DE2634908A1 - Bis carboxy-chromonyl-oxy alkane compsn. - Google Patents

Abstract

The compsn. comprises a chroman deriv. of formula (I) or its acceptable salt, ester or amide, plus a diluent suitable for topical application. - In (I), R1-6 are H, halo, lower alkyl or alkoxy (both opt. substd.), OH, lower alkenyl, benzyloxy, or NO2; X is opt. unsatd. opt. substd. linear or branched polymethylene chain which can be interrupted by >=1 of carbocycles, O-contg. heterocycles, O or CO. - (I) are already used for treating allergies, esp. asthma by inhalation. They are now used to treat conditions such as psoriasis, skin ulcers, and esp. atopic eczema, in humans and animals. A typical compsn. contains 4 w/w % di Na salt of 1,3-bix(2-carboxychromane-5-yl oxy)propan-2-ol in a paraffin base.

Description

_i Eye diseases

(Addition to P 25 48 367.4)

The present invention relates to preparations bzuj. links used to treat skin conditions and certain eye conditions.

Compounds of the general formula:

O-X-0

and their therapeutically acceptable salts, esters and amides, in

12 3 4 5 6

u / elchen R, R, R, R, R and R, which are the same or different each for H or halogen, lower alkyl, hydroxy, lower alkoxy, lower alkenyl, benzyloxy, nitro, substituted lower alkyl or substituted lower alkoxy and X

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^ - he -

for a saturated or unsaturated, substituted or unsubstituted, straight or branched polyniethylene chain, the by one or more carbocyclic rings or oxygen-containing heterocyclic rings, oxygen atoms or carbonyl groups can be interrupted are for the treatment of allergic diseases, especially allergic asthma, by administration suggested u / orden by inhalation of a powder formulation or a misty aqueous formulation.

Surprisingly, it has now been found that the compounds of Formula I show pharmacological activity when administered externally to the skin of a mammal and so for treatment chronic skin diseases in humans and animals (e.g. cats and dogs) are indicated. Next u / were found that the connections of formula I when administered locally for the treatment of eye diseases administered u / earth in which allergic Conditions or immune responses play a role.

The present invention therefore provides a method of treatment chronic skin diseases or eye diseases in which allergic or immune reactions play a role, the characterized in that an effective amount of a compound of general formula I or a pharmaceutically acceptable one Salt, ester or amide thereof on the skin or the eyes of the patient locally applied.

Preference is given to compounds of the formula I in which R to R, which can be the same or different, each for H or a halogen atom (such as chlorine, bromine, 3od or fluorine), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or tert-butyl),

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Hydroxy, lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy) or a substituted lower one
Alkyl or lower alkoxy group (iuie hydroxy-lower alkoxy,
lower-alkoxy-lower-alkoxy, carboxy-lower-alkoxy, hydroxy-lower-alkyl or halo-lower-alkyl, e.g. chlorine, bromine,
Iodine or fluoro-lower alkyl), a lower alkenyl group (like allyl or methylallyl), benzyl or nitro and X is a saturated or unsaturated, substituted or unsubstituted,
denotes straight or branched polymethylene chain which can be interrupted by one or more carbocyclic rings or oxygen-containing heterocyclic rings (such as benzene, dioxane, tetrahydrofuran or dihydropyran rings), oxygen atoms or carbonyl groups.

Usually no more than one of the substituents R through R has
and no more than one of the substituents R to R has a meaning other than hydrogen and is hydrogen or halogen

or an alkyl, hydroxy, alkoxy or substituted alkoxy (mie defined above)

group / and X has the above meaning.

In the particularly preferred compounds of the formula I, all substituents R to R are hydrogen. _?

X can stand for many different groups. For example, it can be a straight or branched, saturated or unsaturated carbon / water chain are sou / ie such a chain, which by one or more oxygen atoms, carbony! group or carbocyclic or heterocyclic Rings is interrupted and by one or more halogen atoms (such as chlorine, bromine, 3od or fluorine) or hydroxy or

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lower alkyl groups (like methoxy, ethoxy, propoxy, isopropoxy, Butoxy, tert-butoxy usui.) Be substituted. Special examples for X are groups of the formulas:

-CH ₂ -CH = CH-CH ₂ - -CH ₂ CH ₂ CH-CCH ₃ ) -CH ₂ CH ₂

-CH ₂ COCH ₂ -

CH ₂ CH ₂ -CH ₂ -CH (OC ₂ H ₅ ) -CH ₂ -

CH ₂ OH

-CH ₂ -C-CH ₂ -CH ₂ Cl

-CH ₂ CHOHCH ₂ - -CH ₂ CHOHCH ₂ OCH ₂ CHDHCh ₂ -

The group X is preferably a straight or branched hydrocarbon chain that can be interrupted by one or more oxygen atoms and contains 3-7 carbon atoms. Is expedient

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such a chain a by one or more hydroxyl groups, substituted polymethylene uiobei a particularly preferred chain containing 2-hydroxy-trimethylene chain _{(-CH2 CHOHCH2} -) is.

The chain -0-X-O- can have different or corresponding positions connect on the chromone molecules.

Thus, the compounds of the formula preferred according to the invention are I those of the general formula II:

OCH ₀ CHOHCH ₉ O

Suitable pharmaceutically acceptable salts include, for example, ammonium salts, Alkali metal salts (such as sodium, potassium and lithium), alkaline earth metal salts (such as magnesium and calcium) and salts with organic Amines, (e.g. mono-, di- or trialkyl-C -amines, piperi-

I - o

din and trialkanol-C .., .- amine salts). Notable esters include

(low)
simple / alkyl esters (such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl esters). As amides, simple amides (e.g. amides with ammonia and lower alkylamines, ethylamine, etc.) and more complex amides with amino acids (such as glyine) can be admonished.

According to the invention particularly preferred compounds of the formula I and Derivatives of the same are, for example:

Dinatrium salt of 1,3-bis (2-carbaxychromon-5-yloxy) propane 1,3-bis (2-carboxychromon-5-yloxy) 2-hydroxypropane disodium salt

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1,3-bis (2-carboxychromon-5-yloxy) -2-hydroxypropane 'calcium salt of 1,3-bis _(2-C arboxychromon-5-yloxy) -2-hydroxypropane magnesium salt of 1,3-bis ( 2-carboxychromon-5. _y loxy) 2-hydroxy _P ropan Dipiperidinsalz v / on 1,3-bis (2-carboxychromon-5-yloxy) 2-hydroxypropane

1,12-bis ^ -carboxydiromon-S-yloxy) -2, ll-dihydroxy-4,9- -dxoxadodecane

1,4-bis (2-carboxychromon-5-yloxy) butane 1,5-bis (2-carboxycliroinon-5-yloxy) pentane 1,6 -bis (2-carboxychromon-5-yloxy) hexail

1,10-bis (2-CaTbOXyChTOmOn-S ^ lOXy) decane. · '

JL _t 7-bis oxäheptan ydroxy-4 (2-carboxychxonK) n-5-yloxy) -2,6-di ⁿ

1, 5-bis (2-CaTbOXyChTOmOn-S ^ loxy) -3-oxapentane. 1,4-bis (2-carboxychromon-S-yloxy) -2, 3-dihydroxybutane '1, 4-bis (2-caTboxychromon-5-yloxy) -2-hydiOxybutan 1, 5-bis (2-carboxychromon-7 -yloxy) pentane 1 _t 10-bis (2-carboxychronK) n-5-yloxy) -3,8-dioxa-4,7-

1, S-bis (2-carboxy-8-clilorochroinon-5-yloxy) pentane 1- ^ -carboxychroinon-S-yloxy) -3- ^ -carboxychromone ^ -yloxy) · hydrpxypropane

l ^ -Carboxychromon-S-yloxy) -5- (2-carboxychromon-7-yloxy) -

1,3-bis (2-carboxy-7-metii> ^ hTonion-5-yloxy) -2-hydroxy- propane

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1,3-bis ^ -carboxy-S-ethylchromon-S-yloxy) -2-hydroxy-
- ' propane

1- (2-Carboxychromon-5-ylox> 0 -3- ^ -carboxy-S-etiiyl-chromon-S-.yloxy) -2-hydroxypropane

1,5-bis (2-carboxycliromon-8-yloxy) pentane

1,5-bis (2-carboxy-8-methylc] iromon-7-yloxy) pentane

1,3-bis (2-carboxy-8-methylchronx3n-7-yloxy) -2-hydroxypropane

1,5-bis (2-carboxyro] non-5-yloxy) -3-methylpentane

1,3-bis ^ -carboxy-ö-cMorodiromon ^ -yloxy) -2-hydroxypropaiir
dinatriura salt j

1- (2-carboxychromon-5-yloxy) -3- (2-carboxy-6-chlorochronK) n- 1

-7-yioxy) -2-h: ydrji} cypropane disodium salt j

1,5-bis (2-carboxychromon-6-yloxy) pentane 1

1,3-bis (2-carboxychrornone-7-yloxy) -2-hydroxypropane · i

1,2-bis (2-carboxychromon-5-yloxymethyl) benzeno 1 \

1,3-bis (2-carboxychromon-6 -yloxy) -2-hydroxypropane {

Disodium salt of 1- (2-carboxychromon-5-yloxy) -3- (2-carboxy-

chromon-6-yloxy) -2-hydroxypropane

Disodium salt of 1- (2-carboxychromon-5-yloxy) -3- (2-carboxy-

chromon-8-yloxy) -2-hydroxypropane

1,8-bis (2-carboxyehromon-5-yloxy) octane

1,9-bis- (2-cSEboxychromon-5-yloxy) -nonane

1,2-bis (2-carboxychromon-5-yloxy) ethane

1, 3-bis (2-carboxychromon-5-yloxy) -2-hydroxy-chlormsthy1-2

methylpropane dipotassium salt trahydrate

Disodium salt of 1,3-bis- (2-carboxychromon-5-yloxy) -2-ethoxy-

propane

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Diisodium salt of 1,3-bis- (2-carboxychromon-5-yloxy) -2-oxypropane Diethyl ester of 2,5-bis (2-carboxychromon-5-yloxy-methyl) -dioxane 1,3-6is- (2-carboxy-7-raethoxychromon-5-yloxy) propan-2-ol 1,5-bis (2-carboxy-7-raethoxychrotnon-5-yloxy) pentane 1,3-bis- (2-carboxy-5- (2-hydroxypropoxy) -chromon-7-yloxy) -pro | »an-2-al

1,3-bis- (2-carboxy-7- (2-hydroxypropoxy) -cromon-5-yloxy) -propan-2-ol

1,5-bis (2-carboxy-5-raethoxychromon-7-yloxy) pentane 4-, 5-bis (2-carboxy-7- (2-hydroxypropoxy) -chromon-6-yloxy) - -pentane

1,3-bis- (5-benzyloxy-2-carboxychromon-7-yloxy) -propan-2-ol 1,3-bis- (2-carboxy-5-methoxychromon-7-yloxy) -propan-2- ol 1,3-bis- (2-carboxy-5-hydroxychromon-7-yloxy) -propan-2-ol 1,3-bis- (8-allyl-2-carboxychroraon-5-yloxy) -propane-2- ol 1 _f 3-Bis- (8-allyl-2-carboxychromon-7-yIoxy) -propan-2-ol 1- (8-allyl-2-carboxychromon-7-yloxy) -3- (2-carboxychromon-7 -yloxy) -propan-2-ol
1,3-bis (2-carboxy-8-methaliylchromon-7-yloxy) propan-2-ol

1- (8-Allyl-2-carboxychromon-7-yloxy) -3- (2-carboxychromon-6-yloxy) -propan-2-ol

1,5-bis (8-allyl-2-carboxychromon-7-yloxy) pentane 1,3-bis (2-carboxy-8-nitrochromon-5-yloxy) propan-2-ol.

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The compound of formula I or a pharmaceutically acceptable one Salt, an ester or an amide thereof can be applied topically to the skin or Human or animal (e.g. cat or dog) eye tissue can be applied in any suitable formulation. The connection of the formula I is preferably formulated according to the invention as an ointment, in u / elcher the finely ground compound of formula I is dispersed in a wax, fat, protein or paraffin base, in particular a soft paraffin base. The salt base can include liquid paraffin, hard paraffin, and wool fat.

According to the invention, a preparation is preferably used which has a major proportion (for example 70-90 %. W / W) of a white or yellow soft paraffin and a smaller proportion of a liquid paraffin (5-15 % w / w) and a hard Paraffins (0-12 % vol / wt) included.

-The salts can also contain other liquid components, such as water or contain a polyethylene glycol to keep the consistency of the base to improve to provide a solvent for the active ingredient so that it can be sterilized by filtration and / or to change the rate of release of the active ingredient from the base.

The compound of formula I can also be used as a cream of the oil-in-water type or water-in-oil type. Suitable emulsifiers of the former type include sodium, potassium, ammonium and triethanolamine soaps, polysorbates and cationic, anionic and non-ionic emulsifying waxes. Suitable emulsifiers for the the latter type include calcium soaps, wool fat, wool alcohols, Beeswax and certain sorbitan esters.

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The ointment and cream preparations may optionally contain an effective proportion of a pharmaceutically acceptable preservative or sterilizing agent suitable for an ointment or cream; Preservatives are, for example: (i) chlorobutol (2,2,2-trichloro-1,1-dimethylethanol hemihydrate), which is contained in the preparation in et u / a 0.5 % Geui./Geui. can be present; (ii) Chlorocresol, which in the preparation contains about 0.05-0.2 % Geiu .- / Geui. can be present; and

(iii) methyl p-hydroxybenzoate, alone or in combination with propyl p-hydroxybenzoate. The total concentration of the hydroxybenzoate esters in the preparation can be between about 0.08-0.2 % w / w. lie.

Other suitable preservatives include thiomersal.

The compound of formula I can also be used as a lotion or liniment by dissolving the dispersion of the same in an aqueous or oily base. A suitable preservative can be used in the formulation - ethanol and / or glycerin can be used in the aqueous base

(Peanut oil) den. Suitable oil bases are arachis oil, castor oil and others Vegetable oils. Thickeners can be used where pastes or gels are desired be incorporated into an aqueous base. These ingredients can also be used as stabilizers for emulsions to serve. Suitable agents include "carbopol", bentonite, soluble Cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose), "Veegum" and polyvinyl alcohol.

If necessary, other components, such as humectants, Antioxidants, perfumes and pigments, present

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The compounds of the formula I can also be used as a dust formulation formulated ujerden (which, however, are not suitable for use in the eye is), in which two or more ingredients are intimately mixed in fine powder form. The connection of the Formula I as a solution or suspension in a liquid carrier applied to the "surface of a solid support and the coated Particles are dried. Solid carriers that are usually sterilized are talc, starch, lactose, zinc oxide, Light kaolin, and calcium carbonates

A particularly suitable semi-solid base is based on a fatty alcohol / glycol mixture. Suitable fatty alcohols include saturated ones Alkanals with 16-24 carbon atoms and suitable glycols include 1,2-propylene glycol, 1,3-propylene glycol, polyethylene glycols with molecular weights of 100-800 and dipropylene glycol. Fatty alcohol and glycol are present between 15-45: 45-85 parts by weight, preferably 20-35 / 55-80 parts. If necessary, a plasticizer, e.g. a polyethylene glycol with a molecular weight of 800-20,000 or 1,2,6-hexanetriol, and / or a means for better Penetration ("penetrant") are present.

The compound of formula I or its salt, ester or amide can be used in the present compositions in an amount of 0.5-20 wt -.% To be present.

Typical formulations of the compounds of Formula I for application on the skin are shown in the following examples:

70981 5/1026

example 1

.Ointment * C—

Compound of Formula I.

liquid paraffin BP 10

Wool fat BP-

white soft paraffin BP.

Example 2

ointment miscible with water

Compound of Formula I 10

Polyethylene glycol 400 40

Polyethylene glycol 4000 50

Example 3

watery cream

Compound of the formula I emulsifying ointment BP *

Chlorocresol 1

purified water

Example 4

oily cream

Compound of Formula I 10

Wool alcohols BP - 3

hard paraffin BP 12

white soft paraffin BP 10

liquid paraffin BP 30

purified water

Example 5

aqueous lotion

Compound of Formula I. 10

Glycerin "" 20

Alcohol (96 %) 20

Sodium carboxymethyl cellulose 1

purified water 49

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B 8 i game 6

Oliqe Lotion% gem./vol.

Compound of Formula I 15

Arachis Oil "'85

Example 7 Dust powder

Compound of Formula I 10

Zinc oxide "., 25

purified talc 10

sterilizable Corn starch 55

At game 1 8

Fatty alcohol / glycol base

Compound of Formula I 10

Stearyl alcohol 27

Propylene glycol 63

The compound of the formula I is usually present in the above formulations between 5-20 % by weight, in particular 10-15% by weight.

Typical formulations of the compounds of formula I for topical Application to the eye tissue are illustrated in the following examples:

Example 9

% By weight / gladly »

Disodium salt of 1 ^ -Bis - ^ - carbaxychromon-S-yloxyJ-propan ^ -ol . '4.0

white soft paraffin BP 81.0

liquid paraffin BP '10.0

hard paraffin PB 5.0 example 10

1,3-bis- (2-carboxychromon-5-yloxy) propan-2-ol disodium salt. 4 _f 0

purified water q.s.

Based on ing

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basis % Weight / weight

Polyethylene glycol 400 - » 4 ^ f% 5.0

'do it soft paraffin BP "80.0

liquid paraffin BP "10.0

hard paraffin BP - 5.0

The compound of formula I is in the formulations for topical use Use on the eye in an amount of 0.5-50 wt .- ^, preferably 2-6 wt .-? £, present

Where solid particles of the compound are present, e.g. in a suspension or dispersion or powder formulation, they have preferably an average particle size between 0.01-10 micrometers.

The preparations according to the invention can by any suitable method, e.g. by dry mixing of the solid constituents or grinding them together or by emulsifying an aqueous one Solution of the compound of formula I with an appropriate oil base, 'are prepared.

The compound of formula I or the derivative thereof is preferably simply rubbed into the skin of the patient Ointment, cream or paste applied over the affected skin area. The connection can also be impregnated in gauze or a gauze pad and these are applied to the infested surface; or a powder containing the active ingredient can be applied to the Dust the infested area. For local use on eye tissue ointments and creams are preferred.

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The amount of the compound of Formula I used will depend on the severity and surface area of the disease being treated The application can be repeated at intervals during the day, e.g. 1-6 times a day. For use in the eye has a dose of about 0.5-4.0 mg of active ingredient in the diseased eye 1 to 4 times, preferably twice, daily proved to be satisfactory. Of course one can more frequent dose can be used.

The compounds of formula I or their pharmaceutically acceptable ones Derivatives are used in the treatment of various diseases in humans and animals. The dermatoses to be treated include those of the skin mast cells and / or antibody / antigen reactions including eczema, drug furuncle, psoriasis, dermatitis herpetiformis, pemphigus, and chronic skin ulcers, especially those of humans in tropical climates. The compounds of formula I or their derivatives are special suitable in the treatment of atopic eczema in humans.

Diseases of the external eye in which the invention Procedure appropriate include vernal catarrh (vernal keratoconjunctivitis) and marginal corneal ulceration or infiltration. Other diseases to be treated according to the invention include the reddened "allergic" eyes in connection with hay fever. This refers to those occurring in spring and summer allergic diseases of the eyes in which an external allergen plays a role. Other eye diseases • are the "irritated eyes" or non-specific conjunctivitis, Herpes simplex keratitis and conjunctivitis, herpes zoster keratitis and conjunctivitis, adenovirus infections, fhlyctenular.

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-df *, s

conjunctivitis, withdrawal of self-implantation ("hanograft") of the cornea, trachoma, anterior uveitis and drug sensitivity.

Example 11.

By mixing the disodium salt of 1,3-bis- (2-carboxychromon-5-yloxy) -2-hydroxypropane Ointment formulations with 5 or 10% by weight of dinatrium salt were prepared with a Vaseline base. These ointments were used in case of eczema, especially atopic Eczema sufferers are used by smearing the ointments on the diseased skin areas 2-4 times a day.

In 16 treated patients there was an improvement after 7-10 days and during the 4-month test period with the ointment, the skin improved steadily. In in some cases the improvement was at least as good as it was to be expected from using a steroid ointment.

The present invention therefore also provides a preparation for topical application to human skin or eye tissue and animal, the one compound of the formula I or one pharmaceutical acceptable salt, ester or amide thereof, in particular a compound of the formula II or the disodium salt thereof in admixture with a diluent suitable for topical application to the skin.

The term used here "low in connection with the Values for R to R as well as with esters and amides refers to Groups with 1-6, preferably 1-4, carbon atoms.

Some of the compounds of the formula I and their preparation are described in GBPS 1,144,905.

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ORIGINAL INSPECTED

Claims (1)

Claims - agents for the treatment of chronic skin or eye diseases, in which allergic or immune reactions play a role, characterized in that it is a compound of the formula O-X-0 -C0 ₂ ^H or a pharmaceutically acceptable salt, ester or Amide of the same, in which R to R can be the same or different and each represents H or halogen, lower alkyl, hydroxy, lower alkoxy, lower alkenyl, benzyloxy, nitro, substituted lower alkyl or substituted lower alkoxy and X a saturated or unsaturated, substituted or unsubstituted, straight or branched polymethylene chain means which by one or more carbocyclic rings or oxygen-containing heterocyclic rings, oxygen atoms or carbonyl groups may be interrupted, mixed with a diluent suitable for topical application to skin or eye tissue includes. 2.- Means according to claim 1 in the form of an ointment or cream. 3. Agent according to claim 2 in the form of an ointment, characterized in that the diluent is a wax, fat, protein or paraffin base and the compound of formula I or its salt, ester or amide is dispersed therein. 709815/1026 4 x - gown according to claim 3, characterized in that the encryption> is diluent a soft paraffin base. 5.- Composition according to claim 4, characterized in that that diluent 70-90 geuj .- / £ of a u / white or yellow u / oak paraffin, 5-15 Geu /.-$ of a liquid paraffin and 0-12 Geu /.- j6 of one hard paraffin includes. 6. Agent according to claim 2 in the form of a cream, characterized in that the diluent is an oil-in-water emulsion. 7 · - Agent according to claim 6, characterized in that it is an emulsifier from the group of sodium, potassium, ammonium and tri -ethanolamine soaps, polysorbates and cationic, anionic and Contains directional emulsifying waxes. 8.- Means according to claim 2 in the form of a cream, characterized in that that the diluent is a water-in-Ql emulsion is. 9.- Means according to claim 8, characterized in that it is an emulsifier from the group of calcium soaps, wool fat, wool alcohols, Contains beeswax and sorbitan esters. 10.- Means according to claim 2 to 9, characterized in that there is one or more suitable preservatives or sterilizers includes. 11.- Composition according to claim 1 to 10, characterized in that the active ingredient is present in an amount of 0.5-20 Ge \ u .-% . '"' 709815/1026 12.- Means according to claim 11 for topical use on the skin, characterized in that it contains 5-20 Ge \ u .-% active ingredient. 13.- smock according to claim 12, characterized in that it Contains 10-15 Geuj .- $ active ingredient. 14.- Means according to claim 11, for local use on the Augengeuiebe, characterized in that it is 0.5-10 Geuj · - ^ active Contains component. 15.- Composition according to claim 14, characterized in that it contains 2-6 Gbuj.-jS active ingredient. 16 · - Means according to Claims 1 to 15, characterized in that the compound of formula I has the following formula II OCH ₂ CHOIOl ₂ O and in the form of the free acid, an alkali metal, alkaline earth metal, Ammonium or amine salt or in the form of an amide or alkyl ester is anu / esend. 17.- Means according to claim 16, characterized in that the active ingredient an alkali metal, alkaline earth metal, ammonium or amine salt of 1,3-bis- (2-carboxychromon-5-yloxy) -2-hydroxy- is propane. The patent attorney: 709815/1026