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WO1995026729A1 - Nouveaux derives de prostaglandine servant a traiter le glaucome ou l'hypertension oculaire - Google Patents

Nouveaux derives de prostaglandine servant a traiter le glaucome ou l'hypertension oculaire Download PDF

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Publication number
WO1995026729A1
WO1995026729A1 PCT/SE1995/000347 SE9500347W WO9526729A1 WO 1995026729 A1 WO1995026729 A1 WO 1995026729A1 SE 9500347 W SE9500347 W SE 9500347W WO 9526729 A1 WO9526729 A1 WO 9526729A1
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WO
WIPO (PCT)
Prior art keywords
groups
deoxy
phenyl
derivative
ring
Prior art date
Application number
PCT/SE1995/000347
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English (en)
Inventor
Johan Stjernschantz
Bahram Resul
Original Assignee
Pharmacia Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia Ab filed Critical Pharmacia Ab
Priority to AU21559/95A priority Critical patent/AU2155995A/en
Publication of WO1995026729A1 publication Critical patent/WO1995026729A1/fr

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Classifications

    • 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
    • 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

Definitions

  • Glaucoma or Ocular Hypertension are Glaucoma or Ocular Hypertension.
  • the present invention is related to new derivatives of prostaglandin F 2 ⁇ in which part of the omega chain has been substituted with a ring structure and one or more of the hydroxy groups on carbon atoms 11 or 15 has been removed, as well as their use for treatment of glaucoma or ocular
  • the invention also relates to ophthalmic
  • compositions containing an active amount of said prostaglandin derivatives and to the manufacture thereof are provided.
  • Glaucoma is an eye disorder characterized by increased intraocular pressure, excavation of the optic nerve head, and gradual loss of the visual field. An abnormally high
  • intraocular pressure is commonly known to be detrimental to the eye, and there are clear indications that in glaucoma the intraocular pressure is the most important factor causing degenerative changes in the retina and the optic nerve head.
  • the exact pathophysiological mechanism of open angle glaucoma is, however, still unknown. Unless untreated, glaucoma may lead to blindness, the course of the disease typically being slow with progressive loss of vision.
  • the intraocular pressure (IOP) can be defined according to the formula:
  • IOP Pe + (Ft - Fu) ⁇ R (1)
  • Pe is the episcleral venous pressure
  • Ft the total formation of aqueous humour
  • Fu the part of the aqueous humor which exits the eye through the uveoscleral outflow pathway
  • R is the resistance in the trabecular outflow pathway.
  • the aqueous humour in the anterior and posterior chambers of the eye is formed in the ciliary processes behind the iris. It then flows through the pupil into the anterior chamber and normally exits the eye through the trabecular meshwork and Schlemm's canal into the episcleral veins outside the eye globe. However, part of the aqueous humour may leave the eye through the uveoscleral outflow route (Bill 1975).
  • IOP in humans is normally in the range of 12-22 mmHg. At higher values, e.g. above 22 mmHg, there is an increased risk that the eye may be affected. In one particular form of
  • glaucoma low tension glaucoma, damage may occur at pressure levels that are within the normal physiological range.
  • the opposite situation is also known, i.e. some individuals may exhibit an abnormally high intraocular pressure without any manifest defects in the visual fields or the optic nerve head. Such conditions are usually referred to as ocular hypertension.
  • Glaucoma treatment can be given by means of drugs, laser or surgery.
  • drug treatment the purpose is to lower either the formation of aqueous humour (Ft) or the resistance (R) which according to formula (1) above will result in reduced intraocular pressure; alternatively to increase the outflow of aqueous humour through the uveoscleral route which according to the same formula also reduces the intraocular pressure.
  • Ft aqueous humour
  • R resistance
  • Prostaglandins and in this group especially PGF 2 ⁇ and its derivatives like esters and various analogues, reduce
  • Naturally occurring PGF 2 ⁇ has the general structure:
  • the upper side chain is called the alpha chain and the lower side chain is called the omega chain.
  • R 1 is OOH, the active acid form, or an amide group or an ester moiety comprising an alkyl group, preferably with 1-10 carbon atoms, especially 1-6 carbon atoms, for instance methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl groups.
  • R 2 is hydrogen or a small alkyl group,
  • cyclopentane ring might contain more than one substituent R2.
  • D is a carbon chain with 3-12, preferably 3-8, and
  • the chain D contains a double bond, for instance between carbons 13-14 , or 14-15, or 15-16 or 16-17.
  • the double bond may also be located further to the end of the omega chain in cases of extended chains.
  • the double bond between carbon 13 and 14, corresponding to the naturally occurring PGF 2 ⁇ represents the presently preferred embodiment.
  • the carbon chain is optionally interrupted by preferably not more than one atom selected from the group comprising nitrogen, sulphur or oxygen.
  • the chain may also be substituted by one or more "inert" groups, for instance lower alkyl groups, especially with 1-3 carbon atoms.
  • D may also contain a hydroxy group on carbon 15 in cases when the substituent on carbon 11 is not a hydroxy group.
  • R3 is a ring structure selected from the group comprising (i) aromatic rings, such as a phenyl group which is
  • heteroaromatic rings such as thiazol, imidazole,
  • pyrrolidine, thiophene and oxazole which is unsubstituted or substituted with one or more substituents selected from C1-C5 alkyl groups, C1-C4 alkoxy groups, trifluoromethyl groups, C1-C3 aliphatic acylamino groups, nitro groups, halogen atoms, and a phenyl group; or
  • R 4 is OH, provided that carbon atom 15 is not substitued with OH, or a lower alkyl group. It is further within the scope of the invention to employ prostaglandin derivatives analogous to the formula given above but in which minor modifications have been introduced by
  • inert substituents for instance in such positions that the specificity for the prostaglandin receptor is not appreciably affected.
  • modifications include derivatives with cis and trans configuration of the double bond between carbons 5 and 6 as well as other locations of the double bond on the alpha chain and various substituents on the alpha chain.
  • the invention thus relates to certain deoxy derivatives of PGF2 ⁇ in which not more than one of carbon atoms 11 and 15 may contain a hydroxy group, and in which the omega chain is substituted to contain a ring structure as well as the use of such derivatives for treatment of glaucoma or ocular
  • the method for treatment comprises contacting an effective intraocular pressure reducing amount of a
  • composition comprising a deoxy derivative, as defined above, and an ophthalmologically acceptable carrier, with the eye in order to reduce the eye pressure and to maintain said pressure at a reduced level.
  • This therapy is applicable both to humans and animals.
  • the composition contains about 0.1-100 ⁇ g,
  • the composition is applied topically on the eye 1-3 times daily.
  • the effective amount comprises a dose of about
  • composition is carried out by mixing the prostaglandin derivative with an ophthalmologically
  • Such carrier compounds are known per se and there are a number of systems based on physiologic saline, oil solutions or ointments suggested in the literature for
  • the carrier or vehicle may furthermore contain ophthalmologically compatible
  • preservatives such as e.g. benzalkonium chloride, surfactants, such as polysorbate 80, liposomes or polymers, for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid.
  • surfactants such as polysorbate 80
  • liposomes or polymers for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid.
  • liposomes or polymers for example methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid.
  • methyl cellulose polyvinyl alcohol
  • polyvinyl pyrrolidone polyvinyl pyrrolidone
  • hyaluronic acid hyaluronic acid
  • soluble or insoluble drug inserts for instance gels or gel type matrices, in order to obtain a slow-release system.
  • DIBAL diisobutylaluminium hydride
  • triphenylphosphonium bromide (6.13g, 0.0133mol) in THF (20 mL) under nitrogen at 0-5° C was added potassium t butoxide (1.49 g, 0.013 mol), and the mixture stirred for 30 min. at room temperature.
  • potassium t butoxide (1.49 g, 0.013 mol)
  • the aldehyde 22. (2.4 g, 0.0067 mol) in THF (5 mL), and the mixture was stirred for 3-4 h.
  • the reaction mixture was diluted with ether (60 mL) and washed with saturated ammonium chloride (2 ⁇ 40 mL) and brine (30 mL), the organic layer was dried on sodium sulfate, and filtered. The solvent was removed in vacuo, and the slurry was chromatographed on silicagel (EtOAc:CH2Cl2) to give a colorless oil. which was then dissolved in benzene. Diphenyl sulfide (3.6g, 0.0192mol) was added, and irradiated with UV-365 nm under nitrogene atmosphere for 24hr. (HPLC monitoring), the mixture was diluted with ethyl acetate (80 mL), washed with water (50mL), 5% sodium hydrogencarbonate (40mL) and brine
  • the cat eye reacts with marked miosis (constriction of the pupil) to prostaglandins which stimulate FP receptors.
  • the FP receptor is the receptor for PGF 2 ⁇ , a naturally occurring prostaglandin
  • the trans isomer being approximately 10 times more potent than the cis isomer.
  • PGF 2alpha -induced ocular hypotension Evidence for enhancement of uveoscleral outflow by PGF 2alpha , Arch. Ophthalmol 105:1112-1116.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Dérivés thérapeutiquement efficaces et physiologiquement acceptables de 11-désoxy prostaglandine F2α contenant une chaîne oméga à noyau substitué, et leur utilisation dans la préparation de compositions servant à traiter le glaucome ou l'hypertension oculaire.
PCT/SE1995/000347 1994-03-31 1995-03-31 Nouveaux derives de prostaglandine servant a traiter le glaucome ou l'hypertension oculaire WO1995026729A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21559/95A AU2155995A (en) 1994-03-31 1995-03-31 New prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9401087-3 1994-03-31
SE9401087A SE9401087D0 (sv) 1994-03-31 1994-03-31 New prostaglandin derivatives for the treatment of glaucoma or ocular hypertension

Publications (1)

Publication Number Publication Date
WO1995026729A1 true WO1995026729A1 (fr) 1995-10-12

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PCT/SE1995/000347 WO1995026729A1 (fr) 1994-03-31 1995-03-31 Nouveaux derives de prostaglandine servant a traiter le glaucome ou l'hypertension oculaire

Country Status (3)

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AU (1) AU2155995A (fr)
SE (1) SE9401087D0 (fr)
WO (1) WO1995026729A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023223A1 (fr) * 1995-12-22 1997-07-03 Alcon Laboratories, Inc. Analogues tetrahidrofuranniques substitues de prostaglandines utilises comme hypotenseurs oculaires
WO1998020880A3 (fr) * 1996-11-12 1998-08-20 Alcon Lab Inc 11-halo prostaglandines destinees au traitement du glaucome ou de l'hypertension oculaire
US5814660A (en) * 1995-12-22 1998-09-29 Alcon Laboratories, Inc. 9-oxa prostaglandin analogs as ocular hypotensives
WO1998057930A1 (fr) * 1997-06-18 1998-12-23 Alcon Laboratories, Inc. Analogues tetrahydrofuraniques ceto-substitues de prostaglandines utilises comme hypotenseurs oculaires
WO2000050040A1 (fr) * 1999-02-25 2000-08-31 Synphora Ab Methode et composition de prevention de la formation de cicatrices dans une bulle de filtration de glaucome et une fistule de drainage
WO2006020510A1 (fr) * 2004-08-10 2006-02-23 Allergan Inc. Acide cyclopentane heptan(èn)oique, dérivés de 2-hétéroarylalcényle et leur utilisation comme modulateurs de reception de la prostaglandine
WO2008073752A3 (fr) * 2006-12-11 2008-10-02 Allergan Inc Composés thérapeutiques
US8389566B2 (en) 2005-11-03 2013-03-05 Allergan, Inc. Prostaglandins and analogues as agents for lowering intraocular pressure

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1485352A (en) * 1975-01-20 1977-09-08 Upjohn Co Prostaglandins
US4131737A (en) * 1976-07-19 1978-12-26 American Cyanamid Company 15-Deoxy-16-hydroxy-16-substituted-3-thia-prostanoic acids
GB1595998A (en) * 1977-03-30 1981-08-19 American Cyanamid Co Prostenoic acids and esters
WO1990002553A1 (fr) * 1988-09-06 1990-03-22 Pharmacia Ab Derives de prostaglandine servant au traitement des glaucomes ou de l'hypertension oculaire
EP0471856A1 (fr) * 1990-03-08 1992-02-26 Shionogi & Co., Ltd. Derive de 15-desoxyprostaglandine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1485352A (en) * 1975-01-20 1977-09-08 Upjohn Co Prostaglandins
US4131737A (en) * 1976-07-19 1978-12-26 American Cyanamid Company 15-Deoxy-16-hydroxy-16-substituted-3-thia-prostanoic acids
GB1595998A (en) * 1977-03-30 1981-08-19 American Cyanamid Co Prostenoic acids and esters
WO1990002553A1 (fr) * 1988-09-06 1990-03-22 Pharmacia Ab Derives de prostaglandine servant au traitement des glaucomes ou de l'hypertension oculaire
EP0471856A1 (fr) * 1990-03-08 1992-02-26 Shionogi & Co., Ltd. Derive de 15-desoxyprostaglandine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF LIPID MEDIATORS, Volume 6, 1993, DAVID F. WOODWARD et al., "Intracular Pressure Effects of Selective Prostanoid Receptor Agonists Involve Different Receptor Subtypes According to Radioligand Binding Studies", pages 545-553. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6197812B1 (en) 1995-12-22 2001-03-06 Alcon Laboratories, Inc. Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
WO1997023223A1 (fr) * 1995-12-22 1997-07-03 Alcon Laboratories, Inc. Analogues tetrahidrofuranniques substitues de prostaglandines utilises comme hypotenseurs oculaires
US5814660A (en) * 1995-12-22 1998-09-29 Alcon Laboratories, Inc. 9-oxa prostaglandin analogs as ocular hypotensives
US5866602A (en) * 1995-12-22 1999-02-02 Alcon Laboratories, Inc. Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US5994397A (en) * 1995-12-22 1999-11-30 Alcon Laboratories, Inc. Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US6025392A (en) * 1995-12-22 2000-02-15 Alcon Laboratories, Inc. substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US6369102B2 (en) 1995-12-22 2002-04-09 Alcon Manufacturing, Ltd. Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
WO1998020880A3 (fr) * 1996-11-12 1998-08-20 Alcon Lab Inc 11-halo prostaglandines destinees au traitement du glaucome ou de l'hypertension oculaire
WO1998057930A1 (fr) * 1997-06-18 1998-12-23 Alcon Laboratories, Inc. Analogues tetrahydrofuraniques ceto-substitues de prostaglandines utilises comme hypotenseurs oculaires
US6495563B1 (en) 1999-02-25 2002-12-17 Synphora Ab Method and composition for prevention of scar formation in glaucoma filtration bleb and drainage fistula
WO2000050040A1 (fr) * 1999-02-25 2000-08-31 Synphora Ab Methode et composition de prevention de la formation de cicatrices dans une bulle de filtration de glaucome et une fistule de drainage
WO2006020510A1 (fr) * 2004-08-10 2006-02-23 Allergan Inc. Acide cyclopentane heptan(èn)oique, dérivés de 2-hétéroarylalcényle et leur utilisation comme modulateurs de reception de la prostaglandine
US7183310B2 (en) 2004-08-10 2007-02-27 Allergan, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US7863319B2 (en) 2004-08-10 2011-01-04 Allergan, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US8557860B2 (en) 2004-08-10 2013-10-15 Allergan, Inc. Cyclopentane heptan(ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US8389566B2 (en) 2005-11-03 2013-03-05 Allergan, Inc. Prostaglandins and analogues as agents for lowering intraocular pressure
WO2008073752A3 (fr) * 2006-12-11 2008-10-02 Allergan Inc Composés thérapeutiques
US8193373B2 (en) 2006-12-11 2012-06-05 Allergan, Inc. Therapeutic compounds

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Publication number Publication date
SE9401087D0 (sv) 1994-03-31
AU2155995A (en) 1995-10-23

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