WO2017211765A1 - Ligands sigma utilisés dans le traitement du diabète et du syndrome métabolique - Google Patents

Ligands sigma utilisés dans le traitement du diabète et du syndrome métabolique Download PDF

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WO2017211765A1
WO2017211765A1 PCT/EP2017/063616 EP2017063616W WO2017211765A1 WO 2017211765 A1 WO2017211765 A1 WO 2017211765A1 EP 2017063616 W EP2017063616 W EP 2017063616W WO 2017211765 A1 WO2017211765 A1 WO 2017211765A1
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Prior art keywords
substituted
unsubstituted
compound
diabetes
sigma
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PCT/EP2017/063616
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English (en)
Inventor
Manuel Merlos-Roca
Maria-Isabel Martin-Fontelles
Carlos-Ramón PLATA-SALAMAN
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Laboratorios Del Dr. Esteve, S.A.
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Priority to ES201890077A priority Critical patent/ES2700448R1/es
Publication of WO2017211765A1 publication Critical patent/WO2017211765A1/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
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the use of sigma receptor ligands, and more particularly to some pyrazole derivatives, and to the use of pharmaceutical compositions comprising them for the treatment of diabetes.
  • Diabetes is a metabolic disorder caused by interaction of genetic, environmental, immunological, as well as life-style factors.
  • WHO World Health Organization
  • ADA American Diabetes Association
  • Type 1 diabetes mellitus The body's fails to produce insulin
  • Type 2 diabetes mellitus Results from insulin resistance, combined with relative insulin deficiency
  • Gestational diabetes Occurs during pregnancy. Impaired glucose tolerance (i.e. prediabetes): When a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 diabetes.
  • peripheral neuropathy In the pathological course of diabetes often, further complications may arise such as peripheral vascular disease, diabetic neuropathy, diabetic foot problems, diabetic retinopathy and nephropathy.
  • peripheral neuropathy One of the most common complications of diabetes is peripheral neuropathy. Globally it affects about 20-30 million people, and with the increase in obesity rates and the prevalence of type 2 diabetes, this could double by 2025 (Said, 2007).
  • Hyperglycemia induces macrovascular disorders (myocardial infarction, stroke and peripheral vascular disease) and microvascular impairment causes damage to specific cell groups such as vascular endothelial cells in the retina, mesangial in the renal glomerulus, neuronal axons and cells Schwann in the peripheral nerves, causing retinopathy, nephropathy and neuropathy respectively (Mendez et al., 2014). Furthermore autonomic neuropathy, involving both the sympathetic and parasympathetic nervous system, causes gastrointestinal symptoms, urogenital, cardiovascular and sexual dysfunction (American Diabetes Association, 2013).
  • type 2 diabetes In its initial phase, type 2 diabetes is asymptomatic and can be diagnosed after a long time. In this period, the disease could be demonstrated by measuring the fasting blood glucose test or performing a tolerance to it, because hyperglycemia develops gradually. In these early stages, although not show severe symptoms typical of the disease can develop macro and microvascular complications (American Diabetes Association, 2013).
  • Type-2 diabetes is usually associated with metabolic syndrome (MS); comprising abdominal obesity, hypertension, hyperglycemia, hypertriglyceridemia or decreased HDL cholesterol bound to. Although its specific etiology is unknown, there are probably many different causes; most of these patients are obese or have a higher percentage of fat in the abdominal region which causes insulin resistance. Risk factors include age, obesity and physical inactivity; It is also more common in women with history of gestational diabetes and people with hypertension or dyslipidemia (Federation, 2014,Roberts et al., 2013).
  • MS metabolic syndrome
  • metabolic syndrome is of great importance in medicine.
  • the metabolic syndrome is a widespread disease, particularly in the United States and Europe. Based on survey data from 1988 to 1994 and 2000 census data, the American Centre for Disease Control and Prevention estimates that 47 million people in the US have metabolic syndrome.
  • There is currently a world-wide need for treatment of this syndrome as it is identified as heightening the risk of cardiovascular mortality. Consequently, it is an object of the present invention to provide medicaments, which are suitable for the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes.
  • Another object of the present invention is to provide medicaments suitable for the treatment of diabetes, and more particularly type-2 diabetes.
  • Another object of the present invention is to provide medicaments suitable for controlling the diabetes-associated glycaemia by decreasing the blood glucose levels.
  • 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).
  • 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 ( ⁇ -1 ) 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.
  • sigma-1 receptor o1 R
  • o1 R sigma-1 receptor
  • This family presents a pyrazole group which is characterized by the substitution at position 3 by an alkoxy group directly bounded to nitrogen. These compounds were described in WO 2006/021462.
  • the sigma-receptor ligands of the invention are effective for the treatment of diabetes.
  • the sigma-receptor ligands of the invention are effective for the treatment of diabetes, in particular controlling the associated glycaemia by decreasing the blood glucose levels.
  • the sigma-receptor ligands of the invention can be used as adjuvant therapy in the diabetes treatment.
  • the sigma-receptor ligands of the invention are effective to treat metabolic syndrome, and more particularly the diabetes associated metabolic syndrome.
  • the sigma-receptor ligands of the invention are effective to treat hyperglycemia.
  • the term "diabetes” preferably refers to type-2 diabetes.
  • the invention is directed to a compound binding to the sigma- receptor for use in the treatment of diabetes.
  • the invention is directed to a compound binding to the sigma-receptor according to general formula (I) for use in the treatment of diabetes:
  • R 8 and R 9 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 invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use in controlling the diabetes- associated glycaemia by decreasing the blood glucose levels.
  • the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use to treat metabolic syndrome, preferably metabolic syndrome associated with diabetes.
  • the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use as adjuvant therapy in the diabetes treatment.
  • the invention is directed to a compound binding to the sigma- receptor, in particular those of general formula (I), for use to treat hyperglycemia.
  • the invention is directed to the use in the treatment of diabetes of a pharmaceutical composition
  • a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • the invention is directed to the use in controlling the diabetes- associated glycaemia by decreasing the blood glucose levels of a pharmaceutical composition
  • a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • the invention is directed to the use to treat metabolic syndrome, in particular the diabetes associated metabolic syndrome, of a pharmaceutical composition
  • a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • the invention is directed to the use as adjuvant therapy in the diabetes treatment of a pharmaceutical composition
  • a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • the invention is directed to the use in the treatment of hyperglycemia of a pharmaceutical composition
  • a pharmaceutical composition comprising at least a compound as defined above, wherein the composition further comprises at least a pharmaceutically acceptable carrier, adjuvant and/or vehicle.
  • 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.
  • Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.
  • Another aspect of the invention is a method of treatment of a patient suffering from diabetes by controlling the diabetes-associated glycaemia by decreasing the blood glucose levels, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.
  • Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above as adjuvant therapy.
  • Another aspect of the invention is a method of treatment of a patient suffering from metabolic syndrome, in particular diabetes-associated metabolic syndrome, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.
  • Another aspect of the invention is a method of treatment of a patient suffering from hyperglycemia, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, preferably a sigma ligand of formula (I) as defined above.
  • Figure 1 Evolution of the glycaemia and body weight gain in ZDF treated with saline or with Example 1 and LEAN rats. Lines represent the mean ⁇ SEM of the glucose levels on weeks 7, 10, 13, 14 and 15.
  • the invention is directed to a compound binding to the sigma-receptor for use in the treatment of diabetes, and more particularly type-2 diabetes.
  • Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes.
  • Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in controlling the diabetes-associated glycaemia by decreasing the blood glucose levels.
  • Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use as diabetes adjuvant therapy.
  • Another aspect of the present invention is directed to a compound binding to the sigma-receptor for use in the treatment of hyperglycemia.
  • the term "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. in binding assays for the o1 -receptor performed as described (DeHaven-Hudkins et al., Eur J Pharmacol,' ⁇ 992, 227, 371 ) or binding assays for o2-receptor as described (Radesca et al., J Med Chem, 1991 , 34, 3058).
  • 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 3 [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 3 [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, preferably to the sigma-1 receptor subtype is used in the treatment of diabetes and more particularly type-2 diabetes.
  • the compound binding to the sigma-receptor, preferably to the sigma-1 receptor subtype is used in the treatment of metabolic syndrome, and more particularly metabolic syndrome associated to diabetes, preferably to type-2 diabetes.
  • the compound binding to the sigma- receptor preferably to the sigma-1 receptor subtype
  • the compound binding to the sigma-receptor preferably to the sigma-1 receptor subtype
  • the compound binding to the sigma-receptor preferably to the sigma-1 receptor subtype, is used in the treatment of hyperglycemia.
  • the compound is a compound according to formula (I):
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -COR 8 , -C(0)OR 8 ,
  • R 8 and R 9 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 R-i selected from H, -COR 8 , or substituted or unsubstituted alkyl, preferably it is selected from H, methyl or acetyl.
  • R-i is hydrogen.
  • the compound is characterized in that R 2 is H or alkyl, preferably methyl or H. In a preferred embodiment of the use as defined above 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 R 4 are independently selected from halogen, or substituted or unsubstituted alkyl, more preferably selected from halogen or haloalkyl.
  • R 3 and R 4 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 R 4 together with the phenyl group form an optionally substituted fused ring system. More preferably, 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. Even more preferably, the fused ring system is naphthyl, especially a 2-naphthyl ring system, substituted or unsubstituted.
  • the compound is characterized in that n is selected from 2, 3, 4, more preferably n is 2.
  • the compound is characterized in that R 5 and R 6 , together, form a morpholin-4-yl group.
  • the sigma ligand of general formula (I) is selected from:
  • the compound is 4- ⁇ 2-[5- methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl ⁇ morpholine or its pharmaceutically acceptable salts, solvates or a prodrug thereof.
  • the compound is 4- ⁇ 2- [5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3-yloxy]ethyl ⁇ morpholine hydrochloride or solvates or a prodrug thereof.
  • 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. 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.
  • Cycloalkyi 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 cycloalkyi 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 quaternized ; 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 quaternized, wherein Ra and Rb is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • 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 fluoro, chloro, bromo and iodo ; cyano; hydroxyl ; nitro ; azido ; alkanoyl such as a Ci -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 14 C-enriched carbon or 15 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, ⁇ , ⁇ -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.
  • the compounds of general formula (I) and their salts or solvates can be prepared as disclosed in the previous application WO2006/021462.
  • the obtained reaction products may, if desired, be purified by conventional methods, such as crystallisation and chromatography. Where the above described processes for the preparation of compounds of the invention give rise to mixtures of stereoisomers, 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 encompass all such forms.
  • the terms “treat”, “treating” and “treatment” include the eradication, removal, reversion, alleviation, modification, or control of diabetes, metabolic syndrome, hyperglycemia and/or its related symptoms.
  • the invention relates to the treatment of diabetes-associated glycaemia by decreasing the blood glucose levels.
  • Another aspect of this invention relates to a method of treating diabetes, which method(s) comprises administering to a patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a compound of general formula (I) as above defined or a pharmaceutical composition thereof.
  • Another aspect of the invention is a method of treatment of a patient suffering from diabetes by controlling the diabetes-associated glycaemia by decreasing the blood glucose levels, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.
  • Another aspect of the invention is a method of treatment of a patient suffering from diabetes, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above, as adjuvant therapy.
  • a sigma ligand more particularly a sigma ligand of formula (I) as defined above, as adjuvant therapy.
  • Another aspect of the invention is a method of treatment of a patient suffering from metabolic syndrome, in particular diabetes-associated metabolic syndrome, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.
  • a sigma ligand more particularly a sigma ligand of formula (I) as defined above.
  • Another aspect of the invention is a method of treatment of a patient suffering from hyperglycemia, which comprises administering to the patient in need of such a treatment a therapeutically effective amount of a sigma ligand, more particularly a sigma ligand of formula (I) as defined above.
  • the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of diabetes.
  • the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for controlling the diabetes-associated glycaemia by decreasing the blood glucose levels.
  • the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for diabetes adjuvant therapy.
  • the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of metabolic syndrome, in particular diabetes-associated metabolic syndrome.
  • the invention is directed to a use of a sigma ligand, more particularly the compounds of general formula (I) as above defined, in the preparation of a medicament for the treatment of hyperglycemia.
  • 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 the use as defined above of 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.
  • the 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 microcrystalline 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.
  • the pharmaceutical 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 will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts.
  • Administration of the compounds or 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 of general formula (I) of the invention are administered once daily.
  • the sigma ligand of general formula (I) is administered as a daily dose of from to 100 mg to 600 mg per day. Even more preferably, the sigma ligand of general formula (I) is administered as a daily dose of from 200 mg to 400 mg per day.
  • the compounds and compositions of this invention may be used to provide with other drugs 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.
  • the other drugs are selected among the known drugs currently used in the treatment of diabetes, especially type-2 diabetes.
  • 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:
  • mice were obtained from Charles River Laboratories (Research Models, Barcelona, Spain). The animals were housed in a certified animal care facility, in cages (2-3 animals) and maintained in environmentally controlled conditions (temperature 20 °C, humidity 60%) with a 12-h light/dark cycle until they reached 15 weeks of life. Animals were maintained on Purina 5008 (16.7 kcal% fat) diet and sterile tap water, chow and water being available ad libitum through all the experimental period.
  • hyperglycemia and insulin resistance begins to develop at, approximately, 7 weeks of age and glucose levels typically reach a plateau (more than 300 mg/dl) by 15-16 weeks of age (Peterson et al., 1990).
  • Non-fasting blood glucose levels were daily measured in the morning (9 h) using a glucose strip tester (Glucocard sensor, Arkray, Inc. Kyoto Japan), throughout the experimental period (weeks 7, 10, 13, 14 and 15).
  • Example 2 Glycaemia in ZDF rats treated with Example-1
  • the ZDF rats showed a mean blood glucose concentration of 88.1 ⁇ 5.1 , 329.3 ⁇ 26.0, and 413.6 ⁇ 22.6 mg/dl, on week 7, 10 and 13, respectively, being the difference of week 10 and 13 vs week 7 values statistically significant (p ⁇ 0.001 ).
  • the LEAN mean blood glucose concentration was of 64.8 ⁇ 1 .4, 60.6 ⁇ 1 .3, and 69.9 ⁇ 2.6 mg/dl, on week 7, 10 and 13, respectively. These values were significantly different from those recorded in both saline- and Example 1 -treated ZDF rats (p ⁇ 0.001 ).
  • Non-fasting blood glucose levels in ZDF rats were slight but significantly (p ⁇ 0.01 ) decreased from the first administration of Example 1 in comparison with values recorded in saline treated ZDF animals ( Figure 1 ).
  • a one way ANOVA followed by Bonferroni post hoc test was used for statistical analysis of glycaemia differences between saline and Exaple 1 ZDF treated rats (**p ⁇ 0.01 ).
  • the compound of example 1 shows a significant reduction in the glycaemia.
  • Example 1 the compound of Example 1 and the other compounds of general formula (I) will be useful to treat diabetes, metabolic syndrome, hyperglycemia, etc.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés de formule générale (I) qui présentent une activité pharmacologique à l'égard du récepteur sigma, et qui sont destinés à une utilisation dans le traitement du diabète.
PCT/EP2017/063616 2016-06-07 2017-06-05 Ligands sigma utilisés dans le traitement du diabète et du syndrome métabolique WO2017211765A1 (fr)

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* 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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