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WO2011160974A2 - Dérivés de statines - Google Patents

Dérivés de statines Download PDF

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Publication number
WO2011160974A2
WO2011160974A2 PCT/EP2011/059778 EP2011059778W WO2011160974A2 WO 2011160974 A2 WO2011160974 A2 WO 2011160974A2 EP 2011059778 W EP2011059778 W EP 2011059778W WO 2011160974 A2 WO2011160974 A2 WO 2011160974A2
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compound
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solution
formula
group
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WO2011160974A3 (fr
Inventor
Laura Storoni
Annalisa Bonfanti
Francesca Benedini
Francesca Oliva
Daniela Miglietta
Ennio Ongini
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Nicox SA
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Nicox SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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

Definitions

  • the present invention relates to new statin nitroderivatives . More particularly, the present invention relates to dinitrate statins, pharmaceutical compositions containing them and their use as cholesterol-reducing drugs, as drugs having antioxidant, antithrombotic and anti-inflammatory activity, effects on endothelial function, immunosuppressive properties and for treating and/or preventing acute coronary syndromes, stroke, neurodegenerative disorders, such as Alzheimer's and Parkinson's disease as well as autoimmune diseases, such as multiple sclerosis.
  • Statins is a class of compounds which comprises as main components lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin, atorvastatin, rosuvastatin and cerivastatin (rivastatin) .
  • Statins possess a side group that is structurally similar to HMG-CoA ( 3-hydroxy-3- methylglutaryl coenzyme A) .
  • Fluvastatin, atorvastatin, rosuvastatin and cerivastatin are entirely synthetic compounds containing a heptanoic acid side chain, the remainders being fungal metabolites.
  • statins are inhibitors of HMG-CoA reductase, an enzyme which catalyses an early, rate-limiting step in cholesterol biosynthesis, reduce triglyceride levels and are also indicated for raising HDL- C levels (P.O. Bonetti et al., European Heart Journal (2003) 24, 225-248) .
  • WO 2004/105754 discloses mononitrate statins having improved pharmacological activity and enhanced tolerability and their use for treating and/or preventing several diseases . It has been so surprisingly found that the dinitrate compounds of the invention provide enhanced nitric oxide (NO) release over mononitrate analogs (WO 2004/105754). A consideration of stoichiometry leads to an expectation of a doubling of nitrite levels.
  • Object of the present invention are, therefore, statin nitroderivatives of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof
  • R is selected from the group consisting of (Ila) (Ilf) :
  • w is an integer selected between 0 and 1 ;
  • R 1 and R 2 can be equal or different and are independently selected from the group consisting of hydrogen and C 1 -C4 alkyl ;
  • Y is selected from the group consisting of:
  • R 3 , R 4 , R 5 , R 6 and R 8 are independently a straight or branched C 1 -C 1 0 alkylene;
  • n is an integer from 0 to 1 ;
  • nl is an integer from 0 to 1 ;
  • p is an integer from 0 to 4 ;
  • pi is an integer from 0 to 4 ;
  • R 7 is selected from the group consisting of hydrogen and
  • R 9 is a saturated, unsaturated or aromatic heterocyclic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen or sulphur.
  • Ci-Cio alkylene refers to branched or straight chain Ci-Cio hydrocarbon, such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.
  • Ci-Cio alkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like .
  • heterocyclic refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like.
  • Preferred compounds according to the invention are the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein R is the group (lid) or (lie) .
  • An embodiment of the invention relates to the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein w is 1.
  • R 1 and R 2 which can be equal or different are independently selected from the group consisting of hydrogen and C3 ⁇ 4.
  • Another preferred embodiment of the invention relates to the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein w is 0.
  • Another preferred embodiment of the invention relates the compounds of general formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein Y of the group A) is selected from the group consisting of:
  • Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein
  • Y of the roup B is selected from the group consisting of:
  • Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above wherein Y of the group C) is selected from the group consisting of:
  • Another embodiment of the invention relates to the compounds of Formula (I) or pharmaceutically acceptable salts or stereoisomers thereof as defined above selected from the roup consisting of:
  • Another aspect of the present invention includes the use of the compounds of formula (I) in combination with at least a compound used to treat cardiovascular diseases selected from the group consisting of: ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers, antithrombotics such as aspirin, nitrosated ACE inhibitors, nitrosated renin inhibitors, nitrosated angiotensin II receptor antagonists, nitrosated beta-adrenergic blockers and nitrosated aspirin.
  • ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers, antithrombotics are described in the literature such as The Merck Index (13 th edition) .
  • Suitable nitrosated compounds are disclosed in WO 98/21193, WO 2005/011646, WO 97/16405, WO 2004/106300, WO 2004/110432 and WO 2007/045551.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the compounds and/or compositions of the present invention and one or more of the compounds used to treat cardiovascular diseases reported above.
  • the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
  • the compounds according to the present invention when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
  • organic acids examples include oxalic, tartaric, maleic, succinic, citric acids.
  • inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.
  • the compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers , enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures.
  • object of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adiuvants and/or carriers usually employed in the pharmaceutical field.
  • the daily dose of active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. Usually, total daily dose may be in amounts preferably from 1 to 500 mg.
  • the dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.
  • the compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation or aerosol, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • transdermal administration such as transdermal patches or iontophoresis devices.
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • injectable preparations for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono or diglycerides , in addition fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavouring and the like.
  • statin nitroderivatives possess enhanced anti-inflammatory, antiplatelet and antithrombotic effects as compared to native statins. Moreover, they can be effective also in the other pathologies such as acute coronary syndromes, stroke, peripheral vascular diseases such as peripheral ischemia, all disorders associated with endothelial dysfunctions such as vascular complications in diabetic patients and atherosclerosis, neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) , autoimmune diseases such as multiple sclerosis .
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • M is an alkali metal or alkaline earth metal such as sodium or calcium and R is as above defined;
  • the reaction is carried out in an aprotic polar/non polar solvent such as DMF, THF, toluene at a temperature ranging from -20°C to 60°C;
  • the reaction is completed within a time ranges from 30 minutes to 24 hours.
  • the reaction may be carried out in presence in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) , N' - ( 3-dimethylaminopropyl ) -N-ethylcarbodiimide hydrochloride (EDAC) , N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP .
  • a condensing agent such as dicyclohexylcarbodiimide (DCC) , N' - ( 3-dimethylaminopropyl ) -N-ethylcarbodiimide hydrochloride (EDAC) , N, N' -carbonyldiimidazole (CDI)
  • DCC dicyclohexylcarbodiimide
  • EDAC 3-dimethylaminopropyl
  • CDI N, N' -carbonyldiimidazole
  • the reaction is carried out in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C.
  • an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C.
  • the reaction is completed within a time range from 30 minutes to 36 hours; 2.2) deprotecting the compounds obtained in the step 2.1) .
  • Fluoride ion is the preferred method for removing silyl ether protecting group.
  • the deprotecting of the carboxylic function may be carried out by hydrogenation in presence of Pd/C in an aprotic polar/non polar solvent such as THF at temperature ranging from 0°C to 30 °C and a pressure ranging from 1 to 5 bar;
  • an aprotic polar/non polar solvent such as THF
  • the deprotecting of the carboxylic function may be carried out with palladium tetrakis, in presence of dimedone and triphenylphosphine or in presence of morpholine, in an aprotic polar/non polar solvent such as THF, DMF or CH 2 CI 2 , at temperature ranging from -10 °C to
  • R is as above defined and M is an alkali metal or alkaline earth metal such as sodium or calcium,
  • reaction may be carried out in an aprotic polar/non polar solvent such as THF, DMF or CH 2 CI 2 , at temperature ranging from -80°C to 60°C.
  • an aprotic polar/non polar solvent such as THF, DMF or CH 2 CI 2
  • Hal is selected from Br or CI
  • aprotic polar/non polar solvent such as THF, DMF or CH 2 CI 2 , at temperature ranging from -80°C to 60°C;
  • Y is as above defined in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) , N' - ( 3-dimethylaminopropyl ) -N-ethylcarbodiimide
  • DCC dicyclohexylcarbodiimide
  • reaction is carried out in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C.
  • organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 50°C.
  • reaction is completed within a time range from 30 minutes to 36 hours; 5) deprotecting of the diol function of compound of formula (VII) wherein R is as above defined in presence of fluoride salt of alkylamine such as triethylamine trihydrofluoride or tetrabutylamonium fluoride and acetic acid, in an aprotic polar/non polar solvent such as THF, at temperature ranging from -10°C to 30°C.
  • fluoride salt of alkylamine such as triethylamine trihydrofluoride or tetrabutylamonium fluoride and acetic acid
  • an aprotic polar/non polar solvent such as THF
  • Another embodiment of the invention relates to compounds of formula (VI) wherein R is (He) .
  • atorvastatin calcium salt 5.0 g, 4.33 mmol
  • DMF 75 mL
  • allyl bromine 2.1 g, 17.30 mmol
  • the solution was stirred at room temperature for 72 hours.
  • the solution was diluted with 3 ⁇ 40 (200mL) and extracted with EtOAc (3 x 100 mL) .
  • the combined organic layers were washed with brine (2 x 100 mL) , dried over a 2 S0 4 and concentrated under reduced pressure.
  • the reaction was stirred at room temperature for 24 hours.
  • the solution was diluted with AcOEt (250 mL) and washed with an aqueous solution of 5 % Na3 ⁇ 4P0 4 (2x100 mL) .
  • the organic layer was washed with 3 ⁇ 40 (4x100 mL) and brine, then dried over Na 2 S0 4 and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n-hexane/EtOAc 7/3 to EtOAc during 1.4 L) affording the compound (5) (0.81 g, 58%).
  • the solution was diluted with AcOEt (100 mL) and washed with an aqueous solution of 5 % Na3 ⁇ 4P0 4 (2x50 mL) .
  • the organic layer was washed with 3 ⁇ 40 (4x50 mL) and brine, then dried over Na 2 SC>4 and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient from n- hexane/AcOEt 55/45 to n-hexane/AcOEt 3/7 during 1740 mL) affording the compound (7) (0.31 g, yield 23%).
  • statins dinitrate derivatives disclosed in examples 1-3, 5-8, 10, 11 and 13-16 were tested in vitro in isolated rabbit thoracic aorta preparations (Wanstall J.C. et al . , Br. J. Pharmacol., 134:463-472, 2001) .
  • PSS physiological salt solution
  • Each ring was mounted under 2 g passive tension in 5 ml organ bath. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System. Preparations were allowed to equilibrate for 1 h, then contracted submaximally with noradrenaline (NA, 1 ⁇ ) and, when the contraction was stable, acetylcholine (ACh, 10 ⁇ ) was added. A relaxant response to ACh indicated the presence of a functional endothelium. When a stable precontraction was reached, a cumulative concentration- response curve to each vasorelaxant agent was obtained in the presence of a functional endothelium.
  • Table 1 reports the EC 50 of the tested compounds, the results shown that the dinitrates of the invention showed improved EC 50 values in vessel relaxation assay compared to mononitrate derivatives (Compound A and B) which are greater than two fold. Furthermore, in experiments performed in presence of ODQ (10 ⁇ ) , the vasorelaxant responses to all the tested drugs were inhibited showing that the vasodilative effects are mediated by NO.
  • Example F2 Evaluation of pharmacokinetic parameters
  • Reference compound Atorvastatin .
  • the formulations of the tested compounds were prepared on the day of dosing, immediately before of administration, by dissolving an appropriate amount of the test compound in PEG400/DMA 70/30, in order to obtain the following target concentrations :
  • Test compounds were administered orally to each animal by gavage . Animals were fasted overnight before dosing. On the day of dosing the food was offered about 4 h post dosing. Serial blood samples (about 0.3 mL) were collected from the catheter of each SVC catheterized rat, using syringes containing Na-heparin as anticoagulant, at pre-dose, 15 min, 30 min, 1, 2, 4, 6 and 8 h post-dosing. The samples were then transferred into pre-cooled tubes (containing 7.5 L of a solution of sodium fluorure, 40 mg/mL and DICHLORVOS, 10 mg/mL, in order to inhibit plasma esterase activity, in water for injection), protected from light. The blood was centrifuged at 10000 rpm for 3 min at +4 °C to collect plasma (within 30 min from blood collection) , and plasma samples were stored at -80°C.
  • Plasma samples were thawed in ice bath. Plasma aliquots of 50 yL were protein precipitated in triplicate using 150 yL of acetonitrile to which were also added 10 yL of DMSO, vortex-mixed and centrifuged 10 min at 4°C at 4000 rpm. The supernatant was transferred to a clean plate and injected onto a LC-MS system.
  • Atorvastatin ortho and para hydroxy metabolites levels were quantified using a calibration curve (range 0.01-10 ⁇ ) prepared in rat plasma, spiking an appropriate volume of working solution in 50 yL of plasma and then precipitating the proteins (see below for standard curve preparation) using 150 yL of acetonitrile, vortex-mixed and centrifuged 10 min at 4°C at 4000 rpm. The supernatant was transferred to a clean plate and injected onto a LC-MS system. Analytical conditions were as follows: Column: ACQUITY BEH Phenyl 50 x 2.1 mm (1.7y) @ 40°C
  • Detection was performed using a Waters Quattro Micro API mass spectrometer operated in ESI+ mode.
  • the multiple reaction monitoring (MRM) pair monitored was m/z 559.26- ⁇ 440.2 for atorvastatin and m/z 575.16 -> 440.2 for ortho and para hydroxy metabolites.
  • the autosampler cooler was maintained at 4°C.
  • Table 2 reports a summary of pharmacokinetic parameters of the compounds of the invention and of atorvastatin following single oral administration to SD rats (dose equimolar to atorvastatin 20 mg/kg)
  • Table 3 reports a summary of pharmacokinetic parameters of 2-hydroxy metabolite of atorvastatin formed from the compounds of the invention following single oral administration to SD rats (dose equimolar to atorvastatin 20 mg/kg)

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  • Chemical & Material Sciences (AREA)
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Abstract

Les statines de type dinitrate ci-décrites ont une activité pharmacologique améliorée et peuvent être utilisées pour traiter et/ou prévenir plusieurs maladies, en particulier, les syndromes coronariens aigus, les troubles neurodégénératifs ainsi que pour abaisser les taux de cholestérol.
PCT/EP2011/059778 2010-06-21 2011-06-14 Dérivés de statines Ceased WO2011160974A2 (fr)

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EP10166595 2010-06-21
EP10166595.8 2010-06-21

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WO2011160974A3 WO2011160974A3 (fr) 2012-04-05

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
CN103724278A (zh) * 2013-12-12 2014-04-16 江苏阿尔法药业有限公司 他汀类中间体及其衍生物的制备方法
WO2020069065A1 (fr) * 2018-09-28 2020-04-02 The Regents Of The University Of California Composés et méthodes de traitement d'une maladie gastro-intestinale
CN111788196A (zh) * 2018-01-09 2020-10-16 配体药物公司 缩醛化合物及其治疗用途
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
EP4005633A2 (fr) 2022-02-08 2022-06-01 Sawant, Mohit Manikrao Forme cristalline de l'ester allylique de la rosuvastatine
WO2023152754A1 (fr) * 2022-02-08 2023-08-17 Sawant, Mohit Manikrao Forme cristalline d'ester allylique de rosuvastatine
JP2023115525A (ja) * 2022-02-08 2023-08-21 モヒット・マニクラオ・サワント ロスバスタチンアリルエステルの結晶形態

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