Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • C07D491/02—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 two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

• the present invention relates to a new method of use of morphinans.
• the present invention relates to naltrexone or 17-cyclopropylmethyl-4,5a-epoxy-6- oxomorphinan-3,14-diol and nalmenfene or 17-cyclopropylmethyl-4,5a-epoxy-6- methylenemorphinan-3,14-diol or nalmefene, and their analogs, and pharmaceutical formulations thereof, and use thereof for prevention and treatment of NASH (nonalcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease) and ASH (alcoholic steatohepatitis).
• NASH nonalcoholic steatohepatitis
• NAFLD non-alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• the present invention provides a method of the prevention of inflammatory hepatic injury in NAFLD and its progression to NASH.
• NASH nonalcoholic fatty liver disease
• NASH or NAFLD resembles ASH (Alcoholic Steatohepatitis) or ALD (alcoholic liver disease) respectively but occurs in people who drink little or no alcohol [Ludwig, J., et al.. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc, 1980; 55: p. 434-438].
• NASH While the underlying causes of NASH remain unclear, several factors such as insulin resistance, release of toxic inflammatory proteins by fat cells (cytokines), and oxidative stress (deterioration of cells) inside liver cells may contribute to the morbidity of NASH [http://digestive. niddk. nih. gov/ddiseases/pubs/nash ) .
• steatohepatitis is dependent upon a "second hit" such as oxidative stress or endotoxemia ⁇ Wanless IR, Shiota K.
• the pathogenesis of nonalcoholic steatohepatitis and other fatty liver diseases a four-step model including the role of lipid release and hepatic venular obstruction in the progression to cirrhosis. Semin Liver Dis. 2004; 24:99-106; Duvnjak M, et al. Pathogenesis and management issues for nonalcoholic fatty liver disease. World J Gastroenterol. 2007; 14;13:4539-4550).
• hepatoprotectants such as pentoxifylline, ursodeoxycholic acid, or antioxidants
• hepatoprotectants such as pentoxifylline, ursodeoxycholic acid, or antioxidants
• the two most advanced molecules, obeticholic acid and elafibranor have shown encouraging results on improving hepatic histology. Both compounds appear to clear NASH, with obeticholic acid improving liver fibrosis and elafibranor improving the glycemic and lipid profile [Ratziu V., Novel Pharmacotherapy Options for NASH. Dig Dis Sci. 2016 Mar 22. (Epub ahead of print)].
• Methionine-Choline-Deficient (MCD) diet mouse model is a well accepted model of NASH, as described above(cf. Rivera CA, et al. 2007; Sanches SC et al.
• Nonalcoholic Steatohepatitis A Search for Factual Animal Models. Biomed Res Int. 2015;2015:574832). Consequently the MCD diet mice have been widely used to test hepatoprotectant effects of compounds against NAFLD/NASH. Nalmefene demonstrated efficacy in preventing inflammatory liver damage in theMCD rat model, followed by a second hit with LPS.
• Alcoholic liver disease is a leading cause of liver- related morbidity and mortality worldwide [Arsene et al. Hepatol Int. 2016; 10:538-552).
• the clinical and pathologic spectrum of ALD ranges from alcoholic fatty liver disease (alcoholic steatosis) to cirrhosis (Saberi etal. J Clin Translat Hepatol. 2016; 4:113-122).
• ALD can be divided into alcohol-induced steatosis (microvesicular, macrovesicular), alcoholic steatohepatitis (ASH) and alcoholic cirrhosis.
• the pathology of ALD resembles that of NAFLD/NASH.
• ALD and NAFLD have a similar pathologic spectrum, and they have been described to coexist in the clinical setting (Toshikuni et al World J Gastroenterol 2014;20:8393-8406; Brunt and
• Endotoxin is a crucial mediator of liver injury in alcoholic liver disease as demonstrated by the significant reduction of alcoholic liver injury following elimination of the Gram-negative microbiota by antibiotics, and the sensitization to LPS-induced liver injury following long-term ethanol exposure.
• the elevation of endotoxin appears to be predominantly caused by two mechanisms. First, alcohol consumption leads to changes in the intestinal microbiota with bacterial overgrowth in the upper gastrointestinal tract (Hauge et al.
• the present invention relates to morphinan compounds, and pharmaceutical formulations thereof, and use thereof for prevention and treatment of NASH (non- alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), and ASH (alcoholic steatohepatitis).
• NASH non- alcoholic steatohepatitis
• NAFLD non-alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• the present invention relates to use of a morphinan compound according to the formula (I) in treatment of NALFD, NASH and ASH or conditions or for the production of medicaments, for treatment of such conditions wherein:
• A can be OH or OCH3; R can be H, CH3, or cyclopropylmethyl; X is the oxygen atom, Y is O or CH2, Z can be H or OH.
• the compounds according to the formula (I) can be enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof.
• Formula (I) can be a structure such as one of the following structures:
• Compound A (nalmefene), the compound (I) wherein A is OH, R is cyclopropyl, methyl, X is O, Y is CH2, and Z is OH.
• Formula (I) can be a structure such as one of the following structures:
• Compound B (naltrexone), the compound (I) wherein A is OH, R is cyclopropylmethyl, X is O, Y is O, and Z is OH.
• FIG. 1 shows reduction of TNF-a release in Kupffer Cells.
• Figure 2 shows reduction of LPS-induced p38 MAP kinase phosphorylation in Kupffer cells.
• p38 MAP kinase phosphorylation was monitored at 5 and 20 min;
• Figure 3 sets out representative photomicrographs of HE-stained sections of livers from STAM model of NASH. Sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie- Mayer's Hematoxylin and eosin solution. NAFLD Activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner et al, 2005).
• Figures 4A - 4B shows sirius red-positive area (%) in STAM model of NASH, a)
• Figure 7 shows liver injury assessed by histopathological examination of Compound A/LPS treated rats from this experiment. Histopathology indicates that Compound A prevents hepatic fat accumulation in treated rats as compared to the control. Figure 7 indicates that there are improvement of steatosis by Compound A and improvement of liver injury from LPS-treated fatty liver injury.
• FIG. 7 a) Left top [control (MCD treated rats)]: indicated there is macrovesicular steatosis with a bit of microvesicular steatosis; b) Left bottom [MCD and Compound A treated rats]: slight periportal chronic inflammation (mild nonspecific chronic hepatitis); c) Right Top: MCD+LPS treated rats: black dots (arrow) are dying hepatocytes; the light shade area (rectangle) indicates necrosis. There is hemorrhage and periportal (zone 1) necrosis. No significant congestion or loss of architecture; and d) Right bottom [MCD+LPS+ Compound A treated rats]: slight periportal chronic inflammation.
• Treatments or medicaments produced according to the invention include those for preventing or treating NASH (non-alcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), and/or (ASH) alcoholic steatohepatitis.
• NASH non-alcoholic steatohepatitis
• NAFLD non-alcoholic fatty liver disease
• ASH alcoholic steatohepatitis
• the present invention relates to methods of preventing or treating NASH, NAFLD, and/or ASH, comprising administering to a subject in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of one or more of the specified compounds.
• opioid refers to compounds that exhibit opium or morphine-like properties, including agonist and antagonist activity wherein such compounds can interact with stereospecific and saturable binding sites in the brain and other tissues. Pharmacological properties have previously included drowsiness, respiratory depression, changes in mood and mental clouding without a resulting loss of consciousness.
• opioid-like refers to compounds that are similar in structure and/or pharmacological profile to known opioid compounds.
• 'Treat or “treating” as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, prevention or delay of the onset of the disease, etc.
• a "pharmaceutically acceptable” component means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
• prophylaxis means administering a pharmaceutical to a subject prior to the exhibition of relevant symptoms to reduce the risk of a disease manifesting itself or to reduce its severity if it does manifest itself.
• 'Therapeutically effective amount refers to an amount necessary to prevent, delay or reduce the severity of the condition of interest and also includes an amount necessary to enhance normal physiological functioning.
• Active compounds of the present invention can be water soluble and can also comprise known water-soluble opioid and opioid-like derivatives.
• compounds of the present invention can possess an asymmetric carbon atom(s) and therefore are capable of existing as enantiomers or diastereoisomers.
• compounds of the present invention include enantiomers and diastereoisomers as well as pharmaceutically acceptable salts of the compounds of the present invention.
• Active compounds of the present invention can be administered.
• active compounds of the present invention can be coadministered with compounds now known, or later identified, to be useful for the prevention and or treatment of NASH, NAFLD, and/or ASH.
• nalmefene and naltrexone are well documented compounds and commercially available.
• Other compounds of use in the present invention may be obtained by modification of nalmefene by routine chemical methods or by use of techniques analogous to those described in PCT Publication WO 03/097608.
• active agent includes the pharmaceutically acceptable salts of the compound.
• Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b)
• Active agents used to prepare compositions for the present invention may alternatively be in the form of a pharmaceutically acceptable free base of active agent. Because the free base of the compound is less soluble than the salt, free base compositions are employed to provide more sustained release of active agent to the target area. Active agent present in the target area which has not gone into solution is not available to induce a physiological response, but serves as a depot of bioavailable drug which gradually goes into solution.
• the opioid and opioid-like compounds of the present invention are useful as pharmaceutically active agents and may be utilized in bulk form. More preferably, however, these compounds are formulated into pharmaceutical formulations for administration. Any of a number of suitable pharmaceutical formulations may be utilized as a vehicle for the administration of the compounds of the present invention.
• the compounds of the present invention and the physiologically acceptable salts thereof, or the acid derivatives of either are typically admixed with, inter alia, an acceptable carrier.
• the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
• the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.5% to 95% by weight of the active compound.
• a pharmaceutical composition comprises less than 80% by weight of active compound.
• a pharmaceutical composition comprises less than 50% by weight of active compound.
• active compound may be incorporated in the formulations of the invention, which may be prepared by any of the well-known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
• compositions of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
• Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, tablets, dragees, or syrups each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in- oil emulsion.
• Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
• the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
• a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
• Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
• Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may be administered by means of subcutaneous, intravenous,
• Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood.
• Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
• Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
• Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis [see, for example, Pharmaceutical Research 3(6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis ⁇ tris buffer (pH 6) or ethanol/water and contain from 0.01 to 0.2M active ingredient.
• a sustained-release composition includes, but is not limited to, those in which the active ingredient is bound to an ion exchange resin which is optionally coated with a diffusion barrier to modify the release properties of the resin.
• Carriers and/or diluents which may be used include vaseline, lanoline, glycerin, vegetable oils, or fat emulsions, polyethylene glycols, alcohols, transdermal enhancers, natural or hardened oils or waxes, and combinations of two or more thereof.
• the present invention also provides useful therapeutic methods.
• the present invention provides a method of treating NASH, NALFD,and/or ASH.
• Illustrative avians according to the present invention include chickens, ducks, turkeys, geese, quail, pheasant, ratites ⁇ e.g., ostrich) and domesticated birds (e.g., parrots and canaries), and include birds in ovo. Chickens and turkeys are preferred.
• Any mammalian subject in need of being treated according to the present invention is suitable. Human subjects are preferred. Human subjects of both genders and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult) can be treated according to the present invention.
• the present invention provides pharmaceutical formulations comprising the compounds of formulae described herein, or pharmaceutically acceptable salts thereof, in pharmaceutically acceptable carriers for any suitable route of administration, including but not limited to, oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, intravenous, and transdermal administration.
• methods of this invention comprise administering an effective amount of a composition of the present invention as described above to the subject.
• the effective amount of the composition will vary somewhat from subject to subject, and will depend upon factors such as the age and condition of the subject and the route of delivery. Such dosages can be determined in accordance with routine
• the compounds of the present invention can be administered to the subject in an amount ranging from a lower limit from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10% to an upper limit ranging from about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76
• the compounds comprise from about 0.05 to about 95% by weight of the composition. In other embodiments, the compounds comprise from about 0.05 to about 60% by weight of the composition. In still other embodiments, the compounds comprise from about 0.05 to about 10% by weight of the composition.
• the therapeutically effective dosage of any specific compound will vary somewhat from compound to compound, patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with still higher dosages potentially being employed for oral and/or aerosol administration. Toxicity concerns at the higher level may restrict intravenous dosages to a lower level such as up to about 10 mg/kg, all weights being calculated based upon the weight of the active base, including the cases where a salt is employed. Typically, a dosage from about 0.5 mg/kg to about 5 mg/kg will be employed for intravenous or intramuscular
• a dosage from about 1 mg/kg to about 50 mg/kg may be employed for oral administration.
• compounds of the present invention may be administered at a daily dosage of from about 0.1 mg to about 20 mg per kg of animal body weight, which can be given in divided doses q.d. to q.i.d. or in a sustained release form.
• the total daily dose may be in the range of from about 1 mg to about 1,400 mg, for example from 1 to 50mg daily and in other particular embodiments, the total daily dose is in the range of from about 10 mg to about 100 mg.
• the unit dosage forms suitable for oral administration may comprise about 1 mg to about 1,400 mg of the compound optionally admixed with a solid or liquid pharmaceutical carrier or diluent.
• the compounds of the present invention can be administered in any amount appropriate to administer to the subject for treatment of the condition desired to be treated as determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation. (See, for example, Remington, The Science And Practice of Pharmacy (9th Ed. 1995). However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg to about 20 mg per kg of animal body weight, preferably given in divided doses 1 to 4 times a day or in sustained release form.
• Compound A (nalmefene) and Compound B (naltrexone) are commercially available.
• Example 2 Compound A Reduces stimulated release of TNF-a and MAPK
• TNF- ⁇ The primary motors of the inflammatory response in the liver are the Kupffer cells. TNF- ⁇ has been known to play an important role in liver damage and its plasma
• Kupffer cells were isolated by enzymatic digestion and purified by centrifugal elutriation from normal rats and cultured overnight. They were then stimulated with E. coli LPS either without or with Compound A added to the medium. TNF-ot content in the supernatant was measured at 2, 4, and 6 hours.
• Compound A inhibited the LPS/time-dependent increase in TNF-ot released by Kupffer cells. [After 2 h, excessive accumulation of TNF-a in the cells interfered with the results]. (Figure 1). Compound A also reduced LPS-induced p38 MAP kinase phosphorylation in Kupffer cells ( Figure 2).
• NASH was induced in male C57BL/6 mice by a single subcutaneous injection of 200 pg streptozotocin solution 2 days after birth and feeding with high fat diet (HFD, 57 kcal% fat, Cat# HFD32, CLEA Japan, Japan) after 4 weeks of age.
• the animals were divided into groups of six each and were orally administered vehicle (1% Tween80) at 10 mL/kg or Telmisartan at 10 mg/kg twice daily from 6 to 9 weeks of age.
• Compound A/Nalmefene (NMN) and Compound B/Naltrexone (NTX) were administered subcutaneously at 5 mg/kg twice daily. The animals were sacrificed at week 9.
• HE hematoxylin and eosin
• Liver sections from the Vehicle group showed increased collagen deposition in the pericentral region of liver lobule (Table la; Figure 3).
• the fibrosis area (Sirius red-positive area) was significantly decreased in the Telmisartan and NTX groups compared with the Vehicle group.
• NMN-treated group tended to shown decrease in fibrosis area compared with the Vehicle group.
• Example 4 The Methionine- Choline-Deficient (MCD) diet rat model (cf. Szabo G. et al 2005)
• mice 20 Sprague Dawley rats were administered with Compound A by oral gavage once daily at 0, 5, 10, 20 or 30 mg/kg (4 rats/group) for 4 weeks. All animals were fed a methionine / choline deficient (MCD) diet (from Dyets, Inc) five times per week during the feeding period in order to produce a diet-induced fatty liver. Rats were weighed daily as well as food intake. At the end of four weeks, the rats were administered 2 mg/kg E coli endotoxin (LPS) IP and 6 hours later the rats were euthanized and liver tissue and serum collected. Liver and was harvested at time of death as was blood. Histology samples were also taken.
• MCD methionine / choline deficient
• LPS E coli endotoxin

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