QUINONE BASED NITRIC OXIDE DONATING COMPOUNDS FOR

OPHTHALMIC USE

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.

Conversely, normotensive glaucoma occurs despite the intraocular pressure is kept to reasonably low levels.

The loss of visual field, in one form of primary open angle glaucoma

(POAG), is associated with a sustained increase in the intraocular pressure of the diseased eye. Moreover, elevated intraocular pressure without visual field loss is thought to be indicative of the early stages of this form of POAG.

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. In addition, 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). There is evidence that treatment of normotensive glaucoma by lowering IOP can slow the glaucomatous process. A reduction of at least 30% in IOP is needed to induce a favorable alteration in this disease.

Apart from both these main kinds of glaucoma other pathologies can lead to an elevation of IOP, namely secondary glaucoma including post-uveitic glaucoma and steroid-induced glaucoma. 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, oc-agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.

Several side effects are associated with the drugs conventionally used to treat glaucoma.

Topical beta-blockers show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia.

Topical oc-agonists have a fairly high incidence of allergic or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects.

The side effects associated with 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 . Berkow Editors, Sec. 8, Ch. 100).

Finally, the topical prostaglandin analogs (bimatoprost, latanoprost, travoprost, tafluprost and unoprostone) used in the treatment of glaucoma can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, iritis, uveitis and macular oedema (Martindale, Thirty-third edition, p. 1445).

Diseases of the macula, such as age-related macular degeneration and diabetic macular edema, account for major causes of blindness. The drugs currently used for treating diseases of the macula are steroidal anti-inflammatory drugs such as triamcinolone acetonide or fluocinolone. However 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.

It is known that in the eye nitric oxide (NO) has an important role in certain physiological processes, e.g. regulation of aqueous humor dynamics, vascular tone, retinal neurotransmission, retinal ganglion cell death by apoptosis, phototransduction and ocular immunological responses, on the other hand, the overproduction of NO is involved in several diseases of the eye.

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. 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.

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. Therefore, 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.

Surprisingly, it has now been found that the nitric oxide donors of the present invention lower intraocular pressure and develop significant inferior tolerance than that of nitric oxide donors described in the art.

It has also been surprisingly found that the 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 relates to compounds of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension

(I)

wherein

i is selected from H, methyl, methoxy;

R ₃ is selected from H, methyl, methoxy;

or Ri and R ₃ together form -CH=CH-CH=CH-;

R ₂ is H, methyl;

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

Q is selected from the group consisting of: s [X] _p - (CH ₂ ) _m -CH ₂ ON0 ₂

(II)

CH ₃

CH— ON0 ₂

(HI)

and

(IV)

wherein

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is an integer from 0 to 1 ;

X is O, S or is -CHONO ₂ , with the proviso that when X is -CHONO ₂ then m is 0.

In one embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by the formula (la)

(la)

wherein

selected from H, methyl, methoxy;

selected from H, methyl, methoxy; or Ri and ₃ together form -CH=CH-CH=CH-;

R ₂ is H, methyl;

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is an integer from 0 to 1 ;

X is O, S or is -CHONO ₂ , with the proviso that when X is -CHONO ₂ then m is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by the formula (la)

(la)

wherein

i is selected from H, methyl, methoxy;

R ₃ is selected from H, methyl, methoxy;

or Ri and R ₃ together form -CH=CH-CH=CH-;

R ₂ is H, methyl;

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by the formula (la)

(la)

wherein

i is selected from H, methyl, methoxy;

R ₃ is selected from H, methyl, methoxy;

or Ri and R ₃ together form -CH=CH-CH=CH-;

R ₂ is H, methyl;

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

P is l ;

X is O.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by the formula (lb) or (Ic)

(Ic) wherein:

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is an integer from 0 to 1 ;

X is O, S or is -CHONO ₂ , with the proviso that when X is -CHONO ₂ then m is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (lb) or (Ic)

(Ic)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (lb) or (Ic)

(Ic)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6; m is an integer from 0 to 6; preferably m is an integer from 0 to 3; p is 1 and X is O or S.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (Id) or (Ie)

(Ie)

wherein:

n is an integer from 0 to 10; preferably n is an integer from 0 to 6; m is an integer from 0 to 6; preferably m is an integer from 0 to 3; p is an integer from 0 to 1 ;

X is O, S or is -CHONO ₂ , with the proviso that when X is -CHONO ₂ then m is 0.

In another embodiment of the invention, the compound of formula (I) for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (Id) or

(Ie)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6; m is an integer from 0 to 6; preferably m is an integer from 0 to 3; p is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (Id) or (Ie) o

CH ₃ o (CH ₂ ) _n [X] _p — (CH ₂ ) _m -CH ₂ ON0 ₂

O

(Ie)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is 1 and X is O or S.

In another embodiment of the invention, the compound of formula (I) for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (If)

(if)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

p is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (If)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6;

m is an integer from 0 to 6; preferably m is an integer from 0 to 3;

P is l ;

X is O, S or is -CHONO ₂ , with the proviso that when X is -CHONO ₂ then m is 0.

In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (Ig) or (Ih)

(Ih)

wherein:

n is an integer from 0 to 10; preferably n is an integer from 0 to 6. In another embodiment of the invention, the compound of formula (I) or stereoisomers thereof for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension is a compound represented by formula (Ii), (II) or (Im)

(Im)

wherein

n is an integer from 0 to 10; preferably n is an integer from 0 to 6.

Another embodiment of the invention provides a compound of formula (I) for use in treating hypertensive glaucoma, normotensive glaucoma, secondary glaucoma and ocular hypertension selected from the group:

(1) (2)

(11) (12)

(31) (32)

15

(35) (36) (37)

Furthermore 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.

Another embodiment of the present invention to compounds of formula (I) for the treatment of high intraocular pressure resulting from orbital edema, postsurgical complications, intraocular inflammation, pupillary block or idiopathic causes.

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 antiinflammatory drugs, steroidal anti-inflammatory drugs.

Examples of suitable alpha adrenergic agonist are brimonidine, apraclonidine, clonidine.

Examples of suitable beta blocker are timolol, carteolol, betaxolol, levobunolol. Examples of suitable carbonic anhydrase inhibitor are dorzolamide, acetazolamide, brinzolamide, dorzolamide, dichlorphenamide, methazolamide.

Examples of suitable prostaglandin analogs are bimatoprost, latanoprost, travoprost, unoprostone and tafluprost.

Examples of non-steroidal anti-inflammatory drugs are bromfenac, flurbiprofen, naproxen, ketoprofen.

Examples of steroidal anti-inflammatory drugs are 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, post-surgical 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.

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.

The compounds and the compositions of the present invention compositions may be formulated in solutions or suspensions for intraocular administration. 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.

The 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. The tests performed demonstrated that compounds of formula (I) show a vasodilating activity comparable with that of the isosorbide mononitrate. Further, they manifest a significantly inferior tolerance and/or side effects as compared to those observed with isosorbide mononitrate.

The compounds of formula (I) can be synthesised according to the general methods of synthesis below reported and the examples.

1. Compounds of formula (I)

(I)

wherein n, R _l5 R ₂ and R ₃ are as above defined and Q is the group of formula

(II)

[X] _p — (CH ₂ ) _m -CH ₂ ONO ₂ (II)

wherein p is 0 and m is as above defined, can be synthesized by nitrating a compound (V)

(V)

wherein Y is an halogen atom or Y is -OH.

When Y is a halogen atom the nitrate agent may be, for example, AgNO ₃ in acetonitrile as known in the literature.

When Y is OH, compounds (V) can be nitrated using as nitrate agent a mixture of acetic anhydride and HNO ₃ or triflic anhydride and tetraalkylammonium nitrates salts in the presence of a base such as pyridine, lutidine, 2,6-di-tert-butyl-4-methylpyridine. Alternatively, the hydroxyl group is first converted to the corresponding mesyl or tosyl or triflate group and then nitrated using an appropriated nitrate agent such as known methods tetraalkylammonium nitrate and sodium nitrate.

Compounds of formula (V) wherein Y, n, m, R ₂ and R ₃ are as above defined are known in the literature or are made from methods described in the literature (Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429-6441).

1.1 Alternatively, compounds of formula (I) wherein n, R R ₂ and R ₃ are as above defined and Q is the group of formula (II)

[X] _p — (CH ₂ ) _m -CH ₂ ONO ₂ (II)

wherein p is 0 and m is as above defined, can be prepared by reacting a compound (VI) with a carboxylic acid of formula (VII)

HOOC-(CH ₂ ) _n -(CH ₂ ) _m -CH ₂ ONO ₂ in the presence of salts of peroxydisulfuric acid such as ammonium or potassium salts and AgNO ₃ in an appropriated solvent such as acetonitrile or acetonitrile/water under reflux, as described by Breyer, S. and co-workers in Chem Med Chem, 2009, 4(5), 761-768 or by Duveau D,Y et al in Bioor & Med Chemistry 2010, 18, 6429-6441 or by Kayashima, Tomoko et al. in Bioor & Med Chemistry, 2010 18(10), 6305-6309 when the two groups Ri and R ₃ taken together form -CH=CH-CH=CH-. ₂

Compounds (VII) are known in the literature or they can be obtained by nitration reactions of the correspondent hydroxy acids of formula (Vila) HOOC- (CH ₂ ) _n -(CH ₂ ) _m CH _2- OH or halogen acids of formula (Vllb) HOOC-(CH ₂ ) _n - (CH ₂ ) _m CH _2- Hal by known reactions. Compounds (Vila) and (Vllb) are commercially available or are made from known methods.

Compounds (VI) wherein ₂ is H or methyl and i and R ₃ are methoxy or Ri and R ₃ taken together form -CH=CH-CH=CH- are commercially available.

Compounds (VI) wherein R _! and R ₂ and R ₃ are methyl are known in the literature and can be prepared from commercially available compounds (see for example Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429-6441) and Example 2).

Compounds (VI) wherein R ₂ is methyl and Ri and R ₃ are different and are methyl or methoxy are known in the literature and can be prepared from commercially available compounds (see for example Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429-6441).

2. The compound of formula (I) wherein n, R _{l 5} R ₂ and R ₃ are as above defined and Q is the group of formula (II)

[X] _p - (CH ₂ ) _m -CH ₂ ON0 ₂

s

(II) wherein p is 1, and X is O, can be synthesized by reacting a compound (VHI)with an halogen-alkyl-nitrate of formula (IX) Hal-(CH ₂ ) _m -ONO ₂ , as depicted in the below scheme,

CH ₂ ) _n -O— (CH ₂ ) _m -CH ₂ -ON0 ₂ in the presence of a base, in an appropriated solvent such as acetonitrile, toluene, DMF at temperature ranging from 25 to 100°C as known in the literature for the Williamson reaction.

[Compound (VIII) can be prepared as described above for compounds (V) wherein Y is -OH.]

2.1 Alternatively, the compound of formula (I) can be prepared by the following procedure: o o Y CH ₂ — (CH ₂ ) _n -OH ^R = ff CH ₂ — (CH ₂ ) _n -0— (CH ₂ ) _m -CH ₂ -OPG o o

(viii) (xi)

1 ) deprotection

2) nitration

(I)

The compound (I) can be prepared by reacting a compound of formula (VIII) with a protected halogen-alkyl-alcohol of formula (X) wherein PG is an hydroxyl protective group such as dimethyl-tert-butylsilyl or other silyl derivative, the trityl group or the benzyl group, in the presence of a base in an appropriated solvent such as acetonitrile, toluene, DMF at temperature ranging from 25 to 100°C as known in the literature for the Williamson reaction. The resulting quinone derivatives (XI)is converted to compound of formula (I) by deprotection and nitration with methods known in the literature.

Compounds of formula (VIII) are known in the literature or are made from methods described in the literature (Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429-6441).

3. Compounds of formula (I) wherein n, R _{l 5 2} and R ₃ are as above defined and Q is the group of formula (II)

[X] _p — (CH ₂ ) _m -CH ₂ ONO ₂ (II)

wherein m is 0, p is 1 , and X is -CHONO ₂ can be prepared by reacting a compound (VI) in the presence of salts of peroxydisulfuric acid like ammonium or potassium salts and AgNO in an appropriate solvent such as acetonitrile or acetonitrile/water under reflux, as described for simple carboxylic acids by Breyer, S. and co-workers in Chem Med Chem, 2009, 4(5), 761-768 or by Duveau D,Y et al in Bioor & Med Chemistry 2010, 18, 6429-6441 or by Kayashima, Tomoko et al. in Bioor & Med Chemistry, 2010 18(10), 6305-6309 when the two groups i and R ₃ taken together form -CH=CH-CH=CH-).

₂ ON0 ₂

(I)

Compounds (XV) are known in the literature or they can be prepared by nitration reactions of the correspondent unsaturated acids of formula (XVI) HOOC-(CH ₂ ) _n -CH=CH ₂ by known reactions as for example by directly nitrating with I ₂ and AgNO ₃ or first converting the unsaturated acids of formula (XVI) to the diol (XVII) HOOC-(CH ₂ ) _n -CHOH-CH ₂ OH and then nitrating with HNO ₃ and acetic anhydride.

4. Compound of formula (I) wherein n, R _{l 5 2} and R ₃ are as above defined and Q is the group of formula (II)

s [X]p— (CH ₂ ) _m -CH ₂ ONO ₂

(II)

wherein p is 1, and X is S, can be prepared as depicted in the following scheme

(XII) (XIV)

1 ) deprotection

2) nitration

(I)

wherein Z is an halogen atom or the -O-mesyl or -O-tosyl groups and PGi is an hydroxyl protective group such as dimethyl-tert-butylsilyl or other silyl derivatives or the trityl group.

The compound (I) can be prepared by reacting a compound (XII) with a thiol compound of formula (XIII) with known methods depending on the meaning of Y. The resulting quinone derivative (XIV) is converted into compound of formula (I)) by known deprotection/nitration methods.

Compound (XII) are known in the literature or are made from methods described in the literature (Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429- 6441).

5. The compound of formula (I) wherein n, R _{l 5 2} and R ₃ are as above defined and Q is the formula (III)

(III)

can be prepared according to the below depicted process:

(XXII) wherein R _1; R _2; R ₃ , n are as above defined and PG ₂ is an oxygen protective group such as the methyl or the -boc group.

Compound (XVIII) are first reduced to phenols with, for example, NaBH ₄ or dithionite as described in the literature (see for example Duveau D. Y. Bioor & Med Chemistry 2010, 18, 6429-6441). The hydroxyl groups of compound (XIX) are protected and then oxidized to aldehyde with PCC or other suitable alcohol oxidizing reagents. The aldehyde (XX) is alkylated with a compound MeM (XXIII) wherein M is the group -Li or -Mg and Hal is an halogen atom using known procedures. The alcohol (XXI) is then nitrated with known methods and the compound (XXII) is then deprotected by known methods.

6. The compound of formula (I) wherein n, R _{l 5} R ₂ and R ₃ are as above defined and Q is the group of fo

(IV) can be prepared as depicted in the following scheme:

Compound (XXIV) is oxidized to compound (XXV) and then vinylated by known methods to obtained compound (XXVI). Compound (XXVII) is obtained by classic Williamson reaction and transformed into furan derivative (XXVIII) by known metathesis process. Compound (XXX) is prepared hydroxylation and nitration reaction of compound (XXVIII). Compounds (I) is obtained from hydrolysis and re-oxidation of compound (XXX).

Compounds (XXIV), wherein R _{l 5 2} , and R ₃ are as above defined, are known in the literature or are prepared by known methods Example 1

Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decyl nitrate (compound (6))

Compound (6)

Method A

A dry 500 mL round bottom flask containing 2-(10-hydroxydecyl)-5,6- dimethoxy-3 -methyl cyclohexa-2,5-diene-l,4-dione (7g, 20.7 mmol), 2,6-di-tert- butyl-4-methylpyridine (6.37 g, 31 mmol, 1.5 eq) and tetrabutylammonium nitrate (7.5 g, 24.8 mmol, 1.2 eq) in dichloromethane (250 mL) was cooled to -70°C and maintained at this temperature with stirring during the dropwise addition of a solution of triflic anhydride (4 mL, 24.8 mmol, 1.2 eq) in dichloromethane (30 mL). The reaction mixture was stirred at -70°C for 2 h, and then allowed to warm to room temperature. The reaction mixture was washed with H ₂ O. The organic phase was dried over anhydrous sodium sulfate and the solvent removed in vacuum. The residue was purified by column chromatography (SNAP 340, gradient system from 4/6 ethyl acetate/n-hexane to 60/40 ethyl acetate/n-hexane) to give the titled compound as a reddish oil (6.0 g, 75%).

Method B

Step 1: Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decyl methane sulfonate

A solution of 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl cyclohexa-2,5- diene- 1 ,4-dione (2.0 g, 5.91 mmol) and triethylamine (0.9 mL, 6.5 mmol, 1.1 eq) in dry CH ₂ C1 ₂ (20 mL) was added at 0°C with a solution of methane sulfonyl chloride (505 L, 6.5 mmol, 1.1 eq) in CH ₂ C1 ₂ (5mL) followed by DMAP (10 mg). The reaction was left at room temperature for 16 hrs and then washed successively with water, saturated NaHCO ₃ , water and brine. The residue was purified by column chromatography (SNAP 100, gradient system from 20/80 ethyl acetate/n-hexane to 40/60 ethyl acetate/n-hexane in 10 CV) to give the title compound as an orange solid (2.21 g, 91%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.22 (t, J = 6.6, 2H), 3.99 (s, 6H), 3.00 (s, 3H), 2.44 (t, J = 7.2, 2H), 2.01 (s, 3H), 1.81 - 1.66 (m, 2H), 1.31 (m, 14H).

Step 2: Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decyl nitrate

A stirred solution of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decyl methane sulfonate (2.21 g, 5.3 mmol) in BuOAc/MeCN (3: 1, 5 mL) was added with tetrabutylammonium nitrate (0.32 g, 1.06 mmol, 0.2 eq) and sodium nitrate (0.68 g, 7.95 mmol, 1.5 eq). The reaction was heated at 80°C for 18h and then cooled down to RT. The reaction mixture was diluted with EtOAc and water. The organic layer was extracted, washed twice with water and then with brine, dried (Na ₂ SO ₄ ), filtered and evaporated. The residue was purified by column chromatography (SNAP 100, gradient system from 40/60 ethyl acetate/n-hexane to 60/40 ethyl acetate/n-hexane) to give the titled compound as a reddish oil (1.81 g, 89%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.44 (t, J = 6.6, 2H), 3.98 (s, 6H), 2.43 (d, J

= 7.2, 2H), 2.01 (s, 3H), 1.77 - 1.63 (m, 2H), 1.31 (m, 14H).

¹³ C NMR (75 MHz, CDC1 ₃ ) δ 184.40, 183.92, 144.73, 144.66, 142.35, 138.62, 74.24, 61.10, 29.59, 29.25, 29.19, 28.98, 28.53, 26.47, 26.12, 25.50, 1 1.97.

Example 2

Synthesis of 5-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl) pentyl nitrate (Compound (1))

(1)

Step 1: Synthesis of 2,3,5-trimethyl-p-benzoquinone

To a solution of trimethyl-p-hydroquinone (1.5 g; 6.57 mmol), I ₂ (0.08 g; 0.33 mmol) and H ₂ O ₂ 30% aq. (0.33 ml; 2.90 mmol) in MeOH (20 ml) cooled at 0°C, H ₂ SO ₄ cone. (0.33 ml; 0.93 mmol) was added. The solution was stirred 1 hour at 0°C and 2 hours at room temperature then was diluted with Et ₂ O (50 ml) and H ₂ O (50 ml). The two phases were separated and the aqueous layer was extracted with Et ₂ O (50 ml). The combined organic layers were washed with NaS ₂ O ₃ sat. Solution (50 ml) and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 100 g column, Hex/EtAc 95:5, 10 CV) affording 0.70 g (yield: 71%) of the title compound as an orange solid.

1H NMR (300 MHz, CDC1 ₃ ) δ 6.54 (s, 1H), 2.12 - 1.92 (m, 9H).

Step 2: Synthesis of 6-(nitrooxy)hexanoic acid

To a solution of 6-bromohexanoic acid (0.50 g; 2.56 mmol) in CH ₃ CN (10 ml), AgNO ₃ (0.52 g; 3.07 mmol) was added. The solution was heated at the mw 20 minutes at 122°C. The salts were filtered off and the solvent evaporated. EtOAc was added and the salts were filtered off again, the solvent was evaporated affording 0.40 g (yield: 80%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.46 (t, J = 6.6, 2H), 2.39 (t, J = 7.3, 2H), 1.91 - 1.60 (m, 4H), 1.56 - 1.38 (m, 2H).

Step 3: Synthesis of 5-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4- dienyl)pentyl nitrate.

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.94 g, 6.28 mmol), 6- (nitrooxy)hexanoic acid (1.12 g, 6.28 mmol) and AgNO ₃ (1.28 g, 7.54 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (2.04 g, 7.54 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75°C for 5 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 100 g column, Hex/EtOAc 97:3, 10 cv, Hex/EtOAc 95:5 3 CV) affording 390 mg (yield: 22%) of the title compound as a yellow oil.

1H NM (300 MHz, CDC1 ₃ ) δ 4.45 (m, 2H), 2.48 (t, J = 7.2, 2H), 2.1 1 - 1.92 (m, 9H), 1.87 - 1.66 (m, 2H), 1.53 - 1.35 (m, 4H).

Example 3

Synthesis of 5-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)pentyl nitrate (compound (2))

(2)

To a solution of 2,3-dimethoxy-5-methyl-p-benzoquinone (0.93 g, 5.12 mmol), 6-(nitrooxy)hexanoic acid (0.93 g, 5.12 mmol) (prepared as described in Example 2, Step 2) and AgNO ₃ (1.04 g, 6.14 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.66 g, 6.14 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75°C for 5 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 100 g column, EtOAc in Hex from 5% to 40% in 10 CV) affording 130 mg (yield: 8%) of the title compound as an orange oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.53-4.59 (m, 2H), 3.98 (s, 6H), 2.55-2.38 (m, 2H), 2.02 (s, 3H), 1.87-1.64 (m, 2H), 1.52 - 1.37 (m, 4H).

Example 4

Synthesis of 5-(3-methyl- 1 ,4-dioxo- 1 ,4-dihydronaphthalen-2-yl)pentyl nitrate (Compound (12

(12)

To a solution of 2-methyl-l,4-naphthoquinone(1.06 g, 6.15 mmol), 6-

(nitrooxy)hexanoic acid (0.93 g, 5.12 mmol) and AgNO ₃ (0.88 mg, 5.13 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.66 g, 6.15 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75°C for 5 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 100 g column, Hex:EtOAc 95:5, 5 CV and 90: 10, 5 CV) affording 760 mg (Yield: 48%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 8.19 - 8.02 (m, 2H), 7.77 - 7.62 (m, 2H), 4.53-4.38 (m, 2H), 2.75-2.53 (m, 2H), 2.20 (s, 3H), 1.88-1.66 (m, 4H), 1.64-1.41 (m, 4H).

Example 5: In vitro Antioxidant activity (TBARS test)

The antioxidant properties of compounds (6) (disclosed in example 1) and compound (23) (disclosed in example 19) and reference antioxidant 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. 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 μΜ), and DMSO solutions of the tested compounds. Lipid peroxidation was initiated by adding ADP-FeCl ₃ and NADPH (Method A) or 2.5 μΜ FeSO 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.

The results reported in Table 1, showed that compound (6) (IC ₅₀ =

2 μΜ) and (23) (IC ₅₀ = 1.4 μΜ) proved to inhibit in a concentration-dependent manner the generation of TBARS with a potency (IC ₅₀ = 2 μΜ) that is superior to well known antioxidant compounds as ferulic or caffeic acids, edavarone or melatonin.

^Method B; * tested at ImM concentration;

aChegaev,K. et al. J. Med. Chem. 2009, 52:574-578:

bChegaev,K. et al. J. Pineal Res. 2007, 42:371-385

Example 6: In vitro NO-mediated activity

The ability of compound (6) disclosed in example 1, to induce in vitro vasorelaxation, which is a functional marker of NO release, was assessed on methoxamine -precontracted rabbit aortic rings.

Thoracic aortas from male New Zealand rabbits or male Sprague Dawley

(SD) were used. The aortas were placed immediately in Krebs-HEPES buffer (pH 7.4; composition mM: NaCl 130.0, KC1 3.7, NaHCO3 14.9, KH2PO4 1.2, MgSO4 ^« 7H2O 1.2, Glucose 1 1.0, HEPES 10.0, CaC12 ^« 2H2O 1.6). Connective tissue was removed and aortas were cut into ring segments (4-5 mm in length). Each ring was placed in a 5 mL tissue bath filled with Krebs-HEPES buffer (37°C) aerated with 95% O2 and 5% CO2 and was attached to a force transducer (Grass FT03), connected to a BIOPAC MP 150 System for measurement of the isometric tension. Preparations were allowed to equilibrate for 1 h at a resting tension of 2 g for rabbit aortas and 1 g for rat aortas with changes of the buffer every 15 min. Then the rings were stimulated by exposure to 90 mM KCl (3 times) with intervening washings.

Rabbit aorta. After equilibration, rabbit aortas were precontracted submaximally with methoxamine (3 μΜ) and, when the contraction was stable, acetylcholine (ACh, 3 μΜ) was added. A relaxant response to ACh indicated the presence of a functional endothelium. After washout, the rings were precontracted submaximally with methoxamine 3 μΜ. When a steady-state level of contraction was obtained, a cumulative concentration-response curve to the tested compounds (0.01-100 μΜ) was obtained in the presence of a functional endothelium.

Rat aorta. After equilibration, rat aortas were precontracted with KCl (90mM) and, when the contraction was stable, a cumulative concentration- response curve to acetylcholine (ACh, 0.01-100 μΜ) was added. After washout, the rings were precontracted again with KCl (90mM). When a steady-state level of contraction was obtained, a cumulative concentration-response curve to the tested compounds (0.01-100 μΜ) was obtained.

Data analysis. Results are given as mean ± SEM. Vascular responses are expressed as percentage relaxation and plotted vs concentration. The sensitivity of isolated aorta to different vasodilators is expressed as the concentration that elicited 50% of the maximal responses (EC50). Responses are quantified in terms of EC50 and Emax (maximal vasodilating effect) values, obtained from the concentration-response curve by nonlinear curve fitting, using GraphPad software.

Compound (6) evoked concentration-dependent relaxation with EC ₅₀ =

4.7±0.2 μΜ, achieving 89±1% relaxation at the highest concentration tested of 100 μΜ. Example 7: Effects of compound 6 and isosorbide-5-mononitrate (5- ISMN) in rat L-NAME-induced hypertension

To assess the in vivo NO-dependent activity, Compound (6) was evaluated for systolic blood pressure (SBP) reduction efficacy in a rat model of NO- deprivation induced by L-NAME and compared with 5-ISMN.

Fasted male SD rats (250-300 g, n=3-5 per group), obtained from Harlan Italy (Correzzana, Milan, Italy) were orally treated with tested compounds or vehicle (DMSO:Methocel 1% 2/98 v/v) in a total volume of 4 ml/kg by gavage. At each time point (1, 3, 6 and 24 h) animals were deeply anesthetized with Zoletil® 100 (3 mg/kg), given intramuscularly. Thereafter, a pressure catheter (Samba Sensors, Harvard Apparatus, UK) was introduced into the common carotid artery for central blood pressure measurement. Pressure transducer was connected to a personal computer, in order to allow real time monitor of the pressure tracing. After 10 minutes of basal recording, L-NAME (50 mg/kg) was administered intraperitoneally and the effect on SBP monitored. When the SBP stabilized (5 minutes without variations) the recording was stopped. To further confirm that functional activity was NO-dependent, at each time point blood ¹⁵ N-nitrite levels were measured following the procedure described in Example 12.

The results reported in Table 2 showed that intraperitoneal injection of L- NAME 50 mg/kg to anesthetized rats induced an increase of systolic blood pressure (SBP) of about 70 mmHg (from 129±5 to 197±9 mmHg). When orally administered, the reference NO-donor 5-ISMN (30 mg/kg) counteracted L-NAME induced hypertension until 3 hours after treatment, while Compound (6) (100 mg/kg) induced a more sustained effect, preventing such SBP increase over 6 hours after single oral administration in rats, indicating effective and prolonged systemic NO release. Surprisingly, even if compound (6) released less NO compared to 5-ISMN, as demonstrated by the 15N-nitrite blood levels shown in Table 2, it was able to induce a comparable efficacy on blood pressure. Table 2: Effects of compound (6) and isosorbide-5-mononitrate (5-ISMN) in rat L-NAME-induced hypertension

Delta vs Delta vs Delta vs

Time 15N-nitrite 15N-nitrite basal basal basal

(hours) levels (μΜ) levels (μΜ)

(mmHg) (mmHg) (mmHg)

5-ISMN Comp. (6)

Vehicle

(30 mg/kg) (100 mg/kg)

1 67.8±1 1.6 10.5±6.1 1 1.0±0.5 53.5±4.5 1.3±0.2

14±3.8

3 67.8±1 1.6 6.5±2.4 8.7±0.7 1.4±0.4

38±3.6

6 67.8±1 1.6 51.2±5.7 6.5±0.5 1.1±0.2

24 67.8±1 1.6 83±9 0.34±0.06 67.7±16.8 0.39±0.1

Example 8: In vivo tolerance evaluation

To investigate whether the compound (6) induced nitrate tolerance, as observed for most of the drugs belonging to the nitrate class, the L-NAME-induced hypertension rat model described in Example 7 was performed following a repeated oral treatment. Rats were orally treated for 5 days with vehicle, compound (6) (100 mg/kg) or 5-ISMN (30 mg/kg). Compound (6) counteracted L- NAME-induced hypertension after 5-day oral treatment. Conversely, after 5-day treatment the reference nitrate 5-ISMN did not maintain its efficacy in preventing L-NAME-induced hypertension, suggesting the development of nitrate tolerance. The experiments were performed at the peak effect (1 hour for 5-ISMN and 3 hours for Compound (6)), results are reported in Table 3. Table 3: In vivo tolerance evaluation

Delta vs basal Delta vs basal Delta vs basal

(mmHg) (mmHg) (mmHg)

Treatment

5-ISMN Comp. (6)

Vehicle

(30mg/kg) (lOOmg/kg) acute 67.8±1 1.6 10.5±6.1 14±3.8 repeated 67.8±1 1.6 88±1 1.5 27.8±4

Example 9: Ex vivo tolerance evaluation

Tolerance to nitrate was further investigated assessing the vascular effects of Compound (6) following repeated treatment compared with 5-ISMN. The vascular response to the compound itself was assessed on isolated aortas from rats orally treated for 5 days with Compound (6) (100 mg/kg). The vascular response was performed as described in Example 6.

Arteries of animals treated with the compound (6) showed the same sensitivity to Compound (6) as those arteries of animals treated only with vehicle. On the contrary, the aortas from animals treated with the reference 5-ISMN (30 mg/kg) showed a reduced vascular response to 5-ISMN compared to control arteries, thus confirming the development of nitrate tolerance. Vascular responses were performed lh (ISMN) or 3h (Compound (6)) after the last administration, the concentrations of tested compound that elicited the 50% of the maximal responses (EC50) are shown in Table 4.

Table 4: Ex vivo tolerance evaluation

EC ₅₀ EC ₅₀

(μΜ) (μΜ)

Treatment

5-ISMN Compound (6)

(30mg/kg) (lOOmg/kg)

acute 20±0.6 0.1 1±0.02 repeated 127±48 0.18±0.02 Example 10: Endothelial dysfunction evaluation

Endothelial-dependent vasodilation (vascular response to acetylcholine, ACh) was assessed following 5-day treatment with Compound (6) (100 mg/kg) or 5-ISMN (30mg/kg). A relaxant response to ACh indicated the presence of a functional endothelium. The vascular response was performed as described in Example 6. The maximal vasodilating effect values (Emax) reported in Table 5, showed that Compound (6) did not modify endothelial-dependent vasorelaxation whereas 5-ISMN caused a reduced response to Ach.

Example 11

Synthesis of 6-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl) hexyl nitrate (compound (15))

(15)

Step 1: Synthesis of Ethyl 7-(nitrooxy)heptanoate

To a solution of Ethyl 7-bromoheptanoate (1.40 g; 6.00 mmol) in CH ₃ CN ml), AgNO ₃ (1.23 g; 7.20 mmol) was added. The solution was heated at the mw 22 minutes at 120°C. The salts were filtered off and the solvent evaporated. EtOAc was added and the salts were filtered off again, the solvent was evaporated affording 1.3 g (yield: 100%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.44 (t, 2H), 4.13 (q, 2H), 2.44 - 2.21 (m, 2H), 1.82 - 1.54 (m, 4H), 1.54 - 1.31 (m, 4H), 1.31 - 1.16 (m, 3H).

Step 2: Synthesis of 7-(nitrooxy)heptanoic acid

To a solution of Ethyl 7-(nitrooxy)heptanoate (1.3 g; 6.0 mmol) cooled at 4°C, a solution of LiOH 2M (7.5 ml; 15,0 mmol) was added dropwise. The solution was stirred at 4°C overnight then was acidified with HC1 3N until pH= 1 and the product was extracted with CH ₂ C1 ₂ (5 X 20 ml). The combined organic layers were dried on Na ₂ SO ₄ and concentrated affording 0.91 g (Yield: 79%) of a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.45 (t, 2H), 2.37 (t, 2H), 1.84 - 1.54 (m,

4H), 1.54 - 1.32 (m, 4H).

Step 3: Synthesis of 6-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4- dienyl)hexyl nitrate

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.71 g, 4.71 mmol), 7-

(nitrooxy)heptanoic acid (0.91 g, 4.71 mmol) and AgNO ₃ (0.80 g, 4.71 mmol)in

CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.27 g, 4.71 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (20 ml).

The product was extracted with EtOAc (2 X 15 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex/EtOAc 97:3, 20 cv) affording 560 mg (yield:

40%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.44 (t, 2H), 2.56-2.37 (m, 2H), 2.01 (s, 9H),

1.81 - 1.64 (m, 2H), 1.50-1.37 (m, 6H). Example 12

Synthesis of 4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl) butyl nitrate

(compound (3))

(3)

Step 1: Synthesis of Ethyl-5-(nitrooxy)valerate

To a solution of Ethyl 5 -bromo valerate (0.63 g; 3.00 mmol) in CH ₃ CN (10 ml), AgNO ₃ (0.61 g; 3.6 mmol) was added. The solution was heated at the mw 22 minutes at 120°C. The salts were filtered off and the solvent evaporated. EtOAc was added and the salts were filtered off again, the solvent was evaporated affording 0.55 g (yield: 96%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.53 - 4.38 (m, 2H), 4.14 (q, 2H), 2.45 - 2.24 (m, 2H), 1.85 - 1.64 (m, 4H), 1.26 (q, 3H).

Step 2: Synthesis of 5-(nitrooxy)pentanoic acid

To a solution of Ethyl-5-(nitrooxy)valerate (0.55 g; 2.87 mmol) cooled at

4°C, a solution of LiOH 2N (4.0 ml; 7.50 mmol) was added dropwise. The solution was stirred at 4°C overnight then was acidified with HC1 3N until pH= 1 and the product was extracted with CH ₂ C1 ₂ (5 X 15 ml). The combined organic layers were dried on Na ₂ SO ₄ and concentrated affording 0.47 g (Yield: 100%) of a clear oil

H NMR (300 MHz, CDC1 ₃ ) δ 4.47 (t, 2H), 2.54 - 2.37 (m, 2H), 1.94 - 1.63

(m, 4H).

Step 3: Synthesis of 4-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl)butyl nitrate

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.50 g, 3.34 mmol), 5- (nitrooxy)pentanoic acid (0.47 g, 2.87 mmol) and AgNO ₃ (0.57 g, 3.34 mmol)in CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.08 g, 4.01 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (20 ml). The product was extracted with EtOAc (2 X 15 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex/EtOAc 97:3, 15 cv) affording 220 mg (yield: 24%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.47 (t, 2H), 2.61 - 2.44 (m, 2H), 2.01 (s, 9H), 1.86 - 1.68 (m, 2H), 1.61 - 1.42 (m, 2H).

Example 13

Synthesis of 5-(2,4,5-trimethyl-3,6-dioxocyclohexa- 1 ,4-dienyl)pentane- 1 ,2- diyl dinitrate (compound (10))

(10)

Step 1: Synthesis of 4-nitrophenyl hex-5-enoate

To a solution of 4-Nitrophenol (2.0 g; 14.38 mmol) and 5-hexenoic acid

(1.7 ml; 14.38 mmol)in CH ₂ C1 ₂ (30 ml) cooled at 0°C, Dimethylaminopropyl n- Ethyl Carbodiimide Hydrochloride (ED AC) (3.3 g, 17.26 mmol)and Dimethylaminopyridine (DMAP) (0.35g; 2.88 mmol) were added portionwise. The mixture was stirred two hours at rt then was washed with a 5% solution of NaH ₂ PO ₄ (30 ml), H ₂ O (20 ml) and brine (20 ml). The organic layer was dried on Na ₂ SO ₄ and concentrated affording 3.2 g (quantitative yield) of the title compound as a brown oil which was used without any further purification.

Step 2: Synthesis of 4-nitrophenyl 5,6-bis(nitrooxy)hexanoate

To a solution of 4-nitrophenyl hex-5-enoate (1.0 g; 4.25g) in CH ₃ CN (20 ml) cooled at -10°C, AgNO ₃ (0.87 g; 5.1 mmol) and I ₂ (1.3 g; 5.1 mmol) were added. The mixture was stirred 20 minutes at -10°C then AgNO ₃ (1.3 g; 7.65 mmol) was added and the mixture was heated at 75°C for 24 hours. The salts were filtered off and the solvent evaporated. EtOAc (30 ml) was added, the salts filtered again and the solvent evaporated affording 1.1 g of the title compound which was used without any further purification.

Step 3: Synthesis of 5,6-bis(nitrooxy)hexanoic acid

To a solution of 4-nitrophenyl 5,6-bis(nitrooxy)hexanoate (1.1 g; 3.04 mmol) in THF/EtOH (2: 1 ; 15 ml) cooled at 0°C, NaOH 2N (4.6 ml; 9.12 mmol) was added dropwise. The solution was stirred 30 minutes at 0°C, then the solvent was removed. CH ₂ C1 ₂ (10 ml) and H ₂ O (10 ml) were added to the residue, fum. HC1 was added until pH=l . The two phases were separated and the organic one was extracted with CH2C12 (2 x 10 ml). The combined organic layers were dried on Na ₂ SO ₄ and concentrated affording 470 mg of the title compound which was used without any further purification.

1H NMR (300 MHz, CDC1 ₃ ) δ 5.40-5.19 (m, 1H), 4.83-4.68 (m, 1H), 4.57- 4.40 (m, 1H), 2.54 - 2.35 (m, 2H), 1.94 - 1.66 (m, 4H).

Step 4: Synthesis of 5-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4- dienyl)pentane- 1 ,2-diyl dinitrate

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.29 g, 1.96 mmol), 5,6- bis(nitrooxy)hexanoic acid(0.47 g, 1.96 mmol) and AgNO ₃ (0.33 g, 1.96 mmol)in CH ₃ CN (10 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (0.53 g, 1.96 mmol) in H ₂ O (10 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (10 ml). The product was extracted with EtOAc (2 X 10 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex/EtOAc 90: 10, 15 cv) affording 266 mg (yield: 39%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 5.46 - 5.25 (m, 1H), 4.82-4.67 (m, 1H), 4.57-4.39 (m, 1H), 2.53 (t, 2H), 2.08-1.95 (m, 9H), 1.89 - 1.66 (m, 2H), 1.66 - 1.45 (m, 2H).

Example 14

Synthesis of 3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propyl nitrate (Compound (8))

(8)

Step 1: Synthesis of 4,5-dimethoxy-2-methyltricyclo[6.2.1.02,7] undeca- 4,9-diene-3,6-dione

To a solution of 2,3-dimethoxy-5-methyl-p-benzoquinone (4.0 g, 21.96 mmol) in glacial acetic acid (100 mL) was added freshly distilled cyclopentadiene (2.8 mL, 32.94 mmol, 1.5 eq) and the reaction was stirred overnight at r.t. The reaction was cooled to 0°C and ice/water was added. The aqueous layer was neutralized using 3M aq NaOH and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with water, brine, dried on Na ₂ SO ₄ , filtered and evaporated affording the title compound (5.4 g, yield: 98%) as a dark red oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 6.16 (dd, J = 5.6, 2.9, 1H), 6.01 (dd, J = 5.6, 2.8, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.42 (s, 1H), 3.08 (s, 1H), 2.83 (d, J= 3.9, 1H), 2.07 (d, J= 12.6, 3H), 1.71 - 1.62 (m, 1H), 1.54 (dt, J= 9.2, 1.6, 1H).

Step 2: Synthesis of 2-allyl-4,5-dimethoxy-7-methyltricyclo [6.2.1.02,7]- undeca-4,9-diene-3,6-dione

To a stirred solution of crude 4,5-dimethoxy-2- methyltricyclo[6.2.1.02,7]undeca-4,9-diene-3,6-dione (5.4 g)in dry THF (100 mL) cooled to 0°C was added portionwise potassium tert-butoxide (4.0 g, 32.9 mmol, 1.5 eq). The reaction became dark reddish and was stirred at this temperature for another 30 mins then a solution of allyl bromide (2.9 mL, 35.1 mmol, 1.6 eq) in dry THF (30 mL) was added slowly. The reaction was stirred for 2h before addition of water (30 mL). The aqueous layer was acidified to pH 2 and the solution was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage instrument, SNAP 340 column, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a pale yellow oil (4.22 g, yield: 67%).

1H NMR (300 MHz, CDC1 ₃ ) δ 6.05 (d, J = 6.1, 2H), 5.90 - 5.69 (m, 1H), 5.10 (s, 1H), 5.05 (dd, J = 3.6, 2.1, 1H), 3.94 - 3.87 (m, 5H), 3.12 (d, J = 1.6, 1H), 3.05 - 2.99 (m, 1H), 2.70 (dd, J = 14.5, 7.6, 1H), 2.56 (dd, J = 14.5, 6.7, 1H), 1.76 (m, 1H), 1.50 (s, 3H), 1.49 (s, 1H).

Step 3: Synthesis of 2-Allyl-3-methyl-5,6-dimethoxy-l,4-benzoquinone A solution of 2-allyl-4,5-dimethoxy-7-methyltricyclo[6.2.1.02,7]-undeca- 4,9-diene-3,6-dione (4.1 g, 14.22 mmol) in toluene (50 mL) was heated at reflux for 7 h. The reaction was then cooled down and the solvent evaporated. The residue was purified by flash chromatography (Biotage instrument, SNAP 340 column, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a red oil (4.22 g, yield: 67%). 1H NMR (300 MHz, CDC1 ₃ ) δ 5.83 - 5.65 (m, 1H), 5.07 (dd, J = 3.9, 1.5, 1H), 5.02 (dd, / = 3.6, 1.6, 1H), 3.99 (d, J = 1.1, 5H), 3.23 (t, J = 6.7, 2H), 2.08 -

1.96 (m, 3H).

Step 4: Synthesis of l-Allyl-2,3,4,5-tetramethoxy-6-methyl benzene

To a stirred solution of 2-Allyl-3-methyl-5,6-dimethoxy-l,4-benzoquinone

(27 g, 121.5 mmol) and tetrabutylammonium bromide (2.0 g) in THF/water (1/1, 700 mL each) was added sodium dithionite (21 lg, 1.215 mole, 10 eq). The reaction was stirred for 30 min then cooled to 0°C and NaOH (73 g, 15 eq). After 30 min of stirring, methyl iodide (100 mL, 1.215 mole, 10 eq) was added and the reaction heated overnight at 40°C. The reaction was diluted with water (1 L) and extracted 3 times with Et2O (500 mL each). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, 3 SNAP 340 columns, EtOAc in Hex from 5% to 20% in 10 CV) affording the title compound as a colourless oil (19.7 g, yield: 64%).

1H NMR (300 MHz, CDC1 ₃ ) δ 5.91 (ddt, J = 16.0, 10.2, 5.8, 1H), 5.04 -

4.97 (m, 1H), 4.92 (dq, J = 17.1, 1.8, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.38 (dt, J= 5.8, 1.8, 2H), 2.18 (s, 3H).

Step 5: Synthesis of l-(3-Hydroxypropyl)-2,3,4,5-tetramethoxy-6- methylbenzene

To a stirred solution of l-allyl-2,3,4,5-tetramethoxy-6-methylbenzene (6.8 g, 26.95 mmol) in dry THF (100 mL) was added at 0°C a 0.5 M solution of 9-BBN in THF (108 mL, 53.9 mmol, 2 eq). The reaction was stirred for 16 h at rt. The reaction was cooled to 0°C and simultaneously were added a 3M aqueous NaOH solution (44.1 mL) and a 30% aqueous H ₂ O ₂ solution (44.1 mL). The reaction was stirred for 30 min then water was added and then Et ₂ O (150 mL) and the organic layer was separated. The aqueous layer was reextracted twice with Et ₂ O (50 mL). The combined organic layers were washed with water, brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage instrument, SNAP 340 column, EtOAc in Hex from 30% to 60% in 10 CV) affording the title compound as a colourless oil (5.43 g, yield: 74%).

1H NMR (300 MHz, CDC1 ₃ ) δ 3.91 (s, 3H), 3.89 (s, 3H), 3.83 (d, J = 4.7, 3H), 3.77 (d, J = 6.6, 3H), 3.60 - 3.49 (m, 2H), 2.71 (t, J = 7.1, 2H), 2.40 (t, J = 6.3, 1H), 2.17 (s, 3H), 1.80 - 1.66 (m, 2H).

Step 6: Synthesis of 3-(2,3,4,5-tetramethoxy-6-methylphenyl) propyl methane sulfonate

To a stirred solution of l-(3-hydroxypropyl)-2,3,4,5-tetramethoxy-6- methylbenzene (5.4 g, 20mmol) and Et3N (2.8 mL, 20.4 mmol, 1.02 eq) and DMAP (0.2 g) in dry CH2C12 (50 mL) was added at 0°C dropwise methane sulfonyl chloride (2.31 g, 20.2 mmol, 1.01 eq) and the reaction was stirred for 5 h at this temperature and then diluted with water. The organic layer was separated and washed successively with water, 0.1 M aqueous HC1, water

1H NMR (300 MHz, CDC1 ₃ ) δ 4.27 (t, J = 6.4, 1H), 3.91 (s, 1H), 3.89 (s,

1H), 3.83 (d, J = 4.8, 2H), 3.78 (s, 2H), 3.02 (s, 1H), 2.75 - 2.65 (m, 1H), 2.17 (s, 2H), 1.98 - 1.87 (m, 1H).

Step 7: Synthesis of 3-(2,3,4,5-tetramethoxy-6-methylphenyl) propyl nitrate A stirred solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl) propyl methane sulfonate (1.31 g, 3.77 mmol), tetrabutylammonium nitrate (0.23 g, 0.75 mmol, 0.2 eq) and sodium nitrate (0.43 g, 5.07 mmol, 1.5 eq) in a 3/1 mixture of butyl acetate and acetonitrile (10 mL) was heated at 90°C for 16h and then cooled down to rt. The reaction was diluted with water and the organic layer was separated, washed with water and then dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, EtOAc in nHex from 20% to 30% in 10 CV) affording the title compound as a colourless oil (0.73 g, Yield: 45%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.47 (t, J = 6.5, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.76 - 2.63 (m, 2H), 2.16 (d, J = 1.9, 3H), 1.98 - 1.82 (m, 2H).

Step 8: Synthesis of 3-(4,5-dimethoxy-2-methyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)propyl nitrate (Compound (8))

To a solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propyl nitrate (0.294 g, 0.929 mmol) in acetonitrile/water 1 : 1 (10 mL) cooled to 0°C was added CAN (1.16g, 2.05 mmol, 2 eq). After 3h, the reaction was diluted with H2O/EtOAc and the organic layer was separated, washed with water, brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, EtOAc in nHex from 20% to 30% in 10 CV) affording the title compound as an orange oil (0.198 g, Yield: 74%).

1H NM (300 MHz, CDC1 ₃ ) δ 4.47 (t, J = 6.3, 2H), 4.03 - 3.94 (m, 6H), 2.65 - 2.53 (m, 2H), 2.03 (s, 3H), 1.94 - 1.79 (m, 2H).

Example 15

Synthesis of 6-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)hexyl nitrate (compound (16))

(16)

To a solution of 2,3-dimethoxy-5-methyl-p-benzoquinone (1.04 g, 5.72 mmol), 7-(nitrooxy)heptanoic acid (1.10 g, 5.72 mmol) and AgNO ₃ (0.97 g, 5.72 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.55 g, 5.72 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, EtOAc in Hex from 5% to 50% in 10 CV) affording 125 mg (Yield: 7%)of the title compound ad a red oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.50-4.38 (m, 2H), 3.96 (s, 6H), 2.54-2.36 (m, 2H), 2.01 (s, 3H), 1.83 - 1.64 (m, 2H), 1.52 - 1.31 (m, 6H).

Example 16

Synthesis of 4-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)butyl nitrate (compound (4))

(4)

To a solution of 2,3-dimethoxy-5-methyl-p-benzoquinone (0.54 g, 2.95 mmol), 5-(nitrooxy)pentanoic acid (0.48 g, 2.95 mmol) and AgNO ₃ (0.50 g, 2.95 mmol)in CH ₃ CN (15 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (0.96 g, 3.54 mmol) in H ₂ O (15 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (10 ml). The product was extracted with EtOAc (2 X 10 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, EtOAc in Hex from 5% to 40% in 15 CV) affording 90 mg of a red oil (Yield: 10%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.47 (t, 2H), 3.99 (s, 6H), 2.61 - 2.42 (m, 2H), 2.03 (s, 3H), 1.86 - 1.69 (m, 2H), 1.60 - 1.41 (m, 2H). Example 17

Synthesis of 1 l-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)undecane-l,2-diyl dinitrate (Compound (17))

(17)

Step 1: Synthesis of 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)decanal

To a solution of oxalyl chloride (1.0 mL, 1 1.82 mmol, 2 eq) in dry dichloromethane (40 mL) cooled to -78°C was added over a period of 5 min DMSO (1.68 mL, 23.64 mmol, 4 eq). After 10 min of stirring at this temperature, a solution of idebenone (2.0 g, 5.91 mmol) in CH2C12 (20 mL) was added over a period of 5 min. After another 5 min of stirring, Et3N (6.6 mL, 47.28 mmol, 8 eq) and the reaction stirred for 1 h and then left to warm to rt. Water was added and the organic layer was extracted, washed successively with 0.1 M aqueous HCl, water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 20% to 40% in 10 CV) to afford the title compound as a yellow solid (1.68 g Yield: 84%).

1H NM (300 MHz, CDC1 ₃ ) δ 9.76 (d, J= 1.6, 1H), 3.99 (s, 6H), 2.42 (dt, J = 9.0, 4.4, 4H), 2.01 (s, 3H), 1.68 - 1.58 (m, 2H), 1.35-1.21 (m, 18H).

Step 2: Synthesis of 2,3-dimethoxy-5-methyl-6-(undec-10-enyl)cyclohexa- 2,5-diene- 1 ,4-dione

To a stirred solution of methyltriphenylphosphonium bromide (860 mg, 2.4 mmol, 1.2 eq.) in dry THF was added at 0°C a 1M solution of lithium bis(trimethylsilyl)amide in THF (2.5 mL, 2.6 mmol, 1.3 eq.). After 30 min of stirring, 10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa- 1 ,4-dienyl)decanal (672 mg, 2.0 mmol) was added. The solution became green and then brown. Water was then added to quench the reaction and acidified to pH 4 with HC1 1M. The reaction was extracted with Et2O (3 * 20 mL). The combined organic layers were washed with water and brine, dried (sodium sulfate), filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 15% to 40% in 10 CV) to afford the title compound as a yellow oil (132 mg Yield: 10%).

Step 3: Synthesis of 1 l-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)undecane-l,2-diyl dinitrate (Compound (17)

To a stirred solution of 2,3-dimethoxy-5-methyl-6-(undec-10- enyl)cyclohexa-2,5-diene-l,4-dione (130 mg, 0.39 mmol) and silver nitrate (660 mg, 0.39 mmol, 1 eq) in acetonitrile cooled to -15°C was added iodine (100 mg, 0.39 mmol, 1 eq). The reaction was stirred for 30 min at this temperature then silver nitrate (660 mg, 0.39 mmol, 1 eq) was added and the reaction was heated at 40°C for 8 h. The reaction was cooled down and brine was added. After 30 min of stirring, EtOAc was added and the precipitate filtered off. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 15% to 40% in 10 CV) to afford the title compound as a reddish oil (71 mg Yield: 40%).

1H NM (300 MHz, CDC1 ₃ ) δ 5.27 (ddt, J = 10.0, 6.7, 3.3, 1H), 4.74 (dt, J = 12.8, 2.9, 1H), 4.47 (ddd, J = 12.8, 6.7, 4.2, 1H), 3.99 (s, 6H), 2.45 (t, J = 7.2, 2H), 2.01 (s, 3H), 1.81 - 1.61 (m, 2H), 1.50 - 1.19 (m, 14H). Example 18

Synthesis of 1 l-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)undecan-2-yl nitrate (Compound (18))

(18)

Step 1: Synthesis of 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methylbenzene- 1,4-diol

Step 2: Synthesis of tert-butyl 2-(10-hydroxydecyl)-5,6-dimethoxy-3- methyl- 1 ,4-phenylene dicarbonate

To a stirred solution of 2-(10-hydroxydecyl)-5,6-dimethoxy-3- methylbenzene- 1 ,4-diol (1 g, 2.94 mmol) and Et ₃ N (0.9 mL, 6.47 mmol, 2.2 eq) in dry THF (40 mL) was added at 0°C a solution of Boc ₂ O (1.34 g, 6.17 mmol, 2.1 eq) in dry THF (5 mL). The reaction was stirred overnight at rt and then diluted with H ₂ O/EtOAc. The organic layer was separated and washed with HCl 0.1M, water, saturated aqueous NaHCO ₃ , water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 20% to 40% in 10 CV) to afford the title compound as a colorless oil (1.26 g, Yield: 79%).

Step 3: Synthesis of tert-butyl 2,3-dimethoxy-5-methyl-6-(10-oxodecyl)- 1 ,4-phenylene dicarbonate

To a stirred solution of synthesis of tert-butyl 2-(10-hydroxydecyl)-5,6- dimethoxy-3 -methyl- 1 ,4-phenylene dicarbonate (900 mg, 1.66 mmol) in dry CH ₂ C1 ₂ cooled to 0°C was added PCC (0.54 g, 2.5 mmol, 1.5 eq) and the reaction was stirred for 6 h at this temperature. The solid were then filtered off and washed with CH2C12. The organic layer was washed with water, HC1 1M, water and brine, dried on sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 50 column, EtOAc in Hex from 15% to 30% in 10 CV) to afford the title compound as a colourless oil (640 mg, Yield: 71%).

Step 4: Synthesis of tert-butyl 2-(10-hydroxyundecyl)-5,6-dimethoxy-3- methyl- 1 ,4-phenylene dicarbonate

To a stirred solution of tert-butyl 2,3-dimethoxy-5-methyl-6-(10-oxodecyl)- 1 ,4-phenylene dicarbonate 430 mg, 0.835 mmol) in dry THF (10 mL) cooled to - 78°C was added slowly a 3M solution of methylmagnesium iodide in Et ₂ O (0.4 mL, 1.2 mmol, 1.2 eq) and the reaction was stirred for 1 h at this temperature then left to turn back to rt. The reaction was quenched by addition of water and then 1M aqueous HC1 to dissolve magnesium salts. EtOAc was added and the organic layer extracted, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, EtOAc in Hex from 10% to 30% in 10 CV) to afford the title compound as a colourless oil (364 mg, Yield: 79%).

Step 5: Synthesis of tert-butyl 2,3-dimethoxy-5-methyl-6-(10- (nitrooxy)undecyl)- 1 ,4-phenylene dicarbonate

To a stirred solution of tert-butyl 2-(10-hydroxyundecyl)-5,6-dimethoxy-3- methyl- 1 ,4-phenylene dicarbonate (310 mg, 0.561 mmol), tetrabutylammonium nitrate (180 mg, 5.89 mmol, 1.05 eq) and 2,6-di-tert-butyl-4-methylpyridine (126 mg, 0.617 mmol, 1.1 eq) in dry CH2C12 cooled to -78°C was added dropwise triflic anhydride (0.1 mL, 5.89 mmol, 1.1 eq) and the reaction was stirred for lh at -78°C and left to turn back to rt. The reaction was then quenched with water and the organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 20% to 30% in 10 CV) affording the title compound as a yellowish oil (126 mg, Yield: 21%).

Step 6: Synthesis of 1 l-(4,5-dimethoxy-2-methyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)undecan-2-yl nitrate (Compound (18))

A solution of tert-butyl 2,3-dimethoxy-5-methyl-6-(10-(nitrooxy)undecyl)- 1 ,4-phenylene dicarbonate (250 mg, 0.416 mmol) in EtOAc (10 mL) was treated with a 4M solution of HCl in dioxane (0.41 mL, 1.66 mmol, 3 eq) and was stirred overnight at rt. The reaction was evaporated to dryness and then diluted with Et ₂ O and Ag ₂ O (192 mg, 0.832 mmol, 2 eq) was added and the reaction stirred for 2 h. The silver salts were filtered off and the residue was purified twice by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a red oil (94 mg, Yield: 52%).

1H NMR (300 MHz, CDC1 ₃ ) δ 5.06 (dd, J = 12.6, 6.3, 1H), 3.99 (s, 6H), 2.45 (t, J= 7.2, 2H), 2.01 (s, 3H), 1.76 - 1.46 (m, 6H), 1.45 - 1.20 (m, 18H).

Example 19

Synthesis of 3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propane-l,2-diyl dinitrate (Compound (9))

(9)

Step 1: Synthesis of 2-allyl-5,6-dimethoxy-3-methyl-l,4-phenylene tert- butyl dicarbonate

To a stirred solution of 2-allyl-5,6-dimethoxy-3-methylbenzo-l,4-quinone (1.2 g, 5.4 mmol) in EtOH (20 mL) was added portionwise sodium borohydride (0.51 g, 13.5 mmol, 2.5 eq) and the reaction was stirred for 30 min. The reaction was cooled to 0°C and quenched carefully by the addition of water. EtOAc was added and the organic layer separated, washed with water, brine, filtered and evaporated. The residue was then diluted in dry THF (20 mL) and Et ₃ N (2.26 mL, 16.2 mmol, 3 eq) followed by a solution of Boc ₂ O (3.5 g, 16.2 mmol, 3 eq) in THF were added. The reaction was stirred overnight at rt and then washed with water, HCl 1M, water and brine. The organic layer was dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in n-Hex from 10% to 20% in 10 CV) affording the title compound as a colourless oil (1.27 g, Yield: 55%).

Step 2: Synthesis of 2-(2,3-bis(nitrooxy)propyl)-5,6-dimethoxy-3-methyl- 1 ,4-phenylene tert-butyl dicarbonate

To a stirred solution of 2-allyl-5,6-dimethoxy-3-methyl-l,4-phenylene tert- butyl dicarbonate (500 mg, 1.18 mmol) and silver nitrate (200 mg, 1.18 mmol, leq) in acetonitrile (15 mL) cooled to -15°C was added iodine (300 mg, 1.18 mmol, 1 eq) and the reaction was stirred at this temperature for 30 min then left to rt for 30 min. Silver nitrate (200 mg, 1.18 mmol, 1 eq) was added and the reaction stirred for 16 h at rt. Brine was added and the reaction stirred for 30 min. The salts formed were filtered off, washed with EtOAc and the resulting solution diluted with water (30 mL) and EtOAc (30 mL). The organic layer was separated and washed with brine, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in n-Hex from 10% to 30% in 10 CV) affording the title compound as red oil (361 mg, Yield: 56%).

Step 3: Synthesis of 3-(4,5-dimethoxy-2-methyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)propane-l,2-diyl dinitrate (Compound (9)

A solution of 2-(2,3-bis(nitrooxy)propyl)-5,6-dimethoxy-3-methyl-l,4- phenylene tert-butyl dicarbonate (360 mg, 6.56 mmol) in Et ₂ O was treated with a 4 M solution of HCl in dioxane (0.5 mL) overnight. The reaction was then concentrated to dryness and directly purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc in n-Hex from 20% to 40% in 10 CV) affording the title compound as a red oil (31 mg, Yield: 13%).

Mass spectrum (EI), m/z 348.25 (M+H) ⁺ (C ₁₂ H ₁₄ N ₂ O ₁₀ requires 347.24) Example 20

Synthesis of 3-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dienyl) propoxy)propyl nitrate (Compound (14))

(14)

Step 1: Synthesis of l-[3-(allyloxy)propyl]-2,3,4,5-tetra methoxy-6- methylbenzene

To a stirred solution of allyl alcohol (0.10 g, 1.72 mmol, 1.2 eq) in dry THF was added sodium hydride (0.046 g, 90% in mineral oil, 1.4 eq) and after 10 min, 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propyl methanesulfonate (0.5 g, 1.43 mmol) was added and a catalytic amount of 15-crown-5. The reaction heated at 70°C overnight and then evaporated to dryness. The residue was purified by flash chromatography (Biotage SP4 instrument, column SNAP 100, EtOAc in Hex from 15% to 30% in 8 CV) affording the title compound as a colourless oil (0.415 g, Yield: 93%).

1H NM (300 MHz, CDC1 ₃ ) δ 5.94 (ddd, J = 22.6, 10.7, 5.5, 1H), 5.29 (dd, J = 17.2, 1.2, 1H), 5.17 (dd, J = 10.4, 1.2, 1H), 4.00 (d, J = 5.5, 2H), 3.90 (s, 6H), 3.82 (s, 3H), 3.78 (s, 3H), 3.49 (t, J = 6.5, 2H), 2.65 (dd, J = 9.0, 6.5, 2H), 2.17 (s, 3H), 1.82 - 1.69 (m, 2H). Step 2: Synthesis of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjpropanol

To a stirred solution of l-[3-(allyloxy)propyl]-2,3,4,5-tetramethoxy-6- methylbenzene (0.415 g, 1.34 mmol) in dry THF was added at 0°C a 0.5M solution of 9-BBN in THF (2.9 mL, 1.2 eq) and the reaction was stirred at rt for 18h. The reaction was cooled to 0°C and simultaneously were added a 3M aqueous solution of NaOH (2.2 mL) and a 30% aqueous solution of H2O2 (2.2 mL). After 30 min, the organic layer was diluted with Et2O (30 mL) and water (50 mL) and the organic layer was separated. The aqueous layer was extracted twice with Et2O (30 mL). The combined organic layers were washed with H2O, brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 100, EtOAc in Hex from 20% to 50% in 10 CV) affording the title compound as a colourless oil (0.165 g, Yield: 37%).

1H NMR (300 MHz, CDC1 ₃ ) δ 3.89 (s, 3H), 3.86 (s, 3H), 3.81 (m, 5H), 3.78 (s, 3H), 3.64 (t, J = 5.7, 2H), 3.48 (t, J = 6.4, 2H), 2.68 - 2.58 (m, 2H), 2.16 (s, 3H), 1.91 - 1.80 (m, 2H), 1.80 - 1.64 (m, 3H).

Step 3: Synthesis of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxy] ethyl nitrate

To a solution of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjpropanol (162 mg, 0.493 mmol), tetrabutylammonium nitrate (158 mg, 0.518 mmol, 1.1 eq) and 2,6-di-tert-butyl-4-methylpyridine (106 mg, 0.518 mmol, 1.1 eq) in dry dichloromethane (5 mL) cooled to -78°C was slowly added triflic anhydride (87 μΐ _^ , 0.518 mmol, 1.1 eq). The reaction was stirred at -78°C for 30 min and then left to go back to rt. The reaction was then quenched using water. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 50, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a colorless oil (0.05472 g, Yield: 29%) along with compound 14 as a reddish oil (0.036 g, Yield: 21%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.68 - 4.58 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 - 3.69 (m, 2H), 3.51 (t, J = 6.4, 2H), 2.64 (dd, J= 8.9, 6.7, 2H), 2.17 (s, 3H), 1.81 - 1.68 (m, 2H).

Step 4: Synthesis of 3-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-

1 ,4-dienyl)propoxy)propyl nitrate (Compound (14))

To a solution of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjethyl nitrate (54 mg, 0.144 mmol) in a 1/1 mixture of water and acetonitrile (2 mL) was added at 0°C cerium ammonium nitrate (CAN, 0.171 g, 0.303 mmol, 2.1 eq). The reaction was stirred for 3 h then diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 25 g column, nHex/EtOAc 8/2 to 7/3, 8 CV) affording the title compound as a red oil (37 mg, Yield: 74%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.57 (t, J = 6.4, 2H), 3.99 (s, 3H), 3.99 (s,

3H), 3.49 (t, J = 6.0, 2H), 3.42 (t, J = 6.2, 2H), 2.58 - 2.49 (m, 2H), 2.02 (s, 3H), 1.97 (dd, J= 12.3, 6.2, 2H), 1.74 - 1.61 (m, 2H).

Example 21

Synthesis of 2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propoxy)ethyl nitrate (Compound (20))

(20) Step 1: Synthesis of ((2-(3-(2,3,4,5-tetramethoxy-6- methylphenyl)propoxy)ethoxy)methanetriyl)tribenzene

To a stirred solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propan-l- ol (0.54 g, 2.0 mmol) in dry DMF was added at 0°C sodium hydride (90% in mineral oil, 0.057 g, 2.4 mmol, 1.2 eq) and a catalytic amount of 15-crown-5. The reaction was stirred for 15 min and then [(2-iodoethoxy)(diphenyl) methyljbenzene (0.83 g, 2.0 mmol, 1 eq) was added and the reaction heated at 80°C overnight. Water and Et2O (20 mL of each) were then added at rt and the organic layer separated. The aqueous layer was extracted once with Et2O and the combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 100, EtOAc in Hex from 10% to 30% in 10 CV) affording the title compound as an oil (0.25 g, Yield: 22%).

1H NMR (300 MHz, CDC1 ₃ ) δ 7.56 - 7.43 (m, 6H), 7.34 - 7.16 (m, 12H), 3.91 (s, 3H), 3.89 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.64 (t, J= 5.1, 2H), 3.55 (t, J = 6.4, 2H), 3.25 (t, J = 5.1, 2H), 2.69 (dd, J = 9.1, 6.7, 2H), 2.19 (s, 3H), 1.84 - 1.70 (m, 2H).

Step 2: Synthesis of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjethanol

A solution of ((2-(3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxy)ethoxy)methanetriyl)tribenzene (0.25 g, 0.449 mmol) and pyridinium paratoluenesulfonate (56 mg, 0.224 mmol, 0.5 eq) in a 1/1 mixture of CHC1 ₃ / MeOH was stirred overnight. The reaction was then evaporated to dryness and purified by flash chromatography (Biotage SP4, column SNAP 50, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as an oil (0.121 g, Yield: 86%).

1H NMR (300 MHz, CDC1 ₃ ) δ 3.91 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.74 (dd, J = 8.6, 4.5, 2H), 3.58 - 3.54 (m, 2H), 3.51 (t, J = 6.4, 2H), 2.67 (dd, J= 8.5, 6.9, 2H), 2.21 (t, J=4.5, lH), 2.17 (s, 3H), 1.83 - 1.71 (m, 2H).

Step 3: 2-(3-(2,3,4,5-tetramethoxy-6-methylphenyl)propoxy)ethyl nitrate

To a solution of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjethanol (0.121 g, 0.385 mmol), tetrabutylammonium nitrate (134 mg, 0.435 mmol, 1.1 eq) and 2,6-di-tert-butyl-4-methylpyridine (106 mg, 0.518 mmol, 1.1 eq) in dry dichloromethane (5 mL) cooled to -78°C was slowly added triflic anhydride (87 μΐ _^ , 0.518 mmol, 1.1 eq). The reaction was stirred at -78°C for 30 min and then left to go back to rt. The reaction was then quenched using water. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 50, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a colorless oil (0.072 g, Yield: 37%) along with compound 14 as a reddish oil (0.036 g, Yield: 21%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.67 - 4.59 (m, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 3.76 - 3.68 (m, 2H), 3.51 (t, J = 6.4, 2H), 2.64 (dd, J= 8.9, 6.7, 2H), 1.81 - 1.68 (m, 2H).

Step 4: 2-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propoxy)ethyl nitrate (Compound (20))

To a solution of 2-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propoxyjethyl nitrate (72 mg, 0.144 mmol) in a 1/1 mixture of water and acetonitrile (2 mL) was added at 0°C cerium ammonium nitrate (CAN, 237 mg, 0.42 mmol, 2.1 eq). The reaction was stirred for 3 h then diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 25 g column, nHex/EtOAc 8/2 to 7/3, 8 CV) affording the title compound as a red oil (52 mg, Yield: 79%).

1H NMR (300 MHz, CDC1 ₃ ) δ 4.64 - 4.55 (m, 2H), 3.99 (s, 6H), 3.72 - 3.64 (m, 2H), 3.48 (t, J= 6.1, 2H), 2.55 (t, J= 7.6, 2H), 2.03 (s, 3H), 1.76 - 1.63 (m, 2H). Example 22

Synthesis of 6-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propylthio)hexyl nitrate (Compound (21))

(21)

Step 1: Synthesis of S-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propyl] ethanethioate

To a solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propyl methanesulfonate (synthesized as in example 7, steps l-6)(3.0 g; 8.6 mmol) in DMF (30 ml), Potassium thioacetate (2.0 g; 17.2 mmol) and Nal (0.26 g: 1.7 mmol) were added. The mixture was stirred 3 hours at room temperature then H ₂ O (30 ml) and EtOAc (30 ml) were added. The two phases were separated and the organic layer was extracted with EtOAc (2x 20 ml). The combined organic layers were washed with H ₂ O (5x 20 ml), brine (20 ml), dried on Na ₂ SO ₄ and concentrated under reduced pressure affording 2.8 g (Yield: 100%) of the title compound as a clear oil

1H NMR (300 MHz, CDC1 ₃ ) δ 3.93 - 3.86 (m, 6H), 3.81 (s, 3H), 3.77 (s, 3H), 3.00 - 2.88 (m, 2H), 2.69 - 2.58 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.82 - 1.66 (m, 2H).

Step 2: Synthesis of 3-(2,3,4,5-tetramethoxy-6-methylphenyl) propane-1- thiol

To a solution of S-[3-(2,3,4,5-tetramethoxy-6-methylphenyl) propyl] ethanethioate (0.10 g; 0.30 mmol) in MeOH (2 ml), 3 drops of Sodium methoxide solution 25 wt.% in MeOH were added. The solution was stirred 15 minutes at room temperature then was quenched with Amberlite® IR-120H ion-exchange resin. The resin was filtered off and the solvent evaporated affording 80 mg (Yield: 92%) of the title compound.

1H NMR (300 MHz, CDC1 ₃ ) δ 3.96 - 3.87(m, 6H), 3.82 (s, 3H), 3.78 (s, 3H), 2.73 - 2.64 (m, 2H), 2.64 - 2.52 (m, 2H), 2.17 (s, 3H), 1.84 - 1.70 (m, 2H).

Step 3: Synthesis of 6-(3-(2,3,4,5-tetramethoxy-6-methylphenyl) propylthio)hexan- 1 -ol

To a solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propane-l -thiol (0.59 g; 2.06 mmol) and 6-Bromo-l-hexanol (0.32 μΐ; 2.47 mmol) in DMF (10 ml) cooled at 0°C, Cs ₂ CO ₃ (0.80 g; 2.47 mmol) was added. The mixture was stirred 2 hours at room temperature then H ₂ O (10 ml) and EtOAc (10 ml) were added. The two phases were separated end the aqueous one was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with H ₂ O (5 x 10 ml), brine, dried on Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, EtOAc in Hex from 9% to 60% in 10 CV) affording 590 mg (Yield: 74%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 3.96 - 3.86 (m, 6H), 3.82 (s, 3H), 3.78 (s, 3H), 3.71 - 3.58 (m, 3H), 2.73 - 2.62 (m, 2H), 2.62 - 2.47 (m, 4H), 2.17 (s, 3H), 1.66 - 1.48 (m, 4H), 1.51 - 1.27 (m, 4H).

Step 4: Synthesis of 6-(3-(2,3,4,5-tetramethoxy-6-methylphenyl) propylthio)hexyl nitrate

To a solution of 6-(3-(2,3,4,5-tetramethoxy-6-methylphenyl) propylthio)hexan-l-ol (0.59 g; 1.53 mmol), Et ₄ NNO ₃ (0.35 g; 1.83 mmol) and 2,6- Di-tert-butyl-4-methylpyridine (0.38 g; 1.83 mmol) in dry CH ₂ C1 ₂ (25 ml) under N ₂ atmosphere and cooled at -78 °C, a solution of Trifluoromethansulfonic anhydride (0.30 ml; 1.83 mmol) in CH ₂ C1 ₂ (5 ml) was added dropwise. The mixture was stirred at -78°C 3 hours then a saturated solution of NH ₄ C1 (10 ml) was added and the mixture was allowed to reach room temperature. The two phases were separated and the aqueous one was extracted with CH ₂ C1 ₂ (20 ml). The combined organic phases were washed with brine, dried on Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 25 g column, Hex/EtOAc 94:6, 10 CV) affording 108 mg (Yield: 16%)of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.45 (t, 2H), 3.95 - 3.86 (m, 6H), 3.82 (s, 3H), 3.78 (s, 3H), 2.75 - 2.62 (m, 2H), 2.62 - 2.48 (m, 4H), 2.17 (s, 3H), 1.82 - 1.67 (m, 4H), 1.49 - 1.37 (m, 4H).

Step 5: Synthesis of 6-(3-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)propylthio)hexyl nitrate

To a solution of 6-(3-(2,3,4,5-tetramethoxy-6-methylphenyl) propylthio)hexyl nitrate (0.18 g; 0.41 mmol) in CH ₃ CN:H ₂ 0 1 : 1 (8 ml), cerium ammonium nitrate (0.58 g; 1.02 mmol) was added. The mixture was stirred 3 hours at room temperature then H ₂ O (5 ml) and Et ₂ O (10 ml) were added. The two phases were separated and the aqueous layer was extracted with Et ₂ O (10 ml). The combined organic layers were washed with H ₂ O (10 ml) and brine, dried on Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 25 g column, EtOAc in Hex from 5% to 50% in 10 CV) affording 90 mg (Yield: 55%) of the title compound as an orange oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.45 (t, 2H), 4.05 - 3.94 (m, 6H), 2.63 - 2.44 (m, 6H), 2.04 (s, 3H), 1.81 - 1.51 (m, 6H), 1.51 - 1.35 (m, 4H). Example 23

Synthesis of 10-(3-methyl- 1 ,4-dioxo- 1 ,4-dihydronaphthalen-2-yl)decyl nitrate (Compound (13))

(13)

Step 1: Synthesis of 1 l-(nitrooxy)undecanoic acid

To a solution of 1 1-Bromoundecanoic acid (1.50 g; 5.65 mmol) in CH ₃ CN (20 ml), AgNO ₃ (1.15 g; 6.78 mmol) was added. The solution was heated at the mw 22 minutes at 120°C. The salts were filtered off and the solvent evaporated. EtOAc was added and the salts were filtered off again, the solvent was evaporated affording 1.3 g (yield: 100%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.50 - 4.36(m, 2H), 2.35 (t, 2H), 1.81 - 1.54 (m, 4H), 1.48 - 1.21 (m, 12H).

Step 2: Synthesis of 10-(3 -methyl- 1 ,4-dioxo- 1 ,4-dihydro naphthalen-2- yl)decyl nitrate

To a solution of 2-methyl-l,4-naphthoquinone(0.97 g, 5.65 mmol), 1 1- (nitrooxy)undecanoic acid (1.3 g, 5.65 mmol) and AgNO ₃ (0.96 mg, 5.65 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.83 g, 6.77 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75°C for 5 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 100 g column, Hex:EtOAc 95:5, 10 CV) affording 419 mg (Yield: 20%) of the title compound as a yellow oil.

Mass spectrum (EI), m/z 374.18 (M+H) ⁺ (C ₂ iH ₂₇ NO ₅ requires 373.45)

Example 24

Synthesis of 4-(3 -methyl- 1 ,4-dioxo- 1 ,4-dihydronaphthalen-2-yl) butyl nitrate (Compound (22))

(22)

To a solution of 2-methyl-l,4-naphthoquinone(0.63 g, 3.68 mmol), 5- (nitrooxy)pentanoic acid (synthesized as in Example 4, steps 2 and 3) (0.60 g, 3.68 mmol) and AgNO ₃ (0.62 g, 3.68 mmol)in CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.20 g, 4.41 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (20 ml). The product was extracted with EtOAc (2 X 15 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP 50 g column, Hex:EtOAc 97:3, 24 CV) affording 260 mg (Yield: 24%) of the title compound as a yellow oil.

1H NM (300 MHz, CDC1 ₃ ) δ 8.15-7.99 (m, 2H), 7.77 - 7.61 (m, 2H), 4.50

(t, 2H), 2.79 - 2.57 (m, 2H), 2.20 (s, 3H), 1.93 - 1.74 (m, 2H), 1.74 - 1.49 (m, 2H). Example 25

Synthesis of 6-(3 -methyl- 1 ,4-dioxo- 1 ,4-dihydronaphthalen-2-yl) nitrate (Compound (23

(23)

To a solution of 2-methyl-l,4-naphthoquinone(0.98 g, 5.72 mmol), 7- (nitrooxy)heptanoic acid (synthesized as in Example 3, steps 2 and 3) (1.1 g, 5.72 mmol) and AgNO ₃ (0.97 g, 5.72 mmol)in CH ₃ CN (25 ml) heated at 75°C, a solution of K ₂ S ₂ O8 (1.55 g, 5.72 mmol) in H ₂ O (25 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (25 ml). The product was extracted with EtOAc (2 X 20 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP 100 g column, Hex:EtOAc 97:3, 15 CV) affording 990 mg (Yield: 54%) of the title compound as a yellow oil.

1H NM (300 MHz, CDC1 ₃ ) δ 8.16 - 7.98 (m, 2H), 7.78 - 7.58 (m, 2H), 4.45 (t, 2H), 2.73-2.55 (m, 2H), 2.22 (s, 3H), 1.86 - 1.62 (m, 2H), 1.57 - 1.38 (m, 4H).

Example 26

Synthesis of 3-(3-methyl-l,4-dioxo-l,4-dihydronaphthalen-2-yl)propyl nitrate (Compound (24))

(24) Step 1: Synthesis of co

To a stirred solution of menadione (6.89 g, 40 mmol) in acetic acid was added freshly distilled cyclopentadiene (5 mL, 60 mmol, 1.5 eq) and the reaction was stirred for 2 days. The reaction was then poured in water/ice and extracted with EtOAc (2x200 mL). The combined organic layers were washed twice with saturated aqueous NaHCO ₃ solution, water and brine, dried on sodium sulfate, filtered and evaporated to give the title compound as a pale yellow solid (7.76 g, Yield: 78%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.07 - 7.96 (m, 2H), 7.72 - 7.63 (m, 2H), 6.09 (dd, J = 5.6, 2.9, 1H), 5.90 (dd, J = 5.6, 2.8, 1H), 3.51 (d, J = 18.4, 1H), 3.21 (s, 1H), 3.05 (d, J= 3.8, 1H), 1.80 - 1.71 (m, 1H), 1.60 - 1.51 (m, 3H).

Step 2: Synthesis of compound B

B

To a stirred solution of crude A (Step 1) (5.4 g) in dry THF (100 mL) cooled to 0°C was added portionwise potassium tert-butoxide (4.0 g, 32.9 mmol, 1.5 eq). The reaction became dark reddish and was stirred at this temperature for another 30 mins then a solution of allyl bromide (2.9 mL, 35.1 mmol, 1.6 eq) in dry THF (30 mL) was added slowly. The reaction was stirred for 2h before addition of water (30 mL). The aqueous layer was acidified to pH 2 and the solution was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage instrument, SNAP 340 column, EtOAc in Hex from 20% to 40% in 10 CV) affording the title compound as a pale yellow oil (4.22 g, yield: 67%).

1H NMR (300 MHz, CDC1 ₃ ) δ 7.97 - 7.85 (m, 2H), 7.73 - 7.62 (m, 2H), 6.08 - 6.03 (m, 2H), 5.67 (ddt, J = 17.1, 10.1, 7.0, 1H), 5.35 (ddd, J = 13.8, 1 1.8, 1.5, 1H), 5.00 (dd, J = 23.0, 5.9, 2H), 3.25 (d, J = 1.6, 1H), 3.19 - 3.1 1 (m, 1H), 2.82 (dd, J= 14.5, 7.2, 1H), 2.58 (dd, J = 14.5, 6.9, 1H), 1.88 (t, J = 8.4, 1H), 1.59 - 1.54 (m, 3H).

Step 3: Synthesis of 2-allyl-3-methylnaphthoquinone

A solution of B (Step 2) (0.67 g, 2.4 mmol) in toluene was heated at 120°C for 5h. The solvents were evaporated under reduced pressure and the residue crystallized from hexane/Et ₂ O to give the title compound as a pale yellow solid (480 mg, Yield: 94%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.17 - 8.02 (m, 2H), 7.75 - 7.64 (m, 2H), 5.84 (ddt, J = 16.4, 10.1, 6.3, 1H), 5.08 (ddt, J = 13.7, 12.5, 6.3, 2H), 3.42 (d, J = 6.2, 2H), 2.16 (s, 3H).

Step 4: Synthesis of 2-allyl-l,4-dimethoxy-3-methylnaphthalene

To a stirred solution of 2-allyl-3-methylnaphthoquinone (8.0 g, 37.7 mmol) and tetrabutylammonium chloride (0.5 g) in THF/water (1/1, 500 mL each) was added slowly sodium dithionite (65.6 g, 377 mmol, 10 eq). The reaction was stirred for 30 min at this temperature then cooled to 0°C and soda (22.6 g, 565 mmol, 15 eq) was added portionwise. After 10 min, methyl iodide (46 mL, 754 mmol, 20 eq) was added and the reaction was heated at 40°C overnight. The reaction was then diluted with water (200 mL) and extracted with Et ₂ O (3 x 300 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, 2 x SNAP 340 g columns, nHex:EtOAc 95/5 to 85/15 in 10 CV) affording the title compound as a pale yellow solid (7.5 g, Yield: 82%).

1H NM (300 MHz, CDC1 ₃ ) δ 8.12 - 8.00 (m, 2H), 7.57 - 7.40 (m, 2H), 6.15 - 5.91 (m, 1H), 5.05 (dd, J = 10.2, 1.7, 1H), 4.91 (dd, J = 17.2, 1.8, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.64 (dt, J= 5.4, 1.7, 2H), 2.39 (s, 3H).

Step 5: Synthesis of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propan-l-ol To a solution of 2-allyl-l,4-dimethoxy-3-methylnaphthalene (7.5 g, 30.95 mmol) in dry THF (300 mL) cooled to 0°C was added dropwise a 0.5 M solution of 9-BBN in THF (124 mL, 62 mmol, 2 eq) and the reaction was stirred overnight at rt. The reaction was cooled to 0°C and simultaneously were added a 3M aqueous solution of NaOH (81 mL) and a 30% aqueous solution of H ₂ O ₂ (81 mL). After 60 min of stirring, the organic layer was diluted with Et ₂ O (300 mL) and water (500 mL) and the organic layer was separated. The aqueous layer was extracted twice with Et ₂ O (300 mL). The combined organic layers were washed with water, brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 340, EtOAc in Hex from 20% to 50% in 10 CV) affording the title compound as a colourless oil (5.62 g, Yield: 70%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.14 - 8.01 (m, 1H), 7.77 - 7.65 (m, 1H), 4.53 (td, J = 6.3, 2.8, 1H), 2.84 - 2.70 (m, 1H), 2.19 (d, J = 13.2, 2H), 1.94 (tt, J = 17.6, 8.8, 1H).

Step 6: Synthesis of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propyl methane sulfonate

To a solution of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propan-l-ol (5.6 g, 21.51 mmol), Et ₃ N (3.6 mL, 25.8 mmol, 1.2 eq) and DMAP (0.2 g) in dry CH ₂ C1 ₂ (70 mL) cooled to 0°C was added dropwise a solution of mesyl chloride (5.04 g, 23.6 mmol, 1.1 eq) in CH ₂ CI ₂ (20 mL). The reaction was stirred for 6 h at rt and then diluted with water (100 mL). The organic layer was separated and washed with water, HCl 0.1 M, water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, column SNAP 340, EtOAc in Hex from 20% to 50% in 10 CV) affording the title compound as a colourless oil (5.62 g, Yield: 70%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.1 1 - 7.93 (m, 2H), 7.54 - 7.39 (m, 2H), 4.31 (t, J = 6.3, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.02 (s, 3H), 2.97 - 2.89 (m, 2H), 2.39 (s, 3H), 2.1 1 - 1.96 (m, 2H).

Step 7: Synthesis of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propyl nitrate

A solution of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propyl methane sulfonate (650 mg, 1.92 mmol), tetrabutylammonium nitrate (1 17 mg, 0.38 mmol, 0.2 eq) and sodium nitrate (151 mg, 2.3 mmol, 1.2 eq) in a 1/1 mixture of butyl acetate and acetonitrile (10 mL) was heated overnight at 90°C. The reaction was then cooled down then diluted with water. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 g column, nHex/EtOAc 80/20 to 40/60 in 10 CV) affording the title compound as a clear oil (500 mg, Yield: 89%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.08 - 7.97 (m, 2H), 7.53 - 7.41 (m, 2H), 4.53 (td, J = 6.5, 2.7, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.99 - 2.86 (m, 2H), 2.41 (s, 3H), 2.06 - 1.93 (m, 2H).

Step 8: Synthesis of 3-(3-methyl-l,4-dioxo-l,4-dihydro naphthalen-2- yl)propyl nitrate (compound 21).

To a solution of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propyl nitrate (500 mg, 1.63 mmol) in a 1/1 mixture of water and acetonitrile (10 mL) was added at 0°C cerium ammonium nitrate (CAN, 1.94 g, 3.43 mmol, 2.1 eq). The reaction was stirred for 3 h then diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 g column, nHex/EtOAc 8/2 to 7/3, 8 CV) affording the title compound as a red oil (231 mg, Yield: 89%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.15 - 8.01 (m, 2H), 7.80 - 7.61 (m, 2H), 4.53 (td, J = 6.3, 2.8, 2H), 2.86 - 2.65 (m, 2H), 2.29 - 2.1 1 (m, 3H), 2.08 - 1.84 (m, 2H).

Example 27

Synthesis of 3-(3-(3-methyl-l,4-dioxo-l,4-dihydronaphthalen-2- yl)propoxy)propyl nitrate (Compound (25))

(25)

Step 1: Synthesis of 2-[3-(allyloxy)propyl]-l,4-dimethoxy-3- methylnaphthalene

A solution of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propan-l-ol (Example 21, Step 5)(900 mg, 3.46 mmol) in DMF cooled to 0°C was added portionwise sodium hydride (90% in mineral oil, 1 10 mg, 4.15 mmol, 1.2 eq). After 15 min, allyl bromide (0.36 mL, 4.15 mmol, 1.2 eq) and 15-crown-5 (0.1 mL) were added and the reaction heated at 90°C overnight. The reaction was quenched with water and EtOAc was added. The organic layer was separated and washed with water and then brine. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 g column, nHex/EtOAc 85/15 to 7/3, 8 CV) affording the title compound as a colorless oil (750 mg, Yield: 72%). 1H NMR (300 MHz, CDC1 ₃ ) δ 8.12 - 7.95 (m, 2H), 7.52 - 7.39 (m, 2H), 6.06 - 5.86 (m, 1H), 5.31 (ddd, J= 17.2, 3.3, 1.6, 1H), 5.19 (dd, J= 10.4, 1.5, 1H), 4.02 (dt, J = 5.5, 1.4, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.55 (t, J = 6.4, 2H), 2.99 - 2.81 (m, 2H), 2.43 (s, 3H), 1.88 (tt, J= 12.7, 6.4, 2H).

Step 2: Synthesis of 3-[3-(l,4-dimethoxy-3-methyl-2- naphthyl)propoxy]propan- 1 -ol

To a solution of 2-[3-(allyloxy)propyl]-l,4-dimethoxy-3-methylnaphthalene (1.5 g, 4.99 mmol) in dry THF (40 mL) was added dropwise a 0.5M solution of 9- BBN (26 mL, 13 mmol, 2.2 eq) and the reaction was stirred overnight at rt, then cooled to 0°C. A 3M aqueous solution of sodium hydroxide (8.2 mL, 25 mmol, 5 eq) and a 30% aqueous solution of H2O2 (8.2 mL, 5 eq) were added. The reaction was stirred for 30 min then diluted with water and Et ₂ O. The organic layer was separated and the aqueous layer extracted 3 times with Et ₂ O (10 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 g column, nHex/EtOAc 7/3 to 5/5 in 8 CV) affording the title compound as a white solid (510 mg, Yield: 32%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.09 - 7.97 (m, 2H), 7.50 - 7.40 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.82 (dd, J= 10.9, 5.4, 2H), 3.66 (t, J= 5.7, 2H), 3.53 (t, J = 6.3, 2H), 2.93 - 2.84 (m, 2H), 2.55 (t, J = 5.5, 1H), 2.42 (s, 3H), 1.92 - 1.80 (m, 4H).

Step 3: Synthesis of 3-[3-(l,4-dimethoxy-3-methyl-2- naphthyl)propoxy]propyl nitrate

To a solution of 3-[3-(l,4-dimethoxy-3-methyl-2-naphthyl) propoxy]propan-l-ol (0.51 g, 1.60 mmol), Bu ₄ NNO ₃ (0.586 g, 1.92 mmol, 1.2 eq) and 2,6-Di-tert-butyl-4-methylpyridine (0.362 g, 1.76 mmol) in dry CH ₂ C1 ₂ (20 ml) under N ₂ atmosphere and cooled at -78°C, a solution of trifluoromethansulfonic anhydride (0.29 ml, 1.76 mmol) in CH ₂ C1 ₂ (5 ml) was added dropwise. The mixture was stirred at -78°C for 1 hour then a saturated solution of NH ₄ C1 (10 ml) was added and the mixture was allowed to reach room temperature. The two phases were separated and the aqueous one was extracted with CH ₂ C1 ₂ (20 ml). The combined organic phases were washed with brine, dried on Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, Hex/EtOAc 80/20 to 60/40 in 10 CV) affording the title compound as a clear oil (354 mg, Yield:60%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.1 1 - 7.97 (m, 2H), 7.51 - 7.39 (m, 2H), 4.60 (td, J = 6.5, 3.0, 2H), 3.89 (d, J = 4.9, 3H), 3.87 (s, 3H), 3.58 - 3.45 (m, 4H), 2.88 (dd, J= 8.9, 6.8, 2H), 2.42 (s, 3H), 2.06 - 1.96 (m, 3H), 1.91 - 1.75 (m, 2H).

Step 4: Synthesis of 3-(3-(3-methyl-l,4-dioxo-l,4-dihydronaphthalen-2- yl)propoxy)propyl nitrate (Compound (25)

To a stirred solution 3-[3-(l,4-dimethoxy-3-methyl-2- naphthyl)propoxy]propyl nitrate (354 mg, 0.971 mmol) in a 1 : 1 mixture of water and acetonitrile (10 mL) cooled to 0°C was added cerium ammonium nitrate (1.15 g, 2.04 mmol, 2.1 eq). The reaction was stirred for 3 h at 0°C then diluted with water and EtOAc. The organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, Hex/EtOAc 80/20 to 60/40 in 10 CV) affording the title compound as a yellow oil (275 mg, Yield:85%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.08 (dt, J = 6.0, 3.1 , 2H), 7.74 - 7.64 (m, 2H), 4.54 (td, / = 6.4, 3.0, 2H), 3.49 (dd, J = 10.5, 6.0, 4H), 2.79 - 2.65 (m, 2H), 2.21 (s, 3H), 1.94 (p, J= 6.2, 2H), 1.85 - 1.68 (m, 2H). Example 28

Synthesis of 3-(3-methyl- 1 ,4-dioxo- 1 ,4-dihydronaphthalen-2-yl)propane- 1 ,2-diyl dinitrate (Compound (27)

(27)

Step 1: Synthesis of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propane-l,2-diol To a stirred solution of 2-allyl-l,4-dimethoxy-3-methylnaphthalene (2.42 g, 10 mmol) was added to a solution of ADmix (7g of ADmix a and 7 g of ADmix β) in a 1/1 mixture of water and tBuOH(50 mL each). The reaction was stirred at T for 16 h and the reaction was diluted with water / EtOAc (20 mL each). Sodium dithionite (3.6 g) was added slowly and after 30 min of stirring, the organic layer was extracted, washed with water, brine, filtered and evaporated. The residue was crystallized overnight in Et ₂ O to give the title compound as a white solid (2.03 g, 73%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.1 1 - 7.97 (m, 1H), 7.54 - 7.45 (m, 1H), 3.97 - 3.91 (m, 2H), 3.88 (d, J = 7.8, 2H), 3.70 - 3.56 (m, 1H), 3.56 - 3.43 (m, 1H), 3.06 (d, J = 7.0, 1H), 2.77 (d, J = 5.7, OH), 2.62 (dd, J = 1 1.8, 6.5, OH), 2.44 (s, 2H).

Step 2: Synthesis of 3-(3-methyl-l,4-dioxo-l,4-dihydro naphthalen-2- yl)propane-l,2-diyl dinitrate (Compound (27)).

To a solution of 3-(l,4-dimethoxy-3-methyl-2-naphthyl)propane-l,2-diol (0.59 g, 1.53 mmol), Bu ₄ NNO ₃ (0.73 g, 1.83 mmol, 2.4 eq) and 2,6-Di-tert-butyl- 4-methylpyridine (0.38 g, 1.83 mmol) in dry CH ₂ C1 ₂ (25 ml) under N ₂ atmosphere and cooled at -78°C, a solution of trifluoromethansulfonic anhydride (0.30 ml; 1.83 mmol) in CH ₂ C1 ₂ (5 ml) was added dropwise. The mixture was stirred at - 78°C 3 hours then a saturated solution of NH ₄ C1 (10 ml) was added and the mixture was allowed to reach room temperature. The two phases were separated and the aqueous one was extracted with CH ₂ C1 ₂ (20 ml). The combined organic phases were washed with brine, dried on Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, Hex/EtOAc80/20 to 60/40 in 10 CV) affording the title compound as a red oil (51 mg, Yield: 15%).

Mass spectrum (EI), m/z 360.18 (M-Na) ⁺ (C ₁₄ H ₁₂ N ₂ O ₈ requires 337.25). Example 29

Synthesis of 6-(5-methoxy-2,4-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)hexyl nitrate (Compound (28))

(28)

Step 1: Synthesis of 3,5-dimethyl-2-methoxy-p-benzoquinone

The title compound was synthesized as described in literature (Bioorganic & Medicinal Chemistry 18 (2010) 6429-6441), starting from 2,6 -dimethyl-p- benzoquinone which was treated with acetic

anhydride and boron trifluoride-etheratel4 at 40°C affording 1,2,4- triacetoxy-3,5-dimethylbenzene in 92% yield. l,2,4-triacetoxy-3,5- dimethylbenzene was then treated with sodium hydroxide and dimethyl sulfate in methanol at 23°C to provide 3,5-dimethyl-l,2,4-trimethoxybenzene in 82% yield. Finally, 3,5-dimethyl-l,2,4-trimethoxybenzene was oxidized using phenyliodine diacetate (PIDA) to obtain 3,5-dimethyl-2-methoxy-p-benzoquinone in 65% yield.

Step 2: Synthesis of 6-(5-methoxy-2,4-dimethyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)hexyl nitrate (Compound (28))

To a solution of 3,5-dimethyl-2-methoxy-p-benzoquinone (0.52 g, 3.12 mmol), 7-(nitrooxy)heptanoic acid (synthesized as in Example 3, steps 2 and 3) (0.6 g, 3.12 mmol) and AgNO ₃ (0.53 g, 3.12 mmol)in CH ₃ CN (55 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.00 g, 3.74 mmol) in H ₂ O (55 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (55 ml). The product was extracted with EtOAc (2 X 35 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex:EtOAc 95:5, 10 CV) affording 150 mg (Yield: 15%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.52 - 4.57 (m, 2H), 3.95 (s, 3H), 2.56 - 2.57 (m, 2H), 2.00 (s, 3H), 1.94 (s, 3H), 1.81 - 1.62 (m, 2H), 1.52 - 1.32 (m, 6H).

Example 30

Synthesis of 6-(4-methoxy-2,5-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)hexyl nitrate (Compound (29))

(29) Step 1: Synthesis of 3,6-dimethyl-2-methoxy-p-benzoquinone

The title compound was synthesized as described in literature (Bioorganic & Medicinal Chemistry 18 (2010) 6429-6441), starting from 2,5 -dimethyl-p- benzoquinone which was treated with acetic anhydride and boron trifluoride- etherate at 40°C affording l,2,4-triacetoxy-3,6-dimethylbenzene in 92% yield. l,2,4-triacetoxy-3,6-dimethylbenzene was then treated with sodium hydroxide and dimethyl sulfate in methanol at 23 °C to provide 3,6-dimethyl-l,2,4- trimethoxybenzene in 82% yield. Finally, 3,6-dimethyl-l,2,4-trimethoxybenzene was oxidized using phenyliodine diacetate (PIDA) to obtain 3,6-dimethyl-2- methoxy-p-benzoquinone in 65% yield.

Step 2: Synthesis of 6-(4-methoxy-2,5-dimethyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)hexyl nitrate

To a solution of 3,6-dimethyl-2-methoxy-p-benzoquinone (0.52 g, 3.12 mmol), 7-(nitrooxy)heptanoic acid (synthesized as in Example 3, steps 2 and 3) (0.6 g, 3.12 mmol) and AgNO ₃ (0.53 g, 3.12 mmol)in CH ₃ CN (55 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.00 g, 3.74 mmol) in H ₂ O (55 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (55 ml). The product was extracted with EtOAc (2 X 35 ml). The combined organic layers were washed with NaHCO saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex:EtOAc 95:5, 10 CV) affording 140 mg (Yield: 14%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDC1 ₃ ) δ 4.52 - 4.57 (m, 2H), 3.95 (s, 3H), 2.56 - 2.57 (m, 2H), 2.00 (s, 3H), 1.94 (s, 3H), 1.81 - 1.62 (m, 2H), 1.52 - 1.32 (m, 6H).

Example 31

Synthesis of 10-(4-methoxy-2,5-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)decyl nitrate (Compound (30))

(30)

To a solution of 3,6-dimethyl-2-methoxy-p-benzoquinone (0.52 g, 3.12 mmol), 1 1 -(nitrooxy)undecanoic acid (synthesized as in Example 18, step 1) (0.48 g, 2.89 mmol) and AgNO ₃ (0.49 g, 2.89 mmol)in CH ₃ CN (15 ml) heated at 75°C, a solution of K ₂ S ₂ O8 (0.94 g, 3.47 mmol) in H ₂ O (15 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (15 ml). The product was extracted with EtOAc (2 X 20 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP 50 g column, Hex:EtOAc 97:3, 10 CV) affording 350 mg (Yield: 33%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) 5 4.51 - 4.37 (m, 2H), 3.95 (s, 3H), 2.55 - 2.36

(m, 2H), 2.03 (s, 3H), 1.94 (s, 3H), 1.80 - 1.63 (m, 2H), 1.48 - 1.16 (m, 14H). Example 32

Synthesis of 10-(5-methoxy-2,4-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)decyl nitrate (Compound (31))

(31)

To a solution of 3,5-dimethyl-2-methoxy-p-benzoquinone (0.67 g, 4.03 mmol), 1 l-(nitrooxy)undecanoic acid (synthesized as in Example 18, step 1) (1.00 g, 4.03 mmol) and AgNO ₃ (0.68 g, 4.03 mmol)in CH ₃ CN (25 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.31 g, 4.83 mmol) in H ₂ O (25 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (25 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP 50 g column, Hex:EtOAc 97:3, 10 CV) affording 460 mg (Yield: 31%) of the title compound as a yellow oil.

1H NM (300 MHz, CDC1 ₃ ) δ 4.51 - 4.37 (m, 2H), 3.95 (s, 3H), 2.55 - 2.36 (m, 2H), 2.03 (s, 3H), 1.94 (s, 3H), 1.80 - 1.63 (m, 2H), 1.48 - 1.16 (m, 14H). Example 33

Synthesis of 8-(4-methoxy-2,5-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)octyl nitrate (Compound (32))

(32)

Step 1: Synthesis of 9-bromononanoic acid

To a solution of 9-Bromo-l-nonanol (1.50 g, 6.72 mmol) in acetone (27 ml) cooled at 0°C, a saturated solution of NaHCO ₃ (9 ml), NaBr (0.14 g, 1.34 mmol) and 2,2,6,6-Tetramethyl-l-piperidinyloxy-free radical (TEMPO) (0.10 g, 0.67 mmol) were added. Then trichloroisocyanuric acid (3.1 g, 13.44 mmol) was added portionwise. The mixture was stirred 30 minutes at 0°C and 3 hours at room temperature then was cooled at 0°C and 2-Propanol (8 ml) was added slowly. The mixture was stirred at 0°C for further 30 minutes then the white precipitate was filtered off and the mixture concentrated under reduced pressure. H ₂ 0 (10 ml) and CH ₂ C1 ₂ (10 ml) were added to the residue. The two phases were separated and the aqueous layer was extracted with CH ₂ C1 ₂ (2 x 10 ml). The combined organic layers were dried on Na ₂ SO ₄ and concentrated affording 1.60 g (Yield: 100%) of the title compound as a white solid.

1H NMR (300 MHz, DMSO) δ 3.49 (t, 2H), 2.23 - 2.08 (m, 2H), 1.84 - 1.68 (m, 2H), 1.57 - 1.14 (m, 10H).

Step 2: Synthesis of 9-(nitrooxy)nonanoic acid

To a solution of 9-bromononanoic acid (1.60 g; 6.72 mmol) in CH ₃ CN (30 ml), AgNO ₃ (1.53 g; 8.96 mmol) was added. The solution was heated at the mw 22 minutes at 120°C. The salts were filtered off and the solvent evaporated. EtOAc was added and the salts were filtered off again, the solvent was evaporated affording 1.45 g (yield: 98%) of the title compound as a clear oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.50 - 4.37 (m, 2H), 2.41 - 2.29 (m, 2H), 1.79 - 1.54 (m, 4H), 1.44 - 1.25 (m, 8H).

Step 3: Synthesis of 8-(4-methoxy-2,5-dimethyl-3,6-dioxo cyclohexa- 1 ,4- dienyl)octyl nitrate

To a solution of 3,6-dimethyl-2-methoxy-p-benzoquinone (0.54 g, 3.26 mmol), 9-(nitrooxy)nonanoic acid (0.72 g, 3.26 mmol) and AgNO ₃ (0.55 g, 3.26 mmol)in CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.06 g, 3.91 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (20 ml). The product was extracted with EtOAc (2 X 25 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex:EtOAc 97:3, 15 CV) affording 300 mg (Yield: 25%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.52 - 4.39 (m, 2H), 4.01 (s, 3H), 2.46 (t, 2H), 2.05 (s, 3H), 1.95 (s, 3H), 1.84 - 1.65 (m, 2H), 1.49 - 1.23 (d, 10H).

Example 34

Synthesis of 8-(5-methoxy-2,4-dimethyl-3,6-dioxocyclohexa-l,4- dienyl)octyl nitrate (Compound (19))

(19) To a solution of 3,5-dimethyl-2-methoxy-p-benzoquinone (0.54 g, 3.26 mmol), 9-(nitrooxy)nonanoic acid (0.72 g, 3.26 mmol)(synthesized as in Example 35, steps 2 and 3) and AgNO ₃ (0.55 g, 3.26 mmol)in CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.06 g, 3.91 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, was then allowed to cool to room temperature, and was poured in H ₂ O (20 ml). The product was extracted with EtOAc (2 X 25 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex:EtOAc 97:3, 15 CV) affording 80 mg (Yield: 7%) of the title compound as a yellow oil.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.52 - 4.39 (m, 2H), 4.01 (s, 3H), 2.46 (t, 2H), 2.05 (s, 3H), 1.95 (s, 3H), 1.84 - 1.65 (m, 2H), 1.49 - 1.23 (d, 10H).

Example 35

Synthesis of 10-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl) decyl nitrate (Compound (5))

(5)

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.95 g, 6.33 mmol), 1 1- (nitrooxy)undecanoic acid (synthesized as in Example 18, Step 1)(1.39 g, 5.65 mmol) and AgNO ₃ (0.96 g, 5.65 mmol)in CH ₃ CN (50 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.83 g, 6.77 mmol) in H ₂ O (50 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex/EtOAc 97:3, 15 cv) affording 600 mg (yield: 27%) of the title compound as an orange oil.

Mass spectrum (EI), m/z 352.19 (M+H) ⁺ (C ₁₉ H ₂₉ NO ₅ requires 351.44)

Example 36

Synthesis of 8-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4- dienyl)octyl nitrate (compound (33))

To a solution of 2,3-dimethoxy-5-methyl-p-benzoquinone (0.774 g, 4.01 mmol), 9-(nitrooxy)nonanoic acid (0.90 g, 4.01 mmol)(synthesized as in Example 28, steps 2 and 3) and AgNO ₃ (0.68 g, 4.01 mmol)in CH ₃ CN (25 ml) heated at 75°C, a solution of K ₂ S ₂ O ₈ (1.30 g, 4.81 mmol) in H ₂ O (25 ml) was added dropwise. The reaction mixture was stirred at 75°C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ sat. solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SP1 instrument, SNAP 50 g column, Hex/EtOAc 9: 1 in 15 CV) affording 80 mg (Yield: 6%)of the title compound ad a red oil.

1H NM (300 MHz, CDC1 ₃ ) δ 4.50-4.36 (m, 2H), 3.99 (s, 6H), 2.53-2.36 (m, 2H), 2.01 (s, 3H), 1.81 - 1.62 (m, 2H), 1.45 - 1.26 (m, 10H). Example 37

Synthesis of 8-(2,4,5-trimethyl-3,6-dioxocyclohexa-l,4-dienyl) octyl nitrate (Compound (34))

To a solution of 2,3,5-trimethyl-p-benzoquinone (0.49 g, 3.27 mmol), 9- (nitrooxy)nonanoic acid (0.72 g, 3.27 mmol)(synthesized as in Example 28, steps 2 and 3)and AgNO ₃ (0.55 g, 3.27 mmol)in CH ₃ CN (20 ml) heated at 75°C, a solution of K ₂ S ₂ O8 (1.06 g, 3.92 mmol) in H ₂ O (20 ml) was added dropwise. The reaction mixture was stirred at 75 °C for 3 hours, then it was allowed to cool to room temperature, and was poured in H ₂ O (50 ml). The product was extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with NaHCO ₃ saturated solution and brine, dried on Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography (Biotage SPl instrument, SNAP 50 g column, Hex/EtOAc 97:3, 10 cv) affording 195 mg (yield: 17%) of the title compound as an orange oil.

1H NM (300 MHz, CDC1 ₃ ) δ 4.51-4.39 (m, 2H), 2.53-2.4 l(m, 2H), 2.02 (s, 9H), 1.80 - 1.65 (m, 2H), 1.47 - 1.27 (m, 10H). Example 38

Synthesis of 2-[2-(4,5-dimethoxy-2-methyl-3 ,6-dioxocyclohexa- 1 ,4-dien- 1 - yl)ethyl]-4-(nitrooxy)tetrahydrofuran-3-yl nitrate (Compound (35))

(35)

Step 1: Synthesis of 3-(2,3,4,5-tetramethoxy-6-methylphenyl) propanal To a stirred solution of l-(3-Hydroxypropyl)-2,3,4,5-tetramethoxy-6- methylbenzene (4.0 g, 14.8 mmol) in CH ₂ C1 ₂ (100 mL) cooled to 0°C was added pyridinium chlorochromate (4.8 g, 22.2 mmol, 1.5 eq) and the reaction was stirred for 6 h at rt. The reaction was filtered on a bed of celite and evaporated to dryness. The residue was purified by flash chromatography (Biotage SP4, SNAP 340 column, nHex/EtOAc from 15% to 30% in 10 CV) to afford the title compound as a colourless oil (3.28 g, Yield: 83%).

1H NM (300 MHz, CDC1 ₃ ) δ 9.82 (t, J = 1.4, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 3.83 (s, 3H), 3.78 (s, 3H), 2.90 (dd, J = 9.9, 5.7, 2H), 2.64 - 2.55 (m, 2H), 2.16 (s, 3H).

Step 2: Synthesis of 5-(2,3,4,5-tetramethoxy-6-methylphenyl) pent-l-en-3-ol To a solution of 3-(2,3,4,5-tetramethoxy-6-methylphenyl)propanal (1.00 g, 3.72 mmol) in dry THF (20 mL) cooled to -78°C was added a 1M solution of vinylmagnesium bromide in THF (5 mL, 5 mmol, 1.3 eq). The reaction was stirred for 1 h at -78°C and then quenched by addition of water. EtOAc was added and the organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex / EtOAc 80/20 to 55/45 in 10 CV) to afford the title compound as a colourless oil (0.76 g, Yield: 69%).

1H NMR (300 MHz, CDC1 ₃ ) δ 5.94 (ddt, J= 17.2, 10.6, 5.4, 1H), 5.76 (ddd, J = 17.7, 10.3, 7.5, 1H), 5.34 - 5.13 (m, 4H), 4.12 - 4.04 (m, 1H), 3.92 - 3.89 (m, 4H), 3.89 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.64 (qdd, J = 13.1, 10.8, 5.8, 2H), 2.16 (s, 3H), 1.83 - 1.59 (m, 2H).

Step 3: Synthesis of 2-[3-(allyloxy)pent-4-enyl]-3,4,5,6-tetramethoxy-l- methylbenzene

To a stirred solution of 5-(2,3,4,5-tetramethoxy-6-methylphenyl)pent-l-en-

3-ol (0.76 g, 2.57 mmol) in dry THF (10 mL) cooled to -10°C was added dropwise a 40% solution of NaHMDS in THF (0.565 g, 3.08 mmol, 1.2 eq). The reaction was stirred for 5 min then 15-crown-5 (51 \\L, 0.26 mmol, 0.1 eq) and allyl bromide (0.26 g, 3.08 mmol, 1.2 eq). The reaction was stirred at rt overnight and water and EtOAc were added. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex/EtOAc from 15% to 35% in 10 CV) to afford the title compound as a colourless oil (0.65 g, Yield: 75%).

1H NMR (300 MHz, CDC1 ₃ ) δ 5.94 (ddt, J= 17.2, 10.6, 5.4, 1H), 5.76 (ddd,

J = 17.2, 10.3, 7.5, 1H), 5.34 - 5.20 (m, 3H), 5.16 (ddd, J = 10.4, 3.1, 1.4, 1H), 4.14 - 4.03 (m, 1H), 3.90 (d, J = 2.2, 4H), 3.89 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.64 (qdd, J= 13.1, 10.8, 5.8, 2H), 2.16 (s, 3H), 1.83 - 1.59 (m, 2H).

Step 4: Synthesis of 2-[2-(2,3,4,5-tetramethoxy-6-methylphenyl)ethyl]-2,5- dihydrofuran

To a degassed solution of 2-[3-(allyloxy)pent-4-enyl]-3,4,5,6-tetramethoxy- 1-methylbenzene (0.65 g, 1.93 mmol) in dry CH2C12 (6 mL) was added Grubbs catalyst 1 ^st generation (0.153 g, 0.19 mmol, 0.05 eq) and the reaction was refluxed for 2h. The reaction was cooled to rt and evaporated to dryness. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex/EtOAc from 10% to 25% in 8 CV) to afford the title compound as a colourless oil (0.52 g, Yield: 87%).

1H NM (300 MHz, CDC1 ₃ ) δ 5.95 - 5.89 (m, 1H), 5.85 (ddd, J = 6.3, 3.7,

2.3, 1H), 4.89 (dd, J = 6.7, 3.0, 1H), 4.78 - 4.59 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H), 2.66 (qdd, J = 13.0, 10.0, 6.3, 2H), 2.17 (s, 3H), 1.79 - 1.61 (m, 2H).

Step 5: Synthesis of 2-[2-(2,3,4,5-tetramethoxy-6-methylphenyl) ethyl]tetr

To a solution of Admix β (5.44g, 1.4g/mmol) in a 1 : 1 mixture of water / tBuOH (20 mL each) was added 2-[2-(2,3,4,5-tetramethoxy-6- methylphenyl)ethyl]-2,5-dihydrofuran (1.2 g, 3.9 mmol) and then methane sulfonamide (74 mg, 0.2 eq). The reaction was stirred overnight at rt and then diluted with water / EtOAc. To the reaction was added sodium dithionite (1.2 g) and stirring continued for 30 min. The organic layer was separated and the aqueous layer extracted with EtOAc (20 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex/EtOAc from 40% to 90% in 12 CV) to afford the title compound as a colourless oil (1.16 g, Yield: 87%). The two diastereoisomers were not separated.

1H NMR (300 MHz, CDC1 ₃ ) δ 4.70 (s, 1H), 4.41 (td, J= 1 1.9, 5.4, 1H), 4.28 - 4.05 (m, 6H), 3.93 - 3.71 (m, 28H), 3.71 - 3.56 (m, 2H), 3.16 (d, J = 5.3, 1H), 2.81 - 2.55 (m, 7H), 2.18 (2 s, 6H), 1.93 - 1.71 (m, 4H).

Step 6: 2-[2- 4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l ,4-dien-l- yl)ethyl]-4-(nitrooxy)tetr

To a stirred solution of racemic 2-[2-(2,3,4,5-tetramethoxy-6- methylphenyl)ethyl]tetrahydrofuran-3,4-diol (1.15 g, 3.36 mmol), Bu ₄ NNO ₃ (2.35 g, 7.7 mmol, 2.2 eq) and 2,6-di-tert-butyl-4-methylpyridine (1.51 g, 7.35 mmol, 2.05 eq) in dry CH ₂ C1 ₂ (40 mL) cooled to -78°C was added dropwise a solution of trifluoromethansulfonic anhydride (1.21 mL, 7.2 mmol, 2.0 eq) in dry CH ₂ C1 ₂ (5 mL). The reaction was stirred at -78°C for 1 h and left to go back to rt in 30 min. The reaction was quenched by addition of a saturated solution of NH ₄ C1 (5 mL) and the organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc/nHex: 25/75 to 60/40 in 12 CV) to give the title compound as a red oil (153 mg, Yield: 1 1%). Only diastereoisomer 1 was isolated.

1H NMR (300 MHz, CDC1 ₃ ) δ 5.60 (dd, J = 10.8, 7.9, 1H), 5.21 - 5.12 (m,

1H), 4.38 (dd, / = 10.9, 6.0, 1H), 4.00 (s, 5H), 3.97 - 3.85 (m, 2H), 2.73 - 2.50 (m, 2H), 2.03 (s, 3H), 1.97 - 1.81 (m, 1H), 1.73 (ddd, J= 19.9, 1 1.4, 7.2, 1H).

Example 39

Synthesis of 2-[2-(l ,4-dimethoxy-3-methyl-naphthalen-2-yl)-ethyl]-3,4-bis- nitrooxy-tetr

(36) (37)

Step 1: Synthesis of 3-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)- propionaldehyde

To a stirred solution of 3-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)- propan-l-ol (4.3 g, 16.5 mmol) in dry DCM cooled to 0°C was added pyridinium chlorochromate (5.34 g, 24.8 mmol, 1.5 eq). The reaction was stirred for 5 h at rt then filtered on a bed of celite. The filtrate was evaporated under reduced pressure and the residue purified by flash chromatography (Biotage SP4, SNAP 340 column, nHex / EtOAc 85/15 to 70/30 in 8 CV) to afford the title compound as a colourless oil (1.76 g, Yield: 41%).

1H NMR (300 MHz, CDC1 ₃ ) δ 9.88 (s, 1H), 8.09 - 7.92 (m, 2H), 7.54 - 7.40 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.19 - 3.03 (m, 2H), 2.80 - 2.62 (m, 2H), 2.38 (s, 3H).

Step 2: Synthesis of 5-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)-pent-l- en-3-ol

To a solution of 3-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)- propionaldehyde (1.76 g, 6.82 mmol) in dry THF (40 mL) cooled to -78°C was added a 1M solution of vinylmagnesium bromide in THF (18 mL, 18 mmol, 2.6 eq). The reaction was stirred for 1 h at -78°C and then quenched by addition of water. EtOAc was added and the organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex / EtOAc 80/20 to 55/45 in 10 CV) to afford the title compound as a colourless oil (1.65 g, Yield: 85%).

1H NM (300 MHz, CDC1 ₃ ) δ 8.03 (dtd, J = 10.4, 6.8, 3.4, 3H), 7.56 - 7.40 (m, 3H), 5.90 (ddd, J= 17.1, 10.5, 5.5, 1H), 5.26 (dt, J= 17.2, 1.5, 1H), 5.10 (dd, J = 10.5, 1.4, 1H), 4.10 - 3.99 (m, 1H), 3.98 - 3.89 (m, 4H), 3.87 (s, 4H), 3.05 - 2.85 (m, 3H), 2.43 (s, 3H), 1.83 - 1.73 (m, 2H).

Step 3: Synthesis of 2-(3-allyloxy-pent-4-enyl)-l,4-dimethoxy-3 -methyl- naphthalene

To a stirred solution of 5-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)-pent-l- en-3-ol (1.65 g, 5.76 mmol) in dry THF (40 mL) cooled to -10°C was added a 40% solution of sodium bis-trimethylsilylamide in THF (3.81 mL, 8.17 mmol, 1.4 eq). After 10 min of stirring, 15crown-5 (0.127 g, 0.58 mmol, 0.1 eq) and allyl bromide (0.99g, 8.17 mmol, 1.2 eq) were added and the reaction stirred overnight at rt. The reaction was then diluted with water and extracted with EtOAc (2x20 mL). The combined organic layers were washed with water and brine, dried on sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex / EtOAc: 80/20 to 65/35 in 10 CV) to afford the title compound as a colourless oil (0.89 g, Yield: 40%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.15 - 7.92 (m, 2H), 7.51 - 7.37 (m, 2H), 5.97 (ddt, J = 17.2, 10.6, 5.4, 1H), 5.79 (ddd, J = 17.5, 10.3, 7.5, 1H), 5.36 - 5.13 (m, 4H), 4.1 1 (dddd, J = 8.1, 5.1, 4.3, 2.7, 2H), 3.95 - 3.78 (m, 8H), 2.98 - 2.77 (m, 2H), 2.42 (s, 3H), 1.95 - 1.66 (m, 2H).

Step 4: Synthesis of 2-[2-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)-ethyl]- 2, 5 -dihydro-furan

A solution of 2-(3-allyloxy-pent-4-enyl)-l,4-dimethoxy-3 -methyl- naphthalene (0.889 g, 2.73 mmol) and Grubbs catalyst 1 ^st generation (99 mg, 0.121 mmol, 0.05 eq) were heated at reflux for 2 h then cooled to rt and evaporated to dryness. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex / EtOAc: 85/15 to 65/35 in 10 CV) to afford the title compound as a colourless oil (0.749 g, Yield: 92%).

1H NM (300 MHz, CDC1 ₃ ) δ 8.10 - 7.96 (m, 2H), 7.52 - 7.39 (m, 2H), 5.95 (dd, J = 6.2, 1.7, 1H), 5.91 - 5.81 (m, 1H), 5.03 - 4.89 (m, 1H), 4.82 - 4.57 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.01 - 2.77 (m, 2H), 2.42 (s, 3H), 1.92 - 1.69 (m, 2H).

Step 5: Synthesis of 2-[2-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)-ethyl]- tetrahydro-furan-3 ,4-diol

To a solution of ADmix β (3.5 g, 1.4 g/mmol of substrate) in a 1 : 1 mixture of water and tBuOH (7.5 mL each) was added 2-[2-(l,4-dimethoxy-3-methyl- naphthalen-2-yl)-ethyl]-2,5-dihydro-furan (0.749 g, 2.5 mmol) and methanesulfonamide (14 mg, 0.15 mmol, 0.2 eq). The reaction was stirred overnight at rt and then diluted with water and EtOAc. The reaction was carefully quenched with sodium metabisulfite (2.3 g) and stirred for another 30 min. The organic layer was separated and washed with water and brine, dried on sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, nHex / EtOAc: 60/40 to 10/90 in 10 CV) to afford the title compound as a colourless oil (0.68 g, Yield: 82%).

1H NMR (300 MHz, CDC1 ₃ ) δ 8.03 (ddt, J = 5.7, 3.5, 2.6, 2H), 7.46 (dt, J = 9.9, 3.2, 2H), 4.41 (dd, J = 1 1.7, 5.5, 1H), 4.28 - 4.05 (m, 3H), 3.97 - 3.80 (m, 8H), 3.75 (dd, J = 9.5, 5.3, 1H), 3.65 (dt, J = 12.5, 5.4, 1H), 2.93 (qdd, J = 13.2, 9.1, 5.9, 2H), 2.46 - 2.41 (m, 3H), 2.00 - 1.80 (m, 2H).

Step 6: Synthesis of 2-[2-(l,4-dimethoxy-3-methyl-naphthalen-2-yl)-ethyl]- 3,4-bis-nitrooxy-tetrahydro-furan To a stirred solution of racemic 2-[2-(l ,4-dimethoxy-3-methyl-naphthalen- 2-yl)-ethyl]-tetrahydro-furan-3,4-diol (200 mg, 0.602 mmol), Bu ₄ NNO ₃ (404 mg, 1.32 mmol, 2.2 eq) and 2,6-di-tert-butyl-4-methylpyridine (271 mg, 1.32 mmol, 2.2 eq) in dry CH ₂ C1 ₂ (10 mL) cooled to -78°C was added dropwise a solution of trifluoromethansulfonic anhydride (205 μΐ _^ , 1.25 mmol, 2.1 eq) in dry CH ₂ C1 ₂ (3 mL). The reaction was stirred at -78°C for 1 h and left to go back to rt in 30 min. The reaction was quenched by addition of a saturated solution of NH ₄ C1 (5 mL) and the organic layer was separated, washed with water and brine, dried on sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP4, SNAP 100 column, EtOAc/nHex: 25/75 to 60/40 in 12 CV) to give: Fl : Compound 36, red oil (34 mg, Yield: 14%)

1H NM (300 MHz, CDC1 ₃ ) δ 8.09 (dd, J = 8.6, 5.1, 2H), 7.72 (dd, J = 5.6, 3.3, 2H), 5.71 - 5.57 (m, 1H), 5.30 - 5.16 (m, 1H), 4.40 (dd, J = 1 1.0, 6.0, 1H), 4.01 (td, J = 7.8, 4.0, 1H), 3.93 (dd, J = 1 1.0, 4.4, 1H), 2.92 - 2.66 (m, 2H), 2.22 (s, 3H), 2.08 - 1.91 (m, 2H), 1.91 - 1.72 (m, 1H).

¹³ C NMR (75 MHz, CDC1 ₃ ) δ 185.01, 184.53, 145.56, 143.91, 133.53, 133.52, 132.1 1, 132.04, 126.35, 126.29, 81.03, 77.87, 77.85, 77.61, 68.87, 31.27, 22.98, 12.62.

and the second diastereoisomer F2: Compound 37, pale yellow solid (30 mg, Yield: 13%)

1H NMR (300 MHz, CDC1 ₃ ) δ 8.13 - 8.05 (m, 2H), 7.75 - 7.68 (m, 2H), 5.74 - 5.65 (m, 2H), 4.22 - 4.09 (m, 3H), 4.07 - 4.00 (m, 1H), 2.87 (ddd, J = 12.7, 9.0, 6.8, 1H), 2.78 - 2.66 (m, 1H), 2.23 (s, 3H), 1.93 - 1.82 (m, 2H).

¹³ C NMR (75 MHz, CDC1 ₃ ) δ 185.02, 184.63, 145.59, 144.13, 133.53, 133.48, 132.12, 132.03, 126.30, 79.03, 78.89, 78.81, 67.80, 27.45, 23.41, 12.61.

Example 40

Intraocular pressure (IOP) lowering activity in hypertonic saline-induced IOP increase in rabbits. This animal model of elevated IOP was used for assessing the intraocular pressure (IOP) lowering activities of some compounds of the invention, timolol, dorzolamide and 5- isosorbide mononitrate.

Tested compounds:

- compounds (6), (20) and (25)

timolol and dorzolamide that are drugs commonly used for the treatment of glaucoma and ocular hypertension.

Isosorbide mononitrate (5-ISMN) that is a commonly used nitric oxide donor drug.

Timolol, dorzolamide and 5-ISMN were tested as reference compounds.

Adults male New Zealand White rabbits weighting 1.8-2.0 Kg were used in the experiments.

IOP was measured using a Tono-Pen XL prior to hypertonic saline injection (basal) and at 30, 60, 120 and 240 min thereafter. Vehicle (5% cremophor-EL; 0.3% DMSO; 0.2mg/ml BAK in PBS pH 6.0) and all the tested compounds dissolved in the vehicle were instilled as eye drops immediately after hypertonic saline injection. Eyes were randomly assigned to different treatment groups. Vehicle and the tested compounds were directly instilled into the conjunctiva pocket at the desired doses. One drop of 0.4 % oxybuprocaine hydrochloride (Novesine, Sandoz) was instilled in each eye immediately before each set of pressure measurements.

Results are reported in Table 6, the ocular hypotensive activities of the tested compounds are expressed as IOP change at 60 and 120 minutes after topical administration versus vehicle and versus the basal IOP.

As shown in Table 1, the IOP-lowering effect of the compounds of the invention is comparable to that of timolol and higher than that of dorzolamide. Furthermore, 2 hours after instillation the IOP-lowering effect in the groups treated with the compounds of the invention is higher than in the groups treated with timolol, dorzolamide and 5-ISMN, showing prolonged IOP-lowering effect of the compounds of the invention with respect to the reference compounds.

The experimental results revealed that a potent ocular hypotensive effect and a prolonged action were obtained by using the compounds of the invention.

Example 41

Intraocular pressure (IOP) lowering activity in ocular normotensive New Zealand rabbits.

Tested compounds:

- compound (6)

timolol that is a drug commonly used for the treatment of glaucoma and ocular hypertension.

Isosorbide mononitrate (5-ISMN) that is a commonly used nitric oxide donor drug.

Timolol, dorzolamide and 5-ISMN were tested as reference compounds.

Adults male New Zealand White rabbits weighting 1.8-2.0 Kg were used in the experiments.

IOP was measured using a pneumatonometer 30 CLASSIC™ before topical application (basal) and a different time point (30, 60, 120, 240 and 300 min) thereafter. Vehicle (5% cremophor-EL; 0.3% DMSO; 0.2mg/ml BAK in PBS pH 6.0) or tested compounds dissolved in the vehicle were instilled as eye drops into the conjunctiva pocket. Eyes were randomly assigned to different treatment groups. One drop of 0.4 % oxybuprocaine hydrochloride (Novesine, Sandoz) was instilled in each eye immediately before each set of pressure measurements.

The test results are reported in Table 7, the ocular hypotensive activity is expressed as IOP changes at 30, 60, 120 and 300 minutes after topical administration versus vehicle and versus IOP at basal.

The experiment results showed that, 5 hours after instillation the compound of the invention maintained its ocular hypotensive activity and the IOP-lowering effect in the group treated with the compound of the invention is higher than in the groups treated with timolol and 5-ISMN, demonstrating prolonged IOP-lowering effect of the compound of the invention with respect to the reference compounds.

The experimental results revealed that a prolonged IOP-lowering effect was obtained by using the compounds of the invention.

Table 7

Intraocular pressure (IOP) lowering activity in ocular normotensive New Zealand rabbits

ΔΔ (mmHg) ΔΔ (mmHg) ΔΔ (mmHg) ΔΔ (mmHg)

Compound

30 min 60 min 120 min 300 min

Compound 6

-1.8 ± 0.4 -1.6 ± 0.3 -1.3 ± 0.5 -1.5 ± 0.4 NCX 1443

timolol -0.4 ± 0.4 -0.7 ± 0.4 -0.9 ± 0.4 -0.05 ± 0.4

ISMN -1.5 ± 0.3 -1.7 ± 0.4 -0.6 ± 0.4 -0.8 ± 0.4