WO2009156466A1 - Pharmaceutical compositions for the treatment of neurodegenerative diseases - Google Patents

Pharmaceutical compositions for the treatment of neurodegenerative diseases Download PDF

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WO2009156466A1
WO2009156466A1 PCT/EP2009/057959 EP2009057959W WO2009156466A1 WO 2009156466 A1 WO2009156466 A1 WO 2009156466A1 EP 2009057959 W EP2009057959 W EP 2009057959W WO 2009156466 A1 WO2009156466 A1 WO 2009156466A1
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alkyl
general formula
dithiol
compounds
group
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PCT/EP2009/057959
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French (fr)
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Giancarlo Santus
Piero Del Soldato
Anna Sparatore
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Ctg Pharma S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates

Definitions

  • Neurodegenerative diseases are characterized by a progressive and irreversible loss of neurons in specific regions of the brain.
  • the main neurodegenerative pathologies are Parkinson's disease, Alzheimer's disease, Huntington's chorea and the amyotrophic lateral sclerosis. They present a typical case history of neurodegeneration in anatomically or functionally related regions and include common and debilitating symptoms.
  • the pharmacologically available treatments for these diseases are symptomatic and they are not capable to modify the course and progression of the underlying disease.
  • Parkinson's disease is characterized by an extensive loss of dopaminergic neurons, the neurons responsible of dopamine's synthesis, and it is clear that this implies a deficit of dopamine having four principal features: bradikinesia, muscular stiffness, tremor at rest (usually not present with voluntary movements), abnormalities of postural position (walking and balancing disturbs) .
  • the drugs used in the treatment of Parkinson's disease include: dopaminergic drugs (.Levodopa), dopamine receptor agonists (bromocriptine, pergolide), muscarinic receptor antagonists (trihexyphenidyl, benzatropine) , drugs that cause the release of dopamine.
  • Levodopa a precursor of dopamine, in combination with a peripheral inhibitor of decarboxylases (benzaseride or carbidopa) represents the Standard treatment for Parkinson's disease. Moreover, levodopa, the most important and efficacious drug for the treatment of Parkinson's disease, could be responsible of severe contraindications such as accelerating the evolution of the disease itself.
  • Alzheimer's disease leads to a loss of cognitive functions and short term memory impairment, while memory of past events is relatively well preserved and its main characteristic is a gradual onset of the disease with a continuous progression.
  • One of the first approaches to treat this disease was the use of compounds precursors of acetylcholine synthesis, such as choline hydrochloride and lecithin, (that have not shown significant clinical activity) .
  • bethanechol with intracerebroventricular administration and cholinesterase inhibitors such as physostigmine (with mild memory improvements) and taurine (characterized by modest improvements and relevant side effects) have been evaluated and studied.
  • Drugs inhibitors of cholinesterase most recently used in therapy are galantamine, rivastigmine, eptastigmine.
  • Huntington's chorea is mainly an hereditary pathology characterized by a gradual onset of movement disorders and cognitive impairment during middle age.
  • oxidative stress represents a common pathogenetic factor for the various neurodegenerative pathologies. This condition is characterized by tissue reduced glutathione depletion.
  • the new H 2 S releasing compounds object of the present invention, can be used for the treatment of various neurodegenerative diseases such as for example Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis.
  • This invention also relates to processes for preparing these compounds and to related pharmaceutical compositions .
  • polysulfurated groups contained in compounds object of the present invention, contain 2 or more atoms of sulphur selected in the group of organic thiosulfonates or dithiole-thione derivatives such as 5-
  • A is a residue of a drug used in the field of neurodegenerative diseases, said drug belonging to one of the following classes: dopamine precursors such as for example levodopa, and dopa-decaboxylase inhibitors such as for example carbidopa, benserazide etc.; dopamine agonists such as for example bromocriptine, pergolide etc.;
  • MAO-B inhibitors such as, for example, selegiline, rasagiline etc.; cholinesterases inhibitors such as for example galantamine, rivastigmine, donezepil etc.; catechol 0-methyl transferase (COMT) inhibitors such as for example entacapone, tolcapone etc.; and antimuscarinics such as for example amantadine, biperidine, benzatropine, trihexylfenidyl etc.; wherein
  • X is a group capable to link to ⁇ Y or ⁇ W, selected from a group comprising -COO-; -0 ⁇ ; -CONH-; -OCO-; -OCOO-; -CO-; Y is zero; - (C n - ) alkyl-, - (C n - ) alkyl-CO-, -0- (C n O alkyl-0-, -00C- (C n OaIkVl-COO-; -0- (C n O alkyl-, -HN- (C n O alkyl-, -00C- (C n O alkyl-; - (C n O alkyl-0-CO- (C n - ) alkyl-; - (C n O alkyl-CO-0- (C n Oalkyl- wherein (C n Oalkyl and (C n O alkyl are straight or branched, and n'
  • R is a straight or branched alkyl, such as methyl, ethyl, propyl; alkenyl, alkinyl; alkylaryl, alkenylaryl, alkinylaryl; arylalkyl, arylalkenyl, arylalkinyl; or cycloalkyl, cycloalkenyl, cycloalkinyl; or aromatic and/or heterocyclic ring, all substituted or unsubstituted; or more in particular, as a further preferred embodiment,
  • W is a dithiole-thione derivative of formula:
  • Rl is -H; -COOH; -NH 2 ; -OH; -SH;
  • C n O alky1 and ( C n" ) alky1 are (CH 2 ) nA ⁇ , (CH 2 ) nA" respectively, wherein nA' and nA'', the same or different to each other, are 1- 10, and more preferably Y is selected from the group comprising - (CH 2 ) nA , -, - (CH 2 ) nA ⁇ -C0-, -0- (CH 2 ) nA , -0-, -00C- (CH 2 ) nA , -COO-; ⁇ 0- (CH 2 ) nA ' -, -HN- (CH 2 ) nA , -, -00C- (CH 2 ) nA , -; ⁇ (CH 2 ) nA ,-O-CO-(CH 2 ) nA ,,-; - (CH 2 ) nA
  • a further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention are compounds of general formula (I) wherein the group X-Y-W is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2- carboxyethyl) methanethiosulfonate, S- ( 2- aminoethyl ) methanethiosulfonate and S- (2- hydroxyethyl ) methanethiosulfonate .
  • a further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention are compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5-(p- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (4- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (3-thioxo-3H- l,2-dithiol-4-yl)benzoic acid, 4- (3-thioxo-3H-l, 2- dithiol-5-yl) benzoic acid, 1, 3-dithiol-2-thione-5- carboxylic acid, 3-thioxo-3H-l, 2-dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol-4-carboxylic acid.
  • the polysulfurated group W is selected from the group comprising di
  • a further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention are the compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising allyl disulfide, allyl trisulfide, allyl tetrasulfide derivatives.
  • a further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention are the compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising the allyl sulfide derivatives of the corresponding precursor having formula: 2- (2-allyldisulfanil) -ethanol, 3- (2- allyldisulfanil ) -propanoic acid, 2- (2- allyldisulfanil ) ethylamine .
  • neurodegenerative diseases such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis.
  • A is a residue of a drug used in the field of neurodegenerative diseases, said drug selected among antimuscarinic and NMDA receptor antagonists such as for example memantine, dexanabinol, remacemide etc. being X, Y and W as above defined, for the preparation of a pharmaceutical composition for preventing, treating or reducing neurodegenerative diseases such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis.
  • antimuscarinic and NMDA receptor antagonists such as for example memantine, dexanabinol, remacemide etc.
  • X, Y and W as above defined
  • the parent compound, the drug used in the field of neurodegenerative diseases, originating the residue A can be used in its original form or in a proper modification to allow the chemical manipulation with the moiety containing the polysulfurated group.
  • the residue A and the moiety containing the polysulfurated group (W) can be linked via different linking groups such as esters, amides, imides, sulfonamides, azo groups, carbamates, carbonates, anhydrides, acetals, thioacetals, etc.
  • Bi-functional linkers (X, Y), known to the skilled person in the field, (such as ethyl, propyl or butyl diols; diamines; hydroxy amines; etc.) can be optionally present when they are necessary to link the residue A to the polysulfurated group (W) .
  • the products can be used in racemic mixture or in form of single enantiomer.
  • Salts of organic thiosulfonates such as, for example, S- (2-carboxyethyl ) methanethiosulfonate, S- (2- aminoethyl ) methanethiosulfonate with the different derivatives above-described, are also part of the present invention.
  • salts of dithiolthiones such as, for example, 1, 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol-4- carboxylic acid with the different derivatives above- described are also part of the present invention.
  • the present invention it has been found that it is possible to link an organic polysulfurated group to the residue A for treating neurodegenerative diseases.
  • the resulting compounds have good bioavailability, increased safety and maintain good efficacy .
  • the main advantages of the compounds of the present invention are related to their biological activity.
  • compositions comprising at least one compound of the above-said derivative of the group A compounds (according to the present invention as for general formula (I) and the preferred compounds as described above) including salts thereof, as an active ingredient, moreover, as a further object of the present invention, in combination with pharmaceutically acceptable adjuvant (s) or carrier (s).
  • a further object of the present invention is the use as a medicament of compounds derivative according to general formula (I) and of the preferred compounds as described above.
  • a further object of the present invention is the use of compounds according to the present invention as for general formula (I), and of the preferred compounds as described above, for the preparation of pharmaceutical compositions, and the relevant corresponding method, for preventing, treating or reducing neurodegenerative diseases also in combination with other agents used for the treatment of neurodegenerative diseases.
  • the compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which will depend upon the route of administration and the nature of the disease to be treated.
  • compositions can be prepared by conventional methods, using compatible and pharmaceutically acceptable excipients or vehicles .
  • compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporaneous solutions, injectable, rectal, nasal, ocular, vaginal, transdermal preparations etc..
  • a preferred route of administration is the oral route .
  • neurodegenerative diseases such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis
  • Step 1 Preparation of 4- (3-thioxo-3H-l, 2-dithiol-4- yl) benzoic acid.
  • This product (ethyl 4-isopropyl benzoate, 940 mg; 5.16 mmol) is added dropwise to stirred melted sulfur (1.2 g) at 146°C and the reaction mixture is stirred at 220°C for 24 hours. The temperature is lowered to 110 0 C and 3 ml of toluene and 7 ml of acetone are added. After stirring the reaction mixture at room temperature for 4 h, unreacted sulphur is filtered and the obtained solution is evaporated to dryness. The residue is purified by column chromatography on silica gel, eluting with CH 2 Cl 2 -cyclohexane (6:4) to give a compound with m.p. 157.5-159.5°C .
  • Step 2 Preparation of L-dopa methyl ester hydrochloride .
  • L-Dopa 700 mg; 3.55 mmol
  • methanol 35 ml at 0°C under nitrogen.
  • SOCl 2 2.4 ml of SOCl 2 are added dropwise and, at the end, the reaction mixture is heated under reflux for 2 hours. After evaporation to dryness a white powder of the desired product is obtained.
  • Step 3 Preparation of methyl 3- (3, 4-dihydroxyphenyl) -2- (4- (3-thioxo-3H-l, 2-dithiol-4-yl) benzamido propanoate .
  • 1.5 eq. of 1-hydroxybenzotriazole (HOBt) monohydrate (185 mg) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) (1.2 eq.; 232 mg) and the product prepared in step 2 (200 mg; 0.8 mmol) are added to a solution of the compound prepared in step 1 (205 mg; 0.8 mmol) in anhydrous dimethylformamide (DMF) (4 ml) .
  • DMF dimethylformamide
  • Step 2 Preparation of methyl 3- (3, 4-dihydroxyphenyl) -2- (2- (methoxy-4- (3-thioxo-3H-l, 2-dithiol-5- yl)phenoxy) acetamido)propanoate .
  • 1-hydroxybenzotriazole (HOBt) monohydrate 185 mg, 1.5 eq.
  • l-ethyl-3- 3-dimethylaminopropyl
  • carbodiimide EDAC 232 mg, 1.2 eq.
  • 1-hydroxybenzotriazole (HOBt) monohydrate 185 mg, 1.5 eq.
  • l-ethyl-3- (3-dimethylaminopropyl) carbodiimide EDAC 232 mg, 1.2 eq.
  • 200 mg (0.8 mmol) of L-Dopa methylester hydrochloride prepared as in step 2 of example 1 are added to a solution of the compound prepared in step 1 (142.6 mg; 0.8 mmol) in 4 ml of anhydrous DMF .
  • the resulting suspension clears up after addition of triethylamine (TEA 0.22 ml, 2 eq.).
  • the reaction is maintained at room temperature for 24 hours under nitrogen.
  • Step 2 Preparation of methyl 2- (3- (allyldisulfanyl) propanamido) -3- (3, 4-dihydroxyphenyl )propanoate .
  • 1-hydroxybenzotriazole (HOBt) monohydrate 185 mg, 1.5 eq.
  • l-ethyl-3- (3-dimethylaminopropyl) carbodiimide EDAC 232 mg, 1.2 eq.
  • 200 mg (0.8 mmol) of L-Dopa methylester hydrochloride prepared as in step 2 of example 1 are added to a solution of the compound prepared in step 1 (142.6 mg; 0.8 mmol) in 4 ml of anhydrous DMF .

Abstract

New hybrid compounds that release H2S for the treatment of neurodegenerative diseases.

Description

TITIiB OF THE INVENTION
"Pharmaceutical compositions for the treatment of neurodegenerative diseases" Background of the invention This invention relates to new hybrid compounds that release H2S for the treatment of neurodegenerative diseases. Neurodegenerative diseases are characterized by a progressive and irreversible loss of neurons in specific regions of the brain. The main neurodegenerative pathologies are Parkinson's disease, Alzheimer's disease, Huntington's chorea and the amyotrophic lateral sclerosis. They present a typical case history of neurodegeneration in anatomically or functionally related regions and include common and debilitating symptoms. Presently the pharmacologically available treatments for these diseases are symptomatic and they are not capable to modify the course and progression of the underlying disease.
Parkinson's disease is characterized by an extensive loss of dopaminergic neurons, the neurons responsible of dopamine's synthesis, and it is clear that this implies a deficit of dopamine having four principal features: bradikinesia, muscular stiffness, tremor at rest (usually not present with voluntary movements), abnormalities of postural position (walking and balancing disturbs) . The drugs used in the treatment of Parkinson's disease include: dopaminergic drugs (.Levodopa), dopamine receptor agonists (bromocriptine, pergolide), muscarinic receptor antagonists (trihexyphenidyl, benzatropine) , drugs that cause the release of dopamine.
Levodopa, a precursor of dopamine, in combination with a peripheral inhibitor of decarboxylases (benzaseride or carbidopa) represents the Standard treatment for Parkinson's disease. Moreover, levodopa, the most important and efficacious drug for the treatment of Parkinson's disease, could be responsible of severe contraindications such as accelerating the evolution of the disease itself.
Alzheimer's disease leads to a loss of cognitive functions and short term memory impairment, while memory of past events is relatively well preserved and its main characteristic is a gradual onset of the disease with a continuous progression. One of the first approaches to treat this disease was the use of compounds precursors of acetylcholine synthesis, such as choline hydrochloride and lecithin, (that have not shown significant clinical activity) . Later on, bethanechol, with intracerebroventricular administration and cholinesterase inhibitors such as physostigmine (with mild memory improvements) and taurine (characterized by modest improvements and relevant side effects) have been evaluated and studied. Drugs inhibitors of cholinesterase most recently used in therapy are galantamine, rivastigmine, eptastigmine. Huntington's chorea is mainly an hereditary pathology characterized by a gradual onset of movement disorders and cognitive impairment during middle age.
If the onset of symptoms happens before age 20 the choreic movements are less pronounced while bradikinesia and dystonia predominate.
Subjects affected by the disease become often irritable, anxious and depressed; during 15-30 years this pathology leads to total disability.
The treatment is purely symptomatic; presently there are no products that slow down the progression of the disease, and many drugs may compromise the patient's functions due to the side effects. Mainly anxiolytic benzodiazepines, neuroleptics and drugs that reduce dopamine's amount are used. As recently evidenced (Valko M et al. "Free radicals and antioxidants in normal physiological functions and human disease".
Int J Biochem Cell Biol. 2007;39 (1) : 44-84.) oxidative stress represents a common pathogenetic factor for the various neurodegenerative pathologies. This condition is characterized by tissue reduced glutathione depletion.
Several side effects are related to the use of conventional drugs used for the treatment of neurodegenerative diseases. It remains therefore in the field of neurodegenerative diseases the need to improve tolerability reducing the side effects and the need to increase the clinical activity of the drugs presently used. Summary of the invention Object of the present invention are new compounds that release H2S capable not only to eliminate or at least to reduce the side effects of the parent compounds, but also to improve the pharmacological activity thereof.
In particular, it has been found that the new H2S releasing compounds, object of the present invention, can be used for the treatment of various neurodegenerative diseases such as for example Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis. This invention also relates to processes for preparing these compounds and to related pharmaceutical compositions .
In particular the polysulfurated groups, contained in compounds object of the present invention, contain 2 or more atoms of sulphur selected in the group of organic thiosulfonates or dithiole-thione derivatives such as 5-
(p-hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (4- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (3-thioxo-3H- l,2-dithiol-4-yl)benzoic acid, 4- (3-thioxo-3H-l, 2- dithiol-5-yl) benzoic acid, 1, 3-dithiol-2-thione-5- carboxylic acid, 3-thioxo-3H-l, 2-dithiole-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiole-4-carboxylic acid or allylsulfides .
Description of the invention Object of the present invention are compounds that release H2S having general formula (I) :
A-X-Y-W (I) wherein
A is a residue of a drug used in the field of neurodegenerative diseases, said drug belonging to one of the following classes: dopamine precursors such as for example levodopa, and dopa-decaboxylase inhibitors such as for example carbidopa, benserazide etc.; dopamine agonists such as for example bromocriptine, pergolide etc.;
MAO-B inhibitors such as, for example, selegiline, rasagiline etc.; cholinesterases inhibitors such as for example galantamine, rivastigmine, donezepil etc.; catechol 0-methyl transferase (COMT) inhibitors such as for example entacapone, tolcapone etc.; and antimuscarinics such as for example amantadine, biperidine, benzatropine, trihexylfenidyl etc.; wherein
X is a group capable to link to ~Y or ~W, selected from a group comprising -COO-; -0~ ; -CONH-; -OCO-; -OCOO-; -CO-; Y is zero; - (Cn- ) alkyl-, - (Cn- ) alkyl-CO-, -0- (CnO alkyl-0-, -00C- (CnOaIkVl-COO-; -0- (CnO alkyl-, -HN- (CnO alkyl-, -00C- (CnO alkyl-; - (CnO alkyl-0-CO- (Cn- ) alkyl-; - (CnO alkyl-CO-0- (CnOalkyl- wherein (CnOalkyl and (CnO alkyl are straight or branched, and n' and n'', the same or different to each other, are 0-10; W is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates or an allyl sulphide derivative: more in particular, as a further preferred embodiment, W is an organic thiosulfonate moiety having formula:
-S-SO2-R (II) wherein -S-SO2-R is linked to A-Y-; R is a straight or branched alkyl, such as methyl, ethyl, propyl; alkenyl, alkinyl; alkylaryl, alkenylaryl, alkinylaryl; arylalkyl, arylalkenyl, arylalkinyl; or cycloalkyl, cycloalkenyl, cycloalkinyl; or aromatic and/or heterocyclic ring, all substituted or unsubstituted; or more in particular, as a further preferred embodiment,
W is a dithiole-thione derivative of formula:
Figure imgf000008_0001
wherein
Z is S (sulphur) and at least 1 Z is C=S (thione), m is 0, 1-10; T is:
-OOC-; or
Figure imgf000008_0002
wherein
Rl is -H; -COOH; -NH2; -OH; -SH;
R2 is hydrogen; -COOH; alkyl, alkenyl, alkynyl; aryl; fluoro, chloro, bromo; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano; nitro; acyl; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur; or more in particular, as a further preferred embodiment, W is an allyl sulfide derivative of formula: CH2=CH- (CpO alky1- (S)n,'- (Cp- ) alkyl-R3 (V) wherein (Cp<)alkyl and (CP")alkyl are straight or branched, and p' and p'', the same or different to each other, are 1-10; m' = 2-4 ; R3 is: zero, ~0- ; -00C-; -N-; their stereoisomers and related salts.
As a further preferred embodiment of the compounds of general formula (I) of the present invention ( CnO alky1 and ( Cn") alky1 are (CH2)nA<, (CH2)nA" respectively, wherein nA' and nA'', the same or different to each other, are 1- 10, and more preferably Y is selected from the group comprising - (CH2) nA ,-, - (CH2) nA<-C0-, -0- (CH2) nA ,-0-, -00C- (CH2) nA ,-COO-; ~0- (CH2) nA'-, -HN- (CH2 ) nA ,-, -00C- (CH2 ) nA ,-; ~(CH2)nA,-O-CO-(CH2)nA,,-; - (CH2 ) nA,-CO-O- (CH2 ) nA, ,- wherein nA' and nA'', the same or different to each other, are 1-10.
A further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention are compounds of general formula (I) wherein the group X-Y-W is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2- carboxyethyl) methanethiosulfonate, S- ( 2- aminoethyl ) methanethiosulfonate and S- (2- hydroxyethyl ) methanethiosulfonate . A further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention, are compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5-(p- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (4- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (3-thioxo-3H- l,2-dithiol-4-yl)benzoic acid, 4- (3-thioxo-3H-l, 2- dithiol-5-yl) benzoic acid, 1, 3-dithiol-2-thione-5- carboxylic acid, 3-thioxo-3H-l, 2-dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol-4-carboxylic acid.
A further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention, are the compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising allyl disulfide, allyl trisulfide, allyl tetrasulfide derivatives.
A further preferred embodiment of the compounds for the treatment of neurodegenerative diseases according to the present invention, are the compounds of general formula (I) wherein the polysulfurated group W is selected from the group comprising the allyl sulfide derivatives of the corresponding precursor having formula: 2- (2-allyldisulfanil) -ethanol, 3- (2- allyldisulfanil ) -propanoic acid, 2- (2- allyldisulfanil ) ethylamine .
It is a further object of the present invention the use, alone or in combination with other agents, of the compound 5- (p-hydroxyphenyl-3H-l, 2-dithiol-3-thione) having formula:
Figure imgf000011_0001
for the preparation of a pharmaceutical composition for preventing, treating or reducing neurodegenerative diseases such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis. It is a further object of the present invention the use, alone or in combination with other agents, of the compounds of general formula (I) wherein A is a residue of a drug used in the field of neurodegenerative diseases, said drug selected among antimuscarinic and NMDA receptor antagonists such as for example memantine, dexanabinol, remacemide etc. being X, Y and W as above defined, for the preparation of a pharmaceutical composition for preventing, treating or reducing neurodegenerative diseases such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis.
In the present invention the parent compound, the drug used in the field of neurodegenerative diseases, originating the residue A can be used in its original form or in a proper modification to allow the chemical manipulation with the moiety containing the polysulfurated group. The residue A and the moiety containing the polysulfurated group (W) can be linked via different linking groups such as esters, amides, imides, sulfonamides, azo groups, carbamates, carbonates, anhydrides, acetals, thioacetals, etc. The polysulfurated group, i.e. the thiosulfonate moiety or dithiol-thionic derivative, can be also directly linked by an ionic bond to the residue A of the drug used for treating neurodegenerative diseases, as salt when X and Y=O.
Bi-functional linkers (X, Y), known to the skilled person in the field, (such as ethyl, propyl or butyl diols; diamines; hydroxy amines; etc.) can be optionally present when they are necessary to link the residue A to the polysulfurated group (W) .
As a further object of the present invention are the preferred compounds according to general formula (I) such as : methyl 3- (3, 4-dihydroxyphenyl) -2- ( 4- (3-thioxo-3H-l, 2- dithiol-4-yl) benzamido) propanoate
Figure imgf000013_0001
methyl 3- (3, 4-dihydroxyphenyl) -2- (2-thioxo-l, 3-dithiol-4- carboxamido) propanoate
Figure imgf000013_0002
methyl 2- (3- (allyldisulfanyl) propanamido) -3- (3, 4- dihydroxyphenyl ) propanoate
Figure imgf000013_0003
methyl 3- (3, 4-dihydroxyphenyl) -2- (2- (methoxy-4- ( 3-thioxo- 3H-I, 2-dithiol-5-yl) phenoxy) acetamido) propanoate
Figure imgf000013_0004
(S) -methyl 3- (3, 4-dihydroxyphenyl) -2- ( ( 4- (3-thioxo-3H- 1, 2-dithiol-5-yl) phenoxy) carbonylamino) propanoate
Figure imgf000014_0001
When the compounds include at least one asymmetric carbon atom, the products can be used in racemic mixture or in form of single enantiomer.
It is a further object of the present invention the pharmaceutical acceptable salts of compounds having formula (I), such as for example salts with alkaline metals and alkaline earth metals, non-toxic amines and aminoacids, inorganic acids such as hydrochloric acid, phosphoric acid, etc., or organic acids such as fumaric acid, citric acid, tartaric acid, maleic acid, etc. Salts of organic thiosulfonates such as, for example, S- (2-carboxyethyl ) methanethiosulfonate, S- (2- aminoethyl ) methanethiosulfonate with the different derivatives above-described, are also part of the present invention. Salts of dithiolthiones such as, for example, 1, 3-dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol-4- carboxylic acid with the different derivatives above- described are also part of the present invention.
According to the present invention it has been found that it is possible to link an organic polysulfurated group to the residue A for treating neurodegenerative diseases. The resulting compounds have good bioavailability, increased safety and maintain good efficacy . The main advantages of the compounds of the present invention are related to their biological activity.
Further object of the present invention are pharmaceutical compositions comprising at least one compound of the above-said derivative of the group A compounds (according to the present invention as for general formula (I) and the preferred compounds as described above) including salts thereof, as an active ingredient, moreover, as a further object of the present invention, in combination with pharmaceutically acceptable adjuvant (s) or carrier (s).
It is a further object of the present invention the use as a medicament of compounds derivative according to general formula (I) and of the preferred compounds as described above. A further object of the present invention is the use of compounds according to the present invention as for general formula (I), and of the preferred compounds as described above, for the preparation of pharmaceutical compositions, and the relevant corresponding method, for preventing, treating or reducing neurodegenerative diseases also in combination with other agents used for the treatment of neurodegenerative diseases.
The compounds of the present invention can be administered in the form of any pharmaceutical formulation, the nature of which will depend upon the route of administration and the nature of the disease to be treated.
These pharmaceutical compositions can be prepared by conventional methods, using compatible and pharmaceutically acceptable excipients or vehicles .
Examples of such compositions include capsules, tablets, syrups, powders and granulates for the preparation of extemporaneous solutions, injectable, rectal, nasal, ocular, vaginal, transdermal preparations etc.. A preferred route of administration is the oral route .
It is a further object of the present invention the process of the synthesis of compounds as for general formula (I), and of the preferred compounds, as described above, wherein said process comprises the reaction of a drug used in the field of neurodegenerative diseases or its derivatives, precursor of residue A, with a corresponding precursor of an organic thiosulfonate or of a dithiolthione or of a trithiocarbonate or of an allyl sulfide, moiety W or Y-W, or the reaction of a corresponding precursor of an organic thiosulfonate or of a dithiolthione or of a trithiocarbonate or of an allyl sulfide, moiety W, with a drug used in the field of neurodegenerative diseases, precursor of residue A, or its derivative, eventually modified with X and/or Y, being A, W and X/Y as defined above.
It is a further object of the present invention the use of compounds of general formula (I), and the preferred compounds as described above, for preventing, treating or reducing neurodegenerative diseases, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis, also in combination with other agents used for the treatment of neurodegenerative diseases, as well as the method for preventing, treating or reducing neurodegenerative diseases, such as, for example, Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrofic lateral sclerosis, said method comprising the use of compounds of general formula (I) and the preferred compounds as described above.
The following non-limitative examples further describe the invention and enable a person skilled in the art to carry out the invention. EXAMPLE 1. Synthesis of methyl 3- (3, 4-dihydroxyphenyl) -2- (4-(3-thioxo-3H-l,2-dithiol-4-il) benzamido propanoate .
Step 1: Preparation of 4- (3-thioxo-3H-l, 2-dithiol-4- yl) benzoic acid.
4-isopropylbenzoic acid (1.0 g; 6.09 mmol) is suspended in 25 ml of ethanol and to this suspension 0.140 g of H2SO4 cone, are added. The reaction is performed at 1000C, stirring for 9 hours. The solution is evaporated to dryness and the residue is dissolved in CH2Cl2. The organic phase is washed with a saturated NaHCO3 solution and then with cold water, dried on anhydrous sodium sulphate and finally evaporated to dryness to obtain an oily colourless product. This product (ethyl 4-isopropyl benzoate, 940 mg; 5.16 mmol) is added dropwise to stirred melted sulfur (1.2 g) at 146°C and the reaction mixture is stirred at 220°C for 24 hours. The temperature is lowered to 1100C and 3 ml of toluene and 7 ml of acetone are added. After stirring the reaction mixture at room temperature for 4 h, unreacted sulphur is filtered and the obtained solution is evaporated to dryness. The residue is purified by column chromatography on silica gel, eluting with CH2Cl2-cyclohexane (6:4) to give a compound with m.p. 157.5-159.5°C . Finally a suspension of this compound (100 mg, 0.35 mmol) in 4.5 ml of acetic acid and 0.72 ml of 9M H2SO4 is stirred at 1000C for 4 hours . After cooling, the solution is diluted with water and extracted with a mixture of CH2Cl2-methanol (9:1) . The organic phase is dried on anhydrous sodium sulphate, evaporated to dryness and the residue is washed with ether and CH2Cl2 to obtain a yellow-orange solid, 4- (3- thioxo-3H-l, 2-dithiol-4-yl) benzoic acid, with m.p. 240- 245°C.
Step 2: Preparation of L-dopa methyl ester hydrochloride . L-Dopa (700 mg; 3.55 mmol) is suspended in methanol 35 ml at 0°C under nitrogen. 2.4 ml of SOCl2 are added dropwise and, at the end, the reaction mixture is heated under reflux for 2 hours. After evaporation to dryness a white powder of the desired product is obtained.
Step 3: Preparation of methyl 3- (3, 4-dihydroxyphenyl) -2- (4- (3-thioxo-3H-l, 2-dithiol-4-yl) benzamido propanoate . 1.5 eq. of 1-hydroxybenzotriazole (HOBt) monohydrate (185 mg) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC) (1.2 eq.; 232 mg) and the product prepared in step 2 (200 mg; 0.8 mmol) are added to a solution of the compound prepared in step 1 (205 mg; 0.8 mmol) in anhydrous dimethylformamide (DMF) (4 ml) . A suspension is formed that clears up after addition of triethylamine (TEA) (0.22 ml, 2 eq. ; 163 mg) . The reaction is maintained at room temperature for 4 hours under nitrogen. Subsequently DMF is evaporated and the raw product is treated with methylene chloride. The organic phase is washed with water, hydrochloric acid IN and water again and finally is dried on anhydrous sodium sulphate and evaporated to dryness. The raw product is chromatographed on silica gel with eluting mixture dichloromethane/methanol (97:3), washed with ethyl ether. The product has a melting point of 160-1650C. EXAMPLE 2. Synthesis of methyl 3- (3, 4-dihydroxyphenyl) -2- (2- (methoxy-4- (3-thioxo-3H-l, 2-dithiol-5- yl) phenoxy) acetamido) propanoate Step 1: preparation of 2- [2-methoxy-4- (3-thioxo-3H-l, 2- dithiol-5-yl)phenoxy] acetic acid.
Eugenol (3 g, 2.8 ml; 18.27 mmol) is added to a solution of NaOH (741 mg; 18.52 mmol) in methanol (20 ml) and, after stirring under nitrogen for about 10 minutes, methyl bromo acetate (3.74, 2.25 ml; 24.44 mmol) is added heating at 55°C for 2 hours. The reaction is followed by TLC. At the end of the reaction the solvent is evaporated under vacuum and the obtained white raw residue is dissolved in a cold solution of NaOH 0. IN and extracted with ethyl ether. The organic phase is washed with cold water, dried on anhydrous sodium sulphate and evaporated to dryness to obtain an oily residue that is chromatographed on silica gel using as eluting mixture cyclohexane/methylene chloride (3:1). Elemental sulphur (2.06 g; 64.44 mmol) is melted in a flask of 100 ml stirring at a temperature of 146°C. 2-(4- allyl-2-methoxyphenoxy) methyl acetate (2.06 g; 8.72 mmol) previously prepared is added dropwise and the mixture is heated at 2200C for 2 hours under stirring. At the end of the reaction, after cooling to room temperature, toluene 2 ml and acetone 4.7 ml are added. The obtained suspension is maintained under stirring at room temperature overnight and the unreacted sulphur is filtered and washed with acetone. The filtered product is evaporated to dryness and chromatographed on silica gel using as eluting mixture methylene chloride/cyclohexane (98:2). A red crystalline product with m.p. 165-166°C is obtained. To a suspension of 2- [2-methoxy-4- (3-thioxo-3H-l, 2- dithiol-5-yl) phenoxy] methyl acetate (587 mg; 1.79 mmol) in acetic acid (24.4 ml) are added 4 ml of 50% H2SO4 and the mixture is heated under stirring at 1000C for 1 hour and 30 minutes. At the end of the reaction the mixture is cooled in ice bath and the formed precipitate is filtered, washed with water and ethyl ether obtaining a brown crystalline product having m.p. 198-2000C. Step 2: Preparation of methyl 3- (3, 4-dihydroxyphenyl) -2- (2- (methoxy-4- (3-thioxo-3H-l, 2-dithiol-5- yl)phenoxy) acetamido)propanoate . 1-hydroxybenzotriazole (HOBt) monohydrate (185 mg, 1.5 eq. ) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC 232 mg, 1.2 eq. ) and 200 mg (0.8 mmol) of L-Dopa methylester hydrochloride prepared as in step 2 of example 1 are added to a solution of the compound prepared in step 1 (241 mg; 0.8 mmol) in 4 ml of anhydrous DMF. The resulting suspension clears up after adding triethylamine (TEA) (0.22 ml, 2 eq.). The reaction is maintained at room temperature for 24 hours under nitrogen. At the end of the reaction DMF is evaporated and methylene chloride is added. The organic phase is washed with water, hydrochloric acid IN and again with water and the product is dried on anhydrous sodium sulphate and is evaporated to dryness. The product is chromatographed on silica gel eluting with a mixture dichloromethane/methanol (98:2) and washed with ethyl ether. The product has a melting point of 153-155°C. EXAMPLE 3. Synthesis of methyl 3- (3, 4-dihydroxyphenyl) -2- (2-thioxo-l, 3-dithiol-4-carboxamido)propanoate Step 1: Preparation of 2-thioxo-l, 3-dithiol-4-carboxylic acid.
A mixture of dimethylacetylene dicarboxylate (2.9 g; 20 mmol) and of ethylene trithiocarbonate (2.8 g; 20 mmol) in toluene (10 ml) is heated at reflux for 6 hours. After cooling the solution is concentrated by evaporation and petroleum ether is added keeping the product in ice bath. A yellow product precipitate that after filtration and washing with petroleum ether has a m.p. 82-84°C. 3g of this product (12 mmol) are suspended in a mixture of concentrated hydrochloric acid (12.9 ml), acetic acid (6 ml) and water (18 ml) heating at reflux for 2 hours and 45 minutes. After cooling the bicarboxylic acid crystallizes and is filtered and washed with a small quantity of water; after drying it has a m.p. 154.2- 154.6°C dec.. The bicarboxylic acid is cautiously heated in a pyrex test tube at 1400C for 20 minutes. Development of gas is observable and, at the end, the desired product is obtained and transferred in a flask. The product is treated with 50 ml of a saturated solution of sodium bicarbonate, filtered on celite and the solution is acidified with HCl 6N up to pH 1. A brown precipitate is obtained and filtered, washed with a small quantity of water and, after drying, is ricrystallized from toluene (m.p. 195-197°C) . Step 2: Preparation of methyl 3- (3, 4-dihydroxy phenyl) -2- (2-thioxo-l, 3-dithiol-4-carboxamido) propanoate .
1-hydroxybenzotriazole (HOBt) monohydrate (185 mg, 1.5 eq. ) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC 232 mg, 1.2 eq. ) and 200 mg (0.8 mmol) of L-Dopa methylester hydrochloride prepared as in step 2 of example 1 are added to a solution of the compound prepared in step 1 (142.6 mg; 0.8 mmol) in 4 ml of anhydrous DMF . The resulting suspension clears up after addition of triethylamine (TEA 0.22 ml, 2 eq.). The reaction is maintained at room temperature for 24 hours under nitrogen. At the end of the reaction DMF is evaporated and methylene chloride is added. The organic phase is washed with water, hydrochloric acid IN and again with water and the product is dried on anhydrous sodium sulphate and is evaporated to dryness. The raw product is chromatographed on silica gel, eluting with a mixture methylene chloride/methanol (98:2). Pentane is used to help crystallization and after solvents removal, the product has a melting point 66-700C.
EXAMPLE 4. Synthesis of methyl 2-(3- (allyldisulfanyl)propanamido) -3- (3, 4-dihydroxyphenyl) propanoate . Step 1: Preparation of 3- (allyldisulfanyl) propanoic acid.
A solution of 3-mercaptopropanoic acid (0.49 g; 4.6 mmol) in 5 ml of ethyl ether is added dropwise to a solution of allyldisulfide (2.4 g; 13.6 mmol) in a mixture of ether (10 ml) and methanol (20 ml), followed by a solution of NaOH 10 M (0.46 ml). The reaction mixture is stirred under nitrogen at room temperature for 24 hours. The solvents are evaporated to dryness and the raw product is treated with ether and washed with HCl IN. The ethereous phase is dried on sodium sulphate and evaporated to dryness. The resulting oil is chromatographed on silica gel, eluting with dichloromethane/methanol mixture. The product is a colourless oil. Step 2: Preparation of methyl 2- (3- (allyldisulfanyl) propanamido) -3- (3, 4-dihydroxyphenyl )propanoate .
1-hydroxybenzotriazole (HOBt) monohydrate (185 mg, 1.5 eq. ) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAC 232 mg, 1.2 eq. ) and 200 mg (0.8 mmol) of L-Dopa methylester hydrochloride prepared as in step 2 of example 1 are added to a solution of the compound prepared in step 1 (142.6 mg; 0.8 mmol) in 4 ml of anhydrous DMF .
The resulting suspension clears up after addition of triethylamine (TEA) (0.22 ml, 2 eq.). The reaction is maintained at room temperature for 24 hours under nitrogen. At the end of the reaction DMF is evaporated and methylene chloride is added. The organic phase is washed with water, hydrochloric acid IN and again with water and the product is dried on anhydrous sodium sulphate and is evaporated. The raw product is chromatographed on silica gel, eluting with a mixture methylene chloride/methanol (98.5:1.5). A semisolid product is obtained. EXAMPLE 5. Biological activity. Cellular tolerability and neuroprotective activity from oxidative stress induced by hydrogen peroxide (H2O2) on neuronal cells SH-SY5Y were evaluated, following the method described by Jia Z et al. [Brain Res. 1197 (2008), 159-169], in particular for what concerns the cellular colture and the evaluation of cellular integrity. Neuronal cells cultivated in the plates were pre-treated with the products under investigation dissolved in DMSO 0.5% at 50 micromolar concentration, and thereafter the cellular integrity, in absence or presence of H2O2, at 80 micromolar concentration, was evaluated. The results reported in the following table are expressed as % versus controls (cells without any treatment).
Figure imgf000026_0001
Figure imgf000027_0001
As can be seen all the tested products have an excellent tolerability and neuroprotective activity at the tested concentration. On the opposite L-dopa is poorly tolerated and without neuroprotective activity at the concentration tested.

Claims

1. Compounds of general formula: A-X-Y-W (I) wherein A is a residue of a drug used in the field of neurodegenerative diseases, said drug belonging to one of the following therapeutic classes: dopamine precursors, dopa-decarboxylase inhibitors, dopamine agonists, MAO-B inhibitors; cholinesterases inhibitors; catechol 0-methyl transferase (COMT) inhibitors; antimuscarinics ;
X is a group capable to link to ~Y or ~W, selected from a group comprising -COO-; -0~ ; -CONH-; -OCO-; -OCOO-; -CO-;
Y is zero; - (Cn ' ) alkyl-, - (Cn ' ) alkyl-CO-, -0- (Cn ' ) alkyl- 0-, -0OC-(Cn' )alkyl-COO-; -0- (Cn ') alkyl-, -HN- (Cn ' ) alkyl-
, -0OC-(Cn' ) alkyl-; - (Cn ' ) alkyl-0-CO- (Cn ' ' ) alkyl-;
- (Cn' )alkyl-C0-0-(Cn' ' ) alkyl- wherein (Cn') alkyl and
(Cn'') alkyl are straight or branched, and n' and n'', the same or different to each other, are 0-10; W is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates or an allyl sulphide derivative, their stereoisomers and related salts.
2. Compounds of general formula (I) according to claim 1, wherein A is a residue of a drug used in the field of neurodegenerative diseases said drug is selected from the group comprising: levodopa, carbidopa, benserazide, bromocriptine, pergolide, selegiline, rasagiline, galantamine, rivastigmine, donezepil, entacapone, tolcapone, amantadine, biperidine, benzatropine, trihexylfenidyl .
3. Compounds of general formula (I) according to claim 1, wherein W is an organic thiosulfonate moiety having formula:
-S-SO2-R (II) wherein -S-SO2-R is linked to A-Y-; R is a straight or branched alkyl, selected form the group comprising methyl, ethyl, propyl; alkenyl, alkinyl; alkylaryl, alkenylaryl, alkinylaryl; arylalkyl, arylalkenyl, arylalkinyl; or cycloalkyl, cycloalkenyl, cycloalkinyl; or aromatic and/or heterocyclic ring, all substituted or unsubstituted.
4. Compounds of general formula (I) according to claim 1, wherein W is a dithiole-thione derivative having formula :
Figure imgf000029_0001
where in
Z is S (sulphur) and at least 1 Z is C=S (thione), m is 0, 1-10;
T is: -00C-; or
Figure imgf000030_0001
wherein
Rl is -H; -COOH; -NH2; -OH; -SH;
R2 is hydrogen; -COOH; alkyl, alkenyl, alkynyl; aryl; fluoro, chloro, bromo; hydroxyl, alkyloxy, alkenyloxy, aryloxy, acyloxy; amino, alkylamino, arylamino; thio; cyano; nitro; acyl; amido; and a 5 or 6-membered aromatic or non-aromatic ring containing 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or sulphur.
5. Compounds of general formula (I) according to claim 1, wherein W is an allyl sulfide derivative of formula :
CH2=CH- (Cp ') alkyl- (S) m' -(Cp' ' ) alkyl-R3 (V) wherein (Cp') alkyl and (Cp'') alkyl are straight or branched, and p' and p'', the same or different to each other, are 1-10; m' = 2-4 ; R3 is: zero, ~0- ; -00C-;
-N-.
6. Compounds of general formula (I) according to claim 5, wherein the polysulfurated group W is selected from the group comprising allyl disulfide, allyl trisulfide, allyltetrasulfide derivatives.
7. Salts of compounds of general formula (I) according to claim 1, wherein said salts are pharmaceutical acceptable salts of compounds of formula (D .
8. Salts according to claim 7, said salts comprising salts of compounds of formula (I) with alkaline metals; alkaline earth metals; non-toxic amines; aminoacids; inorganic acids comprising hydrochloric acid, phosphoric acid; organic acids comprising fumaric acid, citric acid, tartaric acid, maleic acid.
9. Compounds of general formula (I) according to claim 3, wherein the group X-Y-W is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2- carboxyethyl) methanethiosulfonate, S- ( 2- aminoethyl ) methanethiosulfonate and S- (2-hydroxyethyl) methanethiosulfonate .
10. Compounds of general formula (I) according to claim 4, wherein the polysulfurated group W is selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5-(p- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (4- hydroxyphenyl) -3H-1, 2-dithiol-3-thione, 4- (3-thioxo-3H- 1, 2-dithiol-4-yl) benzoic acid, 4- (3-thioxo-3H-l, 2- dithiol-5-yl) benzoic acid, 1, 3-dithiol-2-thione-5- carboxylic acid, 3-thioxo-3H-l, 2-dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiol-4-carboxylic acid.
11. Compounds of general formula (I) according to claim 5, wherein the polysulfurated group W is selected from the group comprising allyl sulphide derivatives of the corresponding precursor having formula: 2- (2- allyldisulfanyl ) ethanol; 3- ( 2-allyldisulfanyl) propanoic acid; 2- (2-allyldisulfanyl) ethylamine .
12. Compound of general formula (I) according to claim 1, that is methyl 3- ( 3, 4-dihydroxyphenyl) -2- ( 4- (3- thioxo-3H-l, 2-dithiol-4-yl) benzamido propanoate .
13. Compound of general formula (I) according to claim 1, that is methyl 3- (3, 4-dihydroxyphenyl) -2- (2- thioxo-1, 3-dithiol-4-carboxamido) propanoate .
14. Compound of general formula (I) according to claim 1, that is methyl 2- ( 3- (allyldisul- fanyl ) propanamido) -3- (3, 4-dihydroxyphenyl) propanoate .
15. Compound of general formula (I) according to claim 1, that is methyl 3- (3, 4-dihydroxyphenyl) -2- (2- (methoxy-4- (3-thioxo-3H-l, 2-dithiol-5-yl ) phenoxy) acetamido) propanoate .
16. Compound of general formula (I) according to claim 1, that is (S) -methyl 3- (3, 4-dihydroxyphenyl ) -2- ( (4- (3-thioxo-3H-l, 2-dithiol-5-yl) phenoxy) carbonilamino) propanoate .
17. Pharmaceutical composition comprising at least one compound of general formula (I) according to claims
1-16 as an active ingredient and eventually one or more pharmaceutically acceptable adjuvant (s) or carrier (s).
18. Compound of general formula (I) according to claims 1-16, for use as a medicament.
19. Use of a compound of general formula (I) according to claims 1-16, for the manufacture of a medicament for preventing, treating or reducing neurodegenerative diseases.
20. Use of a compound of general formula (I) according to claims 1-16, for the manufacture of a medicament for preventing, treating or reducing neurodegenerative diseases in combination with other drugs used in the field of neurodegenerative diseases.
21. Use according to claims 19 and 20, wherein the neurodegenerative diseases are Parkinson's disease,
Alzheimer's disease, Huntington's chorea and the amyotrophic lateral sclerosis.
22. Use of the compound 5- (p-hydroxyphenyl-3H-l, 2- dithiol-3-thione) having formula:
Figure imgf000034_0001
for the preparation of a pharmaceutical composition for preventing, treating or reducing neurodegenerative diseases .
23. Use of compounds of general formula:
A-X-Y-W (I) wherein
A is a residue of a drug used in the field of neurodegenerative diseases said drug selected among antimuscarinics, NMDA receptor antagonists, in particular memantine, dexanabinol, remacemide;
X is a group capable to link to ~Y or ~W, selected from a group comprising -COO-; -0~ ; -CONH-; -0C0-; -OCOO-; -CO-; Y is zero; - (Cn ' ) alkyl-, - (Cn ' ) alkyl-CO-, -0- (Cn ' ) alkyl- 0-, -0OC-(Cn' )alkyl-COO-; -0- (Cn ') alkyl-, -HN- (Cn ' ) alkyl- , -0OC-(Cn' ) alkyl-; - (Cn ' ) alkyl-0-CO- (Cn ' ' ) alkyl-; - (Cn' )alkyl-C0-0-(Cn' ' ) alkyl- wherein (Cn') alkyl and (Cn'') alkyl are straight or branched, and n' and n'', the same or different to each other, are 0-10; W is a polysulfurated group containing 2 or more atoms of sulphur, selected from the group comprising an organic thiosulfonate moiety or a dithiole-thione derivative cyclic or linear or trithiocarbonates or an allyl sulphide derivative, their stereoisomers and related salts, for the preparation of a pharmaceutical composition for preventing, treating or reducing neurodegenerative diseases .
24. Use according claims 22 or 23, wherein the neurodegenerative diseases are Parkinson's disease, Alzheimer's disease, Huntington's chorea and the amyotrophic lateral sclerosis.
25. Process for the synthesis of compounds of general formula (I) according to claims 1-16, said process comprising the reaction of a drug used in the field of neurodegenerative diseases or its derivatives, precursor of residue A, with the corresponding precursor of an organic thiosulfonate or of a dithiol-thione or of a trithiocarbonate or of an allyl sulfide, moiety W or Y- W, or the reaction of a corresponding precursor of an organic thiosulfonate or dithiol-thione or trithiocarbonate or allylsulfide, moiety W, with a drug used in the field of neurodegenerative diseases, precursor of residue A, or its derivative eventually modified with X and/or Y, wherein A, W and X/Y have the meaning according to claim 1.
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