EP1917239A1 - Derives nitres de fluoroprostaglandines - Google Patents

Derives nitres de fluoroprostaglandines

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Publication number
EP1917239A1
EP1917239A1 EP06765591A EP06765591A EP1917239A1 EP 1917239 A1 EP1917239 A1 EP 1917239A1 EP 06765591 A EP06765591 A EP 06765591A EP 06765591 A EP06765591 A EP 06765591A EP 1917239 A1 EP1917239 A1 EP 1917239A1
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European Patent Office
Prior art keywords
group
formula
integer
compound
ono
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German (de)
English (en)
Inventor
Francesca Benedini
Valerio Chiroli
Wesley K.M. Agouron Pharm.Inc. A. Pfizer Co CHONG
Achim Agouron Pharm. Inc. A Pfizer Co KRAUSS
Michael R. Agouron Pharm.Inc. A Pfizer Co NIESMAN
Ennio Ongini
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Nicox SA
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Nicox SA
Pfizer Inc
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Publication of EP1917239A1 publication Critical patent/EP1917239A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • 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.
  • lOP intraocular pressure
  • Glaucoma occurs when an imbalance in production and drainage of fluid in the eye (aqueous humor) increases eye pressure to unhealthy levels.
  • 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, ⁇ -agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.
  • drugs which either reduce the production of aqueous humor within the eye or increase the fluid drainage, such as beta-blockers, ⁇ -agonists, cholinergic agents, carbonic anhydrase inhibitors, or prostaglandin analogs.
  • Topical beta-blockers show serious pulmonary side effects, depression, fatigue, confusion, impotence, hair loss, heart failure and bradycardia.
  • Topical ⁇ -agonists have a fairly high incidence of allergic or toxic reactions; topical cholinergic agents (miotics) can cause visual side effects.
  • 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).
  • topical prostaglandin analogs used in the treatment of glaucoma, can produce ocular side effects, such as increased pigmentation of the iris, ocular irritation, conjunctival hyperaemia, ulceris, 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 15 ⁇ 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 2 ⁇ 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 2 ⁇ 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 2 ⁇ have a long-lasting effect of lowering intraocular pressure and they have a little effect on melanogenesis.
  • tafluprost which is a 15-deoxy-15,15-difluoro-prostaglandin-F 2 ⁇ derivative.
  • the results of the pharmacological tests demonstrate that tafluprost has a high lOP-reducing efficacy and weak melanogenic side effect.
  • An object of the present invention is, therefore, fluoroprostaglandins nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is the prostaglandin residue of formula (II):
  • R 1 is selected from:
  • 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;
  • 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;
  • 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;
  • 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-
  • 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 ;
  • 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)
  • 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)
  • 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)
  • n 3 is an integer from 1 to 6, preferably from 1 to 4, and R 2 is as defined above; h)
  • 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
  • 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
  • C 1 -C 2O alkylene 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.
  • CrCio alkyl 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.
  • cycloalkylene 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 .
  • heterocyclic 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.
  • aryloxyalkyl group 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.
  • aralkyl group 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.
  • 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.
  • 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.
  • 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
  • Ri is a 3-chlorophenoxymethyl group
  • R 2 and R 3 are hydrogen atoms; R 4 and R 5 are fluorine atoms; or
  • R 1 is a phenoxymethyl group
  • R 2 and R 3 are hydrogen atoms
  • R 4 and R 5 are fluorine atoms
  • 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
  • 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)
  • 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)
  • 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 ) ⁇ 1 ; and with the proviso that when X is -NR 1 -, wherein R 1 is as above defined, Y cannot be f); g)
  • 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)
  • 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
  • Y 2 is selected from:
  • 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)
  • 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)
  • 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:
  • 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)
  • n is an integer from 1 to 4; R 2 is hydrogen; h)
  • 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
  • the compounds of the present invention can be synthesized as follows.
  • 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
  • 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.
  • a condensing agent such as N 1 N'- carbonyldiimidazole (CDI) or dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl) - N-ethylcarbodiimide hydrochlo ride
  • 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.
  • 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.
  • a catalyst such as N 1 N- dimethylamino pyridine (DMAP).
  • DMAP N 1 N- dimethylamino 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 -20°C to +4O°C.
  • the reaction is completed within a time range from 30 minutes to 36 hours.
  • a organic base such as N,N-dimethylamino pyridine (DMAP), triethylamine, pyridine.
  • DMAP N,N-dimethylamino 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.
  • 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.
  • DBU 1,8-diazabiciclo[5.4.0]undec-7-ene
  • 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.
  • Z 1 is a chlorine atom or a bromine atom the reaction is carried out in presence an iodine compound such as Kl.
  • 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.
  • a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF.
  • 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.
  • 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 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 reaction temperature is usually from -5O 0 C to 0°C.
  • 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.
  • 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')
  • 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.
  • the reaction temperature is usually from -50 0 C to O 0 C.
  • Z 3 -Y-Q (Vl) wherein Z 3 is HO or Z 1 , Y Q and Z 1 are as above defined, and
  • 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
  • a dehydrating agent as dicyclohexylcarbodiimide (DCC) or N'-(3-dimethylaminopropyl)-N- ethylcarbodiimide hydrochloride (EDAC)
  • DMAP N,N-dimethylamino pyridine
  • 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.
  • 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.
  • a catalyst such as N,N-dimethylamino pyridine (DMAP).
  • DMAP N,N-dimethylamino 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 -2O 0 C to +40 0 C.
  • the reaction is completed within a time range from 30 minutes to 36 hours.
  • the reaction temperature is from -2O 0 C to +40°C, preferably from 5°C to +25°C.
  • the reaction is completed within
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • ophthalmic acceptable vehicle refers to any substance or combination of substances which are non-reactive with the compounds and suitable for administration to patient.
  • 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.
  • compositions contain 0.1-0.30 ⁇ g, especially 1-10 ⁇ g, per application of the active compound.
  • the treatment may be advantageously carried out in that one drop of the composition, corresponding to about 30 ⁇ l, is administered about 1 to 2 times per day to the patient's eye.
  • 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.
  • 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.
  • 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.
  • Tafluprost acid 115 mg, 0.28 mmol
  • 4-bromobutyl nitrate 110.8 mg 18.5% w/w in dichloromethane, 0.56 mmol
  • DMF 20 ml
  • K 2 CO 3 96.75 mg, 0.7 mmol
  • Kl 46.5 mg, 0.28 mmol

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Abstract

La présente invention concerne les dérivés nitrés de fluoroprostaglandines dotés d’une activité pharmacologique accrue et d’une tolérance accrue. Ces dérivés peuvent être utilisés pour le traitement du glaucome et de l’hypertension oculaire.
EP06765591A 2005-06-29 2006-06-19 Derives nitres de fluoroprostaglandines Withdrawn EP1917239A1 (fr)

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US20110293549A1 (en) 2009-02-03 2011-12-01 Athena Cosmetics, Inc. Composition, method and kit for enhancing hair
WO2011057386A1 (fr) * 2009-11-13 2011-05-19 Oral Delivery Technology Ltd. Composition et dispositif prophylactique pour l'amélioration de performance sexuelle ou de plaisir sexuel
AU2010358560B2 (en) * 2010-08-02 2015-02-12 Ac Patent Holding Inc. Composition, method and kit for enhancing hair
JO3350B1 (ar) 2011-03-07 2019-03-13 Merck Sharp & Dohme مشتقات حلقية غير متجانسة محتوية على مجموعات أمينو أولية ومركبات داي أزينيومديولات
CN102675404B (zh) * 2012-05-10 2014-04-09 福建天泉药业股份有限公司 一种甘草次酸硝酸丁酯的制备方法
US9115109B2 (en) * 2013-08-15 2015-08-25 Chirogate International Inc. Processes and intermediates for the preparations of isomer free prostaglandins
WO2016155906A1 (fr) 2015-03-31 2016-10-06 Nicox S.A. Dérivés de fluprosténol donneurs d'oxyde nitrique
WO2016156104A1 (fr) 2015-03-31 2016-10-06 Nicox S.A. Dérivés d'acide libre latanoprost donneurs d'oxygène
EP3088388A1 (fr) 2015-04-30 2016-11-02 NicOx S.A. Dérivés de prostaglandines donneurs d'oxyde nitrique
MX2018003462A (es) 2015-09-22 2018-09-06 Graybug Vision Inc Compuestos y composiciones para el tratamiento de trastornos oculares.
JP7055802B2 (ja) 2016-11-08 2022-04-18 ボシュ・アンド・ロム・インコーポレイテッド 正常眼圧緑内障を処置するための一酸化窒素放出プロスタグランジン誘導体

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