WO2008071421A1 - Nitrate esters of carbonic anhydrase inhibitors - Google Patents

Nitrate esters of carbonic anhydrase inhibitors Download PDF

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WO2008071421A1
WO2008071421A1 PCT/EP2007/010915 EP2007010915W WO2008071421A1 WO 2008071421 A1 WO2008071421 A1 WO 2008071421A1 EP 2007010915 W EP2007010915 W EP 2007010915W WO 2008071421 A1 WO2008071421 A1 WO 2008071421A1
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compound
ono
integer
group
formula
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Claudiu Supuran
Francesca Benedini
Stefano Biondi
Ennio Ongini
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Nicox S.A.
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    • 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
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Abstract

Nitroderivatives of carbonic anhydrase inhibitors having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, cancer, epilepsy, high-altitude disorders and neuromuscular diseases.

Description

NITRATE ESTERS OF CARBONIC ANHYDRASE INHIBITORS
The present invention relates to new carbonic anhydrase inhibitors (CAIs) derivatives. More particularly, the present invention relates to nitroderivatives of CAIs, pharmaceutical compositions containing them and their use as drugs for treating glaucoma, ocular hypertension, age- related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, cancer, epilepsy, high-altitude disorders and neuromuscular diseases.
In higher vertebrates, including humans, 14 different Carbonic anhydrase (CA) isoenzymes or CA-related proteins (CARP) were described, with very different subcellular localisation and tissue distribution. There are several cytosolic forms (CA I-III, CA VII), four membrane-bound isoenzymes (CA IV, CA IX, CA XII and CAXIV) , one mitochondrial form (CA V) and one secreted CA isozyme (CA
VI) {Supuran CT. ; Scozzafava A. Expert Opin. Ther. Patents
(2002) 12, 217-242) . Carbonic anhydrase is found in many tissues that secrete acidic or alkaline fluids, including the ocular ciliary epithelium.
The physiological function of the CA I is still unknown. The expression of CA XII has been linked to tumour invasiveness, similarly to that of CA IX.
CA II and CA IV are involved in the formation of agueous humor. The human isozyme hCA IV is abundant in a multitude of tissues, such as nasal mucosa, oesophageal epithelium, kidneys, pancreas, salivary glands, heart muscle (endothelial and muscle cells) , eyes, lungs, brain capillaries, and colon, playing important physiological functions related to the nasal chemiosensitivity to CO2, the antireflux defense, bicarbonate reabsorption, NH4 + output, pH regulation, production of ocular fluids, gas exchange.
CA Va and CA Vb are the targets for new antiobesity agents, whereas CA VII for the development of antiepileptic drugs . S-Glutathiolation of CA III was shown to occur rapidly in hepatocytes under oxidative stress.
With CAIs a class of compounds is intended, comprising as main components acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide and brinzolamide.
Many CAIs were clinically developed as antiglaucoma drugs but other applications were also found such as epilepsy, neuromuscular diseases and high-altitude disorders
(Martindale, The complete drug reference, 33rd edition, 826- 827) .
Several side effects are associated with oral carbonic anhydrase inhibitors include fatigue, anorexia, depression, paresthesias and serum electrolyte abnormalities (The Merck
Manual of Diagnosis and Therapy, Seventeenth Edition, M. H. Beers and R. Berkow Editors, Sec. 8, Ch. 100) .
WO 2006/052899 discloses novel nitrosated and/or nitrosylated compounds or pharmaceutically acceptable salts thereof, and novel compositions, for treating ophthalmic disorders comprising at least one nitrosated and/or nitrosylated compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent selected from the group consisting of an α-adrenergic receptor agonist, an ACE inhibitor, an antimicrobial, a β-adrenergic antagonist, a carbonic anhydrase inhibitor, a non-steroidal anti-inflammatory drug, a prostaglandin, a COX-2 inhibitor and a steroid.
It is an object of the present invention to provide new derivatives of CAIs able not only to eliminate or at least reduce the side effects associated with the conventionally carbonic anhydrase inhibitors, but also to possess an improved pharmacological activity. It has been surprisingly found that the compounds of the invention have a significantly improved overall profile as compared to carbonic anhydrase inhibitors both in terms of wider pharmacological activity, enhanced tolerability and long- acting ocular hypotensive activity. In particular, it has been recognized that the carbonic anhydrase inhibitors nitroderivatives can be employed for treating eye disorders in particular, glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies; cancer, epilepsy, high-altitude disorders and neuromuscular diseases.
An object of the present invention is a method for treating eye disorders and cancer in a patient in need thereof comprising administering a therapeutically effective amount of a carbonic anhydrase inhibitor able to release nitric oxide.
A carbonic anhydrase inhibitor is a compound having an inhibition constant (Ki) against at least one of the isoenzymes CAII, CAIV, CAIX and CAXII in the range of 0.01- 200 nM. The carbonic anhydrase activity is measured according to the test on carbonic anhydrase inhibition as reported below.
A carbonic anhydrase inhibitor able to release nitric oxide is a compound having an EC50 value in the range of 1- 50μM, in a vasorelaxation assay. The vasorelaxation is measured according to the test on vascular tone as reported below.
More particularly, object of the present invention is nitroderivatives of carbonic anhydrase inhibitors of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
R- (X-Y-ONO2) s
(I) wherein s is an integer equal to 1 or 2, preferably s is 1; R is selected from the group consisting of:
Figure imgf000005_0001
Figure imgf000006_0001
wherein n is an integer from 0 to 4 ; m is an integer equal to 0 or 1;
R1, R2 and R3 are the same or different and are H, Cl, Br, I,
F, CF3, SO2NH2;
X1 is -O- or -NH-; N1 is -OH, -COOH, -O-, -C(O)-, -NHR1 or -NR1- wherein R1 is H or C1-C6 alkyl;
R' is H or a group -(X-Y-ONO2) ;
X is -C(O)-, -O-, -NR1-, -S-, -C(O)O- or -C(O)S-; with the proviso that: i) when the group -(X-Y-ONO2) is bound to N1, then: - N1 is -O- or -NR1- and X is -C(O)-, -C(O)O- or -C(O)S-, wherein R1 is H or C1-C6 alkyl, preferably R1 is H, preferably X is -C(O)- or -C(O)O-; - N1 is -C(O)- and X is -O- , -NR1-, -S-, -C(O)O- or -C(O)S-, wherein R1 is H or C1-C6 alkyl, preferably R1 is H, preferably X is -O- or -NR1-; ii) when R' is a group -(X-Y-ONO2) then X is -C(O)-, -C(O)O- or -C(O)S-, preferably X is -C(O)- or -C(O)O-; iii) when s is 2, then -X and -Y- of the two groups
-(X-Y-ONO2) can be the same or different; preferably R is (IIA) or (IIB);
Y is a bivalent radical having the following meaning: a) straight or branched C1-C20 alkylene, preferably straight or branched C1-C10 alkylene; straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, -ONO2 or T, wherein T is -OC(O) (C1-C10 alkyl) -ONO2 or -O(C1-C10 alkyl) -ONO2, preferably straight or branched C1-C10 alkylene substituted with one or more of the substituents selected from -ONO2 or -OC(O)(C1-C10 alkyl)-ONO2 or -O (C1-C10 alkyl) -ONO2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl; b)
Figure imgf000007_0001
c)
Figure imgf000007_0002
wherein n0 is an integer from 0 to 20, preferably n0 is an integer from 0 to 5, n1 is an integer from 1 to 20, preferably n1 is an integer from 1 to 10 or from 1 to 5; d)
Figure imgf000008_0001
wherein
Xi = -OC(O)- or -C(O)O-, preferably Xi is -C(O)O-; n2 is an integer from 0 to 2, preferably n2 is 1;
R2 is H or CH3, preferably R3 is -CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 20, preferably n1 is an integer from 1 to 10; e)
Figure imgf000008_0002
wherein:
Y1 is -CH2-CH2-(CH2)n2a- or -CH=CH- (CH2) n 2a- wherein n2a is from 0 to 2, preferably n2a is 0 or 1; Xi is -OC(O)- or -C(O)O-, n2 is an integer from 0 to 2, preferably n2 is 1 R2 is H or CH3, preferably R2 is CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 20; when Y is selected from the bivalent radicals mentioned under b)-e), then the -ONO2 group is bound to -(CH2)n 1; f)
Figure imgf000009_0001
wherein: n1 is an integer from 1 to 20, preferably n1 is an integer from 1 to 10;
R3 is H or CH3, preferably R3 is H,
R0 is H or -COCH3, preferably R0 is -COCH3 ; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to - (CH2)n 1; g)
Figure imgf000009_0002
wherein X2 is -O- or -S-, n3 is an integer from 1 to 6, preferably n3 is 1,
R2 is H or CH3, preferably R2 is H; h)
Figure imgf000010_0001
wherein: n4 is an integer from 0 to 10, preferably n4 is an integer from 0 to 5; n5 is an integer from 1 to 10, preferably n5 is an integer from 1 to 5;
R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000010_0003
wherein n5 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
Figure imgf000010_0002
Figure imgf000011_0001
(Y (Y13) preferably Y2 is (Y1), (Y2), (Y4), (Y5) , (Y6) or (Y13). Preferred compounds of formula (I) are those wherein Y has the following meaning: a) straight or branched C1-C10 alkylene, straight or branched C1-C10 alkylene substituted with one or more substituents selected from -ONO2 -OC(O) (C1- C10 alkyl) -ONO2 or -O (C1-C10 alkyl) -ONO2; b)
Figure imgf000011_0002
c)
Figure imgf000011_0003
wherein n0 is an integer from 0 to 5, and n1 is an integer from 1 to 5; d)
Figure imgf000011_0004
wherein:
Xi = -OC(O)- or -C(O)O-;
Z is -(CH2)n 1- or the bivalent radical defined above under b) wherein n1 is an integer from 1 to 10 and n2 is 1, and R2 is H or CH3; e)
Figure imgf000012_0001
wherein:
Y1 is -CH2-CH2- (CH2) n 2a- or -CH=CH- (CH2) n 2a- wherein n2a is 0 or 1;
Xi is -OC(O)- or -C(O)O-, n2 is 1, R2 is CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 10; with the proviso that: when Y is selected from the bivalent radicals mentioned under b) -e) , then the terminal -ONO2 group is bound to - (CH2)n 1; f)
Figure imgf000012_0002
Figure imgf000013_0001
wherein: n1 is an integer from 1 to 10; R3 is H,
R0 is H or -COCH3, preferably R0 is -OCOCH3; ; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to - (CH2)n 1; g)
Figure imgf000013_0003
wherein X2 is -O- or -S-, n3 is 1 and R2 is H; h)
Figure imgf000013_0002
wherein : n4 is an integer from 0 to 5 ; n5 is an integer from 1 to 5 ; R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000014_0003
wherein n5 is as defined above; Y2 is selected from
Figure imgf000014_0001
An object of the present invention refers to nitroderivatives of carbonic anhydrase inhibitors of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
R-(X-Y-ONO2)s
(I) wherein s is 1 ; R is
Figure imgf000014_0002
wherein in formula (IIA)
R1, R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 4 of the phenyl ring, R' is H; n is 0, N1 is -C(O)-, and N1 binds the group -(X-Y-ONO2);
X is -O-, -S- or -NR1- wherein R1 is H or C1-C6 alkyl; or
R1, R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 4 of the phenyl ring, R' is H; n is 0 or 1, N1 is -O- and N1 binds the group -(X-Y-ONO2);
X is -C(O)-, -C(O)O- or -C(O)S-; or
R1 is Cl and R1 is in position 4 of the phenyl ring, R2 and
R3 are H; m is 0 and the group -SO2NHR' is in position 3 of the phenyl ring, R' is H; n is 0, N1 is -C(O)- and N1 binds the group -(X-Y-ONO2);
X is -O-, -S- or -NR1- wherein R1 is H or C1-C6 alkyl; or
R1 R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 3 of the phenyl ring, R' is H; n is 3, N1 is -C(O)-, and N1 binds the group -(X-Y-ONO2);
X is -O-, -S- or -NR1- wherein R1 is H or C1-C6 alkyl; Y is selected from: a) straight or branched C1-C10 alkylene, straight or branched C1-C10 alkylene substituted with one or more substituents selected from -ONO2 -OC(O) (C1- C10 alkyl) -ONO2 or -O (C1-C10 alkyl) -ONO2; b)
Figure imgf000016_0001
C )
Figure imgf000016_0002
wherein n0 is an integer from 0 to 5, and n1 is an integer from 1 to 5; d)
Figure imgf000016_0003
wherein:
Xi = -OC(O)- or -C(O)O-;
Z is -(CH2)n 1- or the bivalent radical defined above under b) wherein n1 is an integer from 1 to 10 and n2 is 1,
R2 is H or CH3, preferably R2 is CH3; e)
Figure imgf000016_0004
wherein:
Y1 is -CH2-CH2- (CH2 ) n 2a- or -CH=CH- (CH2 ) n 2a- wherein n2a is 0 or 1 ; Xi is -OC(O)- or -C(O)O-, n2 is 1, R2 is CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 10; with the proviso that: when Y is selected from the bivalent radicals mentioned under b) -e) , then the terminal -ONO2 group is bound to - (CH2)n 1; f)
Figure imgf000017_0001
wherein: n1 is an integer from 1 to 10;
R3 is H,
R0 is H or -COCH3, preferably R0 is -COCH3 ; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to -
(CH2)n 1; g)
Figure imgf000017_0002
wherein X2 is -O- or -S-, n3 is 1, R2 is H; h)
Figure imgf000018_0001
wherein: n4 is an integer from 0 to 5; n5 is an integer from 1 to 5;
R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000018_0003
wherein n5 is as defined above; Y2 is selected from
Figure imgf000018_0002
Another object of the present invention deals with nitroderivatives of carbonic anhydrase inhibitors of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof R-(X-Y-ONO2)s (I) wherein s is 1 ; R is
Figure imgf000019_0001
(II B) wherein in formula (IIB) N1 is -C(O)- and N1 binds the group -(X-Y-ONO2); R' is H;
X is -O-, -NR1-, -S- wherein R1 is H or a or C1-C6 alkyl; or N1 is -COOH; R' is the group -(X-Y-ONO2);
X is -C(O)-, -C(O)O- or -C(O)S-; Y is a) straight or branched C1-C10 alkylene, - straight or branched C1-C10 alkylene substituted with one or more substituents selected from -ONO2 or -OC(O) (C1-C10 alkyl) -ONO2 or -O(C1-C10 alkyl) -ONO2; b)
Figure imgf000019_0002
c)
Figure imgf000020_0001
wherein n0 is an integer from 0 to 5, and n1 is an integer from 1 to 5; d)
Figure imgf000020_0002
wherein:
X1 = -OC(O)- or -C(O)O-;
Z is -(CH2)n 1- or the bivalent radical defined above under b) wherein n1 is an integer from 1 to 10 and n2 is 1,
R2 is H or CH3, preferably R2 is CH3; e)
Figure imgf000020_0003
wherein:
Y1 is -CH2-CH2-(CH2)n 2a- or -CH=CH- (CH2) n 2a- wherein n2a is 0 or 1;
Xi is -OC(O)- or -C(O)O-, n2 is 1, R2 is CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 10; with the proviso that: when Y is selected from the bivalent radicals mentioned under b) -e) , then the terminal -ONO2 group is bound to - (CH2)n 1; f)
Figure imgf000021_0001
wherein: n1 is an integer from 1 to 10;
R3 is H,
R0 is H or -COCH3, preferably R0 is -COCH3 ; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to - (CH2)n 1; g )
Figure imgf000021_0002
wherein X2 is -O- or -S- , n3 is 1 and R2 is H; h )
Figure imgf000022_0001
wherein : n4 is an integer from 0 to 5 ; n5 is an integer from 1 to 5 ;
R4 , R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000022_0003
wherein n5 is as defined above; Y2 is selected from
Figure imgf000022_0002
The term "C1-C20 alkylene" as used herein refers to branched or straight chain C1-C20 hydrocarbon, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n- hexylene and the like.
The term "C1-C10 alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
The term "cycloalkylene" as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C1-C10) - alkyl, preferably CH3.
The term "heterocyclic" as used herein refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like. The following are the most preferred compounds according to the present invention:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
As stated above, the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines . The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred. The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the scope of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I), including mixtures enriched in a particular isomer.
The invention also relates to the use of the compounds of formula (I) as antiglaucoma agents or as drugs able to reduce the intraocular pressure and to maintain said pressure on a reduced level.
The invention also relates to the use of the compounds of formula (I) as drugs for treating glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies .
As mentioned above, objects of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adjuvants and/or carriers usually employed in the pharmaceutical field.
The daily dose of active ingredient administered to a host can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. The dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state . The compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation spray o aerosol, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. Topical preparations can be administered as solutions, suspensions or emulsions (dispersions) in an ophthalmically acceptable vehicle. The term "ophthalmically acceptable vehicle" as used herein refers to any substance or combination of substances which are non-reactive with the compounds and suitable for administration to patients. Preferred are aqueous vehicles suitable for topical application to the patient's eyes.
Other ingredients which may be desirable to use in the ophthalmic compositions of the present invention include antimicrobials, preservatives, co-solvents, surfactants and viscosity building agents.
Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques . Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent o solvent. Among the acceptable vehicles and solvents are water, Ringer' s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, in addition fatty acids such as oleic acid find use in the preparation of injectables .
Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and the like.
It is further contemplated that the compounds of the present invention can be used with other medicaments known to be useful in the treatment of glaucoma or ocular hypertension, either separately or in combination. For example the compounds of the present invention can be combined with (i) beta-blockers, such as timolol, betaxolol, levobunolol and the like described in U.S. Pat. No. 4,952,581; (ii) prostaglandin analogs, such as bimatoprost, latanoprost, travoprost or unoprostone (iii) α-adrenergic agonists including clonidine derivatives, such as apraclonidine or brimonidine described in U.S. Pat. No. 5,811,443. Also contemplated is the combination with nitrooxy derivatives of the above reported compounds, for example nitrooxy derivatives of beta-blockers described in US 6,242,432 or nitrooxy derivatives of prostaglandin analogs described in WO 2005/068421.
It is also contemplated that the compounds of the present invention can be used with other medicaments known to be useful in the treatment of cancer, either separately or in combination.
The compounds of the present invention can be synthesized as follows.
Synthesis procedure
1. The compound of general formula (I) as above defined wherein: X is -CO-, s is 1, Y and R are as above defined and N1 is - O- or -NR1- wherein R1 is as above defined can be obtained by a process comprising:
Ia. reacting a compound of formula B with a compound of formula (Ilia) :
B + HOOC-Y-ONO2
(IIIa)
wherein Y is as above defined; B is equal to R with N1 is - OH or -NR1H and R' is H or PG wherein PG is an sulfonamido protective group such as dimethylformamidine, in presence of a condensing agent like dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -Nf -ethylcarbodimide hydrochloride (EDAC) or N, N' -carbonyldiimidazole (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5 °C to 50°C in the presence or not of a base as for example DMAP and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol. The nitric acid ester compounds of formula (Ilia) can be obtained from the corresponding alcohols of formula HOOC-Y- OH (IIIb), that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C or reacting the corresponding halogen derivatives of formula HOOC-Y-HaI (IIIc) wherein Hal is an alogen atom preferable Cl, Br, I, that are commercially available, with AgNO3 as already described in the international application No. WO 2006/008196.
1b. reacting a compound of formula B as above defined with a compound of formula (IIId): B + ACt-CO-Y-ONO2 (IIId )
wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :
Figure imgf000052_0001
The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2 and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol. The compounds of formula (IIId) can be obtained as described in the international application No. WO 2006/008196.
Ic. reacting a compound of formula R-X-Y-HaI (IVa), wherein R and X are as above defined, with AgNO3 as already described. Compounds (IVa) can be obtained by reacting compound B with compounds (IIIc), as above defined, with a condensing reagent such as DCC or CDI as above described and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol. Id. reacting a compound of formula R-X-Y-OH (Va) , wherein R and X are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described. Compounds (Va) can be obtained by reacting compound B with compounds (IIIb), as above defined, with a condensing reagent as above described and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol.
2. The compound of general formula (I) as above defined wherein:
X is -COO-, s is 1, Y and R are as above defined and N1 is - O- or -NR1 can be obtained by a process comprising:
2a. reacting a compound of formula B with a compound of formula (VIa) :
B + Act—CO O—Y—ONO2
(VIa) wherein B is equal to R with N1 is -OH or -NR1H and R' is H or PG which is an sulfonamido protective group such as dimethylformamidine; Act and Y are as above described. The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2 and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol.
The synthesis of compounds (VIa) has already been described in the international application No. WO 2006/008196. 2b. reacting a compound of formula R-X-Y-HaI (VIla) wherein R, X, Y and Hal are as above defined, with AgNO3 as above described. The compounds of formula (VIla) can be obtained by reacting compound B with compounds Act-CO-O-Y-Hal (VIlla) . The reaction is generally carried out in presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C as above described and optionally deprotecting the compounds by reaction with hydrochloric acid in methanol .
Compound (VIlla) are commercially available or can be synthesized as already described in WO 2005/011646.
3. The compound of general formula (I) as above defined wherein:
X is -O-, s is 1, Y and R are as above defined and N1 is -
CO-, can be obtained by a process comprising: 3a. reacting a compound of formula B with a compound of formula (VIIIb) :
B + HO-Y-ONO2
(VIIIb)
wherein Y is as above defined; B is equal to R with N1 = - COOH and R' = H; in presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazole (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 50°C in the presence or not of a base as for example DMAP. The nitric acid ester compounds of formula (VIIIb) can be obtained from the corresponding alcohols of formula HO-Y-OH (VIIIc) , that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C or reacting the corresponding halogen derivatives of formula HO-Y-HaI (VIIId) wherein Hal is an alogen atom preferable Cl, Br, I, that are commercially available, with AgNO3 as already described in the international application No. WO 2006/008196.
3b. reacting a compound of formula R-X-Y-HaI (IXa), wherein R and X are as above defined, with AgNO3 as already described. Compounds (IXa) can be obtained by reacting compound B with compounds (VIIId) , as above defined, with a condensing reagent such as DCC or CDI as above described.
3c. reacting a compound of formula R-X-Y-OH (Xa) , wherein R and X are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65 °C as already described. Compounds (Xa) can be obtained by reacting compound B with compounds (VIIIc) , as above defined, with a condensing reagent as above described.
4. The compound of general formula (I) as above defined wherein:
X is -NR1-, s is 1, Y and R are as above defined and N1 is - CO-, can be obtained by a process comprising: 4a. reacting a compound of formula B with a compound of formula (XIa) :
B + R1HN Y-ONO2
(XIa) wherein Y is as above defined; B is equal to R with N1 = - COOH and R' = H; in presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazol (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 50°C in the presence or not of a base as for example DMAP.
The nitric acid ester compounds of formula (XIa) can be obtained from the corresponding alcohols of formula R1HN-Y- OH (XIb) , that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C or reacting the corresponding halogen derivatives of formula R1NH-Y-HaI (XIc) wherein Hal is an alogen atom preferable Cl, Br, I, that are commercially available, with AgNO3.
4b. reacting a compound of formula R-X-Y-HaI (XIIa) , wherein R and X are as above defined, with AgNO3 as already described. Compounds (XIIa) can be obtained by reacting compound B with compounds (XIc) , as above defined, with a condensing reagent such as DCC or CDI as above described.
4c. reacting a compound of formula R-X-Y-OH (XIIIa) , wherein R and X are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described. Compounds (XIIIa) can be obtained by reacting compound B with compounds (XIb) , as above defined, with a condensing reagent as above described.
5. The compound of general formula (I) as above defined wherein: X is -CO-, s is 1, Y and R are as above defined can be obtained by a process comprising:
5a. reacting a compound of formula B with a compound of formula (Ilia) :
B + HOOC-Y-ONO2
(IIIa)
wherein Y is as above defined; B is equal to R with R' = free valence and N1 = -O-PG1, -CO-PG2 or -NR1-PG3 wherein PG1 is an hydroxyl protective group such as TBDMS, PG2 is an carboxyl protective group such as 2- (p-toluenesulfonyl) ethyl ester, PG3 is an amino protective group such as BOC; in presence of a condensing agent like dicyclohexylcarbodiimide
(DCC) , N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDAC) or N, N' -carbonyldiimidazole (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from - 5°C to 50°C in the presence or not of a base as for example DMAP and hydrolysing the protective group as known in the literature.
The nitric acid ester compounds of formula (Ilia) can be obtained from the corresponding alcohols of formula HOOC-Y- OH (IIIb), that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from -50°C to 0°C or reacting the corresponding halogen derivatives of formula HOOC-Y-HaI (IIIc) wherein Hal is an alogen atom preferable Cl, Br, I, that are commercially available, with AgNO3 as already described in the international application No. WO 2006/008196.
5b. reacting a compound of formula B as above defined with a compound of formula (IIId) : B + ACt-CO-Y-ONO2 ( IIId)
wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :
Figure imgf000058_0001
The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2 and hydrolysing the protective group as known in the literature.
The compounds of formula (IIId) can be obtained as described in the international application No. WO 2006/008196.
5c. reacting a compound of formula R-X-Y-HaI (IVa), wherein R, X and Y are as above defined, with AgNO3 as already described. Compounds (IVa) can be obtained by reacting compound B with compounds (IIIc), as above defined, with a condensing reagent such as DCC or CDI as above described and hydrolysing the protective group as known in the literature. 5d. reacting a compound of formula R-X-Y-OH (Va) , wherein R, X and Y are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described and hydrolysing the protective group as known in the literature. Compounds (Va) can be obtained by reacting compound B with compounds (IIIb), as above defined, with a condensing reagent as above described.
6. The compound of general formula (I) as above defined wherein:
X is -COO-, s is 1, Y and R are as above defined can be obtained by a process comprising: 6a. reacting a compound of formula B with a compound of formula (VIa) :
B + Act—X—Y—ONO2
(VIa) wherein Act, X and Y are as above described; B is equal to R with R' = free valence and N1 = -O-PG1, -CO-PG2 or -NR1-PG3 wherein PG1 is an hydroxyl protective group such as TBDMS, PG2 is an carboxyl protective group such as 2- (p- toluenesulfonyl) ethyl ester, PG3 is an amino protective group such as BOC. The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2 and hydrolysing the protective group as known in the literature. The synthesis of compounds (VIa) has already been described in the international application No. WO 2006/008196.
6b. reacting a compound of formula R-X-Y-HaI (VIla) wherein R, X, Y and Hal are as above defined, with AgNO3 as above described.
The compounds of formula (VIla) can be obtained by reacting compound B with compounds Act-X-Y-Hal (VIlla) . The reaction is generally carried out in presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C as above described and hydrolysing the protective group as known in the literature. Compound (VIlla) are commercially available or can be synthesized as already described in WO 2005/011646.
7. The compound of general formula (I) as above defined wherein:
X is -CO-, s is 2, Y and R are as above defined and N1 is - O- or -NR1- wherein R1 is as above defined can be obtained by a process comprising:
7a. reacting a compound of formula B with a compound of formula (Ilia) :
B + HOOC-Y-ONO2
(IlIa)
wherein Y is as above defined; B is equal to R with N1 is - OH or -NR1H and R' is H, in presence of a condensing agent like dicyclohexylcarbodiimide (DCC), N-(3- dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDAC) or N, N' -carbonyldiimidazole (CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 50°C in the presence or not of a base as for example DMAP. The nitric acid ester compounds of formula (Ilia) can be obtained as above described.
7b. reacting a compound of formula B as above defined with a compound of formula (IIId) :
B + ACt-CO-Y-ONO2 (IIId)
wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :
Figure imgf000061_0001
The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2 The compounds of formula (IIId) can be obtained as above described
7c. reacting a compound of formula R-(X-Y-HaI)s (VIlla), wherein R, X, Y and Hal are as above defined, s is 2, with AgNO3 as already described. Compounds (VIlla) can be obtained by reacting compound B with compounds (IIIc), as above defined, with a condensing reagent such as DCC or CDI as above described.
7d. reacting a compound of formula R-(X-Y-OH)3 (IXa), wherein R, X and Y are as above defined, s is 2, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between -60° to 65°C as already described. Compounds (IXa) can be obtained by reacting compound B with compounds (IIIb), as above defined, with a condensing reagent as above described
8. The compound of general formula (I) as above defined wherein:
X is -COO-, s is 2, Y and R are as above defined and N1 is - O- or -NR1 can be obtained by a process comprising: 8a. reacting a compound of formula B with a compound of formula (VIa) :
B + Act—CO O—Y—ONO2
(VIa) wherein B is equal to R with N1 is -OH or -NR1H and R' is H; Act and Y are as above described. The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C or in a double phase system H2O/Et2O at temperatures range between 20°- 40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)3 or Bi(OTf)3 in solvents such as DMF, CH2Cl2. The synthesis of compounds (VIa) has already been described in the international application No. WO 2006/008196.
8b. reacting a compound of formula R-(X-Y-HaI)3 (Xa) wherein R, X, Y and Hal are as above defined, s is 2, with AgNO3 as above described.
The compounds of formula (Xa) can be obtained by reacting compound B with compounds Act-CO-O-Y-Hal (VIlla) . The reaction is generally carried out in presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2Cl2 at temperatures range between 0°-65°C as above described.
Compound (VIlla) are commercially available or can be synthesized as already described in WO 2005/011646.
Compounds B of formula (HA) wherein N1 is -NH2, -OH or - COOH; R1, R2 and R3 are the same or different and are H, Cl, Br, I, F, CF3, SO2NH2; n is an integer from 0 to 2, m = 0, and R' is H can be prepared as described in D. Vullo et al. Bioorg. Med. Chem. Lett. 15 (2005) 963-969.
Compound B of formula (HB) wherein N1 is -NH2 and R' is H can be prepared as described in D. Vullo et al. Bioorg. Med. Chem. Lett. 15 (2005) 963-969. Compound B of formula (HC) wherein N1 is -NH2, n = 1 and R' is H can be prepared as described in D. Vullo et al . Bioorg. Med. Chem. Lett. 15 (2005) 963-969.
Compound B of formula (HD) wherein N1 is -NH2, m = 1 and R' is H can be prepared as described in B. Masereel et al . J. Med. Chem. (2002) 45, 312-320. Compound B of formula (HD) wherein N1 is - NH2, m = 0 and R' is H can be prepared as described in D. Vullo et al. Bioorg. Med. Chem. Lett. 15 (2005) 963-969. Compound B of formula (HE) wherein N1 is -COOH and R' is H can be prepared as described in A. Casini et al. Bioorg. Med. Chem. Lett. 13 (2003) 2867-2873.
Compound B of formula (HF) wherein N1 is -OH, m = 1, X1 is -O- and R' is H can be prepared as described in B. Masereel et al. J. Med. Chem. (2002) 45, 312-320.
Compound B of formula (HF) wherein N1 is -OH, m = 0 and R' is H can be prepared as described in D. Vullo et al. Bioorg. Med. Chem. Lett. 15 (2005) 963-969. Compound B of formula (HG) wherein N1 is -NH2 and R' is H can be prepared as described in D. Vullo et al. Bioorg. Med. Chem. Lett. 15 (2005) 963-969.
Example 1
Synthesis of compound of formula (1):
Figure imgf000064_0001
A) 4-Bromobutanol
Tetrahydrofuran (12.5 g , 173 mmol) was charged under nitrogen in a reactor cooled to 5-10°C. Hydrogen bromide
(7.0 g, 86.5 mmol) was then added slowly and the reaction medium was stirred over a period of 4.5 hours at 5-10°C. The mixture was diluted with 22.5 g of cold water and the pH of this solution was adjusted to pH=5-7 by adding 27.65% sodium hydroxide (2.0 g) keeping the temperature at 5-10°C. The solution was then extracted twice with dichloromethane (13.25 g) . The combined organic phases were washed with 25% brine (7.5 g) , adjusted to pH=6-7 with 27.65% sodium hydroxide and dried over magnesium sulfate. Dichloromethane was distilled off and crude 4-bromobutanol (10.3 g, 66.9 mmol) was obtained in a yield of about 77%.
B) 4-Bromobutyl nitrate
In reactor cooled to -5 to 5°C, nitric acid fuming (8.5 g, 135 mmol) was slowly added to a solution of 98% sulfuric acid (13.0 g, 130 mmol) in dichloromethane (18.0 g, 212 mmol). 4-bromobutanol (10.2 g, 66.6 mmol) was then added to this mixture and the reaction medium was stirred at -5 to 5°C over a period of 2-5 hours. The mixture was poured into cold water (110 g) keeping the temperature between -5 °C and 3 °C. After decantation, the upper aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, adjusted to pH=6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulfate. Dichloromethane was distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g, 64.1 mmol) was recovered in a yield of about 96%.
C) 5-(4-carboxyl(4-nitrooxybutyl)benzenesulphonamido)-1,3,4- thiadiazole-2-sulphonamide
To a solution of 5-(4-carboxybenzenesulphonamido)-1,3,4- thiadiazole-2-sulphonamide (0.05 g, 0.14 mmol) in DMF (3 ml), 4-bromo-butylnitrate (0.33 g, 25% w/w in methylene chloride, 0.28 mmol) and cesium carbonate (0.068 g, 0.21 mmol) ) were added. The reaction was stirred at room temperature for 12 hours. The solution was treated with HCl 1N and diethyl ether , the organic layer was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent methylene chloride/methanol 10/2. The product (0.05 g) was obtained. 1H-NMR (DMSO) δ: 8.02 (2H, d) ; 7.85 (4H, m) ; 4.60 (2H, t); 4.32 (2H, t) ; 1.80 (4H, m) .
Example 2 Synthesis of compound of formula (11) :
Figure imgf000066_0001
D) Ferulic acid 4-(bromo)butyl ester
To a solution of ferulic acid (Ig, 5.15mmol) in tetrahydrofurane (40ml), triphenylphosphine (2.7g, 10.3mmol) and tetrabromomethane (3.41g, 10.3mmol) were added. The mixture was stirred at room temperature for 4 hours. The mixture was filtered and the solvent was evaporated under vacuum. The crude residue was purified by silica gel chromatography, eluent n-hexane/ethyl acetate 7/3. The product (0.77g) was obtained as a yellow solid. (Yield 46%) M.p.=83-88°C
E) Ferulic acid 4-(nitrooxy)butyl ester
A solution of compound A (0.8g, 2.43mmol) and silver nitrate (1.2g, 7.29mmol) in acetonitrile (50ml) was stirred at 40°C, in the dark, for 16 hours. The precipitate (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 75/25. The product (0.4g) was obtained as white powder (yield 53%) M.p.=63-64°C F) To a solution of 5- (4-carboxybenzenesulphonamido) -1, 3, 4- thiadiazole-2-sulphonamide (0.05 g, 0.137 mmol) in DMF (3 ml), ferulic acid 4- (nitrooxy) butyl ester (0.043 g, 0.137 mmol), DMAP (cat. amount) and EDAC (0.04 g, 0.205 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was treated with water and ethyl acetate, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent methylene chloride/methanol 9/1. The product (0.03 g) was obtained.
1H-NMR (DMSO) δ: 8.20 (2H,d); 7.95 (2H,d); 7.80 ((2H,s); 7.18 (1H, d) ; 7.10 (1H, s) ; 7.42 (2H, m) ; 6.75 (1H, d); 4.60 (2H, t); 4.20 (2H, t) ; 3.81 (3H, s) ; 1.75 (4H, m) .
Example 3
Synthesis of compound of formula (35):
Figure imgf000067_0001
G) 4-Sulphonamidobenzoic acid 4- (chloromethyl) benzyl ester
To a solution of 4-sulphonamidobenzoic acid (0.1 g, 0.5 mmol) in DMF (5 ml), alpha, alpha1 dichloro p-xilene (0.27 g, 1.5 mmol) and cesium carbonate (0.25 g, 0.75 mmol)) were added. The reaction was stirred at room temperature for 20 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography, eluent ethyl acetate/n-hexane 3/7. The product (0,05 g) was obtained. H) 4-Sulphonamidobenzoic acid 4-(nitrooxymethyl)benzyl ester
A solution of compound G) (0.05 g, 0.15 mmol) and silver nitrate (0.08 g, 0.44 mmol) in acetonitrile (2.5 ml) was stirred at 40°C, in the dark, for 5 hours. The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 7/3. The product (0.04g) was obtained. 1H-NMR (DMSO) δ: 8.20 (2H,d); 7.98 (2H,d); 7.56 ((6H,m); 5.62 (2H, s) ; 5.39 (2H, s) .
Example 4 Synthesis of compound of formula (79) :
Figure imgf000068_0001
I) 4-bromobutyrric acid 4-sulphonamidobenzyl ester To a solution of 4-(hydroxymethyl)benzensulphonamide
(0.2 g, 1.07 mmol) in DMF (5 ml), 4-bromobutyrric acid (0.18 g, 1.07 mmol), and DCC (0.267 g, 1.29 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was treated with water and ethyl acetate, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent methylene chloride/methanol 94/6. The product (0.035 g) was obtained.
L) 4-(nitrooxy)butyrric acid 4-sulphonamidobenzyl ester A solution of compound I) (0.035 g, 0.09 mmol) and silver nitrate (0.02 g, 0.14 mmol) in acetonitrile (2.5 ml) was stirred at 40°C, in the dark, for 16 hours. The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent methylene chloride/methanol 94/6. The product (0.025 g) was obtained.
1H-NMR (DMSO) δ: 7.80 (2H,d); 7.41 (2H,d); 7.30 ((2H, s); 5.75 (2H, s); 4.63 (2H, t) ; 2.32 (2H,t); 1.94 (4H,m ).
Example 5
Synthesis of compound of formula (27):
Figure imgf000069_0001
To a solution of 4-sulphonamidobenoic acid (0.2 g, 0.99 mmol) in DMA (10 ml)potassium carbonate (0.27 g, 2 mmol) , potassium iodide (0.15 g, 1 mmol) and 4-bromo-butylnitrate
(0.33 g, 20% w/w in methylene chloride, 2 mmol) were added.
The reaction was stirred at room temperature for 24 hours.
The solution was treated with ethyl acetate and water , the organic layer was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent methylene chloride/methanol 10/1. The product (0.22 g) was obtained.
1H-NMR (DMSO) δ: 8.15 (2H, m) ; 7.98 (2H, m) ; 7.55 (2H, m) ; 4.60 (2H, t); 4.32 (2H, t) ; 1.82 (4H, m) .
Example 6
Synthesis of compound of formula (37):
Figure imgf000070_0001
To a solution of 4-sulphonamidobenzoic acid (0.1 g, 0.497 mmol) in DMA (10 ml), ferulic acid 4- (nitrooxy) butyl ester, compound B), (0.155 g, 0.497 mmol), DMAP (cat. amount) and DCC (0.114 g, 0.548 mmol) were added. The reaction was stirred at room temperature for 36 hours. The solution was treated with water and ethyl acetate, the organic layers were dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent methylene chloride/methanol 10/1. The product (0.085 g) was obtained.
1H-NMR (DMSO) δ: 8.28 (2H, d) ; 8.02 (2H, d) ; 7.61 (4H, m) ; 7.35 (2H, m) ; 6.75 (1H, d) ; 4.59 (2H, t) ; 4.19 (2H, t) ; 3 :82 (3H, S) ; 1.76 (4H, m) .
Example 7
Synthesis of compound of formula (162) :
Figure imgf000070_0002
The compound was synthesized using procedure described in Example 1 staring from 5- (3-carboxybenzenesulphonamido) - 1, 3, 4-thiadiazole-2-sulphonamide and 4-bromo-butylnitrate (compound B) .
1H-NMR (DMSO) δ: 8.30 (1H, s); 8.02 (2H, dd) ; 7.80 (2H, m) ; 7.12 (1H, t); 4.60 (2H, t) ; 4.32 (2H, t) ; 1.80 (4H, m) . Example 8
Synthesis of compound of formula (172):
Figure imgf000071_0001
The compound was synthesized using procedure described in Example 2 staring from 5- (3-carboxybenzenesulphonamido) - 1, 3, 4-thiadiazole-2-sulphonamide and ferulic acid 4- (nitrooxy) butyl ester (compound E). 1H-NMR (DMSO) δ: 8.42 (1H, s) 8.18 (2H,dd); 7.95 (1H, d); 7.75 (2H,m); 7.60 (1H, s); 7.40 (2H, m) ; 6.75 (1H, d); 4.60 (2H, t); 4.20 (2H, t) ; 3.81 (3H, s); 1.80 (4H, m) .
Example 9 Synthesis of compound of formula (205): 4-(nitrooxy)butyrric acid 4-aminosulfonylphenyl ester
Figure imgf000071_0002
M) 4-bromobutyrric acid 4-aminosulfonylphenyl ester
4-Hydroxy-benzene-sulfonamide (500 mg, 2,86 mmol) and 4-bromo-butanoic acid (477 mg, 2,86 mmol) were dissolved in
15 ml of DMA. EDAC was added portion wise (1,645 g, 8,58 mmol) followed by catalytic amount of DMAP and the resulting suspension stirred at room temperature for 48 hours. 300 ml of ethyl acetate was added and the organic solution was extracted with water, 5% aqueous HCl and water. The organic layer was dried with anhydrous sodium sulphate and the solvent evaporated. The crude residue was purified by flash chromatography, eluent methylene chloride/methanol 20/1. The compound M (785 mg) was obtained (85%) . 4- (nitrooxy)butyrric acid 4-aminosulfonylphenγl ester Compound M (300 mg, 0,93 mmol) was suspended in 10 ml of acetonitrile and AgNO3 (236 mg, 1,39 mmol) was added. The mixture was stirred and heated at 40°C for 3 days. The solution was filtered and the solvent evaporated. The crude was purified by flash chromatography eluent methylene chloride/methanol 15/1. The product (189 mg) was obtained
(66%) .
1H NMR: δ 7.90 (2H, d) , 7.45 (2H, s), 7.35 (2H, d) , 4.65 (2H, t), 2.80 (2H, t), 2.05 (2H m)
Example 10
Synthesis of compound of formula (206) : 5-nitrooxypentanoic acid 4-aminosulfonylphenyl ester
Figure imgf000072_0001
N) 5-bromopentanoic acid 4-aminosulfonylphenyl ester
To a solution of 5-bromo-valeric acid (535 mg, 2,86 mmol) in 15 ml of DMA, in a 50ml round bottom flask, was added 4-hydroxy-benzene-sulfonamide (500 mg, 2,86 mmol). EDAC (1,645 g, 8,58 mmol) was then added portion wise followed by a catalytic amount of DMAP and the resulting suspension was stirred at room temperature for 24 hours. 300 ml of ethyl acetate was added and the organic solution was extracted with water, 5% aqueous HCl and water. The organic layer was dried with anhydrous sodium sulphate and the solvent evaporated. The crude residue was purified by flash chromatography eluent methylene chloride/methanol 20/1. Compound N (640 mg) was obtained (67%).
5-nitrooxypentanoic acid 4-aminosulfonylphenyl ester Compound N (300 mg, 0,89 mmol) was dissolved in 10 ml of acetonitrile and AgNO3 (227 mg, 1,34 mmol) was added. The mixture was stirred and heated at 40°C for 2 days. The solution was filtered and the solvent evaporated. The crude was purified by flash chromatography eluent methylene chloride/methanol 15/1. The product (160 mg) was obtained
(56%) .
1H NMR: δ 7.90 (2H, d) , 7.40 (2H, s) , 7.35 (2H, d) , 4.60 (2H, t), 2.70 (2H, t), 1.8 (4H, m)
Example 11
Synthesis of compound of formula (207) : 6-nitrooxyhexanoic acid 4-aminosulfonylphenyl ester
Figure imgf000073_0001
O) 6-bromohexanoic acid 4-aminosulfonylphenyl ester
4-Hydroxy-benzene-sulfonamide (500 mg, 2,86 mmol) and 6-bromo-hexanoic acid (558 mg, 2,86 mmol) were dissolved in 15 ml of DMA. EDAC (1,645 g, 8,58 mmol) was added portion wise followed by a catalytic amount of DMAP and the resulting suspension was stirred at room temperature for 24 hours. 300 ml of ethyl acetate was added and the organic solution was extracted with water, 5% aqueous HCl and water. The organic layer was dried with anhydrous sodium sulphate and the solvent evaporated. The crude residue was purified by flash chromatography eluent methylene chloride/methanol 20/1. Compound O (705 mg) was obtained (70%) . 6-nitrooxyhexanoic acid 4-aminosulfonylphenyl ester
Compound O (300 mg, 0,86 mmol) was dissolved in 15 ml of acetonitrile and AgNO3 (219mg, 1,29 mmol) was added. The mixture was stirred and heated at 40°C for 2 days. A further equivalent of AgNO3 (146mg, 0.86 mmol) was added and the solution was heated at 40°C for 24 hours. The solution was filtered and the solvent evaporated. The crude was purified by flash chromatography eluent methylene chloride/methanol 15/1. The product (147 mg) was obtained (52%).
1H NMR: δ 7.90 (2H, d) , 7.40 (2H, s) , 7.35 (2H, d) , 4.60
Example 12
Synthesis of compound of formula (208): 3-[4-(p- Aminosulfonyldihydrocinnamoil) -3-methoxy] phenyl-2-propenoic acid 4- (nitrooxy) butyl ester
Figure imgf000074_0001
p-Aminosulfonyldihydrocinnamic acid (295 mg, 1,28 mmol) and 3- (4-Hydroxy-3-methoxyphenyl) -2-propenoic acid 4- (nitrooxy) butyl ester (400 mg, 1,28 mmol) were dissolved in 10 ml of DMF. EDAC (370 mg, 1,93 mmol) was added followed by a catalytic amount of DMAP and the suspension was stirred at room temperature for 72 hours. 400 ml of ethyl acetate was added and the organic solution was extracted with water, 5% aqueous HCl and water. The organic layer was dried with anhydrous sodium sulphate and the solvent evaporated. The crude residue was purified by flash chromatography eluent ethyl acetate/petroleum ether 45/55. The product(396 mg) was obtained (59%). 1HNMR: δ 7.80 (2H, m) , 7.70 (1H, d) , 7.50 (3H, m) , 7.30 (3H, m) , 7.10 (1H, m) , 6.75 (1H, d) , 4.6 (2H, m) , 4.3 (2H, m) , 3.8 (3H, s), 3.0 (4H, m) , 1.8 (4H, m)
Pharmacological experiments
Evaluation of the carbonic anhydrase inhibition against isoenzymes CA I, II, IX and XII.
An SX.18MV-R Applied Photophysics stopped flow instrument has been used for assaying the CA CO2 hydration activity. Phenol red (0.2 inM) was used as indicator (pH 6.8-8.4), working at the absorbance maximum of 557 nm. The buffer solution was constituted by 10 mM HEPES, 0.1 M Na2SO4, and TRIZMA hydrochloride 0.01 M, adjusting the pH solution at 7.5 with NaOH (0,1 M) .
The CA-catalyzed CO2 hydration reaction was followed for a period of 1-20 s, depending on the isoform used. Satured CO2 solution in bidistilled water at 20°C was used as substrate.
Stock solutions of inhibitor (1 mM) were prepared with buffer solution with 10-20% (v/v) DMSO, and dilutions up to
0.1 nM. To allow for the formation of the E-I complex, inhibitor and enzyme solutions were preincubated during 15 min at room temperature prior to assay. Enzyme concentrations were 0.1 μM for CA I and II, 10 μM for CA IV and 1 μM for CA IX and CA XII. The human CA I and II are commercialy available, whereas the hCA IV, hCA IX (tumor) and hCA XII (tumor) are cloned isoforms.
Each experiment was done in triplicate. As reported in Table 1, the compounds of the invention show inhibitory activity in the nanomolar range against at least one of the isoforms.
Table 1
Figure imgf000076_0001
IC5O is the concentration which inhibits 50% of the response .
Test on vascular -tone
The ability of the carbonic anhydrase inhibitors nitroderivatives to induce vasorelaxation in comparison to native CAI, was tested in vitro in isolated rabbit thoracic aorta preparations (Wanstall J. C. et al., Br. J. Pharmacol., 134:463-472, 2001). Male New Zealand rabbits were anaesthetized with thiopental-Na (50 mg/kg, iv) , sacrificed by exsanguinations and then the thorax was opened and the aorta dissected. Aortic ring preparations (4 mm in length) were set up in physiological salt solution (PSS) at 37°C in small organ chambers (5 ml) . The composition of PSS was (mM) : NaCl 130, NaHCO3 14.9, KH2PO4 1.2, MgSO4 1.2, HEPES 10, CaCl2 , ascorbic acid 170 and glucose 1.1 (95% O2 /5% CO2 ; pH 7.4). Each ring was mounted under 2 g passive tension. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System. Preparations were allowed to equilibrate for 1h, and then contracted submaximally with noradrenaline (NA, 1 μM) and, when the contraction was stable, acetylcholine (ACh, 10 μM) was added. A relaxant response to ACh indicated the presence of a functional endothelium. Vessels that were unable to contract NA or showed no relaxation to Ach were discarded. When a stable precontraction was reached, a cumulative concentration-response curve to either of the vasorelaxant agents was obtained in the presence of a functional endothelium. Each arterial ring was exposed to only one combination of inhibitor and vasorelaxant. Moreover, the effect of the soluble guanylyl cyclase inhibitor ODQ (1-H- (1,2,4)-oxadiazol(4,3-a)quinoxalin-1-one) on vasorelaxation elicited by the compounds was examined preincubating the aortic rings with ODQ (10 μM) for 20 min.
Responses to relaxing agents are expressed as a percentage of residual contraction and plotted against concentration of test compound. EC50 values (where EC50 is the concentration producing 50% of the maximum relaxation to the test compound) were interpolated from these plots.
During the experimental period, the plateau obtained with NA was stable without significant spontaneous loss of contraction in the aortic rings. Under these experimental conditions, the carbonic anhydrase inhibitors did not produce relaxation at any of the concentration tested, the curve being not different from that built up in the presence of vehicle alone.
The nitroderivatives of the invention have EC50 values in the range of 1-50μM. Furthermore, in experiments performed in the presence of ODQ (10 μM) , the vasorelaxant responses to tested compounds were inhibited.

Claims

1. Use of a carbonic anhydrase inhibitor able to release nitric oxide for the preparation of a medicament for treating eye disorders and cancer,
2. Use according to claim 1, wherein the eye disorder is selected from glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy or retinal vasculopathies .
3. Use according to claim 1 wherein carbonic anhydrase inhibitor able to release nitric oxide is a compound having an inhibition constant (Ki) against at least one of the isoenzymes CAII, CAIV, CAIX and CAXII in the range of 0.01- 200 nM.
4. Use according to claim 1 wherein the carbonic anhydrase inhibitor able to release nitric oxide is a compound having an EC50 value in the range of 1-50μM.
5. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: R-(X-Y-ONO2)s (I) wherein s is an integer equal to 1 or 2 ; R is selected from the group consisting of :
Figure imgf000079_0001
Figure imgf000080_0001
wherein n is an integer from 0 to 4; m is an integer equal to 0 or 1;
R1, R2 and R3 are the same or different and are H, Cl, Br, I,
F, CF3, SO2NH2;
X1 is -O- or -NH-; N1 is -OH, -COOH, -O-, -C (O) -, -NHR1 or -NR1- wherein R1 is H or C1-C6 al kyl ;
R' is H or a group - (X-Y-ONO2) ;
X is -C(O)-, -O-, -NR1-, -S-, -C(O)O- or -C(O)S-, wherein R1 is H or C1-C6 alkyl; with the proviso that i) when the group -(X-Y-ONO2) is bound to N1 then:
- N1 is -O- or -NR1- and X is -C(O)-, -C(O)O- or -C(O)S-, wherein R1 is H or C1-C6 alkyl;
- N1 is -C(O)- and X is -O-, -NR1-, -S-, -C(O)O- or -C(O)S-, wherein R1 is H or C1-C6 alkyl; ii) when R' is -(X-Y-ONO2) then X is -C(O)-, -C(O)O- or -
C(O)S-; iii) when s is 2, then -X and -Y- of the two groups
-(X-Y-ONO2) can be the same or different; Y is a bivalent radical having the following meaning: a) straight or branched C1-C20 alkylene; straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, -ONO2 or T, wherein T is -OC(O)(C1-C10 alkyl) -ONO2 or -O(C1-C10 alkyl) -ONO2; - cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched C1-C10 alkyl; b)
Figure imgf000081_0001
C)
Figure imgf000081_0002
wherein n0 is an integer from 0 to 20, n1 is an integer from 1 to 20, d)
Figure imgf000081_0003
wherein
X1 = -OC(O)- or -C(O)O-; n2 is an integer from 0 to 2;
R2 is H or CH3;
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 20; e)
Figure imgf000081_0004
Figure imgf000082_0001
wherein:
Y1 is -CH2-CH2- (CH2) n 2a- or -CH=CH- (CH2) n 2a- wherein n2a is from 0 to 2,
X1. is -OC(O)- or -C(O)O-, n2 is an integer from 0 to 2, R2 is H or CH3,
Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 20; when Y is selected from the bivalent radicals mentioned under b)-e), then the terminal -ONO2 group is bound to - (CH2)n 1; f)
Figure imgf000082_0002
wherein: n1 is an integer from 1 to 20,
R3 is H,
R0 is H or -COCH3; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to - (CH2)n 1; g)
Figure imgf000083_0002
wherein X2 is -O- or -S-, n3 is an integer from 1 to 6, R2 is H or -CH3; h)
Figure imgf000083_0001
wherein: n4 is an integer from 0 to 10; n5 is an integer from 1 to 10;
R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl; wherein the -ONO2 group is linked to
Figure imgf000083_0003
wherein n5 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from
Figure imgf000084_0001
6. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 5, wherein s is 1; R is
Figure imgf000084_0002
wherein in formula ( IIA)
Ri, R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 4 of the phenyl ring, R' is H; n is 0 , N1 is -C (O) - and N1 binds the group - (X-Y-ONO2) ;
X is -O-, . -S- or -NR1- wherein R1 is H or C1-C6 alkyl; or
R1, R2 and R3 are H; R1 is 0 and the group -SO2NHR' is in position 4 of the phenyl ring, R' is H; n is 0 or 1,
N1 is -O- and N1 binds the group -(X-Y-ONO2);
X is -C(O)-, -C(O)O- or -C(O)S-; or
R1 is Cl and R1 is in position 4 of the phenyl ring,
R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 3 of the phenyl ring, R' is H; n is 0, N1 is -C(O)- and N1 binds the group -(X-Y-ONO2);
X is -O-, -S- or -NR1- wherein R1 is H or C1-C6 alkyl; or
R1 R2 and R3 are H; m is 0 and the group -SO2NHR' is in position 3 of the phenyl ring, R' is H; n is 3 , N1 is ~C {0) - and N1 binds the group - (X-Y-ONO2 ) ;
X is -O-, -S- or -NR1- wherein R1 is H or C1-C6 alkyl ; Α compound of general formula ( I ) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 5 wherein wherein s is 1 ;
R is
Figure imgf000085_0001
(II B) wherein in formula (IIB) N1 is -C(O)- and N1 binds the group -(X-Y-ONO2); R' is H; X is -O-, -NR1-, -S-; or
N1 is -COOH; R' is -(X-Y-ONO2) ; X is -C(O)-, -C(O)O- or -C(O)S-; 8. A compound of general formula (I)- or a pharmaceutically acceptable salt or stereoisomer thereof according to claims 5 to 7, wherein Y has the following meaning: ' a) straight or branched C1-C10 alkylene, - straight or branched C1-C10 alkylene substituted with one or more of the substituents selected from -ONO2 or -OC(O) (C1-C10 alkyl)-ONO2 or -O(C1-C10 alkyl)-ONO2; b)
Figure imgf000086_0001
c)
Figure imgf000086_0002
wherein n0 is an integer from 0 to 5, and n1 is an integer from 1 to 5; d)
Figure imgf000086_0003
wherein : X1 = -OC(O)- or -C(O)O-;
Z is -(CH2)n 1- or the bivalent radical defined above under b) wherein n1 is an integer from 1 to 10 and n2 is 1, and R2 is H or CH3; e)
Figure imgf000087_0001
wherein:
Y1 is -CH2-CH2- (CH2) n 2a- or -CH=CH- (CH2) n 2a- wherein n2a is 0 or
1;
X1 is -OC(O)- or -C(O)O-, n2 is 1, R2 is CH3; Z is -(CH2)n 1- or the bivalent radical defined above under b) , wherein n1 is an integer from 1 to 10; with the proviso that: when Y is selected from the bivalent radicals mentioned under b)-e), then the terminal -ONO2 group is bound to - (CH2)n 1; f)
Figure imgf000087_0002
(f") wherein: n1 is an integer from 1 to 10; R3 is H, R0 is -COCH3 ; with the proviso that when Y is selected from the bivalent radicals mentioned under f) , then -ONO2 group is bound to - (CH2)n 1; g)
Figure imgf000088_0001
wherein X2 is -O- or -S-, n3 is 1 and R2 is H; h)
Figure imgf000088_0002
wherein : n4 is an integer from 0 to 5; n5 is an integer from 1 to 5; R4, R5, R6, R7 are H; wherein the -ONO2 group is linked to
Figure imgf000088_0003
wherein n5 is as defined above; Y2 is selected from
Figure imgf000089_0001
9. A compound according to claim 6, selected from the group consisting of compounds of formula
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
10. A compound according to claim 7, selected from the group consisting of compounds of formula
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
11. Α compound of general formula (I) according to claims 5 to 10 for use as a medicament.
12. Use of a compound according to claims 5 to 10 for preparing a drug for the treatment or prophylaxis of glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, cancer, epilepsy, high-altitude disorders and neuromuscular diseases.
13. Use of a compound according to claims 5 to 10 as a drug for the treatment or prophylaxis of glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, cancer, epilepsy, high-altitude disorders and neuromuscular diseases.
14. A pharmaceutical composition comprising a compound according to claims 5 to 10 and a pharmaceutically acceptable carrier.
15. A pharmaceutical composition according to claim 14 in a suitable form for the oral, parenteral, rectal, topic and transdermic administration, by inhalation spray or aerosol or iontophoresis devices.
16. A pharmaceutical composition according to claim 14 wherein the compound of general formula (I) is administered as a solution, suspension or emulsion in an ophthalmically acceptable vehicle.
17. A pharmaceutical composition comprising a mixture of a compound of general formula (I) according to claims 5 to 10 and (i) a beta-adrenergic antagonists or (ii) a prostaglandin analog or (iii) an α-adrenergic agonist or a nitrooxy derivative thereof.
18. A pharmaceutical composition according to claim 17 wherein the beta-adrenergic antagonists is timolol and the nitrooxy derivative thereof is a nitrooxy derivative of timolol.
19. A pharmaceutical composition according to claim 17 wherein the prostaglandin analog is latanoprost and the nitrooxy derivative thereof is a nitrooxy derivative of latanoprost analog.
20. A pharmaceutical composition comprising a compound of general formula (I) according to claims 5 to 10 and at least a compound used to treat cancer.
21. A pharmaceutical kit for simultaneous, successively or previously administration of a composition according to claim 14 and (i) a beta-adrenergic antagonists or (ii) a prostaglandin analog or (iii) an α-adrenergic agonist or a nitrooxy derivative thereof.
22. Α pharmaceutical kit comprising a compound of general formula (I) according to claim 5, a compound used to treat cancer as combined preparation for simultaneous, separated, sequential use for the treatment of cancer.
23. Use of a carbonic anhydrase inhibitor able to release nitric oxide as a drug for treating eye disorders and cancer.
24. Use according to claim 23, wherein the eye disorder is selected from glaucoma, ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies .
25. Use according to claim 23 wherein carbonic anhydrase inhibitor able to release nitric oxide is a compound having an inhibition constant (Ki) against at least one of the isoenzymes CAII, CAIV, CAIX and CAXII in the range, of 0.01-200 nM.
26. Use according to claim 23 wherein the carbonic anhydrase inhibitor able to release nitric oxide is a compound having an EC50 value in the range of 1-50μM.
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008130332A1 (en) * 2007-04-20 2008-10-30 Unimed Pharma, Spol. S R.O. Subsituted sulphonamides, process for their preparation, pharmaceutical composition comprising thereof and their use
WO2010034118A1 (en) * 2008-09-24 2010-04-01 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
WO2011098610A1 (en) * 2010-02-12 2011-08-18 Universita Degli Studi Di Firenze Carbonic anhydrase inhibitors
US8062653B2 (en) * 2009-02-18 2011-11-22 Bezwada Biomedical, Llc Controlled release of nitric oxide and drugs from functionalized macromers and oligomers
WO2012087115A1 (en) 2010-12-24 2012-06-28 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Cancer targeting using carbonic anhydrase isoform ix inhibitors
CN102675404A (en) * 2012-05-10 2012-09-19 福建天泉药业股份有限公司 Preparation method of glycyrrhetinic acid butyl nitrate
WO2012175654A1 (en) 2011-06-23 2012-12-27 Facultes Universitaires Notre-Dame De La Paix Tetraline sulfonamide derivatives for use in the treatment of proliferative disorders
WO2014136076A2 (en) 2013-03-07 2014-09-12 Consiglio Nazionale Delle Ricerche Assembly comprising an absorber of near infrared (nir) light covalently linked to an inhibitor of carbonic anhydrase
WO2015025283A2 (en) 2013-08-20 2015-02-26 Stichting Maastricht Radiation Oncology "Maastro-Clinic" Dual action carbonic anhydrase inhibitors
CN104478727A (en) * 2014-12-22 2015-04-01 江西本草天工科技有限责任公司 Ferulic acid derivatives capable of releasing nitrogen monoxide and application thereof
US9085508B2 (en) 2008-09-24 2015-07-21 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
WO2017017505A1 (en) 2015-07-28 2017-02-02 Vilnius University Selective inhibitors of carbonic anhydrase

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002409A2 (en) * 2002-06-27 2004-01-08 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2005021004A1 (en) * 2003-08-21 2005-03-10 Pharmacia Corporation Method for preventing or treating an optic neuropathy
WO2005068421A1 (en) * 2004-01-05 2005-07-28 Nicox, S.A. Prostaglandin nitrooxyderivatives
WO2006052899A2 (en) * 2004-11-08 2006-05-18 Nitromed, Inc. Nitrosated and nitrosylated compounds, compositions and methods for the treatment of ophthalmic disorders
WO2006091716A2 (en) * 2005-02-24 2006-08-31 Nitromed, Inc. Nitric oxide enhancing diuretic compounds, compositions and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002409A2 (en) * 2002-06-27 2004-01-08 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
WO2005021004A1 (en) * 2003-08-21 2005-03-10 Pharmacia Corporation Method for preventing or treating an optic neuropathy
WO2005068421A1 (en) * 2004-01-05 2005-07-28 Nicox, S.A. Prostaglandin nitrooxyderivatives
WO2006052899A2 (en) * 2004-11-08 2006-05-18 Nitromed, Inc. Nitrosated and nitrosylated compounds, compositions and methods for the treatment of ophthalmic disorders
WO2006091716A2 (en) * 2005-02-24 2006-08-31 Nitromed, Inc. Nitric oxide enhancing diuretic compounds, compositions and methods of use

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BOLLA MANLIO ET AL: "Therapeutic potential of nitrate esters of commonly used drugs.", CURRENT TOPICS IN MEDICINAL CHEMISTRY 2005, vol. 5, no. 7, 2005, pages 707 - 720, XP002473907, ISSN: 1568-0266 *
BURGAUD J L ET AL: "NITRIC-OXIDE RELEASING MOLECULES: A NEW CLASS OF DRUGS WITH SEVERAL MAJOR INDICATIONS", CURRENT PHARMACEUTICAL DESIGN, BENTHAM SCIENCE PUBLISHERS, SCHIPHOL, NL, vol. 8, no. 3, 2002, pages 201 - 213, XP001122072, ISSN: 1381-6128 *
CASINI ANGELA ET AL: "Carbonic anhydrase inhibitors: topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide.", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1 SEP 2003, vol. 13, no. 17, 1 September 2003 (2003-09-01), pages 2867 - 2873, XP002473908, ISSN: 0960-894X *
DHAWAN VIJAY ET AL: "Selective nitros(yl)ation induced in vivo by a nitric oxide-donating cyclooxygenase-2 inhibitor: a NObonomic analysis.", FREE RADICAL BIOLOGY & MEDICINE 1 NOV 2005, vol. 39, no. 9, 1 November 2005 (2005-11-01), pages 1191 - 1207, XP002473906, ISSN: 0891-5849 *
MASEREEL B ET AL: "Carbonic anhydrase inhibitors: Anticonvulsant sulfonamides incorporating valproyl and other lipophilic moieties", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 45, 2002, pages 312 - 320, XP002274910, ISSN: 0022-2623 *
VULLO D ET AL: "Carbonic anhydrase inhibitors. Inhibition of the transmembrane isozyme XII with sulfonamides-a new target for the design of antitumor and antiglaucoma drugs?", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 15, no. 4, 15 February 2005 (2005-02-15), pages 963 - 969, XP004730373, ISSN: 0960-894X *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2474574C2 (en) * 2007-04-20 2013-02-10 ЮНИМЕД ФАРМА, спол. с.р.о. Substituted sulphonamides, method for production thereof, medicinal agents containing said sulphonamides and use thereof
WO2008130332A1 (en) * 2007-04-20 2008-10-30 Unimed Pharma, Spol. S R.O. Subsituted sulphonamides, process for their preparation, pharmaceutical composition comprising thereof and their use
AU2008241590B2 (en) * 2007-04-20 2012-06-21 Unimed Pharma, Spol. S R.O. Substituted sulphonamides, process for their preparation, pharmaceutical composition comprising thereof and their use
US9085508B2 (en) 2008-09-24 2015-07-21 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
CN102203055A (en) * 2008-09-24 2011-09-28 奈翠根尼斯公司 Nitric oxide releasing amino acid ester compound, composition and method of use
WO2010034118A1 (en) * 2008-09-24 2010-04-01 Oral Delivery Technology Ltd. Nitric oxide releasing amino acid ester compound, composition and method of use
US8062653B2 (en) * 2009-02-18 2011-11-22 Bezwada Biomedical, Llc Controlled release of nitric oxide and drugs from functionalized macromers and oligomers
US8303978B2 (en) 2009-02-18 2012-11-06 Bezwada Biomedical, Llc Controlled release of nitric oxide and drugs from functionalized macromers and oligomers
WO2011098610A1 (en) * 2010-02-12 2011-08-18 Universita Degli Studi Di Firenze Carbonic anhydrase inhibitors
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