8-substituted-2,6-methano-3-benzazocines and 3-substituted morphinanes as opioid receptor binding agents

Description

Field of the Invention

[0001] The invention relates to opioid receptor binding compounds derived from a benzomorphan or morphinan structure. The compounds are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives, anti-cocaine, and anti-addiction medications.

Background of the Invention

[0002] Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds having opiate or opiate-like activity have been identified. For example, international patent application WO 97/25331 discloses heterocycle-condensed morphinoid derivatives. US patent US 4,032,529 describes N-alkylated-8-animated-2,6-methano-3-benzazocines and their use as analgesics. Many opioid receptor-interactive compounds including those used for producing analgesia (e.g., morphine) and those used for treating drug addiction (e.g., naltrexone and cyclazocine) in humans have limited utility due to poor oral bioavailability and a very rapid clearance rate from the body. This has been shown in many instances to be due to the presence of the 8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the corresponding 3-OH group in morphinanes (e.g., morphine).

[0003] The high polarity of these hydroxyl groups retards oral absorption of the parent molecules. Furthermore, the 8-(or 3-)OH group is prone to sulfonation and glucuronidation (Phase II metabolism), both of which facilitate rapid excretion of the active compounds, leading to disadvantageously short half-lives for the active compounds. Unfortunately, the uniform experience in the art of the past seventy years has been that removal or replacement of the 8-(or 3-)OH group has lead to pharmacologically inactive compounds.

Summary of the Invention

[0004] We have now found that the 8-(or 3-)hydroxyl group may be replaced by a thiocarboxamide group as defined by the claims. Not only do the claimed compounds have unexpectedly high affinity for opioid receptors, compounds containing these groups in place of OH are far less susceptible to Phase II metabolism and are generally more orally bioavailable. The compounds of the invention are therefore useful as analgesics, anti-pruritics, anti-diarrheal agents, anticonvulsants, antitussives, anorexics and as treatments for hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain (including neuropathic pain), irritable bowel syndrome and gastrointestinal motility disorders. Drug addiction, as used herein, includes alcohol and nicotine addiction. There is evidence in the literature that the compounds may also be useful as immunosuppressants and antiinflammatories and for reducing ischemic damage (and cardioprotection), for improving learning and memory, and for treating urinary incontinence.

[0005] In one aspect, the invention relates
a compound of formula:

wherein

A

is chosen from

Q

is S;

R² and R^2a

are both hydrogen or taken together R² and R^2a are =O;

R³

is chosen from hydrogen, C₁-C₆ alkyl; alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;

R⁴

is chosen from hydrogen, hydroxy, amino, C₁-C₄ alkoxy, C₁-C₂₀ alkyl and C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;

R⁵

is C₁-C₆ alkyl;

R⁶

is C₁-C₆ alkyl;

R⁷

is hydrogen; or
together R⁴, R⁵, R⁶ and R⁷ may form one ring, said ring having optional additional substitution; and

R¹⁶

is chosen from hydrogen and NH₂.

[0006] Subclasses of the foregoing structure include:

II. 2,6-methano-3-benzazocines of the structure shown above, in which R⁴, R⁵, R⁶ and R⁷ do not form additional rings;

III. morphinans in which R⁵ and R⁶ form one ring:

IV. morphinans in which R⁵, R⁶ and R⁷ form two rings:

and

V. morphinans wherein R⁴ and R¹¹ form an additional sixth ring, which may be saturated or unsaturated:

or

[0007] In addition to the major subclasses, there are compounds (not claimed) such as

and

which the person of skill recognizes as closely related to the major subclasses, but which defy easy description in a common Markush structure.

[0008] In another (non-claimed) aspect, the disclosure relates to a method for preparing a second compound that interacts with an opioid receptor when a first compound that interacts with an opioid receptor is known. When the first compound contains a phenolic hydroxyl, the method comprises converting the phenolic hydroxyl to a residue chosen from the group described as the variable A above.

[0009] In another (non-claimed) aspect, the disclosure relates to a method for decreasing the rate of metabolism of a compound that interacts at an opioid receptor. When the first compound contains a phenolic hydroxyl, the method comprises converting the phenolic hydroxyl to a residue chosen from the group described as the variable A above.

[0010] In another (non-claimed) aspect, the disclosure relates to methods for inhibiting, eliciting or enhancing responses mediated by an opioid receptor comprising:

(a) providing a first compound that inhibits, elicits or enhances an opioid receptor response;

(b) preparing a second compound that interacts with an opioid receptor by converting a phenolic hydroxyl group on the first compound to a residue described as A above; and

(c) bringing the second compound into contact with the opioid receptor.

[0011] In another aspect, the invention relates to the use of a compound according to the claims for the preparation of a medicament for the treatment of a disease or a condition mediated by an opioid receptor.

[0012] In another (non-claimed) aspect, the disclosure relates to processes for converting opioid-binding phenols or phenols on a benzomorphan or morphinane to a carboxamide. The carboxamide conversion processes comprise either:

(a) reacting the phenol with a reagent to convert it to a group displaceable by CN^-;

(b) reacting that group with Zn(CN)₂ in the presence of a Pd(0) catalyst to provide a nitrile; and

(c) hydrolyzing the nitrile to a carboxamide; or:

(a) reacting the phenol with a reagent to convert the phenol to a triflate;

(b) reacting the triflate with carbon monoxide and ammonia in the presence of a Pd(II) salt and a Pd(0) catalyst to provide a carboxamide; or

(a) reacting the phenol with a reagent to convert the phenol to a triflate;

(b) reacting the triflate with carbon monoxide and hexamethyldisilazane in the presence of a Pd(II) salt and a Pd(0) catalyst to provide a silylated carboxamide precursor; and

(c) hydrolyzing the silylated carboxamide precursor to provide a carboxamide.

[0013] Similar processes convert phenols to amidines and thioamides by reacting the foregoing nitrile with hydroxylamine to produce a hydroxyamidine or reacting the foregoing carboxamide with a pentavalent phosphorus-sulfur reagent to produce a thioamide. For the purpose of the invention an "opioid-binding phenol" is one that exhibits binding at an opioid receptor below 25 nM.

Detailed Description of the Invention

[0014] From many years of SAR studies, it is known that the hydroxyl of morphinans and benzomorphans interacts with a specific site in the opiate receptor. Previous exploration of the tolerance of this site for functional groups other than phenolic hydroxyls has almost uniformly resulted in the complete or near-complete loss of opioid binding. We have now surprisingly found that the hydroxyl can be replaced with a thiocarboxamido group. Although a fairly wide range of primary and secondary carboxamides, as well as carboxylates, aminomethyl, hydroxymethyl and even dihydroimidazolyl exhibit binding in the desired range below 25 nanomolar, optimal activity is observed with a thiocarboxamido group.

[0015] Since the hydroxyl functionality of benzomorphans and morphinans can be chemically converted to an amide by a simple, flexible and convenient route described below, and since thiocarboxamido, hydroxyamidino and formamido compounds are also easily synthesized as described below, the door is opened to improving the bioavailability of virtually any of the known and new therapeutic agents that rely on opioid binding for their activity. Moreover, since the receptor seems to tolerate some variation beyond the α-carbon of A, one may contemplate further modulating receptor specificity, affinity and tissue distribution by varying the properties of the alkyl or aryl substituents on A. Residue A may be selected from -NHCHS and -NHCNH₂S.

[0016] It is known in the art that compounds that are µ, δ and κ agonists exhibit analgesic activity; compounds that are selective µ agonists exhibit anti-diarrheal activity and are useful in treating dyskinesia; µ antagonists and κ agonists are useful in treating heroin, cocaine, alcohol and nicotine addiction; κ agonists are also anti-pruritic agents and are useful in treating hyperalgesia. In general, the dextrorotatory isomers of morphinans of type III above are useful as antitussives and anticonvulsants.

[0017] Opioid receptor ligands having known high affinity are shown in the following charts 1 and 2. Replacement of OH in these compounds produces compounds that exhibit similar activity and better bioavailability.

[0018] Other opioid receptor ligands are described in Aldrich, J.V. "Analgesics" in Burger's Medicinal Chemistry and Drug Discovery, M.E.Wolff ed., John Wiley & Sons 1996, pages 321-44.

[0019] We have examined the opioid receptor binding of a series of analogs of known compounds that interact at opioid receptors in which the OH is replaced by the R-group shown in Tables 1-4. Examples 1 to 19b and 21 to 34 are not covered by the claims. The standards are shown in Table 5.

Table 1.

	Cyclazocine subseries (general structure A):
	example	A=	[3H] DAM GO (µ)	[3H]Naltrindole (δ)	[3H]U69,593 (κ)
	1	CN	540 ± 50	2700 ± 1400	71 ± 13
	2	COOH	58 ± 1.8	320 ± 14	31 ± 0.87
	3	CO2CH3	45 ± 0.92	59 ± 2.1	2.0 ± 0.21
	4	CONH2	0.41 ± 0.07	8.3 ± 0.49	0.53 ± 0.06
	4	CONH2	0.32 ± 0.04	NT	0.60 ± 0.04
	4	CONH2· HCl	0.34 ± 0.01	4.9 ± 0.80	0.42 ± 0.02
	4a	(-)CONH2	0.17 ± 0.04	2.6 ± 0.6	0.28 ± 0.01
	4b	(+)CONH2	63 ± 5.4	570 ± 50	67 ± 1.6
	5	C(=S)NH2	0.22 ± 0.02	4.0 ± 0.48	0.67 ± 0.01
	6	CONHOH	12 ± 0.32	210 ± 40	6.9 ± 0.61
	7	CONHNH2	60 ± 9.3	450 ± 62	19 ± 1.4
	8	CONHCH3	24 ± 1.6	63 ± 4.1	2.6 ± 0.19
	9	CONHCH2C6H5	20 ± 2.2	140 ± 18	78 ± 7.6
	10	CONHCH2(4-MeOC6H4)	19 ± 1.5	150 ± 17	110 ± 3.1
	11	CONHCH2CH2N(CH3)2	26 ± 2.9	350 ± 51	44 ± 11
	12	CONH(CH2)3N(CH3)2	370 ± 54	3000 ± 230	310 ± 64
	13	2-(4,5-H2)-imidazolyl	23 ± 1.9	55 ± 5.1	11 ± 0.69
	14	C(=NOH)NH2	3.8 ± 0.42	16 ± 0.67	0.90 ± 0.15
	15	CH2NH2	31 ± 5.4	390 ± 47	17 ± 2.9
	16	CH2OH	21 ± 2.0	210 ± 29	7.6 ± 0.80
	17	COC6H5	33 ± 0.90	490 ± 43	19 ± 2.6
	18	C(=NOH)C6H5	86 ± 3.8	180 ± 15	7.2 ± 0.40
	19	NHCHO	1.9 ± 0.14	37 ± 3.9	0.85 ± 0.080
	19a	(-)NHCHO	1.1 ± 0.04	9.8 ± 0.28	0.49 ± 0.012
	19b	(+)NHCHO	2300 ± 180	> 10,000	900 ± 8.7
	20	NHCHS	0.76 ± 0.09	16 ± 0.30	0.63 ± 0.15
	21	NHSO2CH3	15 ± 1.2	780 ± 170	21 ± 1.5

Table 2

1-Keto subseries:
example	A=	[3H]DAMGO (µ)	[3H]Naltrindole (δ)	[3H]U69,593 (κ)
22	CN (KC)	680 ± 61	3400 ± 410	59 ± 0.77
23	CONH2 (KC)	1.4 ± 0.07	20 ± 2.3	1.8 ± 0.10
24	CONH2(EKC)	1.2 ± 0.12	9.8 ± 0.50	0.70 ± 0.08

Table 3

Merz subseries
	example	A=	[3H]DAMGO (µ)	[3H]Naltrindole (δ)	[3H]U69,593 (κ)
	25	(-)-(2"S)-8-OH	0.19 ± 0.01	3.6 ± 0.40	0.09 ± 0.01
	26	(-)-(2"S)-8-CONH2	0.052 ± 0.013	2.0 ± 0.15	0.089 ± 0.004
	27	(-)-(2"R)-8-OH	4.0 ± 0.54	67 ± 4.3	1.5 ± 0.07
	28	(-)-(2"R)-8-CONH2	2.9 ± 0.17	34 ± 0.10	2.8 ± 0.24
	29	(-)-(2"S)-8-CH2NH2	28 ± 2.3	300 ± 27	18 ± 1.9

Table 4

4,5a-Epoxymorphinan subseries:
	example	A=	[3H]DAMGO (µ)	[3H]Naltrindole (δ)	[3H]U69,593 (κ)
	30	3-CONH2 (morphine)	34 ± 1.8	1900 ± 81	2000 ± 97
	31	3-CONHCH3 (morphine)	440 ± 9.2	> 10,000	>10,000
	32	3-CONH2 (naltrexone)	1.9 ± 0.21	110 ± 8.1	22 ± 0.85
	33	3-CO2Et (naltrexone)	24 ± 1.7	970 ± 155	16 ± 0.70
	34	3-CONH2 (naltrindole)	47 ± 2.7	0.33 ± 0.04	99 ± 7.9

Table 5

Standards:
		[3H]DAMGO (µ)	[3H]Naltrindole (δ)	[3H]U69,593 (κ)
	(±)-Cyclazocine	0.32 ± 0.02	1.1 ± 0.04	0.18 ± 0.020
	(+)-Cyclazocine	360 ± 16	1100 ± 63	76 ± 8.2
	(-)-Cyclazocine	0.10 ± 0.03	0.58 ± 0.06	0.052 ± 0.009
	(±)-EKC	0.78 ± 0.10	3.4 ± 0.41	0.62 ± 0.11
	(±)-ketocyclazocine	3.3 ± 0.66	20 ± 2.7	1.0 ± 0.24
	naltrexone (3-OH)	0.17 ± 0.03	11 ± 1.1	0.31 ± 0.03
	naltrindole (3-OH)	13 ± 1.1	0.13 ± 0.02	4.6 ± 0.23

[0020] Example 4 was tested several times independently to confirm the K_i's. Inspection of the results in Table 1 indicates not only that affinity is preserved in the compounds of the invention, but also that receptor selectivity can be modulated.

[0021] The affinities of the compounds of the invention are determined by the method described in Wentland et al. Biorgan. Med. Chem. Lett. 9. 183-187 (2000). Antinociceptive activity is evaluated by the method described in Jiang et al. [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022]. Compound 4 was found to exhibit an ED₅₀ of 0.21 nmol in the mouse acetic acid writhing test when administered i.c.v. Its "parent" cyclazocine exhibited an ED₅₀ of 2.9 nmol i.c.v. The time courses in producing antinociception in the mouse writhing test were compared for compound 4 and cyclazocine. Mice were injected with 1.0 mg/kg of either compound 4 or cyclazocine, given by i.p. administration. An increase in the duration of action from ca. 2 hr to 15 hr was observed for compound 4 compared to cyclazocine.

Definitions

[0022] Throughout this specification the terms and substituents retain their definitions.

[0023] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s-and t-butyl, cyclobutyl and the like. Preferred alkyl groups are those of C₂₀ or below. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

[0024] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.

[0025] Aryl and heteroaryl mean a 5- or 6-membered aromatic or heteroaromatic ring containing 0-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S. The aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

[0026] Arylalkyl means an alkyl residue attached to an aryl ring. Examples are benzyl, phenethyl and the like. Heteroarylalkyl means an alkyl residue attached to a heteroaryl ring. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.

[0027] Heterocycle means a cycloalkyl or aryl residue in which one to two of the carbons is replaced by a heteroatom such as oxygen, nitrogen or sulfur. Heteroaryls form a subset of heterocycles. Examples of heterocycles that fall within the scope of the invention include pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine, thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like.

[0028] Substituted alkyl, aryl, cycloalkyl, or heterocyclyl refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, hydroxy, loweralkoxy, carboxy, carboalkoxy, carboxamido, cyano, carbonyl, -NO₂, -NR¹R²; alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, heteroaryloxy, or substituted phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0029] Virtually all of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. In general it has been found that the levo isomer of morphinans and benzomorphans is the more potent antinociceptive agent, while the dextro isomer may be useful as an antitussive or antispasmodic agent. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

Abbreviations

[0030] The following abbreviations and terms have the indicated meanings throughout:

Ac

= acetyl

BNB

= 4-bromomethyl-3-nitrobenzoic acid

Boc

= t-butyloxy carbonyl

Bu

= butyl

c-

= cyclo

DAMGO

= Tyr-ala-Gly-NMePhe-NHCH₂OH

DBU

= diazabicyclo[5.4.0]undec-7-ene

DCM

= dichloromethane = methylene chloride = CH₂Cl₂

DEAD

= diethyl azodicarboxylate

DIC

= diisopropylcarbodiimide

DIEA

= N,N-diisopropylethyl amine

DMAP

= 4-N,N-dimethylaminopyridine

DMF

= N,N-dimethylformamide

DMSO

= dimethyl sulfoxide

DPPF

= 1,1'-bis(diphenylphosphino)ferrocene

DVB

= 1,4-divinylbenzene

EEDQ

= 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline

Fmoc

= 9-fluorenylmethoxycarbonyl

GC

= gas chromatography

HATU

= O(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HOAc

= acetic acid

HOBt

= hydroxybenzotriazole

Me

= methyl

mesyl

= methanesulfonyl

MTBE

= methyl t-butyl ether

NMO

= N-methylmorpholine oxide

PEG

= polyethylene glycol

Ph

= phenyl

PhOH

= phenol

PfP

= pentafluorophenol

PPTS

= pyridinium p-toluenesulfonate

PyBroP

= bromo-tris-pyrrolidino-phosphonium hexafluorophosphate

rt

= room temperature

sat'd

= saturated

s-

= secondary

t-

= tertiary

TBDMS

= t-butyldimethylsilyl

TFA

= trifluoroacetic acid

THF

= tetrahydrofuran

TMOF

= trimethyl orthoformate

TMS

= trimethylsilyl

tosyl

= p-toluenesulfonyl

Trt

= triphenylmethyl

U69,593

=

[0031] In the general processes described below, the preferred reagent to convert a phenol to a group displaceable by CN^θ is trifluoromethansulfonic anhydride, which is usually employed in the presence of base. Other reagents are known to persons of skill in the art to convert phenols to groups that may be displaced by cyanide anion. The advantage of the trifluoromethansulfonic anhydride procedure is that it allows displacement under conditions that are mild enough to avoid destruction of the rest of the molecule for most species of interest. Other reagents are operable, but require more robust substrates than may be of interest in a particular case. The consideration of which to use is within the skill of the artisan. A preferred Pd(0) catalyst for use in the displacement with zinc cyanide is tetrakis(triphenylphosphine)palladium. In the direct displacements with carbon monoxide and ammonia or an ammonia equivalent, the preferred Pd(0) catalyst is generated in situ from Pd(OAc)₂ or PdCl₂ and 1,1'-bis(diphenylphosphino)ferrocene. Other Pd(0) ligands include DPPF, DPPP, triphenylphosphine, 1,3-bis(diphenylphosphino)propane, BINAP and xantphos. The preferred pentavalent phosphorus-sulfur reagents for converting carboxamides to thiocarboxamides are Lawesson's reagent arid phosphorus pentasulfide.

[0032] It may happen that residues in the substrate of interest require protection and deprotection during the conversion of the phenol to the desired bioisostere. Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes which involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991].

[0033] The compounds disclosed herein are synthesized by one of the routes described below:

Chemical Syntheses

[0034] Proton NMR [Varian Unity-500 (500 MHz) NMR] data, direct insertion probe (DIP) chemical ionization mass spectra (Shimadzu GC-17A GC-MS mass spectrometer), and infrared spectra (Perkin-Elmer Paragon 1000 FT-IR spectrophotometer) were consistent with the assigned structures of all test compounds and intermediates. ¹H NMR multiplicity data are denoted by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad). Coupling constants are in hertz. Carbon, hydrogen, and nitrogen elemental analyses for all novel targets were performed by Quantitative Technologies Inc., Whitehouse, NJ, and were within ± 0.4% of theoretical values except as noted; the presence of water was conformed by proton NMR. Melting points were determined on a Meltemp capillary melting point apparatus and are uncorrected. Optical rotation data were obtained from a Perkin-Elmer 241 polarimeter. Reactions were generally performed under a N₂ atmosphere. Amines used in the Pd-catalyzed amination reactions and racemic-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP) were purchased from Aldrich Chemical Company and used as received unless otherwise indicated. Tris(dibenzylideneacetone) dipalladium (0) [Pd₂(dba)₃], Pd(OAc)₂, 1,1'-bis(diphenylphosphino)ferrocene (DPPF), were purchased from Strem Chemicals, Incorporated. Toluene and Et₂O were distilled from sodium metal. THF was distilled from sodium/benzophenone ketyl. Pyridine was distilled from KOH. Methylene chloride was distilled from CaH₂. DMF and DMSO were distilled from CaH₂ under reduced pressure. Methanol was dried over 3Å molecular sieves prior to use. Silica gel (Bodman Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for flash column chromatography.

[0035] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile [1]. The triflate [36] of cyclazocine [35] (470 mg, 1.166 mmol), obtained by the method of Wentland et al.[Bioorgan. Med. Chem. Lett. 9,183-187 (2000)], was dissolved in 20 mL DMF and Zn(CN)₂ (272.6 mg, 2.322 mmol) and Pd(PPh₃)₄ (53.9 mg, 0.0466 mmol) were added. After heating in 120° C for 2 h, the reaction was allowed to stir at 25°C overnight. A mixture of EtOAc and NaHCO₃ solution was then added. The organic phase was washed with brine and then dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to dryness. Flash column chromatography gave 1 as a colorless oil (260 mg, 80%). ¹H-NMR (500 MHz, CDCl₃) d 7.52 (b,1H), 7.37 (dd, J=7.8, 1.5 Hz, 1H), 7.14 (d, J=8.1, 1H), 3.15 (m, 1H), 2.96 (d, J = 19.0 Hz, 1H), 2.66-2.74 (m, 2H), 2.45 (m, 1H), 2.30 (m, 1H), 1.84-1.98 (m, 3H), 1.38 (s, 3H), 1.29 (m, 1H), 0.85 (m, 1H), 0.82 (d, J = 7.1 Hz, 3H), 0.51 (m, 2H), 0.10 (m, 2H). IR (film) 2961, 2918, 2225 cm^-1. CI-MS, m/z (relative intensity) 281 (M+1, 100%). Anal. Calcd. for C₁₉H₂₄N₂.0.125H₂O: C 80.78, H 8.59, N 9.92. Found: C 80.75, H 8.63, N 9.89.

[0036] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamide [4]. Compound 1 (80 mg, 0.286 mmol) was dissolved in about 1 mL t-butyl alcohol. KOH (58.8 mg, 1.05 mmol) was then added. The reaction mixture was stirred at reflux for about 20 min and the solvent was evaporated and CH₂Cl₂ and MeOH and NaCl solution were added. The organic phase was washed with brine and then dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to dryness to give 4 as white foam (80 mg, 95%). ¹H-NMR (500 MHz, CD₃OD) d 7.81 (m, 1H), 7.62 (m, 1H), 7.17 (m, 1H), 3.22 (m, 1H), 3.04 (m, 1H), 2.66-2.82 (m, 2H), 2.50 (m, 1H), 2.35 (m, 1H), 1.86-1.98 (m, 3H), 1.34 (s, 3H), 1.36 (m, 1H), 0.88 (m, 1H), 0.84 (d, J = 7.0 Hz, 3H), 0.54 (m, 2H), 0.16 (m, 2H). ¹³C-NMR (500 MHz, CD₃OD) d 172.71, 143.32, 142.34, 133.01, 128.61, 126.61, 126.18, 60.67, 58.09, 46.92, 42.74, 42.38, 37.69, 25.92, 25.07, 14.62, 9.67, 4.64, 4.52. IR (film) 1654.2 cm^-1. CI-MS, m/z (relative intensity) 299 (M+1, 100%). Anal. Calcd. for C₁₉H₂₆N₂O.0.25H₂O: C 75.37, H 8.76, N 9.26. Found: C 75.27, H 9.02, N 9.03.

[0037] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamide [1] (alternate procedure). A flask containing triflate 36 (100 mg), Pd(OAc)₂ (10.2 mg), and 1,1'-bis(diphenylphosphino)-ferrocene(DPPF, 25 mg) was purged with argon. The argon was replaced with gaseous CO and the reaction vessel was closed to the atmosphere. Dry DMSO (1.25 mL) was added via syringe and gaseous ammonia was added to the resulting mixture via a canula. A balloon was used to keep the additional volume contained. The mixture was stirred for 17 h at 70 °C followed by cooling to 25 °C. The reaction mixture was diluted with water and the product was extracted into ethyl acetate. The organic extracts was washed with aqueous NaHCO₃ and dried (Na₂SO₄). Concentration of the solvent in vacuo gave 90 mg of a crude product. This material was purified via flash chromatography (25:1:0.1 - CH₂Cl₂:MeOH: conc NH₄OH) to provide 47 mg (65.3%) of compound 4.

[0038] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxylic acid methyl ester [3]. A modification of a known procedure (Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1986, 27, 3931-3934) was used in this preparation. Under an argon atmosphere, triethylamine (0.30 mL, 2.15 mmol) was added to a mixture of the 8-triflate ester of cyclazocine [36] (0.403 g, 1.0 mmol), palladium acetate (0.0068 g, 0.03 mmol), 1, 1'-bis(diphenylphosphino)ferrocene (0.00166 g, 0.03 mmol) and methanol (1 mL, 22.2 mmol) in DMF (1 mL). The solution was purged with carbon monoxide for 15 min and stirred under a CO balloon at 70 °C for 5 h. The reaction mixture was taken up in 20 mL of ethyl acetate and washed with saturated sodium bicarbonate solution and water. The organic phase was dried with sodium sulfate and evaporated to give crude product as a brown oil. Chromatography on silica gel using CH₂Cl₂:MeOH:NH₄OH (conc)/40:1:0.1 provided the desired compound 3 (0.235 g, 86.6 %) as a colorless oil: ¹H NMR (500 MHz, CDCl₃) * 7.93 (d, J = 1.7 Hz, 1H), 7.76 (dd, J₁ = 1.7 Hz, J₂ = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 3.89 (s, 3H), 3.15 (m, 1H), 2.96 (d, J = 19.0 Hz, 1H), 2.73 (d, J = 6.1 Hz, 1H), 2.70 (m, 1H), 2.46 (dd, J₁ = 7.3 Hz, J₂ = 12.4 Hz, 1H), 2.31 (dd, J₁ = 6.6 Hz, J₂ = 12.4 Hz, 1H), 1.96 (m, 1H), 1.91 (m, 2H), 1.43 (s, 3H), 1.33 (m, 1H), 0.86 (m, 1H), 0.83 (d, J = 7.1 Hz, 3H), 0.51 (d, J = 8.1 Hz, 2H), 0.11 (m, 2H); IR (film) <_max 2916, 1720, 1270 cm^-1; MS (CI) m/z 314 (M + H)⁺; Anal. calc. for C₂₀H₂₇NO₂: C, 76.64; H, 8.68; N, 4.47. Found: C, 76.37; H, 8.93; N, 4.38.

[0039] (±)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-methanol [16]. Under a blanket of N₂ at 0 °C, (±)-3-(cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxylic acid methyl ester [3] (0.1062 g, 0.34mmol), LiAlH₄ powder (0.0258 g, 0.68mmol) and dry THF (0.77 mL) were placed in a one-neck round bottom flask equipped with condenser and stir bar. The ice/water bath was removed and the reaction was stirred at reflux for 24 h. The mixture was cooled to 25 °C and quenched by adding water dropwise until effervescence ceased. The mixture was then treated with 10% H₂SO₄ and stirred at 25 °C for 3 hours. The mixture then was extracted with diethyl ether (2X) and the organic layer was dried (Na₂SO₄) and the solvent was removed in vacuo. The crude product was purified by flash column chromatography using CH₂Cl₂:MeOH/10:1 as eluent to provide the desired product [16] (0.0557 g, 57%) as a light yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.24 (d, J=17 Hz, 1H), 7.10 (m, 1H), 7.08 (d, J=21.2 Hz, 1 H), 4.64 (s, 2H), 3.14 (m, 1H), 2.91 (d, J=18.5 Hz, 1H), 2.68 (m, 2H), 2.47 (m, 1H), 2.31 (m, 1H), 1.92 (m, 6H), 1.34 (m, 3H), 0.84 (d, J=7.1 Hz), 0.50 (m, 2H), 0.11 (m, 2H); Anal. calc. for C₁₉H₂₇NO: C, 79.95; H, 9.53; N, 4.91. Found: C, 79.70; H, 9.50; N, 4.68.

[0040] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-N-hydroxy-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamidine [14]. A modification of a known procedure (Jendralla, H.; Seuring, B.; Herchen, J.; Kulitzscher, B.; Wunner, J. Tetrahedron 1995, 51, 12047-12068) was used in this preparation. A mixture of (+)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile [1] (0.230 g, 0.82 mmol), hydroxyamine hydrochloride (0.100 g, 1.44 mmol) and triethylamine (0.30 mL, 2.15 mmol) in 1 mL of absolute ethanol was stirred at reflux under an argon atmosphere for 5 h. The reaction mixture was concentrated in vacuo and the residue was taken up in 15 mL of CH₂Cl₂ and washed with water. The organic phase was dried (Na₂SO₄) and evaporated to give crude product. Flash column chromatography using CH₂Cl₂:MeOH:NH₄OH (conc)/25:1:0.1 provided the desired compound 14 (0.216 g, 84 %) as a white foam: ¹H NMR (500 MHz, CDCl₃) δ 9.48 (br s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.33 (dd, J₁ = 1.5 Hz, J₂ = 7.8 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 4.84 (s, 2H), 3.19 (m, 1H), 2.94 (d, J = 18.8 Hz, 1H), 2.72 (m, 2H), 2.48 (dd, J₁ = 6.3 Hz, J₂ = 12.5 Hz, 1H), 2.34 (dd, J₁ = 6.6 Hz, J₂ = 12.5 Hz, 1H), 2.01 (m, 3H), 1.42 (s, 3H), 1.34 (d, J = 11.4 Hz, 1H), 0.92 (m, 1H), 0.84 (d, J = 6.8 Hz, 3H), 0.51 (m, 2H), 0.12 (m, 2H); IR (film) ν_max 3365, 2921, 1634, 1577 cm^-1; MS (CI) m/z 314 (M + H)⁺; Anal. calc. for C₁₉H₂₇N₃O: C, 72.81; H, 8.68; N, 13.47. Found: C, 72.96; H, 8.67; N, 13.18.

[0041] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-thiocarboxamide [5]. A modification of a known procedure (Varma R. S.; Kumar, D. Organic Lett. 1999, 1, 697-700) was used in this preparation. A mixture of (±)-3-(cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carboxamide [4] (0.0298 g, 0.1 mmol) and Lawsson's reagent (0.0320 g, 0.08 mmol) in 1 mL of toluene was sealed in a glass tube under an argon atmosphere. The glass tube was put in a microwave oven and irradiated for 7 min. Additional Lawsson's reagent (0.0160 g, 0.04 mmol) was added and the reactants was allowed to be irradiated for additional 7 min. The reaction mixture was taken up in 10 mL of CH₂Cl₂ and washed with water. The organic phase was dried with sodium sulfate and evaporated to give crude product. Chromatography on silica gel using CH₂Cl₂:MeOH:NH₄OH (conc)/40:1:0.1 the provided desired compound 5 (0.022 g , 70.1 %) as a yellow crystalline solid: mp 171-173 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.78 (d, J = 1.9 Hz, 1H), 7.64 (brs, 1H), 7.60(dd, J₁ = 1.9 Hz, J₂ = 8.1 Hz, 1H), 7.19 (brs, 1H), 7.09 (d, J = 8.1 Hz, 1H), 3.16 (m, 1H), 2.95 (d, J = 19.0 Hz, 1H), 2.70 (m, 2H), 2.46 (dd, J₁ = 6.1 Hz,J₂ = 12.4 Hz, 1H), 2.32 (dd, J₁ = 6.3 Hz, J₂ = 12.4 Hz, 1H), 1.92 (m, 3H), 1.43 (s, 3H), 1.34 (m, 1H), 0.85 (m, 1H), 0.83 (d, J = 7.1 Hz, 3H), 0.51 (m, 2H), 0.10 (m, 2H); IR (film) ν_max 3172, 2920, 1617, 1424 cm^-1; MS (CI) m/z 315 (M + H)⁺; Anal. calc. for C₁₉H₂₆N₂S·0.75 H₂O: C, 69.58; H, 8.45; N, 8.54. Found: C, 69.54; H, 8.15; N, 8.26.

[0042] (±)-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-methylamine [15]. (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-carbonitrile [1] (0.154 g, 0.55mmol) was dissolved in Et₂O (1.1 mL) to obtain a 0.5 M solution. This solution was added dropwise via syringe to a vigorously stirred solution of 1.0 M LiAlH₄ in Et₂O (1.1 mL, 1.1 mmol) at 0 °C. After stirring at room temperature for 10 min, water was added dropwise to quench the reaction. The resulting solution was then extracted with EtOAc several times and the combined EtOAc layers were dried (Na₂SO₄), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (CH₂Cl₂:MeOH:Et₃N/10:1:0.2) to yield the desired product 15 (0.105 g, 67%) as a brown oil: ¹H NMR (500 MHz, CDCl3) δ 7.16 (s, 1H), 7.04 (m, 2H), 3.82 (s, 2H), 3.16 (s, 1H), 2.91 (d, J = 8.3Hz, 1H), 2.70 (m, 2H), 2.49 (m, 1H), 2.34 (m, 1H), 1.92 (m, 5H), 1.39 (m, 4H), 0.85 (m, 4H), 0.51 (d, J = 7.6 Hz, 2H), 0.11 (m, 2H); IR (film) ν_max 3075, 2962, 2917, 2814, 1574, 1499, 1462, 1428, 1380, 1333, 1218, 1101, 1075, 1018, 963 cm^-1; Anal. calc. for C₁₉H₂₈N₂·0.5H₂O: C,77.77; H, 9.96; N, 9.54. Found: C,78.18; H, 10.17; N, 9.39.

[0043] (±)-N-[3-(Cyclopropylmethyl)-1,2,3,4,5,6,-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-yl]-formamide [19]. A modification of a known procedure (Chakrabarty, M.; Khasnobis, S.; Harigaya, Y.; Kinda, Y. Synthetic Comm. 2000, 30, 187-200.) was used in this preparation. (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethyl-2,6-methano-3-benzazocin-8-amine [37] (0.091 g, 0.337 mmol) was treated with 96% formic acid (20 mL) and was heated at 100 °C for 14 h. The solution was then poured onto crushed ice and basified with solid NaHCO₃. The organic material was extracted into EtOAc (3X) and the extracts were washed with water and dried (Na₂SO₄). After concentration in vacuo, the crude product was purified by flash column chromatography (CH₂Cl₂:MeOH:NH₄OH/10:1:0.05) to yield the desired product 19 as a brown oil (0.065 g, 65%): ¹H NMR (500 MHz, CDCl₃) δ 8.62 (d, J = 11.5 Hz, 0.5H, CHO of one rotomer), 8.34 (d, J = 1.7 Hz, 0.5H, CHO of other rotomer), 8.17 (d, J = 10.5 Hz, 0.5H, NH of one rotomer), 7.57 (br s, 0.5H, NH of other rotomer), 7.36 (m, 1H), 7.04 (m, 1H), 6.89 (m, 1H), 3.15 (m, 1H), 2.90 (m, 1H), 2.72 (m, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 1.95 (m, 3H), 1.32 (m, 4H), 0.85 (m, 4H), 0.51 (m, 2H), 0.11 (m, 2H); IR (film) ν_max 3265, 2963, 2922, 1694, 1682, 1614, 1538, 1503, 1462, 1402, 1380, 1311, 1218, 1100, 1074, 1020, 964, 888, 808 cm^-1; MS (CI) m/z 299 (M + H)⁺; Anal. calc. for C₁₉H₂₆N₂O · 0.125H₂O: C, 75.90; H, 8.88; N, 9.32. Found: C, 76.00; H, 8.95; N, 9.13.

[0044] The remaining compounds of Table 1 were prepared in similar fashion, except Example 8, which was made by the CO/palladium route, but with a slight variation using 2.0 M CH₃NH₂ in THF, rather than gaseous CH₃NH₂, and DMF rather than DMSO; mp = 155-156 °C; 25.6 % yield. 24 - [the (±)-8-CONH₂ analogue of ethylketocyclazocine (R² and R^2a = O; R⁶ = Et)] was made by the nitrile hydrolysis route, mp = 194-196 °C; Step 1 - 89.1 %, Step 2 - 81.4 %. 23 - [the (±)-8-CONH₂ analogue of ketocyclazocine (R² and R^2a= O; R⁶ = Me)] was made by the nitrile hydrolysis route, mp = 206-207 °C; Step 1 - 99.7 %, Step 2 - 94.2 %. It was also made by the CO/Pd route in 34.7 % yield.

[0045] In general, the chemistry described above works in the presence of the variety of functional groups found on known core structures. The exceptions would be morphine and congeners having a free 6-OH, which can be protected by a TBDPS (t-butyldiphenylsilyl) group [see Wentland et al J. Med. Chem. 43, 3558-3565 (2000)].

Claims

1. A compound of formula:

wherein

A is chosen from

Q is S;

R² and R^2a are both hydrogen or taken together R² and R^2a are =O;

R³ is chosen from hydrogen, C₁-C₆ alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;

R⁴ is chosen from hydrogen, hydroxy, amino, C₁-C₄ alkoxy, C₁-C₂₀ alkyl and C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;

R⁵ is C₁-C₆ alkyl;

R⁶ is C₁-C₆ alkyl;

R⁷ is hydrogen; or
together R⁴, R⁵, R⁶ and R⁷ may form one ring, said ring having optional additional substitution; and

R¹⁶ is chosen from hydrogen and NH₂.

2. A compound according to claim 1 wherein A is -NHCHS.

3. A 2,6-methano-3-benzazocine according to claim 1 or 2 wherein:

R⁴ is chosen from hydrogen, hydroxy, C₁-C₄ alkoxy, C₁-C₂₀ alkyl and C₁-C₂₀ alkyl substituted with hydroxy or carbonyl;

R⁵ is C₁-C₆ alkyl;

R⁶ is C₁-C₆ alkyl; and

R⁷ is hydrogen.

4. A 2,6-methano-3-benzazocine according to claim 3 wherein:

R³ is chosen from hydrogen, cyclopropyl, phenyl, vinyl, dimethylvinyl, hydroxycyclopropyl, furanyl, and tetrahydrofuranyl;

R⁴ is chosen from hydrogen and 3-oxo-5-cyclopentyl-1-pentanyl;

R⁵ is methyl; and

R⁶ is methyl or ethyl.

5. A morphinan according to claim 1 or 2 wherein together R⁵ and R⁶ form one ring and R⁷ is hydrogen, said morphinan having the structure:

6. A morphinan according to claim 5 wherein

R² and R^2a are hydrogen;

R³ is chosen from hydrogen, cyclopropyl, cyclobutyl, vinyl and tetrahydrofuranyl; and

R⁴ is hydrogen, hydroxy or amino.

7. A morphinan compound having the structure:

or a morphinan compound having the structure:

wherein

A is chosen from

Q is S;

R² and R^2a are both hydrogen or taken together R² and R^2a are =O;

R³ is chosen from hydrogen, C₁-C₆ alkyl, alkenyl, aryl, heterocyclyl, benzyl and hydroxyalkyl;

R⁴ is hydrogen, hydroxy, amino or C₁-C₄ alkoxy;

R⁹ is hydrogen or C₁-C₆ alkyl;

R¹⁰ is chosen from hydrogen, C₁-C₆ alkyl and hydroxy(C₁-C₆ alkyl); or
together, R⁹ and R¹⁰ form a spiro-fused carbocycle of 5 to 10 carbons;

R¹¹ is hydrogen;

R¹² is chosen from hydroxy, C₁-C₄ alkoxy and -NR¹³R¹⁴;
or
together, R¹¹ and R¹² form a carbonyl or a vinyl substituent; or
together, R⁴ and R¹¹ form a sixth ring; and,

R¹⁶ is chosen from hydrogen and NH₂.

8. A morphinan according to claim 7, wherein R¹¹ and R¹² form a carbonyl substituent, of formula:

9. A morphinan according to claim 8 wherein

R² and R^2a are both hydrogen;

R⁴ is chosen from hydrogen, hydroxy, amino and C₁-C₄ alkoxy; and

R⁹ and R¹⁰ are both hydrogen or

together, R⁹ and R¹⁰ form a spiro-fused carbocycle of 5 to 10 carbons.

10. A morphinan according to claim 9 wherein R⁹ and R¹⁰ are both hydrogen.

11. A morphinan according to claim 7, wherein R¹¹ and R¹² form a vinyl substituent, of formula:

12. A morphinan according to claim 11 wherein

R² and R^2a are both hydrogen;

R⁴ is hydroxy; and

R⁹ and R¹⁰ are both hydrogen.

13. A morphinan according to claim 7 wherein

R² and R^2a are both hydrogen;

R⁴ is hydroxy;

R⁹ and R¹⁰ are both hydrogen; and

R¹² is chosen from: -NH₂, -N(CH₂CH₂Cl)₂, and -NHC(O)CH=CHCOOCH₃.

14. A compound according to any of claims 1 to 13 as a medicament.

15. Use of a compound according to any of claims 1 to 13 for the preparation of a medicament for the treatment of a disease or a condition mediated by an opioid receptor.

16. Use according to claim 15 wherein said disease or condition is chosen from the group consisting of pain, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, coughing, hyperalgesia and drug addiction.

Ansprüche

1. Eine Verbindung der Formel:

wobei

A ausgewählt ist aus

Q S ist;

R² und R^2a beide Wasserstoff oder R² und R^2a gemeinsam =O sind;

R³ ausgewählt ist aus Wasserstoff, C₁-C₆-Alkyl, Alkenyl, Aryl, Heterocyclyl, Benzyl und Hydroxyalkyl;

R⁴ ausgewählt ist aus Wasserstoff, Hydroxy, Amino, C₁-C₄-Alkoxy, C₁-C₂₀-Alkyl und C₁-C₂₀-Alkyl substituiert mit Hydroxy oder Carbonyl;

R⁵ C₁-C₆-Alkyl ist;

R⁶ C₁-C₆-Alkyl ist;

R⁷ Wasserstoff ist; oder
R⁴, R⁵, R⁶ und R⁷ gemeinsamen einen Ring bilden, wobei besagter Ring optional zusätzliche Substitution aufweist;

R¹⁶ ausgewählt ist aus Wasserstoff und NH₂.

2. Eine Verbindung nach Anspruch 1, wobei A-NHCHS ist.

3. Ein 2,6-Methano-3-Benzazocin nach Anspruch 1 oder 2 ist, wobei:

R⁴ ausgewählt ist aus Wasserstoff, Hydroxy, C₁-C₄-Alkoxy, C₁-C₂₀-Alkyl und C₁-C₂₀-Alkyl substituiert mit Hydroxy oder Carbonyl;

R⁵ C₁-C₆-Alkyl ist;

R⁶ C₁-C₆-Alkyl ist; und

R⁷ Wasserstoff ist.

4. Ein 2,6-Methano-3-Benzazocin nach Anspruch 3, wobei:

R³ ausgewählt ist aus Wasserstoff, Cyclopropyl, Phenyl, Vinyl, Dimethylvinyl, Hydroxycyclopropyl, Furanyl, und Tetrahydrofuranyl;

R⁴ ausgewählt ist aus Wasserstoff und 3-Oxo-5-cyclopentyl-1-pentanyl;

R⁵ Methyl ist; und

R⁶ Methyl oder Ethyl ist.

5. Ein Morphinan nach Anspruch 1 oder 2 ist, wobei R⁵ und R⁶ gemeinsam einen Ring bilden und R⁷ ein Wasserstoff ist, wobei besagtes Morphinan folgende Struktur aufweist:

6. Ein Morphinan nach Anspruch 5, wobei

R² und R^2a Wasserstoff sind;

R³ ausgewählt ist aus Wasserstoff, Cyclopropyl, Cyclobutyl, Vinyl und Tetrahydrofuranyl; und

R⁴ Wasserstoff, Hydroxy oder Amino ist.

7. Eine Morphinan-Verbindung der Struktur:

oder eine Morphinan-Verbindung der Struktur:

wobei

A ausgewählt ist aus

Q S ist;

R² und R^2a beide Wasserstoff oder R² und R^2a gemeinsam =O sind;

R³ ausgewählt ist aus Wasserstoff, C₁-C₆-Alkyl, Alkenyl, Aryl, Heterocyclyl, Benzyl und Hydroxyalkyl;

R⁴ Wasserstoff, Hydroxy, Amino oder C₁-C₄-Alkoxy ist;

R⁹ Wasserstoff oder C₁-C₆-Alkyl ist;

R¹⁰ ausgewählt ist aus Wasserstoff, C₁-C₆-Alkyl und Hydroxy(C₁-C₆-Alkyl); oder R⁹ and R¹⁰ gemeinsam einen Spiro-fusionierten Kohlenstoffzyklus von 5 bis 10 Kohlenstoffen bilden;

R¹¹ Wasserstoff ist;

R¹² aus Hydroxy, C₁-C₄-Alkoxy und -NR¹³R¹⁴ ausgewählt ist;
oder
R¹¹ and R¹² gemeinsam einen Carbonyl- oder einen Vinyl-Substituenten bilden; oder
R⁴ und R¹¹ gemeinsam einen sechsten Ring bilden, und,

R¹⁶ ausgewählt ist aus Wasserstoff und NH₂.

8. Ein Morphinan nach Anspruch 7, wobei R¹¹ und R¹² einen Carbonyl-Substituenten bilden mit der Formel:

9. Ein Morphinan nach Anspruch 8, wobei

R² und R^2a beide Wasserstoff sind;

R⁴ ausgewählt ist aus Wasserstoff, Hydroxy, Amino und C₁-C₄-Alkoxy; und

R⁹ und R¹⁰ beide Wasserstoff sind oder

R⁹ and R¹⁰ gemeinsam einen Spiro-fusionierten Kohlenstoffzyklus von 5 bis 10 Kohlenstoffen bilden.

10. Ein Morphinan nach Anspruch 9 wobei R⁹ und R¹⁰ beide Wasserstoff sind.

11. Ein Morphinan nach Anspruch 7, wobei R¹¹ und R¹² einen Vinyl-Substituenten bilden mit der Formel:

12. Ein Morphinan nach Anspruch 11, wobei

R² und R^2a beide Wasserstoff sind;

R⁴ Hydroxy ist; und

R⁹ und R¹⁰ beide Wasserstoff sind.

13. Ein Morphinan nach Anspruch 7, wobei

R² und R^2a beide Wassersoff sind;

R⁴ Hydroxy ist;

R⁹ und R¹⁰ beide Wasserstoff sind; und

R¹² ausgewählt ist aus: -NH₂, -N(CH₂CH₂Cl)₂, und -NHC(O)CH=CHCOOCH₃.

14. Eine Verbindung gemäß einem der Ansprüche 1 bis 13 als Medikament.

15. Verwendung einer Verbindung gemäß einem der Ansprüche 1 bis 13 zur Herstellung eines Medikaments zur Behandlung einer Erkrankung oder eines Zustands der durch einen Opioidrezeptor bewirkt wird.

16. Verwendung gemäß Anspruch 15 wobei besagte Erkrankung oder Zustand ausgewählt ist aus der Gruppe, bestehend aus Schmerz, Juckreiz, Diarrhöe, Reizdarmsyndrom, gastrointestinaler Motilitätsstörung, Fettleibigkeit, Atemdepression, Krämpfen, Husten, Hyperalgesie und Drogensucht.

Revendications

1. Composé de formule :

dans laquelle

A est choisi parmi

Q est S ;

R² et R^2a sont tous les deux un atome d'hydrogène, ou pris ensemble R² et R^2a sont =O ;

R³ est choisi parmi un atome d'hydrogène, un groupe alkyle en C₁-C₆, un groupe alcényle, un groupe aryle, un groupe hétérocyclyle, un groupe benzyle et un groupe hydroxyalkyle ;

R⁴ est choisi parmi un atome d'hydrogène, un groupe hydroxy, un groupe amino, un groupe alcoxy en C₁-C₄, un groupe alkyle en C₁-C₂₀ et un groupe alkyle en C₁-C₂₀ substitué par un groupe hydroxy ou carbonyle ;

R⁵ est un groupe alkyle en C₁-C₆ ;

R⁶ est un groupe alkyle en C₁-C₆ ;

R⁷ est un atome d'hydrogène ; ou

R⁴, R⁵, R⁶ et R⁷ peuvent ensemble former un cycle, ledit cycle ayant une substitution supplémentaire facultative ; et

R¹⁶ est choisi parmi un atome d'hydrogène et NH₂.

2. Composé selon la revendication 1, dans lequel A est -NHCHS.

3. 2,6-méthano-3-benzazocine selon la revendication 1 ou 2, dans laquelle :

R⁴ est choisi parmi un atome d'hydrogène, un groupe hydroxy, un groupe alcoxy en C₁-C₄, un groupe alkyle en C₁-C₂₀ et un groupe alkyle en C₁-C₂₀ substitué par un groupe hydroxy ou carbonyle ;

R⁵ est un groupe alkyle en C₁-C₆ ;

R⁶ est un groupe alkyle en C₁-C₆ ; et

R⁷ est un atome d'hydrogène.

4. 2,6-méthano-3-benzazocine selon la revendication 3, dans laquelle :

R³ est choisi parmi un atome d'hydrogène, un groupe cyclopropyle, un groupe phényle, un groupe vinyle, un groupe diméthylvinyle, un groupe hydroxycyclopropyle, un groupe furanyle, et un groupe tétrahydrofuranyle ;

R⁴ est choisi parmi un atome d'hydrogène et groupe 3-oxo-5-cyclopentyl-1-pentanyle ;

R⁵ est un groupe méthyle ; et

R⁶ est un groupe méthyle ou éthyle.

5. Morphinane selon la revendication 1 ou 2, dans lequel R⁵ et R⁶ ensemble forment un cycle et R⁷ est un atome d'hydrogène, ledit morphinane ayant la structure :

6. Morphinane selon la revendication 5, dans lequel

R² et R^2a sont un atome d'hydrogène ;

R³ est choisi parmi un atome d'hydrogène, un groupe cyclopropyle, un groupe cyclobutyle, un groupe vinyle et un groupe tétrahydrofuranyle ; et

R⁴ est un atome d'hydrogène, un groupe hydroxy ou un groupe amino.

7. Composé de morphinane ayant la structure :

ou un composé de morphinane ayant la structure :

dans lesquelles

A est choisi parmi

Q est S ;

R² et R^2a sont tous les deux un atome d'hydrogène, ou pris ensemble R² et R^2a sont =O ;

R³ est choisi parmi un atome d'hydrogène, un groupe alkyle en C₁-C₆, un groupe alcényle, un groupe aryle, un groupe hétérocyclyle, un groupe benzyle et un groupe hydroxyalkyle ;

R⁴ est un atome d'hydrogène, un groupe hydroxy, un groupe amino ou groupe alcoxy en C₁-C₄ ;

R⁹ est un atome d'hydrogène ou un groupe alkyle en C₁-C₆ ;

R¹⁰ est choisi parmi un atome d'hydrogène, un groupe alkyle en C₁-C₆ et un groupe hydroxy(alkyle en C₁-C₆) ; ou

R⁹ et R¹⁰ ensemble forment un carbocycle condensé en spiro de 5 à 10 atomes de carbone ;

R¹¹ est un atome d'hydrogène ;

R¹² est choisi parmi un groupe hydroxy, un groupe alcoxy en C₁-C₄ et -NR¹³R¹⁴;
ou

R¹¹ et R¹² ensemble forment un substituant carbonyle ou vinyle ; ou

R⁴ et R¹¹ ensemble forment un sixième cycle ; et

R¹⁶ est choisi parmi un atome d'hydrogène et NH₂.

8. Morphinane selon la revendication 7, dans lequel R¹¹ et R¹² forment un substituant carbonyle, de formule :

9. Morphinane selon la revendication 8, dans lequel

R² et R^2a sont tous les deux un atome d'hydrogène ;

R⁴ est choisi parmi un atome d'hydrogène, un groupe hydroxy, un groupe amino et un groupe alcoxy en C₁-C₄ ; et

R⁹ et R¹⁰ sont tous les deux un atome d'hydrogène, ou

R⁹ et R¹⁰ ensemble forment un carbocycle condensé en spiro de 5 à 10 atomes de carbone.

10. Morphinane selon la revendication 9, dans lequel R⁹ et R¹⁰ sont tous les deux un atome d'hydrogène.

11. Morphinane selon la revendication 7, dans lequel R¹¹ et R¹² forment un substituant vinyle, de formule :

12. Morphinane selon la revendication 11, dans lequel

R² et R^2a sont tous les deux un atome d'hydrogène ;

R⁴ est un groupe hydroxy ; et

R⁹ et R¹⁰ sont tous les deux un atome d'hydrogène.

13. Morphinane selon la revendication 7, dans lequel

R² et R^2a sont tous les deux un atome d'hydrogène ;

R⁴ est un groupe hydroxy ;

R⁹ et R¹⁰ sont tous les deux un atome d'hydrogène ; et

R¹² est choisi parmi : -NH₂, -N(CH₂CH₂Cl)₂, et -NHC(O)CH=CHCOOCH₃.

14. Composé selon l'une quelconque des revendications 1 à 13 comme médicament.

15. Utilisation d'un composé selon l'une quelconque des revendications 1 à 13, pour la préparation d'un médicament pour le traitement d'une maladie ou d'une affection médiée par un récepteur des opioïdes.

16. Utilisation selon la revendication 15, dans laquelle ladite maladie ou ladite affection est choisie dans le groupe constitué de la douleur, du prurit, de la diarrhée, du syndrome du côlon irritable, d'un trouble de la motilité gastro-intestinale, de l'obésité, de la dépression respiratoire, des convulsions, de la toux, de l'hyperalgésie et de la toxicomanie.