IE922252A1 - Anti-glaucomatous pharmaceutical compositions and the¹process for obtaining them - Google Patents

Abstract

THE INVENTION RELATES TO THE FIELD OF THERAPEUTIC CHEMISTRY. IT MORE PARTICULARLY CONCERNS THE PRODUCTION OF PHARMACEUTICAL COMPOSITIONS FOR OCULAR APPLICATION. IT IS INTENDED FOR A PROCESS FOR OBTAINING COMPOSITION FOR CHARACTERIZED OCULAR APPLICATION IN THAT IT CONTAINS AT LEAST ONE COMPOUND OF STEREO STRUCTURE SELECTED, IN ASSOCIATION OR MIXED WITH AN EXCIPIENT OR A PHARMACEUTICALLY ACCEPTABLE INERT VEHICLE. THE COMPOSITIONS ACCORDING TO THE INVENTION ADDRESS THE TREATMENT OF GLAUCOMA

Description

The invention relates to the domaine of therapeutic chemistry and in particular to the pharmacotechnology domain.

A specific subject of the invention is pharmaceutical compositions for ocular use, characterized in that they contain as active ingredient at least one compound of steroid structure chosen from the group constituted by: A - 19-NOR PREGNA 4,6-DIENES OF GENERAL FORMULA I ch2 r2 in which R-j represents a hydroxy, alkoxy, acyloxy radical R2 represents hydrogen or a lower alkyl radical R and R' together form a ketone, hydroxyimino, alkoxyimino or acyloxyimino group or separately, when R = H, R1 is a hydroxy, alkoxy or acyloxy group and R3 represents a lower alkyl radical having 1 to 3 carbon atoms; B- 19-NOR 4,6-DIENES OF GENERAL FORMULA II in which R2 represents a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, as a linear or branched chain R7 represents a lower alkyl radical, identical to or different from R2, having 1 to 6 carbon atoms, as a linear or branched chain and R3 is defined as previously; C - THE COMPOUNDS OF 19-NOR PREGNENE STRUCTURE OF GENERAL FORMULA III ch2~r2 in which R-| represents a hydroxy, alkoxy, acyloxy or alkyl radical having 1 to 4 atoms R2 represents hydrogen or a lower alkyl radical as a linear or branched chain having 1 to 4 carbon atoms Z represents hydrogen, an alkyl radical or an acyl radical and the dotted line represents an optional carbon-carbon double bond; - 4 D - 19-NOR PREGNENE DERIVATIVES OF GENERAL FORMULA IV in which R-| represents a hydroxy, alkoxy, acyloxy or alkyl radical having 1 to 4 carbon atoms R2 represents hydrogen or a lower alkyl radical, as a linearor branched chain, having 1 to 4 carbon atoms and the dotted line symbolizes an optional carbon-carbon double bond; E - 6-HALOMETHYL 19-NOR PREGNENE DERIVATIVES OF GENERAL FORMULA V (V) THE COMPOUNDS OF 19-NOR ANDROSTENE STRUCTURE in which X represents a halogen atom R-j and R2 are defined as previously and the dotted line symbolizes an optional carbon-carbon double bond; - 5 CORRESPONDING TO GENERAL FORMULA VI OR4 =N-0H or in which R-] represents hydrogen, a lower alkyl or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms R' represents a hydrogen or a lower alkynyl R represents a methyl or ethyl R5 represents two hydrogens or the group =0, in which R4 represents hydrogen or the acyl organic carboxylic acid and R3 represents hydrogen or =CH2; G - PREGNADIENES OF GENERAL FORMULA VII remainder of an (VII) in which R represents a lower alkyl or lower cycloalkyl radical R-1 and R3 are defined as previously; - 6 Η - PREGNENE DERIVATIVES OF GENERAL FORMULA VIII in which the dotted line represents an optional double bond and R-| is defined as previously; I - 3,20-DIOXO DELTA4-PREGNENE COMPOUNDS CORRESPONDING TO. GENERAL FORMULA IX in which R-| represents a free, etherified or esterified hydroxyl radical or a lower alkyl radical R3 represents hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and the dotted line symbolizes 2 hydrogens or a carbon-carbon double bond; J - 11,18-EPOXYANDROSTENE COMPOUNDS OF GENERAL FORMULA X - 7 OH in which the wavy line symbolizes an alpha or beta orientation and R represents hydrogen or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms; K - CORTICOSTEROIDS OF GENERAL FORMULA XI in which R represents hydrogen or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms; and L - ANDROSTENE COMPOUNDS OF GENERAL FORMULA XII in which R-| represents hydrogen, a lower alkyl radical, a methoxy alkyl, an acyl derived from an organic carboxylic acid or alkyl carbonic acid R represents hydrogen or an optionally substituted lower alkyl radical R3 represents hydrogen, a halogen or a lower alkyl and the wavy line symbolizes an alpha or beta orientation combined or mixed with a pharmaceutically acceptable inert excipient or vehicle, intended for use by ocular route.

To this end, the pharmaceutical compositions are, according to the invention, preferably presented in solid form for extemporaneous dissolution, semi-solid or liquid form, the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula IX, formula X, formula XI or formula XII being in the form of a suspension or dissolved in solution, distributed in flasks, tubes or single-dose systems.

Among the compounds of general formula I, there can be mentioned quite particularly the derivatives of 17alphahydroxy 19-nor pregna 4,6-diene 3,20-dione of general formula la in which R7 represents a hydrogen atom, an acyl radical having 1 to 8 carbon atoms. and R3 is a methyl or propyl radical Among the compounds of general formula III, there can be mentioned quite especially: a) the derivatives of 17alpha-hydroxy 19-nor pregna 4,6-diene 3,20-dione of general formula IIIa in which R7 represents a hydrogen atom, an alkyl radical having 1 to 8 carbon atoms, a 2-tetrahydropyranyl radical or an acyl radical derived from a saturated or unsaturated, aliphatic carboxylic acid, having 1 to 10 carbon atoms, optionally substituted by an aryl or cycloalkyl radical Z is defined as previously.

These products are described in the French Patent Application - 10 No. 91 09097 filed in the name of the Applicant company on 18th July 1991 . b) the derivatives of 17alpha-hydroxy 21-methyl 19-nor pregna-4,6 diene 3,20-diones of general formula Illb in which R4 represents a hydrogen atom, a lower alkyl radical, a methoxymethyl radical, a 2-tetrahydropyranyl radical or an acyl radical of an organic carboxylic acid having 1 to 10 carbon atoms Z is defined as previously.

These compounds are contained in the general formula of the French Patent Application No. 91 09097 filed on 18th July 1991 in the name of the Applicant company. c) the derivatives of 17alpha and 21-alkylates of 19-nor pregna-4,6 diene 3,20-diones of general formula IIIC - 11 in which R1 and R each represent a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms, as a linear or branched chain R-| represents a lower alkyl radical, identical to or different from R' and R, having 1 to 3 carbon atoms, as a linear or branched chain Z is defined as previously.

These compounds are contained in the general formula of the French Patent Application No. 91 09097 filed on 18th July 1991 in the name of the Applicant company. d) the 19-nor pregna 4-ene derivatives of general formula IIId in which R-| is an alkyl radical, a hydroxy, an alkoxy, an acyloxy and the wavy line indicates an alpha or beta orientation and Z is defined as previously.

These compounds are included in the French Patent Application No. 91 09097 filed on 18th July 1991 in the name of the Applicant company .

Among the compounds of general formula IX, there can be mentioned in particular: - 17alpha-hydroxy progesterone - 17alpha-acetoxy progesterone - 17alpha-methoxy progesterone - 6alpha-methyl 17alpha-acetoxy progesterone - 12 - 6-methyl 17alpha-acetoxy 3,2-dioxo pregna 4,6-diene - 6alpha, 17alpha-dimethyl 3,20-dioxo pregna 4-ene Among the compounds of general formula X, there can be mentioned in particular the isoaldosterone of formula as well as its aliphatic or aromatic esters.

Among the compounds of general formula (XI), there can be mentioned in particular Cortexolone cs2-oh and its aliphatic or aromatic mono- or diesters.

Among the compounds of general formula V, there can be mentioned quite particularly: 3,20-dioxo 17alpha-acetoxy 6-chloromethyl 4,6-diene of formula Va 19-nor pregna - and 3,20-dioxo 17alpha-acetoxy 6-fluoromethyl 19-nor pregna 4,6-diene of formula Vb Among the compounds of general formula VI, there can be mentioned in particular: - 19-nor testosterone - 17alpha-ethynyl 19-nor testosterone - 3beta,17beta-diacetoxy 17alpha-ethynyl 19-nor delta4androstene - 3-oximido 17alpha-ethynyl 19-nor testosterone - 3-oxo 17alpha-ethynyl 17beta-hydroxy 13-ethyl gona 4-ene 11-methylene 17alpha-ethynyl 17beta-hydroxy 13beta-ethyl gona 4-ene. e) Among the compounds of general formula XII, there can be mentioned more particularly: a) 3-oxo androsta 4-enes of general formula XIIa in which represents hydrogen, an optionally substituted alkyl radical or an acyl radical derived from an organic carboxylic acid or an alkyl carbonic acid having 1 to 8 carbon atoms and R3 is defined as previously; b) 3-oxo 17beta-alkyl androsta 4-enes of general formula XIIb (XIIb> in which R-j represents hydrogen or an acyl radical defined as above R is a lower alkyl radical optionally substituted by a halogen or an acyl R3 is hydrogen or a lower alkyl.

The preparations thus obtained have added to them, if necessary, mineral salts or organic derivatives in order to achieve isotonicity with lacrimal secretions, preservatives or stabilizers and/or anti-oxidants.

As stabilizers, there can be mentioned more particularly chelating agents such as ethylene diaminotetraacetic acid and its salts. As anti-oxidants, there can be mentioned ascorbic acid, alkali metal metabisulphites, alkali metal hypophosphites, sodium salicylate, sodium gentisate or isopropyl gallate.

In what precedes and except for indication to the contrary, a lower alkyl radical possesses 1 to 6 carbon atoms such as a methyl, ethyl, isopropyl, terbutyl, isobutyl, n-pentyl, neopentyl or n-hexyl radical.

A halogen is a fluorine or chlorine atom.

An acyl remainder of an organic carboxylic acid contains 1 to 10 atoms in the carbonated part such as for example an acetyl, a propionyl, a hexanoyl, a benzoyl, a dichloroacetyl, a vanilloyl, an isovanilloyl, a trimethoxy benzoyl, a naphthoyl (alpha or beta), a furoyl, a nicotinoyl or a thenoyl.

An alkyl remainder of an alkyl carbonic acid contains 1 to 8 carbon atoms in the alkyl chain, such as for example a cycloalkylmethyl carbonic radical or a cycloalkyl propyl carbonic radical.

The compositions according to the invention concern the treatment of intraocular hypertensions and glaucomatous diseases. They contain from 0.05 to 1% of steroid active ingredient. They are prepared by putting an active ingredient in solution or in suspension in a suitable aqueous solvent.

It is known that three types of glaucoma exist: 1. primary glaucomas which represent 86% of all glaucomas. Two types can be distinguished from this category which - 16 are quite particularly important: - open-angle glaucoma (OAG) - closed-angle glaucoma (CAG) 2. secondary glaucomas 3. congenital glaucomas The clinical signs of these diseases are those of an optical neuropathy with: - lowering of visual acuity - deficiency of the field of vision - alteration of the optical nerve fibres leading progressively to blindness.

An intraocular pressure (IOP) of greater than 15 mmHg + 2.5 mmHg is observed in the majority of cases.

All of the current treatments aim at normalizing this IOP which is the most immediately quantifiable sign and which guarantees the effectiveness of the treatment.

Current local treatments have pharmacological effects similar to those of hormones of the autonomous nervous system, whether sympathomimetic or para-sympathomimetic (adrenaline, epinephrine, pilocarpine ..).

The discovery over the last ten years of the action of betablocking products has also reinforced the importance of the sympatho- and para-sympathomimetic systems at the ocular level.

The general treatments used (per os or as a perfusion) aim, like the local treatments, at decreasing the formation of the aqueous humor (an exception is made for pilocarpine).

All these treatments have inconveniences which make regular - 17 medical supervision necessary. The use of these products presents numerous and significant contra-indications: beta-blockers: bronchial asthma, cardio-vascular insufficiency, etc ... - antiglaucomatous sympathomimetics (closed-angle glaucoma) - anti-glaucomatous para-sympathomimetics (iridocyclitis) and numerous undesirable effects (corneo-conjunctival reactions, mydriasis or miosis of the iris, ocular dryness, modification of the field of vision, cardiovascular effects, general respiratory effects, dermatological effects ...) which vary according to the nature of the product.

The pharmaceutical compositions according to the invention aim at improving this situation. They have at least an equal effectiveness, but above all their tolerance and their innocuity at the doses tested are significantly better. Moreover, they address both open-angle and closed-angle glaucomas and show practically none of the undesirable effects and the contra-indications mentioned above.

Previous studies had already attempted to demonstrate the regulatory role of progesterone on the IOP of a normal eye. Progesterone and even the hormone of the corpus luteum had already been used. It was noted that these products lowered the intraocular pressure in an objective but above all ephemeral way, which effect the authors attributed to the diuretic action of progestative agents, the parasympathicotropic action of lutein which diminishes mydriasis due to atropine in rats and finally to the antagonist effect of the hypotensive action on the eye of folliculin (cf. Arztlich Wochenschrift 5. (1950) 34). More recently, TZU LUNG CHIANG, (Prostaglandins 4, 3 (1973) 415), has shown that progesterone inhibited the hypertensive response of the eye to the intra-venous perfusion of PGA2. However, in order to bring about a significant although short-lasting effect, the doses of progesterone administered were considerable (25 mg/kg). The same author (Europ. J. of Pharmacology 22 (1973) 304) confirmed that progesterone antagonized the increase in - 18 intraocular pressure.

The effects of progesterone appear to result from a synergy with the effect of epinephrine or ephedrine, administered locally.

The conclusions of the authors are that the effectiveness of the treatment with progesterone against intraocular hypertension, in response to prostaglandins, was limited. A very high dose of progesterone administered frequently was necessary. According to these same authors, the action of progesterone would result in a synergy with circulating catecholamines .

Moreover, PGE, administered by perfusion through a vein, completely inhibits the increase in the level of protein production in the aqueous humor.

In addition, this ocular action of the progestomimetic products seems to be independent of the known properties of progesterone and above all have no correlation with a progestomimetic effect. This is why the effectiveness of the pharmaceutical compositions according to the invention is not relative to the known level of affinity of the active ingredient for the progesterone receptor or to the level of progesterone activity.

This action seems to be exerted on the structures responsible for the evacuation of the aqueous humor. It was therefore interesting to discover and experiment with similar steroid products to determine those which would be the most effective and in particular androstane derivatives which it was thought lacked progesterone action.

The useful dose ranges from 1 to 5 drops per day in each eye of a solution or suspension containing 0.05 to 1% of an active ingredient of general formulae I to XII. Preferably, the solutions or suspensions contain 0.1 to 0.5% of active - 19 ingredient of general formulae I to XII.

Two experimental models are used to test the compounds according to the invention: experimental glaucoma model in a rabbit by injection of a 5% glucose solution: this model, described by BONOMI et Coll., shows that the injection of 5% glucose in a rabbit causes an increase in intraocular pressure of 8 mmHg in 5 to 10 minutes, then a return to normal in about 40 minutes. The mechanism of this modification of the IOP is explained by the reduction of osmolarity of the blood by hemodilution as well as a decrease in the ease of flow of the aqueous humor by hydration of the trabeculum cells. experimental glaucoma model by injection of alphachymotrypsin: the glaucoma is caused one month before the tests are carried out by injection, in the posterior chamber of an eye, of a proteolytic enzyme, alpha-chymotrypsin. This causes lysis of the lens zonule, a dislocation of the lens in the posterior chamber and a hypertension by mechanical obstruction of the iridocorneal angle.

On these models, the compounds according to the invention, at a concentration of 0.1 to 0.5%, cause a rapid and significant decrease, linked to the concentration, of the intraocular pressure.

Quite particularly: 17alpha-methyl 17beta-hydroxy 3-oxo androsta 4-ene and its esters, 6-pivaloyloxymethyl 3,20-dioxo 17alpha-acetoxy 19-nor pregna 4,6-diene cortexolone and its esters 17alpha-hydroxy progesterone and 3,20-dioxo 6-hydroxymethy1 17alpha-acetoxy 19-nor pregna 4,6-diene bring about a significant drop in intraocular pressure in the animal which has been made hypertensive and the decreases - 20 obtained are highly significant from a statistical point view (p <0.01). of

Claims (1)

1.A subject of the invention is: 1. ) Pharmaceutical compositions for ocular use, characterized in that they contain as active ingredient at least one compound of steroid structure chosen from the group constituted by: A - 19-NOR PREGNA 4,6-DIENES OF GENERAL FORMULA I ch r ! in which R-j represents a hydroxy, alkoxy, acyloxy radical R2 represents hydrogen or a lower alkyl radical R and R’ together form a ketone, hydroxyimino, alkoxyimino or acyloxyimino group or separately, when R = H, R' is a hydroxy, alkoxy or acyloxy group and R3 represents a lower alkyl radical having 1 to 3 carbon atoms; B- 19-NOR 4,6-DIENES OF GENERAL FORMULA II in which R2 represents a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms, as a linear or branched chain R7 represents a lower alkyl radical, identical to or. different from R2, having 1 to 6 carbon atoms, as a linear or branched chain and R3 is defined as previously; C - THE COMPOUNDS OF 19-NOR PREGNENE STRUCTURE OF GENERAL FORMULA III CH 3 -R 2 in which R-| represents a hydroxy, alkoxy, acyloxy or alkyl radical having 1 to 4 atoms R2 represents hydrogen or a lower alkyl radical as a linear or branched chain having 1 to 4 carbon atoms Z represents hydrogen, an alkyl radical or an acyl radical and the dotted line represents an optional carbon-carbon - 23 double bond; D - 19-NOR PREGNENE DERIVATIVES OF GENERAL FORMULA IV in which R-| represents a hydroxy, alkoxy, acyloxy or alkyl radical having 1 to 4 carbon atoms R2 represents hydrogen or a lower alkyl radical, as a linear or branched chain, having 1 to 4 carbon atoms and the dotted line symbolizes an optional carbon-carbon double bond; E - 6-HALOMETHYL 19-NOR PREGNENE DERIVATIVES OF GENERAL FORMULA V in which X represents a halogen atom R-| and R2 are defined as previously and the dotted line symbolizes an optional carbon-carbon double bond; - 24 F - THE COMPOUNDS OF 19-NOR ANDROSTENE STRUCTURE CORRESPONDING TO GENERAL FORMULA VI 0R 4 =N-OH or in which Rl represents hydrogen, a lower alkyl or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms R' represents a hydrogen or a lower alkynyl R represents a methyl or ethyl R5 represents two hydrogens or the group =0, in which R4 represents hydrogen or the acyl organic carboxylic acid and R3 represents hydrogen or CH2; G - PREGNADIENES OF GENERAL FORMULA VII remainder of an (VII) in which R represents a lower alkyl or lower cycloalkyl radical - 25 Ri and R3 are defined as previously; H - PREGNENE DERIVATIVES OF GENERAL FORMULA VIII in which the dotted line represents an optional double bond and Rq is defined as previously; I - 3,20-DIOXO DELTA4-PREGNENE COMPOUNDS CORRESPONDING TO GENERAL FORMULA IX J - 11,18-EPOXYANDROSTENE COMPOUNDS OF GENERAL FORMULA X in which Rq represents a free, etherified or esterified hydroxyl radical or a lower alkyl radical R3 represents hydrogen or a lower alkyl radical having 1 to 4 carbon atoms and the dotted line symbolizes 2 hydrogens or a carbon-carbon double bond; - 26 OH in which the wavy line symbolizes an alpha or beta orientation and R represents hydrogen or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms; K - CORTICOSTEROIDS OF GENERAL FORMULA XI ch 2 -or in which R represents hydrogen or an acyl radical derived from an organic carboxylic acid having 1 to 10 carbon atoms; and L - ANDROSTENE COMPOUNDS OF GENERAL FORMULA XII in which R-, represents hydrogen, a lower alkyl radical, a methoxy alkyl, an acyl derived from an organic carboxylic acid or carbonic acid R represents hydrogen or an optionally substituted lower alkyl radical R3 represents hydrogen, a halogen or a lower alkyl and the wavy line symbolizes an alpha or beta orientation combined or mixed with a pharmaceutically acceptable inert excipient or vehicle, intended for use by ocular route. 2. ) A pharmaceutical composition according to claim 1 in which the active ingredient is a 17alpha-hydroxy 6-methyl 3,20-dioxo 19-nor pregna 4,6-diene of formula I a in which R3 and R7 have the previous definitions. 3. ) A pharmaceutical composition according to claim 1 in ,E 922252 - 28 which the active ingredient is a derivative of 17alphahydroxy 3,20-dioxo 19-nor pregna 4,6-diene of general formula III a in which Z and R7 are defined as previously. 4. ) A pharmaceutical composition according to claim 1 in which the active ingredient is a derivative of 17alphahydroxy 3,20-dioxo 21-methyl 19-nor pregna 4,6-diene of general formula 111^ in which Z and R4 are defined as previously. 5. ) A pharmaceutical composition according to claim 1 in which the active ingredient is an alkylated derivative of 3,20-dioxo 19-nor pregna 4,6-diene of general formula III C in which Z, R', R, R-| are defined as above. 6. ) A pharmaceutical composition according to claim 1 in which the active ingredient is a 19-nor pregna 4-ene. derivative of general formula III^ in which Z and Rq are defined as previously. 7. ) A pharmaceutical composition according to claims 1 and 3 in which the active ingredient is 6-pivaloyloxy methyl 17alpha-hydroxy 3,20-dioxo 19-nor pregna 4,6-diene. 8. ) A pharmaceutical composition according to claim 1 in which the active ingredient is 17alpha-acetoxy 6-methyl 3,20dioxo 19-nor pregna 4,6-diene. 9. ) A pharmaceutical composition according to claim 1 in IE - 30 which the active ingredient is isoaldosterone. 10. ) A pharmaceutical composition according to claim 1 in which the active ingredient is corticosterone. 11. ) A pharmaceutical composition according to one of claims 1 to 10 in which an isotonicity agent is added to the lacrymal secretions . 12. ) A pharmaceutical composition according to one of claims 1 to 11 to which a stabilizer is added. 13. ) A pharmaceutical composition according to one of claims 1 to 11 to which an antioxidant is added. 14. ) A pharmaceutical composition according to one of claims 1 to 13 in which the content of active ingredient according to one of claims 1 to 10 ranges from 0.05 to 1%. 15. ) Use of a steroid compound according to one of formulae I to XII according to claim 1 for the preparation of a medicament relating to the treatment of intraocular hypertension and to the treatment of glaucomatous diseases. 16. ) Process for preparing a pharmaceutical composition according to one of claims 1 to 14 in which the steroid active ingredient is dissolved or put in suspension in a suitable aqueous solvent. -3117. 18. 18. 19. 19. A composition substantially as hereinbefore described with reference to the Examples. A use substantially as hereinbefore described with reference to the Examples. A process substantially as hereinbefore described with reference to the Examples.