WO2017021002A1 - Utilisation de ligands des récepteurs sigma dans la dyslipidémie - Google Patents

Utilisation de ligands des récepteurs sigma dans la dyslipidémie Download PDF

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Publication number
WO2017021002A1
WO2017021002A1 PCT/EP2016/001322 EP2016001322W WO2017021002A1 WO 2017021002 A1 WO2017021002 A1 WO 2017021002A1 EP 2016001322 W EP2016001322 W EP 2016001322W WO 2017021002 A1 WO2017021002 A1 WO 2017021002A1
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substituted
compound
unsubstituted
administered
use according
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PCT/EP2016/001322
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English (en)
Inventor
Antonio GUZMAN-CANO
Jose-Miguel Vela-Hernandez
Manuel Merlos-Roca
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Laboratorios Del Dr. Esteve, S.A.
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Priority to EP16745628.4A priority Critical patent/EP3328365A1/fr
Publication of WO2017021002A1 publication Critical patent/WO2017021002A1/fr

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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of sigma receptor ligands, and more particularly to some pyrazole derivatives, to pharmaceutical compositions comprising them, and to their use for increasing the HDL-C and/or decreasing triglycerides plasma levels in the prevention and treatment of atherosclerotic cardiovascular disease (ACVD).
  • ACVD atherosclerotic cardiovascular disease
  • cardiovascular disease Despite considerable improvements in medical care over the past 25 years, cardiovascular disease (CVD) remarks a major public health challenge, being one of the leading causes of death in the world.
  • cardiovascular disease or disorder includes but not limits to coronary heart disease, stroke, high blood pressure, dyslipidemia, congestive heart failure and peripheral vascular disease.
  • Cholesterol, in both free and esterified forms, and triglycerides are the two main lipids in plasma. They are transported in lipoproteins, pseudomicellar lipid-protein complexes, in which the main apolipoproteins (apo B- 100/48, apo A-I, apo A-II, apo E and apo Cs) are integral components. Apo A-I and apo A-II are components of HDL (High Density Lipoprotein) and the apo A-I/A-II lipoprotein classes are closely inter-related via several metabolic pathways.
  • HDL High Density Lipoprotein
  • HDL-C High Density Lipoprotein-Cholesterol
  • statin therapy has either have an increase in adverse events risks (myopathy, hepatotoxicity, gastro-intestinal side effects, gout, cholesterol gallstones, triglycerides raise, etc.) and/or modest effects on triglycerides and HDL-C levels
  • HDL-C raising per se, may represent a key determinant of the clinical benefits associated with lipid-modifying therapy (Chapman,M.J. et al.; Eur. Heart J. Access published April 29, 2011; pages 1-23).
  • This family presents a pyrazol group which is characterized by the substitution at position 3 by an alkoxy group directly bounded to nitrogen. These compounds have been described in WO 2006/021462.
  • the sigma ( ⁇ ) receptor is a cell surface and endoplasmic reticulum receptor expressed in the central nervous system (CNS) among other tissues. From studies of the biology and function of sigma receptors, evidence has been presented that sigma receptor ligands may be useful in the treatment of psychosis and movement disorders such as dystonia and tardive dyskinesia, and motor disturbances associated with Huntington's chorea or Tourette's syndrome and in Parkinson's disease (Walker, J.M. et al, Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma receptor ligand rimcazole clinically shows effects in the treatment of psychosis (Hanner, M. et al. Proc. Natl. Acad.
  • the sigma binding sites have preferential affinity for the dextrorotatory isomers of certain opiate benzomorphans, such as (+)SKF 10047, (+)cyclazocine, and (+)pentazocine and also for some narcoleptics such as haloperidol.
  • the sigma receptor has at least two subtypes, which may be discriminated by stereoselective isomers of these pharmacoactive drugs.
  • SKF 10047 has nanomolar affinity for the sigma 1 ( ⁇ -l) site, and has micromolar affinity for the sigma ( ⁇ -2) site.
  • Haloperidol has similar affinities for both subtypes.
  • Endogenous sigma ligands are not known, although progesterone has been suggested to be one of them.
  • Possible sigma-site-mediated drug effects include modulation of glutamate receptor function, neurotransmitter response, neuroprotection, behavior, and cognition (Quirion, R. et al. Trends Pharmacol. Sci. , 1992, 13:85-86).
  • the existence of sigma receptors in the CNS, immune and endocrine systems have suggested a likelihood that it may serve as link between the three systems.
  • the sigma-receptor ligands of the invention are effective for the prevention or the treatment of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidaemia, by increasing the HDL-C plasma levels and/or reducing the triglycerides plasma levels.
  • ACVD atherosclerotic cardiovascular disease
  • the present invention provides sigma-receptor ligands, its pharmaceutical compositions and methods of using such compositions that are effective in the treatment or prevention of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia, because its HDL-C plasma levels increase and/or triglycerides plasma levels decrease.
  • ACVD atherosclerotic cardiovascular disease
  • the invention is directed to a compound binding to the sigma-receptor for use in the treatment or prevention of atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia.
  • ACVD atherosclerotic cardiovascular disease
  • the compound increases HDL-C plasma levels and/or decreases triglycerides plasma levels.
  • the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist.
  • the compound is selected from selective Sigma neutral antagonist receptor ligands.
  • the compound binds selectively to the sigma- 1 receptor subtype.
  • Rs and R9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the compound is 4- ⁇ 2- [5 -methyl- 1- (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine or one of its pharmaceutically acceptable salts or hydrates for use in the treatment or prevention of dyslipidemia.
  • this is 4- ⁇ 2-[5-methyl-l -(naphthalen-2-yl)-lH-pyrazol-3- yloxy]ethyl ⁇ morpholine hydrochloride and/or the compound is administered to a woman, and/or is administered at a dosage of between 300 and 500 mg/day.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined above, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • Figure 1 Total Cholesterol plasma determination in a 4 weeks (4w) toxicity study in monkeys.
  • Figure 2 HDL-C fraction plasma determination in a 4w toxicity study in monkeys.
  • Figure 3 LDL-C fraction plasma determination in a 4w toxicity study in monkeys.
  • Figure 4 HDL-C/LDL-C ratio plasma determination in a 4w toxicity study in monkeys.
  • Figure 5 Total Cholesterol plasma determination in a 13 weeks (13w) toxicity study monkeys.
  • Figure 6 HDL-C fraction plasma determination in a 13w toxicity study in monkeys.
  • Figure 7 LDL-C fraction plasma determination in a 13w toxicity study in monkeys.
  • Figure 8 HDL-C/LDL-C ratio plasma determination in a 13w toxicity study in monkeys.
  • the invention is directed to a compound binding to the sigma-receptor for use in the treatment or prevention atherosclerotic cardiovascular disease (ACVD), especially the dyslipidemia.
  • ACVD atherosclerotic cardiovascular disease
  • cardiovascular disease refers to any disease or disorder of the heart or blood vessels (/. e. arteries and veins) or any symptom thereof.
  • Non-limiting examples of cardio vascular related diseases or disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidaemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction and other cardio vascular events.
  • treatment and/or prevention of dyslipidemia refers to any kind of effect of the compounds of the invention regarding the increase of HDL-C plasma levels and/or the decrease of triglycerides plasma levels as defined above.
  • compound binding to the sigma receptor refers to any compound that binds with high affinity to the sigma-receptor, preferably to the sigma- 1 receptor subtype.
  • binding with high affinity to the sigma receptor refers to compounds of the invention that can replace a ligand in competitive binding assays, preferably in competitive radioligand-binding assays as exemplary described in WO2006/021462, e.g.
  • binding of the compounds of the invention, with respect to binding to the sigma- 1 receptor subtype is measured by competing with the binding of [H]-(+)-pentazocine, e.g. in radioligand-assays as described in the art (e.g. in DeHaven-Hudkins et al., 1992).
  • compounds of the invention when assayed at a concentration of 10 "7 M yield at least 25%, more preferably at least 45%, even more preferably at least 65%, yet even more preferably at least 75%, most preferably at least 85% binding to the sigma- 1 receptor in [H]-(+)-pentazocine radioligand-assays as defined above.
  • binding selectively to the Sigma receptor refers to compounds of the invention that shows nanomolar affinity for its target while showing either a percentage of inhibition less than 50% when tested at 1 micromolar in a panel of other non-specific targets or when there is one hundred times less affinity or functional activity for those non- specific targets.
  • the compound binding to the sigma-receptor is used in the treatment or prevention of an atherosclerotic cardiovascular disease.
  • the invention is directed to the use of the compound binding to the sigma-receptor in the treatment or prevention of dyslipidemia.
  • the compound binding to the sigma-receptor is used for increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels.
  • the HDL-C plasma levels are increased and/or the triglycerides plasma levels are decreased by the use of the compound.
  • the compound binding to the sigma-receptor is used for increasing the HDL-C plasma levels.
  • the compound binding to the sigma-receptor is used for decreasing the triglycerides plasma levels.
  • the compound binding to the sigma-receptor is used in the treatment of an atherosclerotic cardiovascular disease. In a preferred embodiment the compound binding to the sigma-receptor is used in the treatment of dyslipidaemia. In a preferred embodiment the compound binding to the sigma-receptor is used in the prevention of an atherosclerotic cardiovascular disease.
  • the compound binding to the sigma-receptor is used in the prevention of dyslipidemia.
  • the compound is selected from a sigma receptor antagonist, a neutral antagonist, an inverse agonist or a partial antagonist.
  • the compound binds to the sigma- 1 receptor subtype.
  • the compound binds selectively to the sigma- 1 receptor subtype.
  • R 8 and R9 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, aromatic or non-aromatic heterocyclyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, and halogen; or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the compound is characterized in that Ri selected from H, -COR 8 , or substituted or unsubstituted alkyl, preferably it is selected from H, methyl or acetyl.
  • Ri is hydrogen.
  • the compound is characterized in that R 2 is H or alkyl, preferably methyl or H.
  • the compound is characterized in that R 3 and R 4 are situated in the meta and para positions of the phenyl group.
  • the compound is characterized in that R 3 and R4 are independently selected from halogen, or substituted or unsubstituted alkyl, more preferably selected from halogen or haloalkyl.
  • the compound is characterized in that both R 3 and R4 together with the phenyl group form an optionally substituted fused ring system.
  • said fused ring system is selected from a substituted or unsubstituted fused aryl group and a substituted or unsubstituted aromatic or partially aromatic fused heterocyclyl group.
  • Said fused ring system preferably contains two rings and/or from 9 to about 18 ring atoms, more preferably 9 or 10 ring atoms.
  • the fused ring system is naphthyl, especially a 2-naphthyl ring system, substituted or unsubstituted.
  • n is selected from 2, 3, 4, more preferably n is 2.
  • the compound is characterized in that R 5 and R , together, form a morpholin-4-yl group.
  • the sigma ligand of general formula (I) is selected from:
  • the compound is 4- ⁇ 2-[5- methyl-l -(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof.
  • the compound is 4- ⁇ 2-[5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3- yloxy]ethyl ⁇ morpholine or its pharmaceutically acceptable salts or solvates.
  • the compound is 4- ⁇ 2-[5- methyl- 1 -(naphthalen-2-y 1)- 1 H-pyrazol-3 -yloxy]ethyl ⁇ morpholine hydrochloride or solvates or a prodrug thereof.
  • the compound is 4- ⁇ 2-[5-methyl-l-(naphthalen-2-yl)-l H-pyrazol-3- yloxy]ethyl ⁇ morpholine hydrochloride or solvates thereof.
  • EMBODIMENT X refers to 4- ⁇ 2-[5-methyl-l -(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ mo holine or one of its pharmaceutically acceptable salts or hydrates for use in the treatment or prevention of dyslipidemia.
  • EMBODIMENT X refers to 4- ⁇ 2-[5-methyl-l-(naphthalen-2- yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine hydrochloride for use in the treatment or prevention of dyslipidemia.
  • the compound is administered to a mammal of female gender, preferably is administered to a woman and/or
  • the compound is administered at a dosage of 10 to 125 mg/kg/day, or is administered at a dosage of 300 to 500 mg/day.
  • the compound is administered to a mammal of female gender
  • the compound is administered to a woman at the age of over 18 years.
  • the compound is administered by oral administration
  • the compound is administered in form of a tablet or capsule.
  • the compound is administered one, two, three or four times per day
  • this includes administration of the compound in any fitting pharmaceutical formulation for 1- 4 times per day thus within 24 hours.
  • the compound is administered once or twice per day, or only once per day. It is also preferred if at least one of the applications of the compound is done in the morning.
  • this includes daily administration of the compound in any fitting pharmaceutical formulation and optionally more than once per day as long as the administration is done for a period of time exceeding or equal to 4 weeks. In other preferred options the administration is done for a period of time exceeding or equal to 6 or 13 weeks.
  • the compound is administered at a dosage of 10 to 125 mg/kg/day
  • this includes administration at any dosage within this dosage range.
  • Other preferred dosage ranges include administration at a dosage of 30 to 125 mg/kg/day or at a dosage of 80 and 125 mg/kg/day. It could also include selected dosages selected from 10, 20, 30, 80, 100 or 125 mg/kg/day, preferably selected from 80, 100 or 125 mg/kg/day.
  • the compound is administered at a dosage of 1 to 10 mg/kg/day, preferably at 2 to 8 mg/kg/day, most preferably at 3 to 7 mg/kg/day.
  • the compound is administered at a dosage of 250 to 750 mg/day, preferably at a dosage of 300 to 500 mg/day, or more preferably at a dosage of 300 to 500 mg/day or most preferably at a dosage of 400 mg/day.
  • EMBODIMENT X is an embodiment, wherein the compound is administered daily for at least 4 weeks to a woman at a dosage of 80 and 125 mg/kg/day.
  • the compound is administered by oral administration once or twice per day.
  • EMBODIMENT X is an embodiment, wherein 4- ⁇ 2-[5-methyl-l - (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine or one of its pharmaceutically acceptable salts or hydrates is for use in the treatment or prevention of dyslipidemia, wherein the compound is the hydrochloride salt and/or the compound is administered daily for at least 4 weeks and/or is administered to a woman and/or is administered at a dosage of 80 and 125 mg/kg/day.
  • the compound is administered by oral administration and/or is administered once or twice per day.
  • a most preferred embodiment is an embodiment, wherein 4- ⁇ 2-[5-methyl-l-(naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine or one of its pharmaceutically acceptable salts or hydrates is for use in the treatment or prevention of dyslipidemia, wherein the compound is administered to a woman.
  • the compound is administered orally once per day at a dosage of 400 mg.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i- propyl, n-butyl, t-butyl, n-pentyl, etc.
  • Alkyl radicals may be optionally substituted by one or more substituents such as a aryl, halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto, alkylthio, etc.
  • aryl If substituted by aryl it corresponds to an "arylalkyl or aralkyl” radical, such as benzyl and phenethyl.
  • alkenyl refers to an alkyl radical having at least two carbon atoms and having one or more unsaturated bonds.
  • Cycloalkyl refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl.
  • the cycloalkyl radical may be optionally substituted by one or more substituents such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.
  • Aryl refers to single and multiple ring radicals, including multiple ring radicals that contain separate and/or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms, such as phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical.
  • the aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl, alkoxycarbonyl, etc.
  • Heterocyclyl refers to a stable 3-to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8 -membered ring with one or more heteroatoms, more preferably a 5-or 6-membered ring with one or more heteroatoms. It may be aromatic or not aromatic.
  • the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quatemized ; and the heterocyclyl radical may be partially or fully saturated or aromatic.
  • heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole, imidazole, etc.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Amino refers to a radical of the formula-NH 2 , -NHRa or -NRaRb, optionally quatemized, wherein Ra and Rb is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Halo or hal refers to bromo, chloro, iodo or fluoro.
  • fused ring system refers to a polycyclic ring system that contains fused rings. Typically, the fused ring system contains 2 or 3 rings and/or up to 18 ring atoms. As defined above, cycloalkyl radicals, aryl radicals and heterocyclyl radicals may form fused ring systems. Thus, fused ring system may be aromatic, partially aromatic or not aromatic and may contain heteroatoms.
  • a spiro ring system is not a fused-polycyclic by this definition, but fused polycyclic ring systems of the invention may themselves have spiro rings attached thereto via a single ring atom of the system.
  • fused ring systems are, but are not limited to, adamantyl, naphthyl (e.g. 2-naphthyl), indenyl, fenanthryl, anthracyl, pyrenyl, benzimidazole, benzothiazole, etc.
  • substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e.
  • halogen such as fiuoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a C 1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having
  • the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or l4 C- enriched carbon or l 5 N-enriched nitrogen are within the scope of this invention.
  • pharmaceutically acceptable salts, solvates, prodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein.
  • non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by methods known in the art.
  • salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- toluenesulphonate.
  • mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulphonate and p- toluenesulphonate.
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery” Taylor & Francis (april 2002).
  • the compounds of the invention may be in crystalline form either as free compounds or as solvates and it is intended that both forms are within the scope of the present invention.
  • Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate.
  • the compounds of general formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs.
  • the compounds of the present invention represented by the above described general formula (I) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E).
  • the single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention.
  • reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography.
  • these isomers may be separated by conventional techniques such as preparative chromatography. If there are chiral centers the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such crystalline form in pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • the compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms.
  • Another aspect of this invention relates to a method of treating or preventing an atherosclerotic cardiovascular disease, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of treating or preventing a dyslipidemia, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of increasing the HDL-C plasma levels which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • Another aspect of this invention relates to a method of decreasing the triglycerides plasma levels, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a preferred embodiment relates to the method of treating of an atherosclerotic cardiovascular disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a more preferred embodiment relates to the method of treating of dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a preferred embodiment relates to the method of preventing an atherosclerotic cardiovascular disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • a more preferred embodiment relates to the method of preventing dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound as above defined or a pharmaceutical composition thereof.
  • One of the most preferred embodiments of the invention refers to method of treating or preventing dyslipidemia, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of 4- ⁇ 2-[5-methyl-l -(naphthalen-2-yl)- lH-pyrazol-3-yloxy] ethyl ⁇ morpholine or one of its pharmaceutically acceptable salts or hydrates.
  • the compound is 4- ⁇ 2-[5-methyl-l - (naphthalen-2-yl)-lH-pyrazol-3-yloxy]ethyl ⁇ morpholine hydrochloride for use in the treatment or prevention of dyslipidemia.
  • a preferred embodiment of the method of treating or preventing dyslipidemia described above is an embodiment
  • the compound is administered at a dosage of 10 to 125 mg/kg/day, preferably at a dosage of 30 to 125 mg/kg/day, more preferably at a dosage of 80 and 125 mg/kg/day or at a dosage selected from 10, 20, 30, 80, 100 or 125 mg/kg/day, preferably at a dosage selected from 80, 100 or 125 mg/kg/day, or ⁇ wherein the compound is administered at a dosage of 1 to 10 mg/kg/day, preferably at a dosage of 3 to 7 mg/kg/day or at a dosage from 250 to 750 mg/day, preferably at a dosage from 300 to 500 mg/day or at a dosage of 400 mg/day.
  • an even more preferred embodiment of the method of treating or preventing dyslipidemia described above is an embodiment, wherein the compound is administered daily for at least 4 weeks to a woman either at a dosage of 80 and 125 mg/kg/day or at a dosage of 400 mg/day.
  • the compound is administered by oral administration once or twice per day.
  • the invention is directed to a use of the compounds as above defined in the preparation of a medicament for the treatment or prevention of an atherosclerotic cardiovascular disease.
  • the invention is directed to a use of the compounds as above defined in the preparation of a medicament for the treatment or prevention of dyslipidemia.
  • the invention is directed to a use of the compounds as above defined in the preparation of a medicament for increasing the HDL-C plasma levels and/or decreasing the triglycerides plasma levels.
  • the invention is directed to a use of the compounds as above defined in the preparation of a medicament for increasing the HDL-C plasma levels. In another aspect the invention is directed to a use of the compounds as above defined in the preparation of a medicament for decreasing the triglycerides plasma levels.
  • a preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the treatment of an atherosclerotic cardiovascular disease.
  • a more preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the treatment of dyslipidemia.
  • a preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the prevention of an atherosclerotic cardiovascular disease.
  • a more preferred embodiment relates to a use of the compounds as above defined in the preparation of a medicament for the prevention of dyslipidemia.
  • the present invention further provides pharmaceutical compositions comprising a compound of this invention, or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomers thereof together with a pharmaceutically acceptable carrier, adjuvant, or vehicle, for administration to a patient.
  • the invention is thus directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined above, wherein the composition further comprises a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • pharmaceutical compositions are in oral form, either solid or liquid.
  • Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or macrocrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form.
  • Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.
  • compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of the diseases to be treated.
  • an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer.
  • active compounds will typically be administered once or more times a day for example 1 , 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
  • the compounds are administered once daily.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time.
  • Compound 63 can be prepared as disclosed in the previous application WO2006/021462 (Compound 63 is example 61 in WO2006/021462). Its hydrochloride can be obtained according the following procedure:
  • Example 2 Total Cholesterol, HDL-C and LDL-C plasma determination in a 4-weeks toxicity study with Example 1.
  • Example 1 was administered by oral route (gavage) to three groups of 3 males and 3 females each, at doses of 20, 80 and 125 mg/kg/day.
  • a fourth group received the vehicle (water) acting as control group.
  • 2 males and 2 females were initially assigned to the control and high-dose groups to be subjected to a 2-weeks recovery period after the end of treatment.
  • On week 4 of treatment after overnight food deprivation, blood samples were obtained from all animals and collected into tubes containing lithium heparin as anticoagulant.
  • Example 1 treatment produced increases in the total plasma cholesterol, which were due to increases in the HDL-C fraction, mainly in females ( Figure 2). On the contrary, LDL-C fraction was reduced in both males and females ( Figure 3). Overall, HDL-C/LDL-C ratio dose-dependently increased in both sexes after 4w Example 1 treatment ( Figure 4).
  • Example 3 Total Cholesterol, HDL-C and LDL-C plasma determination in a 13- weeks toxicity study with Example 1.
  • Example 1 was administered by oral route (gavage) to three groups of 3 males and 3 females each, at doses of 10, 30 and 100 mg/kg/day.
  • a fourth group received the vehicle (water) acting as a control group.
  • 2 males and 2 females were assigned to the control and high dose groups to be subjected to a 4- week recovery period after the end of treatment.
  • blood samples were obtained from all animals and collected into tubes containing lithium heparin as anticoagulant. All tubes were agitated mechanically for at least five minutes and the sample subsequently centrifuged at 2000 g for 10 minutes in order to separate the plasma.
  • Example 1 was administered at 400 mg in capsules for 28 days orally once daily.
  • Example 1 was administered at 400 mg in capsules for 28 days orally once daily in the morning before food intake.
  • Example 1 was administered at 400 mg for 28 days orally once daily in the morning.
  • Haematology Haemoglobin red blood cells count, haematocrit, white blood cells (WBC) count and differential WBC, mean cell volume (MCV), mean corpuscular haemoglobin (MCH), MCH concentration (MCHC) and platelets count,
  • Urinalysis Dipstick determination of pH, protein, glucose, leukocytes, nitrites, ketones, blood. If the results of the dipstick are abnormal, a biochemistry urinalysis +/- a microbiology analysis will be performed if needed.
  • Urine pregnancy test, urinalysis and coagulation parameters were performed locally at the local laboratory at each investigational site.
  • a validated central laboratory processed and provides results for the haematology and biochemistry clinical laboratory tests.
  • Example 1 the 4-wk treatment of human volunteers with Example 1 produced in all studies A, B, and C a reduction of the triglycerides (table 1). This effect was in all cases more pronounced than the effect seen in placebo. Finally, changes on LDL-C were more variable among these three studies (when a decreasing effect in LDL-C was observed, this was only seen with Example 1 but no with placebo) and ranged from:

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Abstract

L'invention concerne des composés de formule générale (I) présentant une activité pharmacologique à l'égard du récepteur sigma, pour utilisation dans le traitement et la prévention de la dyslipidémie.
PCT/EP2016/001322 2015-07-31 2016-07-29 Utilisation de ligands des récepteurs sigma dans la dyslipidémie WO2017021002A1 (fr)

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US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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WO2006021462A1 (fr) 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs de récepteur sigma
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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