Nitric oxide donating derivatives of latanoprost free acid

Abstract

The present invention relates to 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid, their use for the treatment of glaucoma and ocular hypertension and formulation containing 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid.

Claims

1. A compound of formula (I) or salts thereof ##STR00033## wherein R is CH(CH3)2 or H; Ra is selected from A1): (CHR1)-NH(CO)(CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 A2): (CH2)2-NH(CO)(CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 A3): (CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 wherein R1 is H or CH3, p is 1 or 0, q is 1 or 0, m is an integer ranging from 1 to 10; n is an integer ranging from 1 to 6.

2. A compound of formula (I) according to claim 1, wherein R is CH(CH3)2 and Ra is A1): (CHR1)-NH(CO)(CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 wherein R1 is H or CH3, p is 1 or 0, q is 1 or 0, m is an integer ranging from 1 to 10; n is an integer ranging from 1 to 6.

3. A compound of formula (I) according to claim 2, wherein Ra is selected from the following group of linkers: ##STR00034##

4. A compound of formula (I) according to claim 1, wherein R is CH(CH3)2 and Ra is A2): (CH2)2-NH(CO)(CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 wherein p is 1 or 0, q is 1 or 0, m is an integer ranging from 1 to 10; n is an integer ranging from 1 to 6.

5. A compound of formula (I) according to claim 4, wherein Ra is selected from the following group of linkers: ##STR00035##

6. A compound of formula (I) according to claim 1, wherein R is CH(CH3)2 and Ra is A3): (CH2)m-[O(CH2)n]p-(CHONO2)q-CH2-ONO2 wherein p is 1 or 0, q is 1 or 0, m is an integer ranging from 1 to 10; n is an integer ranging from 1 to 6.

7. A compound according to claim 6, wherein Ra is selected from the following group of linkers: ##STR00036##

8. A compound of formula (I) according to claim 1, wherein R is H.

9. A compound of formula (I) according to claim 8, wherein Ra is selected from the following group of linkers having structure A1: ##STR00037##

10. A compound of formula (I) according to claim 8, wherein Ra is selected from the following group of linkers having structure A2: ##STR00038##

11. A compound of formula (I) according to claim 8, wherein Ra is selected from the following group of linkers having structure A3: ##STR00039##

12. A compound of formula (I) according to claim 1, selected from the following group of compounds: (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(6-(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (1)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(5,6-bis(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (2)); (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(2-(2-(nitrooxy)ethoxy)acetamido)propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (3)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(3-(2,3-bis(nitrooxy)propoxy) propanamido)propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (4)); (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(6-(nitrooxy)hexanamido)acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (5)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(2-(5,6-bis(nitrooxy)hexanamido)acetoxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (6)); (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(2-(2-(nitrooxy)ethoxy) acetamido)acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (7)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(2-(3-(2,3-bis(nitrooxy)propoxy) propanamido)acetoxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (8)); (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(6-(nitrooxy)hexanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (9)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(5,6-bis(nitrooxy)hexanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (10)); (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(2-(nitrooxy)ethoxy) acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (11)); (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(2,3-bis(nitrooxy)propoxy)propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (12)).

13. A compound of formula (I) according to claim 1, for use as medicament.

14. A compound of formula (I) according to claim 1, for use in the treatment of ocular hypertension.

15. A compound of formula (I) according to claim 1, for use in the treatment of ocular hypertension or glaucoma.

16. A compound of formula (I) for the use according to claim 15, wherein glaucoma is primary open angle glaucoma, normal intraocular tension glaucoma, pseudoexfoliation glaucoma, acute angle-closure glaucoma or chronic closed angle glaucoma.

17. A topical ocular pharmaceutical composition comprising a compound of formula (I) according to claim 1 as active principle and a pharmaceutically acceptable excipient or a combination of excipients.

18. A composition comprising a compound of formula (I) according to claim 1 and at least another active agent selected from the following classes of drugs: Beta-adrenergic antagonists, Adrenergic agonists, Alpha2-selective adrenergic agonists, Carbonic Anhydrase Inhibitors, Cholinergic agonists, Cholinesterase inhibitors.

19. A composition according to claim 18 for use in the treatment of ocular hypertension or glaucoma.

Description

(1) Thus, this invention provides 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid useful for the treatment of glaucoma and elevated intraocular pressure.

(2) It has now been found that 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid are efficacious and potent ocular hypotensive agents and therefore the 15-nitrooxyderivatives of latanoprost and 15-nitrooxyderivatives of latanoprost free acid of the present invention can be employed for treating ocular hypertension and glaucoma, in particular chronic open-angle glaucoma.

(3) An embodiment of the invention relates to compounds of formula (I) or salts thereof

(4) ##STR00001##

(5) wherein

(6) R is CH(CH.sub.3).sub.2 or H; preferably R is CH(CH.sub.3).sub.2;

(7) Ra is selected from

(8) A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(9) A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(10) A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(11) wherein

(12) R.sup.1 is H or CH.sub.3,

(13) p is 1 or 0,

(14) q is 1 or 0,

(15) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(16) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(17) Preferred linkers having structure A1 are below reported:

(18) ##STR00002##

(19) preferred linkers having structure A2 are below reported:

(20) ##STR00003##

(21) preferred linkers having structure of the group A3 are below reported:

(22) ##STR00004##

(23) Another embodiment of the invention relates to compounds of formula (I) wherein

(24) R is CH(CH.sub.3).sub.2;

(25) Ra is A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(26) wherein

(27) R.sup.1 is H or CH.sub.3,

(28) p is 1 or 0,

(29) q is 1 or 0,

(30) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(31) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(32) Another embodiment of the invention relates to compounds of formula (I) wherein

(33) R is CH(CH.sub.3).sub.2 and

(34) Ra is selected from the following group of linkers having structure A1:

(35) ##STR00005##

(36) An embodiment of the invention relates to compounds of formula (I) wherein

(37) R is CH(CH.sub.3).sub.2;

(38) Ra is A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(39) wherein

(40) p is 1 or 0,

(41) q is 1 or 0,

(42) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(43) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(44) An embodiment of the invention relates to compounds of formula (I) wherein

(45) R is CH(CH.sub.3).sub.2 and

(46) Ra is selected from the following group of linkers having structure A2:

(47) ##STR00006##

(48) An embodiment of the invention relates to compounds of formula (I) wherein

(49) R is CH(CH.sub.3).sub.2;

(50) Ra is A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(51) wherein

(52) p is 1 or 0,

(53) q is 1 or 0,

(54) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(55) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(56) An embodiment of the invention relates to compounds of formula (I) wherein

(57) R is CH(CH.sub.3).sub.2 and

(58) Ra is selected from the following group of linkers having structure A3:

(59) ##STR00007##

(60) Another embodiment of the invention relates to compounds of formula (I) or salts thereof wherein

(61) R is H;

(62) Ra is A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(63) wherein

(64) R.sup.1 is H or CH.sub.3,

(65) p is 1 or 0,

(66) q is 1 or 0,

(67) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(68) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(69) Another embodiment of the invention relates to compounds of formula (I) wherein

(70) R is H and

(71) Ra is selected from the following group of linkers having structure A1:

(72) ##STR00008##

(73) An embodiment of the invention relates to compounds of formula (I) or salts thereof wherein

(74) R is H;

(75) Ra is A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(76) wherein

(77) p is 1 or 0,

(78) q is 1 or 0,

(79) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(80) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(81) An embodiment of the invention relates to compounds of formula (I) wherein

(82) R is H and

(83) Ra is selected from the following group of linkers having structure A2:

(84) ##STR00009##

(85) An embodiment of the invention relates to compounds of formula (I) or salts thereof wherein

(86) R is H;

(87) Ra is A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(88) wherein

(89) p is 1 or 0,

(90) q is 1 or 0,

(91) m is an integer ranging from 1 to 10; preferably m is from 1 to 6;

(92) n is an integer ranging from 1 to 6; preferably n is 1 or 2.

(93) An embodiment of the invention relates to compounds of formula (I) wherein

(94) R is H and

(95) Ra is selected from the following group of linkers having structure A3:

(96) ##STR00010##

(97) Another embodiment of the inventions relates to a compound of formula (I) selected from the following group of compounds: (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(6-(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (1))

(98) ##STR00011## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(5,6-bis(nitrooxy)hexanamido) propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (2))

(99) ##STR00012## (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(3-(2-(2-(nitrooxy)ethoxy) acetamido)propanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (3))

(100) ##STR00013## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(3-(2,3-bis(nitrooxy)propoxy) propanamido)propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (4))

(101) ##STR00014## (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(6-(nitrooxy)hexanamido) acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (5))

(102) ##STR00015## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(2-(5,6-bis(nitrooxy)hexanamido)acetoxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (6))

(103) ##STR00016## (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(2-(2-(nitrooxy)ethoxy) acetamido)acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (7))

(104) ##STR00017## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(2-(3-(2,3-bis(nitrooxy)propoxy) propanamido)acetoxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (8))

(105) ##STR00018## (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(6-(nitrooxy)hexanoyloxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (9))

(106) ##STR00019## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(5,6-bis(nitrooxy)hexanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (10))

(107) ##STR00020## (Z)-isopropyl 7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-(2-(2-(nitrooxy)ethoxy)acetoxy)-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound (11))

(108) ##STR00021## (Z)-isopropyl 7-((1R,2R,3R,5S)-2-((3R)-3-(3-(2,3-bis(nitrooxy)propoxy)propanoyloxy)-5-phenylpentyl)-3,5-dihydroxycyclopentyl)hept-5-enoate (Compound (12))

(109) ##STR00022##

(110) The term salt has the meaning normally understood by those of ordinary skill in the art. Pharmaceutically acceptable salts of acidic functional groups may be related to organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, lithium, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines.

(111) Included within the scope of the present invention are the individual enantiomers of the compounds of formula (I), as well as their racemic and non-racemic mixtures.

(112) Another embodiment provides the use of compound of formula (I) for treating ocular hypertension.

(113) Another embodiment provides the use of compound of Formula (I) for treating glaucoma in particular primary open angle glaucoma, normal intraocular tension glaucoma, pseudoexfoliation glaucoma, acute angle-closure glaucoma, chronic closed angle glaucoma.

(114) The compound may be provided as part of a pharmaceutical composition as described therein.

(115) In forming the compositions for topical administration, the compounds of the present invention are generally formulated as between about 0.00003 to about 3 percent by weight (wt %) solutions in water at a pH between 4.5 to 8.0. The compounds are preferably formulated as between about 0.003 to about 1 wt % and, most preferably, between about 0.004 and about 0.3 wt %.

(116) In another aspect, there is provided a topical ocular pharmaceutical composition. The pharmaceutical composition includes a compound of Formula (I) or salts thereof and a pharmaceutically acceptable excipient. Acceptable excipients may include preservatives, dissolving agents and viscosity agents.

(117) Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid or other agents known to those skilled in the art. Such preservatives are typically employed at a concentration between about 0.001% and about 1.0% by weight. Dissolving agents include: polysorbates for example polyoxyethylene sorbitan monolaurate, and polyoxyethylene sorbitan monooleate for polysorbate 80, polyoxylated castor oil such as polyoxyethylene hydrogenated castor oil 40 and polyoxyethylene hydrogenated castor oil 60, polyoxyl stearate, macrogol, propyleneglycol; or other agents known to those skilled in the art. The dissolving agent may be used solely or in combination with one or more other dissolving agents.

(118) Viscosity agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art.

(119) The ophthalmic composition of the present invention may further contain other additives. Examples of the additives may include osmotic adjusting agents such as sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, borax, sodium hydroxide, hydrochloric acid, isosorbitol, propylene glycol, mannitol, sucrose and glucose; buffering agents such as sodium monohydrogen phosphate and sodium dihydrogen phosphate.

(120) The compound of the present invention can also be used in combination with the following classes of drugs: Beta-adrenergic antagonists including carteolol, levobunolol, metipranolol, timolol hemihydrate; Adrenergic agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin; and Alpha.sub.2-selective adrenergic agonists such as apraclonidine and the like; Carbonic Anhydrase Inhibitors including such as acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide; Cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine; Cholinesterase inhibitors such as demecarium, echothiophate, physostigmine.

(121) Another embodiment of the invention relates to a composition comprising a compound of formula (I) and at least another active agent selected from the following classes of drugs: Beta-adrenergic antagonists including carteolol, levobunolol, metipranolol, timolol hemihydrate; Adrenergic agonists including non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin; and Alpha.sub.2-selective adrenergic agonists such as apraclonidine and the like; Carbonic Anhydrase Inhibitors including such as acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide; Cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine; Cholinesterase inhibitors such as demecarium, echothiophate, physostigmine.

(122) General Synthesis

(123) 1) The compound of formula (I) wherein R is CH(CH.sub.3).sub.2 and Ra is selected from the groups A1), A2) or A3):

(124) A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(125) A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(126) A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(127) wherein:

(128) R.sup.1, m, n, p and q are as above defined;

(129) can be prepared by reacting a compound of formula (II), wherein Ra is as above defined, with methanol or other alcohols:

(130) ##STR00023##

(131) Compounds of formula (II), wherein Ra is as above defined, can be generally prepared by reacting a compound of formula (III) with compounds of formula (IVa-c):
HOOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVa)
HOOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVb)
HOOC(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVc)

(132) as depicted in the below reported scheme:

(133) ##STR00024##

(134) The reaction is carried out in a aprotic polar/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from 0 C. to 80 C.

(135) Alternatively, the compounds of formula (II) can be generally prepared by reacting a compound of formula (III) with compounds of formula (Va-c):
XOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Va)
XOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vb)
XOC(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vc)

(136) wherein X is Cl, p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, as depicted in the below reported scheme:

(137) ##STR00025##

(138) When X=Cl, the reaction is carried out in presence of a base such as DMAP, pyridine or triethylamine or K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 in an aprotic/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, at a temperature ranging from 20 C. to 60 C.

(139) When X is selected from p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, the reaction is carried out in a aprotic polar/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, in presence of DMAP at temperature ranging from 0 C. to 80 C.

(140) The compound of formula (III) is known in the literature (see WO2012/139164-A1) and can be also prepared by reacting latanoprost with butylboronic acid following a general procedure reported in Organic Syntheses, Coll. Vol. 10, p. 613 (2004).

(141) Compounds of formula (IVa) and (IVb) can be prepared by basic hydrolysis of correspondent compounds of formula (VIa) and (VIb):
=MeOOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(VIa)
=MeOOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(VIb)

(142) wherein R.sup.1, m, n, p, q are as above defined.

(143) Compounds of formula (VIa) and (VIb) can be prepared by reacting compounds (IVc) or (Vc) with commercially available compounds of formula (VIIa) or (VIIb):
=MeOOC(CHR.sup.1)NH.sub.2(VIIa)
=MeOOC(CH.sub.2).sub.2NH.sub.2(VIIb)

(144) wherein R.sup.1 is as above defined, according to methods well known in the art.

(145) Alternatively compounds of formula (IVa) and (IVb) can be prepared by acid hydrolysis of correspondent compounds of formula (VIc) and (VId):
=t-ButOOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(VIc)
=t-ButOOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(VId)

(146) wherein R.sup.1, m, n, p, q are as above defined.

(147) Compounds of formula (VIc) and (VId) can be prepared by reacting compounds (IVc) or (Vc) with commercially available compounds of formula (VIIc) or (VIId):
=t-ButOOC(CHR.sup.1)NH.sub.2(VIIc)
=t-ButOOC(CH.sub.2).sub.2NH.sub.2(VIId)

(148) wherein R.sup.1 is as above defined, according to methods well known in the art.

(149) Compounds (IVc) are known in the art or can be prepared from known compounds by known methods such as for example from the corresponding alcohols of formula (VIIIa),
HOCH.sub.2(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(VIIIa)

(150) wherein m, n, p and q are as above defined, by oxidation with known agents such as TEMPO or Ruthenium (IV) oxide/Sodium periodate.

(151) 2) The compound of formula (I) wherein R is H and Ra is selected from the groups A1), A2) or A3):

(152) A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(153) A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(154) A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(155) wherein:

(156) R.sup.1, m, n, p and q are as above defined;

(157) can be prepared by deprotecting an allyl or isoprenyl ester of formula (IX), wherein Ra is as above defined and Y is H or CH.sub.3, with methods known in the literature (see for example: T. W. Greene, P. G. M. Wuts Protective groups in organic Synthesis, 4th edition, J. Wiley & Sons, New York, 2006) and eventually reacting the deprotected compound in MeOH as already described for compound (II):

(158) ##STR00026##

(159) Compounds of formula (IX), wherein Ra is as above defined, can be generally prepared by reacting a compound of formula (X) with compounds of formula (IVa-c):
HOOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVa)
HOOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVb)
HOOC(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(IVc)

(160) as depicted in the below reported scheme:

(161) ##STR00027##

(162) The reaction is carried out in a aprotic polar/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, in presence of DCC, EDAC, HBTU, HATU or other coupling reagents, in presence of catalytic amount of DMAP at temperature ranging from 0 C. to 80 C.

(163) Alternatively, the compounds of formula (IX) can be generally prepared by reacting a compound of formula (X) with compounds of formula (Va-c):
XOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Va)
XOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vb)
XOC(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vc)

(164) wherein X is Cl, p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy as depicted in the below reported scheme:

(165) ##STR00028##

(166) When X=Cl, the reaction is carried out in presence of a base such as DMAP, pyridine or triethylamine or K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 in an aprotic/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, at a temperature ranging from 20 C. to 60 C.

(167) When X is selected from p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, the reaction is carried out in a aprotic polar/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, in presence of DMAP at temperature ranging from 0 C. to 80 C.

(168) The compound of formula (X) can be prepared as already described for analogous compound (III) by reacting a compound (XI) with butylboronic acid following a general procedure reported in Organic Syntheses, Coll. Vol. 10, p. 613 (2004).

(169) ##STR00029##

(170) Compound (XI) can be prepared from latanoprost acid by known methods, as by reacting latanoprost acid with allyl chloride (YH) or 2-Butene, 1-chloro-3-methyl-(YCH.sub.3) in the presence of an organic or inorganic base following general procedures known in the literature (see for example: T. W. Greene, P. G. M. Wuts Protective groups in organic Synthesis, 4th edition, J. Wiley & Sons, New York, 2006).

(171) Alternatively the compound of formula (I) wherein R is H and Ra is selected from the groups A1), A2) or A3):

(172) A1): (CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(173) A2): (CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(174) A3): (CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2

(175) wherein:

(176) R.sup.1, m, n, p and q are as above defined;

(177) can be prepared by reacting compound (XII) with MeOH as already described for compound (II):

(178) ##STR00030##

(179) Compounds of formula (XII), wherein Ra is as above defined, can be generally prepared by reacting a compound of formula (XIII) with compounds of formula (Va-c):
XOC(CHR.sup.1)NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Va)
XOC(CH.sub.2).sub.2NH(CO)(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vb)
XOC(CH.sub.2).sub.m[O(CH.sub.2).sub.n].sub.p(CHONO.sub.2).sub.qCH.sub.2ONO.sub.2(Vc)

(180) wherein X is Cl, p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy

(181) as depicted in the below reported scheme:

(182) ##STR00031##

(183) When X=Cl, the reaction is carried out in presence of a base such as DMAP, pyridine or triethylamine or K.sub.2CO.sub.3, Cs.sub.2CO.sub.3 in an aprotic/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, at a temperature ranging from 20 C. to 60 C.

(184) When X is selected from p-nitrophenoxy, pentafluorophenoxy or 2,5-pyrrolidinedione, 1-oxy, the reaction is carried out in a aprotic polar/non polar solvent such as THF, DMF or CH.sub.2Cl.sub.2, in presence of DMAP at temperature ranging from 0 C. to 80 C.

(185) The compound of formula (XIII) can be prepared as already described for analogous compound (III) by reacting latanoprost acid (XIV) with butylboronic acid following a general procedure reported in Organic Syntheses, Coll. Vol. 10, p. 613 (2004).

(186) ##STR00032##