WO2014169976A1 - Composés donneurs d'oxyde nitrique à base de quinone - Google Patents

Composés donneurs d'oxyde nitrique à base de quinone Download PDF

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Publication number
WO2014169976A1
WO2014169976A1 PCT/EP2013/076555 EP2013076555W WO2014169976A1 WO 2014169976 A1 WO2014169976 A1 WO 2014169976A1 EP 2013076555 W EP2013076555 W EP 2013076555W WO 2014169976 A1 WO2014169976 A1 WO 2014169976A1
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Prior art keywords
compound
methyl
trimethyl
formula
nitrooxy
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PCT/EP2013/076555
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English (en)
Inventor
Nicoletta Almirante
Laura Storoni
Gael Ronsin
Daniela Miglietta
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Nicox Science Ireland
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Publication of WO2014169976A1 publication Critical patent/WO2014169976A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C203/00—Esters of nitric or nitrous acid
    • C07C203/02—Esters of nitric acid
    • C07C203/04—Esters of nitric acid having nitrate groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to nitric oxide donor compounds, to processes for their preparation and to their use in the treatment of vascular diseases and in particular in the treatment of pathological conditions where a deficit of NO function plays an important role in their pathogenesis.
  • NO plays multiple physiological roles in regulating numerous and diverse organ functions, defects in the NO pathway lead to the development of many different pathological conditions. These disorders include hypertension, atherosclerosis, coronary artery diseases, cardiac failure, pulmonary hypertension, stroke, impotence, vascular complications in diabetes mellitus, gastrointestinal ulcers, asthma, and other central and peripheral nervous system disorders.
  • Organic nitrates are proven medicinal substances for the treatment of dysfunctions of the circulatory system preferably cardiovascular and coronary dysfunctions. They display their effect both by relieving the heart via a reduction in the preload and after load and by improving the oxygen supply to the heart via coronary dilatation.
  • Nitrate tolerance develops despite an elevation in the drug plasma concentration reflecting a decrease in vascular sensitivity to previously therapeutic levels. This can be prevented or reduced by inclusion of a nitrate free period in the dosing schedule
  • Nitrate-tolerant individuals are more susceptible to enhanced vasoconstriction whenever the plasma nitrate concentration is allowed to fall, the so-called rebound effect. This is reflected by increased sensitivity to a number of circulating vasoconstrictor substances such as catecholamines and angiotensin II. Clinically the rebound effect may be more important than is currently recognized.
  • Evidence suggests that even intermittent nitrate patch therapy results in increased vasoconstrictor sensitivity during the patch-off period. [Munzel T, Mollnau H, Hartmann M, et al. Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production. J Am Coll Cardiol. 2000; 36:628-634].
  • Organic nitrates also cause unpleasant important side effects that include headache, hypotension, flush and nausea. Headache is the most prominent side effect and is caused by cerebral vasodilatation.
  • nitrate tolerance and the other side effects have restricted the clinical use and effectiveness of nitrates.
  • nitric oxide donor compounds which can produce extended release of NO and do not give rise to any nitrate tolerance are needed.
  • EP 0 362 575 and EP 0 451 760 claim compounds which contain sulphydryl groups and prevent nitrate tolerance or diminish a nitrate tolerance which has already occurred.
  • Patent application WO-A-92/04337 discloses organic nitrated derivatives of the thiazolidine ring with vasodilating activity and a reduced tolerance.
  • Patent EP 1 120 419 discloses isosorbide mononitrates wherein the free hydroxyl group is esterified with either carboxylic acids or with thioacids wherein said ester groups are in trans position with respect to the nitrate group.
  • UK patent application no. GB 2 349 385 A discloses antioxidant nitrate or nitrite ester for use as vasodilator agents in the treatment of pathological conditions associated with endothelial dysfunction, in particular heart diseases.
  • the disclosed compounds contain a superoxide scavenger moiety and a nitrate or nitrite group and the two parts are stably linked in order to reduce the degradation of the molecules under physiological conditions.
  • the stable link increases the activity of the anti-oxidant scavenger that can avert reactive oxygen species-mediated NO consumption of further production of deleterious species.
  • the present invention provides new nitric oxide donor compounds having a better pharmacological activity in term of less tolerance associated with the use of organic nitrates and a longer duration of action than that of nitric oxide donors described in the art.
  • the present invention relates to compounds of formula (I)
  • Ri is methyl
  • P 2 is H or methyl
  • P 3 is methyl
  • P4 and P 5 are methyl and n is 1 , or
  • P4 is H
  • P 5 is selected from phenyl, para-fluorophenyl, para-methoxyphenyl, para- isopropylphenyl, para-trifluoromethylphenyl and para-methylphenyl and n is 2;
  • n is an integer from 1 to 10, preferably m is an integer from 1 to 6;
  • p is 0 or 1 ; R is H or methyl.
  • Another embodiment of the invention provides a compound of formula (I)
  • Ri, R 2 and R 3 are methyl
  • R 4 and R 5 are methyl and n is 1 ;
  • n is an integer from 1 to 10, preferably 1 to 6;
  • p is 0 or 1 ;
  • R6 is H or methyl.
  • Another embodiment of the invention provides a compound of formula (I)
  • Ri, R 2 and R 3 are methyl
  • R 4 and R 5 are methyl and n is 1 ;
  • n is an integer from 1 to 10, preferably 1 to 6;
  • Another embodiment of the invention provides a compound of formula (I)
  • Ri, R 2 , R 3 are methyl
  • R 4 is H
  • R 5 is selected from phenyl, para-fluorophenyl, para-methoxyphenyl, para-isopropylphenyl, para-trifluoromethylphenyl and para-methylphenyl and n is 2; m is an integer from 1 to 10, preferably 1 to 6;
  • p is 0 or 1 ;
  • R6 is H or methyl.
  • Another embodiment of the invention provides a compound of formula (I)
  • Ri, R 2 , R3, are methyl
  • R 4 is H, R5 is selected from phenyl, para-fluorophenyl, para-methoxyphenyl, para- isopropylphenyl, para-trifluoromethylphenyl and para-methylphenyl and n is 2;
  • n is an integer froml to 10, preferably 1 to 6;
  • Another embodiment of the invention provides a compound of formula (I) selected from the group:
  • the compounds of formula (I) increase the nitric oxide bioavailability and they are able to directly release NO and stimulate guanylate cyclase in the skeletal muscle.
  • the compounds of formula (I) have an antioxidant activity comparable to the antioxidant activity of well known antioxidant compounds like ferulic and caffeic acid or edaravone.
  • pulmonary hypertension the treatment and/or prevention of dysfunctions of the circulatory system involving vasculopathies preferably pulmonary arterial hypertension, Sickle cell disease, systemic sclerosis, scleroderma, muscular dystrophies such as Duchenne's muscular dystrophy and Becker's muscular dystrophy, cardiac allograft vasculopathy, pathological conditions plays an important role in their pathogenesis, and/or tissue damage due to ischemia and/or due to ischemia-reperfusion.
  • the compounds of formula (I) can be used in combination with at least a therapeutic agent selected from non steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, endothelin receptor antagonists, hydroxyurea.
  • compositions may be administered by different routes.
  • they may be administered orally in form of pharmaceutically preparations such as tablets, capsules, syrups and suspensions, parenterally in form of solutions or emulsions, etc. They may also be administered topically in form of creams, pomades, balsams, and transdermically for example through the use of patches or bandages.
  • the preparations may comprise physiologically acceptable carriers, excipients, activators, chelating agents, stabilizers, etc. In case of injections there may be incorporated physiologically acceptable buffers, solubilizing agents or isotonics.
  • compositions according to the present invention may further comprise a non steroidal anti-inflammatory drug (NSAID), a steroid drug, a thrombolytic agent such as plasminogen activator urokinase, streptokinase,reteplase or anistreplase.
  • NSAID non steroidal anti-inflammatory drug
  • a steroid drug such as plasminogen activator urokinase, streptokinase,reteplase or anistreplase.
  • a thrombolytic agent such as plasminogen activator urokinase, streptokinase,reteplase or anistreplase.
  • compositions according to the invention may further comprise a hypolipidemic agent preferably simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, eptastatin, lifibrol, acifran, acitemate, glunicate or rosuvastatin.
  • a hypolipidemic agent preferably simvastatin, lovastatin, atorvastatin, pravastatin, fluvastatin, eptastatin, lifibrol, acifran, acitemate, glunicate or rosuvastatin.
  • the daily dose may be varied depending on the specific symptoms, the age, the body weight of the patients, the specific mode of administration, etc., and a daily normal dose for an adult person could be between 0.1 to 1000 mg, and could be administered as one dose only or divided into several doses during the day.
  • PG is a suitable hydroxyl protective group and m, p and Re are as above defined by reaction with nitric acid and acetic anhydride in a temperature range from
  • the hydroxyl group is first converted to the corresponding mesyl or tosyl or triflate group and then nitrated using known methods, as for example tetraalkylammonium nitrate and sodium nitrate followed by the removal of the protecting group by methods well known in the art.
  • Compound of formula (Vila) wherein m is as previously defined, p is 1 and Re is H or CH 3 can be synthesized by reacting the corresponding alkenyl-alcohol of formula (VHIb) with a dihydroxylating reagent such as ADmix a or ⁇ or KMn0 4 , Os0 4 in a 1/1 mixture of protic/aprotic solvents like tBuOH, H 2 0, optionally in the presence of an activator like methanesulfonamide at temperature ranging from -20 to 30°C, optionally followed by a chiral separation of the diols (Vila) ⁇
  • a dihydroxylating reagent such as ADmix a or ⁇ or KMn0 4 , Os0 4 in a 1/1 mixture of protic/aprotic solvents like tBuOH, H 2 0, optionally in the presence of an activator like methanesulfonamide at temperature ranging from -20 to 30°C, optionally followed by
  • VHIb Compounds of formula (VHIb) are prepared from compounds (Villa) by protecting the free hydroxyl group with a suitable PG group already defined with known methods (see for example: T.W. Greene, P. G. M. Wuts "Protective groups in organic Synthesis", 4th edition, J. Wiley & Sons, New York, 2006).
  • OPG OPG
  • D is Zn, Mg, or Cu, preferably Zn;
  • Z is R or a halogen, preferably CI, in the presence of a chiral amino alcohol catalyst such as (lS,2R)-(-)-(dibutylamino)-l- phenyl-l-propanol or (li?,25)-(+)-(dibutylamino)-l -phenyl- 1-propanol or an achiral catalyst in an aprotic/ non polar solvent such as toluene, THF or Et 2 0 at temperature ranging from -80°C to 65°C
  • Compound of formula (XVIIIa) can be prepared by oxidation of carboxylic acids of formula (XVII) wherein R l s R 2 , R 3 and Rs are as above described according to the procedure disclosed by Jurd and Wong, AustJ.Chem. 1980, 33, 137, as depicted in Scheme 6.
  • Carboxylic acids of formula (XVII) can be prepared by acid-catalyzed coupling reaction between hydroquinone (III) and the commercially available ⁇ -lactone (XVI)
  • Step 2 Synthesis of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l- yl)butanoic acid
  • Step 6 Synthesis of 4-(nitrooxy)butyl 3-methyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanoate (Compound (1))
  • Step 2 Synthesis of 6-(nitrooxy)hexyl 3-methyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa- 1 ,4-dienyl)butanoate
  • Step 3 Synthesis of 6-(nitrooxy)hexyl 4-phenyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanoate (Compound 3)
  • Step 3 6-(Nitrooxy)hexyl 4-(4-fluorophenyl)-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanoate (Compound 4)
  • Step 4 Synthesis of 4-(nitrooxy)butyl 4-phenyl-4-(2,4,5-trimethyl-3,6- dioxocyclohexa-l,4-dienyl)butanoate (Compound 5)
  • 4-phenyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l- yl)butanoic acid (synthesized as in Example 3, steps 1 and 2) (0.27 g; 0.86 mmol) and 4- hydroxybutyl nitrate (0.15 mg; 0.86 mmol) in CH 2 C1 2 (4 ml), l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) (0.25 g; 1.30 mmol) and DMAP cat.
  • EDC l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Step 7 Synthesis of (5S,6R)-6-hydroxy-5-terbutyldiphenyl silyloxyheptyl 4- nitrobenzoate and (5S,6S)-6-hydroxy-5-terbutyldiphenylsilyloxyheptyl 4-nitrobenzoate
  • the diastereoisomers were separated by preparative HPLC (conditions: column Phenomenex Gemini phenyl- hexyl 100x21.2 mm/5m.
  • Mobile phase A: water + 0.1% Formic acid; B: methanol + 0.1% formic acid.
  • the diastereoisomers were separated by preparative HPLC (conditions: column Phenomenex Gemini phenyl-hexyl 100x21.2 mm/5m to give the major diastereoisomer as a white solid (1.09 g, 66%).
  • Step 10 Synthesis of (lR,2S)-6-hydroxy-l-methyl-2-(nitrooxy) hexyl nitrate
  • Step 11 Synthesis of (5S,6R)-5,6-bis(nitrooxy)heptyl 3-methyl-3-(2,4,5-trimethyl- 3,6-dioxocyclohexa-l,4-dienyl)butanoate (compound 7)
  • Step 1 Synthesis of (R)-5,6-bis(nitrooxy)hexyl 3-methyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa- 1 ,4-dienyl)butanoate To a stirred solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien- l-yl)butanoic acid (237 mg; 0.95mmol) and (2R)-6-hydroxyhexane-l,2-diyl dinitrate (213 mg; 0.95 mmol) in DCM (5 ml) cooled to 0°C, ED AC (162 mg; 1.04mmol) and a catalytic amount of DMAP were added.
  • antioxidant properties of compound (1) (Example 1), its precursor (3-methyl- 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l-yl)butanoic acid, (Intermediate 2) (Example 1 , Step 2) and reference antioxidant compounds were assessed after NADPH- induced lipidic peroxidation of membrane lipids in rat hepatic microsomes using the detection of 2-thiobarbituric acid reactive substances (TBARS) by visible spectroscopy.
  • TBARS 2-thiobarbituric acid reactive substances
  • Hepatic microsomal membranes from male Wistar rats were prepared by differential centrifugation (8000 g, 20 min; 120000 g, 1 h) in a HEPES/sucrose buffer (10 ⁇ , 250 mM, pH 7.4) and stored at -80°C. Incubation was performed at 37°C in a Tris-HCl/KCl (100 mM/150 mM, pH 7.4) containing microsomal membranes (2 mg prot/mL), sodium ascorbate (100 ⁇ ), and DMSO solutions of the tested compounds.
  • Lipid peroxidation was initiated by adding ADP-FeCl 3 and NADPH (Method A) or 2.5 ⁇ FeS0 4 (Method B) (as described by Boschi D. et al, J. Med. Chem. 2006, 49:2886-2897). Aliquots were taken from the incubation mixture at 5, 15, and 30 min and treated with trichloroacetic acid (TCA) 10% w/v. Lipid peroxidation was assessed by spectrophotometric (543 nm) determination of the TBARS consisting mainly of malondialdehyde (MDA). TBARS concentrations (expressed in nmol/mg protein) were obtained by interpolation with a MDA standard curve. The antioxidant activity of tested compounds was evaluated as the percent inhibition of TBARS production with respect to control samples, using the values obtained after 30 min of incubation. IC 50 values were calculated by nonlinear regression analysis.
  • Results are expressed as IC 50 of inhibition of TBARS production after 30 min incubation at 37°C
  • Method A inhibition of rat hepatic lipid peroxidation induced by ADP-FeCl 3 and NADPH.
  • Method B inhibition of rat hepatic lipid peroxidation induced by FeS04 and ascorbic acid
  • N-labelled compounds (l)-(7) were dissolved in a mixture of 1% aqueous methocel and DMSO 98 / 2 (v/v) and orally administered to cannulated male SD rats at a dose of 30 mg/kg.
  • 100 ⁇ _, of blood sample were immediately protein crushed using using 300 ⁇ _, of acetonitrile, vortex mixed and centrifuged 10 min at 4°C (3200g); The supernatant was transferred to a clean plate pending the nitrite quantification.
  • the quantification is based on conversion of 15 N0 2 ⁇ to 15 N-naphthotriazole using
  • a calibration curve (CC) for 15 N-naphthotriazole in mouse blood was prepared in the range 0.01 - 30 ⁇ .
  • working solutions (WS) of 15 N-naphthotriazole in DMSO were prepared by serial dilution of a lOmM stock solution to the following final concentrations:
  • the raw data (average peak area at each time point) were interpolated using
  • the 15 N-nitrite-to- 15 N-naphthotriazole conversion factor (CF) used is the average of the CF obtained at the three different concentrations of the spiked samples.
  • All the compounds are able to release nitric oxide after oral administration in a range (Cmax).
  • cGMP and 15 N- labelled nitrites were measured in tibialis anterior muscle homogenates following a single oral administration with the 15N-labeled Compound (1).
  • 15 N-labelled nitrites were also quantified. The quantification is based on conversion of 15 N0 2 ⁇ to 15 N-naphthotriazole using 1 ,2-diaminonaphtalene in acidic conditions, followed by quantification by LC-MS/MS. A group of samples of rat skeletal muscle freshly spiked with known concentration of 15 N0 2 " was added to evaluate the degree of conversion of nitrite to naphthotriazole.
  • Skeletal muscles were protein precipitated using 300 ⁇ _, of acetonitrile, vortex mixed and centrifuged for 10 minutes at 4°C (3200g).
  • a calibration curve (CC) for 15 N-naphthotriazole in mouse blood was prepared in the range 0.01 - 30 ⁇ .
  • working solutions (WS) of 15 N-naphthotriazole in DMSO were prepared by serial dilution of a lOmM stock solution to the following final concentrations:
  • the raw data (average peak area at each time point) were interpolated using
  • the 15 N-nitrite-to- 15 N-naphthotriazole conversion factor (CF) used is the average of the CF obtained at the three different concentrations of the spiked samples.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur des composés donneurs d'oxyde nitrique ayant une structure à base de quinone, sur des procédés pour leur préparation et sur leur utilisation dans le traitement d'états pathologiques dans la pathogenèse desquels une carence en NO joue un rôle important.
PCT/EP2013/076555 2013-04-18 2013-12-13 Composés donneurs d'oxyde nitrique à base de quinone WO2014169976A1 (fr)

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RU2648453C1 (ru) * 2016-12-19 2018-03-26 Гульфия Нагимовна Афлятумова Способ ранней диагностики различных форм эссенциальной артериальной гипертензии у детей и подростков

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GB2349385A (en) * 1999-04-30 2000-11-01 Teijin Ltd Organic nitrates and nitrites useful against heart disease
WO2003088961A1 (fr) * 2002-04-19 2003-10-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composes beta-agonistes contenant des groupes donneurs d'oxyde nitrique et des groupes piegeurs d'especes d'oxygene reactifs et leur utilisation dans le traitement de troubles respiratoires
WO2009111576A2 (fr) * 2008-03-05 2009-09-11 Edison Pharmaceuticals, Inc. Dérivés de p-quinone 2-substituée pour le traitement de maladies de stress oxydatif
WO2011092690A1 (fr) * 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions et procédés pour la prévention et le traitement de l'hypertension pulmonaire
WO2012037665A1 (fr) * 2010-09-24 2012-03-29 Oral Delivery Technology Ltd. Oxyde nitrique libérant un ester d'acide aminé pour le traitement de l'hypertension pulmonaire et autres états respiratoires

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WO2003088961A1 (fr) * 2002-04-19 2003-10-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composes beta-agonistes contenant des groupes donneurs d'oxyde nitrique et des groupes piegeurs d'especes d'oxygene reactifs et leur utilisation dans le traitement de troubles respiratoires
WO2009111576A2 (fr) * 2008-03-05 2009-09-11 Edison Pharmaceuticals, Inc. Dérivés de p-quinone 2-substituée pour le traitement de maladies de stress oxydatif
WO2011092690A1 (fr) * 2010-01-26 2011-08-04 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd Compositions et procédés pour la prévention et le traitement de l'hypertension pulmonaire
WO2012037665A1 (fr) * 2010-09-24 2012-03-29 Oral Delivery Technology Ltd. Oxyde nitrique libérant un ester d'acide aminé pour le traitement de l'hypertension pulmonaire et autres états respiratoires

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