2.8Hz, 1H), 6.83(dd, J ═ 8.4, 2.8Hz, 1H), 5.76, and 5.74(AB q, J ═ 6.8Hz, 2H), 3.15 to 3.06(m, 2H), 2.77 to 2.67(m, 2H), 2.63 to 2.55(m, 2H), 2.28(d, J ═ 13.2Hz, 1H), 1.79 to 1.74(m, 1H), 1.66 to 1.50(m, 3H), 1.39 to 1.26(m, 5H), 1.18(d, J ═ 6.8Hz, 6H), 1.05 to 1.01(m, 1H).

MH+344。

Example 45

(+) -Neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

Step 1: (+) -Neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

To (+) -3-hydroxy-N- (benzyloxycarbonyl) morphinan from example 1 (12.0g, 31.8mmol) and cesium carbonate (11.4g, 35.0mmol) in acetone (150mL) was added iodomethyl pivalate (8.46g, 35.0mmol) at room temperature (see Bristol-Myers Squibb Company, US5470845A1(1995/11/28), appl.; US1994-266843 (1994/07/05)). The reaction mixture was stirred vigorously at room temperature overnight. Acetone was then removed by vacuum rotary evaporation. To the residue was added saturated NaHCO₃And (3) solution. The mixture was extracted with EtOAc (150 mL. times.2). The combined organics were washed with 1N HCl solution (100mL) over MgSO₄Dried, filtered and concentrated in vacuo to afford the crude product which was further purified by preparative reverse phase HPLC to afford the title compound as a yellow gum (13.2g, 84%).

¹H NMR(400MHz，CDCl₃) δ 7.39-7.32(m, 5H), 7.02(t, J ═ 8.8Hz, 1H), 6.97(s, 1H), 6.84(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.72(AB q, J ═ 6.4Hz, 2H), 5.20-5.09(m, 2H), 4.37(br d, J ═ 43.6Hz, 1H), 3.95-3.84(m, 1H), 3.15-3.05(m, 1H), 2.72-2.59(m, 2H), 2.34(d, J ═ 12.0Hz, 1H), 1.73-1.42(m, 6H), 1.39-1.25(m, 3H), 1.21(s, 9H), 1.11-1.00(m, 1H).

MH+492。

Example 46

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester

(+) -Neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester from example 46 (13.2g, 26.8mmol) was hydrogenated over 10% Pd/C (2.0g) in EtOH (100mL) at room temperature (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with EtOH (300 mL). The combined EtOH solution was concentrated in vacuo. The residue was further purified by reverse phase preparative HPLC to provide the title compound as a pale yellow gum (4.31g, 45%).

¹H NMR(300MHz，CDCl₃) δ 7.05(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.7Hz, 1H), 6.83(dd, J ═ 8.4, 2.7Hz, 1H), 5.76, and 5.71(AB q, J ═ 6.4Hz, 2H), 3.16 to 3.08(m, 2H), 2.80 to 2.54(m, 4H), 2.28(d, J ═ 13.2Hz, 1H), 1.81 to 1.76(m, 1H), 1.66 to 1.50(m, 3H), 1.42 to 1.26(m, 4H), 1.21(s, 9H), 1.09 to 1.00(m, 1H).

MH+358。

Example 47

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester TFA

The compound from example 45 was reacted in IPA (40mL) over 10% Pd/C (470mg) at room temperature

(+) -Neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester (4.66g, 9.48mmol) was hydrogenated (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with IPA (20 mL). The combined IPA solution was concentrated under vacuum. The residue was further purified by preparative reverse phase HPLC using 0.1% TFA to afford the title compound as a colorless gum (3.79g, 85%).

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.06(d, J ═ 2.8Hz, 1H), 6.95(dd, J ═ 8.4, 2.8Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.70-3.68(m, 1H), 3.33-3.26(m, 1H), 3.10(dd, J ═ 13.2, 3.2Hz, 1H), 2.95(br d, J ═ 19.2Hz, 1H), 2.74-2.67(m, 1H), 2.46(d, J ═ 14.0Hz, 1H), 1.94(d, J ═ 12.0, 1H), 1.87-1.78(m, 1H), 1.71, 1.60 (d, 1.5H), 1.9, 1H), 1.07(m, 1.9, 1H).

MH+358。

The following compounds of examples 48-78 were obtained by repeating the procedures of example 45 and example 47.

Example 48

(+) -3, 3-dimethylbutyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃)δ9.45(br，2H)，7.11(d，J＝8.4Hz，1H)，6.94(d，J＝2.8Hz，1H)，6.90(dd，J＝8.4，2.8Hz，1H)，5.75(s，2H)，3.15-3.06(m，2H)，2.77-2.67(m，2H)，2.63-2.55(m，2H)，2.24(d，J＝4.0Hz，2H)，1.79-1.74(m，1H)，1.66-1.50(m，3H)，1.39-1.26(m，5H)，1.28-1.24(m，1H)，1.05(s，9H)。

MH+372。

Example 49

(+) -hexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.34(br, 5H), 7.01(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.73(AB q, J ═ 6.4Hz, 2H), 5.13(br, 2H), 4.40(br, 1H), 3.89(br, 1H), 3.09(d, J ═ 8.8Hz, 1H), 2.70-2.62(m, 2H), 2.34(t, J ═ 7.6Hz, 2H), 1.75-1.40(m, 6H), 1.39-1.23(m, 9H), 1.06-0.90(m, 2H), 0.85(t, J ═ 8.3H), 3.4 Hz, 1H.

MH+506。

Example 50

(+) -hexanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.20(br, 2H), 7.10(d, J ═ 8.4Hz, 1H), 6.93(d, J ═ 2.0Hz, 1H), 6.90(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.63(br, 2H), 3.17-3.07(m, 5H), 2.75(br, 2H), 2.34(d, J ═ 7.6Hz, 2H), 2.06(d, J ═ 12.4Hz, 2H), 1.97-1.88(m, 2H), 1.68-1.23(m, 7H), 1.09-0.92(m, 2H), 0.86(t, J ═ 6.8, 3H).

MH+372。

Example 51

(+) -2-Propylpentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃)δ7.34(br，5H)，7.01(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.74(AB q, J ═ 6.8Hz, 2H), 5.12(br, 2H), 4.39(br, 1H), 3.88(br, 1H), 3.12-3.06(m, 1H), 2.70-2.62(m, 2H), 2.43-2.31(m, 2H), 1.70-1.18(m, 17H), 1.09-0.97(m, 1H), 0.81(t, J ═ 7.2Hz, 6H).

MH+534。

Example 52

(+) -2-Propylpentanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 8.89(br, 1H), 8.50(br, 1H), 7.10(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.91(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.74(AB q, J ═ 6.8Hz, 2H), 3.72(br, 1H), 3.25-3.15(m, 2H), 3.06(br d, J ═ 19.2Hz, 1H), 2.79-2.77(m, 1H), 2.44-2.34(m, 2H), 2.02(d, J ═ 12.0Hz, 1H), 1.94-1.86(m, 1H), 1.68(d, J ═ 13.2, 1H), 1.66(d, 1H), 1.01-1H), 1.15(m, 1H), 1.6H, 1H), 1.15(m, 1H), 1H, 1.6H, 1H), 1.15(m, 1H).

MH+400。

Example 53

(+) -2-ethylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃)δ7.34(br，5H)，7.01(d，J＝8.0Hz，1H)，6.95(d，J＝2.4Hz，1H)，6.83(dd，J＝8.4，2.4Hz，1H) 5.77 and 5.74(AB q, J ═ 6.4Hz, 2H), 5.13(br, 2H), 4.40(br, 2H), 3.88(br, 2H), 3.12-3.06(m, 2H), 2.69-2.62(m, 2H), 2.33(d, J ═ 12.8Hz, 1H), 2.27-2.20(m, 1H), 1.70-1.45(m, 6H), 1.38-1.22(m, 4H), 1.08-0.96(m, 1H), 0.84(t, J ═ 7.6Hz, 6H).

MH+506。

Example 54

(+) -2-Ethylbutyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 8.67(br, 1H), 7.80(br, 1H), 7.11(d, J ═ 8.4Hz, 1H), 6.96(d, J ═ 2.4Hz, 1H), 6.91(dd, J ═ 8.4, 2.8Hz, 1H), 5.78 and 5.74(AB q, J ═ 6.8Hz, 2H), 3.70(br, 1H), 3.24-3.13(m, 2H), 3.07(br d, J ═ 19.2Hz, 1H), 2.77-2.75(m, 1H), 2.35(d, J ═ 14.0Hz, 1H), 2.28-2.21(m, 1H), 2.03(d, J ═ 12.4Hz, 1H), 1.94-1.86(m, 69.86H), 1.84(m, 1H), 1.01-6H, 1H), 1.84 (t, 1H), 1.1.84 (m, 1H), 1.1.6.8 (t, 1H).

MH+372。

Example 55

(+) -Cyclohexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.36-7.32(m, 5H), 7.09-6.99(m, 1H), 6.94(s, 1H), 6.86-6.81(m, 1H), 5.74 and 5.72(AB q, J ═ 6.4Hz, 2H), 5.16-5.12(m, 2H),4.36(br d，J＝42.0Hz，2H)，3.94-3.84(m，2H)，3.12-3.09(m，2H)，2.67-2.49(m，3H)，2.37-2.30(m，2H)，2.05(d，J＝13.6Hz，2H)，1.89(d，J＝11.2Hz，1H)，1.88-1.79(m，1H)，1.70-1.17(m，11H)，1.09-1.00(m，1H)。

MH+518。

example 56

(+) -Cyclohexanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 11.06(br, 1H), 8.73(br, 1H), 7.13(dd, J ═ 25.2, 8.4Hz, 1H), 6.96-6.88(m, 2H), 5.75 and 5.71(AB q, J ═ 6.8Hz, 2H), 3.68(br, 1H), 3.23-3.02(m, 2H), 2.76(br, 1H), 2.57-2.50(m, 1H), 2.36-2.31(m, 2H), 2.06-2.03(m, 2H), 1.90-1.13(m, 17H), 1.09-1.01(m, 1H).

MH+384。

Example 57

(+) -Cyclopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃)δ7.37-7.30(m，5H)，7.01(t，J＝9.2Hz，1H)，6.95(s，1H)，6.83(dd，J＝8.4，2.4Hz，1H)，5.74(s，2H)，5.16-5.12(m，2H)，4.36(br d，J＝42.0Hz，2H)，3.96-3.83(m，2H)，3.12-3.04(m，2H)，2.79-2.57(m，3H)，2.33(d，J＝12.4Hz，2H)，1.90-1.23(m，12H)，1.06-1.03(m，1H)，0.88-0.85(m，1H)。

MH+504。

Example 58

(+) -Cyclopentanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 8.79(br, 1H), 8.42(br, 1H), 7.11(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.91(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.69(br, 1H), 3.23-3.12(m, 3H), 2.81-2.73(m, 2H), 2.34(d, J ═ 13.6Hz, 1H), 2.04(d, J ═ 12.4Hz, 1H), 1.98-1.35(m, 15H), 1.30-1.20(m, 1H), 1.11-1.01(m, 1H).

MH+370。

Example 59

(+) -2-Ethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.36-7.32(m, 5H), 7.02-6.99(m, 1H), 6.95(s, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.74(AB q, J ═ 6.8Hz, 2H), 5.12(br, 2H), 4.36(br d, J ═ 41.6Hz, 1H), 3.93-3.84(m, 1H), 3.12-3.07(m, 1H), 2.71-2.64(m, 2H), 2.35-2.26(m, 2H), 1.67-1.15(m, 16H), 1.08-0.99(m, 1H), 0.86-0.78(m, 6H).

MH+534。

Example 60

(+) -2-Ethylhexanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 8.76(br, 1H), 7.11(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.0Hz, 1H), 6.92(dd, J ═ 8.4, 2.0Hz, 1H), 5.81(br, 1H), 5.78, and 5.75(AB q, J ═ 6.8Hz, 2H), 3.73(br, 1H), 3.25-3.08(m, 2H), 2.81-2.73(m, 1H), 2.36-2.27(m, 2H), 2.06(d, J ═ 12.0Hz, 1H), 1.96-1.91(m, 1H), 1.69-0.99(m, 17H), 0.86-0.77(m, 6H).

MH+400。

Example 61

(+) -butyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.34(br, 5H), 7.02(d, J ═ 8.0Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.84(dd, J ═ 8.4, 2.4Hz, 1H), 5.76 and 5.73(Ab q, J ═ 6.4Hz, 2H), 5.13(br, 2H), 4.41(br, 1H), 3.88(br, 1H), 3.09(d, J ═ 14.8Hz, 1H), 2.70-2.66(m, 2H), 2.33(t, J ═ 7.6Hz, 2H), 1.71-1.22(m, 12H), 1.08-0.99(m, 1H), 0.92(t, J ═ 7.6, 3H).

MH+478。

Example 62

(+) -butyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.76(br, 1H), 8.23(br, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.92(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.75(AB q, J ═ 6.8Hz, 2H), 3.75(br, 1H), 3.27-3.18(m, 2H), 3.05(br d, J ═ 19.2Hz, 1H), 2.81(br, 1H), 2.37-2.33(m, 3H), 2.02-2.00(m, 1H), 1.90(t, J ═ 12.0Hz, 1H), 1.70-1.37(m, 8H), 1.30-1.24(m, 1H), 1.02-3.93 (t, 1H), 1.93 (t, J ═ 12.0Hz, 1H).

MH+344。

Example 63

(+) -pentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.33(br, 5H), 7.02(d, J ═ 6.8Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.73(Ab q, J ═ 6.4Hz, 2H), 5.12(br, 2H), 4.36(br d, J ═ 40.4Hz, 1H), 3.87(br, 1H), 3.11-3.07(m, 1H), 2.71-2.65(m, 2H), 2.37-2.31(m, 3H), 1.77-1.22(m, 13H), 1.08-1.02(m, 1H), 0.88(t, J ═ 7.6, 3H).

MH+492。

Example 64

(+) -pentanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.65(br, 1H), 8.40(br, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.92(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.74(AB q, J ═ 6.8Hz, 2H), 3.74(br, 1H), 3.29-3.17(m, 2H), 3.05(br d, J ═ 19.2Hz, 1H), 2.81-2.79(m, 1H), 2.38-2.34(m, 3H), 2.03-2.01(m, 1H), 1.94-1.86(m, 1H), 1.71-1.21(m, 11H), 1.11-1.02(m, 1H), 1.88 (t, 7H), 7.6H, 7H).

MH+358。

Example 65

(+) -2-methylbutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.34(br, 5H), 7.01(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.4Hz, 1H), 5.76 and 5.73(AB q, J ═ 6.8Hz, 2H), 5.13(br, 2H), 4.40(br, 1H), 3.88(br, 1H), 3.09(dd, J ═ 18.0, 2.8Hz, 1H), 2.70-2.59(m, 2H), 2.43-2.38(m, 1H), 2.33(d, J ═ 12.8Hz, 1H), 1.72-1.22(m, 11H), 1.14(d, J ═ 6.8, 3H, 1.08 (t, 0.86H), 1.86 (t, 3.86H), 3.86H (t, 3.0H).

MH+492。

Example 66

(+) -2-methylbutyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 8.53(br, 1H), 7.95(br, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.96(d, J ═ 2.4Hz, 1H), 6.92(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.74(AB q, J ═ 6.8Hz, 2H), 3.74(br, 1H), 3.26-3.17(m, 2H), 3.08(br d, J ═ 19.2Hz, 1H), 2.79(br, 1H), 2.45-2.34(m, 2H), 2.06-2.01(m, 1H), 1.95-1.89(m, 1H), 1.71-1.39(m, 8H), 1.29-1.23(m, 1H), 1.01(m, 1H), 1.86 (t, 1H), 3.6H, 1H), 3.7.6 (t, 6H, 1H), 1H).

MH+358。

Example 67

(+) -Cyclopropanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.37-7.33(m, 5H), 7.03(d, J ═ 8.4Hz, 1H), 6.94(s, 1H), 6.85(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H), 5.20-5.12(m, 2H), 4.37(br d, J ═ 42.0Hz, 1H), 3.94-3.84(m, 1H), 3.14-3.06(m, 1H), 2.78-2.54(m, 2H), 2.33(d, J ═ 12.4Hz, 1H), 1.67-1.23(m, 10H), 1.07-1.03(m, 3H), 0.91-0.87(m, 2H).

MH+476。

Example 68

(+) -Cyclopropanecarboxylic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃)δ10.35(br，1H)，8.32(br, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.94-6.91(m, 2H), 5.75 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.73(br, 1H), 3.25-3.19(m, 2H), 3.04(br d, J ═ 19.2Hz, 1H), 2.81-2.75(m, 1H), 2.35(d, J ═ 13.6Hz, 1H), 2.01-1.99(m, 1H), 1.91-1.85(m, 1H), 1.70-1.24(m, 8H), 1.10-1.01(m, 3H), 0.95-0.90(m, 2H).

MH+342。

Example 69

(+) -3-methylbutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.34(br, 5H), 7.01(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.4Hz, 1H), 6.83(dd, J ═ 8.4, 2.8Hz, 1H), 5.75 and 5.73(AB q, J ═ 6.4Hz, 2H), 5.13(br, 2H), 4.40(br, 1H), 3.88(br, 1H), 3.09(br d, J ═ 15.6, 1H), 2.70-2.59(m, 2H), 2.33(d, J ═ 12.4Hz, 1H), 2.23(d, J ═ 7.2Hz, 2H), 2.13-2.06(m, 1H), 1.71-1.22(m, 9H), 1.92(m, 1.09, 1H), 1.02 (d, 8H, 6H), 6.8H).

MH+492。

Example 70

(+) -3-methylbutyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃)δ12.86(br，1H)，8.48(br，1H)，7.10(d，J＝8.8Hz，1H)，6.94(d，J＝2.4Hz，1H)，6.91(dd，J＝8.4，2.4Hz，1H)，5.74(s，2H)，3.71(br，1H)，3.23-3.14(m，2H)，3.04(br d，J＝19.2Hz，1H)，2.78-2.76(m，1H)，2.34(d，J＝14.0Hz，1H)，2.23(d，J＝7.2Hz，2H)，2.13-2.05(m，1H)，2.01-2.00(m，1H)，1.92-1.85(m，1H)，1.69-1.34(m，6H)，1.29-1.23(m，1H)，1.10-0.97(m，1H)，0.92(d，J＝6.8Hz，6H)。

MH+358。

Example 71

(+) -2-phenylbutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.42-7.20(m, 10H), 6.94(d, J ═ 8.0Hz, 1H), 6.87(dd, J ═ 6.8, 2.4Hz, 1H), 6.71-6.68(m, 1H), 5.74 and 5.67(AB q, J ═ 6.8Hz, 2H), 5.13(br, 2H), 4.41(br, 1H), 3.86(br, 1H), 3.48(t, J ═ 7.6Hz, 1H), 3.07(brd, J ═ 14.4Hz, 1H), 2.68-2.64(m, 2H), 2.28-2.22(m, 1H), 2.15-2.04(m, 1H), 1.84-1.77(m, 1H), 1.69-1.8 (m, 8H), 1.91, 0.84-0.97 (m, 0H), 0.97(m, 1H).

MH+554。

Example 72

(+) -2-phenylbutyric acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃)δ8.54(br，1H)，7.52(br，1H)，7.27-7.24(m，5H)，7.03(dd，J＝8.4，2.4Hz，1H)，6.85(dd，J＝9.2，2.4Hz，1H)，6.78-6.74(m，1H)，5.74-5.68(m，2H)，3.71(br，1H)，3.48(t，J＝7.6Hz，1H)，3.21-3.13(m，2H)，3.03(d，J＝19.2Hz，1H)，2.74(br，1H)，2.28-2.23(m，1H)，2.16-1.99(m，2H)，1.92-1.75(m，2H)，1.67(d，J＝11.2Hz，1H)，1.54-1.35(m，4H)，1.27-1.16(m，1H)，1.04-0.96(m，2H)，0.88-0.74(m，3H)。

MH+420。

Example 73

(+) -1-adamantanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃) δ 7.30(br, 5H), 6.99(d, J ═ 6.0Hz, 1H), 6.96(d, J ═ 2.4Hz, 1H), 6.82(dd, J ═ 8.4, 2.4Hz, 1H), 5.76 and 5.68(Ab q, J ═ 6.4Hz, 2H), 5.12(br, 2H), 4.41(br, 1H), 3.86(br, 1H), 3.09(br, 1H), 2.70-2.65(m, 2H), 2.34(d, J ═ 13.2Hz, 1H), 1.99(br, 1H), 1.88(d, J ═ 2.4Hz, 6H), 1.73-1.64(m, 8H), 1.58-1.50(m, 5H), 1.35(m, 1.03-1H), 1.09 (m, 1H).

MH+570。

Example 74

(+) -1-adamantanecarboxylic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.93(br, 1H), 8.50(br, 1H), 7.11(d, J ═ 8.4Hz, 1H), 6.96(d, J ═ 2.4Hz, 1H), 6.90(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.67(AB q, J ═ 6.4H), respectivelyz，2H)，3.71(br，1H)，3.24-3.14(m，2H)，3.04(br d，J＝19.2Hz，1H)，2.78-2.76(m，1H)，2.35(d，J＝14.0Hz，1H)，2.00(br，1H)，1.95-1.87(m，8H)，1.73-1.64(m，8H)，1.57-1.25(m，7H)，1.11-1.02(m，1H)。

MH+436。

Example 75

(+) -acetic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.00(br, 1H), 7.13(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.8Hz, 1H), 6.92(dd, J ═ 8.4, 2.8Hz, 1H), 5.77 and 5.73(AB q, J ═ 6.4Hz, 2H), 4.00(br, 1H), 3.67(br, 1H), 3.24-3.07(m, 3H), 2.85-2.76(m, 1H), 2.36(d, J ═ 13.2Hz, 2H), 2.13(s, 3H), 2.09-2.04(m, 1H), 1.96-1.88(m, 1H), 1.68(d, J ═ 12.4, 1H), 1.60-1.37(m, 4H), 1.31.03-1H (m, 1H), 1.31-1.31.31H).

MH+316。

Example 76

(+) -3-Cyclohexylpropionic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃) δ 9.06(br, 1H), 7.12(d, J ═ 8.4Hz, 1H), 6.95(d, J ═ 2.4Hz, 1H), 6.92(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.74(AB q, J ═ 6.4Hz, 2H), 5.39(br, 1H), 3.66(br, 1H), 3.23-3.07(m, 3H), 2.78-2.75(m, 1H), 2.39-2.34(m, 3H), 2.05(d，J＝12.4Hz，1H)，1.95-1.87(m，1H)，1.77-1.37(m，13H)，1.31-1.04(m，7H)，0.90-0.82(m，1H)。

MH+412。

Example 77

(+) -3, 5, 5-Trimethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester

¹H NMR(400MHz，CDCl₃)δ7.39-7.28(m，5H)，7.02(t，J＝8.8Hz，1H)，6.95(s，1H)，6.85(dd，J＝8.4，2.0Hz，1H)，5.79-5.71(m，2H)，5.20-5.09(m，2H)，4.37(br d，J＝42.8Hz，1H)，3.96-3.83(m，1H)，3.14-3.05(m，1H)，2.73-2.57(m，2H)，2.38-2.33(m，2H)，2.20-2.15(m，1H)，2.08-2.00(m，1H)，1.72-1.20(m，10H)，1.12-1.02(m，2H)，0.95(d，J＝6.4Hz，3H)，0.86(s，9H)。

MH+548。

Example 78

(+) -3, 5, 5-Trimethylhexanoic acid (morphinan-3-yloxy) methyl ester TFA

¹H NMR(400MHz，CDCl₃)δ9.63(br，1H)，8.84(br，1H)，7.12(d，J＝8.4Hz，1H)，6.96(d，J＝2.4Hz，1H)，6.93(dd，J＝8.4，2.4Hz，1H)，5.79-5.72(m，2H)，3.68(br，1H)，3.24-3.05(m，3H)，2.82-2.73(m，1H)，2.38-2.34(m，2H)，2.22-2.16(m，1H)，2.05-2.02(m，1H)，1.92-1.86(m，1H)，1.68(d，J＝12.8Hz，1H)，1.60-1.21(m，8H)，1.13-1.01(m，2H)，0.96(d，J＝6.4Hz，3H)，0.87(s，9H)。

MH+414。

Example 79

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate TFA

(+) -isopropyl [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate from example 1 (16.9g, 34.2mmol) was hydrogenated over 10% Pd/C (1.7g) in 1, 4-dioxane (100mL) at room temperature (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with 1, 4-dioxane (50 mL). The combined 1, 4-dioxane solutions were concentrated in vacuo. The residue was further purified by preparative reverse phase HPLC using 0.1% TFA to afford the title compound as a colorless gum (8.86g, 55%).

¹H NMR(400MHz，CDCl₃) δ 9.11(br, 2H), 7.12(d, J ═ 8.4Hz, 1H), 6.95-6.93(m, 2H), 5.76 and 5.70(AB q, J ═ 6.4Hz, 2H), 4.95-4.89(m, 1H), 3.68(br, 1H), 3.23-3.11(m, 3H), 2.75(br, 1H), 2.35(d, J ═ 13.6Hz, 1H), 2.08(d, J ═ 12.0Hz, 1H), 1.98-1.90(m, 1H), 1.66(d, J ═ 12.8Hz, 1H), 1.58-1.37(m, 5H), 1.30(d, J ═ 6.0, 6H), 1.27-1.24(m, 1.24H), 1.03-1H (m, 07H).

MH+360。

Example 80

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -tartaric acid

The method comprises the following steps: (+) -isopropyl (morphinan-3-yloxy) methyl carbonate TFA (300mg, 0.634mmol) from example 79 was dissolved in EtOAc (20mL) and saturated NaHCO₃The solution (20 mL. times.2) was washed. To the EtOAc layer was added L- (+) -tartaric acid (95.2mg, 0.634 mmol). The mixture was stirred at 40 ℃ for 10min and cooled to room temperature. The precipitated solution was filtered and washed with EtOAc (10mL) to provide the title compound as a white solid (268mg, 83%).

The method 2 comprises the following steps: (+) -isopropyl [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate from example 1 (1.72g, 3.48mmol) was hydrogenated in IPA (25mL) over 10% Pd/C (170mg) at room temperature (balloon). After completion of the reaction, the reaction mixture was filtered through celite and washed with IPA (20 mL). To the combined IPA solution, L- (+) -tartaric acid (522mg, 3.48mmol) was added. The mixture was stirred at 40 ℃ for 30 minutes. The mixture was concentrated under vacuum. To the residue was added EtOAc (20 mL). The solution was filtered and washed with EtOAc (10mL) to afford the title compound as a white solid (1.61g, 91%).

[α]_D ²⁷+24.0°(c＝1.0，MeOH)；mp 159℃；IR(KBr)v_max 3525，3179，2933，2456，1760，1455，1431，1271，1219，1043cm^-1；¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.4Hz, 1H), 6.95(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.89-4.82(m, 1H), 4.39(s, 2H), 3.70-3.68(m, 1H), 3.25(d, J ═ 6.0Hz, 1H), 3.11(dd, J ═ 13.6, 4.0Hz, 1H), 2.99(br d, J ═ 18.8Hz, 1H), 2.74-2.66(m, 1H), 2.45(d, J ═ 14.4Hz, 1H), 1.96(d, J ═ 18.8Hz, 1H), 1.42(m, 1H), 1H), 1.42 (d, 1H), 1H), 1.45 (d, 14.4.4, 1H, 1.96(d, 1H), 1.9, 1H), 1.42H, 1H), 1H, 1.42(m, 1H), 1H, 6H), 1H, 1;¹³C NMR(400MHz，CD₃OD)δ176.1，156.5，153.9，139.5，129.4，128.9，114.8，113.5，88.4，73.1，72.5，51.3，41.2，38.4，37.6，36.6，35.5，27.7，25.9，25.6，21.7，20.7；HR-FAB-MS m/z：360.2173[M+H]⁺(C₂₁H₃₀NO₄the calculated value of (a): 360.2175).

MH+360。

The following compounds of examples 81-92 were obtained by repeating the procedure of example 80.

Example 81

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate HCl

¹H NMR(400MHz，CDCl₃) δ 9.62(br, 2H), 7.12(d, J ═ 8.4Hz, 1H), 6.95-6.92(m, 2H), 5.76 and 5.70(AB q, J ═ 6.4Hz, 2H), 4.95-4.89(m, 1H), 3.72(br, 1H), 3.26-3.14(m, 3H), 2.73(br, 1H), 2.33(d, J ═ 12.4Hz, 1H), 2.16(d, J ═ 12.0Hz, 1H), 2.03-1.98(m, 1H), 1.65(d, J ═ 10.8Hz, 1H), 1.57-1.36(m, 5H), 1.30(d, J ═ 6.4Hz, 6H), 1.26-1.22(m, 1.06H), 1.06(m, 1H).

MH+360。

Example 82

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate carboxylic acid

¹H NMR(400MHz，CD₃OD) δ 8.51(s, 1H), 7.18(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.4Hz, 1H), 6.96(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.4Hz, 2H), 4.93-4.82(m, 1H), 3.69-3.67(m, 1H), 3.32-3.25(m, 1H), 3.12-3.07(m,1H)，2.97(br d，J＝19.2Hz，1H)，2.75-2.67(m，1H)，2.46(br d，J＝17.2Hz，1H)，1.96-1.92(m，1H)，1.86-1.78(m，1H)，1.71(d，J＝14.4Hz，1H)，1.61-1.38(m，5H)，1.33-1.29(m，1H)，1.26(d，J＝6.0Hz，6H)，1.14-1.04(m，1H)。

MH+360。

example 83

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate citric acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.4Hz, 1H), 6.96(dd, J ═ 8.4, 2.4Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.88-4.83(m, 1H), 3.71-3.68(m, 1H), 3.25(d, J ═ 6.8Hz, 1H), 3.13-3.09(m, 1H), 2.98(br d, J ═ 19.2Hz, 1H), 2.86-2.68(m, 7H), 2.45(d, J ═ 13.6Hz, 1H), 1.97-1.94(m, 1H), 1.87-1.79(m, 1H), 1.60(m, 1H), 1.6H, 1H, 1.7H, 1.6 (m, 1H), 1.7H, 1.6H, 1.26, 1H, 1.7H, 1.

MH+360。

Example 84

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate fumaric acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.03(s, 1H), 6.96(d, J ═ 8.4Hz, 1H), 6.66(s, 1H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H),4.89-4.86(m，1H)，3.69-3.67(m，1H)，3.12-3.08(m，1H)，3.00-2.95(m，1H)，2.74-2.68(m，1H)，2.45(d，J＝13.6Hz，1H)，1.97-1.93(m，1H)，1.84-1.80(m，1H)，1.75-1.66(m，1H)，1.60-1.32(m，6H)，1.26(d，J＝6.0Hz，6H)，1.18-1.05(m，2H)。

MH+360。

example 85

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate monosodium fumarate

¹H NMR(400MHz，CD₃OD) δ 7.26(d, J ═ 8.4Hz, 1H), 7.03(s, 1H), 6.96(d, J ═ 8.4Hz, 1H), 6.66(s, 2H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.93-4.86(m, 1H), 3.69-3.67(m, 1H), 3.12-3.08(m, 1H), 2.99-2.94(m, 1H), 2.75-2.67(m, 1H), 2.45(d, J ═ 14.4Hz, 1H), 1.96-1.93(m, 1H), 1.86-1.78(m, 1H), 1.75-1.67(m, 1H), 1.61-1.30(m, 6H), 1.26(d, 6.18H), 1H), 1.18-1H).

MH+360。

Example 86

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate 4-methylbenzenesulfonic acid

¹H NMR(400MHz，CD₃OD) δ 7.70(d, J ═ 8.4Hz, 2H), 7.23(d, J ═ 7.6Hz, 2H), 7.17(d, J ═ 8.4Hz, 1H), 7.02(d, J ═ 2.4Hz, 1H), 6.95(dd, J ═ 8.4, 2.8Hz, 1H), 5.76 and 5.72(AB q, J ═ 6.8H), respectivelyHz，2H)，4.89-4.83(m，1H)，3.68-3.66(m，1H)，3.24(d，J＝6.4Hz，1H)，3.11-3.07(m，1H)，2.95(br d，J＝19.2Hz，1H)，2.75-2.67(m，1H)，2.44(d，J＝13.6Hz，1H)，1.94-1.90(m，1H)，1.85-1.77(m，1H)，1.69(d，J＝14.0Hz，1H)，1.59-1.28(m，6H)，1.24(d，J＝8.0Hz，6H)，1.08-1.04(m，1H)。

MH+360。

Example 87

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate stearic acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.8Hz, 1H), 7.03(d, J ═ 2.4Hz, 1H), 6.96(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.73(AB q, J ═ 7.2Hz, 2H), 4.88-4.83(m, 1H), 3.68-3.66(m, 1H), 3.26(d, J ═ 6.4Hz, 1H), 3.09(dd, J ═ 13.6, 3.6Hz, 1H), 2.96(br d, J ═ 19.2Hz, 1H), 2.74-2.67(m, 1H), 2.46(d, J ═ 14.0, 1H), 2.18(t, J ═ 7.6, 1H), 1.91, 1H, 7.95-2.78 (m, 1H), 1H, 7.9, 1H, 7.6H, 1H, 7.78 (d, 1H), 1H, 7H, 7H.

MH+360。

Example 88

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate disodium citrate

¹H NMR(400MHz，D₂O)δ7.21(d，J ═ 8.4Hz, 1H), 7.00(s, 1H), 6.95(d, J ═ 8.4Hz, 1H), 5.76 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.92-4.81(m, 1H), 3.71(m, 1H), 3.30(s, 4H), 3.24-3.23(m, 1H), 3.16-3.12(m, 1H), 3.04-2.99(m, 1H), 2.71-2.64(m, 1H), 2.40(d, J ═ 13.6Hz, 1H), 2.01-1.97(m, 1H), 1.91-1.83(m, 1H), 1.68-1.65(m, 1H), 1.58-1.38(m, 5H), 1.26(m, 6H), 1.19 (d, 6H), 1H), 2.19-2.19 (m, 1H).

MH+360。

Example 89

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (-) -malic acid

¹H NMR(400Mz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.8Hz, 1H), 6.96(dd, J ═ 8.4, 2.8Hz, 1H), 5.76 and 5.73(AB q, J ═ 6.8Hz, 2H), 4.89-4.83(m, 1H), 4.31(dd, J ═ 10.0, 5.2Hz, 1H), 3.70-3.68(m, 1H), 3.26(d, J ═ 6.0Hz, 1H), 3.10(dd, J ═ 12.8, 4.0Hz, 1H), 2.97(br d, J ═ 19.2Hz, 1H), 2.81-2.67(m, 2H), 2.55-2.51(m, 2H), 1.45H (m, 1H), 1H (1H), 1H, 6.7 (d, 1H, 7(d, 7H), 7(d, 7, 1H), 1H) in that respect

MH+360。

Example 90

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -lactic acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.04(d, J ═ 2.4Hz, 1H), 6.96(dd, J ═ 8.4, 2.4Hz, 1H), 5.76, and 5.73(AB q, J ═ 6.8Hz, 2H), 4.88-4.84(m, 1H), 4.05(q, J ═ 6.8Hz, 1H), 3.69-3.67(m, 1H), 3.32-3.26(m, 1H), 3.10(dd, J ═ 13.2, 3.2Hz, 1H), 2.96(br d, J ═ 19.2Hz, 1H), 2.75-2.67(m, 1H), 2.46(d, J ═ 14.0, 1H), 1H (1H), 4.93, J ═ 19.2Hz, 1H), 1H, 2.67(m, 1H), 2.46(d, 14.0, 1H), 1H, 6.93 (J ═ 6.6, 1H), 1H, 6, 1H, 6H, 1H, 6H, 1H.

MH+360。

Example 91

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate succinic acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.4Hz, 1H), 6.96(dd, J ═ 8.4, 2.4Hz, 1H), 5.76 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.90-4.82(m, 1H), 3.66(br, 1H), 3.32-3.29(m, 1H), 3.08(dd, J ═ 12.8, 3.6Hz, 1H), 2.95(br d, J ═ 19.2Hz, 1H), 2.75-2.68(m, 1H), 2.50(s, 4H), 2.49-2.44(m, 1H), 1.92(d, J ═ 11.2, 1H), 1.84(m, 1H), 1.50 (s, 4H), 2.49-2.44(m, 1H), 1.92(d, J ═ 11.2, 1H), 1.84(m, 1H), 1.6H), 1.13, 1H), 1H (m, 1H), 1.6H, 1H), 1H, 1.6H, 1H.

MH+360。

Example 92

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate salicylic acid

¹H NMR(400MHz，CD₃OD) δ 7.82(dd, J ═ 8.0, 2.4Hz, 1H), 7.32-7.27(m, 1H), 7.17(d, J ═ 8.4Hz, 1H), 7.03(d, J ═ 2.8Hz, 1H), 6.95(dd, J ═ 8.4, 2.8Hz, 1H), 5.75 and 5.72(AB q, J ═ 6.8Hz, 2H), 4.89-4.83(m, 1H), 3.70-3.68(m, 1H), 3.26(d, J ═ 6.0Hz, 1H), 3.10(dd, J ═ 12.8, 3.6Hz, 1H), 2.96(br d, J ═ 19.2, 1H), 2.74-2.68(m, 1H), 1H, 45, 1H, 13.7 (d, 1H), 1H, 6H, 1H, 6H, 1H, 6H, 1.

MH+360。

Example 93

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester succinic acid

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetate from example 62 (240mg, 0.509mmol) was dissolved in EtOAc (20mL) and saturated NaHCO₃The solution (20 mL. times.2) was washed. To the EtOAc layer was added succinic acid (60.1mg, 0.509 mmol). The mixture was stirred at 40 ℃ for 10min and cooled to room temperature. The precipitated solution was filtered and washed with EtOAc (10mL) to provide the title compound as a white solid (243mg, 100%).

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.05(d, J ═ 2.0Hz, 1H), 6.94(dd, J ═ 8.4, 2.4Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.69-3.67(m, 1H), 3.25(d, J ═ 6.4Hz, 1H), 3.10(dd, J ═ 13.2, 3.6Hz, 1H), 2.97(br d, J ═ 19.2Hz, 1H), 2.72-2.65 (hd, J ═ 19.2Hz, 1H), 2.72-2.65 (H)(m，1H)，2.50(s，4H)，2.45(d，J＝13.6Hz，1H)，1.95(d，J＝12.4Hz，1H)，1.87-1.79(m，1H)，1.70(d，J＝12.4Hz，1H)，1.58-1.38(m，4H)，1.34-1.21(m，2H)，1.17(s，9H)，1.10-1.04(m，1H)。

MH+358。

The following compounds of examples 94-105 were obtained by repeating the procedure of example 93.

Example 94

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester HCl

¹H NMR(400MHz，CD₃OD) δ 7.19(d, J ═ 8.4Hz, 1H), 7.04(br, 1H), 6.93(d, J ═ 7.2Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.4Hz, 2H), 3.72(br, 1H), 3.30-3.25(m, 1H), 3.13(d, J ═ 9.6Hz, 1H), 3.06(br d, J ═ 19.2Hz, 1H), 2.73-2.66(m, 1H), 2.44(d, J ═ 14.0Hz, 1H), 2.04(d, J ═ 12.8Hz, 1H), 1.95-1.87(m, 1H), 1.68(d, J ═ 11.2Hz, 1H), 1.58-1.58 (m, 1H), 1.9-1H, 1H), 1.05(m, 1H).

MH+358。

Example 95

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester carboxylic acid

¹H NMR(400MHz，CD₃OD)δ8.30(s，1H)，7.18(d，J＝8.4Hz，1H)，7.05(d，J＝2.4Hz，1H)，6.95(dd，J＝8.4，2.4Hz，1H)，5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.70-3.67(m, 1H), 3.32-3.25(m, 1H), 3.10(dd, J ═ 13.2, 3.2Hz, 1H), 2.96(br d, J ═ 19.2Hz, 1H), 2.73-2.66(m, 1H), 2.46(d, J ═ 14.0Hz, 1H), 1.94(d, J ═ 12.4Hz, 1H), 1.87-1.78(m, 1H), 1.68(d, J ═ 11.2Hz, 1H), 1.60-1.40(m, 5H), 1.29-1.21(m, 1H), 1.17(s, 9H), 1.12-1.06(m, 1H).

MH+358。

Example 96

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester citric acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.4Hz, 1H), 7.05(d, J ═ 2.4Hz, 1H), 6.94(dd, J ═ 8.4, 2.4Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.69(br, 1H), 3.30-3.20(m, 1H), 3.11(dd, J ═ 13.2, 3.2Hz, 1H), 2.98(br d, J ═ 19.2Hz, 1H), 2.82-2.65(m, 7H), 2.45(d, J ═ 14.0Hz, 1H), 1.96(d, J ═ 12.0Hz, 1H), 1.88-1.80(m, 1H), 1.70(d, J ═ 14.0Hz, 1H), 1.88-1H, 1.70(d, J ═ 12.0Hz, 1H), 1.06, 1H, 1.9, 1H), 1.9 (m, 1H).

MH+358。

Example 97

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester fumaric acid

¹H NMR(400MHz，CD₃OD)δ7.18(d，J＝8.4Hz，1H)，7.05(d，J＝2.4Hz，1H)，6.95(dd, J ═ 8.4, 2.4Hz, 1H), 6.67(s, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.70-3.67(m, 1H), 3.32-3.26(m, 1H), 3.10(dd, J ═ 13.6, 3.6Hz, 1H), 2.96(br d, J ═ 19.2Hz, 1H), 2.73-2.66(m, 1H), 2.46(d, J ═ 13.6Hz, 1H), 1.94(d, J ═ 12.4Hz, 1H), 1.87-1.79(m, 1H), 1.71(d, J ═ 13.6Hz, 1H), 1.60-1.41(m, 5H), 1.32-1.26(m, 1H), 1.17 (m, 1H), 1.07-1H).

MH+358。

Example 98

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester monosodium fumarate

¹H NMR(400MHz，CD₃OD) δ 7.16(d, J ═ 8.4Hz, 1H), 7.04(d, J ═ 2.4Hz, 1H), 6.92(dd, J ═ 8.8, 2.4Hz, 1H), 6.65(s, 2H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 3.56-3.55(m, 1H), 3.29-3.22(m, 1H), 3.01(dd, J ═ 13.6, 3.2, 1H), 2.92(br d, J ═ 18.8Hz, 1H), 2.69-2.62(m, 1H), 2.43(d, J ═ 13.6Hz, 1H), 1.91(d, J ═ 12.4Hz, 1H), 1.83-1.83 (m, 1H), 1.70 (m, 1H), 1.43 (d, J ═ 13.6Hz, 1H), 1.91(d, J ═ 12.4Hz, 1H), 1.83-1.75(m, 1H), 1.9H, 1H), 1.9 (m, 1H), 1.9H, 1H.

MH+358。

Example 99

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester 4-methylbenzenesulfonic acid

¹H NMR(400MHz，CD₃OD) δ 7.72(d, J ═ 8.0Hz, 2H), 7.22(d, J ═ 8.0Hz, 2H), 7.10(d, J ═ 8.4Hz, 1H), 6.99(d, J ═ 2.4Hz, 1H), 6.87(dd, J ═ 8.4, 2.4Hz, 1H), 5.77 and 5.71(AB q, J ═ 6.4Hz, 2H), 3.38-3.36(m, 1H), 3.14(dd, J ═ 18.8, 6.4Hz, 1H), 2.91-2.85(m, 2H), 2.61-2.53(m, 1H), 2.37-2.34(m, 4H), 1.87-1.84(m, 1H), 1.76-1.69(m, 1H), 1.62 (m, 1H), 1.19-1H), 1.18, 1H (d, 1.18, 1H), 1H), 1.19(m, 1H), 1H.

MH+358。

Example 100

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester stearic acid

¹H NMR(400MHz，CD₃OD) δ 7.13(d, J ═ 8.4Hz, 1H), 7.01(d, J ═ 2.4Hz, 1H), 6.89(dd, J ═ 8.4, 2.4Hz, 1H), 5.78 and 5.72(AB q, J ═ 6.8Hz, 2H), 3.37-3.36(m, 1H), 3.23-3.17(m, 1H), 2.89-2.85(m, 2H), 2.64-2.56(m, 1H), 2.40(d, J ═ 13.6Hz, 1H), 2.14(t, J ═ 7.6Hz, 2H), 1.88-1.84(m, 1H), 1.77-1.21(m, 38H), 1.17(s, 9H), 1.12-1.04(m, 1H), 1.7, 3H (t, 3H).

MH+358。

Example 101

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester disodium citrate

¹H NMR(400MHz，CD₃OD) δ 7.13(d, J ═ 8.4Hz, 1H), 7.01(d, J ═ 2.4Hz, 1H), 6.98(dd, J ═ 8.4, 2.4Hz, 1H), 5.78 and 5.72(AB q, J ═ 6.8Hz, 2H), 3.41 to 3.39(m, 1H), 3.30(s, 4H), 3.20(dd, J ═ 18.8, 6.0Hz, 1H), 2.92 to 2.86(m, 2H), 2.64 to 2.57(m, 1H), 2.40(d, J ═ 13.6Hz, 1H), 1.88 to 1.85(m, 1H), 1.77 to 1.67(m, 2H), 1.57 to 1.21(m, 6H), 1.17(s, 9, 1.04 to 1H), 1.04(m, 1H).

MH+358。

Example 102

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester L- (+) -tartaric acid

¹H NMR(400MHz，CD₃OD) δ 7.18(d, J ═ 8.0Hz, 1H), 7.04(d, J ═ 2.0Hz, 1H), 6.93(dd, J ═ 8.4, 2.4Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 4.32(s, 2H), 3.68(br, 1H), 3.29-3.22(m, 1H), 3.12-3.08(m, 1H), 2.99(br d, J ═ 19.2Hz, 1H), 2.70-2.63(m, 1H), 2.44(d, J ═ 13.6Hz, 1H), 2.00-1.96(m, 1H), 1.89-1.81(m, 1H), 1.70(d, J ═ 13.6Hz, 1H), 1.59-1H (m, 1H), 1.06-1.06 (m, 1H), 1.70(d, J ═ 6, 1.6, 1H), 1.59, 1.4.4H, 1H), 1H.

MH+358。

Example 103

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester L- (-) -malic acid

¹H NMR(400MHz，CD₃OD)δ7.18(d，J＝8.4Hz，1H)，7.05(d, J ═ 2.4Hz, 1H), 6.94(dd, J ═ 8.4, 2.4Hz, 1H), 5.79 and 5.73(AB q, J ═ 6.8Hz, 2H), 4.28(dd, J ═ 7.6, 4.8Hz, 1H), 3.70-3.68(m, 1H), 3.29-3.25(m, 1H), 3.14-3.08(m, 1H), 2.97(br d, J ═ 19.2Hz, 1H), 2.78(dd, J ═ 16.0, 5.2Hz, 1H), 2.73-2.66(m, 1H), 2.54-2.44(m, 2H), 1.95(d, J ═ 12.4Hz, 1H), 1.87-1.78(m, 1H), 1.9, 1H, 1.9, 1H), 1.9, 1H, and.

MH+358。

Example 104

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester L- (+) -lactic acid

¹H NMR(400MHz，CD₃OD) δ 7.12(d, J ═ 8.8Hz, 1H), 7.00(d, J ═ 2.4Hz, 1H), 6.88(dd, J ═ 8.4, 2.8Hz, 1H), 5.77 and 5.71(AB q, J ═ 6.8Hz, 2H), 4.01(q, J ═ 6.8Hz, 1H), 3.41 to 3.38(m, 1H), 3.30 to 3.29(m, 1H), 3.18(dd, J ═ 18.8, 6.4Hz, 1H), 2.93 to 2.86(m, 2H), 2.63 to 2.56(m, 1H), 2.39(d, J ═ 13.6Hz, 1H), 1.90(d, J ═ 12.4Hz, 1H), 1.79(m, 1H), 1.6H), 1.90(d, J ═ 12.4, 1H), 1.79(m, 1H), 1.6H, 1.6 (d, 1.6H), 1.6H, 1H, 1.6H.

MH+358。

Example 105

(+) -Neopentanoic acid (morphinan-3-yloxy) methyl ester salicylic acid

¹H NMR(400MHz，CD₃OD) δ 7.81(dd, J ═ 8.0, 2.0Hz, 1H), 7.27-7.23(m, 1H), 7.17(d, J ═ 8.4Hz, 1H), 7.05(d, J ═ 2.4Hz, 1H), 6.94(dd, J ═ 8.4, 2.4Hz, 1H), 6.77-6.72(m, 2H), 5.79 and 5.73(AB q, J ═ 6.4Hz, 2H), 3.65(br, 1H), 3.25(d, J ═ 6.0Hz, 1H), 3.08(dd, J ═ 13.2, 3.6Hz, 1H), 2.95(br d, J ═ 19.2Hz, 1H), 2.72-2.65(m, 1H), 1H (m, 45.2, 1H), 1H (d, 1.85, 1H), 1.7 (d, 1H), 1H.

MH+358。

Claims (6)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

a is a direct bond or oxygen;

R₁selected from hydrogen, -C (O) OC_1-10Alkyl and-C (O) OC_1-4Alkyl-phenyl; and is

R₂Is selected from C_1-10Alkyl group, (CH)₂)_n-phenyl and C_3-10Carbocycle, wherein n is 0-4.

2. The compound of claim 1, wherein the compound has formula (Ia):

wherein R is₁And R₂As defined in claim 1.

3. The compound of claim 1, wherein the compound has formula (Ib):

wherein R is₁And R₂As defined in claim 1.

4. A compound selected from the group consisting of:

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate;

(+) - (morphinan-3-yloxy) methylpropyl carbonate;

(+) -cyclopropylmethyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclopentyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclohexyl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclohexylmethyl (morphinan-3-yloxy) methyl carbonate;

(+) -hept-4-yl (morphinan-3-yloxy) methyl carbonate;

(+) -decahydronaphthalen-2-yl (morphinan-3-yloxy) methyl carbonate;

(+) -decahydronaphthalen-1-yl (morphinan-3-yloxy) methyl carbonate;

(+) -cyclopentylmethyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -cyclobutylmethyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -2-ethylhexyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -butyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -isobutyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -sec-butyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -cycloheptyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) - (morphinan-3-yloxy) methylphenethylcarbonate trifluoroacetic acid;

(+) - (morphinan-3-yloxy) methyl 1-phenylprop-2-yl carbonate trifluoroacetic acid;

(+) -ethyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -methyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -cyclobutyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -hexyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) - (morphinan-3-yloxy) methylpent-2-yl carbonate trifluoroacetic acid;

(+) -decyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -methyl isobutyrate (morphinan-3-yloxy) methyl ester;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -3, 3-dimethylbutyric acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -hexanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -2-propylpentanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -2-ethylbutanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -cyclohexanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -cyclopentanecarboxylic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -2-ethylhexanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -butyric acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -pentanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -2-methylbutanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -cyclopropanecarboxylic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -3-methylbutanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -2-phenylbutyric acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -1-adamantanecarboxylic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -acetic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -3-Cyclohexylpropionic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -3, 5, 5-trimethylhexanoic acid (morphinan-3-yloxy) methyl ester trifluoroacetic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate trifluoroacetic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -tartaric acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate HCl;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate carboxylic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate citric acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate fumarate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate monosodium fumarate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate 4-methylbenzenesulfonic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate stearic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate disodium citrate;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (-) -malic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate L- (+) -lactic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate succinic acid;

(+) -isopropyl (morphinan-3-yloxy) methyl carbonate salicylic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester succinic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester HCl;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester carboxylic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester citric acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester fumarate;

monosodium (+) -pivalic acid (morphinan-3-yloxy) methyl ester fumarate;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester 4-methylbenzenesulfonic acid;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester stearic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester disodium citrate;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (+) -tartaric acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (-) -malic acid;

(+) -pivalic acid (morphinan-3-yloxy) methyl ester L- (+) -lactic acid;

(+) -neopentanoic acid (morphinan-3-yloxy) methyl ester salicylic acid;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylisopropyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclopentyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclohexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyldecalin-1-yl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclopentylmethyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 2-ethylhexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylbutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl isobutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl sec-butyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcycloheptylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylphenethylcarbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl 1-phenylprop-2-yl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ethyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylcyclobutyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl hexyl carbonate;

(+) - [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methylpent-2-yl carbonate;

(+) -isobutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -neopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -hexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-propylpentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-ethylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclohexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclopentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-ethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -butyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -pentanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-methylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -cyclopropanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -3-methylbutanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -2-phenylbutyric acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester;

(+) -1-adamantanecarboxylic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester; and

(+) -3, 5, 5-trimethylhexanoic acid [ N- (benzyloxycarbonyl) morphinan-3-yloxy ] methyl ester.

5. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of parkinson's disease.