Therapeutic compounds

The invention provides novel compounds of formula I: that are opioid receptor ligands. The invention also provides pharmaceutical compositions comprising such compounds as well as methods for treating diseases associated with opioid receptor function by administering such compounds to a mammal in need of treatment. Compounds of the invention are useful to modulate (e.g. agonize or antagonize) opioid receptor function.

BACKGROUND OF THE INVENTION

The opium poppy, Papaver somniferum, has been used for centuries for the relief of pain and to induce sleep (Casy, A. F.; Parfitt, R. T. Opioid analgesics: chemistry and receptors; Plenum Press: New York, 1986; xv, 518). Among the most important constituents in opium are the alkaloids morphine and codeine. Many of the agonists and antagonists derived from these alkaloids are essential for the practice of modern medicine. While many potent agonists are effective analgesics, they have undesirable side effects, such as tolerance, dependence, and respiratory depression. (Stein, C.; Schafer, M.; Machelska, H.Nat. Med.2003, 9, 1003-1008).

Endogenous opioid peptides are known and are involved in the mediation or modulation of a variety of mammalian physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the processes that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, respiratory depression, learning and memory, mental illness, epileptic seizures and other neurological disorders and cardiovascular responses.

Intensive research of the last two decades has given us a better understanding of opioid receptor structure, distribution, and pharmacology (Waldhoer, M.; Bartlett, S. E.; Whistler, J. L.Annu. Rev. Biochem.2004, 73, 953-990). Three types of opioid receptors known as mu (μ), delta, (δ), and kappa (κ) and receptor subtypes have been identified, and the mRNA encoding these receptors has been isolated. There is substantial pharmacological evidence for subtypes of each (Reisine, T. Neurotransmitter Receptors V: Opiate Receptors.Neuropharmacology1995, 34, 463-472). It has become clear that each receptor mediates unique pharmacological responses and is differentially distributed in the central nervous system (Goldstein, A.; Naidu,A., Mol. Pharmacol.1989, 36, 265-272; and Mansour, A.; Fox, C. A.; Akil, H.; Watson, S. J.,Trends Neurosci.1995, 18, 22-29).

There are several structural classes of nonpeptidic opioid receptor ligands (Eguchi, M.,Med. Res. Rev.2004, 24, 182-212; Kaczor, A.; Matosiuk, D.,Curr. Med. Chem.2002, 9, 1567-1589; and Kaczor, A.; Matosiuk, D.,Curr. Med. Chem.,2002, 9, 1591-1603). The oldest class of compounds are those derived from morphine. Examples of other structural classes include fentanyl, cyclazocine, SNC 80, U50,488H, and 3FLB. The common structural motif in all of these ligands is the presence of a basic amino group.

Currently, there is a need for new opioid receptor ligands that have fewer side effects than known ligands. Such ligands would be useful for the treatment of diseases and conditions associated with the activity of opioid receptors. Such ligands would also be useful as pharmacological tools for the further study of opioid pharmacology.

SUMMARY OF THE INVENTION

The present invention provides compounds that act as opioid receptor ligands. Accordingly there is provided a compound of the invention which is a compound of formula I:

R3is H or (C1-C6)alkyl;

R4is H or (C1-C6)alkyl;

R5is H or (C1-C6)alkyl;

X is —O—, —S—, or —NRa—;

each Ruand Rvis independently H or (C1-C6)alkyl;

or a salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula I; or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier.

The invention also provides a method for modulating the activity of an opioid receptor comprising contacting the receptor (in vitro or in vivo) with an effective modulatory amount of a compound of formula I or a salt thereof.

The invention also provides a therapeutic method for treating a disease or condition in a mammal wherein modulation of the action of an opioid receptor is desired (e.g. pain, drug addiction, alcohol addiction, drug abuse, alcohol abuse, opioid-induced constipation, irritable bowel syndrome, nausea, vomiting, pruritic dermatoses, depression, smoking addiction, sexual dysfunction, stroke, obesity, diabetes, trauma, eating disorders, opioid overdose, shock, spinal damage, diarrheic syndromes, bowel motility disorders including post-operative ileus and constipation, visceral pain including post-operative pain, and inflammatory bowel disorders) comprising administering to the mammal, an effective amount of a compound of formula I; or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.

The invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament useful for the treatment of a disease or condition in a mammal wherein modulation of the action of an opioid receptor is desired.

The invention also provides a method for binding a compound of formula I or a pharmaceutically acceptable salt thereof to mammalian tissue comprising opioid receptors, in vivo or in vitro, comprising contacting the tissue with an amount of a compound of formula I or a pharmaceutically acceptable salt thereof effective to bind to said receptors. Tissue comprising a compound of formula I or a pharmaceutically acceptable salt thereof bound to opioid receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with opioid receptor activity, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent.

The invention also provides a detectably labeled (e.g. a radiolabeled) compound comprising a compound of formula I; or a salt thereof, that comprises or is linked to one or more detectable groups.

The invention also provides synthetic processes and synthetic intermediates disclosed herein. Certain compounds of formula (I) are useful as intermediates for preparing other compounds of formula (I).

The invention also provides the compounds prepared in the Examples herein, as well as methods for modulating opioid receptor activity with such compounds.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described. Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.

Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.

Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(Y) wherein Y is absent or is H, O, (C1-C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived there from, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.

Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

A specific value for R1is formyloxy, acetoxy, RcC(═O)O—, or RbS(═O)2O—.

A specific value for R1is acetoxy, propanoyloxy, methylsulfonyloxy, or benzoyloxy.

A specific value for R1is benzoyloxy, 3-pyridylcarbonyloxy, or phenylaminocarbonyloxy.

A specific value for R2is carboxy, (C1-C6)alkoxycarbonyl; or RdReNC(═O)—.

A specific value for R2is methoxycarbonyl.

A specific value for R4is H or methyl.

A specific value for R3is methyl.

A specific value for R4is methyl.

A specific value for R5is H.

A specific value for R5is methyl.

A specific value for R5is H.

A specific value for R6is 3-furyl.

A specific value for X is —O—.

A specific compound of formula (I) is a compound of formula (II):

wherein R1-R6have any of the values or specific values defined herein; or a salt thereof.

Specific compounds of the invention also include compounds of formula I that comprise or that are linked to one or more detectable groups or isotopes. Such detectable compounds may be used as imaging agents or as probes for evaluating opioid receptor structure and function. For example, one or more detectable groups can be incorporated into the core of the compound, or can be attached to the compound directly, through a linking group, or through a chelating group. Suitable detectable groups include deuterium, tritium, iodine-125, iodine-131, iodine-123, astatine-210, carbon-11, carbon-14, nitrogen-13, or fluorine-18. Additionally, groups such as Tc-99m and Re-186 can be attached to a linking group or bound by a chelating group which is then attached to the compound of formula I directly or by means of a linker. Suitable radiolabeling techniques are routinely used in radiopharmaceutical chemistry.

In one embodiment the invention also provides a compound of formula V:

wherein R2-R6and X have any of the values or specific values described herein. Compounds of formula V (e.g. Compound 8) are useful as intermediates for preparing salvinorin analogs.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

The compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes. For example, the compounds can be formulated for administration as a metered aerosol or liquid spray, as drops, in ampoules, in an autoinjector device or as suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.

The compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, may be adapted to provide a depot preparation for intramuscular injection. Furthermore, compounds of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will typically be continuous rather than intermittent throughout the dosage regimen.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the useful methods of preparation include vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

The compound can be administered in unit dosage form; for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 μM, about 1 to 50 μM, or about 2 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).

Processes for preparing compounds of formula I are provided as further embodiments of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.

A compound of formula I can generally be prepared by as illustrated in the following Scheme I.

Compounds of the invention can also be administered in combination with other therapeutic agents, for example, other agents that are useful for the modulation of opioid activity. Examples of such agents include morphine, codeine, fentanyl, hydromorphone, naloxone, naltrexone, and nalmefene. Accordingly, in one embodiment, the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or the pharmaceutically acceptable salt thereof and the other therapeutic agent or agents to an animal to modulate opioid receptor activity.

The ability of a compound of the invention to act as a modulator of opioid receptor activity can be determined using pharmacological models which are well known to the art. For example, representative compounds of the invention were evaluated as described by Harding W W, et al.,J. Nat. Prod.2006, 69:107-112; and they were found to have opioid antagonist activity. Accordingly compounds of the invention may be useful as therapeutic agents for the treatment of diseases wherein the modulation of opioid activity is indicated. Such diseases include but are not limited to, pain, drug addiction, alcohol addiction, drug abuse, alcohol abuse, opioid-induced constipation, irritable bowel syndrome, nausea, vomiting, pruritic dermatoses, depression, smoking addiction, sexual dysfunction, stroke, obesity, diabetes, trauma, eating disorders, opioid overdose, shock, spinal damage, diarrheic syndromes, bowel motility disorders including post-operative ileus and constipation, visceral pain including post-operative pain, and inflammatory bowel disorders. Additionally, compounds of the invention may be useful as pharmacological tools for the further investigation of opioid receptor function.

Unless otherwise indicated, all reagents were purchased from commercial suppliers and were used without further purification. All melting points were determined on a Thomas—Hoover capillary melting apparatus and are uncorrected. The1H NMR and13C NMR spectra were recorded at 300 MHz on a Bruker Avance-300 spectrometer or on a Bruker AMX-600 spectrometer using CDCl3as solvent, δ values in ppm (TMS as internal standard), and J(Hz) assignments of1H resonance coupling. HMBC and HMQC data were collected on the AMX-600 spectrometer. Thin-layer chromatography (TLC) was performed on 0.25 mm Analtech GHLF silica gel plates. Spots on TLC were visualized with vanillin/H2SO4in EtOH. Silica Gel (32-63μ particle size) from Bodman Industries (Atlanta, Ga.) was used for column chromatography. HPLC was carried out on an Agilent 1100 Series Capillary HPLC system with diode array detector. Peaks were detected at 209, 214 and 254 nm. MPLC was performed on a RT Scientific PurChrom 150-GCS system equipped with a silica gel column (1.1 cm×30 cm). Elemental analyses were performed by Atlantic Microlabs, Norcross, Ga.

Preparation of 1-Deoxy-1,10-dehydro-salvinorin A (1)

To a stirred solution of 1α-hydroxysalvinorin A (3, 291 mg, 0.67 mmol) and DMAP (488 mg, 4 mmol) in dry acetonitrile (6 mL) under argon was added methanesulfonic anhydride (313 mg, 1.8 mmoles). The reaction was stirred at reflux for 1 h, when complete conversion to the mesylate was indicated by TLC. This was followed by the addition of trimethyphenylammonium chloride (257 mg, 1.5 mmoles) and another 1 hour of reflux. The reaction mixture was evaporated and distributed between DCM (8 mL) and 1 M phosphoric acid (35 mL). The organic phase was washed with saturated sodium carbonate solution (20 mL), and the aqueous phases were extracted, in turn with DCM (2×4 mL). The combined and dried (sodium sulfate) organic phases were evaporated to a residue which was purified by column chromatography on silica gel (eluent: DCM/EtOAc, 9:1) gave Compound 1 (213 mg, 0.51 mmol, 76% overall). A portion of the product was recrystallized from EtOAc/hexanes to give pure material, mp 129-131° C.

The intermediate compound 3 was prepared as follows.

a. 1α-Hydroxy-Salvinorin A (3). A mixture of salvinorin A (1.7828 g, 4 mmol) and THF (40 mL) was magnetically stirred at gentle reflux for 5 minutes. To this was added an aqueous solution of sodium borohydride (760 mg, 20 mmoles in 6 mL) in portions. After stirring at reflux for 10 minutes following the first addition, a second addition of aqueous sodium borohydride was made (152 mg, 4 mmol in 0.7 mL) and reflux was continued for 5 minutes. The reaction mixture was immediately chilled in an ice bath and progress of the reaction was checked by TLC. The reaction was mixture diluted with ethyl acetate (50 mL) and extracted with saturated sodium chloride (2×30 mL). The aqueous phases were extracted, in turn, with ethyl acetate (2×15 mL) and the combined organic phases were dried (sodium sulfate) and evaporated to a foam (1.70 g). The crude product was chromatographed on silica (50 g) packed in DCM containing 10% EtOAc. Elution with DCM containing increasing amounts of EtOAc gave fractions that were combined based on TLC analysis. Early fractions contained the desired product (1.34 g, 3.08 mmoles, 77%) contaminated with a small amount of starting material, while later fractions contained lactols (158 mg, 0.36 mmole, 9%) reduced at C-17 as well as C-1, and finally an isomer of the desired product (161 mg, 0.37 mmole, 9%) in which the acetate group has migrated from C-2 to C-1. A sample of the major product, 1α-hydroxy-SVA (3) was crystallized from EtOAc/hexanes, mp 110-111° C.

Preparation of 1-Deoxy-1,10-dehydrosalvinorin B (2)

A stirred solution of DMAP (122 mg, 1 mmole) in DMSO (3 mL) under argon was rapidly heated to 170° C. After 3 min, compound 6 (240 mg, 0.50 mmole) was added and stirring was continued for 10 min. The rapidly cooled reaction mixture was poured into a mixture of saturated aqueous NaCl (40 mL) and 1 M phosphoric acid (7 mL). The resulting aqueous mixture was extracted with EtOAc (20 mL) and the organic phase was washed with a mixture of saturated NaCl (20 mL) and saturated NaHCO3(7 mL). The aqueous phases were extracted, in turn, with EtOAc (10 mL). The combined organic phases were dried (Na2SO4) and evaporated to a residue (208 mg), which was purified by column chromatography, eluting with CH2Cl2containing increasing amounts of EtOAc to afford 143 mg (76%) of 2 and 43 mg (22%) of 8.

The intermediate compound 6 was prepare as follows.

A mixture of salvinorin A (1.7828 g, 4 mmoles) and THF (40 mL) was magnetically stirred at gentle reflux for 5 min. To this was added an aqueous solution of NaBH4(760 mg, 20 mmoles in 6 mL) in portions. After stirring at reflux for 10 min following the first addition, a second addition of aqueous NaBH4was made (152 mg, 4 mmoles in 0.7 mL) and reflux was continued for 5 min. The reaction mixture was immediately chilled in an ice bath and progress of the reaction was checked by TLC. The reaction was mixture diluted with EtOAc (50 mL) and extracted with saturated sodium chloride (2×30 mL). The aqueous phases were extracted, in turn, with EtOAc (2×15 mL) and the combined organic phases were dried (Na2SO4) and evaporated to a foam. The crude product was purified by column chromatography (CH2Cl2with increasing amounts of EtOAc) to give 1.34 g of 3 (77%) as a white solid, mp 110-111° C. The1H and13C spectra of 3 were in agreement with previously reported data (Valdes, L. J., III, et al.,J. Org. Chem.1984, 49, 4716).

Preparation of 2-keto-1-deoxy-1,10-dehydrosalvinorin A (9)

Preparation of 1-Deoxy-1,10-dehydroherkinorin (10)

The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I (‘Compound X’), for therapeutic or prophylactic use in humans.

(vi) Aerosolmg/canCompound X=20.0Oleic acid10.0Trichloromonofluoromethane5,000.0Dichlorodifluoromethane10,000.0Dichlorotetrafluoroethane5,000.0
The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.