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WO2015155234A1 - 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
WO2015155234A1
WO2015155234A1 PCT/EP2015/057611 EP2015057611W WO2015155234A1 WO 2015155234 A1 WO2015155234 A1 WO 2015155234A1 EP 2015057611 W EP2015057611 W EP 2015057611W WO 2015155234 A1 WO2015155234 A1 WO 2015155234A1
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Prior art keywords
compound
methyl
dimethoxy
nitrooxy
dien
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2015/057611
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English (en)
Inventor
Marco BLANGETTI
Roberta Fruttero
Alberto Gasco
Marta GIORGIS
Loretta Lazzarato
Barbara Rolando
Nicoletta Almirante
Laura Storoni
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Nicox Science Ireland Ltd
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Nicox Science Ireland Ltd
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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
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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 of formula (I) for the use in the treatment and/or prophylaxis of glaucoma and ocular hypertension.
  • the present invention also relates to combinations comprising nitric oxide donor compounds of formula (I) and one or more further active ingredients for the use in the treatment and/or prophylaxis of glaucoma and ocular hypertension.
  • Glaucoma including normotensive and hypertensive glaucoma, is a disease of the eye characterized by a progressive loss of visual field due to irreversible damage to the optic nerve to the point where, if untreated, may result in total blindness.
  • Hypertensive glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels.
  • POAG primary open angle glaucoma
  • Normotensive glaucoma is a chronic progressive optic neuropathy resulting in typical optic nerve head changes, retinal nerve fiber layer defects, and characteristic visual field defects.
  • the chamber angle is open and IOP values within statistical normal limits (lower than 22 mmHg) (Lee et al. 1998; for review, see Hoyng and Kitazawa 2002).
  • Prior art treatment of glaucoma consists in lowering the intraocular pressure by administering drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, a-agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.
  • drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, a-agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.
  • Topical beta-blockers show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia.
  • Topical a-agonists have a fairly high incidence of allergic or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects.
  • oral carbonic anhydrase inhibitors include fatigue, anorexia, depression, paresthesias and serum electrolyte abnormalities (The Merck Manual of Diagnosis and Therapy, Seventeenth Edition, M. H. Beers and R. Berkow Editors, Sec. 8, Ch. 100).
  • topical prostaglandin analogs used in the treatment of glaucoma can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, ulceris, uveitis and macular oedema (Martindale, Thirty-third edition, p. 1445).
  • the drugs currently used for treating diseases of the macula are steroidal anti-inflammatory drugs such as triamcinolone acetonide or fluocinolone.
  • steroidal anti-inflammatory drugs such as triamcinolone acetonide or fluocinolone.
  • intravitreal triamcinolone injections are associated with many ocular complications including elevation of intraocular pressure.
  • Elevated intraocular pressure is a common post-surgical complications following ocular surgery such as pars plana vitrectomy, vitreoretinal surgery, retinal detachment surgery, panretinal photocoagulation.
  • NO nitric oxide
  • US patent 4,590,207 discloses ophthalmic solution containing isosorbide mononitrate as an active ingredient for treating and/or preventing intraocular hypertension and glaucoma.
  • US patent application 2002/0168424 discloses the use of a mixture of a nitric oxide (NO) donor such as nitrovasodilators like minoxidil, nitroglycerin, L- arginine, isosorbide dinitrate, or nitroprusside, and a cyclic guanosine 3',5'- monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) inhibitor such as sildenafil citrate for treating glaucoma or ocular hypertension.
  • NO nitric oxide
  • cGMP cyclic guanosine 3',5'- monophosphate
  • PDE5 phosphodiesterase type 5
  • the disclosed combinations promotes systemic vascular relaxation, enhanced blood flow to the optic nerve, dilation of the trabecular meshwork, the Schlemm's canal and uveoscleral outflow channel tissues, enhanced aqueous humor drainage and thus lowered intraocular pressure (IOP) in mammalian eye.
  • IOP intraocular pressure
  • Organic nitrates have been used for over a century in the treatment of cardiac diseases however, it is known that the classical organic nitrates used in therapy, such as glycerol trinitrate, isosorbide dinitrate or isosorbide-5-mononitrate, undergo tolerance and lose their activity upon repeated administration. 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.
  • WO 2013/060673 discloses nitric oxide donor compounds having a quinone based structure and their use in the treatment of vascular diseases, in particular WO 2013/060673 discloses that these compounds have reduced tolerance and improve the muscle function of mdx mice which are genetically and biochemically homologous to human Duchenne Muscle Dystrophy.
  • the technical problem underlying the present invention is to provide effective therapeutic agents for the use in the treatment and/or prophylaxis of hypertensive glaucoma, normotensive glaucoma secondary glaucoma and ocular hypertension.
  • nitric oxide donors of the present invention lower intraocular pressure than that of nitric oxide donors described in the art.
  • nitric oxide donors of the present invention have additional beneficial anti-inflammatory and antioxidant properties that work synergistically with the delivery of nitric oxide to promote regulation of aqueous humor outflow through the trabecular meshwork, cells repairing and protection.
  • the present invention provides nitric oxide donors having a better pharmacological activity than that of nitric oxide donors described in the art.
  • the present invention relates to compounds of formula (I)
  • Ri is selected from H, methyl or methoxy
  • R 3 is selected from H, methyl or methoxy
  • R 2 is H, methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O or a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p is 0 or 1;
  • X is O, NH or S
  • R4 is H or methyl
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • Ri is methyl
  • R 3 is methyl
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O or a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • X is O, NH or S
  • R4 is H or methyl
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O or a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p is 0 or 1 ;
  • X is O, NH or S
  • R4 is H or methyl
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • Ki methoxy
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p 0 or 1.
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p 0 or 1.
  • Rt is methoxy
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • X is O or NH.
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • X is O or NH.
  • R 3 is methoxy
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • p is 0 or 1 ;
  • R 4 is H or methyl
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • Ri is methyl
  • R 3 is methyl
  • R 2 is methyl, m is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p 0 or 1.
  • Ri is methyl
  • R 3 is methyl
  • R.2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • Ri is methyl
  • R 3 is methyl
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • X is O or NH.
  • R 3 is methyl
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • X is O or NH.
  • Ri is methyl
  • R 3 is methyl
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • the present invention relates to compounds of formula (I)
  • R 2 is methyl
  • n is an integer from 1 to 10; preferably m is an integer from 3 to 10;
  • W is:
  • Y is O or a covalent bond
  • n is an integer from 1 to 10;
  • nl is an integer from 1 to 10
  • p is 0 or 1 ;
  • X is O, NH or S
  • R 4 is H or methyl
  • R 5 is H, -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 .
  • Another embodiment of the invention provides a compound of formula (I) selected from the group:
  • the present invention also relates to compounds of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension.
  • the present invention relates to compounds of formula (I) for the use in the treatment and/ or prophylaxis of age related macular degeneration, diabetic retinopathy, retinal vein occlusion, macular degeneration, inflammatory retinal disease, uveitis.
  • the present inventions also relates to compositions comprising a nitric oxide donor of formula (I) in combination with one or more further active ingredients selected from the group consisting of alpha adrenergic agonist, beta blocker, carbonic anhydrase inhibitor, prostaglandin analogs, non-steroidal anti-inflammatory drugs, steroidal anti- inflammatory drugs.
  • a nitric oxide donor of formula (I) in combination with one or more further active ingredients selected from the group consisting of alpha adrenergic agonist, beta blocker, carbonic anhydrase inhibitor, prostaglandin analogs, non-steroidal anti-inflammatory drugs, steroidal anti- inflammatory drugs.
  • alpha adrenergic agonist examples include brimonidine, apraclonidine, clonidine.
  • beta blocker examples include timolol, carteolol, betaxolol, levobunolol.
  • suitable carbonic anhydrase inhibitor examples include dorzolamide, acetazolamide, brinzolamide, dorzolamide, dichlorphenamide, methazolamide.
  • prostaglandin analogs examples include bimatoprost, latanoprost, travoprost, unoprostone and tafluprost.
  • non-steroidal anti-inflammatory drugs examples include bromfenac, flurbiprofen, naproxen, ketoprofen.
  • steroidal anti-inflammatory drugs examples include dexamethasone, fluocinolone acetonide, triamcinolone acetonide, budesonide, prednisolone.
  • Another embodiment of the present invention is a composition above reported for use in the treatment and/or prophylaxis of hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension.
  • Another embodiment of the present invention is a composition above reported for use in the treatment and/ or prophylaxis of secondary glaucomas, age related macular degeneration, diabetic retinopathy, macular degeneration, inflammatory retinal disease, uveitis.
  • Another embodiment of the present invention is a composition above reported for use in the treatment of high intraocular pressure resulting from orbital edema, postsurgical complications, intraocular inflammation, pupillary block, or idiopathic causes.
  • Another embodiment of the present invention provides pharmaceutical formulation for topical, periocular or intraocular administration comprising at least a nitric oxide donor of formula (I) and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
  • Another embodiment of the present invention provides pharmaceutical formulation for topical, periocular or intraocular administration comprising at least a nitric oxide donor of formula (I) one or more further active ingredients selected from the group consisting of alpha adrenergic agonist, beta blocker, carbonic anhydrase inhibitor, prostaglandin analogs, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
  • a nitric oxide donor of formula (I) one or more further active ingredients selected from the group consisting of alpha adrenergic agonist, beta blocker, carbonic anhydrase inhibitor, prostaglandin analogs, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs and at least an ophthalmically acceptable component and/or ophthalmically acceptable vehicle.
  • the preferred route of administration of the compounds and compositions of the present invention is topical or intravitreal.
  • the compounds and compositions of the present invention can be administered as solutions, suspensions, or emulsions (dispersions) for topical use.
  • the compounds for use in the current invention can also be administered via periocular administration, and may be formulated in solutions or suspensions for periocular administration.
  • Formulations useful for periocular administration will generally be periocular injection formulations or surgical irrigating solutions.
  • Periocular administration refers to administration to tissues near the eye, such as administration to the tissues or spaces surrounding the eyeball and within the orbit. Periocular administration can take place by injection, deposit, or any other mode of placement.
  • compositions useful for intraocular administration will generally be intraocular injection compositions or surgical irrigating solutions.
  • an “ophthalmically acceptable” component refers to a component which will not cause any significant ocular damage or ocular discomfort at the intended concentration and over the time of intended use. Solubilizers and stabilizers should be non-reactive.
  • An “ophthalmically acceptable vehicle” refers to any substance or combination of substances which are non-reactive with the compounds and suitable for administration to a patient.
  • nitric oxide donors of the present invention will generally be contained in the topical, periocular, or intraocular formulations contemplated herein in an amount of from about 0.001 to about 10.0% weight/volume. Preferred concentrations will range from about 0.1 to about 5.0% w/v.
  • n, nl, p are as above defined,
  • X is O, NH or S
  • R 2 R 3 and m are as above defined, with a compound of formula (III), (IV) or (IVa)
  • n, nl, p and X are as above defined and Boc is the t-butyl Carbamate group, in the presence of an organic or inorganic base as known for carbonate formation.
  • Boc is the t-butyl Carbamate group, in the presence of an organic or inorganic base as known for carbonate formation.
  • Ri R 2 R 3 and m are as above defined, with phosgene or triphosgene in the presence of an organic or inorganic base, in solvent such as CH 2 C1 2 , chloroform, toluene, at temperature between -10 and 50°C as known in the literature for chlorocarbonate formation.
  • W is:
  • Y is a covalent bond
  • n, nl, p are as above defined,
  • X is O, NH or S
  • n, p, R 4 are as above defined and R 5 is -C(0)CH 3 or -C(0)0-C(CH 3 ) 3 in an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2 , in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from -0°C to 80°C.
  • an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2
  • a Compound (IX) can be prepared by reacting a compound of formula (VII), wherein n, and p are as above defined,
  • R 4 and R 5 are as above defined, in an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2 , in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from -0°C to 80°C.
  • an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2
  • DCC aprotic polar/non polar solvent
  • EDAC EDAC
  • HBTU HBTU
  • HATU HATU
  • n, p are as above defined, in an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2 , in presence of DCC, ED AC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from -0°C to 80°C.
  • an aprotic polar/non polar solvent such as THF, DMF or CH 2 C1 2
  • a Compound of formula (XI) can be prepared by reacting a compound of formula (V) above defined with compounds of formula (XII)
  • R and R 5 are as above defined and PG is an oxygen protective group such as the THP ether, in an aprotic polar/non polar solvent such as THF, DMF or CH2CI2, in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from -0°C to 80°C, eventually removing the THP protective group with known methods.
  • Step 1 Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decyl carbonochloridate
  • Step 2 Synthesis of 2,3-bis(nitrooxy)propyl 10-(4,5-dimethoxy-2-methyl-3,6- dioxocyclohexa- 1 ,4-dien- 1 -yl)decyl carbonate
  • Step 1 Synthesis of N-[3-(nitrooxy)propyl]-B-alanine nitric acid salt 0.4 g (2.7 mmol) of N-(3-hydroxypropyl)- ⁇ -alanine (obtained as described by Pratt and co. in J Chem. Soc. Perk. Trans 1, 1988, 13) were added to 10 ml of fuming nitric acid cooled at - 15°C. The solution was allowed to reach r.t. and was kept under stirring for 18 hours. After that period the solvent was distilled under reduced pressure and the residue was dropped into 100 ml of diethyl ether at -15°C and triturated to obtain a white solid (0.45 g, 65%).
  • Step 2 Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxo cyclohexa-1,4- dienyl)decyl 3 -(3 -(nitrooxy)propylamino)propanoate
  • the colorless oil was readily dissolved in 15 ml of CH 2 C1 2 , the solution was cooled in an ice bath and EDC HCl (1.5 eq.) and DMAP (0.1 eq.) were added and the mixture was stirred for 1 hour; after that period idebenone (1 eq.) was added and the solution was stirred for 4 days.
  • the solvent was removed under reduced pressure, the residue was taken up with 20 ml of CH 2 C1 2 and washed with IN HC1 (1 x 10 ml), brine, dried over Na 2 S0 4 and evaporated under reduced pressure.
  • Step 1 Synthesis Of 10-(4,5-dimethoxy-2-methyl-3,6-dioxo-cyclohexa-l,4-dien- 1 -yl)decyl 2-(tert-butoxycarbonylamino)-3 -hydroxy-propanoate
  • N-(tert-butoxycarbonyl)-0-tetrahydro-2H-pyran-2-yl-serine (0.09 g, 0.3 mmol) was solubilized in CH 2 C1 2 ; the solution was cooled in an ice bath and EDC HCl (1.2 eq.) and DMAP (0.15 eq.) were added. After 1 hour idebenone (0.1 g, 0.3 mmol) was added and the solution was allowed to reach r.t. and kept under stirring for 16 hours.
  • Step 3 Synthesis of [2-(tert-butoxycarbonylamino)-3-[10-(4,5-dimethoxy-2- methyl-3 ,6-dioxo-cyclohexa- 1 ,4-dien- 1 -yl)decoxy] -3 -oxo-propyl] 6-methyloctanoate 0.14 g (0.51 mmol) of 6,7-bis(nitrooxy)heptanoic acid (obtained in Step 2) were dissolved in 15 ml of CH 2 C1 2 with few drops of DMF. The solution was cooled in an ice bath and EDC HCl (1.5 eq.) and DMAP (0.1 eq.) were added.
  • Step 1 Synthesis of l,4-Dimethoxy-2,3,5-trimethylbenzene
  • Step 2 Synthesis of l-Bromo-2,5-dimethoxy-3,4,6-trimethyl benzene
  • Step 3 Synthesis of l-Allyl-2,5-dimethoxy-3,4,6-trimethyl benzene
  • Step 4 Synthesis of l,4-Dimethoxy-2-(3-hydroxypropyl)-3,5,6-trimethylbenzene
  • Step 6 Synthesis of 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l-yl)propyl- 4-(nitrooxy)butanoate (compound 8)
  • Step 2 Synthesis of 3-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dien-l-yl)propyl 5-(nitrooxy)pentanoate
  • Step 2a Synthesis of 1,2,3, 4-tetramethoxy-5-methylbenzene
  • Step 4 Synthesis of l-Allyl-2,3,4,5-tetramethoxy-6-methyl benzene
  • l-allyl-2,3,4,5-tetramethoxy-6-methyl benzene can be prepared in 4 steps following the procedure described in Method B.
  • Step lb Synthesis of 4,5-dimethoxy-2-methyltricyclo[6.2.1.02,7] undeca-4,9- diene-3,6-dione
  • Step 2b Synthesis of 2-allyl-4,5-dimethoxy-7-methyltricyclo [6.2.1.02,7]- undeca-4,9-diene-3,6-dione
  • Step 3b Synthesis of 2-Allyl-3-methyl-5,6-dimethoxy-l,4-benzoquinone
  • Step 4b Synthesis of l-Allyl-2,3,4,5-tetramethoxy-6-methyl benzene
  • Step 5b synthesis of l-(3-Hydroxypropyl)-2,3,4,5-tetramethoxy-6- methylbenzene
  • Step 7 Synthesis of 3-(4,5-Dimethoxy-2-methyl-3,6-dioxocyclo hexa-l,4-dien-l- yl)propyl 4-(nitrooxy)butanoate (compound (10))
  • Step 2 Synthesis of 3-(4,5-Dimethoxy-2-methyl-3,6-dioxocyclo hexa-l,4-dien-l- yl)propyl 5-(nitrooxy)pentanoate (compound (11))
  • Step 2 Synthesis of 3-(4,5-Dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l- yl)propyl 6-(nitrooxy)hexanoate (corresponding to compound (12)
  • the antioxidant properties of compound of the invention and of reference antioxidant compounds were assessed in an in vitro test.
  • Tested compounds (1), (2), (3), (4), (8), (9) and (14).
  • Reference antioxidant compounds ferulic, caffeic acids, edavarone, melatonin and idebenone.
  • the antioxidant properties of the tested compounds were assessed after NADPH- induced lipidic peroxidation of membrane lipids in rat hepatocytes using the detection of 2-thiobarbituric acid reactive substances (TBARS) by visible spectroscopy.
  • Hepatic microsomal membranes from male Wistar rats (200-250 g) were prepared by differential centrifugation (8000g, 20 min; 120000g, 1 h) in a HEPES/sucrose buffer (10 mM, 250 mM, pH 7.4) and stored at -80°C.
  • vasodilating activities of compounds (2) and compound (4) were evaluated in an in vitro test performed on rat aortic rings.
  • Thoracic aortas were isolated from male Wistar rats weighing 180-200 g.
  • the endothelium was removed and the vessels were helically cut: three strips were obtained from each aorta.
  • the aortic strips were allowed to equilibrate for 120 min and then contracted with 1 ⁇ L-phenylephrine. When the response to L-phenylephrine reached a plateau, cumulative concentrations of the tested compounds were added. Results are expressed as EC 50 ⁇ SE ( ⁇ ).
  • ODQ 1 ⁇ lH-[l,2,4]oxadiazolo[4,3-a]quinoxalin-l-one
  • Vasodilating potencies expressed as EC 50 are reported in Table 2. When the vasodilator experiments were repeated in the presence of 1 ⁇ ODQ a decrease in the vasodilator potencies was observed suggesting that the vasodilating effect of the compounds is NO-cGMP mediated.
  • IOP Intraocular pressure
  • the present study evaluated the intraocular pressure lowering effect of single application of compound (12) and of ISMN (isosorbide-5-mononitrate) used as reference compound, in an animal model of elevated IOP.
  • IOP was measured using a Tono-Pen XL prior to hypertonic saline injection (basal) and at 30, 60, 90 and 120 min thereafter.
  • Vehicle 5% cremophor-EL; 0.3% DMSO; 0.2mg/ml Benzalkonium chloride in PBS pH 6.0, or compound (12) and ISMN were instilled as eye drops immediately after hypertonic saline injection. Eyes were randomly assigned to different treatment groups. Vehicle or compounds were directly instilled into the conjunctiva pocket at the desired doses.
  • One drop of 0.2% oxybuprocaine hydrochloride (Novesine, Sandoz) diluted 1 : 1 with saline was instilled in each eye immediately before each set of pressure measurements.
  • Results are reported in Table 3 and they are expressed as IOP change (at 30 and 60 minutes following topical administration) versus vehicle and versus IOP at basal before hypertonic saline injection.
  • IOP Intraocular pressure

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Abstract

La présente invention concerne des composés donneurs d'oxyde nitrique ayant une structure à base de quinone, leur procédés de préparation et leur utilisation dans le traitement et/ou la prophylaxie du glaucome et de l'hypertension oculaire.
PCT/EP2015/057611 2014-04-09 2015-04-08 Composés donneurs d'oxyde nitrique à base de quinone Ceased WO2015155234A1 (fr)

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CN118221701A (zh) * 2024-03-18 2024-06-21 浙江大学医学院附属邵逸夫医院 一种双响应的低耐药一氧化氮供体及其制备方法和应用

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CN118221701A (zh) * 2024-03-18 2024-06-21 浙江大学医学院附属邵逸夫医院 一种双响应的低耐药一氧化氮供体及其制备方法和应用

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