Kappa opioid receptor ligands

IS 2 300 436 T3

DESCRIPTION

Kappa Opioid Receptor Ligands.

Background of the invention

Scope of the invention

The present invention relates to compounds that bind with high affinity and / or specificity to kappa opiate receptors.

Background of the invention

The study of the compounds that exert their functions through the opioid receptor system has gone on for almost eight decades. Although this has been a broad effort, the fundamental driving force for this endeavor relates to the elimination or reduction of the side effect profile produced by the most frequently used or abused opiates morphine (1) and heroin (2) in Figure 1. Among the many side effects produced by Compounds 1 and 2, addiction, tolerance, and respiratory depression are of greatest concern when considering heroin abuse. Although its use declined in the late 1970s, increases in both purity and availability of this drug have promoted a serious resurgence of illegal use. In the study and treatment of substance abuse, opiate receptor antagonists such as naltrexone (3) (Fig. 1) have played a predominant role. In recent years, researchers studying the physiological mechanisms underlying addiction have looked for selective antagonists of each of the three opioid receptor subtypes mu, delta, and kappa. Extensive research efforts along these lines led to the discovery of several such compounds, including the examples cyprodime (mu, 4), naltrindole (delta, 5), and norbinaltorphimine (kappa, 6) (Fig. 1). Of the three, the kappa receptor has provided only reluctantly antagonists and, of the known examples, all derive from modification of the norbinaltorphimine prototype (nor-BNI, 6).

Portoghese in its pioneering work provided not only second and third generation kappa antagonists (5 '[(N2-butylamidino) methyl] naltrindole (7) and C5'-guanidinylnaltrindole (GNTI, 8), but also convincing evidence that the residue Glu297 at the 6 transmembrane helix of the kappa receptor is the main targeting site that influences the kappa selectivity found at 6-8 (Fig. 1). In terms of the message targeting concept applied by Portoghese to opiate small molecules, it is the pendant amine functionality (marked with asterisks in the schematic) present at 6-8 that functions as a kappa targeting element by interacting with the Glu297 residue that it is present at the kappa receptor, but not at the mu receptor.

In terms of substance abuse treatment, selective kappa receptor antagonists have been the least studied mainly due to the limited bioavailability of 6 and its analogues. However, growing evidence that the endogenous kappa opiate system opposes the actions of mu agonists like 2 suggests that selective antagonists of the kappa receptor system could suppress or eliminate withdrawal symptoms arising from an overactive kappa receptor system. and therefore promote abstinence and avoid relapse. Therefore, the development of novel kappa antagonists having improved pharmacokinetic profiles would be of great value.

As is obvious from the above examples, the morphinan substructure of 3 has served as the primary template upon which selective antagonists have been built. Contrary to these efforts, the inventors' work in this field began from the relatively unstudied class of opioid antagonists of N-substituted trans (3,4) -dimethyl-4- (3-hydroxyphenyl) piperidine discovered by Zimmerman and cabbage. Compounds like 9a and 9b (Fig. 1) were novel opiate antagonists because their intrinsic antagonist activity was not mediated by the structure of their N substituent (specifically, the N-methyl (9a) and N-cyclopropylmethyl (9b) analogs in the phenylpiperidine series are both antagonists cigars). Furthermore, no N substituent has been discovered that converts this series of compounds to an agonist. Compounds 10-12 (Fig. 1) represent some of the structures tested to date. In this regard, it has recently been shown by the inventors that compounds bearing the substituent at N trans-cinnamyl, as found at 13 (Fig. 1), most closely reproduced the potency at the mu opiate receptor of the substituted analogs. in N flexible (10-12). Indeed, the comparable mu receptor potencies demonstrated by the trans- (3,4) -dimethyl-4- (3-hydroxyphenyl) piperidine analogs possessing the trans-cinnamyl moiety led the inventors to speculate that, in their conformation Biologically active compounds such as 10-12 have the connecting chain and attached ring at their N substituent extended away from the piperidine nitrogen in a manner consistent with the trans-cinnamyl backbone as found at 13.

Opioid receptor antagonist and agonist compounds containing a bridged piperidinyl or piperidinyl group have been disclosed in WO 99/45925.

In more recent studies comparing opiate receptor potency and selectivity to N-substituent changes in this series of antagonists, the inventors found 14-21 (Fig. 1). These compounds were derived from screening compound libraries that were biased toward opiate antagonist activity by incorporating trans- (3,4) -dimethyl-4- (3-hydroxyphenyl) piperidine into each ligand. In biological assays, these compounds (14-21) were found to possess selectivity for the kappa opioid receptor subtype in binding assays.

IS 2 300 436 T3

Summary of the invention

It is an object of the invention to provide compounds that bind to kappa opiate receptors with high affinity.

It is another object of the invention to provide compounds that bind to kappa opiate receptors with high specificity.

It is another object of the invention to provide compounds that bind to kappa opiate receptors with high affinity and specificity in functional assays.

The objects of the present invention, and others, are achieved with compounds of the structures described herein, particularly compounds 14-21, which have the above advantages. To the inventors' knowledge, compounds 14, 18, 19 and 20 have the highest affinity and selectivity for the kappa opiate receptor of all the compounds reported so far (Table 1). Compound 14 was also studied in the [³⁵ SIGTPyS and, in particular, it maintained selectivity for kappa between the binding and functional assays and showed a K value of 0.006 nM for the kappa receptor and a K, mu / kappa ratio of 570 (Table 3).

Brief description of the figures

A more complete appreciation of the invention and many of the accompanying advantages thereof will be readily obtained as the same is better understood by reference to the following detailed description, when considered in connection with the accompanying drawings, in the that:

Figure 1: chemical structure of compounds (1) - (21);

Figure 2: synthetic route to compounds (14-20);

Figure 3: synthetic route to compound 21.

Detailed description of the invention

The present invention provides opiate kappa antagonists that bind to opiate kappa receptors with high affinity and / or specificity. The compounds of the present invention are those represented by formula (I):

Ys r₃

<img file="ES2300436T3_D0001.tif" />

N

OQ (I) where Q is H or CO-C alkyl_1-8;

IS 2 300 436 T3

<img file="ES2300436T3_D0002.tif" />

Yi is H, OH, Br, Cl, F, CN, CF₃, DO NOT₂, N₃, OR₈, CO₂R₉, Ci_ alkyl₆, NR10R11, NHCORi₂, NHCO₂R₁₂, CONRi₃R_m, CH₂(CH₂)_nY₂;

Y₂ is H, CF₃, CO₂R₉, C alkyl_1-6, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₂, CONR₁₃R₁₄, CH₂OH, CH₂OR₈, CAR₂R₉;

Y3 is H, OH, Br, Cl, F, CN, CF3, NO2, N3, OR8, CO2R9, C1-6 alkyl, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2 (CH2)_nY2;

R2 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl or CH2-aryl substituted with one or more Y1 groups;

R3 is H, C1 8 alkyl, C3 8 alkenyl, C3 8 alkynyl or CH2-aryl substituted with one or more Y1 groups;

in which R₂ and R₃ can be linked together to form a C alkyl group_{2 8};

R₄ is hydrogen, C alkyl_1-8, CO₂-alkyl C_1-8-aryl substituted with one or more Y groups₁, CH₂-aryl substituted with one or more groups Y1 or CO2-C1 8 alkyl;

Z is N, O, or S; when Z is O or S, there is no R₅;

R₅ is H, C alkyl_1-8, alkenyl C_3-8, C alkynyl_3-8, CH₂CO₂-C alkyl_1-8, CO₂-C alkyl_1-8 or CH₂-aryl substituted with one or more Y groups₁ (when Z is O or S, there is no R₅):

n is 0, 1, 2, or 3;

R6 is a group selected from the group consisting of the structures (a) - (bbb):

<img file="ES2300436T3_D0003.tif" />

IS 2 300 436 T3

<img file="ES2300436T3_D0004.tif" />

IS 2 300 436 T3

<img file="ES2300436T3_D0005.tif" />

IS 2 300 436 T3

<img file="ES2300436T3_D0006.tif" />

IS 2 300 436 T3

<img file="ES2300436T3_D0007.tif" />

IS 2 300 436 T3

<img file="ES2300436T3_D0008.tif" />

X₁ is hydrogen, C alkyl_1-8, alkenyl C_{3 8}, C alkynyl_{3 8};

X₂ is hydrogen, C alkyl₁_₈, alkenyl C₃_₈, C alkynyl₃_₈; or

IS 2 300 436 T3

X₁ and X₂ together they form = O, = S, = NH;

R₇ is H, C alkyl_1-8, CH₂-aryl substituted with one or more Y substituents₁, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₃, CONR14R15, CH2 (CH2) nY2, C (= NH) NRi₆R_n;

R₈ is H, C alkyl_1-8, CH₂-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF₃, DO NOT₂, N₃, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R₉ is H, C alkyl_1-8, CH₂-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF₃, DO NOT₂, N₃, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R₁₀ is H, C alkyl_1-8, CH₂-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF₃, DO NOT₂, N₃, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R11 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R12 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R13 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R14 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R₁₅ is H, C alkyl_1-8, CH₂-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF₃, DO NOT₂, N₃, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R16 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6;

R17 is H, C1-8 alkyl, CH2-aryl substituted with one or more substituents H, OH, Br, Cl, F, CN, CF3, NO2, N3, C alkyl_1-6 or CH₂(CH₂)_nY₂', in which Y₂'is H, CF₃ or C alkyl_1-6.

Preferably, the compounds of the present invention are those represented by formula I as shown above, wherein R₁, R₄, R₅, Y₁, Y₂, Z, n, X₁, X₂ and R₇-R₁₇ They are as indicated above;

Y3 is H;

R₂ and R₃ are each independently H, C alkyl_1-8, alkenyl C_3-8, C alkynyl_3-8, CH₂-aryl substituted with one or more Y1 substituents; Y

R₆ is a group having a formula selected from the group consisting of structures (a) - (cc) above.

More preferably, the compounds of the present invention are those represented by formula I as shown above, where Y₁, Y₂, R₄, R₅, Z, n, X₁, X₂ and R₈-R₁₅ They are as indicated above;

<img file="ES2300436T3_D0009.tif" />

Y3 is H;

R₂ and R₃ are each independently H or C alkyl_1-8, in which R₂ and R₃ they cannot both be H at the same time;

R6 is a formula selected from structures (a) - (r) shown above; Y

R₇ is H, C alkyl_1-8, CH₂-aryl substituted with one or more Y substituents₁, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₃, CONR14R15 or CH2 (CH2)_nY2.

IS 2 300 436 T3

Even more preferably, the compounds of the present invention are those represented by formula I as shown above, wherein Y₁, Z, n, X₁, X₂ and R₈ -R₁₅ They are as indicated above;

R₁ is C alkyl_1-8;

Y2 is H, CF3, CO2R9, C1_ alkyl₆, NR10R11, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9;

Y3 is H;

R₂ and R₃ are each independently H or methyl, where R₂ and R₃ they cannot both be H at the same time;

R₄ is H, C alkyl_1-8, CO₂-C alkyl_1-8, CH₂-aryl substituted with one or more Y substituents₁ and the stereocenter adjacent to R₄ is in an (S) configuration;

R₅ is H, C alkyl_1-8, CH₂CO₂-C alkyl_1-8;

R₆ is a group having a formula selected from the group consisting of structures (a) - (c) and (h) - (o);

R₇ is H, C alkyl_1-8, CH₂-aryl substituted with one or more Y substituents₁, NR₁₀R₁₁, NHCOR₁₂, NHCO₂R₁₃, CONR14R15 or CH2 (CH2)_nY2.

Most preferably, the compounds of the present invention are those represented by formula I as shown above, wherein Y₁, Z, n, X₁, X₂ and R₈-R₁₄ They are as indicated above;

R1 is methyl;

Y2 is H, CF3, CO2R9, C1_ alkyl₆, NR_wR_n, NHCOR12, NHCO2R12, CONR13R14, CH2OH, CH2OR8, COCH2R9;

Y3 is H;

R₂ and R₃ are each H or methyl, such that when R₂ is H, R₃ let it be methyl and vice versa;

R₄ is C alkyl_1-8, CO₂-C alkyl_1-8 and the stereocenter adjacent to R₄ has an (S) configuration;

R₅ it's H;

R₆ is a group having a formula selected from the group consisting of (a) and (b); Y

R₇ is H, C alkyl_1-8, CH₂-aryl substituted with one or more Y substituents₁ or CH₂(CH₂)_nY₂.

The most preferred set of compounds are the compounds of formulas 14-21 as shown in Fig. 1.

As used throughout this description, the terms "alkyl group" or "alkyl radical" comprise all structural isomers thereof, such as linear, branched and cyclic alkyl groups and moieties. Unless otherwise indicated, all alkyl groups described herein may have 1 to 8 carbon atoms, including all specific values ​​and sub-ranges between them such as 2, 3, 4, 5, 6, or 7 carbon atoms. carbon.

The alkenyl group or alkynyl group can have one or more double or triple bonds, respectively. As will be readily appreciated, when an alkenyl or alkynyl group is attached to a heteroatom, a double or triple bond does not form with the carbon atom attached directly to the heteroatom.

The aryl group is a hydrocarbon aryl group such as a phenyl, naphthyl, phenanthrenyl or anthracenyl group, which may have one or more C alkyl group substituents_1-4.

The compounds of the present invention are opiates which are preferably antagonists that are selective for the kappa receptor. The selectivity κ / μ can be at least 2: 1, but is preferably greater, for example, at least 5: 1, 10: 1, 25: 1, 50: 1, 100; 1, 200: 1 or even 500: 1. The κ / μ selectivity can be at least 2: 1, but is preferably higher, for example at least 5: 1, 10: 1, 25: 1, 50: 1, 100: 1, 200; 1, 250 : 1, 500: 1 or even 1000: 1.

The compounds of the present invention can be synthesized, for example, according to the reaction sequence shown in Figure 2 and Figure 3.

The compounds of the present invention can be in the form of a pharmaceutically acceptable salt by protonation of the amines with a suitable acid. The acid can be an inorganic acid or an organic acid. Suitable acids include, for example, hydrochloric, hydroiodic, hydrobromic, sulfuric, phosphoric, citric, acetic, fumaric, and formic acids.

IS 2 300 436 T3

The receptor selectivities discussed above are determined based on the indicated receptor binding affinities or their selectivity in opiate functional assays.

The compounds of the present invention can be used to bind to opiate receptors. Such binding can be achieved by contacting the receptor with an effective amount of the compound of the invention. Of course, said contacting is preferably carried out in an aqueous medium, preferably at ionic strength, pH, etc. physiologically relevant.

The compounds of the invention can also be used to treat patients who have disease states that are ameliorated by binding to opiate receptors or in any treatment in which temporary suppression of the kappa opiate receptor system is desired. Such disease states include opiate addiction (such as heroin addiction) or cocaine addiction. The compounds of the present invention can also be used as cytostatic agents, as antimigraine agents, as immunomodulators, as immunosuppressants, as antiarthritic agents, as antiallergic agents, as viricides, to treat diarrhea, as antipsychotics, as antischizophrenics, as antidepressants, as uropathic agents , as cough suppressants, as anti-addictive agents, as anti-smoking agents, to treat alcoholism, as hypotensive agents, to treat and / or prevent paralysis resulting from traumatic ischemia, as general neuroprotection against ischemic trauma, as adjuncts to treatment with hyperalgesia nerve growth factor and nerve grafts, as antidiuretics, as stimulants, as anticonvulsants, or to treat obesity . Additionally, the present compounds can be used in the treatment of Parkinson's disease as an adjunct to L-dopa for the treatment of dyskinesia associated with L-dopa treatment.

The compounds can be administered in an effective amount by any of the conventional techniques well established in the medical field. For example, the compounds can be administered orally, intravenously, or intramuscularly. When so administered, the compounds of the invention may be combined with any of the well-known pharmaceutical carriers and additives commonly used in such pharmaceutical compositions. For a discussion of dosage forms, carriers, adjuvants, pharmacodynamics, etc., see KirkOthmer, "Encyclopedia of Chemical Technology," 4^to edition, vol. 18, 1996, p. 480-590, incorporated herein by reference. The patient is preferably a mammal, with human patients being especially preferred. Effective amounts are readily determined by those of skill in the art. Studies by the present inventors show no toxicity or lethality by the present compounds at amounts up to 300 mg / kg in mice.

The compounds of the present invention can be administered as a single daily dosage, or as multiple daily dosages. When administered as multiple dosages, the dosages can be equal doses or doses of varying amount, based on the time between doses (specifically, when there is a long time between doses, such as overnight while sleeping, the dose administered will be higher. to allow the compound to be present in the patient's blood stream for the longest period of time at effective levels). Preferably, the compound and compositions containing the compound are administered in a single dose or 2-4 equal doses per day.

Suitable compositions containing the present compounds further comprise a physiologically acceptable carrier such as water or conventional pharmaceutical solid carriers and, if desired, one or more buffers and other excipients.

Examples

This invention having been generally described, a further understanding may be obtained by reference to certain specific examples which are provided herein for purposes of illustration only, and which are not intended to be limiting unless otherwise specified.

Chemistry

Coupling of (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) piperidine (22) with eerc-butoxycarbonyl-protected L-valine (Boc-protected) using benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (reagent BOP) in THF and removal of the Boc protecting group with trifluoroacetic acid (TFA) in methylene chloride, followed by reduction using a solution of borane-dimethyl sulfide complex in tetrahydrofuran (THF), provided the intermediate amine 3- [1- (2S-amino-3-methylbutyl) -3R, 4R-dimethyl-4-piperidinyl] phenol (23) in 74% yield (Figure 2). From this versatile intermediate, (3R) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1- piperidinyl] -methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (14), (3S) -7-hydroxy-N - ((1S) -1 {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) - 1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (15) and (3R) -N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4- dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (16) by first coupling with Boc-D-7-hydroxy-1,2,3 acid, 4-tetrahydroisoquinoline-3-carboxylic (para 14), Boc-L-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (for 15) or Boc-D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (for 16) respectively , followed by removal of Boc protecting groups with TFA as described above. Treatment of intermediate (3R) -7-hydroxy-3 {[((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl Erc-butyl} -2-methyl-propyl) amino] carbonyl) -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate (24) with lithium aluminum hydride in refluxing THF, followed by basic work-up, afforded (3R) -3 - {[((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] -methyl} -2

ES 2 300 436 T3 methylpropyl) amino] methyl} -2-methyl-1,2,3,4-tetrahydro-7-isoquinolinol (20). The compounds (3R) -2- (N, N-dimethylglycyl) 7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl- 1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3isoquinolinecarboxamide (17), (3S) -7-hydroxy-N - ((1S) -1 - {[(3R, 4 R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -

2-methylpropyl) -2-methyl-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (18) and (3R) -3 - {[((1 S) -1 - {[(3R, 4R ) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) amino] methyl} -1,2,3,4-tetrahydro-7-isoquinolinol (19) were derived each of (3R) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2 -methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (14) by different synthetic routes. For example, compound 19 was prepared by reducing 14 with borane in THF as described above. Compound 18 was prepared by treating with formalin and sodium triacetoxyborohydride, followed by basic work-up. Compound 17 was prepared from 14 by a BOP-mediated coupling with N, N-dimethylglycine. As shown in Figure 3, the compound (3R) -7-hydroxy-N - ((1S) -1 - {[(3S, 4S) -4- (3-hydroxyphenyl) -3,4-dimethyl -1-piperidinyl] methyl} -2methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (21) according to the same synthetic route used to obtain 14. Thus, coupling of (-) - (3S, 4S) -dimethyl-4- (3-hydroxyphenyl) piperidine (25) with tert-butoxycarbonyl protected L-valine using BOP reagent in THF and removal of Boc protecting group with TFA , followed by borane reduction, provided the amine intermediate 3- [1- (2S-amino-3-methylbutyl) -3S, 4S-dimethyl-4-piperidinyl] phenol (26). Coupling with Boc-D-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid provided (3R) -7-hydroxy-3 {[((1S) -1 - {[(3S, 4S Tert-butyl) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] -methyl} -2-methylpropyl) amino] carbonyl} -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate ( 27), which then provided (3R) -7-hydroxy-N - ((1S) -1 - {[(3S, 4S) 4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2- methylpropyl) -1,2,3,4-tetrahydroisoquinolinecarboxamide (21) after removal of the Boc protecting group with TFA as described above.

biology

The binding affinities of the novel kappa antagonists 14-21 and the standard kappa antagonist nor-BNI (6) at mu, delta and kappa opiate receptors were determined using competitive binding assays following procedures outlined above, Table 1. The Measures of antagonism were obtained by monitoring the ability of selected test compounds to inhibit stimulation of [³⁵S] GTP-yS produced by selective agonists (D-Ala², MePhe⁴, Gly-ol⁵) enkephalin (DAMGO, mu receptor), (+) - 4 - [(aR) -a- (2s, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl] -N, N- diethylbenzamide (SNC-80, delta) and 5a, 7a, 8j6 - (-) - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro- [4,5] dec-8-yl] benzeneacetamide (U69.593, kappa) in guinea pig caudate nucleus (Table 2) and in cloned human recipients, Table 3.

Results and Discussion

Inspection of the binding data in Table 1 for the standard antagonist nor-BNI (6) indicates that it has a much higher affinity for the kappa receptor (K, = 1.09) over the mu receptor (K, = 65). or the delta receptor (K, = 86). Thus, in this assay the standard kappa antagonist behaves as expected with a 60-fold selectivity for the kappa receptor versus the mu receptor and a 79-fold selectivity for the kappa receptor versus delta. Comparison of the data for novel compounds 14-21 reveals that all of these compounds possess higher delta / kappa selectivity over 6 and many possess higher mu / kappa selectivity. In terms of kappa receptor binding affinity, many of the novel compounds, eg, 14 and 18-20, possess much higher affinity than the standard kappa antagonist nor-BNI (6). Furthermore, 18-20 are much more selective for the kappa receptor for mu and delta. With a K value of 2.1 nM at the kappa receptor, compound 16 is slightly less potent than nor-BNI (6); however, it is also much more selective for the kappa receptor. Compounds and 21, which are diastereomers of 14, possess a weaker affinity for the kappa receptor and / or less selectivity. These discoveries show the novelty of 14 and its analogues.

In a functional assay using guinea pig membranes (Table 2), the standard antagonist nor-BNI (6) shows a 28-fold increase in its K, with respect to that observed in the binding assay. However, at the mu and delta receptors, the K's of 6 of 16.7 nM and 10.2 nM represent only 4-fold and 8.5-fold increases, respectively. In general, this translates into a significant increase in the selectivity of mu versus kappa and delta versus kappa in this assay relative to their performance in the binding assay. The novel compound 14 also shows an improvement in its K, by the kappa receptor in this assay over the binding assay (K = 0.02 nM). Coupled with the observation that the K, by compound (14) at the mu or delta receptors does not increase substantially, it results in a selectivity of mu against kappa of more than 100 times and a selectivity for the delta receptor against kappa record of&gt; 15,000 times.

In the most relevant functional assay using cloned human opiate receptors, the novel antagonist 14 demonstrates a 3.4-fold increase in affinity for the kappa receptor over the functional assay using guinea pig membranes. This represents an overall 53-fold improvement in the Ki of the kappa receptor compared to the binding assay, and as before, there is a small shift of Ki by the mu or delta receptors. This effectively drives the selectivities of compound 14 to 570 and&gt; 16,000 fold for mu versus kappa and delta versus kappa, respectively. In this assay, it is then observed that the novel antagonist 14 is both more selective and more potent than the standard antagonist nor-BNI (6), which shows a selectivity of mu versus kappa and delta versus kappa of only 225 and 172 times, respectively. Consequently, compound 14 is, in this assay, the most potent selective kappa opioid receptor antagonist identified to date.

IS 2 300 436 T3

Conclusions

The opioid receptor binding data for compounds 14-21 showed a novel and unexpected high affinity and selectivity for the kappa opiate receptor. For example, compound 18, which has a completely different structure from nor-BNI, is 20 times more potent than the reference compound nor-BNI (6) and has much higher selectivity. Most importantly, the comparison of 14 with nor-BNI in two functional assays shows that this novel class of kappa antagonists also exhibits an even greater degree of unexpectedly high affinity and selectivity for the kappa receptor in these assays. The novel structures of compounds 14-21 and the unexpectedly high affinity and selectivity demonstrated by this new class of compounds for the kappa receptor are sufficient to warrant the definition of 14 and its analogs as prototypical structures that could be used for the design of antagonists of Additional potent and selective kappa.

TABLE 1

Results of radioligand binding to mu, delta and kappa opiate receptors for the standard compound nor-BNI (6) and the novel kappa antagonists 14-21

Κι (nM i EE)

<td>Compound</td><td>P [³H] DAMGO^to</td><td>δ [³H] DADLE^b</td><td>K [³H] U69,593^c</td><td>μ / κ</td><td>δ / κ</td>

<td>6, ñor-</td><td></td><td></td><td></td><td></td><td></td>

<td>BNI</td><td> 65,0615,6</td><td> 8617,3</td><td> 1,0910,14</td><td> 60</td><td> 79</td>

<td> 14</td><td> 3,7310,17</td><td> 301150</td><td> 0,3210,05</td><td> 12</td><td> 940</td>

<td> 15</td><td> 596129</td><td> &gt;4.900</td><td> 9, 811,6</td><td> 61</td><td> 500</td>

<td> 16</td><td> 775175</td><td> &gt;4.900</td><td> 2,110,17</td><td> 369</td><td> &gt;2.333</td>

<td> 17</td><td> 164110,5</td><td> &gt;3.400</td><td> 1511,2</td><td> 11</td><td> &gt;219</td>

<td> 18</td><td> 3711,4</td><td> 616159</td><td> 0,05310,03</td><td> 700</td><td> 11.622</td>

<td> 19</td><td> 107111</td><td> 5.5721713</td><td> 0,6310,05</td><td> 170</td><td> 8.844</td>

<td> 20</td><td> 5912,5</td><td> 2.2311187</td><td> 0,5510,04</td><td> 107</td><td> 4.056</td>

<td> 21</td><td> 13818</td><td> 144115</td><td> 17,512,5</td><td> 7,8</td><td> 8,2</td>

^to [³H] DAMGO (D-Ala², MePhe⁴, Gly-ol⁵) Encephalin. Selective tritiated ligand of the μ-opioid receptor.^b [³H] DADLE [(D-Ala², D-Leu⁵) enkephalin]. Selective tritiated ligand of the δ opioid receptor.^c [³H] U69.593 {[³H] (5α, 7α, 8β) - N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8yl] benzeneacetamide}. Selective tritiated ligand of the κ opioid receptor

IS 2 300 436 T3

TABLE 2

Inhibition by antagonists of [³⁵SJGTP-γ-Ξ in guinea pig caudate nucleus stimulated by selective opioid receptor subtype agonists DAMGO (μ), SNC80 (δ), and U69.593 (κ)

<td></td><td>Ki</td><td>functional</td><td>apparent (nM</td><td colspan="2">± EE)</td>

<td>Compound</td><td>μ</td><td>δ</td><td>K</td><td>μ / κ</td><td>δ / κ</td>

<td></td><td>DAMGO³</td><td>DADLE¹³</td><td>U69.593^c</td><td></td><td></td>

<td>6, ñor-</td><td></td><td></td><td></td><td></td><td></td>

<td>BNI</td><td> 16,7±1,5</td><td>10.2 ± l, 0</td><td> 0,038±0,005</td><td> 439</td><td> 268</td>

<td> 14</td><td> 2,16±0,75</td><td> &gt;300</td><td> 0,02±0,002</td><td> 108</td><td> &gt;15.000</td>

³ DAMGO [(D-Ala², MePhe⁴, Gly-ol⁵) enkephalin]. Selective μ-opioid receptor agonist.^b SNC-80, ([(+) - 4 [aR) -a- (2S, 5R) -4-allyl-2,5-dimethyl-1-1-piperazinyl) -3-methoxybenzyl] -N, W-diethylbenzamide). Selective agonist of the delta opioid receptor.^c U69.593 [(5α, 7α, 8β) - (-) - Nmethyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8yl] benzeneacetamide]. Selective κ opioid receptor agonist

TABLE 3

Inhibition by antagonists of [35S] GTP-yS binding at cloned human opiate receptors stimulated by selective opiate agonists DAMGO (μ), SNS-80 (δ), and U69.593 (κ)

<td></td><td colspan="2">Ki</td><td>functional</td><td>apparent (nM</td><td colspan="2">± EE)</td>

<td colspan="2">Compound</td><td>μ</td><td>δ</td><td>K</td><td>μ / κ</td><td>δ / κ</td>

<td></td><td></td><td>DAMGO³</td><td>DADLE¹³</td><td>U69.593^c</td><td></td><td></td>

<td> 6,</td><td>ñor-</td><td></td><td></td><td></td><td></td><td></td>

<td>BNI</td><td></td><td> 15,8±5,7</td><td> 12,1±3,1</td><td> 0,07±0,03</td><td> 225</td><td> 172</td>

<td> 14</td><td></td><td> 3,42+0,83</td><td> &gt;100</td><td> 0,006±0,001</td><td> 570</td><td> &gt;16.667</td>

^to DAMGO [(D-Ala², MePhe⁴, Gly-ol⁵) enkephalin] is a selective μ-opioid receptor agonist. The apparent functional Ki is the concentration of each compound necessary to produce a 50% attenuation of the binding of [³⁵S] GTP-yS stimulated by DAMGO (10 pm) ^b SNC-80, ([(+) - 4- [aR) -a- (2S, 5R) -4-allyl-2,5-dimethyl-l-piperazinyl) -3-methoxybenzyl] -N, W-diethylbenzamide) is a selective delta opioid receptor agonist. The apparent functional Ki is the concentration of each compound necessary to produce a 50% attenuation of the binding

ES 2 300 436 T3 of [³⁵S] GTP-yS stimulated by SNC80 (10 pm) ^c U69.593 [(5α, 7α, 8β) ~ (-) - N-methyl-N- [7- (1-pyrrolidinyl) 1-oxaspiro [4.5] dec-8-yl] benzeneacetamide]. Selective k opioid receptor agonist. Apparent functional concentration of each compound required to produce 50% attenuation of [³⁵S] GTP-yS stimulated by U69.593 (10 pm)

Experimental part

3- [1- (2S-Amino-3-methylbutyl) -3R, 4R-dimethyl-4-piperidinyl-phenol (23). (+) - (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) piperidine (22) (11.5 mmol), tert-butoxycarbonyl protected L-valine (11.5 mmol) and BOP reagent ( 11.5 mmol) in THF (150 ml) at room temperature, and triethylamine (TEA) or diisopropylethylamine (25.3 mmol) was immediately added thereto. After stirring for 1 h, the reaction mixture was poured into ethyl ether (500 ml) and water (150 ml) in a separatory funnel. The mixture was stirred and the aqueous phase was removed. This procedure was repeated using 150 ml of NaHCO₃ saturated and 150 ml of brine. The organic phase was diluted with hexane until turbidity and dried (Na₂SW₄), concentrated under reduced pressure, then dissolved in 100 ml of chloroform (stored over K₂CO₃) and concentrated again. This was placed in a high vacuum system to remove residual solvent, yielding an off-white foamy solid.

After standing under vacuum in the pump overnight, this non-purified material was dissolved in methylene chloride (45 ml) and cooled to -20 ° C (methanol / ice). Pure trifluoroacetic acid was added thereto in 10 ml portions over 2 min, giving a total addition of 30 ml. The entire mixture was stirred for exactly 30 min and then the cooling bath was removed for exactly 30 min. At this point, the reaction mixture was poured into a 1 L beaker containing a large stir bar and a rapidly stirred mixture of saturated bicarbonate solution (400 ml) and chloroform (150 ml). After the addition was complete, the pH of the mixture was verified to be 10 and adjusted with solid sodium bicarbonate if necessary. This mixture was poured into a separatory funnel. Any organic compounds precipitated in the separatory funnel were clarified using a small amount of methanol. The beaker was then rinsed with a small amount of water, which was added to the separatory funnel. The phases were shaken, separated and the aqueous phase was extracted an additional five times using 3: 1 methylene chloride: THF. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The material was then placed in a high vacuum pump to provide a yellow foamy solid.

The non-purified material from the deprotection step was dissolved in THF (150 ml) and cooled to -20 ° C (methanol / ice). A solution of 2M borane-dimethyl sulfide complex in THF (150 mmol) was added dropwise to this stirred mixture. The solution was then heated under reflux and held for 3 h, after which time the solution was cooled to -20 ° C and methanol (72 ml) was carefully added dropwise thereto. This mixture was stirred for 1 h at room temperature, 16.4 ml of 1M HCl in ethyl ether were added, the solution was allowed to stir for 30 min and the solvents were removed on a rotary evaporator. The resulting residue was partitioned between 3: 1 methylene chloride: tetrahydrofuran and water, the pH was adjusted to 10 with saturated sodium bicarbonate, the aqueous phase was saturated with sodium chloride and extracted several times with methylene chloride: tetrahydrofuran 3 :1. The combined organic phases were dried over sodium sulfate and the solvent was removed. This material was purified by flash chromatography on a silica gel column which was prepared by suspension packing with chloroform. The impure compound was loaded onto the column as a chloroform solution. Elution proceeded with neat chloroform followed by 3% methanol to 10% methanol in chloroform, as necessary to elute the desired compounds. The product fractions were combined and the solvent was removed on a rotary evaporator. This material was dissolved in minimal hot ethyl acetate and allowed to crystallize. The crystalline material was isolated by filtration, followed by washing with a small amount of ice cold ethyl acetate, and used directly in the next step after drying overnight in a vacuum oven. NMR-¹ II (MeOH-d₄) δ 7.126-7.062 (t, 1H), 6.7696.735 (m, 2H), 6.603-6.558 (m, 1H), 2.657-2.179 (m, 8H), 2.000 (bs, 1H), 1.583-1.502 (m, 2H), 1.294 (s, 3H), 0.9780.912 (q, 6H), 0.789-0.761 (d, 3H); NMR-¹³C (MeOH-d4) δ 158.5, 153.3, 130.1, 117.8, 113.8, 113.3, 63.4, 55.8, 54.1, 53.3, 40.0 , 39.5, 33.1, 31.9, 28.1, 19.6, 19.2, 16.8. MS (electrospray) M + 1 = 29.1. Calculated: 291.

(3R) -7-Hydroxy-3 - {[((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl) -2- tert-butyl methylpropyl) amino] carbonyl) -3,4-dihydrohydro-2 (1H) 4-soquinolinecarboxylate (24). Solid BOP reagent (1.65 g, 3.75 mmol) was added to a solution of 23 (0.943 g, 3.25 mmol), Boc-D-7-hydroxy-1,2,3,4-tetrahydro-acid isoquinoline-3-carboxylic acid (1.00 g, 3.41 mmol) and triethylamine (1.57 ml, 11.2 mmol) in dry THF (100 ml). The reaction mixture was stirred under an atmosphere of N₂ at room temperature for 2 h. The mixture was diluted with Et₂O (100 ml), washed with saturated NaHCO3, followed by water, and then the organic phase was collected, dried (Na2SO4) and the solvent was removed at

ES 2 300 436 T3 reduced pressure. The product was then purified by flash chromatography (50% of (80% CHCl3: 18% CH₃OH: 2% NH₄OH) in CHCl₃), yielding 1.52 g (83%) of 24 as a white foam. NMR¹H (CDCl₃) δ 7.14 (t, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 7.0 Hz), 6.75 (m, 2H), 6.63 (m, 3H ), 5.74 (br, 1H), 4.81 (br, 1H),

4.57 (a, 1H), 4.39 (m, 1H), 3.92 (a, 1H), 3.27 (d, 1H, J = 14.9 Hz), 2.94 (dd, 1H, J = 6.2, 15.5 Hz), 2.47-2.16 (m, 5H), 1.97 (m, 2H), 1.76 (m, 2H), 1.51 (s, 9H) , 1.40 (m, 1H), 1.21 (s, 3H), 0.85 (d, 3H, J = 6.2 Hz), 0.80 (d, 3H, J = 6.8 Hz) , 0.79 (m, 3H).

(3R) -7-Hydroxy-N - ((1S) -1 - [(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinylmethyl) -2-methylpropyl) -1, 2,3,4-tetrahydro-3-isoquinolinecarboxamide (14). Trifluoroacetic acid (16.4 ml, 212 mmol) was added dropwise over 10 min to a solution of 24 (1.00 g, 1.77 mmol) in CH₂Cl₂ dry (50 ml) at -20 ° C. The reaction was warmed to room temperature and the solvent was removed under reduced pressure. The product was purified by flash chromatography (50% of (80% CHCl₃: 18% CH₃OH: 2% NH₄OH) in CHCl₃), yielding 14 (0.801 g, 97%) as a white foam. NMR-¹H (CD3OD) δ 7.11 (dt, 1H, J = 7.9 Hz), 6.92 (d, 1H, J = 8.3 Hz), 6.74 (m, 2H), 6.59 ( m, 2H), 6.50 (m, 1H), 4.03 (m, 1H), 3.94 (d, 2H, J = 5.9 Hz), 3.54 (dd, 1H, J = 4 , 8, 10.2 Hz), 2.94 (dd, 1H, J = 4.7, 15.7 Hz), 2.80 (m, 2H), 2.67-2.37 (m, 5H) , 2.27 (dt, 1H, J = 4.2, 12.6 Hz), 1.99-1.85 (m, 2H), 1.57 (d, 1H, J = 12.7 Hz), 1.30 (s, 3H), 0.95 (m, 6H), 0.74 (d, 3H, J = 6.7Hz).

(3S) -7-Hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (15). Boc-L-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (107 mg, 1.364 mmol) was added to a solution of 3- [1- (2S-amino-3-methylbutyl) - 3R, 4R-dimethyl-4-piperidinyl] -phenol (23.100 mg, 0.364 mmol) in 10 ml of dry THF followed by BOP reagent (177 mg, 0.4 mmol) and Tea (0.166 ml, 1.194 mmol). The reaction mixture was stirred for 2 hours at room temperature, then 15 ml of ether was added and the mixture was washed with saturated NaHCO3 and then water. The organic phase was collected, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product (220 mg) was purified using silica gel column chromatography (gradient: CHCl₃ pure at 50% of (CHCl₃: MeOH: NH₄OH, 80: 18: 2) in CHCl₃). This material was dissolved in 5 ml of CH2Cl2 and cooled to -20 ° C, after which TFA (2.7 ml, 0.035 mol) was added dropwise. The reaction flask was left in a MeOH / ice bath for 10 minutes and then allowed to warm to room temperature. The solvent was removed under reduced pressure, the residue was diluted with CH2Cl2 and NaHCO was added thereto₃ saturated. The organic phase was separated and the solvent was removed under reduced pressure, yielding 120 mg of (3S) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] -methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (15). NMR-¹H (MeOH): 7.09 (t, J = 7.8 Hz, 1H), 6.87 (d, J = 4.1 Hz, 1h), 6.77 (s, 1H), 6.74 ( d, J = 0.8 Hz, 1H), 6.58 (dd, J = 8.3, 2.3 Hz, 2H), 6.48 (d, J = 2.3 Hz, 1H), 4, 01-3.95 (m, 1H), 3.90 (s, 2H), 3.51-3.48 (m, 1H), 3.35 (s, 3H), 2.94-2.21 ( m, 9H), 1.96 (d, J = 13 Hz, 1H), 1.28 (s, 3H), 0.89 (t, J = 7.2 Hz, 6H), 0.74 (d, J = 6.9 Hz, 3h). LRMS (ES) m / z 466.2 (m + H)⁺.

(3R) -N - ((1S) -1 - {[(3R, 4R) -4- (3-Hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -1.2 , 3,4-tetrahydro-3isoquinolinecarboxamide (16). 3- [1- (2S-amino-3-methylbutyl) -3R, 4R-dimethyl-4-piperidinyl] phenol (23) was coupled with 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as described for compound 15, and was deprotected with TFA as described above, yielding a crude product that was purified by preparative thin-layer chromatography on silica (50% (CHCl₃: MeOH: NH₄OH 80: 18: 2) in ChC1₃, yielding 0.028 g of (3R) -N - ((1S) -1 {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (16). NMR-¹H (CDCI3): 7.22 (d, J = 8.8 Hz, 1H), 7.05-7.13 (m, 3H), 6.98-7.01 (m, 1H), 6.79 (s, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.65 (dd, J = 7.9, 1.8 Hz, 1H), 4.05-4.14 ( m, 1H), 3.99 (s, 2H), 3.56 (dd, J = 10.7.4.9 Hz, 1H), 3.18 (dd, J = 16.5, 4.8 Hz , 1H), 2.67-2.82 (m, 3H), 2.31-2.54 (m, 4H), 2.18-2.25 (m, 1H), 1.86-1.96 (m, 2H), 1.52 (d, J = 12.9 Hz, 1H), 1.25 (s, 3H), 0.92 (t, J = 7.6 Hz, 6H), 0.67 (d, J = 6.9 Hz, 3H). LRMS (Es): m / z 450.32 (M + h)⁺.

(3R) -2- (N, N_-Dimethylglycyl) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1 -piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (17). (3R) -7-Hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methyl- was coupled propyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (14, 0.100 g, 0.285 mmol) to N, N-dimethylglycine as described above, providing a crude product that was purified by flash chromatography (50% of (CHCl₃: MeOH: NH₄OH 80: 18: 2) in CHCl₃), yielding (3R) -2- (N, N-dimethylglycyl) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl- 1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,

4-tetrahydro-3-isoquinolinecarboxamide (17, 0.101 g, 86%) as a white foam. LRMS (ES) m / z 551.4 (M + H)⁺.

(3S) -7-Hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -2-methyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (18). Formalin (0.02 ml, 0.215 mmol) was added to a stirred solution of (3R) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) - 3,4-dimethyl-1-piperidinyl] methyl} -2-methyl-propyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (14, 100 mg, 0.215 mmol) dissolved in 5 ml of dry DCE. Na (OAc) was added to this mixture₃BH (205 mg, 0.97 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then quenched by the addition of NaHCO₃ sat., until the bubbling stopped. This was then extracted three times with a solution of CH₂Cl₂: THF 3: 1 and the residue was purified using preparative thin layer chromatography on silica gel in 60% (CHCl₃: MeOH: NH₄OH 80: 18: 2) in CHCl₃, yielding (3S) -7-hydroxy-N - ((1S) -1 - {[(3R, 4R) -4 (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl ) Pure -2-methyl-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (18). NMR-¹H (MeOH): 7.09 (t, J = 3.8 Hz, 1H), 6.9 (d, J = 4.5 Hz, 1H), 6.76 (s, 1H), 6.73 ( d, J = 1.5 Hz, 1H),

6.57 (dd, J = 9, 5.3 Hz, 2H), 6.51 (s, 1H), 3.98-3.83 (m, 3H), 3.80 (s, 2H), 3.47 (d, J = 16Hz, 1H), 3.31 (s, 1H), 3.132.44 (m, 11H), 2.37 (t, J = 18Hz, 1H), 1.27 (s, 3H ), 0.90 (t, J = 3Hz, 6H), 0.71 (d, J = 3Hz, 3H). LRMS (ES) m / z 480.3 (M + H)⁺.

ES 2 300 436 T3 (3R) -3 - {[((1S) -1 - {[(3R, 4R) -4- (3-Hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2 -methylpropyl) amino] methyl} -1,2,3,4-tetrahydro-7-isoquinolinol (19). A solution of BH was added dropwise₃-SMe₂ 2M in THF (0.495 ml, 0.99 mmol) to a -20 ° C solution of 14 (46 mg, 0.099 mmol) in 5 ml of dry THF. The reaction was refluxed overnight. It was cooled back to -20 ° C and 0.647 ml of MeOH was added. The contents were stirred at room temperature for 1 hour. 1M HCl in ether (0.142 mL, 0.142 mmol) was added at room temperature and stirred for 30 minutes. The solvent was then removed under reduced pressure. The oil was then dissolved in CH₂Cl₂: THF 3: 1. Then enough NaHCO was added₃ sat. to increase the pH to 10. The organic phase was separated and set aside. The aqueous phase was extracted five times with Ch₂C1₂: THF 3: 1. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure, giving a yellowish foam. The crude product (0.03 g) was purified by preparative thin layer chromatography on silica gel using a solvent gradient, starting from 25% (CHCl₃: MeOH: NH₄OH, 80: 18: 2) in CHCl₃, then 40% and finally 65%. This provided 0.006 g of (3R) -3 - {[((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2 -methylpropyl) amino] methyl} -1,2,3,4-tetrahydro-7-isoquinolinol (19). NMR-¹H (MeOH): 7.12 (t, J = 5.1 Hz, 1H), 6.90 (d, J = 4.1 Hz, 1h), 6.8 (d, J = 3.9 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 6.61 (dd, J = 5.8, 2.2 Hz, 2H), 6.48 (d, J = 1.2 Hz, 1H), 2.88-2.43 (m, 16H), 2.4-1.8 (m, 2H), 1.67 (d, J = 13 Hz, 1H), 1.34 (s , 3H), 1.01 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 3.4 Hz, 3H ). LRMS (ES) m / z 452.3 (M + H)⁺.

(3R) -3 - {[((1S) -1 - {[(3R, 4R) -4- (3-Hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) amino] methyl} -2-methyl-1,2,3,4-tetrahydro-7-isoquinolinol (20). (3R) -7-Hydroxy-3 - {[((1S) -1 - {[(3R, 4R) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} - was dissolved 2-methylpropyl) amino] carbonyl} -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate tert-butyl (24) (57 mg, 0.119 mmol) in 10 ml of dry THF and added dropwise to a suspension of lithium aluminum hydride (30 mg) in THF cooled to -20 ° C. The reaction was heated under reflux overnight and then 1 mL of NaOH was added at -20 ° C, until a flocculent white precipitate was observed and bubbling ceased. This was filtered and the cake was washed with ethyl ether. The combined organic phases were washed with water and dried over MgSO₄. After removing the solvent, the crude material (40 mg) was purified using preparative thin-layer chromatography on silica gel using 40% (CHCl₃: MeOH: NH₄OH, 80: 18: 2) in CHCl₃. LRMS (ES) m / z 480.3 (M + H)⁺.

3- {1- (2S-Amino-3-methylbutyl) -3S, 4S-dimethyl-4-piperidinyl] phenol (26). (+) - (3S, 4S) -dimethyl-4- (3-hydroxyphenyl) piperidine (25) (0.500 g, 2.44 mmol), BOC-L-valine (0.5292 g, 2.44 mmol) were combined ), bOp reagent (1.109 g, 2.44 mmol) and TEA (0.74 ml, 5.36 mmol) with THF (31 ml) and stirred for 1 h at room temperature. The mixture was poured into ether (100 ml) and water (31 ml) and stirred. The organic phase was washed once with saturated NaHCO3 (30 ml) and once with brine (30 ml). Hexane was added to the organic phase until it turned cloudy. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. This was dissolved in dichloromethane (9 ml) and cooled to -20 ° C. Trifluoroacetic acid (6 ml) was added dropwise over 2 min. The reaction was stirred for 30 min at -20 ° C, followed by 30 min of stirring after removing the ice bath. The mixture was poured into saturated NaHCO3 (83 ml) and chloroform (31 ml). The solution was adjusted to pH 10 with NaHCO₃ solid. The mixture was rinsed in a separatory funnel with a small amount of MeOH and the aqueous phase was extracted 5 times with CH₂Cl₂/ THF 3: 1. The organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. This was dissolved in THF (31 ml) and cooled to -20 ° C. Borane-methyl sulfide complex (11.65 ml, 0.0233 mol) was added dropwise and the mixture was refluxed for 3 h. The reaction was cooled to -20 ° C, after which methanol (15 ml) was added dropwise and the mixture was stirred for 1 h at room temperature. 1M HCl (3.42 ml) was added and the reaction was stirred for 30 min at room temperature. The solvent was removed under reduced pressure, then CH₂Cl₂/ THF 3: 1 (20 ml) and water (20 ml). NaHCO was added₃ saturated at pH 9. The organic phase was then removed and the aqueous phase was saturated with NaCl. The aqueous phase was extracted 3 times with Ch₂C1₂/ THF 3: 1. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The off-white yellow foam was purified by silica gel chromatography using a gradient of 0-10% MeOH in CHCl₃, yielding 3- [1- (2S-amino-3-methylbutyl) -3S, 4S-dimethyl-4-piperidinyl] phenol (26) (0.5420 g, 1.87 mmol, 76.6%) as a whitish yellow foam. NMR-¹ H (CDCl₃): 7.13 (t, J = 7.9 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.69 (s, 1H), 6.64 (dd, J = 7.9 Hz, 1H), 4.25 (sa, 3H), 2.89 (d, J = 5.1 Hz, 1H), 2.79 (dd, J = 11.2, 2.5 Hz , 1H), 2.72-2.75 (m, 1H), 2.42 (d, J = 11.2 Hz, 1H), 2.36 (dd, J = 12.4, 2.9 Hz, 1H), 2.22 (d, J = 8.4 Hz, 2H), 1.98 (d, J = 6.5 Hz, 1H), 1.611.72 (m, 1H), 1.56 (d, J = 9.7 Hz, 1H), 1.28 (s, 3H), 0.96 (d, 6.9 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 0 , 79 (d, J = 6.9Hz, 3H).

(3R) -7-Hydroxy-3 - {[((1S) -1 - {[(3S, 4S) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2- tert-butyl methylpropyl) aminO] carbonyl} -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate (27). 3- [1- (2S-amino-3-methylbutyl) -3S, 4S-dimethyl-4-piperidinyl] phenol (26) (0.200 g, 0.69 mmol), Boc-D-7-hydroxy acid were combined 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (0.2119 g, 0.72 mmol), TEA (0.331 ml, 2.37 mmol) and BOP reagent (0.351 g, 0.80 mmol) in THF ( 21 ml) and stirred at room temperature for 2 h. Ether (21 ml) was added and washed once with NaHCO₃ saturated and once with water. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography. 25% of (CHCl₃: MeOH: NH₄OH, 80: 18: 2) in ChC1₃ until the cloudy band was collected, then 33% of (CHCl₃: MeOH: NH₄OH, 80: 18: 2) in CHCl₃ to collect (3S) -7-hydroxy-3 - {[((1S) -1 - {[(3S, 4S) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2- tert-butyl methylpropyl) amino] -carbonyl} -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate (27) (0.2768 g, 0.49 mmol, 71.1%). NMR-¹H (CDCI3): 7.19 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.71-6.82 (m, 5H), 6.46-6.51 (m, 1H), 6.19 (brs, 1H), 4.99 (brs, 1H), 4.81 (brs, 1H), 4.47 (dd, J = 28, 7.16.3 Hz, 2H), 3.79 (bs, 1H), 3.40-3.49 (m, 1H), 2.83-2.87 (m, 1H), 2.50 (bs , 1H), 2.28-2.34 (m, 2H), 2.18 (bs, 2H), 2.032.04 (m, 1H), 1.86-1.88 (m, 2H), 1, 49 (s, 9H), 1.18 (bs, 3H), 0.85 (d, J = 6.9Hz, 3H), 0.84 (d, J = 6.9Hz, 3H), 0, 75 (d, J = 6.9Hz, 3H).

ES 2 300 436 T3 (3R) -7-Hydroxy-N - ((1S) -1 - {[(3S, 4S) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (21). (3S) -7-Hydroxy-3 - {[((1S) -1 - {[(3S, 4S) -4- (3-hydroxyphenyl) -3,4-dimethyl-1-piperidinyl] methyl} - was dissolved Tert-Butyl (27) 2-methylpropyl) amino] -carbonyl} -3,4-dihydrohydro-2 (1H) -isoquinolinecarboxylate (0.2088 g, 0.37 mmol) in dichloromethane (11 mL) and cooled to -20 ° C. TFA (3.50 ml) was added dropwise over 10 min. The reaction was stirred for 10 min at -20 ° C, then stirred for 30 min after removing the cooling bath. The solvent was removed under reduced pressure and the remaining oil was allowed to settle under nitrogen for 5 min. Dichloromethane (11 ml) and NaHCO were added₃ saturated (11 ml) and the aqueous phase was extracted twice with dichloromethane after stirring. The combined organic phases were then discarded as they did not contain the desired product. The aqueous phase was then extracted 3 times with CH₂Cl₂/ THF 3: 1. The organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure, yielding (3R) -7hydroxy-N - ((1S) - {[(3S, 4S) -4- (3-hydroxyphenyl) -3 , 4-dimethyl-1-piperidinyl] -methyl} -2-methylpropyl) -1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (21) (0.120 g, 0.26 mmol, 69.8%) . NMR-¹ H (MeOH): 7.09 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 6.73 ( d, J = 2.3 Hz, 1H), 6.56-6.61 (m, 2H), 6.49 (d, J = 2.3 Hz, 1H), 3.96-4.03 (m , 1H), 3.92 (d, J = 6.5 Hz, 2H), 3.56 (dd, J = 10.0, 4.9 Hz, 1H), 2.93 (dd, J = 15, 7, 4.9 Hz, 1H), 2.83 (d, J = 9.9 Hz, 2H), 2.52-2.66 (m, 2H), 2.18-2.48 (m, 5H ), 1.86-1.97 (m, 2H), 1.53 (d, J = 12.5 Hz, 1H), 1.27 (s, 3H), 0.92 (t, J = 6, 6Hz, 6H), 0.76 (d, J = 7.0Hz, 3H). LRMS (ES) m / z 466.2 (M + H)⁺.

References (1) Aldrich, JV "Analgesics in Burger's Medicinal Chemistry and Drug Discovery", Wolff, ME ed .; John Wiley &amp; Sons; New York, 1996; vol. 3.

(2) Volpicelli, JR; Alterman, AI; Hayashida, M .; O'Brien, CP "Naltrexone in the treatment of alcohol dependence", Arch. Gen. Psychiatry 1992, 49, 876-879.

(3) Volpicelli, JR; Watson, NT; King, AC; Sherman, CE; O'Brien, CP "Effect of naltrexone on alcohol" high "in alcoholics", Am. J. Psychiatry 1995, 152, 613-615.

(4) Marki, A .; Monory, K .; Otvos, F .; Toth, G .; Krassnig, R .; Schmidhammer, H .; Traynor, JR; Roques, BP; Maldonado, R .; Borsodi, A., "Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S] GTPgammaS binding assays", Eur. J. Pharmacol. 1999, 383 (2), 209-214.

(5) Portoghese, PS "The design of δ-selective opioid receptor antagonists", Il Fannaco 1993, 48 (2), 243-251.

(6) Portoghese, PS; Lipkowski, AW, Takemori, AE "Binaltorphimine and nor-binaltorphimine, potent and selective κ-opioid receptor antagonists", Life Sci. 1987, 40 (13), 1287-1292.

(7) Olmsted, SL; Takemori, AE; Portoghese, PS "A remarkable change of opioid receptor selectivity on the attachment of a peptidomimetic κ address element to the δ antagonist, natrindole: 5 '- [N2-alkylamidino) methyl] naltrindole derivatives as a novel class of κ opioid receptor antagonists", J. Med. Chem. 1993, 36 (1), 179-180.

(8) Jones, RM; Hjorth, SA; Schwartz, TW, Portoghese, PS "Mutational evidence for a common kappa antagonist binding pocket in the wild-type kappa and mutant mu [K303E] opioid receptors", J. Med. Chem. 1998, 41 (25), 491, 1- Four.

(9) Schwyzer, R. "ACTH: A short introductory review", Ann. NY Acad. Sci. 1977, 247, 3-26.

(10) Trujillo, KA; Akil, H. "Changes in prodynorphin peptide content following treatment with morphine or amphetamine: possible role in mechanisms of action of drug of abuse", NIDA Res. Monogr. 1989, 95, 550-551.

(11) Smiley, PL; Johnson, M., Bush, L .; Gibb, JW, Hanson, GR, "Effects of cocaine on extrapyramidal and limbic dynorphine systems", J. Pharmacol. Exp. Ther. 1990, 253 (3), 938-943.

(12) Corbett, AD; Paterson, SJ; McKnight, AT; Magnan, J .; Kosterlitz, HW "Dynorphin and dynorphin are ligands for the kappa-subtype of opiate receptor", Nature 1982, 299 (5878), 79-81.

(13) Spanagel, R .; Herz, A .; Shippinberg, TA, "Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway", Proc. Natl. Acad. Sci. USA 1992, 89, 2046-2050.

(14) Spanagel, R .; Shippenberg, TS "Modulation of morphine-induced sensitization by endogenous κ opioid systems in the rat", Neurosci. Lett. 1993, 153, 232-236.

(15) Zadina, JE; Hackler, L .; Ge, L.-J .; Kastin, AJ "A potent and selective endogenous agonist for the μ-opiate receptor", Nature 1997, 386,499-502.

(16) Zinunerman, DM; Nickander, R .; Homg, JS; Wong, DT "New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series" Nature 1978, 275, 332-334.

ES 2 300 436 T3 (17) Zimmerman, DM; Smits, S .; Nickander, R. “Further investigation of novel 3-methyl-4-phenylpiperidine narcotic antagonists. In Proceedings of the 40th Annual Scientific Meeting of the Committee on Problems of Drug Dependence ”, 1978, p. 237-247.

(18) Zimmerman, DM; Smits, SE; Hynes, MD; Cantrell, BE, Reamer, M .; Nickander "Structural requirements for affinity and intrinsic activity at the opiate receptor defined in 4-phenylpiperidine and related series", in "Problems of Drug Dependence 1981, Proceedings of the 43rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc", Harris, LS Ed .; 1981, p. 112-116.

(19) Zimmerman, DM; Smits, SE; Hynes, MD; Cantrell, BE, Reamer, M .; Nickander, R. “Structural requirements for affinity and intrinsic activity at the opiate receptor defined in 4-phenylpiperidine and related series”, in “Problems of Drug Dependence 1981, Proceedings of the 43rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc ", Harris, LS Ed .; "Committee on Problems of Drug Dependence, Inc."; 1982, Vol, NIDA Research Monograph 41, p. 112-118.

(20) Zimmerman, DM; Cantrell, BE; Swartzendruber, JK; Jones, ND; Mendelsohn, LG; Leander, JD; Nickander, RC "Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydroisoquinolines", J. Med. Chem. 1988, 31, 555-560.

(21) Zimmerman, DM; Leander, JD; Cantrell, BE; Reel, JK; Snooody, J .; Mendelsohn, LG; Johnson, BG; Mitch, CH "Structure-activity relationships of the trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine antagonists for μ and κ opioid receptors", J. Med. Chem. 1993, 36 (20), 2833- 2841.

(22) Zimmerman, DM; Hermann, RB; Mitch, CH; Shaw, WN; Mendelsohn, LG; Leander, JD "Opioid receptor antagonists: Comparison of trans-3,4-dimethyl-4-phenylpiperidines and their use in the development of a model of opioid receptors", Pharmacol. Rev. in press.

(23) Thomas, JB; Mascarella, SW; Rothman, RB; Partilla, JS; Xu, H .; McCullough, KB; Dersch, CM; Cantrell, BE; Zimmerman, DM; Carroll, FI "Investigation of the N-substituent conformation governing potency and μ receptor subtype-selectivity in (+) - (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) piperidine opioid antagonists", J.Med. Chem. 1998, 41 (11), 1980-1990.

(24) Thomas, JB; Fall, MJ; Cooper, JB; Rothman, RB; Mascarella, SW; Xu, H .; Partilla, JS; Dersch, CM; McCullough, KB; Cantrell, BE; Zimmerman, DM; Carroll, FI "Identification of opioid κ receptor subtype-selective N-substituent for (+) - (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) -piperidine", J. Med. Chem. 1998, 41 (26 ), 5188-5197.

(25) Werner, JA; Cerbone, LR; Frank, SA; Ward, JA; Labib, P .; Tharp-Taylor, RW; Ryan, CW "Synthesis of trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine opioid antagonists: Application of the cis-terminal elimination of carbonates to alkaloid synthesis", J. Org. Chem. 1996, 61, 587-597.

(26) WO 99/45925.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than specifically described herein.

References cited in description

The list of references cited by the applicant is for the convenience of the reader only. It is not part of the European patent document. Although great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims any liability in this regard.

Patent documents cited in the description • WO 9945925 A

Non-patent bibliography cited in description • KIRK-OTHMER, "Encyclopedia of Chemical Technology", 1996, vol. 18, 480-590.

• ALDRICH, JV "Analgesics" in "Burger's Medicinal Chemistry and Drug Discovery", John Wiley &amp; Sons, 1996, vol. 3.

• VOLPICELLI, JR; ALTERMAN, AI; HAYASHIDA, M .; O'BRIEN, CP "Naltrexone in the treatment of alcohol dependence", Arch. Gen. Psychiatry 1992, vol. 49, 876-879.

ES 2 300 436 T3 • VOLPICELLI, JR; WATSON, NT; KING, AC; SHERMAN, CE; O'BRIEN, CP "Effect of naltrexone on alcohol" high "in alcoholics", Am. J. Psychiatry 1995, vol. 152, 613-615.

• MARKI, A .; MONORY, K .; OTVOS, F .; TOTH, G .; KRASSNIG, R .; SCHMIDHAMMER, H .; TRAYNOR, JR; ROQUES, BP; DAMNED, R .; bOrSOdI, A., "Mu-opioid receptor specific antagonist cyprodime: characterization by in vitro radioligand and [35S] GTPgammaS binding assays", Eur. J. Pharmacol. 1999, vol. 383 (2), 209-214.

• PORTOGHESE, PS "The design of δ-selective opioid receptor antagonists", Il Fannaco 1993, vol. 48 (2), 243251.

• PORTOGHESE, PS; LIPKOWSKI, AW, TAKEMORI, AE "Binaltorphimine and nor-binaltorphimine, potent and selective κ-opioid receptor antagonists", Life Sci. 1987, vol. 40 (13), 1287-1292.

• OLMSTED, SL; TAKEMORI, AE; PORTOGHESE, PS "A remarkable change of opioid receptor selectivity on the attachment of a peptidomimetic κ address element to the δ antagonist, natrindole: 5 '- [N2-alkylamidino) methyl] naltrindole derivatives as a novel class of κ opioid receptor antagonists", J. Med. Chem. 1993, vol. 36 (1), 179180.

• JONES, RM; HJORTH, SA; SCHWARTZ, TW, PORTOGHESE, PS "Mutational evidence for a common kappa antagonist binding pocket in the wild-type kappa and mutant mu [K303E] opioid receptors", J. Med. Chem. 1998, vol. 41 (25), 491.

• SCHWYZER, R. "ACTH: A short introductory review", Ann. NY Acad. Sci. 1977, vol. 247, 3-26.

• TRUJILLO, KA; AKIL, H. "Changes in prodynorphin peptide content following treatment with morphine or amphetamine: possible role in mechanisms of action of drug of abuse", NIDA Res. Monogr. 1989, vol. 95, 550-551. SMILEY, PL;

• JOHNSON, M., BUSH, L .; GIBB, JW, HANSON, GR, "Effects of cocaine on extrapyramidal and limbic dynorphine systems", J. Pharmacol. Exp. Ther. 1990, vol. 253 (3), 938-943.

• CORBETT, AD; PATERSON, SJ; MCKNIGHT, AT; MAGNAN, J .; KOSTERLITZ, HW "Dynorphin and dynorphin are ligands for the kappa-subtype of opiate receptor", Nature 1982, vol. 299 (5878), 79-81.

• SPANAGEL, R .; HERZ, A .; SHIPPINBERG, TA, "Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway", Proc. Natl. Acad. Sci. USA 1992, vol. 89, 2046-2050.

• SPANAGEL, R .; SHIPPENBERG, TS “Modulation of morphine-induced sensitization by endogenous κ opioid systems in the rat”, Neurosci. Lett. 1993, vol. 153, 232-236.

• ZADINA, JE; HACKLER, L .; GE, L.-J .; KASTIN, AJ "A potent and selective endogenous agonist for the μ-opiate receptor", Nature 1997, vol. 386, 499-502.

• ZINUNERMAN, DM; NICKANDER, R .; HOMG, JS; WONG, DT "New structural concepts for narcotic antagonists defined in a 4-phenylpiperidine series" Nature 1978, vol. 275, 332-334.

• ZIMMERMAN, DM; SMITS, S .; NICKANDER, R. “Further investigation of novel 3-methyl-4-phenylpiperidine narcotic antagonists. In Proceedings of the 40th Annual Scientific Meeting of the Committee on Problems of Drug Dependence ”, 1978, 237-247.

• ZIMMERMAN, DM; SMITS, SE; HYNES, MD; CANTRELL, BE, REAMER, M .; NICKANDER "Structural requirements for affinity and intrinsic activity at the opiate receptor defined in 4-phenylpiperidine and related series", in "Problems of Drug Dependence 1981, Proceedings of the 43rd Annual Scientific Meeting of the Committee on Problems of Drug Dependence, Inc", 1981, 112-116.

• ZIMMERMAN, DM; SMITS, SE; HYNES, MD; CANTRELL, BE, REAMER, M .; NICKANDER, R. “Structural requirements for affinity and intrinsic activity at the opiate receptor defined in 4-phenylpiperidine and related series”, in “Problems of Drug Dependence 1981, Proceedings of the 43rd Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Committee on Problems of Drug Dependence, Inc. ”, 1982, Vol. 41, 112-118.

• ZIMMERMAN, DM; CANTRELL, BE; SWARTZENDRUBER, JK; JONES, ND; MENDELSOHN, LG; LEANDER, JD; NICKANDER, RC "Synthesis and analgesic properties of N-substituted trans-4a-aryldecahydro-isoquinolines", J. Med. Chem. 1988, vol. 31, 555-560.

ES 2 300 436 T3 • ZIMMERMAN, DM; LEANDER, JD; CANTRELL, BE; REEL, JK; SNOOODY, J .; MENDELSOHN, LG; JOHNSON, BG; mItCH, CH "Structure-activity relationships of the trans-3,4-dimethyl-4- (3-hydroxyphenyl) -piperidine antagonists for μ and κ opioid receptors", J. Med. Chem. 1993, vol. 36 (20), 2833-2841.

• ZIMMERMAN, DM; HERMANN, RB; MITCH, CH; SHAW, WN; MENDELSOHN, LG; LEANDER, JD "Opioid receptor antagonists: Comparison of trans-3,4-dimethyl-4-phenylpiperidines and their use in the development of a model of opioid receptors", Pharmacol. Rev ..

• THOMAS, JB; MASCARELLA, SW; ROTHMAN, RB; PARTILLA, JS; XU, H .; MCCULLOUGH, KB; DERSCH, CM; CANTRELL, BE; ZIMMERMAN, DM; CARROLL, FI "Investigation of the N-substituent conformation governing potency and μ receptor subtype-selectivity in (+) - (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) -piperidine opioid antagonists", J. Med. Chem 1998, vol. 41 (11), 1980-1990.

• THOMAS, JB; FALL, MJ; COOPER, JB; ROTHMAN, RB; MASCARELLA, SW; XU, H .; PARTILLA, JS; DERSCH, CM; MCCULLOUGH, KB; CANTRELL, BE; ZIMMERMAN, DM; CARROLL, FI "Identification of opioid κ receptor subtype-selective N-substituent for (+) - (3R, 4R) -dimethyl-4- (3-hydroxyphenyl) piperidine", J. Med. Chem. 1998, vol. 41 (26), 5188-5197.

• WERNER, JA; CERBONE, LR; FRANK, SA; WARD, JA; LABIB, P .; THARP-TAYLOR, RW; RYAN, CW "Synthesis of trans-3,4-dimethyl-4- (3-hydroxyphenyl) piperidine opioid antagonists: Application of the cis-terminal elimination of carbonates to alkaloid synthesis", J. Org. Chem. 1996, vol. 61, 587-597.