EP0921797A1

EP0921797A1 - Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical composition for lowering intraocular pressure

Info

Publication number: EP0921797A1
Application number: EP97930361A
Authority: EP
Inventors: Niels Korsgaard; John RÖMER
Original assignee: Novo Nordisk AS
Current assignee: Novo Nordisk AS
Priority date: 1996-07-12
Filing date: 1997-07-07
Publication date: 1999-06-16
Also published as: ZA976170B; JP2000514443A; WO1998002156A1; AU3433997A

Abstract

The present invention provides novel uses of compounds of general formula (I) wherein R?1, R4 and R5¿ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C¿1-6? alkyl, C1-6 alkoxy or (tertiary amino)(C1-6 alkoxy); and R?2 and R3¿ are individually hydrogen or C¿1-6? alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for lowering intraocular pressure.

Description

Use of 3,4-diphenyl chromans for the manufacture of a. pharmaceutical composition for lowering intraocular pressure.

FIELD OF THIS INVENTION

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.

BACKGROUND OF THIS INVENTION

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). Pilocarpine has been used for the treatment of glaucoma for over a hundred years. Pilocarpine is a muscarinic agonist that reduces resistance to aqueous humor outflow by causing contraction of the ciliary muscle, whereby the trabecular meshwork is pulled apart. Although 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. These facts has limited the use of pilocarpine and other muscarinics, and in the past decade other compounds which inhibits the aqueous humor formation have been the drugs of choice. 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. However, this compound causes mydriasis (i.e., an excessive dilation of the pupil) also blurring the vision. Also β-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.

Recently it has been shown that 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. However, clinical studies have indicated that this prostaglandin increases the pigmentation of the iris. The consequences of this observation for the frequency of intraocular melanomas are still uncertain.

None of these treatments aim against the primary cause of the disease namely impaired drainage through the trabecular meshwork. Therefore they only delay, but will not be able to inhibit the progressive loss of vision throughout the years. Furthermore, the pressure lowering effects of the drugs currently in use will often after months or years be insufficient resulting in a necessity for the administration of multiple drugs with increased risk of adverse ef- fects and increased costs and inconvenience for the patient.

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. Fotsis ej aj., The Endogenous Oestrogen Metabolite 2-Methoxyoestradiol Inhibits Angiogenesis and Suppresses Tumour Growth, Letters to Nature, Vol. 3_68_, pp. 237-239 (Mar. 17, 1994) disclose that 2- methoxyoestradiol, an endogenous oestrogen metabolite, inhibits anglogenesis. U.S. Patent No. 4,876,250 discloses that there may be a correlation between angiostatic activity and IOP lowering activity. U.S. Patent No. 5,521 ,168 discloses the use of estrogen metabolites to lower intraocular pressure. DK 163.865B discloses the use of estrogens to treat increased pressure in the eye. Many of the above mentioned compounds which have been found to lower intraocular pressure also have hormonal activity. It would be useful to have compounds which can be used to lower intraocular pressure without exhibiting any hormonal activity.

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. Furthermore 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.

BRIEF DESCRIPTION OF THIS INVENTION

This invention provides the use of compounds of the general formula I wherein R\ R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,^ alkyl, C..₆ alkoxy or (tertiary amino)( C..₆ alkoxy); and R² and R³ are individually hydrogen or C^ alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for lowering intraocular pressure .

DETAILED DESCRIPTION OF THIS INVENTION

The present invention provides the use of a compound of the general formula I wherein R\ R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, trifluoromethyl, lower alkyl, lower alkoxy or (tertiary amino)(lower alkoxy); and R² and R³ 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.

Within the present invention, 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.

Within formula I, R^ , R⁴ and R^ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C.._β alkyl, C ₆ alkoxy or (tertiary amino)( C,.₆ alkoxy); and R^ and R^ are individually hydro- gen or a C ₆ alkyl. As used herein, the term "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. The term "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. Herein, the term "(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 R¹ is lower alkoxy; R² and R³ are lower alkyl, especially methyl; R⁴ is hydrogen; and R^ is (tertiary amino)(lower alkoxy) of the polymethyleneimine type. Within particularly preferred embodiments, R¹ is in the 7-position and is lower alkoxy, particulariy methoxy; each of R² and R³ is methyl, R⁴ is hydrogen, and R⁵ 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 R¹ is C,.₆ alkoxy; R² and R³ are C..₆ alkyl, especially methyl; R⁴ is hydrogen; and R⁵ is (tertiary amino)(C..₆ alkoxy) of the polymethyleneimine type. Within particularly preferred embodiments, R¹ is in the 7-position and is C.._B alkoxy, particularly methoxy; each of R² and R³ is methyl, R⁴ is hydrogen, and R⁵ is in the 4-position and is a (tertiary amino)(C..₆ alkoxy) radical such as 2-(pyrrolidin-1-yl)ethoxy with formula II

(ID

To be included by this invention are all pharmaceutically acceptable salts of the mentioned compounds of formula I. It is preferred to use the compounds of formula I in the.transcσnfiguration. These compounds may be used as racemic mixtures, or the isolated d- or I- enantiomers may be used. The trans-l-enantiomers are more preferred.

A particulariy preferred compound for use within the present invention is centchroman having the formula IV

as stated in claim 1 1.

Although only one enantiomer is shown, it will be understood that the formula IV is used herein to designate the transconfiguration of the 3- and 4-phenyl groups and that both the d- and l-enantiomers, as well as the racemic mixture, are included.

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.

3,822,287 to Bolger, and Ray et al., J jVj≤d_. Chem IS (1976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Patent Specification No. 3,822,287. The optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. If R² is different from R³ and R⁴ is different from R⁵, the general formula I covers 8 optical isomers.

Within the present invention, 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. Examples of such 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. In the alternative, 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. For use within the present invention, 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. and may be provided in such forms as liquids, powders, emulsions, suppositories, liposomes, transdermal patches, controlled release, dermal implants, tablets, etc. One skilled in this art may formulate the compounds of formula I in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990.

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. For example, 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.

Oral administration is also preferred. Thus, the active compound of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule. Typically, a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet. Suitable carriers in this regard 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

Pharmaceutical 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

The pharmaceutical compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week In the alternative, 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

The following examples are offered by way of illustration, not limitation

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- dιmethyl-3-phenyl-4-[4-(2-(pyrrolιdιn-1-yl)ethoxy)phenyl-7-hydroxychroman is a preferred compound The more preferred compound is isolated l-centchroman (l-3,4-trans-2,2- dιmethyl-3-phenyl-4-[4-(2-pyrrolιdιn-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, fumaπc 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.

The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.

Example 1

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. After two weeks of treatment with dexamethasone the intraocular pressure is determined and treatment with the test substances is started in three groups. Test substances are dissolved in oil containing dexamethasone. The first group is treated with 17β- 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.

At the end of the experiment the animals are sacrificed and an autopsy is performed. The eyes are dissected, the canal of Schlemm is localised and a sample of the trabecular meshwork is secured and frozen in vials on dry ice for biochemical determination of contents of proteoglycans. Furthermore, the uterus is isolated, gently blotted dry and weighed. The uterus weight is recorded. Example 2

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.

Claims

The use of compounds of the general formula

wherein R¹, R⁴ and R⁵ are individually hydrogen, hydroxy, halogen, trifluoromethyl, C,.₆ alkyl, C..₆ alkoxy or (tertiary amino)( C,.₆ alkoxy); and R² and R³ are individually hydrogen or C..₆ alkyl, or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for lowering intraocular pressure.

2. The use, according to claim 1 , wherein R in the compound used is C,.₆ alkoxy, R² and R³ are C..₆ alkyl, R⁴ is hydrogen and R⁵ is (tertiary amino) C,.₆ alkoxy.

3. The use according to any one of claims 1 or 2 wherein R¹ is methoxy.

4. The use according to any one of claims 1-3 wherein R² is methyl.

5. The use according to any one of claims 1-4 wherein R³ is methyl.

6. The use according to any one of claims 1-5 wherein R⁴ is hydrogen.

7. The use according to any one of claims 1-6 wherein R⁵ is a group as stated in formula II below: "O (il)

8. The use according to any one of claims 1-7 wherein said compound is an isolated d- or l-enantiomer.

9. The use according to any one of the preceding claims wherein said compound has the general formula III as stated below:

wherein R , R², R , R⁴ and R⁵ each are as defined in above claim 1.

10. The use according to anyone of the preceding claims wherein said compound is

3,4-trans-2,2-dimethyl-3-phenyl-4[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl-7-hydroxychroman.

11. The use according to anyone of the preceding claims wherein said compound is an isolated l-enantiomer.

12. The use according to claim 1 wherein said compound is centchroman 3,4-trans-2,2- dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman having the formula IV as stated below:

13. The use according to claim 12 wherein said compound is an isolated l-enantiomer of 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman.

14. The use according to any one of the preceding claims wherein said composition is in a form suitable for oral administration.

15. The use according to any one of the preceding claims wherein said compound is administered as a dose in a range from about 0.001 to 75 mg/kg patient per day.

16. The use according to any one of the preceding claims wherein said composition is administered one or more times per day or week.

17. The use according to any one of the preceding claims wherein said composition is administered topically to the eye.

18. Method for lowering intraocular pressure by administering to a patient a clinically effective amount of a compound of above formula I stated to be used in any of the preceding use claims, or a pharmaceutically acceptable salt thereof.

19. A method of lowering intraocular pressure which method comprises administering a clinically effective amount of compounds and pharmaceutically acceptable compositions, according to previous claims to a patient in need of such a treatment.

20. Any novel feature or combination of features described herein.

Novo Nordisk A/S