FR2645021A1 - USE OF A POTASSIC AGONIST IN THE TREATMENT OF GLAUCOMA - Google Patents

Abstract

Use of a potassic agonist to reduce and/or control abnormally high intraocular pressure. Cyano-6 (dihydro-1,2 oxo-2 pyridyl-1)-4 dimethyl-2,2 chromene is especially favoured. Said potassic agonist can be used, according to the invention, in combination with an adrenergic beta-blocking agent and/or with an anti-inflammatory agent.

Description

Glaucoma is an eye condition characterized1 among other symptoms, by a slow or rapid increase in intraocular pressure. Glaucoma leads to the destruction of the optic nerve fibers and can cause loss of vision.

 One of the major treatments for glaucoma is to reduce intraocular pressure. The drugs currently known for the treatment of glaucoma present difficulties of use. Thus, for example, pilocarpine has local side effects, while active principles such as epinephrine or an adrenergic beta-blocker: timolol, are difficult to use for certain patients suffering from cardiovascular diseases or who do not support the general cardiovascular effects of these drugs.

 The present invention relates to the use of a potassium agonist for the preparation of a medicament intended to reduce and / or control the abnormally high intraocular pressure.

 The invention also relates to the use of a potassium agonist in combination with another active ingredient for the treatment of glaucoma. The active ingredient used in combination with the compound of the invention may be either a beta-adrenergic blocking agent itself useful for lowering intraocular pressure, or an anti-inflammatory including a steroidal anti-inflammatory or cor: icosterolde for treatment glaucoma, a side effect of which is increased intraocular.

 The invention also relates to a set or kit comprising on the one hand a potassium agonist in a topical ophthalmic excipient and on the other hand an anti-inflammatory in a topical ophthalmic excipient for the treatment of glaucoma.

 The present invention also relates to a pharmaceutical composition containing a potassium agonist and intended for the treatment of increased intraocular pressure consecutive to treatment with steroidal anti-inflammatory drugs.

 A potassium agonist is called a potassium agonist.

 The pharmacological properties of potassium channel agonists are described in Trends in Pharmacological Sciences, 1988, 9, 21-28.

Some of these compounds are described in J. Med. Chem., 1986, 29, 2194-2201.

 Potassium agonists are compounds that facilitate the opening of cellular potassium channels. This results, in particular, in a relaxing effect on the smooth muscles.

The potassium agonist effect of a compound can, for example, be measured by its inhibitory power of spontaneous contractile activities of the isolated portal vein of the rat.

 The potassium agonists the use of which is the object of the present invention are derivatives of chroman, quinoline or pyranopyridine. These compounds are described in several patent applications or patents.

 The general formulas (I) to (XIV) below explain the compounds described in certain patents or patent applications which are cited without limitation.

The values of each of the substituents R: at Rto, of each of the indices m, n, p, of each of the groups A, Al, A2, A3, D, E, G, L,
M, Q, X, Y, Z relate only to the general formula of the compound in which these substituents, indices or groups are used.

dans laquelle
R1 est A - R2 est H ou A - ou R1 et R2 ensemble, forment un groupe alkylene de 3 a 6 atomes
de carbone - R3 est OH ou OAc - F4 est H - ou R3 et R4 ensemble forment une double liaison - R3 est 1H-pyridone-2 yl-1, 1H-pyridazinone-6 yl-1, 1H
pyrimidinone-2 yl-1, 1H-pyrazinone-2 yl-1, 1H-thiopyridone-2
yl-1, ces hétérocycles pouvant être partiellement hydrogénés et
pouvant etre non substitués ou substitués 1 ou 2 fois par A, F,
Cl.Br, 1, OH, OA, OAc, NO2, NH2, NHAc, COOH ou COOA - R6 et R7 représentent chacun H, A, HO, AO, CHO, ACO, ACS, COOH,
COOA, CSOA, ACOO, ACSO, 1-6 C hydroxyalkyle ou oercaptoalkyle,
NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AOSO, AOSO2,
Ac NH, AO-CO-NH, NH2 SO, HNA-SO, A2, NSO, NH2, SO2, HNASO2,
A2NSO2, NH2CO, HNACO, A2NCO, NH2CS, HNA-CS, A2 NCS, ASONH, ASO2NH.Application EP 273262 describes compounds of formula:

in which
R1 is A - R2 is H or A - or R1 and R2 together form an alkylene group of 3 to 6 atoms
carbon - R3 is OH or OAc - F4 is H - or R3 and R4 together form a double bond - R3 is 1H-pyridone-2 yl-1, 1H-pyridazinone-6 yl-1, 1H
pyrimidinone-2 yl-1, 1H-pyrazinone-2 yl-1, 1H-thiopyridone-2
yl-1, these heterocycles can be partially hydrogenated and
can be unsubstituted or substituted 1 or 2 times by A, F,
Cl.Br, 1, OH, OA, OAc, NO2, NH2, NHAc, COOH or COOA - R6 and R7 each represent H, A, HO, AO, CHO, ACO, ACS, COOH,
COOA, CSOA, ACOO, ACSO, 1-6 C hydroxyalkyl or oercaptoalkyle,
NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AOSO, AOSO2,
Ac NH, AO-CO-NH, NH2 SO, HNA-SO, A2, NSO, NH2, SO2, HNASO2,
A2NSO2, NH2CO, HNACO, A2NCO, NH2CS, HNA-CS, A2 NCS, ASONH, ASO2NH.

ACO-alk, nitro-alk, cyano-alk, AC = NOH or AC (= NNH2) - A is an alkyl group from I to 6 C; alk is an alkylene group of I to 6 C; Ac is an alkanoyl from â to 8 C or an aroyl from 7 to
11 C; as well as their salts (C e carbon atom).

dans laquelle - R1 est CN, NO2, alkyl(C1-C6)-S(O)n ou Ar S(O)n - n = 1 ou 2 - Ar est un système aromatique ou hétérocyclique non substitué ou
substitué 1 à 3 fois par un alkyle (C1-C2), un alcoxy (C1-C2), un
halogène, CF3, CN, NO2, un alkyl carbonyle (C1-C2) ou un alkyl
(C1-C2)-S(O)p - p = 1 ou 2 ; - R2 = H, OH, alkyle (C1-C2), alcoxy (C1-C2), un halogène ou NR5R6 - R5 et R6 sont H, un alkyle (C1-C2) ou un alkylcarbonyle (C1-C2) - R3 et R4 sont chacun un alkyle (C1-C4) - X est (CH2)m non substitué ou substitué par un alkyle (C1-C2)
éventuellement interrompu par O, NR7 ou S - m=2à4; - R7 est H ou alkyle (C1-C4). Patent applications EP 277 611 and EP 277 612 describe compounds of formula

in which - R1 is CN, NO2, (C1-C6) alkyl -S (O) n or Ar S (O) n - n = 1 or 2 - Ar is an unsubstituted aromatic or heterocyclic system or
substituted 1 to 3 times with (C1-C2) alkyl, (C1-C2) alkoxy,
halogen, CF3, CN, NO2, an alkyl carbonyl (C1-C2) or an alkyl
(C1-C2) -S (O) p - p = 1 or 2; - R2 = H, OH, (C1-C2) alkyl, alkoxy (C1-C2), halogen or NR5R6 - R5 and R6 are H, alkyl (C1-C2) or alkylcarbonyl (C1-C2) - R3 and R4 are each a (C1-C4) alkyl - X is (CH2) m unsubstituted or substituted by an alkyl (C1-C2)
possibly interrupted by O, NR7 or S - m = 2 to 4; - R7 is H or C1-C4 alkyl.

dans laquelle - D représente, entre N et CO, le groupe - CH = CH - E = CE ou le groupe

- Z représente un halogène ou un groupe cyano, acétyle,
trifluoroacétyle, nitro, alkylthio, carboxy, phosphono,
dialcoxyphosphoryle, alcoxycarbonyle, les groupes alkylthio et
alcoxy contenant de 1 à 3 atomes de carbone ; @ E représente un atome d'azote ou un groupe C (Q) ;; @ G représente l'hydrogène, un groupe méthyle ou un groupe
hydroxyle, L et M représentent chacun indépendamment l'hydrogene
ou un groupe méthyle, un seul des substituants G, L, n pouvant
être méthyle @ Q représente un atome d'aydrogène, d'halogene, un groupe méthyle
ou un groupe hydroxyle ;
et les sels pharmaceutiquement acceptables du groupe phosphono ou carboxy.European patent application 296 975 describes compounds of formula:

in which - D represents, between N and CO, the group - CH = CH - E = CE or the group

Z represents a halogen or a cyano, acetyl group,
trifluoroacetyl, nitro, alkylthio, carboxy, phosphono,
dialkoxyphosphoryl, alkoxycarbonyl, alkylthio groups and
alkoxy containing from 1 to 3 carbon atoms; @ E represents a nitrogen atom or a C (Q) group; @ G represents hydrogen, a methyl group or a group
hydroxyl, L and M each independently represent hydrogen
or a methyl group, only one of the substituents G, L, n possibly
to be methyl @ Q represents an atom of hydrogen, of halogen, a methyl group
or a hydroxyl group;
and the pharmaceutically acceptable salts of the phosphono or carboxy group.

dans laquelle l'un des substituants R1 ou R2 est l'hydrogène. l'autre est choisi
parmi : un alkylcarbonyle, un alcoxycarbonyle, alkylcarbonyloxy,
un alkylhydroxyméthyle. un nitro, un cyano, un trifluorométhyle,
un alkylsulfinyle, un alcoxysulfonyle, un alkylcarbonylamino,
alcoxycarbonylamino ou un axiaosulfxnyle, un aminosulfonyle ou
un aminocarbonyle, la partie amino étant éventuellement
substituée par un ou deux groupes alkyle ou alkysulfinylamino ou
alkylsulfonylamino, alcoxysulfinylamino ou alcoxysulfonylamino
ou éthylényl substitué sur sa partie terminale par un
alkylcarbonyle, un nitro, un cyano, ou un -C(akyl)NOH ou un
C(alkyl) NNH2, les radicaux alkyles contenant de 1 à 6 atomes de
carbone - l'un des substituants R3 et R4 est l'hydrogène ou un alkyle ayant
1 à 4 atomes de carbone, l'autre est un alkyle ayant 1 à 4 atomes
de carbone ou R3 et Ra ensemble constituent avec l'atome de carbone
auquel ils sont liés un spiroalkyle ayant de 3 à 6 atomes de
carbone ; - R5 est l'hydrogène, un alkyle ayant de 1 à 3 atomes de carbone
ou un acyle ayant de 1 à 8 atomes de carbone ; - et n est 1 ou 2 ; le groupe lactame étant en position trans par
rapport au substituant OR5. European patent 76075 describes compounds of formula

in which one of the substituents R1 or R2 is hydrogen. the other is chosen
among: an alkylcarbonyl, an alkoxycarbonyl, alkylcarbonyloxy,
an alkylhydroxymethyl. a nitro, a cyano, a trifluoromethyl,
an alkylsulfinyl, an alkoxysulfonyl, an alkylcarbonylamino,
alkoxycarbonylamino or axiaosulfxnyl, aminosulfonyl or
an aminocarbonyl, the amino part possibly being
substituted by one or two alkyl or alkysulfinylamino groups or
alkylsulfonylamino, alkoxysulfinylamino or alkoxysulfonylamino
or ethylenyl substituted on its terminal part by a
alkylcarbonyl, nitro, cyano, or -C (akyl) NOH or
C (alkyl) NNH2, alkyl radicals containing from 1 to 6 atoms of
carbon - one of the substituents R3 and R4 is hydrogen or an alkyl having
1 to 4 carbon atoms, the other is an alkyl having 1 to 4 atoms
of carbon or R3 and Ra together constitute with the carbon atom
to which they are linked a spiroalkyl having 3 to 6 atoms of
carbon; - R5 is hydrogen, an alkyl having from 1 to 3 carbon atoms
or an acyl having from 1 to 8 carbon atoms; - and n is 1 or 2; the lactam group being in the trans position by
compared to the OR5 substituent.

 According to this patent, a preferred compound is trans cyano-6 dihydro-3,4 dimethyl-2,2 (2-oxo pyrrolidinyl-1) 2 H-benzo (b) pyran-3 ol, which bears the international common name: cromakalime.

 Other patents or patent applications describe compounds close to those which are claimed in EP 76 075.

 Patent application Ep 274 821 describes compounds similar to (III) in which the oxo-2 pyrrolidinyl or oxo-2 piperidinyl ring is substituted by a hydroxyl group.

 Patent application EP 91 748 describes compounds close to those described in EP 76 075.

dans laquelle - l'un des substituants R1 et R2 est l'hydrogène, l'autre est un
alkylcarbonyle, un alcoxycarbonyle, un alkylcarbonyloxy, un
alkplhydroxyméthyle, un nitro, un cyano, un atome de chlore, un
triflurométhyle, un alkylsulfinyle, un alkylsulfonyle, un
alkylcarbonylamino, mun alcoxycarbonylamino, un alkylthio
carbonyle, un alcoxythiocarbonyle, un alkylthiocarbonyloxy, un
alkylthiométhyle, un formyle, un amino-sulfinyle, -sulfonyle ou
-carbonyle, le groupement amino étant éventuellement substitue
par 1 ou 2 alkyles, un alkylsulfinylamino, un alkylsulfonylamino,
un alcoxysulfinylamino, un alcoxysulfonylamino ou un éthylényle
substitue sur sa partie terminale par un alcanoyle, un nitro, un
cyano, un groupement C2=NOH ou C2-NNH2, tous les groupements
alkyles contenant de I à 6 atomes de carbone - ou l'un des substitusnts R1 et R2 est un nitro, un cyano, un
alcanoyle (C1-C3) et l'autre est un méthoxy ou un amino
éventuellement substitue par 1 ou 2 alkyles (C1-C6) ou par un
alcanoyle (C2-C7) - Z est un alkyle en C1 à C6 - X est un atome d'oxygène, un atome de soufre ou un atome d'azote
substitué par R7 - R est un atome d'hydrogene, un alkyle (C1-C7). un alcanoyle
(C2-C7), un phénylakyle (C6-C10), un naphtylcarbonyle, un
benzoyle, un benzylcarbonyle, tous les cycles pouvant être non
substitués ou substitués une ou deux fois par un alkyle (C1-C6),
un alcoxy (C1-C6) ou un atome d'halogéne, ou un
hétéroarylcarbonyle mono- ou bi-cyclique.In EP 107 423 the compounds described correspond to the formula

in which - one of the substituents R1 and R2 is hydrogen, the other is a
alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy,
alkplhydroxymethyl, nitro, cyano, chlorine,
trifluromethyl, alkylsulfinyl, alkylsulfonyl,
alkylcarbonylamino, mun alkoxycarbonylamino, an alkylthio
carbonyl, an alkoxythiocarbonyl, an alkylthiocarbonyloxy, a
alkylthiomethyl, formyl, amino-sulfinyl, -sulfonyl or
-carbonyl, the amino group being optionally substituted
with 1 or 2 alkyls, an alkylsulfinylamino, an alkylsulfonylamino,
an alkoxysulfinylamino, an alkoxysulfonylamino or an ethylenyl
substituted on its terminal part by an alkanoyl, a nitro, a
cyano, a group C2 = NOH or C2-NNH2, all groups
alkyls containing from I to 6 carbon atoms - or one of the substitutes R1 and R2 is a nitro, a cyano, a
alkanoyl (C1-C3) and the other is methoxy or amino
optionally substituted by 1 or 2 alkyls (C1-C6) or by a
alkanoyl (C2-C7) - Z is C1 to C6 alkyl - X is an oxygen atom, a sulfur atom or a nitrogen atom
substituted by R7 - R is a hydrogen atom, a (C1-C7) alkyl. an alkanoyl
(C2-C7), phenylakyl (C6-C10), naphthylcarbonyl,
benzoyl, a benzylcarbonyl, all the cycles can be non
substituted or substituted once or twice by a (C1-C6) alkyl,
an alkoxy (C1-C6) or a halogen atom, or a
mono- or bi-cyclic heteroarylcarbonyl.

dans laquelle : - X peut être un atome d'oxygène ou un atome de soufre ; - Y et 2 sont l'hydrogène ou représentent ensemble une liaison.Application EP 93 535 describes analogous compounds of formula

in which: - X can be an oxygen atom or a sulfur atom; - Y and 2 are hydrogen or together represent a bond.

dans laquelle : - X represente un atome d'oxygène ou un atome de soufre ; - R6 représente l'hydrogène ou un alkyle (C1-C6) - R5 représente l'hydrogène, un alkyle (C1-C6) éventuellement
substitué par un hydroxyle, un alcoxy (C1-C6), un alcoxycarbonyle
(4-C7) ou COOH, ou un allyle (C1-C2) éventuellement substitué par
un atome d'halogène ou alcényle (C2-C7) ou R5 + R6 forment ensemble un polyméthyléne contenant 3 ou 4
atomes de carbone.Patent application EP 126 350 describes analogous compounds of formula

in which: - X represents an oxygen atom or a sulfur atom; - R6 represents hydrogen or a C1-C6 alkyl - R5 represents hydrogen, a C1-C6 alkyl optionally
substituted by a hydroxyl, a (C1-C6) alkoxy, an alkoxycarbonyl
(4-C7) or COOH, or an allyl (C1-C2) optionally substituted with
a halogen or alkenyl atom (C2-C7) or R5 + R6 together form a polymethylene containing 3 or 4
carbon atoms.

 patent application EP 139 992 describes neighboring compounds in which the substituent in position 3 on the chroman is an OR5 group in which R5 is hydrogen, (C1-C4) alkyl or acyl (C1-C8).

dans laquelle Y et Q sont des groupements attracteurs d'électrons.Patent application EP 214 818 describes neighboring compounds of formula

in which Y and Q are electron attracting groups.

dans laquelle @ n = O ou 1 - et R1, R2, R3, R4, R5, R6 ont des significations semblables à celles
décrites ci-dessus pour (III) et (1V). Patent application WO 80 869 describes compounds of formula:

in which @ n = O or 1 - and R1, R2, R3, R4, R5, R6 have meanings similar to those
described above for (III) and (1V).

dans laquelle : - Y représente un atome d'azote ou si R3 est un hydroxyle, un alcoxy
ou un acyloxy, Y représente CH , - l'un des substituants R1 et R2 est un atome d'hydrogène ou un
alkyle en C1 -C4, l'autre est un alkyle en C1-C4, ou R1 + R2
représentent un groupe polyméthylène en C2-C5 - R3 représente un atome d'hydrogène, un hydroxyle, un alcoxy en
C1-C6 ou un acyloxy en C-C7 - R4 représente un cycloalkyle en C3-C8 ou un alkyle en C1-C6,
éventuellement substitue par R7 - R7 représente un hydroxyle, un alcoxy en C1-C6, un amino, un mono
ou di-alkyl (C1-C6) amino, un alcanoylamino (C1-C7), un
cycloalkyloxy (Ca-Cs), un cycloalkylamino ou un dioxo-1,3
isoindolinyl-2 ;;
X X est O ou S ;
a) lorsque Y est N, R5 est (i) l'hydrogène,
(ii) un alkyle éventuellement substitue par un halogène. un
hydroxyle1 un alcoxy (C1-C6), un alcoxycarbonyle (C2-C7), un
carboxy, un amino mono ou di-substitue par un alkylamino (Ca-C6),
(iii) un alcenyle (Ca-Ca),
(iv) un amino, un alkylamino (C1-C6), un cycloalkylamino (C3-C8),
un alcénylamino (C2-C6), un alcanoylamino (C2-C6) (éventuellement
substitué par 1 à 3 atomes d'halogène) ou anilino (éventuellement
substitué par un alkyle C1-C6), un alcoxy (C1-C6) ou un halogène,
ou (v) un aryle, un hétéroaryle éventuellement substitué une ou
plusieurs fois par un alkyle (C1-C6), un alcoxy (C1-C6), un
hydroxyle, un atome d'halogene, un trifluorométhyle, un nitro,
un cyano, un carboxylique acyle (C1-C2), un mono ou di-alkylamino
(C1-C6) ou un mono ou di-alkylcarbamoyle (C1-C6) - R6 représente l'hydrogène ou un alkyle (C1-C6) - ou R5 + R6 représentent CH2(CH2)n Z (CH2)n
m = O à 2, n = O à 2 et m + n - 1 ou 2 ; @ Z représente CH2, O, S ou NR - R est l'hydrogène, un alkyle, en C1-C9, un alcaoyle (C2-C7), un
phénylaîkyle (C1-C4), un naphtoyle, un benzoyle ou un phénacétyle
(éventuellement substitué sur le cycle phényle ou naphtyle par
un ou deux alkyles en C1-C6, un alcoxy, en C1-C6 ou un halogène)
ou un mono- ou bi-cyclique hétéroarylcarbonyle ; ou R5 et R6 forment avec les atomes auxquels ils sont liés un
groupe tétrahydroisoquinoline ou tétrahydroisoquinolinethione,
éventuellement substitué dans la partie benzénique comme cele est
défini pour R avec la précision que Y (R6) CXRs est trans par rapport à R3 lorsque
R3 est un hydroxyle, un alcoxy ou un acyloxy ;
b) lorsque Y est CH, R5 est NR3R9 ou CH2Rlo - R3 est l'hydrogène ou un alkyle (C1-C6) - R9 est un alkyle (C1- C6) ou Ru + R9 constituent un polyméthylène en C4-C5 ou R6 + R9 représentent (CH2)2 ou (CH2)3 - R10 est l'hydrogène ou alkyle (C1-C@) ou R6 + R10 représentent
(CH2)2 ou (CH2)3.Patent application Ep 250 077 describes compounds of formula:

in which: - Y represents a nitrogen atom or if R3 is a hydroxyl, an alkoxy
or an acyloxy, Y represents CH, - one of the substituents R1 and R2 is a hydrogen atom or a
C1-C4 alkyl, the other is C1-C4 alkyl, or R1 + R2
represent a C2-C5 polymethylene group - R3 represents a hydrogen atom, a hydroxyl, an alkoxy in
C1-C6 or a C-C7 acyloxy - R4 represents a C3-C8 cycloalkyl or a C1-C6 alkyl,
optionally substituted by R7 - R7 represents a hydroxyl, a C1-C6 alkoxy, an amino, a mono
or di (C1-C6) amino, an alkanoylamino (C1-C7), a
cycloalkyloxy (Ca-Cs), cycloalkylamino or 1,3-dioxo
isoindolinyl-2 ;;
XX is O or S;
a) when Y is N, R5 is (i) hydrogen,
(ii) an alkyl optionally substituted by a halogen. a
hydroxyle1 alkoxy (C1-C6), alkoxycarbonyl (C2-C7),
carboxy, an amino mono or di-substituted by an alkylamino (Ca-C6),
(iii) an alkenyl (Ca-Ca),
(iv) an amino, an alkylamino (C1-C6), a cycloalkylamino (C3-C8),
an alkenylamino (C2-C6), an alkanoylamino (C2-C6) (optionally
substituted by 1 to 3 halogen atoms) or anilino (optionally
substituted with C1-C6 alkyl, (C1-C6) alkoxy or halogen,
or (v) an aryl, an optionally substituted heteroaryl, or
several times with (C1-C6) alkyl, (C1-C6) alkoxy,
hydroxyl, a halogen atom, a trifluoromethyl, a nitro,
a cyano, an acyl carboxylic (C1-C2), a mono or di-alkylamino
(C1-C6) or a mono or di-alkylcarbamoyl (C1-C6) - R6 represents hydrogen or an alkyl (C1-C6) - or R5 + R6 represent CH2 (CH2) n Z (CH2) n
m = O to 2, n = O to 2 and m + n - 1 or 2; @ Z represents CH2, O, S or NR - R is hydrogen, C1-C9 alkyl, alkaoyl (C2-C7), a
phenylakyl (C1-C4), naphthoyl, benzoyl or phenacetyl
(optionally substituted on the phenyl or naphthyl ring with
one or two C1-C6 alkyls, alkoxy, C1-C6 or halogen)
or a mono- or bi-cyclic heteroarylcarbonyl; or R5 and R6 form with the atoms to which they are linked a
tetrahydroisoquinoline or tetrahydroisoquinolinethione group,
optionally substituted in the benzene part as it is
defined for R with the precision that Y (R6) CXRs is trans with respect to R3 when
R3 is hydroxyl, alkoxy or acyloxy;
b) when Y is CH, R5 is NR3R9 or CH2Rlo - R3 is hydrogen or a C1-C6 alkyl - R9 is a C1-C6 alkyl or Ru + R9 constitute a C4-C5 or R6 + polymethylene R9 represent (CH2) 2 or (CH2) 3 - R10 is hydrogen or alkyl (C1-C @) or R6 + R10 represent
(CH2) 2 or (CH2) 3.

dans laquelle - l'un des substituants R1 ou R2 représente l'hydrogène, un
alkylthiocarbonyle (C1-C6), un alkylthiocarbonyloxy (C1-C6) un
mercaptoalkyle (C2-C7) ou un formyle - l'un des substituants R3 ou R4 est l'hydrogène ou un alkyle
(C1-C4), l'autre est un alkyle (C1-C4) ou CR3R4 est un spiroalkyle
(C3-C8) - Rs est l'hydrogène, un acyle (C1-C3) ou un acyle (C1-C8) - n est 1 ou 2 - le groupe lactame est en position trans vis à vis du substituant OR5. Patent EP 120 426 describes compounds of formula

in which - one of the substituents R1 or R2 represents hydrogen, a
alkylthiocarbonyl (C1-C6), an alkylthiocarbonyloxy (C1-C6) a
mercaptoalkyl (C2-C7) or formyl - one of the substituents R3 or R4 is hydrogen or alkyl
(C1-C4), the other is alkyl (C1-C4) or CR3R4 is spiroalkyl
(C3-C8) - Rs is hydrogen, an acyl (C1-C3) or an acyl (C1-C8) - n is 1 or 2 - the lactam group is in position trans with respect to the substituent OR5.

 Several patent applications describe chroman derivatives substituted at -4 by a piperidyl-4 or pyridyl-4 group. These compounds are also potassium channel agonists.

dans laquelle - Al représente un alkyle (C4-C6) @ A2 représente l'hydrogène, un groupement OAa ou OCOA4 - A3 représente un groupement bicyclique, un groupement
hétérocyclique ou un phényle substitué - A4 représente un alkyle (C1-C6) éventuellement substitué par un
groupement amino ou mono ou di-alkylamino (C1-C6) n = 1 ou 2.The beige patent 817 328 describes compounds of formula:

in which - Al represents a (C4-C6) alkyl @ A2 represents hydrogen, an OAa or OCOA4 group - A3 represents a bicyclic group, a group
heterocyclic or substituted phenyl - A4 represents a (C1-C6) alkyl optionally substituted by a
amino or mono or di-alkylamino group (C1-C6) n = 1 or 2.

Patent applications DE 2,513,220, DE 2,303,176, DE 2,053,405,
GB 2 030 134, GB 1 470 493, BE 832 524, BE 770 076, BE 757 454, describe neighboring compounds.

dans laquelle - R1 représente Cl > Br, CN ou un alcanoyle (C2-C7) - l'un des substituants R3 et R4 est l'hydrogène ou un alkyle
(C1-C4), l'autre est un alkyle (C1-C4) ou R3 et R4 représentent un
pclyméthyléne (C2-C5) - R5 représente un hydroxyle, un alcoxy (C1-C3) ou un alcyloxy
(C1-C8) - R2 est l'hydrogène - ou R2 + R5 forment une liaison n n = 1 ou 2.PCT patent application 8 500 602 describes compounds of formula:

in which - R1 represents Cl> Br, CN or an alkanoyl (C2-C7) - one of the substituents R3 and R4 is hydrogen or an alkyl
(C1-C4), the other is alkyl (C1-C4) or R3 and R4 represent a
pclymethylene (C2-C5) - R5 represents a hydroxyl, an alkoxy (C1-C3) or an alkyloxy
(C1-C8) - R2 is hydrogen - or R2 + R5 form a bond nn = 1 or 2.

dans laquelle - l'un des substituants R1 ou R2 est l'hydrogène ou un alkyle
(C1-C4), l'autre est un alkyle (C-C4) ou R1 et R2 forment ensemble
un polyméthylène (C2-C5)
R3 est l'hydrogène, un groupe hydroxyle, un alcoxy (Cl-C6) ou un
acyloxy (C1-C7) - R4 est l'hydrogène - ou R3 et R4 forment une lisison - R5 est l'hydrogène, un alkyle (C1-C6), léventuellement substitué
1 à 3 fois par un atome d'halogène, par un hydroxyle, par un
alcoxy (C1-C6), par un alccxycarbonyle (C2-C 7), par un carboxy,
par un amino ou un mono- ou di-alkylamino (CI-C6) ou disubstitué
par un polyméthylène (C4-C5)/, un alcényle (C2-C6), un amino
léventuellement mono substitué par un alkyle (C1-C6), un alcenyle
(C2-C6) ou un alcanoyle (C1-C6) éventuellement substitué 1 à 3 fois
par un halogène ou un phényle éventuellement substitue par un
alkyle(CI-C6), un alcoxy (C1-C6) ou un halogéne/, un aryle ou un
hetéroaryle tous deux éventuellement substitués une ou plusieurs
fois par un alkyle (Cl-C6), un alcoxy (C1-C6), un hydroxyle, un
atome d'halogène, un trifluoromethyle, un nitro, un cyano, un
acylcarboxylique (C-C12), un amino ou un aminocarbonyle
éventuellement substitué par un ou deux alkyles (C1-C6) ou lorsque X est l'oxygène, - R5 est un carboxy, un alcoxycarbonyle (C1-C6), un aminocarbonyle
éventuellement substitué par un ou deux alkyles - R6 est l'hydrogène ou un alkyle (Cl-C6) - ou R5 et R6 ensemble représentent CH2-(CH2)n-Z-(CH2)m dans lequel
m et n varient de O à 2 de telle sorte que m + n = 1 ou 2,
et Z = CH2, O, S, ou NR @ R représente l'hydrogène, un alkyle (C1-C9), un alcanoyle
(C2-C7), un phénylaîkyle (C1-C4), un naphtylcarbonyle, un
phénylcarbonyle ou un benzylcarbonyle éventuellement substitué
sur la partie phényle ou naphtyre par un ou deux alkyles (C1-C6),
alcoxy (C1-C6) ou halogène ; - ou bien R est un hététoarylcarbonyle - X est un oxygène ou un soufre - ou R5, R6, X et N ensemble forment une tétrahydroisoquinoline, ou
une tétrahydroisoquinolinethione éventuellement substituée sur
le noyau phényle par R le groupe contenant l'atome d'azote étant en position trans par rapport à R3, lorsque R3 est un hydroxy, un alcoxy (C1-C6) ou un acyloxy (C3-C7).Patent application EP 205 292 describes compounds of formula

in which - one of the substituents R1 or R2 is hydrogen or an alkyl
(C1-C4), the other is alkyl (C-C4) where R1 and R2 form together
polymethylene (C2-C5)
R3 is hydrogen, a hydroxyl group, an alkoxy (Cl-C6) or a
acyloxy (C1-C7) - R4 is hydrogen - or R3 and R4 form a lisison - R5 is hydrogen, alkyl (C1-C6), optionally substituted
1 to 3 times with a halogen atom, with a hydroxyl, with a
alkoxy (C1-C6), with an alkoxycarbonyl (C2-C 7), with carboxy,
by an amino or a mono- or di-alkylamino (CI-C6) or disubstituted
by a polymethylene (C4-C5) /, an alkenyl (C2-C6), an amino
l optionally mono substituted by an alkyl (C1-C6), an alkenyl
(C2-C6) or an alkanoyl (C1-C6) optionally substituted 1 to 3 times
by a halogen or a phenyl optionally substituted by a
(C1-C6) alkyl, (C1-C6) alkoxy or halogen /, aryl or
heteroaryl both optionally substituted one or more
times by an alkyl (Cl-C6), an alkoxy (C1-C6), a hydroxyl, a
halogen atom, trifluoromethyl, nitro, cyano,
acylcarboxylic (C-C12), amino or aminocarbonyl
optionally substituted by one or two alkyls (C1-C6) or when X is oxygen, - R5 is carboxy, alkoxycarbonyl (C1-C6), aminocarbonyl
optionally substituted with one or two alkyls - R6 is hydrogen or (Cl-C6) alkyl - or R5 and R6 together represent CH2- (CH2) nZ- (CH2) m in which
m and n vary from O to 2 so that m + n = 1 or 2,
and Z = CH2, O, S, or NR @ R represents hydrogen, (C1-C9) alkyl, alkanoyl
(C2-C7), phenylakyl (C1-C4), naphthylcarbonyl,
phenylcarbonyl or an optionally substituted benzylcarbonyl
on the phenyl or naphthyre part with one or two alkyls (C1-C6),
alkoxy (C1-C6) or halogen; - or R is a heteroarylcarbonyl - X is an oxygen or a sulfur - or R5, R6, X and N together form a tetrahydroisoquinoline, or
a tetrahydroisoquinolinethione optionally substituted on
the phenyl ring with R, the group containing the nitrogen atom being in the trans position with respect to R3, when R3 is hydroxy, alkoxy (C1-C6) or acyloxy (C3-C7).

 All potassium agonists have the property of being usable for the preparation of medicaments intended for the treatment of glaucoma.

 According to the present invention, the compounds (1) described in patent application EP 273 262, as well as the co-compounds (III) described in patent application EP 296 975 are preferred. Cyano-6 (dihydro-1,2-oxo-2 pyridyl-1) -4 dimethyl-2,2 chromene described in EP 296 975 is particularly preferred. In addition, other preferred compounds are those which inhibit at 50% the spontaneous concentration of the isolated portal vein of the rat at molar concentrations less than or equal to 10 7M. This inhibitory concentration (IC50) can be measured according to the method described in application EP 296 975.

 The potassium agonists known in the prior art are prepared by known and described methods, in particular in the aforementioned patents, or by similar methods derived therefrom.

 The pharmaceutically acceptable salts of the potassium agonists described also form part of the present invention for their use in the treatment of glaucoma.

 The pharmaceutical compositions according to the present invention are administered in the form of ophthalmic pharmaceutical compositions suitable for topical administration to the eye, such as solutions, suspensions or ointments.

 The formulations according to the invention may contain from 0.000001 to IX by weight of a potassium agonist, more particularly from 0.00001 to 0.1 X. Each dosage unit comprises an amount of potassium agorete.between 1 ng and 0.1 mg, preferably between 5 ng and 50 ng.

 The expression "control of elevated intraocular pressure", as used in the present description, signifies the regulation, the reduction and the modulation of elevated intraocular pressure which is the first symptom allowing the diagnosis of glaucoma. The expression also means that the reduction in intraocular pressure obtained according to the invention by the use of a potassium agonist is maintained for a sufficient period of time, for example between the administration of two consecutive doses.

 Potassium agonists can be used in pharmaceutical compositions, either as the only active ingredient intended to reduce intraocular pressure, or in combination with other active ingredients also intended to lower intraccular pressure and acting by a separate mechanism, such as a adrenergic beta-blocking agent, timolol, in the form of maleate, for example.

 The usefulness of a beta-blocker for reducing intraocular pressure is known. Timolol is therefore prescribed in the topical treatment of glaucoma at the rate of one or two drops per day of a 0.25 mg / 100 ml or 0.5 mgflOO ml solution. It is known, however, that this product should be used with caution due to its activity on the cardiovascular system and its side effects.

 According to this aspect of the present invention, it is clear that the use of a potassium agonist associated with that of a beta blocker. such as timolol maleate, may reduce the useful dose of beta-blocker while observing an equivalent reduction in intraocular pressure. This will minimize the side effects due to beta-blocker.

 To carry out such a treatment in combination, the beta-blocker and the potassium agonist are preferably administered together in the form of a composition in a pharmaceutical formulation. The unit dosage form preferably contains: - d 5 g to 125 ug of adrenergic beta-blocker - and 1 ng to 0.1 mg of potassium agonist.

 The amount of each of the active ingredients may vary depending on the severity of the disease and the individual response of the patients.

 The concentrations of each of the active principles of the composition which make it possible to reduce the intraocular pressure are variable, they have a lower limit below which the composition is inactive. This lower limit is approximately 5 X of the effective dose and depends on the potency of the potassium agonist and, possibly, that of the beta-blocker used, the age and size of the patient, as well as the severity of disease.

 The increase in intraocular pressure> associated with ophthalmic or systemic use of steroidal anti-inflammatory drugs, can be reduced by the administration of potassium agonists. Steroidal anti-inflammatory drugs include: hydro-cortisone, cortisone, flunisolide, beclomethasone, alclomethasone, flunisolide, chlorocortolone, diflorasone, alkinolide, fluocinonide, fluocinolone, deoximethasone, medrysone , paramethasone, dichloro-9,21 [(furanylcarbonyl-2) oxy-17] hydroxy-11 methyl-16 α pregnadiene-1,4 dione-3,20 and fluorometholone, as well as their pharmaceutically acceptable salts and esters.

 The elevation of intraocular pressure can occur following any mode of administration of these drugs: systemic administration, usually oral, local injection, for example the injection of a delayed form and particularly during an irje: topical or intravitreal ophthalmic tiofl. A potassium agonist may be administered after steroid therapy to lower the elevated intraocular pressure or it may be co-administered with the steroid to suppress the effect of increasing the intraocular pressure of the steroid, without interfering with its anti-inflammatory activity.

 According to the present invention, any combination of the dosage forms can between used to administer the combination of the anti-inflammatory steroid and the potassium agonist: the two drugs in as oral, or both in topical form, or one in oral form, The other in topical form, or the steroid in the form of a local injection and the potassium agonist in topical form; a preferred combination is the topical administration of the steroid and the potassium agonist. Particularly preferred is a topical ophthalmic composition comprising both the steroid and the postassic agonist.

 The method for reducing and controlling high intraocular pressure, combined with the use of a systemic or ophthalmic anti-inflammatory drug, also includes separate traction administration of this agent and a potassium agonist. This is why the present invention relates to a kit comprising two separate units: a pharmaceutical composition comprising a potassium agonist and a pharmaceutical composition comprising a steroid. Preferably such a kit comprises a topical ophthalmic composition of potassium agonist and a pharmaceutical composition of Most preferably, the kit includes two topical ophthalmic compositions, one comprising the potassium agonist, the other the steroid. A particular advantage of this presentation is to provide a composition based on potassium agonist which can be administered once or twice a day and a steroid composition which can be administered more often; every hour for example.

 According to the invention, the topical formulation can contain different amounts of active principle, either in the same composition, or administered separately.

 The potassium agonist represents from 0.000 001 X to approximately 1 X by weight of the drug, more particularly from 0.000 Ol to 0.1 S. A unit dosage form comprises from 1 ng to 0.1 mg, preferably between 5 ng and 50 ng to apply on the eye. In each individual case, the amount to be administered and the frequency of administration depend on the potency of the potassium agonist used, the severity of the increase in intraocular pressure to be treated and the response of the patient.

 The steroid represents from 0.05 X to about 1.5 X by weight of the drug. A unit dosage form comprises from 20 g to 600 ug to be applied to the eye. In each individual case, the amount to be administered and the frequency of administration depend on the potency of the steroid chosen, the severity of the disease and the response of the patient. For each particular steroid, one can determine which potassium agonis to use and at what concentration.

 According to one aspect of the invention, the two active principles, namely the potassium agonist and the steroid, are administered simultaneously and contained in the same pharmaceutical form, each being present in the pharmaceutical form at its preferred concentration. When the steroid is administered by systemic or topical route, other than ophthalmic, its dosage may vary according to the criteria previously described and known to those skilled in the art.

For solutions and suspensions, the volume represented by a drop of pharmaceltic composition must also be taken into account.

 The effect of lowering the intraocular pressure of a pharmaceutical composition according to the invention can be measured according to the method described in J. Ocul. Pharmacol., 1985, 1 (2), 161-168.

To prepare suitable formulations, the pharmaceutical compositions can be mixed with a vehicle suitable for topical ophthalmic administration. As pharmaceutical vehicles acceptable in this case, mention may be made of water, a mixture of water and water-miscible solvents such as lower alkanols, vegetable oils, mineral oils and comprising from 0.5 to 5
X cn weight of hydroxyethylcellulose, trethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone and other water-soluble polymers, non-toxic and compatible with ophthalmic use, for example cellulose derivatives such as methylcellulose, derived from an alkali metal of carboxymethylcelluose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, acrylates such as polyacrylic acid salts, ethylerylates, polyacrylamides, natural products such as gelatin, alginates, pectins, tragacanth, karaya, xanthan, carrageenan, agar, acacia, starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well as others synthetic derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutral carbopol or mixtures of these polymers. maceutical may also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, texturing agents and others such as, for example, polyethylene glycols 200, 300, 400, 600, carbowax 1000, 1500, 4000, 6000, 10000, antibacterial products like quaternary ammonium, phenylmercuric salts known to have cold sterilizing properties, without being aggressive, timerosal, propyIparaben, benzyl alcohol, phenyl ethanol, isotonic agents like chloride of alkali metal, borate, acetate or gluconate buffers, antioxidants such as sodium metabisulfite, butylated hydroxyanisol, butylated hydroxytoluene or similar agents and other agents conventionally used such as sorbitan monolaurate, triethanolamine oleate, polyethylene sorbitan monopalmitate, an alkali metal salt of dioctyl sulfosuccinate, monothioglyceroi, acid et tetracetic hylenediamine or other.

 In addition, acceptable ophthalmic excipients can be used such as phosphate buffer, isotonic boric acid. an isotonic alkali chloride, or tris for example.

 The pharmaceutical preparation can also be a suspension in which the particles are polymers soluble in water or insoluble in water. Such a suspension can contain microforms such as microparticles or nanoparticles.

 The compositions according to the invention may contain additional therapeutic agents in addition to the potassium agonist. Thus antibiotics, anesthetics or other agents that lower the intraocular pressure may be present.

 The following examples illustrate the invention without, however, limiting it. These examples cite the compound A which is cyamo-6 (1,2-dihydro-1,2-oxo-pyridyl-1) -4 dimethyl-2,2 chroment.

XEHPLE 1
Topical solution
Compound A: 1 mg
P04 H2 Na: 10.4 mg
P04 H Na2: 2.4 mg
chlorobutanol: 5.0 mg
hydroxypropyl methylcellulose: 5.0 mg
distilled qs: 1 ml
NaOH 1 N qs: pH = 7.4
The constituents of the solution are mixed under the usual conditions to obtain an ophthalmic solution.

EXAMPLE 2
Topical solution
Compound A: 1 mg
timolol maleate: 5.0 mg
F04 Na H2: 10.4 mg
F04 Na H: 2.4 mg
chlorobutanol: 5.0 mg
hydroxypropyl methylcellulose: 5.0 mg
distilled water qs: 1 ml
Na OH, 1 N qs: pH = 7.4
The constituents of the solution are mixed under the usual conditions to obtain an ophthalmic solution.

EXAMPLE 3
Topical solution
Compound A: 1 mg
dexametasone disodium phosphate: 1 mg
P04 H2 Na: 10.4 mg
PO4 H Na2: 2.4 mg
chlorobutanol: 5.0 mg
hydroxypropyl methylcel lulose: 5.0 mg
distilled water qs: 1 ml
Na OH 1 N qs: pH = 7.4
The constituents of the solution are mixed under the usual conditions to obtain an ophthalmic solution.

Claims (14)

CLAIMS 1. Use of a potassium agonist for the preparation of a medicament intended to reduce and / or control the abnormally high intraocular pressure. 2. Use of a potassium agonist according to claim t,  characterized in that the potassium agonist is acceptable under  a topical ophthalmic form. 3. Use of a potassium agonist according to one of the claims  I or 2, characterized in that the potassium agonist is  used in combination with ophthalmic excipients  acceptable for topical use. 4. Use of a potassium agonist according to any one of  claims 1 to 3 in combination with a beta-blocking agent  adrenergic. 5. Use according to claim 4, of a potassium agonist  characterized in that the adrenergic beta-blocker is the  timolol maleate. 6. Use of a potassium agonist according to any one of  Claims I to 3 in combination with a steroidal anti-inflammatory. 7. Use according to any one of claims I to 6 of a  derived from chroman, quinoline or pyranopyridine. 8. Use according to any one of claims i to?  of a compound of formula: in which

 - R1 is A - R2 is H or A - or R1 and R2 together form an alkylene group of 3 to 6 atoms  of carbon R3 is OH or OAc - R4 is H - or R3 and R4 together form a double bond - R5 is 1H-pyridone-2 yl-1, 1H-pyridazinone-6 yl-1, 1H  pyrimidinone-2 yl-1, 1H-pyrazinone-2 yl-l. 1H-thiopyridone-2  these heterocycles can be partially hydrogenated and  can be unsubstituted or substituted I or 2 times by A, F,  Cl, Br, I, OH, OA, OAc, N02, NH2, NHAc, COOH or COOA; - R6 and R7 each represent H, A, HO, AO, CHO, ACO, ACS, COOH,  COOA, CSOA, ACOO, ACSO, 1-6 C hydroxyalkyl or mercaptoalkyle,  NO2, NH2, NHA, NA2, CN, F, Cl, Br, I, CF3, ASO, ASO2, AOSO,  AOSO2, AcNH, AO-CO-NH, NH2SO, HNA-SO, A2, NSO, NH2, SO2,  HNASO2, A2NSO2, NH2CO, HNACO, A2NCO, NH2CS, HNA-CS, A2  NCS, ASONH, AS02NH, ACO-alk, nitro-alk, cyano-alk, A-C = NOH or  A-C (= NNH2) - A is an alkyl group of 1 to 6 carbon atoms; alk is a  alkylene group of 1 to 6 carbon atoms; Ac is a  alkanoyl of I to 8 carbon atoms or an aroyl of 7 to 11  carbon atoms; or a pharmaceutically acceptable salt thereof. 9. Use according to any one of claims I to 7, of a compound of formula: in which

 - D represents, between N and CO, the group - C = CH - E = GH - or the group

   - Z represents a halogen or a cyano, acetyl, trifluoro-group  acetyl, nitro, alkylthio, carboxy, phosphono, dialcoxyphospho  ryle, alkoxycarbonyl, alkylthio and alkoxy groups containing  from I to 3 carbon atoms - E represents a nitrogen atom or a group C (Q) ;; - G represents hydrogen, a methyl group or a group  hydroxyl, L and M each independently represent hydrogen  or a methyl group, only one of the substituents G, L, M possibly  be ethyl - Q represents a hydrogen atom, a halogen atom, a methyl group  or a hydroxyl group; or a pharmaceutically acceptable salt from the phosphono or carboxy group. 10. Use of a potassium agonist, according to any one  of claims I to 7 or 9, characterized in that this  potassium agonist is cyano-6 (1,2-dihydro-2-oxo-pyridyl-1)  -4 divechyl-2,2 chromene.  II. A trosse comprising, in separate parts, on the one hand  a potassium agonist in a topical ophthalmic form,  on the other hand, a steroid in a pharmaceutically form  acceptable. 12. A kit according to claim II, characterized in that  the steroid is in a topical ophthalmic form. 13. A pharmaceutical composition useful for the treatment of  the increase in the incraocular pressure including a  agonis te potassium in combination with a beta-blocking compound  adrenergic. 14. A pharmaceutical composition useful for the treatment of  increased intraocular pressure associated with  the use of a steroidal anti-inflammatory including a  potassium agonist and a pharmaceutically acceptable excipient  corn. 15. A pharmaceutical composition according to one of claims  13 or 14, in which the potassium agonist is cyano-6  (1,2-dihydro-2-oxo-pyridyl-1) -4 dinethyl-2,2 chromene. 16. A pharmaceutical composition according to one of claims  13 or 15, in which the beta-adrenergic compound  is timolol maleate.