EP0921797A1 - Emploi de 3,4-diphenyl chromans dans des preparations pharmaceutiques abaissant la tension intraoculaire - Google Patents

Emploi de 3,4-diphenyl chromans dans des preparations pharmaceutiques abaissant la tension intraoculaire

Info

Publication number
EP0921797A1
EP0921797A1 EP97930361A EP97930361A EP0921797A1 EP 0921797 A1 EP0921797 A1 EP 0921797A1 EP 97930361 A EP97930361 A EP 97930361A EP 97930361 A EP97930361 A EP 97930361A EP 0921797 A1 EP0921797 A1 EP 0921797A1
Authority
EP
European Patent Office
Prior art keywords
use according
compound
intraocular pressure
phenyl
alkoxy
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97930361A
Other languages
German (de)
English (en)
Inventor
Niels Korsgaard
John RÖMER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0921797A1 publication Critical patent/EP0921797A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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

Definitions

  • the present invention relates to the use of compounds of the general formula I for lowering intraocular pressure.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • Glaucoma A number of disease states in which an increased intraocular pressure is the common denominator are included in the category of glaucoma.
  • the pressure elevation results from an imbalance between aqueous inflow and outflow through the pupil, the trabecular meshwork and Schlemm's canal.
  • Chronic or primary open-angle glaucoma the most common of adult glaucomas, is asymptomatic and detected only by routine eye examination. It is associated with a relative obstruction to aqueous outflow through the trabecular meshwork and is of unknown cause.
  • Glaucoma is characterized by progressive vision field loss due to nerve dam- age from the elevated intraocular pressure. It is an important cause of blindness world-wide and in the United States it occurs in 1 to 2 percent of people above age 60.
  • Treatment includes the use of topical agents including cholinergic (pilocarpine, carbachol, echothiophate) or adrenergic agonists (epinephrine, dipivefrin) or antagonists e.g. beta adrenergic blockers (timolol, levobunanol, betaxol).
  • cholinergic prilocarpine, carbachol, echothiophate
  • adrenergic agonists epinephrine, dipivefrin
  • beta adrenergic blockers e.g. beta adrenergic blockers
  • pilocarpine is safe and effective it has side effects such as miosis (reduction of pupil size), which blurs the vision. It also has short duration of action, and therefore, has to be administered four-times a day, creating problems with patient com- pliance. Consequently, in spite of the treatment, there is a great risk for irreversible vision loss since pressure can increase dramatically during sleep and periods of irregular instillation.
  • the l-form of epinephrine has adrenergic properties which in glaucoma acts via a reduction of the production of the aqueous humor by reducing blood flow to the ciliary body and is clinically useful.
  • this compound causes mydriasis (i.e., an excessive dilation of the pupil) also blurring the vision.
  • ⁇ -adrenergic antagonists reduces the formation of aqueous humor, but is contraindicated in patients with asthma and chronic obstructive lung diseases and can cause cardiac dysrythmias.
  • prostaglandin F 2a lowers intraocular pressure probably by increasing the uveoscleral outflow, i.e. the unconventional drainage route of the eye, comprising only 5-10% of the normal outflow system.
  • this prostaglandin increases the pigmentation of the iris.
  • the consequences of this observation for the frequency of intraocular melanomas are still uncertain.
  • Treister eJ aj. Intraocular Pressure and Outflow Facility, Arch. Ophthal., Vol. S3, pp. 311-318 (March 1970) disclose that the continuous oral treatment of normal women with mestranol (estrogen) causes a gradual decrease in IOP (Intraocular Pressure).
  • Meyer ej aj. Influence of Norethynodret With Mestranol on Intraocular Pressure in Glaucoma, Arch. Ophthal., Vol. 13. , pp 771-773 (June 1966) disclose that oral administration of mestranol with norethyno- drel to patients with primary open angle glaucoma reduces IOP.
  • Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al., ,Acia Endocrinal (Copenh) 126 (1992), 444 - 450; Grubb, Curr Opin Qbstet Gvnecol 3 (1991) 491 - 495; Sankaran et al.. Contraception 9 (1974). 279 - 289; Indian Patent Specification No. 129187).
  • Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 42 (1989), 781 - 783). Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J M Bon Res 2 (1994), S 394).
  • U.S. patent 5,453,442 describes methods of lowering serum cholesterol and inhibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and en- dometriosis in women by administering compounds of formula I as shown therein.
  • US patent 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diarylchromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of using the compounds for lowering intraocular pressure associated with glaucoma or ocular hypertension.
  • One object of the present invention is to provide compounds which can effectively be used for lowering intraocular pressure.
  • This invention provides the use of compounds of the general formula I wherein R ⁇ R 4 and R 5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C, ⁇ alkyl, C.. 6 alkoxy or (tertiary amino)( C.. 6 alkoxy); and R 2 and R 3 are individually hydrogen or C ⁇ alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for lowering intraocular pressure .
  • the present invention provides the use of a compound of the general formula I wherein R ⁇ R 4 and R 5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino)(lower alkoxy); and R 2 and R 3 are individually hydrogen or lower alkyl, or as a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier for the manufacture of a pharmaceutical composition for lowering and controlling intraocular pressure.
  • compounds of formula I as stated in claim 1 are used for lowering intraocular pressure in a patient e.g. associated with glaucoma or ocular hypertension.
  • the present invention furthermore provides the use of a compound of general formula I for the treatment or prevention of glaucoma or ocular hypertension.
  • the methods of use provided by this invention are practised by administering to a subject in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt thereof, that is effective to reduce ocular pressure.
  • the effect on ocular hypertension contemplated by the present invention includes both medical therapeutic treatment and/or prophylactic treatment as appropriate.
  • R ⁇ , R 4 and R ⁇ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C.. ⁇ alkyl, C 6 alkoxy or (tertiary amino)( C,. 6 alkoxy); and R ⁇ and R ⁇ are individually hydro- gen or a C 6 alkyl.
  • lower alkyl includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec-amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
  • lower alkoxy includes straight and branched chain alkoxy radicals con- taining from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like.
  • Halogen includes chloro, fluoro, bromo and iodo.
  • (tertiary amino)(lower alkoxy) is a lower alkoxy group which is substituted by a tertiary amino radical.
  • the tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N- diethylamino, N,N-dipropylamino and N,N-dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N-methylpiperazine or morpholine.
  • Preferred compounds include those in which R 1 is lower alkoxy; R 2 and R 3 are lower alkyl, especially methyl; R 4 is hydrogen; and R ⁇ is (tertiary amino)(lower alkoxy) of the polymethyleneimine type.
  • R 1 is in the 7-position and is lower alkoxy, particulariy methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and R 5 is in the 4-position and is a (tertiary amino)(lower alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy.
  • Preferred compounds include those in which R 1 is C,. 6 alkoxy; R 2 and R 3 are C.. 6 alkyl, especially methyl; R 4 is hydrogen; and R 5 is (tertiary amino)(C.. 6 alkoxy) of the polymethyleneimine type.
  • R 1 is in the 7-position and is C.. B alkoxy, particularly methoxy; each of R 2 and R 3 is methyl, R 4 is hydrogen, and R 5 is in the 4-position and is a (tertiary amino)(C.. 6 alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy with formula II
  • centchroman having the formula IV
  • 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No.
  • 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, maleic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • a preferable salt is the hydrogen fu- marate salt.
  • 3,4-diarylchromans of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from increased intraocular pressure.
  • 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for topical parenteral, oral, nasal, rectal, subdermal or intradermal or transder- mal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc.
  • the active compound can be formulated in any suitable ophthalmic formulation such as solutions, suspensions, ointments, etc.
  • the formulations can include other components known to those skilled in the art of formulating ophthalmic products.
  • the formulations can include ophthalmically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, and buffers.
  • the formulations are applied topically to the eye of a mammal suffering from glaucoma or ocular hypertension according to the routine discretion of a skilled clinician.
  • the active compound of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers include starch, sugars, dicalcium phosphate, cal- cium stearate, magnesium stearate and the like
  • Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc
  • compositions containing a compound of formula I may be administered one or more times per day or week
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against increased intraocular pressure
  • Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art
  • a typical daily dose will contain a nontoxic dosage range of from about 0 001 to about 75 mg/kg patient per day of a compound of the present invention, preferably in a range from about 0 01 to 75, more preferably in the range from about 0 01 to 50 mg/kg patient per day
  • compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week
  • they may preferably be provided as controlled release formulations suitable for transdermal application Patches are formulated to provide release of active compound over the desired period of time, which can be up to several years
  • Controlled-release formulations are disclosed by, for example, Sanders et al , J Pharm Sci 73 (1964), 1294 - 1297, 1984, U S Patent Specifica- tion No 4,489,056, and U S Patent Specification No 4,210,644, which are incorporated herein by reference
  • Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers Furthermore, 3,4-trans-2,2- d ⁇ methyl-3-phenyl-4-[4-(2-(pyrrol ⁇ d ⁇ n-1-yl)ethoxy)phenyl-7-hydroxychroman is a preferred compound The more preferred compound is isolated l-centchroman (l-3,4-trans-2,2- d ⁇ methyl-3-phenyl-4-[4-(2-pyrrol ⁇ d ⁇ n-1-yl)ethoxy)phenyl]-7-methoxychroman)
  • Examples of pharmaceutically acceptable acid addition salts are salts with non-toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fuma ⁇ c acid, acetic acid, propionic acid, succinic acid, glu- conic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, metha- nesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, fuma ⁇ c acid, acetic acid, propionic acid, succinic acid, glu- conic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, metha- nesulphonic acid and malonic acid.
  • Twenty-four sexually mature female New Zealand White rabbits weighing between 3 and 5 kg each are divided into groups of six and the intraocular pressure is determined by tono- metry in both eyes of each animal. One group is kept as a control group and is treated topi- cally with vehicle alone. In the remaining groups of rabbits both eyes are treated daily topically for two weeks with 0.1% dexamethasone. Dexamethasone instillation results in an increased intraocular pressure in both eyes (corticosteroid-induced glaucoma, PA Knepper et al. Exp Eye Res 27:567, 1978). Intraocular pressure is determined twice weekly during the experiment.
  • test substances are dissolved in oil containing dexamethasone.
  • the first group is treated with 17 ⁇ - estradiol (1%).
  • the second is treated with the l-centchroman (5%) while the third group serve as a control and is treated with dexamethasone alone. All treatments are given topically once daily for 5 weeks. Besides measurements of intraocular pressure twice weekly body weight is recorded once weekly.
  • Example 1 The experiment described in example 1 is repeated in all substantially details except that sexually mature male New Zealand White rabbits are used and that the testes are isolated and weighed after the animals have been sacrificed.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention porte sur de nouvelles utilisations de composés de formule générale (I) dans laquelle R?1, R4 et R5¿ sont individuellement hydrogène, hydroxy, halogène, trifluorométhyle, C¿1-6? alkyle, C1-6 alkoxy, ou (amino tertiaire)(C1-6 alkoxy); et R?2 et R3¿ sont individuellement H ou C¿1-6? alkyle, ou de leurs sels pharmacocompatibles entrant dans la compositions de préparations pharmaceutiques abaissant la tension intra-oculaire.
EP97930361A 1996-07-12 1997-07-07 Emploi de 3,4-diphenyl chromans dans des preparations pharmaceutiques abaissant la tension intraoculaire Withdrawn EP0921797A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK78396 1996-07-12
DK78396 1996-07-12
PCT/DK1997/000304 WO1998002156A1 (fr) 1996-07-12 1997-07-07 Emploi de 3,4-diphenyl chromans dans des preparations pharmaceutiques abaissant la tension intraoculaire

Publications (1)

Publication Number Publication Date
EP0921797A1 true EP0921797A1 (fr) 1999-06-16

Family

ID=8097510

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97930361A Withdrawn EP0921797A1 (fr) 1996-07-12 1997-07-07 Emploi de 3,4-diphenyl chromans dans des preparations pharmaceutiques abaissant la tension intraoculaire

Country Status (5)

Country Link
EP (1) EP0921797A1 (fr)
JP (1) JP2000514443A (fr)
AU (1) AU3433997A (fr)
WO (1) WO1998002156A1 (fr)
ZA (1) ZA976170B (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
CA2581316C (fr) 2004-09-21 2013-09-10 Novogen Research Pty Ltd Derives de chromane substitues, medicaments et utilisation a des fins therapeutiques
EP2635273B1 (fr) 2010-11-01 2020-01-08 MEI Pharma, Inc. Compositions d'isoflavonoïdes et méthodes de traitement du cancer
CN116139125A (zh) 2015-02-02 2023-05-23 梅制药公司 联合治疗

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9802156A1 *

Also Published As

Publication number Publication date
WO1998002156A1 (fr) 1998-01-22
ZA976170B (en) 1998-01-12
JP2000514443A (ja) 2000-10-31
AU3433997A (en) 1998-02-09

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