WO2009156466A1 - Compositions pharmaceutiques pour le traitement de maladies neurodégénératives - Google Patents

Compositions pharmaceutiques pour le traitement de maladies neurodégénératives Download PDF

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Publication number
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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Prior art keywords
alkyl
general formula
dithiol
compounds
group
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PCT/EP2009/057959
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English (en)
Inventor
Giancarlo Santus
Piero Del Soldato
Anna Sparatore
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Ctg Pharma S.R.L.
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Publication of WO2009156466A1 publication Critical patent/WO2009156466A1/fr

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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 .

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne de nouveaux composés hybrides qui libèrent H2S et sont utiles pour le traitement de maladies neurodégénératives.
PCT/EP2009/057959 2008-06-26 2009-06-25 Compositions pharmaceutiques pour le traitement de maladies neurodégénératives WO2009156466A1 (fr)

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ITMI2008A001167 2008-06-26
IT001167A ITMI20081167A1 (it) 2008-06-26 2008-06-26 Composizioni farmaceutiche per il trattamento di malattie neurodegenerative

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788440A (zh) * 2015-04-03 2015-07-22 苏州大学 烟酸衍生物及其应用
WO2019097120A1 (fr) 2017-11-16 2019-05-23 Orion Corporation Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614886A1 (fr) * 1992-07-30 1994-09-14 Drug Delivery System Institute, Ltd. Compose pouvant rester dans la region intracerebrale, et utilisation dudit compose
WO2001009118A2 (fr) * 1999-07-29 2001-02-08 Patrick T Prendergast Composes dithiolthione pour le traitement de troubles neurologiques et pour renforcer la memoire
WO2006119758A2 (fr) * 2005-05-13 2006-11-16 Ellneuroxx Ltd. Derives de dihydroxyphenylalanine
WO2007101606A1 (fr) * 2006-03-06 2007-09-13 Sulfidris S.R.L. Agents anti-inflammatoires thiosulfonate
WO2008009127A1 (fr) * 2006-07-18 2008-01-24 Antibe Therapeutics Inc. Dérivés de sulfure d'hydrogène d'anti-inflammatoires non stéroïdiens

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0614886A1 (fr) * 1992-07-30 1994-09-14 Drug Delivery System Institute, Ltd. Compose pouvant rester dans la region intracerebrale, et utilisation dudit compose
WO2001009118A2 (fr) * 1999-07-29 2001-02-08 Patrick T Prendergast Composes dithiolthione pour le traitement de troubles neurologiques et pour renforcer la memoire
WO2006119758A2 (fr) * 2005-05-13 2006-11-16 Ellneuroxx Ltd. Derives de dihydroxyphenylalanine
WO2007101606A1 (fr) * 2006-03-06 2007-09-13 Sulfidris S.R.L. Agents anti-inflammatoires thiosulfonate
WO2008009127A1 (fr) * 2006-07-18 2008-01-24 Antibe Therapeutics Inc. Dérivés de sulfure d'hydrogène d'anti-inflammatoires non stéroïdiens

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DI STEFANO ANTONIO ET AL: "L-dopa- and dopamine-(R)-alpha-lipoic acid conjugates as multifunctional codrugs with antioxidant properties.", JOURNAL OF MEDICINAL CHEMISTRY 23 FEB 2006, vol. 49, no. 4, 23 February 2006 (2006-02-23), pages 1486 - 1493, XP002546289, ISSN: 0022-2623 *
DRUKARCH B ET AL: "Drug treatment of Parkinson's disease. Time for phase II.", BIOCHEMICAL PHARMACOLOGY 1 MAY 2000, vol. 59, no. 9, 1 May 2000 (2000-05-01), pages 1023 - 1031, XP002546290, ISSN: 0006-2952 *
PINNEN FRANCESCO ET AL: "Synthesis and study of L-dopa-glutathione codrugs as new anti-Parkinson agents with free radical scavenging properties.", JOURNAL OF MEDICINAL CHEMISTRY 17 MAY 2007, vol. 50, no. 10, 17 May 2007 (2007-05-17), pages 2506 - 2515, XP002546291, ISSN: 0022-2623 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788440A (zh) * 2015-04-03 2015-07-22 苏州大学 烟酸衍生物及其应用
WO2019097120A1 (fr) 2017-11-16 2019-05-23 Orion Corporation Nouvelle utilisation et nouvelles formes posologiques pharmaceutiques

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