Opioid receptor antagonist prodrugs

Abstract

Provided herein are prodrugs of opioid receptor antagonists such as nalmefene and naltrexone, pharmaceutical compositions comprising the compounds, and methods for using the compounds to treat behavioral disorders.

Description

Background Art

[0001] There is a need in the medical field for compositions and methods for modulating opioid receptor activity in the treatment of behavioral disorders. Summary of the invention

[0002] Provided herein are prodrugs of opioid receptor antagonists such as nalmefene and naltrexone, pharmaceutical compositions comprising the compounds, and methods for using the compounds to treat behavioral disorders.

[0003] Some compounds of the present invention have excellent properties. For example, some compounds of the present invention have excellent stability in oil-based pharmaceutical compositions such as sesame oil or cottonseed oil.

[0004] Some compounds of the present invention have good pharmacokinetic activity in vivo (eg, rats or dogs), such as prolonged half-life.

[0005] Some compounds of the invention have better safety profiles in vivo (eg, rats or dogs), such as reduced injection site reactions.

[0006] Certain compounds of the present invention have excellent stability either neat or in oil-based pharmaceutical compositions.

[0007] In one aspect, provided herein is a compound or a pharmaceutically acceptable salt thereof having a structure provided in formula (II),

[0008]

[0009] in,

[0010] X is O or CH2;

[0011] R is

[0012] Where R 1 C4-C 10 Alkyl or C4-C 10 and n is 7 to 15; provided that if X is O, then n is not 7.

[0013] In some embodiments, X is O. In some embodiments, X is CH2.

[0014] On the other hand, the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which has a structure provided in formula (IIa),

[0015]

[0016] in,

[0017] X is O or CH2;

[0018] R is:

[0019]

[0020] Where R 1 C4-C 10 Alkyl or C4-C 10 alkenyl; and n is 9-15.

[0021] In some embodiments, X is O. In some embodiments, X is CH2.

[0022] In another aspect, the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which has a structure provided in formula (III),

[0023]

[0024] in,

[0025] X is O or CH2;

[0026] R is selected from:

[0027] -[CH(R 3 )O]zR 4 ;

[0028] -[CH(R 3 )O]zC(=O)OR 4 ;

[0029] -[CH(R 3 )O]zC(=O)NR 4 R 5 ;as well as

[0030] -[CH(R 3 )O]zP(=O)(OR 4 )(OR 5 );

[0031] Where z is 1, 2, 3, 4, 5, 6 or 7;

[0032] R 3 is hydrogen, halogen, alkyl, alkenyl, cycloalkylalkyl or aryl;

[0033] Each R 4 and R 5 are independently selected from hydrogen, alkyl, alkenyl, cycloalkylalkyl or aryl.

[0034] In some embodiments, X is O. In some embodiments, X is CH2.

[0035] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of formula (II), (IIa) or (III) or a compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof.

[0036] Provided herein is a method for treating opioid dependence in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising a compound of formula (II), (IIa) or (III) or a compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0037] One embodiment provides a method of treating a patient, wherein the therapeutic effect of a long-acting opioid antagonist depot in the patient can be overcome by administering an opioid-based analgesic.

[0038] One embodiment provides a method of treating opioid dependence in a patient in need thereof, wherein the patient receives a first injection of an injectable formulation comprising a compound of any one of Formula (II), (IIa) or (III) or a disclosed compound described in Table 1, or a pharmaceutically acceptable salt thereof, wherein the first injection provides therapeutically relevant plasma concentrations for about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months, followed by a second injection of an injectable formulation comprising a compound of any one of Formula (II), (IIa) or (III) or a disclosed compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the second injection provides therapeutically relevant plasma concentrations for at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months.

[0039] One embodiment provides a method of treating opioid dependence in a patient in need thereof, wherein the patient receives a first injection of an injectable formulation of PLGA microspheres loaded with naltrexone, which first injection provides therapeutically relevant plasma concentrations for about 4 weeks, followed by one or more injections of an injectable formulation comprising a compound of any of Formula (II), (IIa) or (III) or a compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof, which provides therapeutically relevant plasma concentrations for about 2 months, about 3 months, about 4 months, or about 5 months or more.

[0040] One embodiment provides a method of treating opioid dependence in a patient in need thereof, wherein the patient receives one or more injections of an injectable formulation comprising at least one compound of any one of Formula (II), (IIa) or (III) or a compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof, wherein the patient was previously treated with an opioid agonist or partial agonist such as buprenorphine or methadone, and the patient is now transitioning off such agonist or partial agonist treatment.

[0041] One embodiment provides a method of treating opioid dependence in a patient in need thereof, wherein the patient receives one or more injections of an injectable formulation comprising at least one compound of any one of Formula (II), (IIa) or (III) or a compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof, wherein the patient was recently addicted to a previous medication-assisted treatment and is credulous, or wherein the patient has recently discontinued opioid analgesics, is at risk for future opioid abuse, and is in need of prevention of future opioid abuse by antagonist treatment.

[0042] Incorporated by Reference

[0043] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference for the specific purpose identified herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Various aspects of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the disclosure will be obtained by reference to the following detailed description setting forth illustrative embodiments in which the principles of the disclosure are utilized and the accompanying drawings set forth below. This patent application document contains at least one drawing in color. Copies of this patent application disclosure with one or more color drawings will be provided by the Office upon request and payment of the necessary fee.

[0045] Figure 1 The nuclear magnetic resonance spectrum of Example 1 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ((E)-octadec-9-en-1-yl) carbonate is provided;

[0046] Figure 2The nuclear magnetic resonance spectrum of Example 2 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl undecyl carbonate is provided;

[0047] Figure 3 The nuclear magnetic resonance spectrum of Example 3 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl undecyl carbonate is provided;

[0048] Figure 4 The nuclear magnetic resonance spectrum of Example 4 (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate undecyl ester is provided; and

[0049] Figure 5 The nuclear magnetic resonance spectrum of Example 5 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate undecyl ester is provided.

[0050] Figure 6 The nuclear magnetic resonance spectrum of Example 6 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl dodecyl carbonate is provided;

[0051] Figure 7 The nuclear magnetic resonance spectrum of Example 7 (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ((E)-octadec-9-en-1-yl) carbonate is provided;

[0052] Figure 8The nuclear magnetic resonance spectrum of Example 8 (E)-octadec-9-enoic acid (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0053] Fig. 9 The nuclear magnetic resonance spectrum of Example 9 (E)-octadec-9-enoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided;

[0054] Fig.10 The nuclear magnetic resonance spectrum of Example 10 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldecyl carbonate is provided;

[0055] Fig.11 The nuclear magnetic resonance spectrum of Example 11 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl dodecyl carbonate is provided;

[0056] Fig.12 The nuclear magnetic resonance spectrum of Example 12 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl stearate is provided;

[0057] Fig.13 The nuclear magnetic resonance spectrum of Example 13 (Z)-docosa-13-enoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0058] Fig.14The nuclear magnetic resonance spectrum of Example 14 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl docosanoate is provided;

[0059] Fig.15 The nuclear magnetic resonance spectrum of Example 15 (E)-octadec-9-enoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0060] Fig.16 The nuclear magnetic resonance spectrum of Example 16 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0061] Fig.17 The nuclear magnetic resonance spectrum of Example 17 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yloctyl carbonate is provided;

[0062] Fig.18 The nuclear magnetic resonance spectrum of Example 18 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldecyl carbonate is provided;

[0063] Fig.19 The nuclear magnetic resonance spectrum of Example 19 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl hexadecyl carbonate is provided;

[0064] Fig. 20The nuclear magnetic resonance spectrum of Example 20 (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0065] Fig.21 The nuclear magnetic resonance spectrum of Example 21 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-ylhexadecyl carbonate is provided;

[0066] Fig. 22 The nuclear magnetic resonance spectrum of Example 22 (Z)-docosa-13-enoic acid (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0067] Fig.23 The nuclear magnetic resonance spectrum of Example 23 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yloctyl carbonate is provided;

[0068] Fig.24 The nuclear magnetic resonance spectrum of Example 24 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl dodecyl carbonate is provided;

[0069] Fig.25 The nuclear magnetic resonance spectrum of Example 25 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl tetradecyl carbonate is provided;

[0070] Fig.26The nuclear magnetic resonance spectrum of Example 26 (E)-octadec-9-enoic acid (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided;

[0071] Fig. 27 The nuclear magnetic resonance spectrum of Example 27 (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl tetradecyl carbonate is provided;

[0072] Fig.28 The nuclear magnetic resonance spectrum of Example 28 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yleicosyl carbonate is provided;

[0073] Fig.29 The nuclear magnetic resonance spectrum of Example 29 (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl dodecyl carbonate is provided;

[0074] Fig.30 The nuclear magnetic resonance spectrum of Example 30 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl tridecyl carbonate is provided;

[0075] Fig.31 The nuclear magnetic resonance spectrum of Example 31 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yltetradecyl carbonate is provided;

[0076] Fig.32The nuclear magnetic resonance spectrum of Example 32 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-ylpentadecanyl carbonate is provided;

[0077] Fig.33 The nuclear magnetic resonance spectrum of Example 33 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl octadecyl carbonate is provided;

[0078] Fig.34 The nuclear magnetic resonance spectrum of Example 34 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl hexadecyl carbonate is provided;

[0079] Fig.35 The nuclear magnetic resonance spectrum of Example 35 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl decyl carbonate is provided;

[0080] Fig.36 The nuclear magnetic resonance spectrum of Example 36 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl oleate is provided;

[0081] Fig.37 The nuclear magnetic resonance spectrum of Example 37 (9Z,12Z)-octadec-9,12-dienoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester is provided;

[0082] Fig.38The NMR spectrum of Example 38 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3,3-dimethylbutanoate is provided;

[0083] Fig.39 The nuclear magnetic resonance spectrum of Example 39 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl 3-cyclopentylpropanoate is provided;

[0084] Fig.40 The nuclear magnetic resonance spectrum of Example 40 (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl tert-butyl carbamate is provided;

[0085] Fig.41 The nuclear magnetic resonance spectrum of Example 41 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl oleate is provided;

[0086] Fig.42 The nuclear magnetic resonance spectrum of Example 42 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3,3-dimethylbutanoate is provided;

[0087] Fig.43 The nuclear magnetic resonance spectrum of Example 43 (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3-cyclopentylpropanoate is provided;

[0088] Fig.44 The nuclear magnetic resonance spectrum of Example 44 (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl dodecanoate is provided;

[0089] Fig.45 The nuclear magnetic resonance spectrum of Example 45 tetradecanoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided;

[0090] Fig.46 The nuclear magnetic resonance spectrum of Example 46 hexadecanoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided.

[0091] Fig.47 The nuclear magnetic resonance spectrum of Example 47 (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl hexadecyl carbonate is provided;

[0092] Fig.48 The nuclear magnetic resonance spectrum of Example 48 dodecanoic acid (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided; and

[0093] Fig.49 The nuclear magnetic resonance spectrum of Example 49 hexadecanoic acid (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)oxy)methyl ester is provided. DETAILED DESCRIPTION

[0094] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and the like. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments thereof are intended to be included. When referring to a number or a numerical range, the term "about" indicates that the number or numerical range referred to is an approximation of the experimental variability (or within statistical experimental error), and thus, in some cases, the number or numerical range will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude certain other embodiments, for example, embodiments of any composition of matter, composition, method or process, etc. described herein "consisting of" or "consisting essentially of the described features."

[0095] definition

[0096] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings indicated below.

[0097] "Amino" refers to a -NH2 group.

[0098] "Cyano" refers to a -CN group.

[0099] "Nitro" refers to a -NO2 group.

[0100] "Oxa" refers to an -O- group.

[0101] "Oxo" refers to a =0 group.

[0102] "Thioxo" refers to a =S group.

[0103] "Imino" refers to a =NH group.

[0104] "Oximo" refers to a =N-OH group.

[0105] "Hydrazino" refers to the =N-NH2 radical.

[0106] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C 15In certain embodiments, an alkyl group includes one to thirteen carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group includes one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group includes one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group includes one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group includes one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group includes one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group includes one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group includes five to fifteen carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group includes five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group includes two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group includes three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from: methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each Ra and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0107] "Alkoxy" refers to a group bonded through an oxygen atom of the formula -O-alkyl wherein alkyl is an alkyl chain as defined above.

[0108] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting of only carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and having two to twelve carbon atoms. In certain embodiments, alkenyl includes two to eight carbon atoms. In other embodiments, alkenyl includes two to four carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, for example, vinyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, penta-1-enyl, five-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a)2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0109] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In certain embodiments, the alkynyl group includes two to eight carbon atoms. In other embodiments, the alkynyl group includes two to six carbon atoms. In other embodiments, the alkynyl group includes two to four carbon atoms. The alkynyl group is connected to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R aand R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0110] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group consisting only of carbon and hydrogen, free of unsaturation and having one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butene, etc. The alkylene chain is connected to the rest of the molecule by a single bond and is connected to the group by a single bond. The connection point of the alkylene chain to the rest of the molecule and the group is through a carbon in the alkylene chain or through any two carbons in the chain. In certain embodiments, the alkylene includes one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene includes one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene includes one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene includes one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene includes one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a )2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a)2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0111] "Alkynylidene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a group consisting of only carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond, and is connected to the group by a single bond. In certain embodiments, the alkynylene includes two to eight carbon atoms (e.g., C2-C8 alkynylene). In other embodiments, the alkynylene includes two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, the alkynylene includes two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, the alkynylene includes two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, the alkynylene includes two carbon atoms (e.g., C2 alkylene). In other embodiments, the alkynylene includes five to eight carbon atoms (e.g., C5-C8 alkynylene). In other embodiments, the alkynylene group includes three to five carbon atoms (e.g., C3-C5 alkynylene). Unless otherwise specifically stated in the specification, the alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -OR a 、-SR a 、-OC(O)-R a 、-N(R a)2. -C(O)R a 、-C(O)OR a 、-C(O)N(R a )2、-N(R a )C(O)OR a 、-OC(O)-N(R a )2、-N(R a )C(O)R a 、-N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl).

[0112] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π electron system conforming to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (as in "aralkyl") is intended to include aryl groups optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t ORa (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise specified.

[0113] "Arylalkyl" refers to a group of the formula -R c -aryl radical, wherein R c is an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain portion of the aralkyl is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl is optionally substituted as described above for aryl groups.

[0114] "Aralkenyl" refers to a group of the formula -R d -aryl radical, wherein R d is an alkenylene chain as defined above. The aryl portion of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain portion of the aralkenyl group is optionally substituted as defined above for alkenyl.

[0115] "Arylalkynyl" refers to a group of the formula -R e -aryl radical, wherein R e is an alkynylene chain as defined above. The aryl portion of the aralkynyl group is optionally substituted as described above for aryl groups. The alkynylene chain portion of the aralkynyl group is optionally substituted as defined above for alkynylene chains.

[0116] "Aralkyloxy" refers to a group of the formula -OR c - a group bonded to the oxygen atom of an aromatic group, wherein R cis an alkylene chain as defined above, for example methylene, ethylene, etc. The alkylene chain portion of the aralkyl is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl is optionally substituted as described above for aryl groups.

[0117] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms, which comprises a condensed ring or a bridged ring system and has three to fifteen carbon atoms. In certain embodiments, the carbocyclyl includes three to ten carbon atoms. In other embodiments, the carbocyclyl includes five to seven carbon atoms. The carbocyclyl is connected to the rest of the molecule by a single bond. The carbocyclyl is saturated (i.e., only contains a single C-C bond) or unsaturated (i.e., contains one or more double bonds or triple bonds). Fully saturated carbocyclyl is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Unsaturated carbocyclyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Polycyclic carbocyclyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyls optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(Ra )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise specified.

[0118] "Carbocycloalkyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl are optionally substituted as defined above.

[0119] "Carbocycloalkynyl" refers to a group of the formula -R c -Carbocyclic group, where R c is an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl are optionally substituted as defined above.

[0120] "Carbocycloalkoxy" refers to a cycloalkyl group of the formula -OR c - a group bonded to the oxygen atom of a carbocyclic group, wherein R cis an alkylene chain as defined above. The alkylene chain and the carbocyclyl are optionally substituted as defined above.

[0121] As used herein, "carboxylic acid bioisostere" refers to a functional group or moiety that exhibits physical, biological, and / or chemical properties similar to a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

[0122]

[0123] wait.

[0124] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0125] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as defined above for an alkyl group.

[0126] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, a heterocyclyl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally comprises a fused or bridged ring system. The heteroatoms in the heterocyclyl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclyl is partially or completely saturated. The heterocyclyl is connected to the rest of the molecule through any atom of the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithienyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include a heterocyclyl as described above optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b-OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise specified.

[0127] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl as defined above containing at least one nitrogen and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through the nitrogen atom in the heterocyclyl. N-heterocyclyl is optionally substituted as described above for heterocyclyl. Examples of such N-heterocyclyls include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0128] "C-heterocyclyl" or "C-attached heterocyclyl" refers to a heterocyclyl as defined above containing at least one heteroatom and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl. C-heterocyclyl is optionally substituted as described above for heterocyclyl. Examples of such C-heterocyclyls include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0129] "Heterocycloalkyl" refers to a group of the formula -R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heterocyclylalkyl is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl is optionally substituted as defined above for the heterocyclyl.

[0130] "Heterocycloalkoxy" refers to a heterocycloalkyl group of the formula -OR c - a group bonded to the oxygen atom of a heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally connected to the alkyl at the nitrogen atom. The alkylene chain of heterocycloalkoxy is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of heterocycloalkoxy is optionally substituted as defined above for the heterocyclyl.

[0131] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group comprising two to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π electron system that conforms to the Huckel theory. Heteroaryls include fused rings or bridged ring systems. The heteroatoms in the heteroaryl are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl is connected to the rest of the molecule through any atom of the ring.Examples of heteroaryl groups include, but are not limited to, azacyclyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzothiophenyl), benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a] pyridyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptatrienol[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctanol[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctanol[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctanol[d] d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methanol-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazacyclyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[ 3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and phenylthio (i.e., thienyl).Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as described above, optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a 2. -R b -N(R a 2. -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a 2. -R b -OR c -C(O)N(R a 2. -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R aR is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise specified.

[0132] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through the nitrogen atom in the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0133] "C-heteroaryl" refers to a heteroaryl group as defined above, and wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for a heteroaryl group.

[0134] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl radical, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0135] "Heteroarylalkoxy" refers to a group of the formula -OR c - a group bonded to the oxygen atom of a heteroaryl group, wherein R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl at the nitrogen atom. The alkylene chain of the heteroarylalkoxy is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy is optionally substituted as defined above for the heteroaryl.

[0136] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomeric forms defined as (R)- or (S)- according to absolute stereochemistry. Unless otherwise stated, the present disclosure is intended to contemplate all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain olefin double bonds, unless otherwise stated, the present disclosure is intended to include E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an olefin double bond. The term "positional isomer" refers to structural isomers around a central ring such as ortho-, meta-, and para-isomers around a benzene ring.

[0137] "Tautomer" refers to a molecule in which a proton transfer from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In cases where tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solubility, and pH. Some examples of tautomeric equilibrium include:

[0138]

[0139] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, such as 2 H content. In a specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and or efficacy, thereby increasing the duration of action of the drug.

[0140] In another embodiment, the compounds disclosed herein are 1 Some or all of the H atoms are 2 H atom replacement. Methods for the synthesis of deuterium containing compounds are known in the art and the following synthetic methods are included by way of non-limiting example only.

[0141] Deuterium substituted compounds were synthesized using various methods such as described in Dean, Dennis C.; ed. "Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development" [In: Curr., Pharm. Des., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. "The Synthesis of Radiolabeled Compounds via Organometallic Intermediates", Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. "Synthesis of radiolabeled compounds" compounds), Journal of Radioanalysis and Nuclear Chemistry (J. Radioanal. Chem.), 1981, 64(1-2), 9-32.

[0142] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterated compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0143] Deuterium transfer reagents suitable for nucleophilic substitution reactions, such as iodomethane-d3 (CD3I), are readily available and can be used to transfer a deuterated carbon atom to a reaction substrate under nucleophilic substitution reaction conditions. The use of CD3I is illustrated in the reaction schemes below by way of example only.

[0144]

[0145] Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium to the reaction substrate under reducing conditions. The use of LiAlD4 is illustrated in the reaction schemes below by way of example only.

[0146]

[0147] Deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aromatic carbon-halogen bonds as illustrated by way of example only in the following reaction schemes.

[0148]

[0149] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are fully substituted with deuterium atoms and contain no non-exchangeable 1 H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by a synthetic method using deuterated synthetic building blocks as starting materials.

[0150] "Pharmaceutically acceptable salts" encompass both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the opioid receptor antagonist prodrug compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0151] "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed by organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginates, gluconates, and galacturonates are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to skilled artisans.

[0152] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts can be prepared by the addition of inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0153] As used herein, "treatment" or "treating" or "alleviate" or "improve" are used interchangeably. These terms refer to an approach to obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit is achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk for a particular disease or to a patient reporting one or more of the physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0154] Opioid Receptor Pharmacology

[0155] The opioid receptors μ, δ, κ and the opioid receptor ORL-1 belong to the superfamily of G protein-coupled receptors (GPCRs) that have seven helical transmembrane domains in their architecture. Most of the research efforts focused on this group of proteins have been directed to the μ receptor, as it mediates the effects of, for example, morphine and fentanyl, respectively. However, over the years, it has become increasingly clear that the entire family of proteins is actively involved in many biological processes. Furthermore, the emergence of selective antagonists suggests that there are drug therapeutic opportunities through both negative and positive modulation of this family of receptors.

[0156] The μ (mu, OP3 or MOP) receptor was originally defined and characterized pharmacologically by Martin, Kosterlitz and their colleagues based on the receptor's high affinity and sensitivity to morphine (Martin et al. "The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog," J. Pharmacol. Exp. Ther. (1976), 197:517-532; Kosterlitz et al. "Endogenous opioid peptides: multiple agonists and receptors," Nature (1977) 267:495-499). Endogenous opioids [Met 5 ]-enkephalin, [Leu 5 ]-enkephalin, including octapeptide amide and BAM-18, β-endorphin [Met 5 Extended forms of ]-enkephalin and truncated forms of dynorphins (e.g., dynorphin-(1-9) and the shorter dynorphins) also have affinity for the μ receptor, consistent with the possible role of each of these peptides as a natural ligand for this receptor type, but these endogenous peptides are not selective for the μ receptor. Two putative natural ligands, endomorphin-1 and endomorphin-2, that appear to mediate their effects exclusively through the μ opioid receptor have also been reported to be present in the brain, but genes, precursor proteins, or other mechanisms for the endogenous synthesis of these natural ligands have not been identified.

[0157] μ receptors are distributed throughout the neuraxis. The highest μ receptor density is found in the thalamus, caudate putamen, neocortex, nucleus accumbens, amygdala, interpeduncular complex, and inferior and superior colliculi (Watson et al. "Autoradiographic differentiation of mu, delta and kappa receptors in the rat forebrain and midbrain", Journal of Neuroscience (J. Neurosci.) (1987), 7: 2445-2464). μ receptors as well as delta and kappa receptors are also present in the superficial layers of the dorsal horn of the spinal cord. A moderate density of μ receptors is found in the periaqueductal gray nucleus and the raphe nucleus. These brain regions have a recognized role in pain and analgesia. Other physiological functions regulated by μ receptors include respiratory and cardiovascular function, intestinal transit, feeding, mood, temperature regulation, hormone secretion, and immune function.

[0158] The delta (delta, OP1 or DOP) opioid receptor was defined using a mouse vas deferens preparation, and enkephalins are generally considered to be the preferred endogenous ligands. The delta receptor is discretely distributed in the central nervous system (CNS), with a significant gradient of receptor density, from high levels in forebrain structures to relatively low levels in most hindbrain regions. The highest density is found in the olfactory bulb, neocortex, caudate putamen, nucleus accumbens, and amygdala (Watson et al. "Autoradiographic differentiation of μ, delta, and kappa receptors in the rat forebrain and midbrain", Journal of Neuroscience (1987), 7: 2445-2464). The thalamus and hypothalamus have a moderate density of delta receptors; in more caudal regions, the interpeduncular and pontine nuclei show high binding in rats, but levels are much lower in mice (Kitchen et al. "Quantitative autoradiographic mapping of mu, delta and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene", Brain Res. (1997), 778:73-88). In the spinal cord, delta receptors are present in the dorsal horn, where they play a role in mediating the analgesic effects of delta agonists.

[0159] The kappa (kappa, OP2 or KOP) opioid receptor was originally proposed on the basis of in vivo studies in dogs with ketocyclazocine and related drugs (Martin et al. "Effects of morphine-like and nalorphine-like drugs in non-dependent and morphine-dependent chronically spinal cord injured dogs," Journal of Pharmacology and Experimental Therapeutics (1976), 197:517-532). Subsequent studies have confirmed the presence of this receptor type in other species including the guinea pig, which was the preferred species for many of the early studies on the kappa opioid receptor. Dynorphins A and B and α-neoendorphin appear to be endogenous ligands for the opioid kappa receptor, but shorter peptides derived from prodynorphin have comparable affinity for the μ and kappa receptors. Kappa receptors are mainly localized in the cerebral cortex, nucleus accumbens, claustrum and hypothalamus of rats and mice (Kitchen et al. "Quantitative autoradiography of μ, δ and κ-opioid receptors in knockout mice lacking the μ-opioid receptor gene", Brain Res. (1997), 778:73-88; Watson et al. "Autoradiographic differentiation of μ, δ and κ receptors in the forebrain and midbrain of the rat", Journal of Neuroscience (1987), 7:2445-2464), and are involved in the regulation of nociception, diuresis, feeding, neuroendocrine and immune system functions (Dhawan et al. International Union of Pharmacology. XII. Classification for opioid receptors, Pharmacol. Rev. (1996), 48:567-592).

[0160] The ORL1 receptor (also known as the nociceptin or orphanin FQ receptor) is the youngest member of the opioid receptor family. Agonist-induced ORL1 internalization is rapid and concentration-dependent. Agonist challenge also reduced the ability of ORL1 to couple inhibition of forskolin-stimulated cAMP production, suggesting that ORL1 undergoes a similar desensitization mechanism compared to the other three opioid receptor subtypes.

[0161] The structure of the ORL1 receptor indicates that it has evolved as part of the opioid receptor family. Sequence comparisons with μ, κ, and δ receptors and other similar G protein-coupled receptors (e.g., of the SOM receptor family) indicate that the ORL1 receptor is more closely related to opioid receptors than other types of G protein-coupled receptors (Birgul et al. "Reverse Physiology in drosophila: identification of a novel allatostatin-like neuropeptide and its cognate receptor structurally related to themammalian somatostatin / galanin / opioid receptor family" Journal of the European Molecular Biology Association (EMBO J.) (1999), 18: 5892-5900). In addition, agonists of the ORL1 receptor induce activation of the same set of transduction pathways activated by μ, κ, and δ receptors, and the endogenous ligand ORL1 has considerable sequence homology with dynorphin A and to a lesser extent with enkephalins. Thus, the ORL1 receptor and its endogenous ligands are closely related to the μ, κ, and δ receptors in an evolutionary sense.

[0162] Despite evidence of evolutionary and functional homology, the ORL1 receptor is not an opioid receptor from a pharmacological perspective. The ORL1 receptor has negligible affinity for naloxone and most other μ, κ, or δ receptor antagonists. However, the ORL1 receptor is expressed in many functional systems in which endogenous opioids exert regulatory effects. Although the function of ORL1 is not fully understood, a regulatory function for ORL1 that is parallel to, but not identical to, that of endogenous opioid peptides seems likely. Despite these functional differences, the Subcommittee found the structural relationship between the ORL1 receptor and the μ, δ, and κ receptors to be compelling.

[0163] Compared to the other three opioid receptor subtypes, ORL1 receptor regulation, although increasingly studied, remains in its infancy. To date, few site-directed mutagenesis studies have been performed, and receptor regulation in primary neurons, dorsal root ganglia, or dorsal horn neurons remains unknown.

[0164] An integral part of the effort to characterize the opioid receptor system has been the discovery of potent, pure antagonists of opioid receptors. Nalmefene (1a) and naltrexone (1b) are both competitive antagonists of μ, δ, and κ opioid receptors and have been used as pharmacological tools to identify and characterize the opioid system.

[0165] Nalmefene is an opioid receptor antagonist that has been used for many years. Nalmefene is available in the form of an injectable for reversing opioid effects and opioid overdose. Nalmefene has also been described in the literature for the treatment of substance abuse disorders such as alcohol dependence and abuse and impulse control disorders such as pathological gambling and shopping addiction. Nalmefene is sold in Europe as Selincro as an on-demand oral pill for alcohol abuse. Its IUPAC name is 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol and has the structure provided in formula (1A).

[0166]

[0167] Naltrexone is an opioid receptor antagonist used primarily to treat alcohol and opioid dependence. Naltrexone is sold in its generic form as naltrexone hydrochloride. and It is sold as a 50 mg film-coated tablet. Once-monthly extended-release naltrexone, sold in the United States as Vivitrol, has gained wide acceptance in opioid use disorders due to increased patient compliance. The IUPAC name of naltrexone is 17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one and has the structure provided in Formula (1B).

[0168]

[0169] Low doses of naltrexone have also been studied in patients with multiple sclerosis, autism, active Crohn's disease, AIDS, rheumatoid arthritis, celiac disease, certain forms of cancer, and autoimmune diseases. Opioids act as cytokines, the immune system's primary communication signals, producing immunomodulatory effects through opioid receptors on immune cells. Very low doses of naltrexone have been shown to boost the immune system and help fight diseases characterized by immune deficiencies.

[0170] Pharmacologically, naltrexone blocks the effects of opioids by binding highly competitively to the μ-opioid receptor. However, clinical studies indicate that oral administration of approximately 50 mg of naltrexone is able to block the pharmacological effects of up to 25 mg of intravenously administered heroin for a period of up to twenty-four hours.

[0171] Although preclinical data suggest involvement of the endogenous opioid system, the mechanism of action of naltrexone in treating alcoholism is unclear. Opioid antagonists have been shown to reduce alcohol consumption in animals, and naltrexone has shown efficacy in maintaining abstinence in human clinical studies.

[0172] Opioid receptor antagonist prodrugs

[0173] Although the use of nalmefene and naltrexone to treat alcohol dependence and opioid dependence has brought great benefits to society, the problem with these drugs is that they have a very short duration of action. Thus, for example, naltrexone, which is well absorbed orally (approximately 96% of the oral dose is absorbed from the gastrointestinal tract), undergoes significant first-pass metabolism, with oral bioavailability estimates ranging from 5% to 40%. The activity of naltrexone is believed to be the result of naltrexone and its 6-β-naltrexol metabolite. The other two minor metabolites are 2-hydroxy-3-methoxy-6-β-naltrexol and 2-hydroxy-3-methyl-naltrexone. The peak plasma levels of naltrexone and 6-β-naltrexol occur within one hour after oral administration; the average elimination half-life values ​​for naltrexone and 6-β-naltrexol are four hours and thirteen hours, respectively. Even with long-acting naltrexone injections, clinicians instruct patients to stop treatment prematurely. Therefore, ultra-long-acting opioid antagonists for treating drug abuse disorders are needed.

[0174] One of the solutions to overcome the problem of short duration of action of nalmefene and naltrexone is to use prodrugs which provide long, sustained and controlled release of the nalmefene and naltrexone opioid receptor antagonists when administered into the body.

[0175] As used in the present disclosure, the term "prodrug" means a compound that is converted into nalmefene or naltrexone under physiological conditions. In some embodiments, the prodrug is inactive when administered to a subject, but is converted into an active compound in vivo, such as by hydrolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable precursor compound, and in some embodiments, there is no pharmacological property of nalmefene or naltrexone. Prodrug compounds generally provide advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgard, H., "Prodrug Design (Design of Prodrugs)" (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0176] Higuchi, T. et al., "Pro-drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and "Bioreversible Carriers in Drug Design," ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 provide a discussion of prodrugs.

[0177] The term "prodrug" is also intended to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. As described herein, prodrugs of nalmefene or naltrexone are prepared by modifying functional groups present in the active compound in such a manner that the modifications are cleaved to the parent active compound. Prodrugs include compounds in which a hydroxyl group is bonded to any group that cleaves to form a free hydroxyl group when the prodrug of the active compound is administered to a mammalian subject.

[0178] Provided herein are prodrugs of the opioid receptor antagonists nalmefene and naltrexone.

[0179] In another aspect, the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which has a structure provided in formula (II),

[0180]

[0181] in,

[0182] X is O or CH2;

[0183] R is

[0184] Where R 1 C4-C 10 Alkyl or C4-C 10 and n is 7 to 15; provided that if X is O, then n is not 7.

[0185] In some embodiments, X is O. In some embodiments, X is CH2.

[0186] In some embodiments, R 1 C4-C 10 Alkyl or C4-C 10 Alkenyl.

[0187] In some embodiments, R 1 C4-C10 In some embodiments, R 1 is a C4-C5 alkyl group. 1 is a C4-C6 alkyl group. 1 is a C4-C7 alkyl group. 1 is a C4-C8 alkyl group. 1 is a C4-C9 alkyl group. 1 is a C5-C6 alkyl group. 1 is a C5-C7 alkyl group. 1 is a C5-C8 alkyl group. 1 is a C5-C9 alkyl group. 1 C5-C 10 In some embodiments, R 1 is a C6-C7 alkyl group. In some embodiments, R 1 is a C6-C8 alkyl group. 1 is a C6-C9 alkyl group. 1 C6-C 10 In some embodiments, R 1 is a C7-C8 alkyl group. 1 is a C7-C9 alkyl group. 1 For C7-C 10 In some embodiments, R 1 is a C8-C9 alkyl group. 1 For C8-C 10 In some embodiments, R 1 For C9-C 10 In some embodiments, R 1 is a C4 alkyl group. In some embodiments, R 1 is a C5 alkyl group. In some embodiments, R 1 is a C6 alkyl group. In some embodiments, R 1 is a C7 alkyl group. 1 is a C8 alkyl group. In some embodiments, R 1 is a C9 alkyl group. In some embodiments, R 1 C 10 alkyl.

[0188] In some embodiments, R 1 C4-C 10 In some embodiments, R 1is C4-C5 alkenyl. In some embodiments, R 1 is C4-C6 alkenyl. In some embodiments, R 1 is C4-C7 alkenyl. In some embodiments, R 1 is C4-C8 alkenyl. In some embodiments, R 1 is C4-C9 alkenyl. In some embodiments, R 1 is C5-C6 alkenyl. In some embodiments, R 1 is C5-C7 alkenyl. In some embodiments, R 1 is C5-C8 alkenyl. In some embodiments, R 1 is C5-C9 alkenyl. In some embodiments, R 1 C5-C 10 In some embodiments, R 1 is C6-C7 alkenyl. In some embodiments, R 1 is C6-C8 alkenyl. In some embodiments, R 1 is C6-C9 alkenyl. In some embodiments, R 1 C6-C 10 In some embodiments, R 1 is C7-C8 alkenyl. In some embodiments, R 1 is C7-C9 alkenyl. In some embodiments, R 1 For C7-C 10 In some embodiments, R 1 is C8-C9 alkenyl. In some embodiments, R 1 For C8-C 10 In some embodiments, R 1 For C9-C 10 In some embodiments, R 1 is C4 alkenyl. In some embodiments, R 1 is a C5 alkenyl group. 1 is a C6 alkenyl group. 1 is C7 alkenyl. In some embodiments, R 1 In some embodiments, R 1 is a C9 alkenyl group. 1 C 10 Alkenyl.

[0189] In some embodiments, n is 7-15. In some embodiments, n is 7-8. In some embodiments, n is 7-9. In some embodiments, n is 7-10. In some embodiments, n is 7-11. In some embodiments, n is 7-12. In some embodiments, n is 7-13. In some embodiments, n is 7-14. In some embodiments, n is 8-9. In some embodiments, n is 8-10. In some embodiments, n is 8-11. In some embodiments, n is 8-12. In some embodiments, n is 8-13. In some embodiments, n is 8-14. In some embodiments, n is 8-15. In some embodiments, n is 9-10. In some embodiments, n is 9-11. In some embodiments, n is 9-12. In some embodiments, n is 9-13. In some embodiments, n is 9-14. In some embodiments, n is 9-15. In some embodiments, n is 10-11. In some embodiments, n is 10-12. In some embodiments, n is 10-13. In some embodiments, n is 10-14. In some embodiments, n is 10-15. In some embodiments, n is 11-12. In some embodiments, n is 11-13. In some embodiments, n is 11-14. In some embodiments, n is 11-15. In some embodiments, n is 12-13. In some embodiments, n is 12-14. In some embodiments, n is 12-15. In some embodiments, n is 13-14. In some embodiments, n is 13-15. In some embodiments, n is 14-15.

[0190] In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15.

[0191] On the other hand, the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which has a structure provided in formula (IIa),

[0192]

[0193] in,

[0194] X is O or CH2;

[0195] R is:

[0196]

[0197] Where R 1 C4-C 10 Alkyl or C4-C10 alkenyl; and n is 9-15.

[0198] In some embodiments, X is O. In some embodiments, X is CH2.

[0199] In some embodiments, R 1 C4-C 10 Alkyl or C4-C 10 Alkenyl.

[0200] In some embodiments, R 1 C4-C 10 In some embodiments, R 1 is a C4-C5 alkyl group. 1 is a C4-C6 alkyl group. 1 is a C4-C7 alkyl group. 1 is a C4-C8 alkyl group. 1 is a C4-C9 alkyl group. 1 is a C5-C6 alkyl group. 1 is a C5-C7 alkyl group. 1 is a C5-C8 alkyl group. 1 is a C5-C9 alkyl group. 1 C5-C 10 In some embodiments, R 1 is a C6-C7 alkyl group. In some embodiments, R 1 is a C6-C8 alkyl group. 1 is a C6-C9 alkyl group. 1 C6-C 10 In some embodiments, R 1 is a C7-C8 alkyl group. 1 is a C7-C9 alkyl group. 1 For C7-C 10 In some embodiments, R 1 is a C8-C9 alkyl group. 1 For C8-C 10 In some embodiments, R 1 For C9-C 10 In some embodiments, R 1 is a C4 alkyl group. In some embodiments, R 1 is a C5 alkyl group. In some embodiments, R 1is a C6 alkyl group. In some embodiments, R 1 is a C7 alkyl group. 1 is a C8 alkyl group. In some embodiments, R 1 is a C9 alkyl group. In some embodiments, R 1 C 10 alkyl.

[0201] In some embodiments, R 1 C4-C 10 In some embodiments, R 1 is C4-C5 alkenyl. In some embodiments, R 1 is C4-C6 alkenyl. In some embodiments, R 1 is C4-C7 alkenyl. In some embodiments, R 1 is C4-C8 alkenyl. In some embodiments, R 1 is C4-C9 alkenyl. In some embodiments, R 1 is C5-C6 alkenyl. In some embodiments, R 1 is C5-C7 alkenyl. In some embodiments, R 1 is C5-C8 alkenyl. In some embodiments, R 1 is C5-C9 alkenyl. In some embodiments, R 1 C5-C 10 In some embodiments, R 1 is C6-C7 alkenyl. In some embodiments, R 1 is C6-C8 alkenyl. In some embodiments, R 1 is C6-C9 alkenyl. In some embodiments, R 1 C6-C 10 In some embodiments, R 1 is C7-C8 alkenyl. In some embodiments, R 1 is C7-C9 alkenyl. In some embodiments, R 1 For C7-C 10 In some embodiments, R 1 is C8-C9 alkenyl. In some embodiments, R 1 For C8-C 10 In some embodiments, R 1 For C9-C 10 In some embodiments, R 1 is C4 alkenyl. In some embodiments, R 1 is a C5 alkenyl group. 1 is a C6 alkenyl group. 1 is C7 alkenyl. In some embodiments, R1 In some embodiments, R 1 is a C9 alkenyl group. 1 C 10 Alkenyl.

[0202] In some embodiments, n is 9-15. In some embodiments, n is 9-10. In some embodiments, n is 9-11. In some embodiments, n is 9-12. In some embodiments, n is 9-13. In some embodiments, n is 9-14. In some embodiments, n is 10-11. In some embodiments, n is 10-12. In some embodiments, n is 10-13. In some embodiments, n is 10-14. In some embodiments, n is 10-15. In some embodiments, n is 11-12. In some embodiments, n is 11-13. In some embodiments, n is 11-14. In some embodiments, n is 11-15. In some embodiments, n is 12-13. In some embodiments, n is 12-14. In some embodiments, n is 12-15. In some embodiments, n is 13-14. In some embodiments, n is 13-15. In some embodiments, n is 14-15.

[0203] In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15.

[0204] In another aspect, the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which has a structure provided in formula (III),

[0205]

[0206] in,

[0207] X is O or CH2;

[0208] R is selected from:

[0209] -[CH(R 3 )O]zR 4 ;

[0210] -[CH(R 3 )O]zC(=O)OR 4 ;

[0211] -[CH(R 3 )O]zC(=O)NR 4 R 5 ;as well as

[0212] -[CH(R 3 )O]zP(=O)(OR 4 )(OR 5 );

[0213] Where z is 1, 2, 3, 4, 5, 6 or 7;

[0214] R 3 is hydrogen, halogen, alkyl, alkenyl, cycloalkylalkyl or aryl;

[0215] Each R 4 and R 5 are independently selected from hydrogen, alkyl, alkenyl, cycloalkylalkyl or aryl.

[0216] In some embodiments, X is O. In some embodiments, X is CH2.

[0217] In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. In some embodiments, z is 4. In some embodiments, z is 5. In some embodiments, z is 6. In some embodiments, z is 7. In some embodiments, z is 1 or 2. In some embodiments, z is 2 or 3. In some embodiments, z is 1, 2, or 3.

[0218] In some embodiments, R 3 is hydrogen, halogen or alkyl. In some embodiments, R 3 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is hydrogen, halogen, alkyl, cycloalkylalkyl or aryl. 3 is hydrogen, halogen, cycloalkylalkyl or aryl. In some embodiments, R 3 In some embodiments, the halogen is fluorine.

[0219] In some embodiments, each R 4 and R 5 In some embodiments, each R 4 and R 5 In some embodiments, each R 4 and R 5 In some embodiments, the alkyl group is C 10 -C 18 In some embodiments, the alkyl group is a C5-C9 alkyl group. In some embodiments, the alkyl group is a C1-C4 alkyl group. In some embodiments, the alkyl group is a C9-C 13 In some embodiments, the alkyl group is C 10 -C12 In some embodiments, the alkyl group is C 10 In some embodiments, the alkyl group is C 11 In some embodiments, the alkyl group is C 12 alkyl.

[0220] In some embodiments, R is: -[CH(R 3 )O]zR 4 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 In some embodiments, R is: -[CH(R 3 )O]zC(=O)NR 4 R 5 In some embodiments, R is: -[CH(R 3 )O]zP(=O)(OR 4 )(OR 5 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 , where R 3 is hydrogen, and R 4 For C9-C 13 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 , where R 3 is hydrogen, and R 4 C 10 -C 12 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 , where R 3 is hydrogen, and R 4 C 10 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 , where R 3 is hydrogen, and R 4 C 11 In some embodiments, R is: -[CH(R 3 )O]zC(=O)OR 4 , where R 3 is hydrogen, and R 4 C 12 alkyl.

[0221] In some embodiments, the opioid receptor antagonist prodrug compounds described herein have the structures provided in Table 1.

[0222] Table 1

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232] In some embodiments, the opioid receptor antagonist prodrug compounds described herein have the structures provided in Table 2.

[0233] Table 2

[0234]

[0235]

[0236]

[0237] Preparation of compounds

[0238] Compounds for use in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" were obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical Company (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (Westchester, PA), Crescent Chemical Co. (Hopaugh, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Technologies Inc. (Washington, D.C.), Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cornwall, England), Lancaster Synthesis (Windham, New Hampshire), Maybridge Chemical Co. Ltd. (Cornwall, England), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Connecticut), Polyorganix (Houston, Texas), Pierce Chemical Co. (Rockford, Illinois), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc.) (New Brunswick, N.J.), TCI America (Portland, Ore.), Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).

[0239] Suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations", 2nd edition, Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd edition, W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd edition, John Wiley & Sons, Inc., New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structures", 2nd edition, John Wiley & Sons, Inc., New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structures", 2nd edition, John Wiley & Sons, Inc., New York, 1992; Chemistry: Mechanisms, and Structure", 4th edition, Wiley-Interscience, New York, 1992. Additional suitable reference books and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein or providing references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", 2nd Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC"Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd edition (1999) Wiley-VCH Publishing Company, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms and Structures" 4th edition (1992) John Wiley & Sons Publishing Company, ISBN: 0-471-60180-2; Otera, J. (ed.) "Modern Carbonyl Chemistry" (2000) Wiley-VCH Publishing Company, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups) (1992) International Science Press (Interscience) ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, "Intermediate Organic Chemistry" 2nd edition (1993) Wiley-International Science Press (Wiley-Interscience), ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, a total of 8 volumes; "Organic Reactions" Reactions" (1942-2000) John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0240] Specific and similar reactants are optionally identified by indexing known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most libraries and university libraries and through online-databases (contact the American Chemical Society in Washington, DC for more details). Chemicals known in the catalog but not commercially available are optionally prepared by custom chemical synthesis companies, many of which standard chemical supply companies (e.g., the companies listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the opioid receptor antagonist prodrug compounds described herein is P. H. Stahl & C. G. Wermuth, Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0241] Pharmaceutical composition

[0242] In certain embodiments, the opioid receptor antagonist prodrug compounds described herein are administered in the form of pure chemicals. In other embodiments, the opioid receptor antagonist prodrug compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practice as described in the following literature: for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005)).

[0243] Provided herein is a pharmaceutical composition comprising at least one opioid receptor antagonist prodrug compound or a stereoisomer thereof, a pharmaceutically acceptable salt, a hydrate, a solvate or an N-oxide, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and is harmless to the recipient (i.e., subject) of the composition.

[0244] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of formula (II), (IIa) or (III) or a compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, the opioid receptor antagonist prodrug compound as described by any one of Formula (II), (IIa) or (III) or the compounds disclosed in Table 1 is substantially pure in that it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis byproducts generated, for example, in one or more steps of the synthesis method.

[0246] Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose or another suitable material that dissolves easily in the digestive tract. In some embodiments, a suitable non-toxic solid carrier is used, the carrier comprising, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Easton, Pennsylvania, Mack Publishing Company (2005)).

[0247] In some embodiments, the opioid receptor antagonist prodrug compound as described in any one of formula (II), (IIa) or (III) or the compounds disclosed in Table 1 are formulated for administration by injection. In some cases, the injection formulation is an aqueous formulation. In some cases, the injection formulation is a non-aqueous formulation. In some cases, the injection formulation is an oil-based formulation such as sesame oil, cottonseed oil, etc.

[0248] The dosage of the composition including at least one opioid receptor antagonist prodrug compound as described herein varies depending on the condition of the patient (eg, human), ie, general health, age, and other factors.

[0249] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). Suitable dosage, suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient and the method of administration. Typically, suitable dosage and treatment regimen provide one or more compositions in an amount sufficient to provide treatment and / or prevention benefits (e.g., clinical outcome improvement, such as complete or partial remission more frequently, or disease-free and / or overall survival longer or symptom severity reduction). Optimal dose is typically determined using experimental models and / or clinical trials. Optimal dose depends on the patient's body mass, body weight or blood volume.

[0250] Dosing and treatment regimen

[0251] In some embodiments, the pharmaceutical compositions described herein are administered for therapeutic applications. In some embodiments, the pharmaceutical compositions are administered once a day, twice a day, three times a day, four times a day or more. The pharmaceutical compositions are administered daily, daily, every other day, two days a week, three days a week, four days a week, five days a week, once a week, every other week, two weeks a month, three weeks a month, once a month, twice a month, three times a month or other more or less interval frequencies; in addition, the pharmaceutical compositions may be administered once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, once a year or with greater than or less than the above-mentioned interval frequencies. The pharmaceutical compositions are administered in at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 18 months, 2 years, 3 years or longer.

[0252] In cases where the patient's condition does not improve, administration of the composition is continued at the physician's discretion; alternatively, the dose of the administered composition is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). In some cases, the length of the drug holiday ranges from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, 365 days, or 366 days. The dosage reduction during the drug holiday is 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0253] Once the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dose or frequency of administration, or both, may be adjusted, based on the symptoms, to a level that retains the improved disease, disorder or condition.

[0254] In some embodiments, the amount of a given opioid receptor antagonist prodrug compound varies depending on factors such as the specific compound, the severity of the disease, the characteristics of the subject or host to be treated (e.g., body weight), but is nevertheless determined routinely in a manner known in the art according to the specific circumstances surrounding the case (including, for example, the specific agent being administered, the route of administration, and the subject or host being treated). In some cases, the desired dose is conveniently provided in a single dose, or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example two, three, four or more sub-doses per day.

[0255] In some embodiments, the amount of a given opioid receptor antagonist prodrug compound will generally be in the range of about 0.02 mg to about 5000 mg per dose. (Note: All prodrug masses are expressed in terms of base moiety equivalents). In some embodiments, the amount of a given opioid receptor antagonist prodrug compound is in the range of about 1 mg to about 5000 mg per dose. In some embodiments, the amount of a given opioid receptor antagonist prodrug compound is in the range of about 10 mg to about 1600 mg per dose. The desired dose can be conveniently provided in a single dose form, or in divided doses administered simultaneously (or in a short period of time) or at appropriate intervals, such as two, three, four or more sub-doses per day.

[0256] In some embodiments, the daily dose suitable for the opioid receptor antagonist prodrug compounds described herein is about 0.01 mg / kg to about 30 mg / kg. In one embodiment, the daily dose is about 0.1 mg / kg to about 165 mg / kg. The indicated daily dose of larger mammals including but not limited to humans is in the range of about 0.5 mg to about 1000 mg, conveniently administered in single doses or divided doses. Suitable unit dosage forms for intramuscular administration include about 1 to about 5000 mg of active ingredient. In one embodiment, the unit dose is about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, about 1000 mg, about 2000 mg, about 2500 mg, about 4000 mg or about 5000 mg.

[0257] The foregoing ranges are only suggestive, as the number of variables regarding a single treatment regimen is large, and considerable deviations from these recommended values ​​are not uncommon. Such dosages vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the practitioner.

[0258] Treatment of behavioral disorders

[0259] In some embodiments, described herein are methods of treating one or more medical conditions in a subject in need thereof, the methods comprising administering to the subject in need thereof an opioid receptor antagonist compound described herein.

[0260] In some embodiments, the medical condition is selected from the group consisting of opioid dependence, alcohol dependence, drug addiction, polydrug addiction, and pain.

[0261] In some embodiments, described herein are opioid receptor antagonist compounds for use in reducing opioid consumption in patients suffering from opioid dependence.

[0262] In some embodiments, described herein are opioid receptor antagonist compounds for use in reducing alcohol consumption in patients suffering from alcohol dependence, pathological gambling, shopping addiction, or other compulsive behavioral disorders.

[0263] Provided herein is a method for treating opioid dependence in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising a compound of Formula (II), (IIa) or (III) or a compound disclosed in Table 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Provided herein is a method wherein the pharmaceutical composition is administered orally. Provided herein is a method wherein the pharmaceutical composition is administered by injection. Provided herein is a method wherein the pharmaceutical composition is administered by intramuscular injection. Provided herein is a method wherein the intramuscular injection is a depot injection. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of 2 days to 3 months. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 2 days. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 4 days. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 7 days. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 10 days. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 1 week. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 2 weeks. Provided herein is a method wherein the depot injection provides a therapeutically effective concentration for a period of about 3 weeks. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 4 weeks. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 5 weeks. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 6 weeks. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 1 month. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 2 months. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 3 months. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 4 months. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 5 months. Provided herein are methods wherein depot injection provides a therapeutically effective concentration for a period of about 6 months or longer.

[0264] Provided herein is a method of treating opioid dependence in a patient in need thereof, the method comprising administering a pharmaceutical composition comprising a compound disclosed in Table 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0265] Table 3

[0266]

[0267]

[0268] Other embodiments and uses will be apparent to those skilled in the art from this disclosure.The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0269] Examples

[0270] I. Chemical Synthesis

[0271] Unless otherwise stated, reagents and solvents received from commercial suppliers were used. Synthetic transformations sensitive to moisture and / or oxygen were performed using anhydrous solvents and oven-dried glassware. Yields were not optimized. Reaction times are approximate and not optimized. Unless otherwise stated, column chromatography and thin layer chromatography (TLC) were performed on silica gel. Spectra are given in ppm (δ), and coupling constants J are reported in Hertz. For proton spectra, solvent peaks were used as reference peaks.

[0272] In some embodiments, the opioid receptor antagonist prodrug compounds disclosed herein are synthesized according to the following examples.

[0273] General scheme 1 for the synthesis of nalmefene prodrugs.

[0274]

[0275] Solution 1

[0276] General scheme 2 for the synthesis of naltrexone prodrugs.

[0277]

[0278] Solution 2

[0279] Example 1: Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ((E)-octadec-9-en-1-yl) carbonate

[0280]

[0281] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (8 g, 21.28 mmol, 1 eq, HCl) in H2O (100 mL) was added K2CO3 (8.82 g, 63.85 mmol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 min. To a mixture of tetrabutylammonium sulfate (24.73 g, 21.28 mmol, 24.49 mL, 50% solution, 1 eq) in DCM (100 mL) was added the latter mixture to the former mixture. (E)-octadec-9-ene-1-yl iodomethyl carbonate (14.44 g, 31.92 mmol, 1.5 equivalents) obtained according to the procedure described in Example 42B was added, and the mixture was stirred for 12 hours. The residue was concentrated in a vacuum to remove DCM, and then dissolved with saturated NaHCO solution (100 mL). The aqueous phase was extracted with 600 mL (200 mL*3) of ethyl acetate. The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated in a vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1 to 1 / 1). The residue was further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation was selected as the method, and the separation system was TFA. NaHCO was added and the pH was adjusted to about 8, and the aqueous phase was extracted with 900 mL (300 mL*3) of ethyl acetate. The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in a vacuum. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl [(E)-octadecan-9-enyl] carbonate (5 g, 7.46 mmol, 35.03% yield) was obtained as a yellow oil. + =665.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 1 .

[0282] Example 2: Step 2A: Synthesis of (4-nitrophenyl) undecyl carbonate

[0283]

[0284] To a mixture of undecane-1-ol (40g, 232.14mmol, 1 equivalent) in DCM (600mL) was added TEA (46.98g, 464.29mmol, 64.62mL, 2 equivalents), chloroformic acid (4-nitrophenyl) ester (70.19g, 348.22mmol, 1.5 equivalents) was added to the previous mixture in batches under N2. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography. The compound (4-nitrophenyl) undecyl carbonate (33.95g, 100.62mmol, 43.34% yield) was obtained as a yellow solid.

[0285] Step 2B: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl undecyl carbonate

[0286]

[0287] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (15 g, 39.70 mmol, 1 eq, HCl) in DCM (150 mL) was added TEA (12.05 g, 119.09 mmol, 16.58 mL, 3 eq) at 25°C under N2. The mixture was stirred at 25°C for 30 minutes. To a mixture of (4-nitrophenyl) undecyl carbonate (26.79 g, 79.39 mmol, 2 eq) in DCM (150 mL) was added and then to the previous mixture and the mixture was stirred at 25°C for 12 hours. The residue is concentrated in vacuo to remove DCM, and then dissolved with saturated NaHCO3 solution. The aqueous phase is extracted with ethyl acetate (200mL*3). The combined organic phase is dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=40:1 to 1:1). The residue is further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation is selected as the method, and the separation system is TFA. NaHCO3 is added to adjust the pH to about 8, and the aqueous phase is extracted with ethyl acetate (200mL*3). The combined organic phase is washed with brine (500mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]undecyl carbonate (7.91 g, 14.63 mmol, 36.85% yield) was obtained as a yellow oil. + =540.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 2 .

[0288] Example 3: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl undecyl carbonate

[0289]

[0290] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (15 g, 39.91 mmol, 1 eq, HCl) in DCM (150 mL) was added TEA (12.11 g, 119.72 mmol, 16.66 mL, 3 eq) at 25°C under N2. The mixture was stirred at 25°C for 30 minutes. To a mixture of (4-nitrophenyl) undecyl carbonate (26.93 g, 79.81 mmol, 2 eq) in DCM (150 mL) was added and then to the previous mixture and the mixture was stirred at 25°C for 12 hours. The mixture was diluted with H2O (800mL) and extracted with DCM (300mL*3). The organic phase was washed with brine (300mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=40 / 1 to 1 / 1). The residue was further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation was selected as the method, and the separation system was TFA. NaHCO3 was added to adjust the pH to about 8, and the aqueous phase was extracted with ethyl acetate (200mL*3). The combined organic phase was washed with brine (500mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]undecyl carbonate (11.40 g, 21.14 mmol, 52.97% yield) was obtained as a yellow oil. + =538.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 3 .

[0291] Example 4: Step 4A: Synthesis of undecyl chloromethyl carbonate

[0292]

[0293] To a mixture of undecane-1-ol (80g, 464.29mmol, 1 equivalent) and pyridine (73.45g, 928.58mmol, 74.95mL, 2 equivalents) in DCM (600mL) was added dropwise chloromethyl chloroformate (119.73g, 928.58mmol, 82.57mL, 2 equivalents) under N2 at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with 1500mL (500mL*3) DCM. The organic phase was separated, washed with 30mL (150mL*2) of brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 1:1). Compound chloromethyl carbonate undecyl ester (80g, 302.13mmol, 65.07% yield) was obtained as a yellow oil.

[0294] Step 4B: Synthesis of iodomethyl carbonate undecyl ester

[0295]

[0296] To a mixture of chloromethyl carbonate undecyl ester (30 g, 113.30 mmol, 1 eq.) in acetone (400 mL) was added NaHCO (11.42 g, 135.96 mmol, 5.29 mL, 1.2 eq.) and NaI (20.38 g, 135.96 mmol, 1.2 eq.) at 25 °C under N2. The mixture was stirred in the dark at 25 °C for 12 hours. The reaction mixture was distributed between EtOAc (400 mL) and H2O (400 mL). The organic phase was separated, washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0). The compound iodomethyl carbonate undecyl ester (60 g, 74.33% yield) was obtained as a yellow oil.

[0297] Step 4C: Synthesis of (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate undecyl ester

[0298]

[0299] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one (8 g, 21.17 mmol, 1 eq, HCl) in H2O (40 mL) was added K2CO3 (8.78 g, 63.52 mmol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 min. Tetrabutylammonium sulfate (24.60 g, 21.17 mmol, 24.36 mL, 50% solution, 1 eq) in DCM (40 mL) was then added in one portion at 25° C. Then iodomethyl carbonate undecyl ester (15.08g, 42.34mmol, 2 equivalents) was added to the mixture, and the mixture was stirred at 25°C for 11.5 hours. The reaction mixture was distributed between 200mL (100mL*2) DCM and 100mL H2O. The organic phase was separated, washed with 40mL brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 1:1). It was then further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation was selected as the method, and the separation system was TFA. NaHCO3 was added to adjust the pH to about 8, the aqueous phase was extracted with ethyl acetate (400mL*3), washed with 300mL brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl undecyl carbonate (6.9 g) was obtained as a yellow oil. + =570.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 4 .

[0300] Example 5: Synthesis Example 5: (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate undecyl ester

[0301]

[0302] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol (8 g, 21.28 mmol, 1 eq, HCl) in H2O (40 mL) was added K2CO3 (8.82 g, 63.85 mmol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 min. Tetrabutylammonium sulfate (24.73 g, 21.28 mmol, 24.49 mL, 50% solution, 1 eq) in DCM (40 mL) was then added in one portion at 25° C. Then iodomethyl carbonate undecyl ester (15.16g, 42.57mmol, 2 equivalents) was added to the mixture, and the mixture was stirred at 25°C for 11.5 hours. The reaction mixture was distributed between 200mL (100mL*2) DCM and 100mL H2O. The organic phase was separated, washed with 50mL brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=50 / 1 to 1:1). It was then further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation was selected as the method, and the separation system was TFA. NaHCO3 was added to adjust the pH to about 8, the aqueous phase was extracted with ethyl acetate (400mL*3), washed with 300mL brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl undecyl carbonate (5.9 g) was obtained as a yellow oil. + =568.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 5 .

[0303] Example 6: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl dodecyl carbonate

[0304]

[0305] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.5 g; 1 H NMR (400MHz, CDCl3): see Figure 6. Briefly, TEA (2.02 g, 19.95 mmol, 2.78 mL, 3 eq.) and dodecyl chloroformate (2.48 g, 9.98 mmol, 1.5 eq.) were added to a mixture of (3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methylbenzofurano[3,2-e]isoquinoline-4a,9-diol (2.5 g, 6.65 mmol, 1 eq., HCl) in DCM (10 mL). The mixture was stirred at -10 °C for 1 hour and then warmed to 25 °C under N2 for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1:1). The compound [(4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldodecyl carbonate] had a purity of 98.570% and was obtained as a yellow oil (1.5 g, 40.56% yield).

[0306] Example 7: Step 7A: Synthesis of (E)-octadec-9-en-1-yl chloromethyl carbonate

[0307]

[0308] Under N2 at 0 ° C to (E)-octadecyl-9-ene-1-ol (22g, 81.94mmol, 1 equivalent) and chloromethyl chloroformate (21.13g, 163.89mmol, 14.57mL, 2 equivalents) in DCM (200mL) in the mixture of pyridine (16.20g, 204.86mmol, 16.54mL, 2.5 equivalents). The reaction was stirred at 25 ° C for 12 hours under N2. The reaction mixture was quenched by adding 400mL H2O, and extracted with 400mL*1DCM. The organic layer merged was washed with 300mL brine, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain oil. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0) to obtain the product. The compound (E)-octadec-9-en-1-yl chloromethyl carbonate (50 g, 138.52 mmol, 84.52% yield) was obtained as a colorless oil.

[0309] Step 7B: Synthesis of (E)-octadec-9-en-1-yl iodomethyl carbonate

[0310]

[0311] Under N2 at 25 ℃ to the mixture of carbonic acid (E)-octadecyl-9-ene-1-yl chloromethyl ester (30g, 83.11mmol, 1 equivalent) and NaI (18.69g, 124.67mmol, 1.5 equivalents) in acetone (300mL) once add NaHCO3 (8.38g, 99.73mmol, 3.88mL, 1.2 equivalents). The mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 500mL H2O and extracted with 800mL (400mL*2) EtOAc. The combined organic layer was washed with 400mL NaCl aqueous solution, dried, filtered and concentrated under reduced pressure to obtain the target product. The compound (E)-octadeca-9-en-1-yl iodomethyl carbonate (29 g, 64.10 mmol, 77.13% yield) was obtained as a pale yellow oil and used in the next step without further purification.

[0312] Step 7C: Synthesis of (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ((E)-octadec-9-en-1-yl) carbonate

[0313]

[0314] To a mixture of (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one; hydrochloride (8 g, 21.17 mmol, 1 eq) and KCO (8.78 g, 63.52 mmol, 3 eq) in H0 (200 mL) was stirred at 25° C. for 0.5 h. Tetrabutylammonium sulfate (12.30 g, 21.17 mmol, 12.18 mL, 1 eq) in DCM (200 mL) was added to the mixture and stirred at 25° C. for 0.5 h. (E)-octadecyl-9-ene-1-yl iodomethyl carbonate (14.37g, 31.76mmol, 1.5 equivalents) is added to mixture, and stirred for 11 hours.Reactant mixture is concentrated under reduced pressure to remove DCM.By residue H o (300mL) dilution, and extract with EtOAc (300mL*3).The organic layer NaCl aqueous solution (300mL) merged is washed, through Na sO dry, filter and concentrate under reduced pressure to obtain residue.The crude product is passed through column chromatography (SiO , petroleum ether / ethyl acetate=10 / 1 to 3: 1) purify to obtain target product. The compound [(3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl [(E)-octadec-9-enyl] carbonate (8.08 g, 12.09 mmol, 57.12% yield) was obtained as a colorless oil. + =666.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 7 .

[0315] Example 8: Synthesis of (E)-octadec-9-enoic acid (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0316]

[0317] To a mixture of (E)-octadec-9-enoic acid (6.28 g, 22.23 mmol, 1.2 eq) in DCM (100 mL) was added DMF (264.03 mg, 3.61 mmol, 277.93 uL, 0.195 eq) and oxalyl chloride (8.46 g, 66.69 mmol, 5.84 mL, 3.6 eq) in portions at 25 °C under N2. The mixture was stirred at 25 °C for 30 minutes and then concentrated under reduced pressure. DCM (100 mL) was added to the residue. To a mixture of (3R, 4aS, 7aR, 12bS) -3- (cyclopropylmethyl) -4a, 9- dihydroxy -2, 4, 5, 6, 7a, 13- hexahydro -1H- 4, 12-methanobenzofurano [3, 2-e] isoquinolin-7-one (7g, 18.53mmol, 1 eq, HCl) in DCM (100mL) was added TEA (3.75g, 37.05mmol, 5.16mL, 2 eq), and then the former mixture was added to the latter mixture in batches at 25°C under N2. The mixture was stirred at 25°C for 12 hours. The residue was concentrated in vacuo to remove DCM and then dissolved with saturated NaHCO3 solution (200mL). The aqueous phase was extracted with ethyl acetate (100mL * 2). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=40 / 1 to 1 / 1). The compound [(E)-octadec-9-enoic acid (3R, 4aS, 7aR, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester] (5.36 g, 8.11 mmol, 43.79% yield) was obtained as a yellow oil. + =606.2 (LCMS). 1 H NMR (400MHz, CDCl3): see Figure 8 .

[0318] Example 9: Synthesis of (E)-octadec-9-enoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0319]

[0320] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (10 g, 26.60 mmol, 1 eq, HCl) in H2O (100 mL) was added K2CO3 (11.03 g, 79.81 mmol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 min. To a mixture of tetrabutylammonium sulfate (30.91 g, 26.60 mmol, 30.61 mL, 50% solution, 1 eq) in DCM (100 mL) was added the latter mixture to the former mixture. (E)-octadecyl-9-enoic acid iodomethyl ester (16.86g, 39.91mmol, 1.5 equivalents) obtained according to the procedure described in Example 41B is added, and the mixture is stirred for 12 hours. By mixture H2O (100mL), collect organic phase, then aqueous phase ethyl acetate (300mL*3), organic phase brine (300mL), through Na2SO4 drying, filter and concentrate under reduced pressure. Residue is purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1 to 1 / 1). Then further purified by preparative HPLC, with MeOH as solvent, select conventional reverse phase separation as method, separation system is TFA. Add NaHCO3 pH is adjusted to about 8, aqueous phase is extracted with ethyl acetate (400mL*3). The organic phase merged is washed with brine (500mL), through anhydrous Na2SO4 drying, filter and concentrate in a vacuum. The compound [(E)-octadec-9-enoic acid (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl ester (7.16 g, 11.15 mmol, 41.91% yield) was obtained as a yellow oil. + =634.4 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig. 9 .

[0321] Example 10: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldecyl carbonate

[0322]

[0323] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.31 g; 1 H NMR (400MHz, CDCl3): see Fig.10 . Briefly, TEA (1.69 g, 16.70 mmol, 2.32 mL, 2 eq.) and decyl chloroformate (2.46 g, 11.13 mmol, 2 eq.) were added to a mixture of (3R, 4aS, 7aR, 12bS)-3-(cyclopropylmethyl)-4a, 9-dihydroxy-2,4,5,6,7a, 13-hexahydro-1H-4,12-methylbenzofurano[3,2-e]isoquinolin-7-one (1.9 g, 5.57 mmol, 1 eq.) in DCM (15 mL) cooled to -10 °C. The mixture was stirred at 25 °C for 5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3 to 0:1). The compound [(4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldecyl carbonate] had a purity of 97.43% and was obtained as a yellow oil (43.63% yield).

[0324] Example 11: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl dodecyl carbonate

[0325]

[0326] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.5 g; 1 H NMR (400MHz, CDCl3): see Fig.11. Briefly, to a mixture of (3R, 4aS, 7aR, 12bS) -3- (cyclopropylmethyl) -4a, 9- dihydroxy -2, 4, 5, 6, 7a, 13- hexahydro -1H-4, 12- methyl bridge benzofuran [3, 2-e] isoquinolin -7-one (2.5 g, 6.62 mmol, 1 eq, HCl) and TEA (1.34 g, 13.23 mmol, 1.84 mL, 2 eq) in DCM (15 mL) was added dodecyl chloroformate (1.56 g, 6.29 mmol, 0.95 eq). The mixture was stirred at -10 ° C for 1 hour, then warmed to 25 ° C, and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 7 / 3 to 0: 1). The crude product was purified by preparative HPLC (column: Gemini 200*30 10μ; mobile phase-[water (10mM NH4HCO3)-CAN]; B% 70-100%, 12 minutes). The compound [(4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl dodecyl carbonate] had a purity of 99.497% and was obtained as a white solid (1.5 g, 40.74% yield).

[0327] Example 12: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl stearate

[0328]

[0329] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.2 g; 1 H NMR (400MHz, CDCl3): see Fig.12 .

[0330] Example 13: Synthesis of (Z)-docosa-13-enoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0331]

[0332] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.3 g;1 H NMR (400MHz, CDCl3): see Fig.13 .

[0333] Example 14: Synthesis of docosanoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0334]

[0335] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.5 g; 1 H NMR (400MHz, CDCl3): see Fig.14 . Briefly, to a mixture of (3R, 4aS, 7aS, 12bS) -3- (cyclopropylmethyl) -7- methylene -2,4,5,6,7a, 13- hexahydro -1H-4,12- methylbenzofuran [3,2-e] isoquinoline -4a, 9- diol (2g, 5.32mmol, 1 eq, HCl) in DCM (10mL) was added TEA (1.62g, 15.96mmol, 2.22mL, 3 eq) and docosanoyl chloride (3.82g, 10.64mmol, 2 eq) at 25°C under N2. The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1:1). The residue was purified using preparative HPLC (TFA conditions: column: Phenomenx luna (2) C18 250*50 10u; mobile phase: [water (0.1% TFA)-CAN]; B%: 65-95%, 20 minutes]). The compound docosanoic acid [(4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester] had a purity of 97.01% and was obtained as a white solid (1.5 g, 41.31% yield).

[0336] Example 15: Synthesis of (E)-octadec-9-enoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0337]

[0338] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.8 g; 1 H NMR (400MHz, CDCl3): see Fig.15 Briefly, TEA (1.08 g, 10.64 mmol, 1.48 mL, 2 eq.) and (E)-octadec-9-enoyl chloride (1.92, 6.38 mmol, 1.2 eq.) were added to a mixture of (3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (2 g, 5.32 mmol, 1 eq., HCl) in DCM (30 mL). The mixture was stirred at 15 °C for 12 h. The reaction mixture was mixed with H2O (80 mL) and extracted with DCM (80 mL×3). The combined organic phases were washed with saturated NaHCO3 solution (60 mL×2) and brine (60 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1:1). The compound was purified again using a preparative HPLC column Phenomenex luna C18, 250×50 mm×10 μm; mobile phase: [water (0.1% TFA)-CAN]; B: 60-90%, 20 minutes). After preparative HPLC, the mixture was concentrated under reduced pressure. The aqueous phase was combined with NaHCO3 to adjust the pH to 8, and the aqueous phase was then extracted with ethyl acetate (30 mL×4). The combined organic phases were washed with brine (20 mL×1), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(E)-octadec-9-enoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester] had a purity of 95% and was obtained as a yellow oil (1.8 g, 29.57 yield).

[0339] Example 16: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl eicosanoate

[0340]

[0341] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.1 g; 1 H NMR (400MHz, CDCl3): see Fig.16 Briefly, to a solution of eicosanoic acid (5 g, 16.00 mmol, 5.92 mL, 1 eq) in DCM (50 mL) was added DMF (116.93 mg, 1.6 mmol, 123.09 μL, 0.1 eq), cooled to 0 °C, (COCl)2 (2.34 g, 18.40 mmol, 1.61 mL, 1.15 eq), TEA (4.86 g, 48.80 mmol, 6.68 mL, 3 eq) and (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3.01 g, 8.00 mmol, 0.5 eq, HCl) were added. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was extracted with H2O (80mL×1) and DCM (80mL×2). The combined organic phase was washed with brine (60mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 1:1). The purity of the compound [eicosanoic acid (4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methyl-benzofuran [3,2-e] isoquinoline-9-yl ester] was 100%, and it was obtained as a white solid (1.1 g, 10.84% ​​yield).

[0342] Example 17: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yloctyl carbonate

[0343]

[0344] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs and obtained as an oil. 1.5 g; 1 HNMR (400MHz, CDCl3): see Fig.17 .

[0345] Example 18: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yldecyl carbonate

[0346]

[0347] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs and obtained as an oil. 1.5 g; 1 HNMR (400MHz, CDCl3): see Fig.18 .

[0348] Example 19: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl hexadecyl carbonate

[0349]

[0350] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.8 g; 1 H NMR (400MHz, CDCl3): see Fig.19. Briefly, a solution of (3R, 4aS, 7aS, 12bS) -3- (cyclopropylmethyl) -7-methylene -2,4,5,6,7a, 13- hexahydro -1H-4,12- methylbenzofuran [3,2-e] isoquinoline -4a, 9- diol (5 g, 13.30 mmol, 1 eq) in DCM (50 mL) cooled to -10 ° C was added TEA (4.04 g, 39.91 mmol, 5.55 mL, 3 eq) and hexadecylcarbonyl chloride (8.11 g, 26.60 mmol, 2 eq). The mixture was then stirred at 25 ° C for 5 hours under N2 atmosphere. The reaction mixture was extracted with H2O (80 mL × 1) and DCM (80 mL × 2). The combined organic phases were washed with brine (60 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue and compound were purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1:1). The residue was purified by preparative HPLC (TFA conditions: column-Phenomenexlune C18 250×50mm×10μm; mobile phase-[water (0.1% TFA)-CAN]; B% 65-95%, 20 minutes). NaHCO3 was added to adjust the pH to 8, and then extracted with EtOAc (20mL×3). The organic layer was evaporated under reduced pressure to obtain the final product. The compound [(4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-ylhexadecyl carbonate] had a purity of 99.723% and was obtained as a white solid (1.8 g, 12.33% yield).

[0351] Example 20: Synthesis of (9Z,12Z,15Z)-octadecane-9,12,15-trienoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0352]

[0353] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.4 g; 1 H NMR (400MHz, CDCl3): see Fig. 20 .

[0354] Example 21: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl hexadecyl carbonate

[0355]

[0356] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 2.15 g; 1 H NMR (400MHz, CDCl3): see Fig.21 Briefly, to a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (2 g, 5.29 mmol, 1 eq., HCl0 in DCM (20 mL) cooled to -10 °C was added TEA (1.61 g, 15.88 mmol, 2.21 mL, 3 eq.) and hexadecylphosgene (3.23 g, 10.59 mmol, 2 eq.). The mixture was then stirred at 25 °C under N2 atmosphere for 5 h. The reaction mixture was extracted with H20 (80 mL×1) and DCM (80 mL×2). The residue was purified by preparative HPLC (TFA conditions: column—Phenomenex luna(2)C18 250×50mm×10μm; mobile phase-[water (0.1% TFA)-CAN]; B% 60-90%, 20 minutes) purification. NaHCO3 was added to adjust the pH to 8, and then extracted with EtOAc (20mL×3). The organic layer was evaporated under reduced pressure to obtain the final product. The compound [carbonic acid (4aS, 7aR, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methyl-benzofuran [3,2-e] isoquinolin-9-yl hexadecyl ester] had a purity of 97.669% and was obtained as a white solid (2.15 g, 65.06% yield).

[0357] Example 22: Synthesis of (Z)-docosa-13-enoic acid (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0358]

[0359] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 2.17 g; 1 H NMR (400MHz, CDCl3): see Fig. 22 .

[0360] Example 23: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yloctyl carbonate

[0361]

[0362] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.33 g; 1 H NMR (400MHz, CDCl3): see Fig.23 .

[0363] Example 24: Step 24A: Synthesis of dodecyl chloromethyl carbonate

[0364]

[0365] To a mixture of dodecan-1-ol (30g, 161.00mmol, 1 equivalent) in DCM (300mL) at 0°C under N2, TEA (32.58g, 322.00mmol, 44.82mL, 2 equivalents) and chloromethyl chloroformate (41.52g, 322.00mmol, 28.63mL, 2 equivalents) were added once. The mixture was heated to 25°C and stirred for 12 hours. The reaction mixture was quenched by adding 200mL of water at 25°C, and then extracted with 100mL (50mL*2) of DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 80:1). The compound chloromethyl carbonate dodecyl ester (10.3g, 36.94mmol, 22.95% yield) was obtained as a colorless oil.

[0366] Step 24B: Synthesis of iodomethyl carbonate dodecyl ester

[0367]

[0368] Under N2 at 25 ° C, NaHCO3 (3.62 g, 43.04 mmol, 1.67 mL, 1.2 equivalents) and NaI (6.45 g, 43.04 mmol, 1.2 equivalents) were added once to a mixture of chloromethyl carbonate dodecyl ester (10 g, 35.87 mmol, 1 equivalent) in acetone (100 mL) at 25 ° C. The mixture was stirred at 25 ° C for 12 hours in the dark. The reaction mixture was filtered to remove insoluble matter and concentrated under reduced pressure to obtain a residue. The residue was dissolved in 50 mL of ethyl acetate, and the organic layer was washed with 60 mL (30 mL * 2) of water, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The compound dodecyl carbonate iodomethyl ester (12.6 g, crude product) was obtained as a light red oil. The crude product dodecyl carbonate iodomethyl ester was used in the next step without further purification. .

[0369] Step 24C: Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate dodecyl ester

[0370]

[0371] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol (4 g, 10.64 mmol, 1 eq, HCl) in H2O (20 mL) was added K2CO3 (4.41 g, 31.92 mmol, 3 eq), and the mixture was stirred for 30 min at 20° C. Tetrabutylammonium sulfate (12.37 g, 10.64 mmol, 12.24 mL, 1 eq) and DCM (20 mL) were added to the mixture, and the mixture was stirred for 10 min at 20° C. Carbonic acid dodecyl iodomethyl ester (9.46g, 25.54mmol, 2.4 equivalents) was added to the mixture at once at 20°C under N2. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with 20mL of water and extracted with 20mL (10mL*2) of DCM. The combined organic layer was dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1:0 to 10:1). The compound carbonate [(3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a, 13-hexahydro-1H-4,12-methyl-bridged benzofuran [3,2-e] isoquinolin-9-yl] oxymethyl ester dodecyl ester (2.92g, 5.00mmol, 47.02% yield) was obtained as a colorless oil. M+H + =582.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.24 .

[0372] Example 25: Step 25A: Synthesis of Tetradecyl Chloromethyl Carbonate

[0373]

[0374] To a mixture of tetradecan-1-ol (30 g, 139.93 mmol, 1 equivalent) in DCM (300 mL) at 0 ° C under N2, TEA (28.32 g, 279.87 mmol, 38.95 mL, 2 equivalents) and chloromethyl chloroformate (36.09 g, 279.87 mmol, 24.89 mL, 2 equivalents) were added once, then heated to 25 ° C for 12 hours. The reaction mixture was quenched by adding 200 mL of water at 25 ° C, and then extracted with 100 mL (50 mL * 2) of DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 80: 1). The compound chloromethyl carbonate tetradecyl ester (11 g, 35.85 mmol, 25.62% yield) was obtained as a colorless oil.

[0375] Example 25B: Synthesis of Tetradecyl Iodomethyl Carbonate

[0376]

[0377] Under N2 at 15 DEG C, to the mixture of chloromethyl carbonate tetradecyl ester (11.1g, 36.17mmol, 1 equivalent) in acetone (100mL), NaHCO3 (3.04g, 36.17mmol, 1.41mL, 1 equivalent) and NaI (5.42g, 36.17mmol, 1 equivalent) are added once. The mixture is stirred at 15 DEG C for 12 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is diluted with 40mL ethyl acetate and washed with 40mL (20mL*2) water. The organic layer is dried, filtered and concentrated under reduced pressure to obtain a residue. The crude product iodomethyl carbonate tetradecyl ester (13.1g, 32.89mmol, 90.92% yield) is obtained as a light red oil, and is used for the next step without further purification.

[0378] Step 25C: Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl tetradecyl carbonate

[0379]

[0380] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3 g, 7.98 mmol, 1 eq, HCl) and tetradecyl iodomethyl carbonate (7.63 g, 19.15 mmol, 2.4 eq) in H2O (30 mL) was added K2CO3 (3.31 g, 23.94 mmol, 3 eq), and the mixture was stirred at 15° C. for 0.5 h. After 0.5 h, tetrabutylammonium sulfate (4.64 g, 7.98 mmol, 4.59 mL, 1 eq) and DCM (30 mL) were added to the mixture, and the mixture was stirred at 15° C. for 10 min. In 40mL iodomethyl esters (7.63g, 19.15mmol, 2.4 equivalents) were added to the mixture at 15 ℃. The mixture was stirred for 12 hours at 15 ℃. The residue was diluted with 10mL water, and extracted with 20mL (10mL*2) DCM. The organic layer was dried, filtered and concentrated under reduced pressure to obtain residue. Residue was passed through column chromatography (SiO , petroleum ether / ethyl acetate=1:0 to 10:1) purifying. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl tetradecyl carbonate (2.0 g, 3.25 mmol, 40.76% yield) was obtained as a colorless oil. + =610.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.25 .

[0381] Example 26: Step 26A: Synthesis of (E)-octadec-9-enoic acid chloromethyl ester

[0382]

[0383] Under N at 25 ℃ to (E)-octadecyl-9-enoic acid (2g, 7.08mmol, 1 equivalent) in DCM (15mL) and H in the mixture of O (8mL) once add NaHCO (2.38g, 28.32mmol, 1.10mL, 4 equivalents) and tetrabutylammonium sulfate (822.29mg, 708.06umol, 50% solution, 0.1 equivalent), then the mixture is cooled to 0 ℃. At 0 ℃, DCM (10mL) containing chlorine (chlorosulfonyloxy) methane (1.17g, 7.08mmol, 1 equivalent) is added to the mixture. The mixture is heated to 25 ℃, and stirred for 18 hours. The reaction mixture is extracted with 30mL (15mL*2) DCM. The organic layer combined is dried over NaSO, filtered and concentrated under reduced pressure to obtain a residue. Compound (E)-octadec-9-enoic acid chloromethyl ester (1.97 g, 5.95 mmol, 84.07% yield) was obtained as a white solid and used in the next step without purification.

[0384] Step 26B: Synthesis of iodomethyl (E)-octadec-9-enoate

[0385]

[0386] Under N at 25 DEG C to (E)-octadec-9-enoic acid chloromethyl ester (14.5g, 43.82mmol, 1 equivalent) in acetone (140mL) mixture, add NaHCO once (4.42g, 52.58mmol, 2.04mL, 1.2 equivalents) and NaI (7.88g, 52.58mmol, 1.2 equivalents). The mixture was stirred at 25 DEG C in the dark for 12 hours. The reaction mixture was filtered to remove insolubles, and concentrated under reduced pressure to obtain residue. The residue was dissolved in ethyl acetate (100mL), and the organic layer was washed with 100mL brine, dried over NaSO, filtered and concentrated under reduced pressure to obtain residue. Compound (E)-octadec-9-enoic acid iodomethyl ester (18.6g, crude product) was obtained as brown oil, and used for the next step without purification.

[0387] Step 26C: Synthesis of (E)-octadec-9-enoic acid (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0388]

[0389] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (10.09 g, 26.71 mmol, 1 eq, HCl) in H2O (100 mL) was added K2CO3 (11.07 g, 80.12 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min. A mixture of tetrabutylammonium sulfate (15.01 g, 12.92 mmol, 50% solution, 4.84e-1 eq) in DCM (100 mL) was added and then the latter mixture was added to the former mixture. (E)-18 carbon-9-enoic acid iodomethyl ester (16.92g, 40.06mmol, 1.5 equivalents) was added, and the mixture was stirred for 12 hours. The mixture was diluted with H2O (800mL), the organic layer was collected, and then extracted with ethyl acetate (300mL*3). All organic phases were washed with saline (300mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1 to 1 / 1). The residue was further purified by preparative HPLC, with MeOH as solvent, conventional reverse phase separation was selected as the method, and the separation system was TFA. NaHCO3 was added and the pH was adjusted to about 8, and the aqueous phase was extracted with ethyl acetate (400mL*3). The combined organic phases were washed with saline (500mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound [(E)-octadec-9-enoic acid (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl ester (10.20 g, 15.85 mmol, 59.35% yield) was obtained as a yellow oil. + =636.4 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.26 .

[0390] Example 27: Synthesis of tetradecyl carbonate (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0391]

[0392] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (4.5 g, 11.91 mmol, 1 eq, HCl) in H2O (30 mL) was added K2CO3 (4.94 g, 35.73 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min. Tetrabutylammonium sulfate (13.84 g, 11.91 mmol, 13.70 mL, 50% solution, 1 eq) and DCM (30 mL) were added in one portion to the mixture at 25°C under N2. The mixture was stirred at 25°C for 10 min. Under N2, at 25 ℃, iodomethyl carbonate tetradecyl ester (11.38g, 28.58mmol, 2.4 equivalent) is once added in mixture.Mixture is stirred at 25 ℃ for 12 hours.Reaction mixture is extracted with 30mL (15mL*2) DCM.The organic layer merged is through Na2SO4 drying, filter and under reduced pressure concentrate to obtain residue.Residue is passed through column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 5:1) purifying. The compound tetradecyl carbonate [(3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl]oxymethyl ester (2.8 g, 4.53 mmol, 38.05% yield, 99% purity) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3): see Fig. 27 .

[0393] Example 28: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yleicosyl carbonate

[0394]

[0395] To a mixture of (4-nitrophenyl)eicosyl carbonate (9.87 g, 21.28 mmol, 4 eq) in DCM (40 mL) was added TEA (538.40 mg, 5.32 mmol, 740.58 uL, 1 eq) and (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (2 g, 5.32 mmol, 1 eq, HCl) in one portion at 15 °C under N2. The mixture was stirred at 15 °C for 12 hours. The reaction mixture was extracted with H2O mL (20 mL*2) DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl]eicosyl carbonate (1.6 g, 2.35 mmol, 44.25% yield) was obtained as a white solid. 1 H NMR (400MHz, CDCl3): see Fig.28 .

[0396] Example 29: Synthesis of (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl carbonate dodecyl ester

[0397]

[0398] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (4.5 g, 11.91 mmol, 1 eq, HCl) in H2O (30 mL) was added K2CO3 (4.94 g, 35.73 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min. Tetrabutylammonium sulfate (13.84 g, 11.91 mmol, 13.70 mL, 50% solution, 1 eq) and DCM (30 mL) were added in one portion to the mixture at 25°C under N2. The mixture was stirred at 25°C for 10 min. Under N2, at 25 ℃, carbonic acid dodecyl iodomethyl ester (10.58g, 28.58mmol, 2.4 equivalents) is once added in mixture.Mixture is stirred at 25 ℃ for 12 hours.Reaction mixture is extracted with 30mL (15mL*2) DCM.The organic layer merged is through Na2SO4 drying, filter and under reduced pressure concentrate to obtain residue.Residue is passed through column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 5:1) purifying. The compound [(3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl]oxymethyl dodecyl carbonate (3.1 g, 5.26 mmol, 44.19% yield, 99.1% purity) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3): see Fig.29 .

[0399] Example 30: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yltridecyl carbonate

[0400]

[0401] To a mixture of (4-nitrophenyl) tridecyl carbonate (5.83 g, 15.96 mmol, 2 eq) in DCM (50 mL) was added TEA (2.42 g, 23.94 mmol, 3.33 mL, 3 eq) and (3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3 g, 7.98 mmol, 1 eq, HCl) at 15 °C under N2. The mixture was stirred at 15 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3:1). The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl]tridecyl carbonate (2.3 g, 4.07 mmol, 50.94% yield) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3): see Fig.30 .

[0402] Example 31: Synthesis of tetradecyl carbonate (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0403]

[0404] To a solution of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3 g, 7.98 mmol, 1 eq., HCl) in DCM (20 mL) was added TEA (1.62 g, 15.96 mmol, 2.22 mL, 2 eq.) and tetradecyl chloroformate (2.21 g, 7.98 mmol, 1 eq.). The mixture was stirred at 15 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was mixed with H2O (80 mL) and extracted with DCM (80 mL*3). The combined organic phases were washed with saturated NaHCO3 solution (60 mL*2) and brine (60 mL*3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=4 / 1 to 0:1). The compound [(3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a, 13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]tetradecyl carbonate (2 g, 3.41 mmol, 42.79% yield) was obtained as a colorless oil. M+H + =580.4 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.31 .

[0405] Example 32: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-ylpentadecanyl carbonate

[0406]

[0407] To a mixture of (4-nitrophenyl)pentadecyl carbonate (6.28 g, 15.96 mmol, 2 eq) in DCM (30 mL) was added TEA (2.42 g, 23.94 mmol, 3.33 mL, 3 eq) and [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3 g, 7.98 mmol, 1 eq, HCl) in one portion at 15° C. under N2. The mixture was stirred at 15° C. for 12 hours. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 2:1). The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]pentadecyl carbonate (2.6 g, 1.80 mmol, 22.49% yield) was obtained as a white solid. + =594.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.32 .

[0408] Example 33: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl octadecyl carbonate

[0409]

[0410] To a solution of (3R, 4aS, 7aS, 12bS) -3- (cyclopropylmethyl) -7- methylene -2,4,5,6,7a, 13- hexahydro -1H-4,12- methylbenzofuran [3,2-e] isoquinoline -4a, 9- diol (2 g, 5.32 mmol, 1 eq., HCl) in DCM (30 mL) was added TEA (1.62 g, 15.96 mmol, 2.22 mL, 3 eq.) and (4-nitrophenyl) octadecyl carbonate (3.48 g, 7.98 mmol, 1.5 eq.). The mixture was stirred at 15 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1: 1) and then by preparative HPLC. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]octadecyl carbonate (0.8 g, 1.22 mmol, 22.93% yield) was obtained as a yellow oil. + =636.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.33 .

[0411] Example 34: Step 34A: Synthesis of hexadecyl chloromethyl carbonate

[0412]

[0413] Under N2, TEA (25.04g, 247.48mmol, 34.45mL, 2 equivalents) and chloromethyl chloroformate (31.91g, 247.48mmol, 22.01mL, 2 equivalents) were added once to a mixture of hexadecane-1-ol (30g, 123.74mmol, 1 equivalent) in DCM (200mL) at 0°C. The mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was quenched by adding 50mL water at 20°C, and then extracted with 100mL (50mL*2) DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 80:1). Compound chloromethyl carbonate hexadecyl ester (18g, 53.74mmol, 43.43% yield) was obtained as a white solid.

[0414] Step 34B: Synthesis of iodomethyl carbonate hexadecyl ester

[0415]

[0416] Under N2 at 15 DEG C, to the mixture of chloromethyl carbonate hexadecyl ester (8g, 23.89mmol, 1 equivalent) in acetone (50mL), NaHCO is added once (2.41g, 28.66mmol, 1.11mL, 1.2 equivalents) and NaI (4.30g, 28.66mmol, 1.2 equivalents). The mixture is stirred at 15 DEG C for 12 hours. The reaction mixture is concentrated under reduced pressure to remove the solvent. The residue is diluted with 20mL ethyl acetate, and washed with 20mL (10mL*2) water. The organic layer is dried, filtered and concentrated under reduced pressure to obtain residue. The crude product hexadecyl iodomethyl carbonate (9g, crude product) is obtained as a light red solid, and is used for the next step without further purification. Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl hexadecyl ester

[0417]

[0418] To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (2.75 g, 7.32 mmol, 1 eq, HCl) and hexadecyl iodomethyl carbonate (7.49 g, 17.56 mmol, 2.4 eq) in H2O (25 mL) was added K2CO3 (3.03 g, 21.95 mmol, 3 eq) and stirred at 15° C. for 0.5 h. After 30 min, tetrabutylammonium sulfate (4.25 g, 7.32 mmol, 4.21 mL, 1 eq) and DCM (25 mL) were added to the mixture and the mixture was stirred for more than 10 min. In 40mL iodine iodide, 10mL iodine ester (7.49g, 17.56mmol, 2.4 equivalents) is added into the mixture at 15 ℃ after 10 minutes under N .Mixture is stirred for 12 hours at 15 ℃.Residue is diluted with 10mL water, and extracted with 20mL (10mL*2) DCM.The organic layer merged is dried, filtered and concentrated under reduced pressure to obtain residue.Residue is passed through column chromatography (SiO , petroleum ether / ethyl acetate=1:0 to 10:1) purifying. The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl hexadecyl carbonate (2.0 g, 3.10 mmol, 42.38% yield) was obtained as a colorless oil. + =638.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.34 .

[0419] Example 35: Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl decyl carbonate

[0420]

[0421] (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl decyl carbonate was prepared in a manner similar to Example 5. To a mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol in H2O was added K2CO3 in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 minutes. Tetrabutylammonium sulfate in DCM was then added in one portion at 25°C. Iodomethyl decyl carbonate was then added to the reaction mixture, and the mixture was stirred at 25° C. until the reaction was complete. The reaction mixture was then subjected to work-up, and the desired product was isolated by chromatography as in Example 5. 1 H NMR (400MHz, CDCl3): see Fig.35 .

[0422] Example 36: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl oleate

[0423]

[0424] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.5 g; 1 H NMR (400MHz, CDCl3): see Fig.36 .

[0425] Example 37: Synthesis of (9Z,12Z)-octadec-9,12-dienoic acid (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0426]

[0427] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.3 g; 1 H NMR (400MHz, CDCl3): see Fig.37 .

[0428] Example 38: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3,3-dimethylbutanoate

[0429]

[0430] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.2 g; 1 H NMR (400MHz, CDCl3): see Fig.38 .

[0431] Example 39: Synthesis of (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3-cyclopentylpropanoate

[0432]

[0433] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs. 1.18 g; 1 H NMR (400MHz, CDCl3): see Fig.39 .

[0434] Example 40: Synthesis of tert-butyl (4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl ester

[0435]

[0436] The title compound was synthesized according to the general scheme 1 for the synthesis of nalmefene prodrugs and obtained as a solid. 3.0 g; 1 HNMR (400MHz, CDCl3): see Fig.40 .

[0437] Example 41: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl oleate

[0438]

[0439] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.5 g; 1 H NMR (400MHz, CDCl3): see Fig.41 .

[0440] Example 42: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3,3-dimethylbutanoate

[0441]

[0442] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.3 g; 1 H NMR (400MHz, CDCl3): see Fig.42 .

[0443] Example 43: Synthesis of (4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl 3-cyclopentylpropanoate

[0444]

[0445] The title compound was synthesized according to the general scheme 2 for the synthesis of naltrexone prodrugs. 1.3 g; 1 H NMR (400MHz, CDCl3): see Fig.43 .

[0446] Example 44: Step 44A: Synthesis of chloromethyl dodecanoate

[0447]

[0448] Under N2 at 25 ℃, to dodecanoic acid (20g, 99.84mmol, 1 equivalent) in DCM (60mL) and H2O (80mL) in a mixture, NaHCO3 (33.55g, 399.37mmol, 15.53mL, 4 equivalents) and tetrabutylammonium sulfate (11.60g, 9.98mmol, 11.49mL, 50% purity, 0.1 equivalents) were added once, and the mixture was then cooled to 0 ℃. At 0 ℃, the reactant of chloro(chlorosulfonyloxy)methane (16.47g, 99.84mmol, 1 equivalent) in DCM (20mL) was added once to the mixture. The mixture was heated to 25 ℃ and stirred for 18 hours. The reaction mixture was extracted with 50mL (25mL*2) DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 80: 1) to obtain the compound chloromethyl dodecanoate (10.8 g, 43.41 mmol, 43.48% yield) as a colorless oil.

[0449] Step 44B: Synthesis of iodomethyl dodecanoate

[0450]

[0451] The mixture of dodecanoic acid chloromethyl ester (9g, 36.18mmol, 1 equivalent) in acetone (80mL) is degassed and purged 3 times with N, and then in the dark by NaHCO (3.04g, 36.18mmol, 1.41mL, 1 equivalent) and NaI (5.42g, 36.18mmol, 1 equivalent) are added to the mixture, and the resulting mixture is stirred at 15 DEG C for 12 hours under N atmosphere in the dark. The reaction mixture is filtered, and concentrated under reduced pressure to remove solvent. Residue is diluted with 0 50mL H o, and extracted with 120mL EtOAc. The organic layer merged is washed with 100mL (50mL*2) H o, dried, filtered and concentrated under reduced pressure to obtain residue. The compound dodecanoic acid iodomethyl ester (9g, crude product) is obtained as a yellow liquid, and is used for the next step without further purification.

[0452] Step 44C: Synthesis of (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl dodecanoate

[0453]

[0454] A mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3.5 g, 10.31 mmol, 1 eq.) and K2CO3 (4.28 g, 30.93 mmol, 3 eq.) in H2O (40 mL) was stirred at 15°C for 3 hours. In 40mL 4-nitropropene (2-nitropropene) ether (2-nitropropene) ether (3-nitropropene) ether (4-nitropropene) ether (5-nitropropene) ether (6-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether ( The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl dodecanoate (1.51 g, 2.70 mmol, 26.14% yield) was obtained as a colorless oil. + =552.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.44 .

[0455] Example 45: Step 45A: Synthesis of chloromethyl tetradecanoate

[0456]

[0457] Under N2, NaHCO (29.43 g, 350.31 mmol, 13.62 mL, 4 equivalents) and tetrabutylammonium sulfate (10.18 g, 8.76 mmol, 10.08 mL, 50% solution, 0.1 equivalent) and DCM (60 mL) were added to the mixture of tetradecanoic acid (20 g, 87.58 mmol, 1 equivalent) in H2O (80 mL). The mixture was cooled to 0 ° C. Under N2, DCM (20 mL) of reactant chloro (chlorosulfonyloxy) methane (14.45 g, 87.58 mmol, 1 equivalent) was added to the mixture once at 0 ° C. The mixture was heated to 25 ° C and stirred for 18 hours. The reaction mixture was extracted with 50 mL (25 mL * 2) DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 80: 1) The compound tetradecanoic acid chloromethyl ester (15.5 g, 55.99 mmol, 63.93% yield) was obtained as a colorless oil.

[0458] Step 45B: Synthesis of iodomethyl myristate

[0459]

[0460] The mixture of tetradecanoic acid chloromethyl ester (8g, 28.90mmol, 1 equivalent) in acetone (70mL) is degassed and purged 3 times with N, and then in the dark by NaHCO (2.43g, 28.90mmol, 1.12mL, 1 equivalent) and NaI (4.33g, 28.90mmol, 1 equivalent) are added to the mixture, and the resulting mixture is stirred at 15 DEG C for 12 hours under N atmosphere in the dark. The reaction mixture is filtered, and concentrated under reduced pressure to remove the solvent. Residue is diluted with 50mL H o, and extracted with 120mL EtOAc. The organic layer merged is washed with 100mL (50mL*2) H o, through Na sO dried, filtered and concentrated under reduced pressure to obtain residue. The crude product is used for the next step without further purification. Compound tetradecanoic acid iodomethyl ester (9g, crude product) is obtained as a yellow solid.

[0461] Step 45C: Synthesis of tetradecanoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0462]

[0463] A mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3.5 g, 9.31 mmol, 1 eq., HCl) and K2CO3 (3.86 g, 27.93 mmol, 3 eq.) in H2O (30 mL) was stirred at 15°C. In 40mL 4-nitropropene ether (20mL) in ... The compound tetradecanoic acid [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl ester (1.5 g, 2.54 mmol, 27.26% yield) was obtained as a colorless oil. + =580.5 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.45 .

[0464] Example 46: Step 46A: Synthesis of chloromethyl hexadecanoate

[0465]

[0466] Under N at 25 ℃ to palmitic acid (20g, 78.00mmol, 23.47mL, 1 equivalent) in DCM (60mL) and H in the mixture of O (80mL) once add NaHCO (26.21g, 311.98mmol, 12.13mL, 4 equivalents) and tetrabutylammonium sulfate (9.06g, 7.80mmol, 8.97mL, 50% purity, 0.1 equivalent), and then the mixture is cooled to 0 ℃. At 0 ℃, the reactant of chloro(chlorosulfonyloxy)methane (12.87g, 78.00mmol, 1 equivalent) in DCM (20mL) is once added to the mixture. The mixture is heated to 25 ℃, and stirred for 18 hours. The reaction mixture is extracted with 50mL (25mL*2) DCM. The organic layer combined is dried over NaSO, filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 80:1) to obtain the compound hexadecanoic acid chloromethyl ester (17.6 g, 57.72 mmol, 74.01% yield) as a white solid.

[0467] Step 46B: Synthesis of iodomethyl hexadecanoate

[0468]

[0469] The mixture of hexadecanoic acid chloromethyl ester (3g, 9.84mmol, 1 equivalent) in acetone (30mL) is degassed and in the dark at 15 DEG C with N2Purge 3 times, and then NaHCO is added to the mixture (826.58mg, 9.84mmol, 382.68uL, 1 equivalent) and NaI (1.47g, 9.84mmol, 1 equivalent), and in the dark at N2Atmosphere, stir 12 hours at 15 DEG C.Reactant mixture is filtered, and the filtrate is concentrated under reduced pressure to remove solvent.Residue is diluted with 20mL H2O, and extracted with 60mL EtOAc.By 40mL (20mL*2) H2O washing of the organic layer merged, dry, filter and concentrate under reduced pressure to obtain residue.Compound hexadecanoic acid iodomethyl ester (3.5g, crude product) is obtained as yellow solid, and is used for next step without further purification.

[0470] Step 46C: Synthesis of hexadecanoic acid (((4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0471]

[0472] A mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (1.8 g, 4.79 mmol, 1 eq., HCl) and K2CO3 (1.99 g, 14.37 mmol, 3 eq.) in H2O (15 mL) was stirred for 30 min. In 40mL 4-nitropropene ether (20mL) 10mL HCl (10mL) 30mL water (10mL) 10mL NH 2Cl 2Cl 30mL ... The compound hexadecanoic acid [(3R, 4aS, 7aS, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl ester (1.6 g, 24.35% yield) was obtained as a colorless oil. M+H+=608.6 (LCMS). 1H NMR (400 MHz, CDCl3): see Fig.46 .

[0473] Example 47: Synthesis of (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl hexadecyl carbonate

[0474]

[0475] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (5.45 g, 14.42 mmol, 1 eq, HCl) in H2O (30 mL) was added K2CO3 (5.98 g, 43.27 mmol, 3 eq) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 min. Tetrabutylammonium sulfate (16.76 g, 14.42 mmol, 16.59 mL, 50% solution, 1 eq) and DCM (30 mL) were added to the mixture at 25° C. and the mixture was stirred at 25° C. for 10 min. Hexadecyl iodomethyl carbonate (14.76 g, 34.62 mmol, 2.4 equivalents) was added to the mixture at 25 ° C., and the mixture was stirred at 25 ° C. for 12 hours. The reaction mixture was extracted with 30 mL (15 mL * 2) of DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5: 1). The compound [(3R, 4aS, 7aR, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methylbenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl hexadecyl carbonate (4.68 g, 7.29 mmol, 50.56% yield) was obtained as a colorless oil. M+H + =640.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.47 .

[0476] Example 48: Synthesis of (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl dodecanoate

[0477]

[0478] A mixture of (3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinoline-4a,9-diol (3.5 g, 10.31 mmol, 1 eq.) and K2CO3 (4.28 g, 30.93 mmol, 3 eq.) in H2O (40 mL) was stirred at 15°C for 3 hours. In 40mL 4-nitropropene (2-nitropropene) ether (2-nitropropene) ether (3-nitropropene) ether (4-nitropropene) ether (5-nitropropene) ether (6-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (6-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether (8-nitropropene) ether (7-nitropropene) ether ( The compound [(3R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl]oxymethyl dodecanoate (1.51 g, 2.70 mmol, 26.14% yield) was obtained as a colorless oil. + =554.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.48 .

[0479] Example 49: Synthesis of hexadecanoic acid (((4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-9-yl)oxy)methyl ester

[0480]

[0481] To a mixture of (3R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofurano[3,2-e]isoquinolin-7-one (5 g, 13.23 mmol, 1 eq, HCl) in H2O (30 mL) was added K2CO3 (5.49 g, 39.70 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 25°C for 30 min. Tetrabutylammonium sulfate (15.38 g, 13.23 mmol, 15.22 mL, 50% solution, 1 eq) and DCM (30 mL) were added in one portion to the mixture at 25°C under N2. The mixture was stirred at 25°C for 10 min. Iodomethyl carbonate hexadecyl ester (12.59 g, 31.76 mmol, 2.4 equivalents) was added to the mixture at once under N2 at 25 ° C. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was extracted with 30 mL (15 mL * 2) of DCM. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5: 1). The compound hexadecanoic acid [(3R, 4aS, 7aR, 12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methylbenzofuran [3,2-e] isoquinolin-9-yl] oxymethyl ester (5.2 g, 6.14 mmol, 46.40% yield) was obtained as a light yellow oil. M+H + =610.3 (LCMS). 1 H NMR (400MHz, CDCl3): see Fig.49 .

[0482] Examples 50-61: Compounds 50-61 listed in Table 2 can be prepared according to General Scheme 1 for the synthesis of nalmefene prodrugs or General Scheme 2 for the synthesis of naltrexone prodrugs with appropriate starting materials.

[0483] II. Biological Evaluation

[0484] Example 1: Plasma and liver S9 fraction stability assay

[0485] HPLC-MS is used to carry out plasma stability determination to the test compound in rat, dog, cynomolgus monkey and human plasma.For rat, 5 aliquots (one for each time point) of 70 μ L are incubated in 96-well polypropylene plates.Test compound (10 μ M, final solvent concentration 1%) is incubated at 37 ° C. Five time points (0 minute, 15 minutes, 120 minutes, 480 minutes and 1440 minutes) are analyzed.For dog, monkey and people, test compound (2 μ M, final solvent concentration 1%) is also incubated at 37 ° C, and is analyzed at five time points (0 minute, 10 minutes, 30 minutes, 60 minutes and 120 minutes).All incubations are carried out in duplicate.Samples are analyzed by HPLC-MS.The percentage of the parent compound remaining after incubation in plasma is determined. Nalmefene dodecanoate and nalmefene palmitate have been previously reported (Gaekens et al., Journal of Controlled Release 232 (2016) 196-202). The results are provided in Tables 4a-d.

[0486] Table 4a - Rat plasma stability

[0487]

[0488]

[0489] Table 4b - Canine Plasma Stability

[0490]

[0491] Table 4c - Monkey plasma stability

[0492]

[0493] Table 4d - Human plasma stability

[0494]

[0495] Liver S9 fraction stability assays were performed using HPLC-MS for test compounds in dogs, cynomolgus monkeys and humans. Test compounds (2 μM, 0.1% DMSO, 1% methanol final concentration) were evaluated for stability in 50 μl phosphate buffer containing 1.0 mg / ml of S9 protein from each of the three species and 5 mM D-glycolic acid-1,4-lactone. Samples were incubated at 37°C for 60 minutes, and the remaining compound % was evaluated.

[0496] Table 4e - Liver S9 Fraction Stability

[0497]

[0498] Example 2: Opioid Receptor Binding Assay

[0499] Receptor binding assays were performed to assess the ability of compounds to inhibit binding to radiolabeled ligands. First, IC50 values ​​for selected compounds were determined for all three opioid receptor subtypes (DOR, MOR, and KOR), and these values ​​were compared to those of the parent molecule, nalmefene. It was generally observed that prodrug derivatization greatly reduced binding affinity to opioid receptors, in some cases by several orders of magnitude.

[0500] equipment

[0501] Unifilter-96GF / C filter plate, Perkin Elmer (Cat. No. 6005174)

[0502] 96-well conical polypropylene plate, Agilent (Cat. No. 5042-385)

[0503] TopSeal-A Sealing Film, PerkinElmer (Cat. No. 6005250)

[0504] TopCount NXT HTS (PerkinElmer)

[0505] MicroBeta 2 (PerkinElmer)

[0506] Cell Collection C961961 (PerkinElmer)

[0507] Reagents

[0508] Stable cell lines were established and cell membranes obtained using these cell lines were prepared.

[0509] 3 H-diprenophrine (PerkinElmer, catalog number: NET1121250UC, batch number: 2143599)

[0510] 3 H-DAMGO (PerkinElmer, catalog number: NET902250UC, lot number: 2139100 )

[0511] 3 H-DADLE (PerkinElmer, catalog number: NET648250UC, lot number: 2060549)

[0512] Tris base (Sigma, catalog number: T6066-1KG), prepare a 1 M stock solution and adjust the pH to 7.4.

[0513] 0.5M EDTA (Invitrogen, catalog number: 15575-038) 1M MgCl2 (Sigma, catalog number: M1028-100ml)

[0514] PEI (Polyethyleneimine) (Sigma, catalog number: P3143 )

[0515] Microscint 20 mixture (PerkinElmer, catalog number: 6013329) Naltrindole (Sigma, catalog number: N115) (±) trans-U-50488 (Sigma, catalog number: D8040)

[0516] DAMGO (Sigma, catalog number: E7384 )

[0517] Assay buffer

[0518]

[0519]

[0520]

[0521] Wash buffer

[0522]

[0523] method

[0524] 1) Membrane and radioligand preparation

[0525]

[0526] 2) Compound preparation

[0527]

[0528] 3) Determination procedure

[0529] 1) According to the plate map for nonspecific binding, transfer 1 μl of compound at the indicated concentration to the assay plate. According to the plate map for total binding, transfer 1 μl of DMSO to the assay plate.

[0530] 2) According to the plate map, dispense 99 μl of the membrane stock solution into the plate.

[0531] 3) Add 100 μl of radioligand.

[0532] 4) Seal the plate. Incubate at room temperature for 1 hour.

[0533] 5) Soak the Unifilter-96GF / C filter plate with 50 μl of 0.3% PEI per well at room temperature for at least 0.5 hours.

[0534] 6) When the binding assay is complete, the reaction mixture is filtered through GF / C plates using a PerkinElmer Filtermate harvester and each plate is then washed 4 times with cold wash buffer.

[0535] 7) Dry the filter plate at 50 degrees for 1 hour.

[0536] 8) After drying, seal the bottom of the filter plate wells using PerkinElmer Unifilter-96 backing sealing tape. Add 50 μl of PerkinElmer Microscint 20 mixture.

[0537] The top of the filter plate was sealed with PerkinElmer TopSeal-A sealing membrane.

[0538] 9) The next day, the PerkinElmer MicroBeta2 reader was used to read the captured 3 H counts.

[0539] 10) Data were analyzed using GraphPad Prism 5. "Inhibition [% control]" was calculated using the following equation: % Inh = (1 - background minus assay value / background minus HC value) * 100.

[0540] result

[0541]

[0542] Table 5a

[0543]

[0544] Table 5b

[0545]

[0546] Table 5c

[0547]

[0548] Example 3: Solubility determination

[0549] A known amount of test material (~40 mg) was weighed into a vial, 100 μL of oil was added, and heated to 60°C, and then the system was slurried to reach equilibrium. More oil was added until a clear solution was obtained or a solubility of <50 mg / mL was obtained. The clear solution was then placed at room temperature (25°C) for 24 hours to confirm whether there was solid precipitation. Once the compound precipitated, additional oil was added to the vial, and then the system was re-balanced at 1000 rpm at room temperature (25°C). The final concentration was determined by the HPLC method described in Tables 6a and 6b below.

[0550] Table 6a

[0551]

[0552] Table 6b

[0553]

[0554] The HPLC methods for compounds 6, 12-20, and 36-43 are provided in Table 7.

[0555] Table 7

[0556]

[0557] The HPLC methods for compounds 10, 21-23, 53, 55, 56, nalmefene and naltrexone are provided in Table 8.

[0558] Table 8

[0559]

[0560] The HPLC methods for compounds 3-5, 8, 24-25, 26-34, 44-51, 54, 55, 57, 59, and 60 are provided in Table 9.

[0561] Table 9

[0562]

[0563]

[0564] Table 10

[0565]

[0566]

[0567]

[0568]

[0569] *Data from an initial failed batch of compound 8 due to unoptimized synthesis

[0570] **Data of the second batch of compound 8 after successful optimization synthesis

[0571] Example 4: Stability determination of drug products

[0572] The compounds were resuspended in oil vehicle, stored at room temperature for the indicated time periods and evaluated by HPLC. Data are presented as absolute percent loss normalized to 30 days. Nalmefene dodecanoate has been previously reported (Gaekens et al., Journal of Controlled Release 232 (2016) 196-202).

[0573] Table 11

[0574]

[0575]

[0576] Table 12

[0577]

[0578] Table 13

[0579]

[0580] Table 14

[0581]

[0582] Example 4: Stability Assay of Drug Substance

[0583] The compounds were stored at room temperature for the indicated time periods and evaluated by HPLC. Data are presented as absolute percent loss normalized to 30 days. Nalmefene dodecanoate has been previously reported (Gaekens et al., Journal of Controlled Release 232 (2016) 196-202).

[0584] Table 15

[0585]

[0586] Table 16

[0587]

[0588]

[0589] Table 17 - HPLC methods for compounds 10, 11, 21, 36 and 53

[0590]

[0591] Table 18 - HPLC methods for compounds 14, 19 and 55

[0592]

[0593]

[0594] Table 19 - HPLC Methods for Compounds 1, 3-9, 15, 17, 18, 23-27, 29, 31, 32, 34, 35, 44-48, 57 and 59

[0595]

[0596] Table 20

[0597]

[0598]

[0599] Example 5: Physical properties of solid drug substances

[0600] Physical properties of the drug substance in solid state were analyzed using polarized light microscopy (PLM), X-ray powder diffractometer (XRPD) evaluation, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). For PLM, samples were dispersed in immersion oil and observed under crossed polarizers using an eyepiece (10x) and an objective lens (20x). For XRPD, samples were run on the diffractometer using the following method: Tube - Cu:K-α Generator - voltage 40kV, current 40mA; scanning range - 3 to 40° sample rotation speed - 15rpm; scanning rate - 10 degrees / minute. For DSC, about 1 mg of sample was tested using a crimped aluminum pan, and covered with a lid with holes, heated from room temperature to 300°C at a rate of 10°C / minute. For TGA, 2-5 mg of sample was placed in an open platinum pan and heated from room temperature to 300°C at a rate of 10°C / minute. Nalmefene palmitate has been previously reported (Gaekens et al., Journal of Controlled Release 232 (2016) 196-202).

[0601] Table 21 - XRPD, TGA and DSC results

[0602]

[0603] Example 5: Polymorph Screening of Solid State Drug Substances

[0604] In order to identify the stable polymorph of solid drug substance, about 50mg compound (nalmefene or naltrexone equivalent) is weighed into a vial. Next, 500 μL of indicated solvent is added, and the suspension is stirred at 700rpm, 50°C for 72 hours. For the sample in the suspension, the solid is separated by a centrifuge (10 minutes, 14000rpm) and dried overnight at 30°C in a vacuum oven. For the sample in the solution, solid is generated by evaporation (removing the stirring rod and covering it with aluminum foil with a pinhole, then drying overnight at 30°C in a vacuum oven). The dried solid is characterized by XRPD, TGA and DSC. The results are presented in Table 22.

[0605] Table 22

[0606]

[0607]

[0608] III. Preparation of pharmaceutical dosage forms

[0609] Example 1: Oral gelation

[0610] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt thereof. Capsules for oral administration are prepared by mixing 1-1000 mg of the active ingredient with starch or other suitable powder blends. The mixture is incorporated into oral dosage units suitable for oral administration, such as hard gelatin capsules.

[0611] Example 2: Solution for injection

[0612] The active ingredient is a compound of Table 1 or a pharmaceutically acceptable salt thereof, and is formulated into a solution in sesame oil, cottonseed oil, castor oil or other pharmaceutically acceptable lipophilic excipients, preferably at a concentration greater than 100 mg / mL. The resulting solution is administered by intramuscular injection.

[0613] The compound was resuspended to 1 mL at a specified concentration (in mg / ml base equivalent) by mixing at 60°C using magnetic stirring (1000 rpm) until a uniform clear solution was obtained, then cooled to room temperature and stored in the dark. The appearance of the oil formulation was observed and recorded at room temperature (25°C) at the beginning, 2 hours and 24 hours. Samples for "assay" measurements were collected at the beginning, 2 hours and 24 hours after resuspension and subjected to HPLC analysis, where the actual concentration was based on the standard curve (assay = concentration (measured by HPLC) / actual concentration (by weight) × 100%). Purity was calculated at the specified time point based on the percentage of the area under the main peak curve from the HPLC spectrum. Injectability was evaluated by passing through a 21-gauge needle. After 7 months at 40°C / 75% relative humidity, the appearance, assay and purity of some specified samples were evaluated. The data are presented in Table 23.

[0614] Table 23

[0615]

[0616]

[0617] Table 24

[0618]

[0619]

[0620] Table 25

[0621]

[0622]

[0623] Table 26A

[0624]

[0625]

[0626] Table 26B

[0627]

[0628]

[0629] Table 26C

[0630]

[0631]

[0632]

[0633] IV. Pharmacokinetic Evaluation

[0634] Example 1: Pharmacokinetic study in rats

[0635] Purpose

[0636] The objective of this study was to determine the pharmacokinetics of test compounds in plasma following intramuscular administration to male Sprague Dawley rats (n=3 unless otherwise stated).

[0637] Adaptation / Isolation

[0638] The animals were assessed for general health and acclimatized for at least 3 days before conducting the study.

[0639] Animal Husbandry

[0640] Animals were housed during the acclimation period and individually housed during the study. The animal room environment was controlled (target conditions: temperature 18°C ​​to 26°C, relative humidity 30% to 70%, 12 hours of artificial light and 12 hours of darkness). Temperature and relative humidity were monitored daily. Water was provided to the animals ad libitum.

[0641] Animal body weight and clinical observations

[0642] Body weights were determined prior to study selection and on the day of dosing. Body weight monitoring was performed weekly.

[0643] Detailed clinical observations covering behavior and activity, reflexes, respiration, skin and fur, facial features, genitourinary system, and other gross lesions were performed on the day of dosing and at each sample collection time point.

[0644] Dosage Administration

[0645] The dose formulation of 400 mg base equivalent / ml (unless otherwise stated) in sesame oil + 1% benzyl alcohol was administered by intramuscular injection. The dose volume was determined by the animal's body weight measured on the morning of dosing.

[0646] Sample collection

[0647] Each blood collection (approximately 0.2 mL per time point) was performed from each animal's jugular vein puncture into a pre-chilled plastic microcentrifuge tube containing 5 μL of 160 mg / mL sodium fluoride / potassium oxalate (NaF / KO=1 / 3), 5% PMSF (100 mM in ethanol) as a stabilizer, and 4 μL of EDTA-K2 as an anticoagulant, and placed on wet ice until centrifugation.

[0648] Plasma processing

[0649] Each collected blood sample was centrifuged at 4°C and 10000rpm for 4 minutes to collect plasma. Plasma was collected at each time point and transferred to a pre-labeled PP tube in dry ice and immediately precipitated with ACN at a ratio of 1:4 (plasma:ACN). Centrifuged again (10 minutes, 12000rpm), and the supernatant was obtained.

[0650] After final collection, all supernatants were stored at approximately -80°C until bioanalysis.

[0651] Bioanalytical methods and sample analysis

[0652] A LC-MS / MS method was developed for the quantitative determination of test compounds in biological matrices. A calibration curve with eight non-zero calibration standards was applied to the method including the LLOQ (0.05 ng / ml). Sample analysis was performed simultaneously with a set of calibration standards and two sets of QC samples using the LC-MS / MS method.

[0653] Data analysis

[0654] The plasma concentration versus time data were analyzed by a noncompartmental approach using Phoenix WinNonlin 6.3 software program. max 、T max 、T 1 / 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) and a plot of plasma concentration versus time.

[0655] The dose of nalmefene dodecanoate was determined by allometric growth of the dog dose in rats as previously reported (Gaekens et al., J. Controlled Release 232 (2016) 196-202). The terminal half-life of the active metabolite of the selected compound was determined and used to estimate the duration of the active metabolite above the minimum effective plasma concentration.

[0656] Table 27

[0657]

[0658] In all studies, no adverse effects on body weight or clinical observations were observed in any rat.

[0659] Time versus nalmefene concentration data for HCL nalmefene at 0.80 mg / kg in 1 mg / ml are provided in Table 28a.

[0660] Table 28a

[0661]

[0662] *Not detected

[0663] The time versus nalmefene concentration data for Compound 59 (nalmefene dodecanoate) at 17 mg / kg in a concentration of 86 mg / ml are provided in Table 28b.

[0664] Table 28b

[0665]

[0666] Table 29 provides the time versus nalmefene concentration data for Compound 6 at 80 mg / kg.

[0667] Table 29

[0668]

[0669] Table 30 provides the time versus nalmefene concentration data for Compound 6 at 123 mg / kg.

[0670] Table 30

[0671]

[0672]

[0673] Time versus nalmefene concentration data for Compound 6 at 165 mg / kg are provided in Table 31.

[0674] Table 31

[0675]

[0676] Time versus nalmefene concentration data for Compound 15 at 80 mg / kg are provided in Table 32.

[0677] Table 32

[0678]

[0679] Table 33 provides the time versus nalmefene concentration data for Compound 15 at 123 mg / kg.

[0680] Table 33

[0681]

[0682]

[0683] Time versus nalmefene concentration data for Compound 15 at 165 mg / kg are provided in Table 34.

[0684] Table 34

[0685]

[0686] Table 35 provides the time versus nalmefene concentration data for Compound 17 at 200 mg / kg.

[0687] Table 35

[0688]

[0689] The time versus nalmefene concentration data for Compound 18 at 80 mg / kg are provided in Table 36.

[0690] Table 36

[0691]

[0692]

[0693] Table 37 provides the time versus nalmefene concentration data for Compound 18 at 123 mg / kg.

[0694] Table 37

[0695]

[0696] The time versus nalmefene concentration data for Compound 18 at 200 mg / kg are provided in Table 38.

[0697] Table 38

[0698]

[0699] The time versus naltrexone concentration data for Compound 23 at 200 mg / kg are provided in Table 39.

[0700] Table 39

[0701]

[0702] Table 40 provides the time versus nalmefene concentration data for Compound 24 at 80 mg / kg.

[0703] Table 40

[0704]

[0705] Time versus nalmefene concentration data for Compound 24 at 123 mg / kg are provided in Table 41.

[0706] Table 41

[0707]

[0708]

[0709] Time versus nalmefene concentration data for Compound 24 at 165 mg / kg are provided in Table 42.

[0710] Table 42

[0711]

[0712]

[0713] The time versus naltrexone concentration data for Compound 29 at 165 mg / kg (400 mg / ml in sesame oil) are provided in Table 43a.

[0714] Table 43a

[0715]

[0716] Time versus naltrexone concentration data for Compound 29 at 165 mg / kg (300 mg / ml in cottonseed oil, n=2) are provided in Table 43b.

[0717] Table 43b

[0718]

[0719]

[0720] Example 2: Canine Pharmacokinetic Study

[0721] Purpose

[0722] The objective of this study was to determine the pharmacokinetics of test compounds in plasma following deep intramuscular administration to Beagle dogs (n=3 unless otherwise stated).

[0723] Adaptation / Isolation

[0724] The animals were assessed for general health and acclimatized for at least 5 days before conducting the study.

[0725] Animal Husbandry

[0726] Animals were housed in pairs during the adaptation period and individually during the study. The relative humidity of the room will be controlled and monitored (the target average range is 40% to 70%, and any deviation beyond this range for more than 3 hours will be recorded as a deviation) and temperature (the target average range is 18° to 26°C, and any deviation beyond this range will be recorded as a deviation), with 10 to 20 ventilations per hour. Unless interrupted by learning activities, the room will be in a 12-hour light / dark cycle. Animals will be fed twice a day. Breeding dogs will be fed approximately 220 grams of certified dog food (Beijing Keao Xieli Feed Co., Ltd. Beijing, PRChina) per day. These amounts can be adjusted as needed based on the food consumption of the group or the individual weight changes of the group or individual and / or the changes in the certified diet. Reverse osmosis (RO) water is available for all animals to use at will. RO water is analyzed every three months, and each batch of feed is analyzed before use. Provide abundant toys.

[0727] Animal body weight and clinical observations

[0728] Body weights were determined prior to study selection and on the day of dosing. Body weight monitoring was performed weekly.

[0729] Detailed clinical observations covering behavior and activity, reflexes, respiration, skin and fur, facial features, genitourinary system, and other gross lesions were performed on the day of dosing and at each sample collection time point.

[0730] Dosage Administration

[0731] The dose formulation (concentration - 400 mg base equivalents / ml in sesame oil + 1% benzyl alcohol, unless otherwise stated) was administered by deep intramuscular administration (unless otherwise stated). At the beginning of the study, the injection vehicle was also administered by the deep intramuscular route (unless otherwise stated) in the contralateral site of each animal. The animals were sedated with 6 mg / kg of Propofol by IV administration. After sedation, the hair around the injection site was carefully removed and the area was gently cleaned. Care was taken to avoid irritation of the skin during shaving and cleaning of the injection site. The dogs will then be dosed by deep IM administration. By tilting the needle toward the femur, enter the central part of the quadriceps femoris or biceps femoris from the surface to a depth of at least 2.5 cm. If the needle hits the femur, just pull back slightly and then inject. The dose volume will be determined by the animal weight collected on the morning of the dosing day. For repeated administrations, the injection site can be rotated to minimize tissue damage.

[0732] Sample collection

[0733] Blood samples were collected from peripheral blood vessels of restrained, unsedated animals at each sampling time point.

[0734] Approximately 0.8 mL of blood will be collected at each time point. All blood samples will be transferred to pre-cooled plastic microcentrifuge tubes containing 20 μL 160 mg / mL sodium fluoride / potassium oxalate (NaF / KO=1 / 3), 5% PMSF (100 mM in ethanol) as a stabilizer, and 16 μL EDTA-K2 (0.5 M) as an anticoagulant, and placed on wet ice until centrifugation.

[0735] Each blood collection will be placed on wet ice before centrifugation.

[0736] Plasma processing

[0737] Each collected blood sample was centrifuged at 4°C and 10000rpm for 4 minutes to collect plasma. Plasma was collected at each time point and transferred to a pre-labeled PP tube in dry ice and immediately precipitated with ACN at a ratio of 1:4 (plasma:ACN). Centrifuged again (10 minutes, 12000rpm), and the supernatant was obtained.

[0738] After final collection, all supernatants were stored at approximately -80°F until bioanalysis.

[0739] Bioanalytical methods and sample analysis

[0740] A LC-MS / MS method was developed for the quantitative determination of test compounds in biological matrices. A calibration curve with eight non-zero calibration standards was applied to the method including the LLOQ (0.05 ng / ml). Sample analysis was performed simultaneously with a set of calibration standards and two sets of QC samples using the LC-MS / MS method.

[0741] Data analysis

[0742] The plasma concentration versus time data were analyzed by a noncompartmental approach using Phoenix WinNonlin 6.3 software program. max 、T max 、T 1 / 2 , AUC (0-t) , AUC (0-inf) , MRT (0-t) , MRT (0-inf) and a plot of plasma concentration versus time.

[0743] Table 44

[0744]

[0745]

[0746] Time versus nalmefene concentration data for Compound 6 at 30 mg / kg are provided in Table 45.

[0747] Table 45*

[0748]

[0749] *Study in progress

[0750] The time versus nalmefene concentration data for Compound 6 at 48 mg / kg (superficial IM injection) are provided in Table 46.

[0751] Table 46

[0752]

[0753] Time versus nalmefene concentration data for Compound 6 at 48 mg / kg (deep IM injection; dog re-dosing from Table 46) are provided in Table 47a.

[0754] Table 47a*

[0755]

[0756] *Study in progress

[0757] Time versus nalmefene concentration data for Compound 6 at 48 mg / kg (deep IM injection; single dose in pups n=2) are provided in Table 47b.

[0758] Table 47b*

[0759]

[0760] *Study in progress

[0761] Time versus nalmefene concentration data for Compound 6 at 96 mg / kg are provided in Table 48.

[0762] Table 48*

[0763]

[0764] *Study in progress

[0765] Time versus nalmefene concentration data for Compound 15 at 30 mg / kg are provided in Table 49.

[0766] Table 49*

[0767]

[0768] *Study in progress

[0769] The time versus nalmefene concentration data for Compound 15 at 48 mg / kg are provided in Table 50a.

[0770] Table 50a*

[0771]

[0772]

[0773] *Study in progress

[0774] The time versus nalmefene concentration data for Compound 15 at 48 mg / kg (replicate study of Table 50a) are provided in Table 50b.

[0775] Table 50b*

[0776]

[0777] *Study in progress

[0778] The time versus nalmefene concentration data for Compound 15 at 96 mg / kg are provided in Table 51.

[0779] Table 51*

[0780]

[0781]

[0782] *Study in progress

[0783] Time versus nalmefene concentration data for Compound 18 at 48 mg / kg are provided in Table 52.

[0784] Table 52

[0785]

[0786] The time versus nalmefene concentration data for Compound 24 at 48 mg / kg (superficial IM injection) are provided in Table 53.

[0787] Table 53

[0788]

[0789]

[0790] The time versus nalmefene concentration data for Compound 24 at 48 mg / kg (deep IM injection) are provided in Table 54.

[0791] Table 54

[0792]

[0793] Table 55 provides the time versus nalmefene concentration data for Compound 45 at 30 mg / kg.

[0794] Table 55*

[0795]

[0796]

[0797] *Study in progress

[0798] Table 56 provides the time versus nalmefene concentration data for Compound 45 at 48 mg / kg.

[0799] Table 56*

[0800]

[0801] *Study in progress

[0802] Table 57 provides the time versus nalmefene concentration data for Compound 45 at 96 mg / kg.

[0803] Table 57*

[0804]

[0805] *Study in progress

[0806] The time versus naltrexone concentration data for Compound 7 at 24 mg / kg are provided in Table 58.

[0807] Table 58*

[0808]

[0809] *Study in progress

[0810] The time versus naltrexone concentration data for Compound 7 at 48 mg / kg (n=2) are provided in Table 59.

[0811] Table 59*

[0812]

[0813] *Study in progress

[0814] The time versus naltrexone concentration data for Compound 8 at 48 mg / kg are provided in Table 60.

[0815] Table 60*

[0816]

[0817] *Study in progress

[0818] Time versus nalmefene concentration data for Compound 1 at 48 mg / kg are provided in Table 61.

[0819] Table 61*

[0820]

[0821] *Study in progress

[0822] The time versus nalmefene concentration data for Compound 3 at 48 mg / kg are provided in Table 62.

[0823] Table 62

[0824]

[0825] The time versus naltrexone concentration data for Compound 4 at 48 mg / kg are provided in Table 63.

[0826] Table 63

[0827]

[0828] **ND=Not Detected

[0829] The time versus naltrexone concentration data for Compound 5 at 48 mg / kg (n=2) are provided in Table 64.

[0830] Table 64

[0831]

[0832]

[0833] Time versus naltrexone concentration data for Compound 35 at 48 mg / kg are provided in Table 65.

[0834] Table 65

[0835]

[0836] Clinical observations for dogs treated with Compound 6 at 30 mg / kg are provided in Table 66.

[0837]

[0838]

[0839] Clinical observations for dogs treated with Compound 6 at 48 mg / kg (superficial IM) are provided in Table 67.

[0840]

[0841]

[0842] Clinical observations for dogs treated with Compound 6 at 48 mg / kg (deep IM; dogs re-dosed from Table 67) are provided in Table 68a.

[0843]

[0844]

[0845] Clinical observations for dogs treated with Compound 6 at 48 mg / kg (deep IM injection; single dose in puppies n=2) are provided in Table 68b.

[0846]

[0847] Clinical observations for dogs treated with Compound 6 at 96 mg / kg are provided in Table 69.

[0848]

[0849]

[0850] Clinical observations for dogs treated with Compound 15 at 30 mg / kg are provided in Table 70.

[0851]

[0852]

[0853] Clinical observations for dogs treated with Compound 15 at 48 mg / kg are provided in Table 71a.

[0854]

[0855]

[0856] Clinical observations for dogs treated with Compound 15 at 48 mg / kg are provided in Table 71b.

[0857]

[0858] Clinical observations for dogs treated with Compound 15 at 96 mg / kg are provided in Table 72.

[0859]

[0860]

[0861] Clinical observations for dogs treated with Compound 18 at 48 mg / kg are provided in Table 73.

[0862]

[0863]

[0864]

[0865]

[0866] Clinical observations for dogs treated with Compound 24 at 48 mg / kg (superficial IM) are provided in Table 74.

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874] Clinical observations for dogs treated with Compound 24 at 48 mg / kg (deep IM) are provided in Table 75.

[0875]

[0876]

[0877]

[0878]

[0879] Clinical observations for dogs treated with Compound 45 at 30 mg / kg are provided in Table 76.

[0880]

[0881] Clinical observations for dogs treated with Compound 45 at 48 mg / kg are provided in Table 77.

[0882]

[0883]

[0884] Clinical observations for dogs treated with Compound 45 at 96 mg / kg are provided in Table 78.

[0885]

[0886]

[0887] Clinical observations for dogs treated with Compound 7 at 24 mg / kg are provided in Table 79.

[0888]

[0889] Clinical observations for dogs treated with Compound 7 at 48 mg / kg are provided in Table 80.

[0890]

[0891]

[0892] Clinical observations for dogs treated with Compound 8 at 48 mg / kg are provided in Table 81.

[0893]

[0894]

[0895] Clinical observations for dogs treated with Compound 1 at 48 mg / kg are provided in Table 82.

[0896]

[0897] Clinical observations for dogs treated with Compound 3 at 48 mg / kg are provided in Table 83.

[0898]

[0899]

[0900]

[0901]

[0902]

[0903] Clinical observations for dogs treated with Compound 4 at 48 mg / kg are provided in Table 84.

[0904]

[0905]

[0906] Clinical observations for dogs treated with Compound 5 at 48 mg / kg are provided in Table 85.

[0907]

[0908]

[0909] Clinical observations for dogs treated with Compound 35 at 48 mg / kg are provided in Table 86.

[0910]

[0911]

[0912]

Claims

1. A compound or a pharmaceutically acceptable salt thereof having the structure provided below, Wherein X is O or CH2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable excipient is cottonseed oil.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutically acceptable excipient is sesame oil.

7. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating opioid dependence in a patient.

8. The use according to claim 7, wherein the medicament is suitable for injection.

9. The use according to claim 8, wherein the medicament is suitable for intramuscular injection.

10. The use according to claim 9, wherein the intramuscular injection is a depot injection.

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