WO2002080919A1 - Composes therapeutiques et procedes - Google Patents

Composes therapeutiques et procedes Download PDF

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Publication number
WO2002080919A1
WO2002080919A1 PCT/US2001/011339 US0111339W WO02080919A1 WO 2002080919 A1 WO2002080919 A1 WO 2002080919A1 US 0111339 W US0111339 W US 0111339W WO 02080919 A1 WO02080919 A1 WO 02080919A1
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compound
alkyl
aryl
cycloalkyl
condition
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PCT/US2001/011339
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English (en)
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Philip S. Portoghese
Robert M. Jones
Shiv Kumar Sharma
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Regents Of The University Of Minnesota
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Priority to PCT/US2001/011339 priority Critical patent/WO2002080919A1/fr
Priority to US10/473,245 priority patent/US7232829B2/en
Publication of WO2002080919A1 publication Critical patent/WO2002080919A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • 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 effects that have been suggested include analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurological disorders, cardiovascular responses, and respiratory depression, see G. T. Shearman et al. J. Pharmacol. Exp. Ther., 243, 591-597, 1987.
  • the kappa opioid receptor is one of the three major opioid receptors that are found in the central nervous system and in the periphery, see Dhawan, B. N.; Cesselin, R.; Raghubir, R.; Reisine, T.; Bradley, P. B.; Portoghese, P. S.; Hamon, M. International Union of Pharmacology. XII. Classification of Opioid Receptors. Pharmacol. Rev. 1996, 48, 567-583. The precise roles of kappa receptors have not yet been established, but it appears that kappa-selective endogenous opioid peptides, such as dynorphin A, function both as neuro- and immuno-modulators.
  • Norbinaltorphimine a bivalent ligand shown in Figure 3, which contains two naltrexone-derived pharmacophores, is a nonpeptide ligand that is highly selective and widely used as a kappa opioid receptor antagonist, see Portoghese, P. S.; Lipkowski, A. W.;
  • kappa receptor agonists that can be used as therapeutic agents such as analgesics, or as pharmacological tools to further investigate kappa receptor binding, structure, and function.
  • potent and selective agonists that can be used to treat conditions associated with kappa receptor function.
  • the invention provides kappa agonist compounds which provide highly selective pharmacological agonism both in vivo and in vitro at the kappa opioid receptor. Accordingly, the invention provides a compound of formula (I):
  • Rj is (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -
  • C 7 cycloalkyl, (C 5 -C 7 )cycloalkenyl, (C 3 -C 6 )cycloalkyl(C ⁇ -C 6 )alkyl, (C 5 - C 7 )cycloalkenyl(C C 6 )alkyl, aryl, heteroaryl, aryl(Q-C 6 )alkyl, orheteroaryl(Cr C 6 )alkyl;
  • R 2 is H, OH, (C ⁇ -C 6 )alkoxy, (C C 6 )alkanoyloxy, NR a R or SR c ;
  • R 3 is H, aryl(d-C 6 )alkyl, (Q-C 6 )alkyl, (C ⁇ -C 6 )alkanoyl, or (Q-
  • R d is H, CN, CONH 2 , COCF 3 , (d-C 6 )alkanoyl, (C C 6 )alkyl, or (CH 2 ) p NR e R f ; or R d together with R$ is -(CH 2 ) q - and forms a ring; p is 1, 2, 3, or 4;
  • R 5 is NR m ;
  • X is O, S, orNY
  • Y is H, (C C 6 )alkyl, or arylCQ-C ⁇ alkyl; n is O, 1, 2, 3, or 4;
  • Rj and R k are each independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl(C C 6 )alkyl, (C 5 - C 7 )cycloalkenylalkyl, aryl, heteroaryl, aryl( -C 6 )alkyl, or heteroaryl(C ⁇ - C 6 )alkyl; and
  • R m is hydrogen or or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein kappa receptor activity is implicated and agonism of kappa receptors is desired 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) for use in medical therapy (preferably for use in treating conditions wherein agonism of kappa receptors is indicated (e.g. for treating pain), as well as the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, wherein agonism of kappa receptors is indicated (e.g. pain).
  • the invention provides delta antagonist compounds which provide highly selective pharmacological antagonism both in vivo and in vitro at the delta opioid receptor.
  • R R 6 and X have any of the values, specific values or preferred values described herein for the corresponding group in a compound of formula (I).
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein delta receptor activity is implicated and antagonism of delta receptors is desired comprising administering to the mammal, an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound of formula (II) for use in medical therapy (preferably for use in treating conditions wherein antgonism of delta receptors is indicated), as well as the use of a compound of formula (II) for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, wherein antagonism of delta receptors is indicated.
  • the invention also provides a method for binding a compound of formula (I) to kappa receptors, in vivo or in vitro, comprising contacting mammalian tissue comprising said receptors with an amount of a compound of formula (I) effective to bind to said receptors.
  • Tissue comprising ligand bound kappa receptors is useful to measure the receptor selectivity of other potential therapeutic agents, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions wherein kappa receptor activity is implicated and agonism of kappa receptors is desired, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent (for example in a competitive binding assay).
  • the invention also provides a method for binding a compound of formula (II) to delta receptors, in vivo or in vitro, comprising contacting mammalian tissue comprising said receptors with an amount of a compound of formula (II) effective to bind to said receptors.
  • Tissue comprising ligand bound delta receptors is useful to measure the receptor selectivity of other potential therapeutic agents, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions wherein delta receptor activity is implicated and antagonism of delta receptors is desired, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent (for example in a competitive binding assay).
  • Applicant has also discovered a method for preparing multi-gram quantities of the kappa antagonist GNTI 3 as its dihydrochloride salt (as well as compounds of formula (I) and formula (II)), which eliminates the need for tedious chromatographic separation. Accordingly, the invention also provides a method for preparing GNTI 3, as well as compounds of formula (I) and formula (II), as described hereinbelow.
  • FIG. 1 Illustrates the synthesis of compounds ofthe invention.
  • FIG. 2 Illustrates the synthesis of compounds ofthe invention.
  • FIG.3 Illustrates the structure of compound 4b (6'- GNTI ) and related comparative compounds 1-3.
  • FIG.4 Illustrates the synthesis of compounds 3, 4a, 4b, and 4c.
  • FIG. 5 Illustrates comparative concentration-response curves of compound 4b compared to morphine in a guinea-pig ileal preparation.
  • Such conditions include, for example, immunoregulatory diseases associated with a depressed autologous mixed lymphocyte response such as rheumatoid arthritis, systemic lupus erythematosis, Sjogren's Syndrome, multiple sclerosis, chronis lymphocytic leukemia, Type I diabetes, Epstein-Barr virus, and AIDS; certain viral infections including coronavirus or cytomegalovirus; cocaine use or addiction.
  • Delta receptor antagonists are also useful as antitussive agents and to prevent the tolerance or physical dependence associated with the administration of a ⁇ -opioid agonist.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, 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(X) wherein X is absent or is H, O, (Q-G alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • (C C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C -C 7 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
  • (Q- C 7 )cycloalkyl(C ⁇ -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl;
  • (CrC 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,
  • C 6 )alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl; heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
  • Ri is (C 2 -C 6 )alkenyl or (C 3 -C 6 )cycloalkyl(C]-C 6 )alkyl. More specifically, Ri is cyclopropylmethyl or allyl. Specifically, R is OH.
  • R 3 is H.
  • R 5 is NH.
  • R m is hydrogen.
  • n 0.
  • n is 1.
  • X is NH.
  • a specific compound ofthe present invention is a compound of formula (I) wherein: R ⁇ is (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 - C 7 )cycloalkyl, (C 5 -C 7 )cycloalkenyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, (C 5 - C 7 )cycloalkenyl(C C 6 )alkyl, aryl, heteroaryl, aryl( -C 6 )alkyl, heteroary ⁇ Q- C 6 )alkyl; R 2 is H, OH, (CrC 6 )alkoxy, (CrC 6 )alkanoyloxy, NR a R b or SR c; R 3 is H, aryl(C ⁇ -C 6 )alkyl, (C ⁇ -C 6 )
  • a specific compound ofthe invention is a compound of formula (I) wherein R 6 is not (C ⁇ -C 6 )alkyl when n is 1, > is NH, and R 5 is NH.
  • a specific compound ofthe invention is a compound of formula (I) wherein R d together with R ⁇ is -(CH 2 ) q - and forms a ring.
  • a specific compound ofthe present invention is 6'-guanidinyl-17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3,14- dihydroxyindolo[2',3':6,73morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 6'-N-ethylguanidinyl-1 - cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3,14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 6'-N-butylguanidinyl-17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3, 14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound of the present invention is 6*-N-butylguanidinyl- 17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3, 14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 6'-N'-cyano-N-[17- (cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3, 14- dihydroxyindolo[2',3':6,7]morphinian]-guanidine.
  • a specific compound ofthe present invention is 6'-N-cyano-N'-[3- (dimethylaminopropyl)]-N"-[17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy- 3 , 14-dihydroxyindolo[2' ,3 ' :6,7]morphinian] -guanidine.
  • a specific compound ofthe present invention is 6'-N-cyano-N'-[2-(l- aminoethylpyrrolidine)]-N"-[17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy- 3,14-dihydroxyindolo[2',3':6,7]morphinian]-guanidine.
  • a specific compound ofthe present invention is 7'-guanidinyl-17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3,14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 7'-N-ethylguanidinyl-17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3,14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound of the present invention is 7'-N-butylguanidinyl- 17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3, 14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 7'-N-butylguanidinyl-17- cyclopropylmethyl-6,7-didehydro-4,5-a-epoxy-3, 14- dihydroxyindolo[2',3':6,7]morphinan ditrifluoroacetate dihydrate.
  • a specific compound ofthe present invention is 7'-N'-cyano-N-[17- (cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,14- dihydroxyindolo[2',3':6,7]morphinian]-guanidine.
  • a specific compound ofthe present invention is 7'-N-cyano-N'-[3- (dimethylaminopropyl)]-N"-[17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy- 3, 14-dihydroxyindolo[2',3' :6,7]morphinian]-guanidine.
  • a specific compound ofthe present invention is 7'-N-cyano-N'-[2-(l- aminoethylpyrrolidine)]-N"-[17-(cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy- 3,14-dihydroxyindolo[2',3':6,7]morphinian]-guanidine.
  • the invention also provides processes and intermediates useful for preparing compounds of formula (I) and formula (II) such as those described in the Examples or illustrated in the figures herein.
  • the indolomorphinan products 10 are subsequently reduced to the primary amines 11 by utilizing the reduction conditions set out in Figure 1 (Scheme 1).
  • This intermediate 7 can also be prepared by the reaction of 5'- amino-NTI compound 5b with l,3-bis(benzyloxycarbonyl)-2-methyl-2- thiopseudourea using the HgCl 2 -assisted coupling reaction, see supra Tetrahedron Lett. 1993, 34, 7677-7680, Tetrahedron Lett. 1992, 33, 5933-5936, and J. Med. Chem. 2000, 43, 2362-2370. Deprotection of intermediate 7 was accomplished by catalytic hydrogenation with 10% Pd/C to afford compound 3.HC1. The overall yield from compound 5b by either ofthe modified routes was from about 65 to about 70 percent.
  • the invention provides a method for preparing a guanidino compound of formula (N):
  • the conversion ofthe amine of formula (III) to the bisprotected compound of formula (IN) can conveniently be carried out by reacting the amine with an excess (e.g. 2-10 equivalents) of di- ⁇ ', ⁇ "-carboxybenzyloxy- ⁇ '"- trifluoromethanesulfonylguanidine, in the presence of a suitable base (e.g. a hindered amine base such as triethylamine) in a suitable solvent (e.g. a halogenated hydrocarbon such as CH C1 2 ).
  • a suitable base e.g. a hindered amine base such as triethylamine
  • a suitable solvent e.g. a halogenated hydrocarbon such as CH C1 2
  • the deprotection ofthe compound of formula (IV) to provide the compound of formula (V) can conveniently be carried out by catalytic hydrogenation (e.g. with 10% Pd/C).
  • Cyanoguanidines of general formula 15 ( Figure 2, scheme 3) maybe obtained from amines 11 by reaction with diphenyl-N-cyanocarbonimidate 14 (see C. J. Durant et al. J. Med. Chem. 1977, 20, 7, 901 and R. L. Webb, C. S. Labaw. J. Het. Chem. 19, 1205, 1982) followed by displacement of phenol from the intermediate by reaction with a primary amine or general formula RsNH .
  • Ureas of general formula 16 ( Figure 2, scheme 4) wherein W is O or S can be readily prepared by reaction of amines 11 with R 6 NCW. Specific variants ofthe above are cited in reaction scheme 5.
  • Cyanoguanidines 15 maybe modified further as depicted in Figure 2, scheme 6 to afford compounds of general formula 19 (see S. N. Thom. Tet. vol 49, 31 , 6885, 1993).
  • Compounds of formula (I) wherein X is O or S can be prepared from intermediates structurally similar to 11 wherein NY has been replaced by O or S. These intermediates can be prepared as generally disclosed in U. S. Patent No. 4,816, 586, which is incorporated by reference herein, which also discloses methods suitable for the preparation of salts of compounds of general formula (I) and (II).
  • 4,5-Epoxy-6-ketomorphinans of general structure 8 ( Figure 1, scheme 1) can be prepared by synthetic methods which are well known in the art of organic chemistry (see U. S. Patent 5,457,208 and citations therein).
  • 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, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula (I) and formula (II) 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.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food ofthe patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage ofthe compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% ofthe weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions ofthe active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance ofthe required particle size in the case of dispersions or by the use of surfactants.
  • the prevention ofthe action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various ofthe other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin ofthe user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages ofthe compounds of formula (I) and formula (II) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount ofthe compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition ofthe patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose can be, for example, in the range of from about 0.01 to about 10 mg/kg, e.g., preferably from about 0.05 to about 1.0 mg/kg of body weight per day, most preferably in the range of 0.1 to 0.5 mg/kg/day.
  • the compounds of formula (I) and (II) can conveniently administered, for example, in unit dosage form; for example, containing 1 to 50 mg, conveniently 2 to 20 mg, most conveniently, 5 to 15 mg of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the activity of a compound ofthe invention at the kappa opioid receptor can be determined using pharmacological models that are well known to the art, or using the procedures described below.
  • the data in Table 1 illustrates that the 5'-regioisomer GNTI compound 3 is a highly potent and selective kappa opioid receptor antagonist.
  • GNTI was approximately four-fold more potent than norBNI 1, with ⁇ / ⁇ and ⁇ / ⁇ selectivity ratios of 718 and 188, respectively.
  • the 4'-regioisomer compound 4a was virtually inactive at all opioid receptor types. While the 7'-regioisomer compound 4c was inactive at mu and kappa-receptors, it was a potent delta opioid receptor antagonist.
  • the 6'-regioisomer compound 4b was found to be an agonist with a 51 -fold greater potency relative to that of morphine, reference FIG 5 in the GPI assay.
  • the finding that the agonist effect of compound 4b was only partially reversed by naltrexone (500 nM) suggested that it was not a mu-selective agonist.
  • the kappa-selective antagonist, norBNI (20 nM) completely reversed the agonist effect.
  • HEK-293 in DMEM (Gibco, BRL) supplemented with 10% Bovine Calf Serum (Hyclone) and 1% penicillin/streptomycin (Gibco, BRL) were maintained at 37 °C and in 5% CO 2 .
  • Cells were seeded at 16% for 24 hours prior to transfection. Fresh media was added 2 hours prior to transfection.
  • Cells were transfected with plasmid DNA (20 ⁇ g/100 mm plate) of either wild type or mutant receptor cDNA using the calcium phosphate precipitation method, see Chen, C; Okayama, H. High Efficiency Transformation of Mammalian Cells by Plasmid DNA. Mol. Cell. Bio. 1987, 7, 2745-2752.
  • HEK cells were washed three times with 25 mM HEPES buffer (pH 7.4) and were resuspended with 8-12 mL of 25 mM HEPES/100 mm plate. Saturation binding assays were performed in triplicate. Nonselective binding was determined using 10 ⁇ M naltrexone. Assays were incubated at room temperature for 90 minutes in a total binding volume of 0.5 mL and were terminated by filtration through a Whatman GF/B filter that had been presoaked in 0.25% poly(ethyleneimine) immediately prior to filtration.
  • substitution at the 4 '-position eliminated binding to all three receptor types.
  • the 6'-regioisomer compound 4b was kappa- selective, but possessed one-tenth the affinity of GNTI for kappa receptors. The results are consistent with the kappa agonist selectivity of compound 4b observed in the GPI.
  • the delta selectivity of regioisomer compound 4c also corresponded well with the functional data. Binding to mu receptors was uniformly low for all regioisomers.
  • Naltrexone was obtained from Mallinckrodt & Co. All reactions were carried out under an inert atmosphere of nitrogen. Triethylamine (NEt 3 ) was distilled from KOH, while dichloromethane and acetonitrile were distilled from calcium hydride prior to their use. Dry dimethyformamide (DMF) was obtained by storing reagent grade material over 3 A sieves for at least 24 h. All other chemicals were either HPLC or reagent grade and used without further purification.
  • Triethylamine NEt 3
  • dichloromethane and acetonitrile were distilled from calcium hydride prior to their use.
  • Dry dimethyformamide (DMF) was obtained by storing reagent grade material over 3 A sieves for at least 24 h. All other chemicals were either HPLC or reagent grade and used without further purification.
  • Thin layer chromatography was performed on analytical Uniplate silica gel GF plates (250 ⁇ m by 2.5 x 20 cm) and preparative thin layer chromatography on 1.0 or 0.5 mm silica gel plates purchased from Analtech. Gravity and low pressure column chromatography were performed over silica gel (200-400 mesh, 60 A, Aldrich) as the stationary phase under N 2 .
  • the reverse phase high pressure liquid chromatography HPLC was performed with Beckman model 110A pumps, a Beckman Analytical Optical Unit (fixed wavelength UV), and a Hewlett-Packard HP 3390A integrating recorder.
  • Example 1 4 -N'-(N M ,N'"-Bis(tert-butoxycarbonyl)guanidino-17- (cyclopropyImethyl)-6,7-didehydro-4,5 ⁇ -epoxy-3,14-hydroxyindoIo- [2',3':6,7]morphinian (6a).
  • Example 2 6 -N , -(N",N'"-Bis(tert-butoxycarbonyl)guanidino-17- (cyclopropylmethyl)-6,7-didehydro-4,5 ⁇ -epoxy-3,14-hydroxyindolo- [2',3':6,7]morphinian (6b).
  • Cbz-protected GNTI 7 (820 mg, 1.10 mmol) was dissolved in MeOH (100 mL). To a Parr hydrogenating bottle, 100 mg of Pd/C (10% by weight) was added and followed by anhydrous MeOH, care was taken to avoid a fire and as a precaution a nitrogen atmosphere can be used in the bottle. Di-Cbz-protected GNTI solution was added to the reaction bottle, stirred well and added dilute HC1 drop wise. The reaction bottle was subjected to hydrogenation at a pressure of 65 psi. After completion ofthe reaction (4 hours), it was left overnight at room temperature.

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Abstract

L'invention concerne des agonistes des récepteurs kappa de la formule (I) et des antagonistes des récepteurs delta de la formule (II). R1-R6 X et n ont l'une quelconque des significations données dans la spécification. Elle concerne également des compositions les renfermant, leurs procédés d'utilisation, ainsi que des procédures de synthèse et des intermédiaires permettant de les préparer.
PCT/US2001/011339 2001-04-06 2001-04-06 Composes therapeutiques et procedes WO2002080919A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003063779A2 (fr) * 2002-01-25 2003-08-07 Regents Of The University Of Minnesota Agents analgesiques selectifs
WO2005015242A1 (fr) * 2003-08-06 2005-02-17 Bayer Healthcare Ag Agents diagnostiques et agents therapeutiques destines a des maladies associees au recepteur opioide kappa 1 (opkr1) couple aux proteines g

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578725A (en) * 1995-01-30 1996-11-26 Regents Of The University Of Minnesota Delta opioid receptor antagonists
US5886001A (en) * 1994-05-18 1999-03-23 Astra Ab Agonist compounds
WO2000008027A1 (fr) * 1998-08-06 2000-02-17 Regents Of The University Of Minnesota Antagonistes du recepteur opioide kappa (op2)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5886001A (en) * 1994-05-18 1999-03-23 Astra Ab Agonist compounds
US5578725A (en) * 1995-01-30 1996-11-26 Regents Of The University Of Minnesota Delta opioid receptor antagonists
WO2000008027A1 (fr) * 1998-08-06 2000-02-17 Regents Of The University Of Minnesota Antagonistes du recepteur opioide kappa (op2)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003063779A2 (fr) * 2002-01-25 2003-08-07 Regents Of The University Of Minnesota Agents analgesiques selectifs
WO2003063779A3 (fr) * 2002-01-25 2005-02-03 Univ Minnesota Agents analgesiques selectifs
WO2005015242A1 (fr) * 2003-08-06 2005-02-17 Bayer Healthcare Ag Agents diagnostiques et agents therapeutiques destines a des maladies associees au recepteur opioide kappa 1 (opkr1) couple aux proteines g

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