FLUOROPROSTAGLANDINS NITRQDERIVATIVES

The present invention relates to new flouroprostaglandins nitroderivatives, pharmaceutical compositions containing them and their use as drugs for treating glaucoma and ocular hypertension.

Glaucoma is optic nerve damage, often associated with increased intraocular pressure (lOP), that leads to progressive, irreversible loss of vision.

Almost 3 million people in the United States and 14 million people worldwide have glaucoma; this is the third leading cause of blindness worldwide.

Glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels.

It is known that elevated IOP can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, α-agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.

Several side effects are associated with the drugs conventionally used to treat glaucoma.

Topical beta-blockers 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 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, Seventeenth Edition, M. H. Beers and R. Berkow Editors, Sec. 8, Ch. 100).

Finally, the topical prostaglandin analogs (bimatoprost, latanoprost, travoprost and unoprostone) used in the treatment of glaucoma, can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, iritis, uveitis and macular oedema (Martindale, Thirty-third edition, p. 1445)

U.S. Pat. No. 3,922,293 describes monocarboxyacylates of prostaglandins F-type and their 15β isomers, at the C-9 position, and processes for preparing them; U.S. Pat. No. 6,417,228 discloses 13-aza prostaglandins having functional PGF _2α receptor agonist activity and their use in treating glaucoma and ocular hypertension. WO 90/02553 discloses the use of prostaglandins derivatives of PGA, PGB, PGE and PGF, in which the omega chain contains a ring structure, for the treatment of glaucoma or ocular hypertension.

WO 00/51978 describes novel nitrosated and/or nitrosylated prostaglandins, in particular novel derivatives of PGE-i, novel compositions and their use for treating sexual dysfunctions.

U.S. Pat. No. 5,625,083 discloses dinitroglycerol esters of prostaglandins which may be used as vasodilators, antihypertensive cardiovascular agents or bronchodilators.

U.S. Pat. No. 6,211 ,233 discloses compounds of the general formula A-X ₁ -NO ₂ , wherein A contains a prostaglandin residue, in particular PGE ₁ , and X ₁ is a bivalent connecting bridge, and their use for treating impotence.

U.S. Pat. No. 5,985,920 and U.S. Pat. No. 5,886,035 disclose 15-deoxy-15,15- difluoro-prostaglandins-F _2α derivatives and their use in the treatment of glaucoma or ocular hypertension. The results of the pharmacological testes reported in the documents show that these fluoroPGF _2α have a long-lasting effect of lowering intraocular pressure and they have a little effect on melanogenesis.

Experimental Eye Research 78 (2004), 767-776 discloses the pharmacological characteristics of tafluprost, which is a 15-deoxy-15,15-difluoro-prostaglandin-F _2α derivative. The results of the pharmacological tests demonstrate that tafluprost has a high lOP-reducing efficacy and weak melanogenic side effect.

It is an object of the present invention to provide new derivatives of prostaglandins able not only to eliminate or at least reduce the side effects associated with these compounds, but also to possess an improved pharmacological activity. It has been surprisingly found that fluoroprostaglandins nitroderivatives have an improved lOP-reducing efficacy and an improved overall profile as compared to the known prostaglandin analogs both in terms of broad range of therapeutic applicability for the treatment of eye diseases and of enhanced activity and tolerability. In particular, it has been recognized that the prostaglandin nitroderivatives of the present invention can be employed for treating glaucoma and ocular hypertension. The compounds of the present invention are indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or with chronic angle-closure glaucoma who underwent peripheral iridotomy or laser iridoplasty.

An object of the present invention is, therefore, fluoroprostaglandins nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-X-(B) _m -Y-ONO ₂

(I) wherein R is the prostaglandin residue of formula (II):

wherein the symbo represents a single bond or a double bond; R ₁ is selected from:

- a aryloxyalkyl group optionally substituted on the aryl moiety with from 1 to 3 halogen atoms or haloalkyl groups; the carbon number of the alkyl moiety of the aryloxyalkyl group (i.e. the alkylene group) is preferably from 1 to 3; the preferred aryloxyalkyl groups are: a phenoxymethyl group, a 3-chlorophenoxymethyl group, a 3-fluorophenoxymethyl group, a 3- (trifluoromethyl) phenoxymethyl group, a 3,5-dichlorophenoxymethyl group, a 3,4- dichlorophenoxymethyl group, a 3,5-difluorophenoxy methyl group, 3,4- difluorophenoxymethyl group, 3,5-bis(trifluoromethyl)phenoxymethyl group and 3,4- bis(trifluoromethyl)phenoxymethyl group;

- a aralkyl group optionally substituted on the aryl moiety with from 1 to 3 halogen atoms or haloalkyl groups or alkoxy groups; the carbon number of the alkyl moiety of the aralky group (i.e. the alkylene group)is preferably from 1 to 4; the preferred aralkyl groups are: a phenylmethyl group, a 2-phenylethyl group, a 3-methylphenylmethyl group, a 2-(3- methylphenyl)ethyl group, 3-(trifluoromethyl) phenylmethyl group, 2-(3- trifluoromethylphenyl)ethyl group, a 3-chlorophenylmethyl group, a 2-(3-chlorophenyl)ethyl group, 2-(3,4-dichlorophenyl)ethyl group or 2-(3,5-dichlorophenyl)ethyl group;

- a C ₃ -C ₈ alkyl group optionally substituted with halogen atoms, a C ₁ -C ₄ linear or branched alkyl group, a C ₅ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxy group, a sulfur atom-containing substituent, a nitrogen atom-containing substituent; preferably R ₁ is a C ₅ -C ₆ alkyl group substituted with one or two methyl group and selected from the group comprising: n-pentyl, 2-methylhexyl, 1,1-dimethylpentyl, 2-methypentyl, 2-methylhexyl;

- a C ₃ -C ₈ alkenyl group optionally substituted with halogen atoms, a C ₁ -C ₄ linear or branched alkyl group, a C ₅ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxy group, a sulfur atom-containing substituent, a nitrogen atom-containing substituent; preferably R-i is a C ₅ -C ₆ alkenyl group substituted with one or two methyl group selected from the group comprising: 1-metyl-3- pentenyl, 1-methyl-3-hexenyl, 1 ,1-dimethyl-3-hexenyl, 2-methyl-3-pentenyl;

a C ₃ -C ₈ alkynyl group optionally substituted with halogen atoms, a C ₁ -C ₄ linear or branched alkyl group, a C ₅ -C ₆ cycloalkyl group, a C ₁ -C ₄ alkoxy group, a sulfur atom- containing substituent, a nitrogen atom-containing substituent; preferably R ₁ is a C ₅ - C ₆ alkynyl group substituted with one or two methyl group selected from the group comprising: 3-pentenyl, 1-methyl-3-hexynyl or 1,1-dimethy-3-hexynyl, 2-metbyl-3- pentenyl; 1-methyl-3-penynyl; 2-methy!-3-hexynyl;

- a C ₃ -C ₈ cycloalkyl group optionally substituted by a C ₁ -C ₄ linear or branched alkyl, the preferred C ₃ -C ₈ cycloalkyl groups are cyclohexyl group or cyclopentyl group; each of R ₂ and R ₃ which are independent of one another, is a hydrogen atom or an aliphatic hydrocarbon type C ₂ -C _2O acyl group, preferably R ₂ and R ₃ are hydrogen atoms; each of R ₄ and R ₅ which are independent of one another, is an hydrogen atom or a fluorine atom with the proviso that at least one of R ₄ and R ₅ is a fluorine atom, preferably R ₄ and R ₅ are fluorine atoms;

X is -O-, -S- or -NR ¹ -, wherein R ¹ is H or linear or branched C ₁ -C ₆ alkyl; m is an integer equal to 0 or 1 , with the proviso that m is equal to 0 when X is -O- or -S-; B is a radical of the formula -CH(R ¹ )COO-, wherein R ¹ is as above defined; Y is a bivalent radical having the following meanings: a) straight or branched C ₁ -C ₂₀ alkylene, preferably C ₁ -Ci _O , being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO ₂ or T, wherein T is -OC(O)(C ₁ -C ₁₀ alkyl)-ONO ₂ or -0(C ₁ -C ₁₀ alkyl)-ONO ₂ ;

C ₅ -C ₇ cycloalkylene group optionally substituted with linear or branched C ₁ -C ₁₀ alkyl group, preferably CH ₃ ; b)

c)

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

wherein

X ₁ = -OCO- or -COO- and R ² is H or CH ₃ ;

Z is -(CH) _n ¹ - or the bivalent radical defined above under b) n ¹ is as defined above and n ² is an integer from O to 2; e)

wherein: Y ¹ is -CH ₂ -CH ₂ -(CHz) _n ² -; or -CH=CH-(CH ₂ ) _n ² -;

Z is -(CH) _n ¹ - or the bivalent radical defined above under b) n ¹ , n ² ,R ² and Xi are as defined above; with the proviso that: i) when Y is selected from the bivalent radicals mentioned under b)-e), then the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _n ¹ ; ii) when Y is selected from the bivalent radicals mentioned under b) or c), n = O and X is

NR ¹ , wherein R ¹ is as above defined, then m = 1 ; iii) when Y is selected from the bivalent radicals mentioned under d) or e), X is NR ¹ , wherein R ¹ is as above defined, then m = 1; f)

wherein: n ¹ and R ² are as defined above, R ³ is H or -COCH ₃ ; with the proviso that the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _n ¹ ; and with the proviso that when X is -NR ¹ -, wherein R ¹ is as above defined Y cannot be f); g)

wherein

X ₂ js -o- or -S-; n ³ is an integer from 1 to 6, preferably from 1 to 4, and R ² is as defined above; h)

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

R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same or different, and are H or straight or branched C ₁ -C ₄ alkyl, preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ are H; wherein the -ONO ₂ group of formula (I) is linked to

wherein n is as defined above;

Y ² 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

The term "C ₁ -C _2O alkylene" as used herein refers to branched or straight C ₁ -C ₂₀ hydrocarbon chain, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.

The term "CrCio alkyl" as used herein refers to branched or straight alkyl groups comprising 1 to 10 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.

The term "cycloalkylene" as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (CrC ₁₀ )-alkyl, preferably CH ₃ .

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 term "aryloxyalkyl group" as used herein refers to groups wherein the aryl moiety is, for example, a benzene ring, a furan ring, a thiophene ring or a naphthalene ring and may have from 1 to 3 halogen atoms, haloalkyl groups, alkoxy groups or hydroxyl groups as substituents on the aryl moiety. The aryl moiety is preferably a phenyl group which is not substituted or substituted with from 1 to 3 halogen atoms or haloalkyl groups. The carbon number of the alkyl moiety (i.e. the alkylene group) of the aryloxyalkyl group is from 1 to 3. The term "aralkyl" group as used herein refers to groups wherein the aryl moiety is, for example, a benzene ring, a furan ring, a thiophene ring or a naphthalene ring and may be substituted with from 1 to 3 halogen atoms, haloalkyl groups, alkoxy groups or hydroxyl groups. The carbon number of the alkyl moiety substituted with the aryl group is preferably from 1 to 4. 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.

Preferred compounds of formula (I) are those wherein_the fluoroprostaglandin precursor is selected from the following moieties R of formula (II) wherein: - the bond between the carbon atoms in positions 13 and 14 is a double bond; R ₁ is a phenoxymethyl group; R ₂ and R ₃ are hydrogen atoms; R ₄ and R ₅ are fluorine atoms; or

- the bond between the carbon atoms in positions 13 and 14 is a double bond; Ri is a 3-chlorophenoxymethyl group;

R ₂ and R ₃ are hydrogen atoms; R ₄ and R ₅ are fluorine atoms; or

- the bond between the carbon atoms in positions 13 and 14 is a single bond; R ₁ is a phenoxymethyl group; R ₂ and R ₃ are hydrogen atoms; R ₄ and R ₅ are fluorine atoms; or

- the bond between the carbon atoms in positions 13 and 14 is a single bond; R ₁ is a 3-chlorophenoxymethyl group;

R ₂ and R ₃ are hydrogen atoms; R ₄ and R ₅ are fluorine atoms;

X is -O- or -NR ¹ -, wherein R ¹ is H or C ₁ -C ₆ alkyl, preferably R ¹ is H or methyl; m is an integer equal to 0 or 1 , with the proviso that m is equal to 0 when X is -O-; B is a radical of the formula -CH(R ¹ )COO-, wherein R ¹ is as above defined; Y is a bivalent radical having the following meanings: a) straight or branched C ₁ -C ₂₀ alkylene, preferably C ₁ -C ₁₀ , being optionally substituted by one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO ₂ or T ₁ wherein T is

-OC(O)(C ₁ -C ₁₀ alkyl)-ONO ₂ or -0(C ₁ -C ₁₀ alkyl)-ONO ₂ ;

C ₅ -C ₇ cycloalkylene group optionally substituted with linear or branched C ₁ -C ₁₀ alkyl group, preferably CH ₃ ; b)

c)

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

wherein

X ₁ = -OCO- or -COO- and R ² is H or CH ₃ ; Z is -(CH) _n ¹ - or the bivalent radical defined above under b) n ¹ is as defined above and n ² is an integer from 0 to 2; e)

wherein: Y ¹ is -CH ₂ -CH ₂ -(CH2) _n ² -; or -CH=CH-(CH ₂ ) _n ² -;

Z is -(CH) _n ¹ - or the bivalent radical defined above under b) n\ n ² ,R ² and X ₁ are as defined above; with the proviso that: i) when Y is selected from the bivalent radicals mentioned under b)-e), then the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _n ¹ ; ii) when Y is selected from the bivalent radicals mentioned under b) or c), n = O and X is NR ¹ , wherein R ¹ is as above defined, then m = 1 ;

iii) when Y is selected from the bivalent radicals mentioned under d) or e) and X is NR ¹ , wherein R ¹ is as above defined, then m = 1 ; f)

wherein: n ¹ and R ² are as defined above, R ³ is H or -COCH ₃ ; with the proviso that the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _π ¹ ; and with the proviso that when X is -NR ¹ -, wherein R ¹ is as above defined, Y cannot be f); g)

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

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

R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same or different, and are H or straight or branched C ₁ -C ₄ alky!, preferably R ⁴ , R ⁵ , R ⁶ , R ⁷ are H; wherein the -ONO ₂ group of formula (I) is linked to

wherein n ⁵ is as defined above;

Y ² 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

preferably Y ² is selected from:

The most preferred compounds of formula (I) are those compounds wherein R has the following formula:

X is -O-, S or -NR ¹ -, wherein R ¹ is H or C ₁ -C ₆ alkyl, preferably R ¹ is H or methyl; m is an integer equal to 0 or 1 , with the proviso that m is equal to 0 when X is -O- or S; B is a radical of the formula -CH(R ¹ )COO-, wherein R ¹ is as above defined; Y is a bivalent radical having the following meanings: a)

- straight or branched C ₁ -Ci ₀ alkylene, being optionally substituted with -ONO ₂ or T, wherein T is -OC(O)(C ₁ -C ₁₀ alkyl)-ONO ₂ Or -O(C ₁ -C ₁₀ alkyl)-ONO ₂ ; b)

c)

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

wherein

X ₁ = -OCO- or -COO- and R ² is H or CH ₃ ; Z is -(CH) _n ¹ - or the bivalent radical defined above under b) wherein n is an integer from O to 5; n ¹ is an integer from 1 to 5; and n ² is an integer from O to 2; e)

wherein:

Y ¹ is -CH ₂ -CH ₂ -(CH ₂ ) _n ² -; or -CH=CH-(CH ₂ ) _n ² -; Z is -(CH) _n ¹ - or the bivalent radical defined above under b) with the proviso that: i) when Y is selected from the bivalent radicals mentioned under b)-e), then the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _n ¹ ; ii) when Y is selected from the bivalent radicals mentioned under b) or c), n = 0 and X is

NR ¹ , wherein R ¹ is as above defined, then m = 1; iii) when Y is selected from the bivalent radicals mentioned under d) or e), X is NR ¹ , wherein R ¹ is as above defined, then m = 1; f)

wherein: n ¹ and R ² are as defined above, R ³ is H or COCH ₃ ; with the proviso that the -ONO ₂ group of formula (I) is bound to -(CH ₂ ) _n ¹ ; and with the proviso that when X is -NR ¹ -, wherein R ¹ is as above defined, Y cannot be f); g)

wherein X ₂ is -O- or -S-,

.3 : n is an integer from 1 to 4; R ² is hydrogen; h)

wherein: n ⁴ is an integer from 0 to 10, preferably from 0 to 3; n ^s is an integer from 1 to 10, preferably from 1 to 3; R ⁴ , R ⁵ , R ⁶ , R ⁷ are the same and are H; and wherein the -ONO ₂ group of formula (I) is linked to

Y ² is a 6 member saturated, unsaturated or aromatic heterocyclic ring, containing one or two atoms of nitrogen and selected from

Preferred compounds of the formula (I), according to the present invention, are given below:

(2 )

The compounds of the present invention can be synthesized as follows.

The compounds of general formula (I) as above defined, can be obtained: a) by reacting a compound of formula (III)

wherein

Ri is as above defined; P is H or a hydroxylic protecting group; W is -OH, Cl, or -OC(O)Ri wherein R ₁ is a linear or branched C ₁ -C ₅ alkyl; with a compound of formula (IV) Z _a -(B) _m -Y-Q

(IV) wherein Y ,B and m are as above defined, Z _a is -OH, -SH, -NHR ¹ wherein R ¹ is as above defined,

Q is -ONO ₂ or Zi wherein Z ₁ is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group; in the presence of a condensing agent, and b) when Q is Z ₁ , by converting the compound obtained in the step a) into a nitro derivative by reaction with a nitrate source. c) optionally deprotecting the compounds obtained in step a) or b). Preferred hydroxylic protecting groups are silyl ethers, such as trimethylsilyl, tert-butyl- dimethylsilyl, or acetyl and those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980.

Alternately the compound of formula (I) wherein X is -0-, m = O, R and Y are as above defined can be obtained: a.1) by reacting a compound of formula (III) wherein W = -OH, P and L are as above defined, with a compound of formula (IV) wherein Z ₃ is Z ₁ , m is O, Y and Q are as above defined, in the presence of a organic or inorganic base, and b) when Q is Z ₁ , by converting the compound obtained in the step a.1) into a nitro derivative by reaction with a nitrate source. c) optionally deprotecting the compounds obtained in step a.1) or b).

In step a) the reaction of a compound of formula (111) wherein W = -OH, P and L are as above defined, with a compound of formula (IV) wherein Z _a , Y, Q, B and m are as above defined, may be carried out in presence of a condensing agent such as N ₁ N'- carbonyldiimidazole (CDI) or dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl) - N-ethylcarbodiimide hydrochlo ride (EDAC) and a catalyst, such as N,N-dimethylamino pyridine (DMAP). The reaction is carried out in a dry inert organic solvent such as N ₁ N'- dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -20 ⁰ C to +4O ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours. In step a) the reaction of a compound of formula (III) wherein W = -OC(O)R ₁ wherein R-i and P are as above defined, with a compound of formula (IV) wherein Z ₃ , Y, B and m are as above defined and Q is -ONO ₂ , may be carried out in presence of a catalyst, such as N ₁ N- dimethylamino pyridine (DMAP). The reaction is carried out in an inert organic solvent such as N.N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated

aliphatic hydrocarbon. The reaction temperature is from -20°C to +4O°C. The reaction is completed within a time range from 30 minutes to 36 hours.

In step a) the reaction of a compound of formula (III) wherein W = Cl and P is as above defined, with a compound of formula (IV) wherein Z _a , Y, B and m are as above defined and Q is -ONO ₂ , may be carried out in presence of a organic base such as N,N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -2O ⁰ C to 4O ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours. In step a.1) The preferred organic bases are for example 1 ,8-diazabiciclo[5.4.0]undec-7-ene (DBU), N,N-diisopropyl ethylamine, diisopropylamine; preferred inorganic base are alkaline- earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate. The reaction is carried out in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -20°C to +40°C, preferably from 5 ⁰ C to 25°C. The reaction is completed within a time range from 1 to 8 hours. When Z ₁ is a chlorine atom or a bromine atom the reaction is carried out in presence an iodine compound such as Kl. In the step b) the nitrate source may be silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C ₁ -C ₁₀ alkyl). The reaction is carried out in the dark and in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF. The reaction temperature is from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate. Step c) the protected hydroxyl groups can be converted to hydroxyl groups by methods described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980. Fluoride ion is the preferred method for removing silyl ether protecting group.

The compounds of formula (III) wherein W = -OH and P = H may be synthesized as described in US patent N° 5,985,920. The synthesis of the (16-phenoxy-15-deoxy-15,15- difluoro-PGF _2α ) 16-phenoxy-15-deoxy-15, 15-difluoro-17,18, 19,20-tetranorprostaglandin-F _2α is also described in Tetrahedron Letters 45 (2004), 1527-1529.

The compounds of formula (III) wherein W = -OH and P is a hydroxylic protecting group may be prepared from the corresponding compounds wherein P = H as well known in the art, for example as described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980. The compounds of formula (III) wherein W = -OC(O)Ri and P is as above defined may be obtained from the corresponding acids wherein W = -OH by reaction with a chloroformate such as isobutylchloroformate, ethylchloroformate in presence of a non- nucleophilic base such as triethylamine in an inert organic solvent such as N ₁ N'- dimethylformamide, tetrahydrofuran, a polyhalogenated aliphatic hydrocarbon at a

temperature from -20°C and 40°C. The reaction is completed within a time range from 1 to 8 hours.

The compounds of formula (III) wherein W = Cl may be obtained from the corresponding acids wherein W = -OH by reaction with a thionyl or oxalyl chloride, halides of P ¹ " or P ^v in solvents inert such as toluene, chloroform, DMF.

The compounds of formula (IV) Z _a -(B) _m -Y-Q, wherein Z _a is -NHR ¹ , m=0, Q is -ONO ₂ , R ¹ and Y are as above defined can be obtained: e) by reacting a compound of formula (IVa)

R ¹ NH-Y-Z ₁

(IVa) wherein R ¹ , Y and Z ₁ are as above defined, in the presence of a nitrate source.

The nitrate source may be silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C ₁ -C ₁₀ alkyl). Preferred nitrate source is silver nitrate. The reaction is carried out in the dark and in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF. The reaction temperature is from room temperature to the boiling temperature of the solvent.

The compound of formula (IVa) wherein R ¹ , Y and Z-i are as above defined, can be synthesized f) by reacting a compound of formula (IVa')

R ¹ NH-Y-OH

(IVa') wherein R ¹ , and Y are as above defined, with thionyl or oxalyl chloride, halides of P'" or P ^v , mesyi chloride, tosyl chloride in solvents inert such as toluene, chloroform, DMF, etc., according to well known methods.

The compounds of formula (IVa') wherein R ¹ , and Y are as above defined, are commercially available or can be synthesized by process well known in the art.

Alternatively, the compounds of formula (IV) Z _a -(B) _m -Y-Q, wherein Z _a is -NHR ¹ , m=0, Q is -ONO ₂ , R ¹ and Y are as above defined can be obtained by reacting the aminoalcohol of formula (IVa') with nitric acid and acetic anhydride according to methods well known in the literature. The reaction temperature is usually from -5O ⁰ C to 0°C.

The compounds of formula (IV) Z _a -(B) _m -Y-Q, wherein Z _a is -OH or -SH, m=0, Q is - ONO ₂ and Y are as above defined can be obtained: g) by reacting a compound of formula (IVb)

Z _a -Y-Z ₁ (IVb) wherein Z _a , Y and Z ₁ are as above defined, in the presence of a nitrate source. The nitrate source may be silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate

(wherein alky! is C ₁ -C ₁₀ alkyl). Preferred nitrate source is silver nitrate. The reaction is carried out in the dark and in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF. The reaction temperature is from room temperature to the boiling temperature of the solvent. The compound of formula (IVb) wherein Z _a , Y and 2i are as above defined, can be synthesized h) by reacting a compound of formula (IVb')

Z _a -Y-OH

(IVb') wherein Z _a and Y are as above defined, with thionyl or oxalyl chloride, halides of P'" or P ^v , mesyl chloride, tosyl chloride in solvents inert such as toluene, chloroform, DMF, etc., according to well known methods.

The compounds of formula (IVb') wherein Z _a and Y are as above defined, are commercially available or can be synthesized by processes well known in the art. Alternatively, the compounds of formula (IV) Z _a -(B) ₁₁₁ -Y-Q, wherein Z _a is -OH, m=0, Q is -ONO ₂ and Y is as above defined, can be obtained by reacting a diol derivative of formula (IVb") HO-Y-OH with nitric acid and acetic anhydride according to methods well known in the literature. The reaction temperature is usually from -50 ⁰ C to O ⁰ C.

The compounds of formula (IV) Z _a -(B) _m -Y-Q, wherein Z _a is -NHR ¹ , m=1, Q, Y, and B are as above defined, and can be obtained by reacting i) a compound of formula (V)

P.,NR ¹ -CH(R ¹ )C(O)-W,

(V) wherein W is -OH, Cl, or -OC(O)R ₁ wherein R ₁ is a linear or branched C ₁ -C ₅ alkyl, R ¹ is as above defined, P ₁ is H or a amino protecting group, with a compound of formula (Vl)

Z ₃ -Y-Q (Vl) wherein Z ₃ is HO or Z ₁ , Y Q and Z ₁ are as above defined, and

I) when Q is Z ₁ , by converting the compound obtained in the step i) to the nitro derivative as above described. m) optionally deprotecting the compounds obtained in step i) or I).

Preferred protecting groups for a amino group are for example tert-butylcarbamate (BOC), such as 2,2,2-trichloroethyl carbamate (TROC) and those described in T. W. Greene

"Protective groups in organic synthesis", Harvard University Press, 1980, The protecting groups for a amino group can be converted to a amino group by conventional methods, for example, as described in T. VV. Greene "Protective groups in organic synthesis", Harvard University Press, 1980;

In step i) the reaction of a compound of formula (V) wherein W = -OH, with a compound of formula (Vl) wherein Z ₃ HO, Y and Q are as above defined, may be carried out in presence of a dehydrating agent as dicyclohexylcarbodiimide (DCC) or N'-(3-dimethylaminopropyl)-N-

ethylcarbodiimide hydrochloride (EDAC) and a catalyst, such as N,N-dimethylamino pyridine (DMAP). The reaction is carried out in a dry inert organic solvent such as N ₁ N'- dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -20 ⁰ C to +40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

In step i) the reaction of a compound of formula (V) wherein W = -OC(O)R ₁ wherein R ₁ is as above defined, with a compound of formula (Vl) wherein Z ₃ is -OH, Q is -ONO ₂ and Y is as above defined, may be carried out in presence of a catalyst, such as N,N-dimethylamino pyridine (DMAP). The reaction is carried out in an inert organic solvent such as N ₁ N'- dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -2O ⁰ C to +40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

In step i) the reaction of a compound of formula (V) wherein W = -OH, with a compound of formula (Vl) wherein Z ₃ is Z ₁ , Q is -ONO ₂ , Z ₁ and Y are as above defined, may be carried out in presence of a organic base such as 1,8-diazabiciclo[5.4.0]undec-7-ene (DBU), N ₁ N- diisopropylethyl amine, diisopropylamine or inorganic base such as alkaline-earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate, in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -2O ⁰ C to +40°C, preferably from 5°C to +25°C. The reaction is completed within a time range from 1 to 8 hours.

When Z ₁ is a chlorine atom or a bromine atom the reaction is carried out in presence an iodine compound such as Kl. The reaction of a compound of formula (V) wherein W = Cl and P-i is as above defined, with a compound of formula HO-Y-Q wherein Q is -ONO ₂ and Y is as above defined, may be carried out in presence of a organic base such as N,N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N ₁ N'- dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -20 ⁰ C to +4O ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (V) wherein W = -OC(O)Ri and P-i = H may be obtained from the corresponding acids wherein W = -OH by reaction with a chloroformate such as isobutylchloroformate, ethylchloroformate in presence of a non-nucleophilic base such as triethylamine in an inert organic solvent such as N,N'-dimethylformamide, tetrahydrofuran, a polyhalogenated aliphatic hydrocarbon. The reaction temperature is from -2O ⁰ C to +40°C. The reaction is completed within a time range from 1 to 8 hours.

The compounds of formula (V) wherein W = Cl may be obtained from the corresponding acids wherein W = -OH by reaction with a thionyl or oxalyl chloride, halides of P'" or P ^v in solvents inert such as toluene, chloroform, DMF.

The compounds of formula (V) wherein W = -OH are commercially available or can be synthesized according to methods well known in the literature

The compounds of formula (Vl) Z ₃ -Y-Q wherein Z ₃ is -OH, Q is -ONO ₂ and Y is as above defined can be obtained: n) by reacting a compound of formula (Via)

HO-Y-OH

(Via) wherein Y is as above defined, with thionyl or oxalyl chloride, halides of P ¹ " or P ^v , mesyl chloride, tosyl chloride in solvents inert such as toluene, chloroform, DMF, etc. o) by converting the compound obtained in the step n) to the mono nitro derivative by reaction with a nitrate source as above described.

Alternatively the compound obtained in the step n) can be nitrated with nitric acid and acetic anhydride according to methods well known in the literature. The reaction temperature is from -50 ⁰ C to O ⁰ C. The compounds of formula (Via) are commercially available, or can be synthesized by well known reactions.

The compounds of formula (Vl) Z ₃ -Y-Q wherein Q is -ONO ₂ , Z ₃ is Z ₁ , Y and Z ₁ are as above defined can be obtained by reacting a compound of formula (VIb)

Z ₁ -Y-Z ₁ (VIb) wherein Z-i is a chlorine atom, a bromine atom or a iodine atom with a nitrate source as above described.

The compounds of formula (VIb) are commercially available or can be synthesized according to methods well known in the literature. 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 preferred route of administration is topical.

The compounds of the present invention can be administered as solutions, suspensions or emulsions (dispersions) in an_ophthalmic acceptable vehicle. The term "ophthalmic 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 patient.

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.

The invention also relates to a method for treating glaucoma or ocular hypertension, said method consisting in contacting an effective intraocular pressure reducing amount of a composition with the eye in order to reduce eye pressure and to maintain said pressure on a reduced level.

The doses of prostaglandin nitroderivatives can be determined by standard clinical techniques and are in the same range or less than those described for the corresponding underivatized, commercially available prostaglandin compounds as reported in the: Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N. J., 58 ^th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, Tenth Ed.

The compositions contain 0.1-0.30 μg, especially 1-10 μg, per application of the active compound.

The treatment may be advantageously carried out in that one drop of the composition, corresponding to about 30 μl, is administered about 1 to 2 times per day to the patient's eye.

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 (see U.S. Pat. No. 4,952,581); (ii) carbonic anhydrase inhibitors, such as brinzolamide; (iii) adrenergic agonists including clonidine derivatives, such as apraclonidine or brimonidine (see 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 such as those described in U.S. Pat. No. 6,242,432.

The following examples are to further illustrate the invention without limiting it.

Example 1 Synthesis of 15,15-difluoro-9α, 11α-dihydroxy-16-phenoxy-17,18,19,20-tetranor-pregna-5Z, 13E-dien-1-oic acid 4-(nitrooxy)butyl ester (corresponding to compound of formula 43)

1.1 Preparation of 4-bromobutanol Tetrahydrofurane (12.5 g, 173 mmol) are charged under nitrogen in a reactor cooled to 5- 10°C. Hydrogen bromide (7.0 g, 86.5 mmol) is then added slowly and the reaction medium is stirred over a period of 4.5 hours at 5-10 ⁰ C. The mixture is diluted with 22.5 g of cold water and the pH of this solution adjusted to pH= 5-7 by adding 27.65% sodium Hydroxide (2.0 g) keeping the temperature at 5-1O ⁰ C. The solution is then extracted twice with dichloromethane (13.25 g). The combined organic phases are washed with 25% brine (7.5 g), adjusted to pH = 6-7 with 27.65% sodium hydroxide and dried over magnesium sulphate. Dichloromethane is distilled off and crude 4-bromobutanol (10.3 g, 66.9 mmol) is obtained in a yield of about 77%.

1.2 Preparation of 4-bromobutyl nitrate

In a reactor cooled to -5 to 5°C, nitric acid fuming (8.5 g, 135 mmol) is slowly added to a solution of 98% sulphuric acid (13.0 g, 130 mmol) in dichloromethane (18 g, 212 mmol). 4- Bromobutanol (10.2 g, 66.6 mmol) is then added to 5 ⁰ C over a period of 2-5 hours. The mixture is poured onto cold water (110 g) keeping the temperature between -5 ⁰ C and 3°C. After decantation, the upper aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water, adjusted to pH= 6-7 by addition of 27.65% sodium hydroxide, washed with brine and dried over magnesium sulphate. Dichloromethane is distilled off under vacuum and crude 4-bromobutyl nitrate (12.7 g, 64.1 mmol) is recovered in a yield of about 96%.

1.3 Preparation of 15,15-difluoro-9α, 11α-dihydroxy-16- phenoxy-17,18,19,20-tetranor-pregna-5Z, 13E-dien-1- oic acid 4-(nitrooxy)butyl ester

Tafluprost acid (115 mg, 0.28 mmol) and 4-bromobutyl nitrate (110.8 mg 18.5% w/w in dichloromethane, 0.56 mmol) were dissolved in DMF (20 ml). K ₂ CO ₃ (96.75 mg, 0.7 mmol) and Kl (46.5 mg, 0.28 mmol) were added. The reaction was stirred at room temperature for

12 hours. The reaction mixture was diluted with ethyl acetate (20 ml), washed with water (2x

20 ml), dried over sodium sulphate and evaporated under vacuum. The crude product was purified by flash chromatography, eluent n-hexane/ethyl acetate 4.5/5.5. The product (50 mg) was obtained as oil.

¹ H-NMR (CDCI ₃ ) δ: 7.32 (3H, m); 7.00 (1H, t); 6.93 (2H, d); 6.11 (1 H, m); 5.78 (1 H, m); 5.40 (2H, m); 4.45 (2H, t); 4.22-4.02 (6H, m); 2.50-2.25 (7H, m); 2.25-1.98 (5H, m); 1.9-1.55 (5H, m).

Example 2

Synthesis of 15, 15-difluoro-9α, 11 α-dihydroxy-16-phenoxy-17,18,19,20-tetranor-pregna-5Z, 13E-dien-1-oic acid [2-methoxy-4-[2-propenoyloxy(4-nitrooxybutyl)]]phenyl ester (corresponding to compound of formula 53)

2.1 Preparation of ferulic acid 4-(bromo)butyl ester

To a solution of ferulic acid (1g, 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

2.2 Preparation of ferulic acid 4-(nitrooxy)butyl ester

A solution of compound 2.1 (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 precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 75/25. The product (0.4g) was obtained as white powder (yield 53%) M.p.=63-64°C

2.3 Preparation of 15,15-difluoro-9α, 11α-dihydroxy-16-phenoxy-17,18,19,20- tetranor-pregna-5Z, 13E-dien-1~oic acid [2-methoxy-4-[2-propenoyloxy(4- nitrooxybutyl)]] phenyl ester

To a solution of tafluprost acid (0,2g, 0.487mmol) in chloroform (40ml), ferulic acid 4- (nitrooxy)butyl ester (0,23g, 0.73mmol) and DMAP (cat. amount) were added. The reaction was cooled at O°C and EDAC (0.14g, 0.76mmol) was added. The reaction was stirred at room temperature for 24 hours. The solution was treated with water and chloroform, the organic layers were anidrified with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 45/55. The product (0,1g) was obtained.

¹ H-NMR (CDCI ₃ ) δ: 7.63 (1H, d); 7.32-7.27 (3H, m); 7.14-6.89 (7H, m); 6.37 (1H, d); 6.11 (1H, m); 5.82 (1 H, m); 5.44 (2H, m); 4.52 (2H, t); 4.27-4.15 (6H, m); 3.90 (3H, s); 2.70-1.90 (14H, m).