WO2009109501A2 - Ocular pharmaceutical compositions - Google Patents

Ocular pharmaceutical compositions Download PDF

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Publication number
WO2009109501A2
WO2009109501A2 PCT/EP2009/052252 EP2009052252W WO2009109501A2 WO 2009109501 A2 WO2009109501 A2 WO 2009109501A2 EP 2009052252 W EP2009052252 W EP 2009052252W WO 2009109501 A2 WO2009109501 A2 WO 2009109501A2
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WO
WIPO (PCT)
Prior art keywords
compound
general formula
dithiol
alkyl
compounds
Prior art date
Application number
PCT/EP2009/052252
Other languages
French (fr)
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WO2009109501A3 (en
Inventor
Piero Del Soldato
Giancarlo Santus
Original Assignee
Ctg Pharma S.R.L.
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Publication date
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Publication of WO2009109501A2 publication Critical patent/WO2009109501A2/en
Publication of WO2009109501A3 publication Critical patent/WO2009109501A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J33/00—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J33/002—Normal steroids having a sulfur-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • Conjunctivitis is one of the most common ocular diseases.
  • Conjunctivitis is an inflammation of the conjunctiva - the transparent membrane that covers the outermost layer of the eye and the inner surface of the eyelids -, that can be acute or chronic.
  • Conjunctivitis can be caused by many factors and the most frequent are the infections (by bacteria, viruses, funguses or parasites), the allergies, the chemical substances (cosmetics, drugs, environmental factors) , but also natural agents of different nature, such as excessive sun exposition or other radiation.
  • Glaucoma is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy.
  • IOP intraocular pressure
  • oxidative stress represents a common pathogenetic factor for the various ocular pathologies. This condition is characterized by tissue depletion of reduced glutathione.
  • Topical ⁇ -blockers for example show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia. Topical ⁇ -agonists have a fairly high incidence of allergic or toxic reactions; topical BE15212
  • cholinergic agents can cause visual side effects .
  • the risks linked to the uses of steroids are related to the presence of viral infections that can be aggravated causing corneal ulceration, with possible damage to the visual field and loss of the eye.
  • the same risk can happen with bacterial, fungal or amoeba infections; in predisposed subjects ophthalmic preparation with steroids can induce steroid glaucoma; after a prolonged use a steroid cataract can be developed.
  • Other side effects include reduction of corneal and scleral thickness .
  • alpha-adrenergic drugs can produce side effects such as systemic hypothension, bradycardia, hyperaemia, anxiety, fatigue etc.
  • Object of the present invention are new compounds that release H2S able not only to eliminate or at least reduce the side effects associated with the parent compounds, but also to possess an improved pharmacological activity.
  • the ocular compounds that release H2S can be employed for treating several ocular pathologies such as, for example, conjunctivitis, glaucoma, ocular hypertension, retinopathy, infections etc.
  • the compounds of the present invention are indicated for the reduction of intraocular pressure in patients either with open-angle glaucoma or with chronic angle- closure glaucoma, who underwent peripheral iridotomy or laser iridoplasty.
  • the compounds of the present invention due to the sulphurated moieties are efficacious in the neuroprotection both at ocular level and on the nervous central system (traumas, Parkinson, Alzheimer etc.) .
  • This invention also relates to processes for preparing these compounds and to pharmaceutical compositions containing these compounds.
  • the polysulfurated groups contained BE15212
  • polysulfurated groups containing 2 or more atoms of sulphur selected from the group comprising organic thiosulfonates or dithiole-thione derivatives such as (5- (p-hydroxyphenyl) -3H-1 , 2-dithiol-3-thione, or 1,3- dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiole-4- carboxylic acid or allyl sulfides.
  • organic thiosulfonates or dithiole-thione derivatives such as (5- (p-hydroxyphenyl) -3H-1 , 2-dithiol-3-thione, or 1,3- dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-di
  • A is a residue of drugs used in ocular field belonging to one of the following classes: corticosteroids such as for example dexamethasone, fluorometholone, betamethasone, hydrocortisone, prednisolone, etc.; betablockers such as for example timolol, betaxolol, carteolol, levobunolol, metipranolol, etc.; carbonic anhydrase inhibitors such as for example dorzolamide, acetazolamide, brinzolamide, etc.; antimuscarinics such as for example atropine, tropicamide, cyclopentolate, etc.; sympathomimetics (alpha adrenergic agonists) such as for example phenylephrine, brimonidine, dipivefrine, BE15212
  • corticosteroids such as for example dexamethasone, fluorometholone, betamethasone, hydrocortisone, prednisol
  • apraclonidine etc.
  • local anesthetics such as for example lidocaine, procaine, etc .
  • antibacterials such as for example chloramphenicol, ciprofloxacin, levofloxacin, gentamycin, etc.
  • antivirals such as for example aciclovir, ganciclovir, etc .
  • miotics such as for example pilocarpine, etc.
  • antihistaminics such as for example antazoline, azelastine, epinastine, ketotifen, etc.
  • anifungals such as for example miconazole, econazole, flucytosine, etc.
  • neuroprotectant agents and MMDA receptor antagonists such as for example memantine, dexacannabinol, racemamide, etc.
  • X is a group capable to link to -Y or ⁇ W, selected from a group comprising -COO-; -0 ⁇ ; -CONH-;
  • Y is zero; ⁇ (C n ⁇ ) alkyl- , - (C n - ) alkyl-CO- , ⁇ 0- (C n - ) alkyl-0-, -00C- (C n Oalkyl-COO-; -0- (C n O alkyl- , -HN- (C n O alkyl- ,
  • (C n" ) 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 BE15212
  • W is an organic thiosulfonate moiety having formula:
  • -S-SO 2 -R (II) wherein -S-SCb-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:
  • Rl is -H; -COOH; -NH 2 ; -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,
  • (C n -) alkyl and (C n -.) alkyl are (CH 2 J n A', (CH 2 )nA " respectively, wherein nA' and nA' ' , the same or different to each other, are 1-
  • Y is selected from the group comprising - (CH 2 ) ⁇ A --, - (CH 2 ) ⁇ . -CO- , -O- (CH 2 ) nA' -0- , -00C- BE15212
  • a further preferred embodiment of the ophthalmic derivatives according to the present invention are the 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 ophthalmic compounds according to the present invention are the 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-l,2-dithiol-3-thione, 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.
  • the polysulfurated group W is selected from the group comprising dithiole-thione derivatives of the corresponding precursors having formula: 5- (p- hydroxyphenyl)-3H-l,2-dithiol-3-thione, 1 , 3-dithiol-2- thione-5-carboxylic acid, 3-thioxo-3H-l , 2-dithi
  • a further preferred embodiment of the ophthalmic compounds according to the present invention are the compounds of general formula (I) wherein the BE15212
  • polysulfurated group W is selected from the group comprising allyl disulfide, allyl trisulfide, allyl tetrasulfide derivatives.
  • a further preferred embodiment of the ophthalmic compounds 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) ethyilamine.
  • the applicant has surprisingly found an activity of prevention, treatment and reduction of ocular diseases, more in particular glaucoma or cataract, through the administration or their use for the preparation of medicaments, of compounds such as: sulphurated compounds capable to inhibit BE15212
  • protein Rel/NF-kB such as the sulphurated derivatives of NSAIDs compounds (that is non selective inhibitors of cyclooxygenase (COX) , ketoprofen, flurbiprofen, suprofen, indobufen, etodolac, indomethacin, naproxen, etc.) as described in the patent application No. EP 1 654 288 Al owned by the applicant, compounds that are sulfurated derivatives of non steroidal antiinflammatory drugs having an lC80( ⁇ M) of COX 2 ⁇ than IC80( ⁇ M) of COX 1, as described in the patent application No. WO 2006/111791A1 owned by the applicant, compounds that are sulfurated derivatives of angiotensin receptor blockers (ARB) .
  • NSAIDs compounds that is non selective inhibitors of cyclooxygenase (COX) , ketoprofen, flurbiprofen, suprofen, indobufen, eto
  • the applicant has surprisingly found an activity of prevention, treatment and reduction of ocular diseases, especially glaucoma or cataract, for the compounds selected from the group comprising ketoprofen ester with 5- (p-hydroxyphenyl) -3H-1, 2-dithiol-3-thione; ketorolac ester with con 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione; 4- (3H-1, 2-dithiol-3-thione-5-yl ) - phenylester of 2- [ (2 , 6-dichlorophenyl) amino] -benzenacetic acid; 4- (3H-1 , 2-dithiol-3-thion-5-yl ) -phenylester of 2 ' , 4 ' -difluoro-4-hydroxy- [1,1' -biphenyl] -3-carboxylic acid; the corresponding 4- (3H-1, 2-dithiol-3-thion-5-yl) - phenyles
  • the ophthalmic parent compound 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 of the ophthalmic compound 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, BE15212
  • polysulfurated group i.e. the thiosulfonate moiety, dithiol-thionic derivative or trithiocarbonates or allyl sulphide derivative
  • thiosulfonate moiety i.e. the thiosulfonate moiety, dithiol-thionic derivative or trithiocarbonates or allyl sulphide derivative
  • 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 of the ophthalmic compound or drug to the polysulfurated group (W) .
  • the compounds include at least one asymmetric BE15212
  • 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 ophthalmic derivatives above-described, are also part of the present invention.
  • dithiolthiones such as, for example, 1, 3-dithiol-2-thione-5-carboxylic acid, 3- thioxo-3H-l , 2-dithiole-5-carboxylic acid, 3-thioxo-3H- 1 , 2-dithiole-4-carboxylic acid with the different ophthalmic derivatives above-described are also part of the present invention.
  • dithiolthiones such as, for example, 1, 3-dithiol-2-thione-5-carboxylic acid, 3- thioxo-3H-l , 2-dithiole-5-carboxylic acid, 3-thioxo-3H- 1 , 2-dithiole-4-carboxylic acid with the different ophthalmic 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 an ophthalmic derivative compound for treating ocular diseases.
  • the resulting compounds have good
  • the main advantages of the compounds of the present invention are related to their biological activity by topical route.
  • compositions comprising at least one compound of the above-said ophthalmic derivative 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 of compounds as for general formula (I), and the preferred compounds as described above, for the preparation of pharmaceutical compositions, and therefore the corresponding method, for preventing, treating or reducing ocular diseases also in combination with other ocular agents .
  • the compounds of the present invention can be administered in the form of any pharmaceutical BE15212 20
  • compositions can be prepared by conventional methods, using compatible and pharmaceutically acceptable excipients or vehicles.
  • a preferred route of administration is the ocular route.
  • the method for treating ocular diseases consists in contacting a compound of formula (I) with the eye.
  • the ocular derivative compound is mixed with an BE15212
  • ophthalmologic compatible vehicle that comprises aqueous solutions, oil solutions, ointments.
  • the vehicle may contain in addition preservatives such as benzalkonium chloride, surfactants like polysorbate 80, liposomes, polymers such as cellulose derivatives, polyvinylpyrrolidone, hyaluronic acid that can be used to increase viscosity. It is also possible to use soluble or insoluble inserts to administer the drug.
  • This product (ethyl 4-isopropyl benzoate, 940 mg; 5.16 mmol) is added dropwise to stirred melted sulfur (1.2 g) at 146 0 C and the reaction mixture is stirred at 220 0 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 0 C.
  • the chloroformic solution is extracted in a separator funnel with cold water, dried with anhydrous sodium sulphate and, after filtration, evaporated to dryness.
  • the residue is chromatographed on silica gel column, eluting with a mixture of CH 2 Cl 2 -MeOH by gradient. The compound is eluted when methanol is 5% .
  • the compound has the following NMR : 1 H NMR(300 MHZ, CDCl 3 ) : ⁇ 1.20 (s, 9H), 3.00-3.20 (m, 2H), 3.45 (t, 4H), 3.70 (t, 4H), 4.70- 4.90 (m, 2H), 5.60-5.70(m, IH), 7.65 (d, 2H), 8.05 (d, 2H) , 8.45 (s, IH) .
  • ESEMPIO 3 Synthesis of 2-(9-fluoro-ll,17-dihydroxy- 10,13,16-trimethyl-3-oxo-6,7,8,9,10, 11,12,13,14,15,16,17- dodecahydro-3ff-cyclo-penta[ ⁇ ]phenanthren-17-yl) -2- oxoethyl 3- (m ⁇ thylsulfonylthio)propanoate.
  • Step 1 Synthesis of 3 -methanesulfonylsulfanyl-propionic acid.
  • Sodium methanethiosulfonate (1.5 g; 11.18 mmol) and 3- bromopropionic acid (900 mg; 5.88 mmol) 97% are dissolved in dimethylformamide (DMF, 9.05 ml) .
  • the reaction is performed at 60° C, stirring under nitrogen for 4 hours.
  • the solution is evaporated to dryness and the residue is dissolved in water, acidified with 10 ml of a 2N KHSO 4 solution and washed with ethyl acetate.
  • the organic phase is extracted with cold 2N KHSO4 solution, then with ice water and finally dried on anhydrous sodium sulphate and evaporated to dryness .
  • An oily yellow product is obtained.
  • Dimethylaminopyridine (5.5 mg) is added to a solution of dexamethasone (353 mg; 0.9 mmol) and of the compound prepared in step 1 (166 mg; 0.9 mmol) in 1.5 ml of dimethyl formamide (DMF) and then, stirring the reaction mixture under nitrogen in ice bath, a solution of 1- (3- dimethylaminoisopropyl) -3-ethyl-carbodiimide hydrochloride (EDAC, 1.35 mmol; 259 mg) in 0.5 ml of DMF is added. The reaction mixture is stirred under nitrogen at room temperature for 24 hours.
  • oxidative stress is a common pathogenetic factor for the various ocular pathologies, and this condition is characterized by a reduced glutathione tissue depletion.
  • the tissue was incubated for 4 hours at 37 0 C in presence of 10 microliters of a potassium phosphate buffer solution at pH 7.5 containing 25 U of xanthine-oxidase and 2.5 microliters of a potassium phosphate solution buffered at pH 7.5 containing 100 U of uricase.
  • the products, tested at the 10 micromolar concentration, were dissolved in DMSO 0.1%.
  • the results expressed as % inhibition of the GSH depletion observed in the group with oxidative stress (XO+U), containing only DMSO 0.1%, are reported in the table.

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Abstract

The present invention relates to novel derivatives of opthalmic compounds for the treatment of ocular diseases.

Description

"Ocular pharmaceutical compositions"
Field of the invention
This invention relates to new compounds that release H2S for the treatment of ocular diseases. Conjunctivitis is one of the most common ocular diseases. Conjunctivitis is an inflammation of the conjunctiva - the transparent membrane that covers the outermost layer of the eye and the inner surface of the eyelids -, that can be acute or chronic. Conjunctivitis can be caused by many factors and the most frequent are the infections (by bacteria, viruses, funguses or parasites), the allergies, the chemical substances (cosmetics, drugs, environmental factors) , but also natural agents of different nature, such as excessive sun exposition or other radiation. Glaucoma is a group of diseases of the optic nerve involving loss of retinal ganglion cells in a characteristic pattern of optic neuropathy. Almost 14 million people worldwide have glaucoma, this is the third leading cause of blindness worldwide. It is known that elevated intraocular pressure (IOP) can be, at least partially, controlled by administering drugs which either reduce the production of aqueous humour within the eye or increase the fluid drainage, such as β-blockers, α-agonists, cholinergic agents, BE15212
carbonic anhydrase inhibitors or prostaglandin analogs. It is now also accepted that glaucoma is linked to neurodegeneration: a progressive optic neuropathy with an irreversible loss of sight as a result of neuronal death. [R. Weinreb "Glaucoma neuroprotection: What is it? Why is it needed?" Can. J Ophthalmol 2007; 42 : 396-8] .Other common pathologies are cataract, a clouding in the crystalline lens, generally aging-related, macular degeneration, that is a loss of vision in the center of the retina (macula), aging-related too. As recently reported (see for example: Sacca SC, Izzotti A., Rossi P., Traverso C. Glaucomatous outflow pathway and oxidative stress. Exp Eye Res. 2007, 84 (3 ) : 389-99; as well as Tezel G. Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences . Prog Retin Eye Res. 2006, 25 (5) : 490-513 ), oxidative stress represents a common pathogenetic factor for the various ocular pathologies. This condition is characterized by tissue depletion of reduced glutathione. Several side effects are associated with the drugs conventionally used to treat ocular diseases. Topical β-blockers, for example show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia. Topical α-agonists have a fairly high incidence of allergic or toxic reactions; topical BE15212
cholinergic agents (miotics) can cause visual side effects .
The side effects associated with oral carbonic anhydrase inhibitors include fatigue, anorexia, depression, paresthesias and serum electrolyte abnormalities (The Merck Manual of Diagnosis and Therapy, Eighteenth Edition, M. H. Beers and R. Porter Editors, Sec. 9, Ch. 103) .
The risks linked to the uses of steroids are related to the presence of viral infections that can be aggravated causing corneal ulceration, with possible damage to the visual field and loss of the eye. The same risk can happen with bacterial, fungal or amoeba infections; in predisposed subjects ophthalmic preparation with steroids can induce steroid glaucoma; after a prolonged use a steroid cataract can be developed. Other side effects include reduction of corneal and scleral thickness .
It is also known that alpha-adrenergic drugs can produce side effects such as systemic hypothension, bradycardia, hyperaemia, anxiety, fatigue etc.
It remains therefore in the ophthalmic field the need to improve tolerability by reducing the side effects and the need to increase the clinical activity of drugs for ocular use. BE15212
Summary of the invention
Object of the present invention are new compounds that release H2S able not only to eliminate or at least reduce the side effects associated with the parent compounds, but also to possess an improved pharmacological activity.
In particular, it has been found that the ocular compounds that release H2S, object of the present invention, can be employed for treating several ocular pathologies such as, for example, conjunctivitis, glaucoma, ocular hypertension, retinopathy, infections etc.
The compounds of the present invention are indicated for the reduction of intraocular pressure in patients either with open-angle glaucoma or with chronic angle- closure glaucoma, who underwent peripheral iridotomy or laser iridoplasty.
The compounds of the present invention due to the sulphurated moieties are efficacious in the neuroprotection both at ocular level and on the nervous central system (traumas, Parkinson, Alzheimer etc.) .
This invention also relates to processes for preparing these compounds and to pharmaceutical compositions containing these compounds. In particular the polysulfurated groups, contained BE15212
in the compounds object of the present invention, are polysulfurated groups containing 2 or more atoms of sulphur selected from the group comprising organic thiosulfonates or dithiole-thione derivatives such as (5- (p-hydroxyphenyl) -3H-1 , 2-dithiol-3-thione, or 1,3- dithiol-2-thione-5-carboxylic acid, 3-thioxo-3H-l, 2- dithiol-5-carboxylic acid, 3-thioxo-3H-l, 2-dithiole-4- carboxylic acid or allyl sulfides.
Detailed 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 drugs used in ocular field belonging to one of the following classes: corticosteroids such as for example dexamethasone, fluorometholone, betamethasone, hydrocortisone, prednisolone, etc.; betablockers such as for example timolol, betaxolol, carteolol, levobunolol, metipranolol, etc.; carbonic anhydrase inhibitors such as for example dorzolamide, acetazolamide, brinzolamide, etc.; antimuscarinics such as for example atropine, tropicamide, cyclopentolate, etc.; sympathomimetics (alpha adrenergic agonists) such as for example phenylephrine, brimonidine, dipivefrine, BE15212
apraclonidine, etc.; local anesthetics such as for example lidocaine, procaine, etc . ; antibacterials such as for example chloramphenicol, ciprofloxacin, levofloxacin, gentamycin, etc.; antivirals such as for example aciclovir, ganciclovir, etc . ; miotics such as for example pilocarpine, etc.; antihistaminics such as for example antazoline, azelastine, epinastine, ketotifen, etc.; anifungals such as for example miconazole, econazole, flucytosine, etc.; neuroprotectant agents and MMDA receptor antagonists such as for example memantine, dexacannabinol, racemamide, etc. ; wherein X is a group capable to link to -Y or ~W, selected from a group comprising -COO-; -0~ ; -CONH-;
0C0-; -0C00-; -CO-;
Y is zero; ~ (Cn< ) alkyl- , - (Cn- ) alkyl-CO- , ~0- (Cn- ) alkyl-0-, -00C- (CnOalkyl-COO-; -0- (CnO alkyl- , -HN- (CnO alkyl- ,
-00C- (Cn- ) alkyl- ; -(CnO alkyl-0-CO- (Cn- - ) alkyl- ;
-(CnOaIkYl-CO-O-(Cn") alkyl- wherein (CnO 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 BE15212
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-SCb-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
(III) or (IV) wherein
Z is S (sulphur) and at least 1 Z is C=S (thione) , m is 0, 1-10; T is :
-OOC- ; or BE15212
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 a allyl sulfide derivative having formula: CH2=CH- (Cp.) alkyl- (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 (Cn-) alkyl and (Cn-.) alkyl are (CH2JnA', (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) ΠA--, - (CH2 ) ^. -CO- , -O- (CH2) nA'-0- , -00C- BE15212
(CH2 )nA' -COO-; -O- (CH2J11A'-, -HN- (CH2JnA'-, -00C-(CH2) ' nA ' ' ~ (CH2) nA--O-CO- (CH2) nA<<-; ~ (CH2 )ΠA' -CO-O- (CH2 )nA"- wherein nA' and nA' ' , the same or different to each other, are 1- 10. A further preferred embodiment of the ophthalmic derivatives according to the present invention are the 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 ophthalmic compounds according to the present invention, are the 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-l,2-dithiol-3-thione, 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.
A further preferred embodiment of the ophthalmic compounds according to the present invention, are the compounds of general formula (I) wherein the BE15212
10
polysulfurated group W is selected from the group comprising allyl disulfide, allyl trisulfide, allyl tetrasulfide derivatives.
A further preferred embodiment of the ophthalmic compounds 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) ethyilamine.
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 ocular diseases.
The applicant has surprisingly found an activity of prevention, treatment and reduction of ocular diseases, more in particular glaucoma or cataract, through the administration or their use for the preparation of medicaments, of compounds such as: sulphurated compounds capable to inhibit BE15212
activation of protein Rel/NF-kB, such as the sulphurated derivatives of NSAIDs compounds (that is non selective inhibitors of cyclooxygenase (COX) , ketoprofen, flurbiprofen, suprofen, indobufen, etodolac, indomethacin, naproxen, etc.) as described in the patent application No. EP 1 654 288 Al owned by the applicant, compounds that are sulfurated derivatives of non steroidal antiinflammatory drugs having an lC80(μM) of COX 2 < than IC80(μM) of COX 1, as described in the patent application No. WO 2006/111791A1 owned by the applicant, compounds that are sulfurated derivatives of angiotensin receptor blockers (ARB) .
In particular the applicant has surprisingly found an activity of prevention, treatment and reduction of ocular diseases, especially glaucoma or cataract, for the compounds selected from the group comprising ketoprofen ester with 5- (p-hydroxyphenyl) -3H-1, 2-dithiol-3-thione; ketorolac ester with con 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione; 4- (3H-1, 2-dithiol-3-thione-5-yl ) - phenylester of 2- [ (2 , 6-dichlorophenyl) amino] -benzenacetic acid; 4- (3H-1 , 2-dithiol-3-thion-5-yl ) -phenylester of 2 ' , 4 ' -difluoro-4-hydroxy- [1,1' -biphenyl] -3-carboxylic acid; the corresponding 4- (3H-1, 2-dithiol-3-thion-5-yl) - phenylesters of lumeracoxib, flufenamic acid, niflumic BE15212
acid;
4- (3-thioxo-3ff-l,2-dithiol-4-yl)benzoic acid 2-butyl-4- chloro-1- [p- (o-lH-tetrazol-5-ylphenyl) -benzyl] -imidazole- 5-methyl ester; 2-butyl-4-chloro-l- [ (2'- (lH-tetrazol-5-yl ) - (1,1'- biphenyl) -4-yl) methyl ] -lH-imidazole-5-carboxylic acid 4- (3H-I , 2-dithiol-3-thion-5-yl) -phenyl ester; 2-butyl-4-chloro-l- [ (2 ' - (lH-tetrazol-5-yl) - (1,1'- biphenyl-4-yl ) methyl ] -liϊ-imidazole-5-carboxylic acid 2- (methylsulfonylthio) -ethyl ester;
3-methanesulfonylsulfanyl-propionic acid 2 -butyl-4- chloro-1- [p- (o-lff-tetrazol-5-ylphenyl) benzyl] - imidazole- 5-methyl ester; 4'- [ (1, 4 '-dimethyl-2' -propyl [2,6' -bi-lH-benzimidazol] -1'- yl ) methyl ] [1, l'-biphenyl] -2 -carboxylic acid 4-(3ff-l,2- dithiol-3-thion-5-yl) -phenyl ester.
In the present invention the ophthalmic parent compound 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 of the ophthalmic compound 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, BE15212
etc. The polysulfurated group, i.e. the thiosulfonate moiety, dithiol-thionic derivative or trithiocarbonates or allyl sulphide derivative, can be also directly linked by an ionic bond to the residue A of the ophthalmic compound 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 of the ophthalmic compound or drug to the polysulfurated group (W) .
As a further object of the present invention are the preferred compounds according to general formula (I), such as : 2- (9-fluoro-ll, 17-dihydroxy-10 , 13 , lβ-trimethyl-3-oxo- 6,7,8, 9, 10, 11,12,13,14, 15, 16 , 17-dodecahydro-3H-cyclo- penta [α]phenanthren-17-yl) -2-oxoethyl 3- (methyl sul fonylthio ) propanoate
Figure imgf000014_0001
2- (9-fluoro-ll, 17-dihydroxy-10 , 13 , 16-trimethyl-3-oxo- 6,7, 8, 9,10, 11,12,13,14, 15, 16 , 17-dodecahydro-3H-cyclo BE15212
14
penta [α] phenanthren-17-yl ) -2 -oxoethyl 4- (3H-thioxo-l,2- di thiol -4-yl ) benzoate
Figure imgf000015_0001
1- ( tert-butylamino) -3- (4-morpholino-l , 2 , 5-thiadiazol-3- yloxy)propan-2-yl 3- (methylsulfonylthio)propanoate
Figure imgf000015_0002
1- (tert-butylamino) -3- {4-morpholino-l, 2, 5-thiadiazol-3- yloxy)propan-2-yl 3- (allyldisulfanyl)propanoate
Figure imgf000015_0003
1- (tert-butylamino) -3- (4-morpholino-l, 2, 5-thiadiazol-3- yloxy)propan-2-yl 4- ( 3 -thioxo-3H-l , 2-dithiol-4- yl ) benzoate
Figure imgf000015_0004
N- ( 5-acetamido-l , 3 , 4-thiadiazol-2-ylsulfonyl ) -3 - BE15212
15
(allyldisulfanyl ) propanamide
CH3-CO NHV^SN^SO2-NH-CO-CH2-CH2-S-S-CH2-CH=CH2
N-N
3- (3-hydroxγ-2-phenylpropanoyloxy) -8-methyl-8-azonia- bicyclo [3.2,1] ottane 3- (allyldisulfanyl )propanoate
Figure imgf000016_0001
. CH2=CH-CH2-S-S-CH2-CH2-COOH
(R) -1- (3-hydroxyphenyl) -2- (methylamino) ethyl 4- (3-thioxo- 3H-l,2-dithiol-4-yl)benzoate
Figure imgf000016_0002
(4- (5-thioxo-5H-l, 2-dithiol-3-yl) -phenyl 2-(5- bromoquinoxalin-6-ylamino) -4, 5-dihydroimidazole-l- carboxylate
Figure imgf000016_0003
2- (allyldisulfanyl) ethyl 2- (5-bromoquinoxalin-6-ylamino) - BE15212
16
4 , 5-dihydroimidazole-l-carboxylate
Figure imgf000017_0001
2- (2, 6-dimethylphenylamino) -N,N-diethyl-2-oxoethanaminium 3- (allyldisulfanyl)propanoate
Figure imgf000017_0002
-CH2-COOH,
4- (5-thioxo-5H-l, 2 -dithiol-3-yl) phenyl l-cyclopropyl-6- fluoro-4-oxo-7- (piperazin-1-yl) -1, 4-dihydroquinoline- 3- carboxylate
Figure imgf000017_0003
2- [ (2 -amino- 6 -oxo-1 , 6-dihydropurin-9-yl)methoxy] ethyl 4-
(3-thioxo-3H-l,2-dithiol-4-yl)benzoate
Figure imgf000017_0004
BE15212
17
5- ( ( (3R145) -4-ethγl-5-oxo-tetraidrofuran-3-yl) methyl) -1- methyl-lH-imidazol-1-ium 3- (methylsulfonylthio) propanoate
Figure imgf000018_0001
.CH3-SO2-S-CH2-CH2-COOH
9 , 13Jb-dihydro-lH-dibenz [c, f] imidazo [1 , 5-a] azepin-3- [3-
(allyltrisulfanil)propionamide]
Figure imgf000018_0002
4- (5-thioxo-5H-l, 2-dithiol-3-yl)phenyl 2- (3- (5-fluoro-2- oxo-1, 2,3, 4-tetrahydropiridin-4-yl) ureido) acetate
Figure imgf000018_0003
3 , 5 -dimethyl triciclo [3.3.1.13'7] decan-1- [3- (allyldisulfanyl)propion] amide 2-CH2-S-S-CH2- CH=CH2
Figure imgf000018_0004
When the compounds include at least one asymmetric BE15212
18
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 of 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 ophthalmic 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-dithiole-5-carboxylic acid, 3-thioxo-3H- 1 , 2-dithiole-4-carboxylic acid with the different ophthalmic 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 an ophthalmic derivative compound for treating ocular diseases. The resulting compounds have good bioavailability, increased safety and maintain good efficacy. BE15212
The main advantages of the compounds of the present invention are related to their biological activity by topical route.
Further object of the present invention are pharmaceutical compositions comprising at least one compound of the above-said ophthalmic derivative 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 of ophthalmic products as for general formula (I) and of the preferred compounds as described above.
A further object of the present invention is the use of compounds as for general formula (I), and the preferred compounds as described above, for the preparation of pharmaceutical compositions, and therefore the corresponding method, for preventing, treating or reducing ocular diseases also in combination with other ocular agents .
The compounds of the present invention can be administered in the form of any pharmaceutical BE15212 20
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.
A preferred route of administration is the ocular route.
It is a further object of the present invention the process of the synthesis of compounds derivative of ophthalmic products as for general formula (I), and of the preferred compounds as described above, said process comprising the reaction of an ophthalmic product or its derivatives 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 a trithiocarbonate or of an allyl sulfide, moiety W, with an ophthalmic product or its derivative, eventually modified with X and/or Y, being said W and X/Y as defined above .
The method for treating ocular diseases, as defined, consists in contacting a compound of formula (I) with the eye. The ocular derivative compound is mixed with an BE15212
ophthalmologic compatible vehicle that comprises aqueous solutions, oil solutions, ointments. The vehicle may contain in addition preservatives such as benzalkonium chloride, surfactants like polysorbate 80, liposomes, polymers such as cellulose derivatives, polyvinylpyrrolidone, hyaluronic acid that can be used to increase viscosity. It is also possible to use soluble or insoluble inserts to administer the drug.
It is a further object of the present invention the use of compounds derivative of ophthalmic products as for general formula (I), and the preferred compounds as described above, for preventing, treating or reducing ocular diseases, also in combination with other ocular agents, as well as the method for preventing, treating or reducing ocular diseases, said method comprising the use of compounds derivative of ophthalmic products as for 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 maleate of l-(tert-butylaπιino) - 3- (4-morpholino-l, 2, 5-thiadiazol-3-yloxy)propan-2-yl 4- (3-thioxo-3ff-l,2-dithiol-4-yl)benzoate. Step 1: Preparation of 4- (3-thioxo-3H-l , 2-dithiol-4- BE15212
22
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 1460C and the reaction mixture is stirred at 2200C 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. 157.5-159.50C. 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 CH2CI2-methanol (9:1) . The organic phase is dried on anhydrous sodium sulphate, BE15212 9
evaporated to dryness and the residue is washed with ether and CH2CI2 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:
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC) (287 mg; 1.5 iranol) in 18 ml of chloroform (CHCI3) purified on basic alumina, is added in a flask containing 4- (3-thioxo-3H-l , 2-dithiol-4-yl) benzoic acid (254 mg; 1.0 mmol) prepared as above described and dimethylaminopyridine (DMAP, 12 mg) . The red suspension is maintained in ice bath under nitrogen for few minutes before adding a timolol free base (316 mg; 1.0 mmol) solution in CHCI3 (2 ml) . The mixture is stirred at room temperature, under nitrogen for 12 h.
The chloroformic solution is extracted in a separator funnel with cold water, dried with anhydrous sodium sulphate and, after filtration, evaporated to dryness. The residue is chromatographed on silica gel column, eluting with a mixture of CH2Cl2-MeOH by gradient. The compound is eluted when methanol is 5% . The compound has the following NMR : 1H NMR(300 MHZ, CDCl3) : δ 1.20 (s, 9H), 3.00-3.20 (m, 2H), 3.45 (t, 4H), 3.70 (t, 4H), 4.70- 4.90 (m, 2H), 5.60-5.70(m, IH), 7.65 (d, 2H), 8.05 (d, 2H) , 8.45 (s, IH) . BE15212
Step 3:
A solution of the compound obtained in the previous step (144 mg, 0.26 mmol) in THF (1.7 ml) is added to a solution of maleic acid (30.5 mg, 0.26 mmol) in THF (0.6 ml) . An orange product precipitates immediately. After stirring for 1 hour at room temperature the product is filtered and washed with THF. The obtained salt has a m.p. of 185-186°C. EXAMPLE 2. Synthesis of 2-(9-fluoro-ll, 17-dihydroxy- 10,13,16-trimethyl-3-oxo-6,7,8,9,10,ll,12,13,14,15,16,17- dodecahydro-3Jf-cyclo-pβnta [α]phenanthren-17-yl) -2- oxoethyl 4- (3ff-thioxo-l,2-dithiol-4-yl)benzoate. 4-(3-thioxo-3H-l,2-dithiol-4-yl)benzoic acid (254 mg; 1.0 mmol), prepared as described in step 1 of example 1, dexamethasone (392.5 mg; 1.0 mmol), dimethylaminopyridine (DMAP, 6 mg) and 40 ml of chloroform (CHCI3, treated on basic alumina) are mixed together in a two neck flask. A solution of IN dicyclohexylcarbodiimide (DCC) in CHCl3 (1.1 mmol; 227 mg) in 1.1 ml of CHCI3 is added to the above suspension. The mixture is stirred at room temperature, under nitrogen for 17 hours .
The suspension is filtered and the product is washed with CHCI3. The chloroformic fractions are evaporated to dryness and then chromatographed on silica column eluting BE15212
with a CH2Cl2-πιetanol mixture by gradient (0.5%-2%) . An orange solid is obtained. 1H NMR(CDCl3) : δ 0.88 (d, 3H), 1.10 (s, 3H), 1.20-1.40 (m, IH), 1.55 (s, 3H), 1.70- 2.00 (m, 4H), 2.05-2.20 (m, IH), 2.30-2.50 (m, 3H), 2.50- 2.70 (m, IH), 3.05-3.20 (m, IH), 4.40 (d, IH), 5.10 (s, 2H), 6.08 (s, IH), 6.35 (d, IH), 7.20 (d, IH), 7.65 (d, 2H), 8.15 (d, 2H), 8.45 (s, IH) .
ESEMPIO 3. Synthesis of 2-(9-fluoro-ll,17-dihydroxy- 10,13,16-trimethyl-3-oxo-6,7,8,9,10, 11,12,13,14,15,16,17- dodecahydro-3ff-cyclo-penta[α]phenanthren-17-yl) -2- oxoethyl 3- (mβthylsulfonylthio)propanoate.
Step 1: Synthesis of 3 -methanesulfonylsulfanyl-propionic acid. Sodium methanethiosulfonate (1.5 g; 11.18 mmol) and 3- bromopropionic acid (900 mg; 5.88 mmol) 97% are dissolved in dimethylformamide (DMF, 9.05 ml) . The reaction is performed at 60° C, stirring under nitrogen for 4 hours. The solution is evaporated to dryness and the residue is dissolved in water, acidified with 10 ml of a 2N KHSO4 solution and washed with ethyl acetate. The organic phase is extracted with cold 2N KHSO4 solution, then with ice water and finally dried on anhydrous sodium sulphate and evaporated to dryness . An oily yellow product is obtained. Step 2: BE15212
Dimethylaminopyridine (5.5 mg) is added to a solution of dexamethasone (353 mg; 0.9 mmol) and of the compound prepared in step 1 (166 mg; 0.9 mmol) in 1.5 ml of dimethyl formamide (DMF) and then, stirring the reaction mixture under nitrogen in ice bath, a solution of 1- (3- dimethylaminoisopropyl) -3-ethyl-carbodiimide hydrochloride (EDAC, 1.35 mmol; 259 mg) in 0.5 ml of DMF is added. The reaction mixture is stirred under nitrogen at room temperature for 24 hours. After evaporation under reduced pressure of DMF, the residue is dissolved in methylene chloride and the organic solution is washed in a separator funnel with cold water. The organic phase is dried on anhydrous sodium sulphate, and after filtration, evaporated to dryness . The obtained product is chromatographed on column of silica gel eluting with a mixture of methylene chloride/methanol . EXAMPLE 4. Biological activity
As previously reported the oxidative stress is a common pathogenetic factor for the various ocular pathologies, and this condition is characterized by a reduced glutathione tissue depletion.
The ability of the tested products to restore the amount of reduced glutathione in ocular tissue damaged by oxidative stress induced by xanthine-oxidase and uricase BE15212
(XO+U) was tested, using the method already described by Varma et al . (Varma SD, Hegde K, Henein M. Oxidative damage to mouse lens in culture. Protective effect of pyruvate. Biochim Biophys Acta. 2003, 1621 (3 ) : 246-52 ) . Briefly, Swiss mice weighting about 22 g. were used. The animals were sacrificed by cervical dislocation, the eyes enucleated and intact lens isolated. The tissue was incubated for 4 hours at 370C in presence of 10 microliters of a potassium phosphate buffer solution at pH 7.5 containing 25 U of xanthine-oxidase and 2.5 microliters of a potassium phosphate solution buffered at pH 7.5 containing 100 U of uricase. The products, tested at the 10 micromolar concentration, were dissolved in DMSO 0.1%. The results expressed as % inhibition of the GSH depletion observed in the group with oxidative stress (XO+U), containing only DMSO 0.1%, are reported in the table.
As can be seen all products tested resulted capable to inhibit completely the depletion of GSH induced by oxidative stress. BE15212
28
Figure imgf000029_0001

Claims

BE1521229CLAIMS :
1. Compounds of general formula:
A-X-Y-W (I) wherein A is a residue of drugs used in ocular field belonging to one of the following classes: corticosteroids, betablockers , carbonic anhydrase inhibitors, antimuscarinics, sympathomimetics (alpha adrenergic agonistis), local anesthetics, antibacterials, antivirals, miotics, anthistaminics, antifungals, neuroprotectant agents and MMDA receptor antagonists; X is a group capable to link to ~Y or ~W, selected from the group comprising -COO-; -O- ; -CONH-; -OCO-; -0C00-; - CO-; Y is zero; - (CnO alkyl- , - (Cn. ) alkyl-CO- , -0- (Cn- ) alkyl-0- , -00C- (Cn')alkyl-COO-; -0- (Cn. ) alkyl- , -HN- (Cn- ) alkyl- , -00C- (CnO alkyl-; - (CnO alkyl-0-CO- (Cn- ) alkyl-;
~ (CnO alkyl-CO-0- (Cn-O alkyl- wherein (CnO alkyl 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, BE15212
their stereoisomers and salts thereof.
2. Compounds of general formula (I) according to claim 1, wherein A is a residue of a drug used in ocular field selected from the group comprising: dexamethasone, fluorometholone, betamethasone, hydrocortisone, prednisolone, timolol, betaxolol, carteolol, levobunolol, metipranolol , dorzolamide, acetazolamide, brinzolamide, atropine, tropicamide, cyclopentolate, phenylephrine, brimonidine, dipivefrine, apraclonidine lidocaine, procaine chloramphenicol, ciprofloxacin, levofloxacin, gentamycin, aciclovir, ganciclovir, pilocarpine, antazoline, azelastine, epinastine, ketotifen, miconazole, econazole, flucytosine, memantine, dexanabinol, remacemide.
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-Sθ2-R is linked to A-Y-; R is a straight or branched alkyl selected from the group consisting of 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. BE15212
4. Compounds of general formula (I) according to claim 1, wherein W is a dithiole-thione derivative having formula:
Figure imgf000032_0001
(III) or (IV) wherein
Z is S (sulphur) and at least 1 Z is C=S (thione) , m is 0, 1-10; 0 T is:
-00C-; or
Figure imgf000032_0002
wherein
Rl is -H; -COOH; -NH2 ; -OH; -SH; 5 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 heteroatoms0 selected from nitrogen, oxygen, or sulphur.
5. Compounds of general formula (I) according to claim 1, wherein W is an allyl sulfide derivative having BE15212
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, -O- ; -OQC-; -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, allyl tetrasulfide 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 or organic acids comprising fumaric acid, citric acid, tartaric acid, maleic acid.
9. Compounds of general formula (I) according to claim 3 , wherein the group W is selected from the group comprising thiosulfonate moieties derived from the corresponding precursors having formula: S- (2- carboxyethyl) methanethiosulfonate, S- (2- BE15212
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-I , 2-dithiol-3-thione, 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 precursors having formula: 2-(2- allyldisulfanyl) ethanol ; 3- (2-allyldisulfanyl)propanoic acid; 2- (2 -allyldisulfanyl) -etilamine .
12. Compound of general formula (I) according to claim 1, wherein said compound is 2- (9-fluoro-11, 17- dihydroxy-10, 13, 16-trimethyl-3-oxo-6 , 7 , 8 , 9 , 10, 11 , 12 , 13 , 14, 15, 16, 17-dodecahydro-3H-cyclopenta [αjphenanthren- 17-yl) -2-oxoethyl 3- (methylsulfonylthio)propanoate.
13. Compound of general formula (I) according to claim 1, wherein said compound is 2- (9-fluoro-11, 17- dihydroxy-10, 13 , 16-trimethyl-3-oxo- 6,7,8,9,10,ll,12,13,14,15,16,17-dodecahydro-3H-cyclo- BE15212
34
penta[α]phenanthren-17-yl) -2-oxoethyl 4- (3H-thioxo-l , 2- dithiol-4-yl ) benzoate .
14. Compound of general formula (I) according to claim 1, wherein said compound is 1- ( tert-butylamino) -3- (4-morpholino-l, 2 , 5-thiadiazol-3-yloxy) propan-2-yl 3- (methylsulfonylthio) propanoate .
15. Compound of general formula (I) according to claim 1, wherein said compound is 1- ( tert-butylamino) -3- ( 4-morpholino-l , 2 , 5-thiadiazol-3-yloxy) propan-2-yl 3- (allyldisulfanyl) propanoate.
16. Compound of general formula (I) according to claim 1, wherein said compound is 1- ( tert-butylamino) -3- (4-morpholino-l , 2 , 5-thiadiazol-3-yloxy) propan-2-yl 4- (3- thioxo-3H-l,2-dithiol-4-yl) benzoate.
17. Compound of general formula (I) according to claim 1, wherein said compound is N- (5-acetamido-l , 3 , 4- thiadiazol-2-ylsulfonyl) -3- (allyldisulfanyl )propanamide.
18. Compound of general formula (I) according to claim 1, wherein said compound is 3- (3-hydroxy-2- phenylpropanoyloxy) -δ-methyl-δ-azonia-bicyclo [3.2.1] ottane 3- (allyldisulfanyl ) propanoate .
19. Compound of general formula (I) according to claim 1, wherein said compound is (J?) -1- (3- hydroxyphenyl ) -2- (methylamino) ethyl 4- (3-th.ioxo-3.H-l , 2- dithiol-4-yl) benzoate. BE15212
20. Compound of general formula (I) according to claim 1, wherein said compound is (4- (5-tioxo-5H-l , 2- dithiol-3-yl ) -phenyl 2- (5-bromoquinoxalin-6-ylamino) -4 , 5- dihydroimidazole-1-carboxylate .
21. Compound of general formula (I) according to claim 1, wherein said compound is 2- (allyldisulfanyl) ethyl 2- (5-bromoquinoxalin-6-ylamino) - 4 , 5-dihydroimidazole-l-carboxylate.
22. Compound of general formula (I) according to claim 1, wherein said compound is 2- (2, 6- dimethylphenylamino) -N,N-diethyl-2-oxoethanaminium 3- ( allyldisulfanyl ) propanoate .
23. Compound of general formula (I) according to claim 1, wherein said compound is 4- (5-tioxo-5H-l , 2- dithiol-3-yl) phenyl l-cyclopropyl-6-fluoro-4-oxo-7- (piperazin-1-yl ) -1 , 4-dihydroquinoline-3 -carboxylate .
24. Compound of general formula (I) according to claim 1, wherein said compound is 2- [ (2-amino-6-oxo-l, 6- dihydropurin-9-yl )methoxy] ethyl 4- (3-tioxo-3H-l , 2- dithiol-4-yl)benzoate.
25. Compound of general formula (I) according to claim 1, wherein said compound is 5- ( ( (3R, 4S) -4-ethyl-5- oxo-tetrahydrofuran-3 -yl ) methyl ) -1-methyl-IH-imidazol-1 - ium 3- (methylsulfonylthio) propanoate .
26. Compound of general formula (I) according to BE15212
36
claim 1, wherein said compound is 9 , 13b-dihydro-lH- dibenz [c, f ] imidazo [1 , 5-a] azepin-3- [3 -allyltrisulfan.il ) - propionamide] .
27. Compound of general formula (I) according to claim 1, wherein said compound is 4- (5-thioxo-5H-l, 2- dithiol-3 -yl ) phenyl 2- (3- (5-fluoro-2-oxo-l , 2 ,3,4- tetrahydropiridin-4-yl ) ureido) acetate.
28. Compound of general formula (I) according to claim 1, wherein said compound is 3,5-dimethyl triciclo[3.3.1.13'7]decan-l-[3-(allyldisulfanyl) propion] amide .
29. Pharmaceutical composition comprising at least a compound of general formula (I) according to claims 1-28 as an active ingredient and eventually one or more pharmaceutically acceptable adjuvant(s) or carrier(s) .
30. Compound of general formula (I) according to claims 1-28 for use as a medicament.
31. Use of a compound of general formula (I) according to claims 1-28 for the manufacture of a medicament for prevention, treatment and reduction of ocular diseases.
32. Use of a compound of general formula (I) according to claims 1-28 for the manufacture of a medicament for prevention, treatment and reduction of ocular diseases, in combination with other ophthalmic BE15212
agents .
33. Use of the compound 5- (p-hydroxyphenyl-3H-l, 2- dithiol-3-thione) having formula:
Figure imgf000038_0001
for the manufacture of a medicament for prevention, treatment and reduction of ocular diseases .
34. Use of one or more compounds selected from the group comprising ketoprofen ester with 5- (p- hydroxyphenyl ) -3H-1, 2-dithiol-3-thione; ketorolac ester with con 5- (p-hydroxyphenyl) -3H-1, 2-dithiol-3-thione; 4- (3H-l,2-dithiol-3-thion-5-yl) -phenyl ester of 2- [(2,6- dichlorophenyl) amino] -benzenacetic acid; 4-(3H-I, 2- dithiol-3-thion-5-yl) -phenylester of 2 ' , 4 ' -difluoro-4- hydroxy- [1, 1 ' -biphenyl] -3-carboxylic acid; the corresponding 4- (3H-1 , 2-dithiol-3-thion-5-yl) - phenylesters of lumeracoxib, flufenamic acid, niflumic acid for the manufacture of a medicament for prevention, treatment and reduction of ocular diseases.
35. Use of one or more compounds selected from the group comprising 4- (3-thioxo-3Jf-l, 2-dithiol-4-yl) benzoic acid 2-butyl-4-chloro-l- [p- (o-lJf-tetrazol-5-ylphenyl) - benzyl] imidazole-5-methyl ester; 2-butyl-4-chloro-l-[ (2'- (lH-tetrazol-5-yl) (1,1'- BE15212
38
biphenyl) -4-yl) methyl ] -lH-imidazole-5-carboxylic acid 4- (3H-1, 2-dithiol-3-thion-5-yl) -phenylester; 2-butyl-4-chloro-l- [ (2 ' - (lH-tetrazol-5-yl) (1,1' -biphenyl- 4-yl ) methyl ] -lH-iinidazole-5-carboxylic acid 2- (methylsulfonylthio) ethyl ester;
3-methanesulfonylsulfanyl-propionic acid 2-butyl-4- chloro-1- [p- ( o-Iff- tetrazol-5-ylphenyl ) benzyl ] - imidazole- 5-methyl ester; 4'- [ (l,4'-dimethyl-2'-propyl[2, 6 ' -bi-lff-benzimidazol] -1'- yl ) methyl] [1,1 '-biphenyl] -2-carboxylic acid 4-(3H-I, 2- dithiol-3-thion-5-yl) -phenyl ester for the manufacture of a medicament for prevention, treatment and reduction of ocular diseases .
36. Process for the synthesis of compounds of general formula (I) according to claim 1-28, comprising at least a reaction between a corresponding precursor of an organic thiosulfonate or dithiol-thione or trithiocarbonate or an allylsulfide, moiety W or Y-W, and an ophthalmic compound or its derivatives or at least a reaction between a corresponding precursor of an organic thiosulfonate or dithiol-thione or trithiocarbonate or an allylsulfide, moiety W, and a corresponding precursor of an ophthalmic compound or its derivative modified with X/Y, wherein W and X/Y have the meaning according to claim 1.
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