Use of nitric oxide releasing compounds in the treatment of chronic pain

FIELD OF THE INVENTION

The present invention relates to the use of nitric oxide releasing antioxidant compounds for the treatment of chronic pain, in particular chronic neuropathic pain. The present invention also relates to compounds having an improved effectiveness in alleviation or/and in the treatment of chronic neuropathic pain.

BACKGROUND OF THE INVENTION

It is known that neuropathic pain is a form of chronic pain arising from a damage or disease of the central or peripheral nervous system. Neuropathic pain comprises a series of painful symptomatologies such as diabetic neuropathic pain, painful post-infarct syndrome, pain caused by chemotherapeutic treatment or pain arising from infections by viral agents, for example herpes, Herpes zoster, etc.

Neuropathic pain generally affects patients for many years, and is a social problem in that symptoms chronicity induces in subjects serious psychological stress.

In the last twenty years, research on neuropathic pain pathogenesis has achieved significant advances. Studies carried out on human and animal models of neuropathic pain have shown that central nervous system reacts to algogen stimuli with a series of biochemical and physiopathologic responses. This ability of the central nervous system to functionally and morphologically adapt to algogen stimuli is known as neuroplasticity and plays an essential role in inducing onset or in maintaining the painful symptomatology.

Carbamazepine, that has been widely used in clinical studies, has shown to be active in treating trigeminal neuralgia, diabetic neuropathic pain, and post-herpetic neuralgia. The administration of this drug has the drawback to present side effects such as somnolence, dizziness, ataxy, nausea and vomiting, thus limiting its use (Martindale XXXth Ed, page 342) .

In the last years, other drugs for the treatment of neuropathic pain have been used. Among these gabapentin, pregabalin and tiagabine can be mentioned as being active as analgesic drug for treating neuropathic pain, mainly against diabetic neuropathic pain and post-herpetic pain. However, also in this case, high dosages are needed, short duration of action and sometime serious adverse effects are important documented drawbacks associated with these compounds. For example somnolence, weariness, obesity, etc. have been observed following gabapentin treatment (Martindale XXXth Ed, page 374) . Despite these disadvantages, no new classes of analgesics have been developed recently; there is clearly a need for additional therapies for the alleviation or/and treatment of chronic neuropathic pain.

It has now been surprisingly found that nitric oxide releasing derivatives of antioxidant compounds have analgesic activities and they are effective as analgesic drugs in the treatment of chronic neuropathic pain.

It has been further surprisingly found that the nitrooxyderivatives of the present invention show an enhanced therapeutic effect in the treatment of neuropathic pain when used in combination with analgesic therapeutic agents compared to the use of either agent alone.

The activity of natural phenolic acids such as ferulic, caffeic, vanillic and cumaric acids as antioxidant drugs is known (Handbook of Antioxidants-Second Edition, 2002). Another class of known antioxidant drugs is represented by hydroquinones (Martindale XXXth Ed, page 1115) .

WO 02/092072 discloses that the nitrooxyderivates of ferulic acid are able to prevent the deposition of the amyloid plaques and to reduce the neurodegenerative process and therefore they can be used for the prevention or treatment of Alzheimer disease.

WO 2005/065361 discloses that nitrooxyderivatives of caffeic acid, resveratrol and phtahalic acid have antineoplastic properties . WO 01/12584 discloses the antioxidant properties of the 4- nitroxybutyl ester of ferulic acid; the document also discloses the use of the nitrooxyderivative for the treatment of oxidative stress and endothelial dysfunctions. However, neither of these patents describes the use of these compounds as specific analgesics for the treatment of chronic pain or chronic neuropathic pain.

WO 03/000642 discloses that the combination of nitric oxide releasing compounds with drugs for the treatment of chronic pain shows a synergic effect and therefore the use of these combinations for the treatment of chronic pain allows to reduce the amount of analgesic compound and consequently the side effects are reduced. WO 03/000642 does not disclose the analgesic properties of the nitrooxyderivatives of antioxidant compounds .

An object of the present invention is the use for the treatment of the chronic pain of compounds of formula (I)

( D or pharmaceutically acceptable salts or stereoisomers thereof, wherein in formula (I) m is an integer equal to 0 or 1 ;

Y ¹ is -CH=CH- (CH2) mi-/ wherein m ¹ is an integer from 0 to 3, or - (CH ₂ ) _m 2-, wherein m ² is an integer from 1 to 3; preferably m ¹ is 0, preferably m ² is 2 ;

Ri, R2, R3, R4 are independently selected from H, OH, -OR ₅ wherein R ₅ is a straight or branched (C1-C10) -alkyl, straight or branched C1-C20 alkyl, preferably -OR ₅ is -OCH ₃ , with the proviso that at least one of Ri, R ₂ , R3, R4 is not H; X is -OC(O)-, -OC(O)O-, -C(O)O-, -C(O)NR ₆ -, -C(O)S- wherein R ₆ is H or a (Ci-C ₅ ) -alkyl, preferably R ₆ is H or -CH ₃ ; Y is a bivalent radical having the following meaning: a) straight or branched C1-C20 alkylene optionally substituted with one or more substituents independently selected from halogen atoms, hydroxy, -ONO ₂ or T, wherein T is -OC(O)-(Ci- Cio alkyl) -ONO ₂ or -0(Ci-Ci ₀ alkyl) -ONO ₂ ; preferably Y is a (C1-C10) alkylene or a (C1-C10) alkylene substituted with a - ONO ₂ ; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains Ti, wherein Ti is straight or branched C1-C10 alkyl, Ti is preferably CH ₃ ; b)

wherein n is an integer from 0 to 20, and n ¹ is an integer from 1 to 20, preferably n is 0 or 1, preferably n ¹ is an integer from 1 to 5; d)

wherein

Xi is -OC(O)- or -C(O)O-, n ² is an integer from 1 to 3 and R ² is H or CH ₃ ; n ¹ is as defined above and n ² is an integer from 0 to 2 ; e)

wherein :

Y ² is -CH ₂ -CH ₂ - (CH ₂ ) _n 2-; or -CH=CH- (CH ₂ ) _n 2- ;

Xi is -OC(O)- or -C(O)O-, n ² is an integer from 1 to 3 and R ² is H or CH ₃ ; when Y is one of the bivalent radicals selected from b) to e) , the -ONO ₂ group is bound to - (CH ₂ ) _n i- group; when Y is one of the bivalent radicals selected from b) to e) , m is 1 ;

g ⁾

wherein X2 is -O- or -S- or NRε- wherein Re is as above defined, preferably X2 is -O-; n is an integer from 1 to 6, preferably from 1 to 4, more preeferably n ³ is 1, R ² is as defined above, preferably R ² is H; h)

wherein : n ⁴ is an integer from 0 to 10; n ⁵ is an integer from 1 to 10; R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same or different, and are H or straight or branched Ci-C ₄ alkyl, preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ are H; wherein the -ONO2 group is linked to

I

-[C] ₅

I ⁿ wherein n ⁵ is as defined above;

Y ³ is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from

(Yii: (Y12: (Y13), preferably Y ³ is (Y4) or (Y13) .

Preferably in formula (I) : Ri is -OCH ₃ , R ₂ is OH, R ₃ and R ₄ are H, m is 0 or m is 1 and Y ¹ is -CH=CH- (CH ₂ ) _m i/ wherein m ¹ is 0, or

Ri and R2 are OH, R ₃ and R ₄ are H, m is 0 or m is 1 and Y ¹ is -

CH=CH- (CH ₂ ) _m i, wherein m ¹ is 0, or Y ¹ is -(CH ₂ ) _m 2- wherein m ² is

2; or Ri, R ₃ and R ₄ are H and R ₂ is OH, m is 0 or m is 1 and Y ¹ is -

CH=CH- (CH ₂ ) mi, wherein m ¹ is 0 or , or Y ¹ is -(CH ₂ ) _m 2- wherein m ² is 2;

Ri, R ₂ and R ₃ are OH, R ₄ is H and m is 0

Ri and R ₃ are -OCH ₃ , R ₂ is OH and R ₄ is H, m is 0 ; Ri is OH, R ₂ is -OCH ₃ , R ₃ and R ₄ are H and m is 0 ;

Ri is OH, R ₂ and R ₃ are H, R ₄ is -OCH ₃ , m is 0 ;

Ri and R ₄ are OH, R ₂ and R ₃ are H, m is 0

Ri and R ₃ are H and R ₂ and R ₄ are OH, m is 0.

The term "C1-C20 alkylene" as used herein refers to branched or straight C1-C20 hydrocarbon chain, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.

The term "C1-C10 alkyl" as used herein refers to branched or straight chain alkyl groups comprising 1 to 10 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like. The term "cycloalkylene" as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C1-C10) -alkyl, preferably CH ₃ . Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines. The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile or tetrahydrofuran with the corresponding organic or inorganic acids. Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.

The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are

also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) .

While the natural antioxidant drugs have no effect on the treatment of neuropathic pain, the correspondent nitrooxyderivatives of formula (I) have shown to be active.

Another object of the present invention relates to combinations comprising a compound of formula (I) and at least one therapeutic agent used to treat neuropathic pain selected between the group of gabapentin, tiagabine and pregabalin and their use for treating chronic pain, in particular chronic neuropathic pain.

The combinations of the present invention are related to equimolar mixtures of the nitrooxyderivative of antioxidant drug of formula (I) and one analgesic drug selected from the group gabapentin, pregabalin and tiagabine. These combinations have proved to have a synergistic effect that has significant advantages in pharmacological activity. In particular, it has been recognized that the combinations have an improved pharmacological profile, with prolonged analgesic activity. Thus, the therapeutic efficacy in the treatment of the neuropathic pain of this combination of agents is enhanced relatively to the use of either agent alone. More particularly, the therapeutic efficacy is synergistically enhanced. Another object of the invention relates to kits comprising at least a compound of formula (I) and at least one analgesic drug selected from the group gabapentin, pregabalin and tiagabine.

The daily dose of active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. Usually, total daily dose may be in amounts preferably from 10 to 5000 mg of each compound.

Preferred combinations include 150 to 1500 mg of nitrooxyderivatives of formula (I) and 100 to 1000 mg of an analgesic drug selected between the group of gabapentin, tiagabine and pregabalin. The dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state .

Another object of the present invention relates to compounds of formula (I)

(I) or pharmaceutically acceptable salts or stereoisomers thereof, wherein in formula (I) m is an integer equal to 0 or 1 ;

Y ¹ is -CH=CH- (CH2) _m i/ wherein m ¹ is an integer from 0 to 3, or - (CH2) _m 2- wherein m2 is an integer from 1 to 3; preferably m ¹ is 0, preferably m ² is 2 ;

Ri, R ₂ , R3, R4 are independently selected from H, OH, -OR ₅ wherein R ₅ is a straight or branched (C1-C10) -alkyl, straight or

branched C1-C20 alkyl, preferably -OR ₅ is -OCH ₃ , with the proviso that at least one of Ri, R2, R3, R4 is not H; X is -OC(O)-, -OC(O)O-, -C(O)O-, -C(O)NR ₆ -, -C(O)S- wherein R ₆ is H or a (Ci-C ₅ ) -alkyl, preferably R ₆ is H or -CH ₃ ; Y is a bivalent radical having the following meaning: b) straight or branched C1-C20 alkylene optionally substituted with one or more substituents independently selected from halogen atoms, hydroxy, -ONO2 or T, wherein T is -OC(O) (Ci- Cio alkyl) -ONO ₂ or -0(Ci-Ci ₀ alkyl) -ONO ₂ ; preferably Y is a (C1-C10) alkylene or a (C1-C10) alkylene substituted with a - ONO ₂ ; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains Ti, wherein Ti is straight or branched C1-C10 alkyl, Ti is preferably CH ₃ ; b)

wherein n is an integer from 0 to 20, preferably n is an integer from 0 to 5, n ¹ is an integer from 1 to 20, preferably n ¹ is an integer from 1 to 5; d)

wherein

Xi is -OC(O)- or -C(O)O-, n ² is an integer from 1 to 3 and R ² is H or CH ₃ ; n ¹ is as defined above and n ² is an integer from 0 to 2 ; e

wherein :

Y ² is -CH ₂ -CH ₂ - (CH ₂ ) _n 2-; or -CH=CH- (CH ₂ ) _n 2- ; Xi is -OC(O)- or -C(O)O-, n ² is an integer from 1 to 3 and R ² is H or CH ₃ ; when Y is one of the bivalent radicals b) to e) , the -ONO ₂ group is bound to the - (CH ₂ ) _n i- group; when Y is one of the bivalent radicals mentioned under b) to e) , m is 1 ; g ⁾

wherein X ₂ is -0- or -S- or NRε- wherein Re is as above defined, preferably X ₂ is -0-, n ³ is an integer from 1 to 6, preferably from 1 to 4, R ² is as defined above, preferably R ² is H; h)

wherein : n ⁴ is an integer from 0 to 10, preferably n ⁴ is 1 ; n ⁵ is an integer from 1 to 10, preferably n ⁵ is an integer from

1 to 5;

R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ are H; wherein the -ONO2 group is linked to

I wherein n ⁵ is as defined above;

Y ³ is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from

⁽ Yi: (Y2: (Y3) (Y4: (Y5)

(YIl) (Y12) (Y13) excluding:

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl ester; (E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl amide; (E) -3- (3, 5-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 5-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl amide;

(E) -3- (3-hydroxy-4-methoxy-phenyl) -2-propenoic acid 3- (nitrooxy-methyl) phenyl ester;

(E) -3- (3-hydroxy-4-methoxy-phenyl) -2-propenoic acid 3- (nitrooxy-methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl ester; (E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl amide;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 4-

(nitrooxy) butyl ester; (E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 3-

(nitrooxy-methyl) phenyl ester;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 6-

(nitrooxy-methyl) -2-pyridinylmethylester hydrochloride;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 2-methoxy- 4- [ (IE) -3- [4- (nitrooxy) butoxy] -3-oxo-l-propenyl] phenyl ester;

(nitrooxy-methyl) phenyl-2-hydroxybenzoate;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy methyl) phenyl ester;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 2- (nitrooxy methyl) phenyl ester;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 4- (nitrooxy methyl) phenyl ester;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy methyl) phenyl amide; (E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 2- (nitrooxy methyl) phenyl amide;

(E) -3- (3, 4-Dihydroxy-phenyl) -2-propenoic acid 4- (nitrooxy methyl) phenyl amide;

(E) -3- (3, 5-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 5-Dihydroxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl amide;

(E) -3- (3-hydroxy-4-methoxy-phenyl) -2-propenoic acid 3-

(nitrooxy-methyl) phenyl ester; (E) -3- (3-hydroxy-4-methoxy-phenyl) -2-propenoic acid 3-

(nitrooxy-methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl ester;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 3- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 2- (nitrooxy- methyl) phenyl amide;

(E) -3- (3, 4-Dimethoxy-phenyl) -2-propenoic acid 4- (nitrooxy- methyl) phenyl amide;

(E) -3- (4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 4-

(nitrooxy) butyl ester;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 3-

(nitrooxy-methyl) phenyl ester;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 6-

(nitrooxy-methyl) -2-pyridinylmethylester hydrochloride;

(E) -3- (4-hydroxy-3-methoxy-phenyl) -2-propenoic acid 2-methoxy-

4- [ (IE) -3- [4- (nitrooxy) butoxy] -3-oxo-l-propenyl] phenyl ester;

3- (nitrooxy-methyl) phenyl-2-hydroxybenzoate .

The preferred compounds of formula (I ^' of the present invention are:

⁽ i: (2)

(25)

(26)

(27) (2!

(29) (3o:

:3i) :32)

:33)

:34) (35:

:36) (37;

(4o: (4i:

(4i: (43:

(44: :45)

(45: 47)

(4! :49)

:52) (53:

:54) (55:

(56: :57)

:58) (59:

(6i: :63)

(64; :65)

(66;

(67;

8) :69)

:69) [ID

(72;

:73)

(74;

:76)

(77:

:78)

:80)

:82)

:84) :85)

:86) (87)

(88) (89:

:90) (9i:

:92) (93:

:ioo) (ioi:

:io2) (103:

:io4) (105:

:io6) (107;

:io8) (109;

:iio)

:ii9) (i2o:

:i3i)

The compounds of general formula (I) of the present invention are synthesized by the synthetic procedures mentioned hereunder.

Experimental part

1) The compounds of general formula (I) as above defined wherein X is -C(O)-O, -C(O)-S, -C(O)-NR ⁶ can be obtained: i) by reacting a compound of formula (III)

(III) wherein Ri, R2, R3, R4, Y ¹ and m are as above defined; W is -OH, Cl, or -OC(O)R ⁸ wherein R ⁸ is R ⁶ , as above defined, or Act, wherein Act is a carboxylic acid activating group used in peptide chemistry as:

;

with a compound of formula (V) Z-Y-Q wherein Y is as above defined, Z is HXi or Zi, wherein Xi is O, S, NR ⁸ wherein R ⁸ is as above defined and Zi is selected from the group consisting of: chlorine, bromine, iodine, mesyl, tosyl; Q is -ONO ₂ or Z _x and ii) when Q is Zi, by converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is Ci-Cio alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate

The reaction of a compound of formula (III) wherein W = OH, Ri, R ₂ , R3, R4, Y ¹ and m are as above defined, with a compound of formula (V) wherein Y and Q are as above defined, Z is HXi wherein Xi is as above defined may be carried out in presence of a dehydrating agent as dicyclohexylcarbodiimide (DCC) or

N' - (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride

(EDAC) and a catalyst, such as N, N-dimethylamino pyridine

(DMAP) or in presence of other known condensing reagents such as O- (7-azabenzotriazol-l-yl) -N, N, N ' , N ' -tetramethyluronium hexafluorophosphate (HATU) .

The reaction is carried out in an inert organic dry solvent such as N, N' -dimethylformamide, tetrahydrofurane, benzene, toluene, dioxane or a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C to 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (III) wherein W = OH are commercially available .

The reaction of a compound of formula (III) wherein W = - OC(O)R ⁸ wherein R ⁸ is as above defined, with a compound of formula (V) wherein Y is as above defined, Z is -OH and Q is - ONO2 may be carried out in presence of a catalyst, such as N, N- dimethylamino pyridine (DMAP) . The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofurane, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C and 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (III) wherein W = -OC(O)R ⁶ may be obtained from the corresponding acids wherein W = OH by reaction with a chloroformate such as isobutylchloroformate, ethylchloroformate in presence of a non-nucleophilic base such as triethylamine in an inert organic solvent such as N, N'- dimethylformamide, tetrahydrofurane or a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C and 40 ⁰ C. The reaction is completed within a time range from 1 to 8 hours . The reaction of a compound of formula (III) wherein W = Act with a compound of formula (V) wherein Y is as above defined, Z is -OH and Q is -ONO2 may be carried out in presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures in the range between 0 ⁰ C and 65°C or in a double phase system H ₂ O/Et2θ at temperatures in the range between 20 ⁰ C and 40 ⁰ C; or in the presence of DMAP and a Lewis acid such as Sc(OTf) ₃ or Bi(OTf) ₃ in solvents such as DMF or CH2CI2. The compounds of formula (III) wherein W = -OC (O) Act may be obtained from the corresponding acids wherein W = OH as know in literature.

The reaction of a compound of formula (III) wherein W = OH with a compound of formula (V) wherein Y is as above defined,

Z is Zi and Q is -ONO2 may be carried out in presence of a organic base such as 1, 8-diazabiciclo [5.4.0 ] undec-7-ene (DBU), N, N-diisopropylethylamine, diisopropylamine or inorganic base such as alkaline-earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate, in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile or a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C to 40 ⁰ C, preferably from 5°C to 25°C. The reaction is completed within a time range from 1 to 8 hours. When Zi is chosen among chlorine or bromine the reaction is carried out in presence of a iodine compound such as KI .

The reaction of a compound of formula (III) wherein W = Cl with a compound of formula (V) wherein Y is as above defined, Z is -OH and Q is -ONO2 may be carried out in presence of a of an organic base such as N, N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane or a polyhalogenated aliphatic hydrocarbon at a temperature from - 20°C to 40°C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (III) wherein W = Cl may be obtained from the corresponding acids wherein W = OH by reaction with thionyl chloride, oxalyl chloride or halides of P ¹¹¹ or P ^v in inert solvents such as toluene, chloroform or DMF. The compounds of formula HO-Y-ONO2, wherein Y is as above defined can be obtained as follows. The corresponding diol derivative, commercially available or synthesized as known in literature, is converted into HO-Y-Zi, wherein Zi is as above defined, by known reactions, for example by reaction with thionyl chloride, oxalyl chloride, halides of P ¹¹¹ or P ^v , mesyl chloride or tosyl chloride, in inert solvents such as toluene,

chloroform, DMF, etc. The conversion to the nitro derivative is carried out as above described. Alternatively the diol derivative can be nitrated by reaction with nitric acid and acetic anhydride in a temperature range from -50 ⁰ C to 0 ⁰ C according to methods known in literature.

Alternatively the alcohol of formula HO-Y-ONO2 wherein Y is a straight or branched C1-C20 alkyl substituted by a ONO2 group having the following formula -Y ² - (CHONO2) -CH ₂ - can be obtained from the alcohol of formula HO-Y ² -CH=CH ₂ by treatment with iodine and silver nitrate in acetonitrile at a temperature between -20 ⁰ C and 8O ⁰ C.

The compounds of formula Z1-Y-ONO2, wherein Y and Zi are as above defined can be obtained from the halogen derivative Zi-Y- HaI, commercially available or synthesized according to methods well known in literature, by conversion to the nitro derivative as above described.

The compounds of formula H-X-Y-Zi, wherein X, Y and Zi are as above defined can be obtained from the hydroxyl derivative H- X-Y-OH, commercially available or synthesized according to methods well known in literature, by known reactions, for example by reaction with thionyl chloride, oxalyl chloride, halides of P ¹¹¹ or P ^v , mesyl chloride or tosyl chloride in inert solvents such as toluene, chloroform, DMF, etc.

2) The compound of general formula (I) as above defined wherein X is -C(O)O- and Y is alkyl C4 can be obtained: i) by reacting a compound of formula (VI)

(VI) wherein Ri, R2, R3, R4, Y ¹ and m are as above defined, with tetrahydrofurane in presence of triphenylphosphine and tetrabromomethane at a temperature from -20 ⁰ C to 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours and ii) by converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source as above described.

3) The compounds of general formula (I) as above defined wherein X is -OC(O)- can be obtained: i) by reacting a compound of formula (VII)

(VI I ) wherein

Ri, R2, R3, R4, Y ¹ and m are as above defined, with a compound of formula (VIII) W-C(O)-Y-Q wherein Y, Q and W are as above defined, and

ii) when Q is Z ₁ , by converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source as above described.

The reaction of a compound of formula (VII) wherein Ri, R2, R3, R ₄ , Y ¹ and m are as above defined, with a compound of formula (VIII) wherein Y, Q and W are as above defined, may be carried out as above described in 1) .

The compounds of formula W-C (O) -Y-ONO2 wherein Y is as above defined and W = OH can be obtained as follows. The corresponding alcohol derivative, commercially available, or synthesized by well known reactions, is converted to HO-C(O)- Y-Zi, wherein Zi is as above defined, by known reactions, for example by reaction with thionyl chloride, oxalyl chloride, halides of P ¹¹¹ or P ^v , mesyl chloride or tosyl chloride in inert solvents such as toluene, chloroform, DMF, etc. The conversion to the nitro derivative is carried out as above described. Alternatively the alcohol derivative can be nitrated by reaction with nitric acid and acetic anhydride in a temperature range from -50 ⁰ C to 0 ⁰ C according to methods well known in literature.

Alternatively the acids of formula HO-C(O)-Y-ONO ₂ wherein Y is a straight or branched C1-C20 alkyl substituted by a -ONO2 group having the following formula -Y ² - (CHONO2) -CH ₂ - can be obtained from the acid of formula HO-C (0) -Y ² -CH=CH ₂ by treatment with iodine and silver nitrate in acetonitrile at a temperature between -20 ⁰ C and 8O ⁰ C.

The compounds of formula W-C (0) -Y-ONO2 wherein Y is as above defined and W = Act can be obtained from the corresponding acid as known in literature. The compounds of formula W-C (0) -Y-ONO2 wherein Y is as above defined and W = Cl can be obtained from the corresponding acid as known in literature.

4) The compounds of general formula (I) as above defined wherein X is -OC(O)O- can be obtained: i) by reacting a compound of formula (VII) with a compound of formula (IX) Acti-C (0) -O-Y-Q wherein Y, Q are as above defined and Acti is as defined in (IVb) and (IVc), and ii) when Q is Zi, by converting the compound obtained in the step i) into nitro derivative by reaction with a nitrate source as above described.

The reaction of a compound of formula (VII) wherein Ri, R ₂ , R3, R4, Y ¹ and m are as above defined, with a compound of formula

(IX) wherein Y, Q and Acti are as above defined, may be carried out as above described in 1) .

The compounds of formula Acti-C (0) -0-Y-ONO ₂ wherein Y and Acti are as above defined can be obtained from the corresponding alcohol as known in literature.

Example 1

Synthesis of ferulic acid 4- (nitrooxy) butyl ester

A) Ferulic acid 4- (bromo) butyl ester

To a solution of ferulic acid (1 g, 5.15 mmol) in tetrahydrofurane (40 ml), triphenylphosphine (2.7 g, 10.3 mmol) and tetrabromomethane (3.41 g, 10.3 mmol) were added. The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the solvent was evaporated under vacuum. The crude residue was purified by silica gel chromatography, eluent n-hexane/ethyl acetate 7/3. The product

(0.77 g) was obtained as a yellow solid. (Yield 46%). M. p. =83-

88 ⁰ C B) Ferulic acid 4- (nitrooxy) butyl ester

A solution of compound A (0.8 g, 2.43 mmol) and silver nitrate (1.2 g, 7.29 mmol) in acetonitrile (50 ml) was stirred at 40 ⁰ C, in the dark, for 16 hours. The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 75/25. The product (0.4 g) was obtained as white powder (yield 53%). M.p.=63-64°C Example 2 Synthesis of ferulic acid 2- (nitrooxy) ethyl ester

C) Ferulic acid 2-bromoethyl ester

To a solution of ferulic acid (2 g, 10.3 mmol) in chloroform (50 ml) 2-bromoethanol (4.36 ml, 61.8 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0 ⁰ C and EDAC

(2.96 g, 15.45 mmol) was added. The reaction was stirred at room temperature for 6 hours. The solution was treated with water and chloroform, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage Horizon System), eluent n-hexane/ethyl acetate 72/28 The product (1.73 g) was obtained (yield 55.8%). D) Ferulic acid 2- (nitrooxy) ethyl ester A solution of compound C (0.240 g, 0.8 mmol) and silver nitrate (0.16 g, 0.96 mmol) in acetonitrile (15 ml) was heated at 120 ⁰ C for 240 sec. with Microwave Emrys™ Creator (Personal Chemistry) . The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage Horizon System) ,

eluent n-hexane/ethyl acetate 75/25. The product (0.127 g) was obtained as white powder (yield 56.4%) Example 3 Synthesis of vanillic acid 4- (nitrooxy) butyl ester

E) Vanillic acid 4- (bromo) butyl ester

To a solution of vanillic acid (1.5 g, 8.92 mmol) in tetrahydrofurane (100 ml), triphenylphosphine (4.7 g, 17.8 mmol) and tetrabromomethane (5.92 g, 17.8 mmol) were added.

The mixture was stirred at room temperature for 4 hours, then filtered and the solvent was evaporated under vacuum. The crude residue was purified by silica gel chromatography, eluent n-hexane/ethyl acetate 8/2. The product (2.44 g) was obtained as a solid. (Yield 90.4%). M.p.=83-88°C

F) Vanillic acid 4- (nitrooxy) butyl ester

A solution of compound E (0.285 g, 0.94 mmol) and silver nitrate (0.4 g, 2.3 mmol) in acetonitrile (15 ml) was heated at 115 ⁰ C for 900 sec. with Microwave Emrys™ Creator (Personal Chemistry) . The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 75/25. The product (0.117 g) was obtained as white powder (yield 43.7%)

Pharmacological Examples

The efficacy of nitrooxyderivatives of antioxidant compounds of formula (I) in the treatment of neuropathic pain was evaluated in the model of hyperalgesic responses following

chronic constriction injuries of the rat sciatic nerve. The pharmacological activity of the compounds of formula (I) was compared to that of the known analgesic drugs. The parent not- derivatized antioxidant drug was used as reference. The efficacy of the equimolar combination of compounds of formula

(I) and analgesic drugs selected between the group of gabapentin, tiagabine and pregabalin was also evaluated, on the same experimental model.

Example Fl

Effects of vehicle, ferulic acid 4- (nitrooxy) butyl ester, ferulic acid and gabapentin on hyperalgesic responses following chronic constriction injuries

Chronic constriction injury (CCI) -induced mechanical hyperalgesia in rats.

The method described by Bennet and Xie (1988) was generally followed. Rats were anesthetized with chloral hydrate (380 mg/kg ip, Sigma) . The right common sciatic nerve was exposed at the level of the middle of the tigh by blunt dissection through the biceps femoris. Proximal to the sciatic' s trifurcation, about 12 mm of nerve was freed of adhering tissue and four ligatures (3/0 silk suture) were tied loosely around it with about 1 mm spacings . Ligatures were tied such that the diameter of the nerve was only barely constricted. The desired degree of constriction retarded, but did not arrest, circulation through the superficial epineural vasculature. The incision was closed in layers. The experiments were then carried out 1 week after surgery. Mechanical hyperalgesia was determined with an analgesimeter

(Ugo Basile, Italy) , using the modified Randall-Selitto method. Briefly, a conical stylus with a hemispherical tip was places upon the middle of hind paw dorsum. The animal was

gently restrained and calibrated pressure of gradually increasing intensity was applied until the rat withdrew the hindpaw. Threshold pressure (g) of both hindpaws was determined every 15 minutes, with two measurements before the treatments (pretest) , and from 15 to 60 minutes after treatment. An arbitrary cut-off value of 240 g was adopted. Results I

Seven days after sciatic nerve ligation, the mechanical paw withdrawal threshold (PWT) of the CCI-lesioned ipsilateral paw (ipsi) was stable and significantly lower than that of the respective contralateral unlesioned paw (contra) . As reported in table I, the administration of ferulic acid 4- (nitrooxy) butyl ester significantly increased ipsi PWT to that observed following the administration of gabapentin at equal dose. Ferulic acid 4- (nitrooxy) butyl ester also enhanced PWT contralateral to the lesion side and differently from gabapentin did not induce any appreciable sedative effect. The effects of ferulic acid 4- (nitrooxy) butyl ester were also greater than that of ferulic acid. Table I.

PWT= Paw Withdrawal Threshold; sc= subcutaneous;

* p<0.05 vs vehicle or ferulic acid

Example F2

Effects of vehicle, ferulic acid 4- (nitrooxy) butyl ester or gabapentin alone or in combination on hyperalgesic responses following chronic constriction injuries

Results II

Table II shows the effects of ferulic acid 4- (nitrooxy) butyl ester, gabapentin and their combination. The administration of ferulic acid 4- (nitrooxy) butyl ester combined with gabapentin elicited greater effects as compared to gabapentin or ferulic acid 4- (nitrooxy) butyl ester administered alone. The combination elicited much longer response as compared to either drug alone being still fully effective 60 min after the administration, time at which the effects of individual drugs had completely disappeared. Table II.

PWT= Paw Withdrawal Threshold; sc= subcutaneous;

* p<0.05 vs respective vehicle; # p<0.05 vs other groups