HU196770B - Process for production of tetrazol-5-carboxamid-derivatives and medical compounds containing this substance - Google Patents

Abstract

Process are claimed for the prodn. of new (but unclaimed 4-acyl-resorcinol ether derivs. of formula (I) and there salts. In (I), R1=lower alkyl; alk = hydroxyalkylene residue opt. interrupted by an O-atom; R2 = 5-tetrazolyl; Ring A is opt. additionally substd. by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and/or halogen. Ring B is opt. additionally substd. by lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, COOH, CN, carbamoyl, halogen-and/or CF3. - The prodn. of 6 specific cpds. (I) is specifically claimed, including N-(3-(3-(4-acetyl-3-hydroxy -2-propyl-phenoxy)-2-hydroxy propoxy)-4- bromo-6-6-methylphenyl)-1H-tetrazol -5-carboxamide and N-(3-(3-(4-acetyl-3-hydroxy -2-propyl-phenoxy)-2hydroxypropoxy)-4 cyano-6-methylphenyl) tetrazole -5-carboxamide. - The cpds. have marked antiallergic activity derived from marked LTD4- and PAF antagonism. (First major country equivalent to PT--81374-A)

Description

The present invention relates to a process for the preparation of novel tetrazole-5-carboxanude derivatives of the general formula (I) and their salts, in particular their pharmaceutically acceptable salts.

R 1 is C 1 -C 4 alkyl, alk is C 3 -C 4 hydroxyalkylene, where the hydroxy group is further away from the α-position relative to the free valencies,

R ₂ is 5-tetrazolyl;

The ring is also substituted in the 2-position with a C 1-4 alkyl group and the

Ring B is further substituted at the 6-position with a C 1-4 alkyl group and optionally substituted at the 4-position with a halogen or cyano group or at the 2-position with a cyano group.

For example, hydroxyalkylene groups are preferably straight chain. Such a group is in particular the following formula.

-CH ₂ -CH (OH> CH ₂₎ In the following, the term "lower" organic compounds and groups derived therefrom are understood to mean, for example, those containing up to 7, in particular up to 4, carbon atoms.

C 1-4 alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl, and also secondary or terrier butyl. In particular, R 1 represents a methyl group and, in the case of an alkyl substituent on ring A, in particular a propyl group.

For example, halogen means up to 53, especially 17 and up to 53, for example fluorine, chlorine, bromine or iodine.

A hydroxyalkylene group in which the hydroxy group is attached farther than the α-position, e.g. the 2-hydroxy-1,3-propylene group or the 2-hydroxy-1,4-butylene group.

Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts such as metal salts, ammonium salts or salts with organic bases. Examples of metal salts are the corresponding alkali metal, alkaline earth metal salts such as lithium, sodium, potassium, magnesium or calcium, as well as pharmaceutically acceptable salts of transition metals (e.g., zinc or copper). for example, organic bases such as mono-, di- or tri-substituted organic amines such as the corresponding alkylamines, hydroxyalkylamines, heterocyclic compounds containing at least one nitrogen atom, such as morpholine, thiomorpholine, are suitable. , piperidine or pyrrolidine, optionally N-substituted amino saccharides, such as N-methyl-D-glucamine, or basic amino acids such as lysine, arginine, histidine or omitin, each of which has L-conjugation. alkylamines, such as mono-, di-, or tri-lower alkylamines such as ethyl, tert-butyl, diethyl, diisopropyl, trimethyl or triethyl, are contemplated. Examples of hydroxyalkylamines are mono-, di- or trihydroxyalkylamines, such as mono-, di-, triethanolamine or diisopropanolamine, or hydroxy (lower alkyl) lower alkyl amines, like that

Ν, Ν-Dimethyl, Ν, Ν-diethylaminoethanol or tri (hydroxymethyl) methylamine are included.

Further salts include pharmaceutically acceptable acid addition salts of compounds of formula (I), such as hydrogen halides, methanesulfonates, N-cyclohexyl sulfaminates, maleinates or maleate.

Depending on the number of these carbon atoms, the compounds of formula (I) having a chiral carbon atom are enantiomeric or non-enantiomeric, respectively, relative to each other. diastereomeric forms or mixtures of these forms, such as diastereomeric mixtures, racemates or racemate mixtures.

The compounds of the invention are valuable pharmacologically. properties. Particularly advantageous are their anti-allergic activity, which can be demonstrated by their significant LTD ₄ antagonism as well as their PAF antagonism (PAF aceter antagonism, in vitro), since the compounds of the present invention exhibit approximately in vitro activity. In the range of 0.0005-0.05 pmol / l, LTD ₄ induced contractions are inhibited. The LTD ₄ antagonist is e.g. can be detected in isolated guinea pig ileum. To do this, the ileum segments taken from guinea-pigs weighing 300-400 g were fixed in a Tyrode's solution in an organ bath (38 'C, 95% Oj and 5% CO ₂ ) and loaded with 1 p of synthetic LTD ₄ (Leukotriene). D ₄ , potassium salt), which is recorded. The extent of the LTD ₄ antagonist activity of the test substance, which is due to the inhibition of these contractions, is measured. These are evaluated as the concentration of the test substance as 1C _SO , which reduces the contraction induced by LTD ₄ by 50% of the starting value. In these experiments, e.g. N- {3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -2-ryanophenyl -1H-tetrazole-5-carboxamide-trixanol an ammonium salt of 0.0054 pmol / 1 lC o _S-value is obtained, the Ni 3- [oxy-2-hydroxypropyl-3- (4-acetyl-3-hydroxy-2-propylphenoxy)] -2-cyano of triethanolammonium phenyl-1H-tetrazole-5-carboxamide, 0.03 gmol / l10C _SO , N- [3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] phenyl} oxamic acid · ethyl ester and N 3 - [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyl] oxy] -2-cyanophenyl] -oxamic acid, both of which are disclosed in U.S. Patent 4,448,729. Compound of United States Patent No. 6,107, 0.087 gmol / l 1 C _SO . N- {4- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyloxy] phenyl} found 0,054 -l 'gmol / l IC5 ₀ value when examining H-tetrazol-5-carboxamide (Compound No. 147973. European patent document).

The ETB ₄ antagonist activity of the new compounds can also be demonstrated in vivo by inhibiting experimental bronchospasm (bronchospasm) induced by LTD ₄ in guinea pigs.

The present invention relates in particular to the preparation of compounds of formula Ia wherein R 1 is lower alkyl up to 4 carbon atoms such as methyl, R ₂ is 5-tetrazolyl, R ₃ is lower alkyl up to 4 carbon atoms such as propyl, R 4 is hydrogen, and R and R ₇ = H, and R does mot «cyano, or R _s rövidszénláncúl up to 4 carbon atoms, eg. methyl, R ₇ is hydrogen, and R ₇ is a halogen atom of up to 53, such as chloro, bromo, or mono, and alk is a particularly straight-chained terminal C 3 or C 4 hydroxy (lower alkyl) group wherein the free valencies with respect to the hydroxyl group (at the 3-position carbon atoms, such as the 2-hydroxy-1,3-propylene group) and their salts, in particular their pharmaceutically acceptable salts.

In particular, the present invention relates to the preparation of compounds of formula Ia and salts thereof, in particular pharmaceutically acceptable base salts thereof, wherein R 1 is lower alkyl of up to 4 carbon atoms, such as methyl, R ₃ is linear alkyl of up to 4 carbon atoms, such as. propyl, R ₂ is 5-tetrazolyl, R, is hydrogen, R _s is a lower alkyl having up to 4 carbon atoms such as a methyl group, R _e is hydrogen, R ₇ is not more than 53 atomic number halogen atom such as chlorine or bromine , or cyano, and alk. is a straight-chain, terminally bonded C 3 -C 4 -hydroxy (lower alkylene) group wherein the free valencies are on the -O-carbon atom of the hydroxyl group, e.g., 2-hydroxy-1,3-propylene; group.

The present invention relates in particular to the preparation of the compounds of formula (I) and their salts as exemplified herein, in particular to their pharmaceutically acceptable base salts.

The compounds of formula (I) and their salts may be prepared by methods known per se, as follows:

a) a (VI) wherein X ₄ represents an esterified or etherified hydroxyl group, the X 4 moiety converted to hydroxy by treatment with a complex metal mesh · geniddel or

b) reacting a compound of Formula VII with a compound of Formula VIII in the presence of a basic condensing agent, wherein one of X 1 and X 1 is a hydroxy group optionally in the form of a metal salt and the other is substituted with a hydroxy group reactively esterified in an ω position; A C 4 -alkoxy group in which the free hydroxyl group is farther from the α-position and closer to the ω-position than the alkoxy oxygen, or

c) a compound of formula IX wherein alk 'is an etherified or esterified hydroxy (C 3 -C 4) alkylene group in which the etherified or esterified hydroxyl group is farther away from the free valence by basic or acidic hydrolysis; or

d) reacting a compound of formula X or a salt thereof with a compound of formula XI in the presence of a basic condensing agent, wherein R _{2 is} as defined above or a group R _{a is} protected in the 1-position, X ₇ is in the case of a carboxyl group which is esterified, amidated, anhydrated or in the form of a metal salt, in the case of a protected R ₂ group it is subsequently deprotected, or

e) a compound of Formula XII wherein X _{e is} -NH-C (= OVR ' ₂ ) wherein R ₂ is 5-tetrazolyl protected at the 1-position by a 4-methoxybenzyl group - acidic; hydrolysis and, if desired, converting the free compound of formula (1) obtained by one of the above processes into a salt.

X ₄ is an etherified hydroxy group, e.g. aliphatically etherified hydroxyl groups, e.g. lower alkoxy groups such as methoxy or lower alkenyloxy groups, especially lower alk-2-enyloxy groups, e.g. allyloxy, phenyl (lower alkoxy) groups, especially optionally substituted phenyl (lower alkoxy) groups such as benzyloxy, and tetrahydropyran-2-yloxy, or the silyloxy tube powder, especially tri (lower alkyl) silyloxy groups such as trimethylsilyloxy group X ₄ as an esterified hydroxy group eg with a carboxylic acid such as an aliphatic or aromatic semester esterified hydroxy groups such as lower alkanoyloxy groups such as acetoxy, optionally substituted benzoyloxy groups, optionally halogenated lower alkoxycarbonyloxy groups such as methoxyethoxy, or tert-butyloxycarbonyloxy, 2,2,2-triiodoethoxy, or 2,2,2-trichloroethoxycarbonyloxy, optionally substituted phenyl (lower) ) alkoxycarbonyloxy groups such as benzyloxycarbonyloxy or optionally substituted phenoxycarbonyloxy.

In the form of the metal salt, Xs _and Xs, respectively. X 'is a hydroxyl group in the compounds of formula (VII), 111 (VIII) or (II). X _{7 is a} carboxyl group in compounds of formula XI, particularly in the form of its alkali metal salt, e.g. as a sodium or potassium salt.

C3-C4-hydroxyalkoxy substituted with esterified hydroxy groups reactive at the ω-position / Xj in the compounds of formula VII; X _{6 in} the compounds of formula (VIII) /, for example, reactive monoesterified dihydroxy (lower alkoxy) groups in which the free hydroxyl group is further away from the α-position than the alkoxy oxygen group and especially the (esterified hydroxy group) ) and (e), wherein X is always a reactive esterified hydroxyl group. Reactive esterified hydroxyl group e.g. a halogen atom such as chlorine, bromine or iodine or an organic sulfonyloxy group such as a (lower alkane) sulfonyloxy group, e.g. methanesulfonyloxy, or optionally substituted benzenesulfonyloxy, e.g. benzene, p-bromobenzene or p-toluenesulfonyloxy.

For example, in the compounds of formula (IX), the -alk 'groups are suitably etherified and / or alkylated. esterified hydroxy (lower alkylene) groups, in particular those of formula (g) wherein X 'represents an etherified or esterified hydroxy group.

X 'etherified hydroxyl group e.g. an hydroxy group etherified with α-aralkanol or silanol, such as an optionally substituted benzyloxy group, or a tri (lower alkyl) silyloxy group, e.g. trimethyl Salil alkyloxy.

An esterated hydroxy group such as a carboxylic acid such as a lower alkanoic acid or a half ester of a carbonic acid such as a lower alkanoyloxy group such as acetoxy or pivaloyloxy, lower alkoxycarbonyloxy group, e.g. tert-butoxycarbonyloxy or optionally substituted benzyloxycarbonyloxy, e.g. benzyloxycarbonyloxy.

X ₇ as an optionally esterified, amide or anhydride carboxyl group in compounds of formula XI is, for example, a free carboxyl group, a lower alkoxycarbonyl group, or an optionally substituted phenol esterified carboxyl group such as phenoxy, 4-nitrophenoxy, or a 2,4-dinitrophenoxycarbonyl group, a carbamoyl group or an activated carbamoyl group such as 1-imidazolyl or a carbamoyl group. 1- (2,5-dimethylimidazolyl) carbonyl or a carboxyl group anhydrated with a hydrogen halide such as a halocarbonyl group, e.g. Hal-C (= O) wherein Hal is chlorine, bromine or iodine, in particular chlorine.

Particularly suitable starting materials of the formula (XI) are those in which the X ₇ carboxyl group is a metal salt, e.g. in the form of a potassium salt or a compound of the formula Xlb.

Examples of protected 5-tetrazolyl groups include, where appropriate, aryl-substituted 1- (α-aralkyl) tetrazolyl (5) groups such as 1-benzyltetrazolyl (5) or 1- (p) methoxy-phenyl) tetrazolyl (5) group.

X _s a group of compounds wherein jréldául -NH-C (= O) ^-R 2 group in which R represents a 1-position protected 5-tetrazolyl, 4-methoxybenzyl group. (XII)

The reactions of the present invention, as well as new starting materials and / or compounds. starting materials known in the art; in a manner analogous to the reaction and preparation of intermediates. In addition, unless specifically mentioned below, the usual excipients, such as catalysts, condensing agents, solvents and / or solvents and / or solvents, may be used. diluents and reaction conditions such as temperature and pressure conditions and, if appropriate, a shielding gas.

Conversion of X ₄ groups to hydroxy according to process a) is carried out in the usual manner, for example by treatment with a metal halide of a complex of formula XIX - wherein M represents an n-value 'coordinately unsaturated metal cation which is the 11a, 11b, Belongs to the group of Illa, 111b, VVb, Va or VIIIIb, e.g. magnesium, zinc ™ - Boron ¹¹¹ - ¹¹¹ aluminum - gallium ^»1 * -, tin ^1» - titanium ^{of 1} '-, antimonV, yggy Iron ¹¹ * -., respectively. iron represents ¹ ion and Y represents a halogen atom of up to 35, such as fluorine or chlorine, e.g. treatment with aluminum trichloride. Preferably, it is always a solvent or diluent or solvent. working in the presence of a solution mediator during cooling or heating, e.g. approx. 0-120 ° C and / or inert gas.

Thus etherified hydroxyl groups e.g. treatment with boron tribromide or aluminum chloride.

The starting materials of the formula (VI) are e.g. prepared by reacting compounds of formula (XV11I) and (VIII), wherein. One of _the substituents X 1 and X 1 is a hydroxyl group optionally in the form of a metal salt and the other is a hydroxyalkoxy group substituted by a hydroxyl group reactively esterified in a ω-position, e.g. a group of formula (I) wherein X is a reactively esterified hydroxyl group, e.g. or a suitable compound of formula (III) under mild reaction conditions, for example, to form a compound of formula (VI) wherein X _{4 is an} etherified hydroxy group. -10 to +10 ° C, or by using a mild Lewis reagent, e.g. dnk-chloride or gailium-chloride, a compound of formula IV [X ₂ = halocarbonyl or -OC (= O> R ₂ )].

(VII) and (VIII) a compound of formula b) reacting starting from starting materials according to process in conventional manner, where X _s, respectively. One of X _e is a hydroxyalkoxy substituted by a hydroxy group reactively esterified at the ω position; in the presence of a basic condensing agent such as an alkali metal or alkaline earth metal hydroxide, or a carbonate such as sodium or potassium hydroxide, potassium carbonate, or kaldum carbonate, preferably in a lower alkanol, e.g. methanol or amyl alcohol, di (lower alkyl ketone such as acetone or diethyl ketone) or N, N-di (lower alkyl) - (lower alkenoic acid amide) or N- (lower alkyl) - (lower alkanoic acid) lactam such as dimethylformamide or N-methylpyrrolidinone.

The starting materials of the formula (VII) are e.g. is prepared by reacting a compound of formula XIII - a Lewis acid, e.g. in the presence of aluminum chloride or dnk chloride, with a compound of formula IV wherein X ₂ is halocarbonyl or -OC (= O) -R 1, and optionally, In the compound of Formula VIII, where X5 is _a hydroxy group, the hydroxy group at the p-position of the R _t -C (= O) group is converted to a hydroxyalkoxy tube substituted with a dihaloalkanol, a halogen atom.

For example, compounds of formula (VIII) may be obtained by reducing the nitro group to an amino group in compound (XX), e.g. with hydrogen in the presence of Raney nickel and the compound of formula XXI with a base, e.g. triethylamine or pyridine, in the presence of a compound (XIb) - wherein Hal is a halogen atom - reagáltajuk, if desired, the obtained (VIII) .vegyületben formula I where X is ₆ hydroxyl groups, the hydroxyl group is reacted with a dihalo-alkanol and - a halogen is converted to a substituted hydroxyalkoxy group.

The Xj and. The conversion of the hydroxy groups Xe into a reactive esterified hydroxy substituted hydroxyalkoxy group can also be carried out stepwise. .

The hydrolysis of the alk group of a compound of formula IX according to process c) can be carried out in a conventional manner, starting from the compounds of formula IX wherein -alk 'represents an alk group substituted by the aforementioned etherified or esterified hydroxy group.

The solvolytic release of the hydroxy group from said etherified or esterified hydroxy groups, such as a silyloxy group,

196.770 alkanoyloxy groups or lower alkoxycarbonyloxy groups, e.g. hydrolysis (reaction with water), if necessary in the presence of an acidic or basic substance and / or heating, e.g. 20-100 ° C. Suitable acidic materials e.g. mineral acids such as hydrohalic acids, e.g. oxysates of hydrochloric acid or sulfur or phosphorus, e.g. sulfuric or phosphoric acid, or organic sulfonic or carboxylic acids, such as lower alkanesulfonic acids, or optionally substituted benzenesulfonic acids; lower alkanoic acids, e.g. toluene sulfonic acid or acetic acid. Basic hydrolyzing agents e.g. hydroxides or carbonates of alkali metals, e.g. potassium carbonate, sodium hydroxide or potassium hydroxide; and alcoholates such as alkali metal lower alkanolates, e.g. Sodium methoxide.

For example, the starting materials of formula (IX) are prepared by reacting compounds of formula (VII) and (VIII) wherein one of the substituents X ₅ and X _{6 is} optionally in the form of a metal salt and the other in a reactively esterified form. a -O-alk'-X group having a hydroxy group (X), that is to say ether reacting with a hydroxyl group reacting at the ω-position and additionally etherified at a different position. alkoxy substituted with an esterified hydroxy group. This is e.g. may be a group of formula (1).

The reaction of the corresponding compounds of formula (VII) and (VIII) and their preparation are carried out in a manner analogous to process (b).

The reaction of compounds of formula (X) and (XI) according to process (d) is carried out in a manner known per se, in particular in the literature for analogous reactions, optionally in the presence of a condensing agent, optionally in the 1-position protected 5- (halocarbonyl) ) with tetrazole, e.g. a basic condensing agent such as a tertiary organic nitrogen base e.g. in the presence of triethylamine or pyridine.

Preferably, the 1-protected 5- (halocarbonyl) tetrazoles are prepared in situ, e.g. 1-protected, e.g. an alkali metal salt of α-aralkalized 1H-tetrazole-5-carboxylic acid, e.g. by reacting its potassium salt with oxalyl chloride in the presence of pyridine. The 1-protecting group of the 5-tetrazolyl group (R 1) is finally, e.g. it can be cleaved by treatment with trifluoroacetic acid / anisole.

Starting materials of the formula (X) are e.g. It may be prepared by reaction of (VII) and (XX) is a compound of formula with one another, wherein X] and X ₆ substituents are hydroxyl group is optionally in metal salt form, to another one substituted reactive esterified hydroxy hydroxyalkoxy group or a an epoxyalkoxy group, e.g. a group of formula (h) or (i) wherein X is a reactively esterified hydroxyl group, e.g. and X 'is an epoxyethyl group, and in the resulting compound of formula XXVI, the nitro group is reduced to an amino group, e.g. hydrogen gas in the presence of a hydrogenation catalyst such as palladium on activated carbon or, in particular, Raney nickel, e.g. tetrahydrofuran. .

In the compound of formula XII, hydrolysis of the X _g group according to process e) is carried out e.g. trifluoroacetic acid / anisole.

The starting materials of formula (ΧΠ) can be prepared by reacting a compound of formula (X) or an acid addition salt thereof with a (ΧΓ) a compound of formula - COOH in which X ₇ is optionally esterified, amidated, anhydrized or salt form reacting in a manner analogous to that described for process d).

If necessary, we tend to work in tendon in a solvent at normal temperature or during cooling or heating; In a temperature range of 0 ° to 100 ° C, in a closed container and / or inert gas, e.g. nitrogen.

Depending on the choice of starting materials and working methods, the compounds of formula I in the form of one of the possible isomers,. ^va 8) 'as a mixture of these, e.g. depending on the number of asymmetric carbon atoms, such as pure optical isomers such as antipodes or mixtures of isomers such as racemates, diastereomeric mixtures or racemate mixtures may occur.

The resulting diastereomeric mixtures can be resolved into the pure isomers, diastereomers or racemates, e.g. by chromatography and / or fractional crystallization.

The resulting racemates can be separated into optical antipodes, e.g. by crystallization from an optically active solvent, microorganisms, or reaction of an acidic final product with an optically active base which forms a salt with a racemic acid, and separation of the salts thus obtained, e.g. on the basis of their different solubilities, the diastereomers from which the antipodes can be liberated by the use of a suitable reagent are separated, preferably the more effective of the two antipodes.

The resulting free compounds of formula (1) may be converted into salts, e.g. gg treated with a base or a suitable salt of a carboxylic acid in the presence of a solvent or diluent.

The compounds of formula (I), including their salts, may also be obtained in the form of their hydrates, or they may contain a solvent used for crystallization.

Due to the close association between the new free compounds of formula I and those in the form of salts, the compounds of formula I, as described above and below, are intended to be understood as meaning the free compounds of formula I or salts thereof. and the corresponding salts thereof. free compounds should be understood.

The invention also relates to an embodiment of the process according to the invention, wherein a salt and / or a racemate or a salt thereof is used. or in particular under reaction conditions.

Preferably, starting materials are used and the reaction conditions are selected to provide compounds of formula (I) as described above, which are particularly preferred.

The present invention also relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of the present invention are those for topical and topical administration, as well as for enteral administration, such as oral or rectal administration, and for administration by inhalation and inhalation of pa60.

-5196.770 in warm-blooded patients and comprising the pharmacologically active ingredient alone or in combination with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the type of warm-blooded animal, its age éni, individual condition and the mode of administration.

For example, the novel pharmaceutical compositions of the present invention contain, for example, ca. 10% to 95% +, preferably ca. 20% -90%. The pharmaceutical compositions of the present invention may be prepared in aerosol or spray form or in unit dosage form such as dragees, tablets, capsules or suppositories, and in ampoules.

The pharmaceutical compositions of the invention are known in the art, e.g. is prepared by conventional mixing, granulating, dragee-gelling, dissolving or lyophilizing processes. Thus, pharmaceutical compositions suitable for oral use can be obtained by combining the active ingredient with a solid carrier, optionally granulating the resulting mixture and mixing the active ingredient with the active ingredient. the granules are processed into tablets or dragee cores, if desired and necessary, after the addition of a suitable excipient.

Suitable carriers are in particular fillers such as sugar, e.g. lactose, sucrose, mannitol or Serbite, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; and binders such as. starch germ, e.g. corn starch, wheat, rice or potato starch, gelatin, tragagant, methylcellulose and / or polyvinylpyrrolidone and / or, if desired, disintegrants such as the aforementioned starches, and carboxymethyl starch, cross-linked polyvinylpyrrolidone , agar, alginic acid, or a salt thereof such as sodium alginate. Excipients are primarily flow control and lubricants, e.g. silica, talc, stearic acid or its salts such as magnesium or calcium stearate and / or polyethylene glycol. The dragee seeds may be coated with a suitable, optionally gastro-resistant coating comprising, inter alia, concentrated sugar solutions, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, suitable organic solvents, or mixed solvents. , or cellulose formulations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, suitable for use in coating herbicide resistant coatings. Dyes or pigments are added to the tablets or dragee coatings for identification or to indicate different doses of the active ingredient.

Other oral pharmaceutical compositions include hard gelatin capsules and soft, closed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Hard gelatine capsules may contain the active ingredient in the form of granules, e.g. excipients such as lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilizers may also be added.

As pharmaceutical compositions for rectal administration, e.g. suppositories which are a combination of the active ingredient and a suppository base are contemplated. Suitable suppository bases are e.g. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or long-chain alkanols. Gelatin rectal capsules containing a combination of the active ingredient with a base mass may also be used, such as base masses. liquid · triglycerides, polyethylene glycols or paraffinic hydrocarbons.

Aqueous solutions of a water-soluble active ingredient, e.g. a water-soluble salt; and suspensions of the active ingredient as suitable oily injection suspensions containing a suitable lipophilic solvent or vehicle such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions which increase the viscosity of the material, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran and optionally stabilizers.

Respiratory tract inhalation compositions which are administered by the nose or orally, e.g. aerosols or sprays which disperse the active ingredient in powder, solution or suspension droplets. In addition to the active ingredient, the powder-dispensing compositions conventionally contain a liquid propellant having a boiling point lower than room temperature and, optionally, carriers such as liquid or solid nonionic or anionic surfactants and / or solids. Formulations in which the active ingredient is in the form of a solution further comprise a suitable active ingredient and, if necessary, an additional solvent and / or stabilizer. Alternatively, compressed air may be used instead of propellant gas, which may be produced by a suitable sealing and switching device as required.

Pharmaceutical formulations for topical and topical application e.g. the following: skin care lotions and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion and ointments (preferably containing a preservative), eye drops containing the active ingredient in the form of an aqueous or oily solution and ointments preferably in sterile form for the treatment of powder, aerosols and sprays (similar to those described above for the treatment of respiratory tract) and coarse powders for rapid inhalation through the nostrils and nasal solutions containing the active ingredient in aqueous or oily solution and lozenges for topical treatment of the mouth, which generally contain the active ingredient in a sugar, gum arabic or tragagant mass, to which flavoring agents may be added, and lozenges which contain an active ingredient, e.g. Gelatin and glycerol or sugar & gum arabic.

The invention also relates to the use of the novel compounds of formula (I) and their salts as pharmaceutically active compounds, in particular as antiallergic agents, preferably in the form of pharmaceutical compositions. The daily dose, which is approx. Add 70 kg of warm blood to approx. 200 to approx. 1200 mg.

The following examples illustrate the invention described above, but are not intended to limit the scope of the invention in any way. Temperatures are given in degrees Celsius.

The compounds of formula (I) or the formula (I) thereof. the yields of these salts according to the process of the invention are generally in the range of about 20% to about 80% of the theoretical value, but it cannot be excluded that the yields may be improved by optimizing the process of the invention.

Example 1

12.8 g (19.1 mmol) of N-3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methyl- A solution of phenyl-1- (4-methoxybenzyl) -tetrazole-5-carboxamide in 250 ml of trifluoroacetic acid and 25 ml of anisole is refluxed for 30 minutes. The reaction mixture was concentrated under reduced pressure to a volume of ca. 300 ml of ether and 400 ml of petroleum ether are added and the crystals are filtered off. The resulting N- (3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl) -1H- tetrazole-5-carboxamide, m.p. 155-158 ° C, 1 H NMR (δ versus TMS, DMSO-d ₆ ): 0.85 (triplet, 3H), 1.45 ( multiplet, 2H), 2.25 (singlet, 3H), 4.0-4.7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.65 (doublet, 1H), 7.30 ( singlet, 1H), 7.55 (singlet, 1H), 7.85 (doublet, 1H), 10.75 (singlet, 1H), 12.80 (singlet, 1H)], dissolved in 100 mL of acetone and 10 mL of acetone dissolved in one equivalent of triethanolamine. After addition of ether, crystallization occurs.

Thus, N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H-tetrazole -5-carboxamide triethanolammonium salt as having a melting point of 76 ⁰ (dec).

Analogously, starting from N- {3- [3T4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] chloro-6-methylphenyl-1- (4-methoxy) of benzyl) tetrazole-5-carboxamide to N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-chloro-6-methyl j phenyl-1H-tetrazol-5-carboxamide, oil ΙΗ NMR (δ TMS contrast, _DMS0-d6): 0.85 (triplet, 3H), 1.45 (m, 2H) , 2.25 (singlet, 3H), 2.55 (multiplet, 2H), 2.60 (singlet, 3H), 4.0-4.7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.65 (doublet, 1H), 7.25 (singlet, 1H), 7.35 (singlet, 1H), 7.85 (doublet, 1H), 10.70 (singlet, 1H), 12.80 (singlet) (1H) and its triethanolammonium salt.

The starting material is e.g. prepared as follows;

A solution of 2-bromo-4-methyl-5-nitrophenol (16.2 g, 70 mmol) in ethanol (130 mL) was mixed with 0.32 g (7.4 mmol) of a 55% oily sodium hydride dispersion. A solution of 18.4 g (73.5 mmol) of 4- (2,3-epoxypropoxy) -2-hydroxy-3-propylacetophenone in 150 ml of ethanol is then added dropwise over two hours using a reflux condenser. It is then heated for 8 hours under reflux. The reaction product was cooled in vacuo to ca. Concentrate to 100 ml and pour over ice. The aqueous phase was acidified with dilute hydrochloric acid and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate and evaporated in vacuo. Recrystallization from ether gave 3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy) -4-bromo-6-methyl-nitrobenzene, m.p. and: 104-106 ° C.

Analogously, 3- [3- (3-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-chloro-6-nitro-benzene is obtained, m.p. 103-105 ° C (starting from 2-chloro-4-methyl-5-nitrophenol).

23.3 g (48.3 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-nitro- To a solution of benzene in 240 ml of tetrahydrofuran was added 2.0 g of Raney nickel and hydrogenated at room temperature. The catalyst was filtered off and washed with tetrahydrofuran. The combined filtrate was concentrated in vacuo, taken up in ether and the precipitated crystals were filtered off. 3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-aniline is obtained, m.p. 80 ° C,

It is obtained analogously starting from 3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-nitrobenzene. 3- (4-acetyl-3-hydroxy-2-propylphenoxy) - 2-oxy-hydroxypropyl] -4-chloro-6-methyl-aniline, which had a melting point of 94-95 C. ^b

Potassium [1- (4-methoxybenzyl-tetrazole) -5-carboxylate (10.6 g, 38.8 mmol) was suspended in benzene (170 mL) and pyridine (1.5 mL) and 3.38 mL (0-5 °) was added. Oxalyl chloride (38.8 mmol) and stirred at room temperature for 30 minutes, concentrated under reduced pressure, taken up in benzene and re-evaporated under reduced pressure, dissolved in dichloromethane (135 mL) and added dropwise at 0-5 ° for 10 min. 85 g (28.4 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -hydroxy-propyloxy] -4-bromo-6-methyl-aniline and 2.7 mL (33 mmol) of pyridine in 100 ml of dichloromethane was stirred at room temperature for 3 hours, diluted with dichloromethane and washed three times with water, the organic phase was dried over sodium sulfate and evaporated under reduced pressure. ethyl acetate (6: 1) was used to give 400 g of silica gel The lysate was evaporated and the residue crystallized from ethanol to give N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6- methylphenyl 1- (4-methoxybenzyl) tetrazole-5-carboxamide, m.p. 114-116.

In an analogous manner, starting from 3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methylaniline is obtained from N- [3 - [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -} - 4-chloro-6-methyl-phenyl-1- (4-methoxy-benzyl) - tetrazol-5-carboxamide.

Example 2

7.1 g (11.1 mmol) of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyanophenyl} -1 Dissolve (4-methoxybenzyl) tetrazole-5-carboxamide in 150 ml trifluoroacetic acid and 15 ml anisole and reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure to ca. 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The resulting N- {3- [3- (4-acetyl-3-hydroxy-1-propylphenoxy) -2-hydroxypropyloxy] -2-danophenyl] -1H-tetrazole-5-carboxamide was obtained. M.p .: 210-213 DEG-50 mL of acetone is heated and 1 equivalent of triethylamine in 20 mL of acetone is added. After the addition of ether, crystallization begins. Thus, N- [3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyano-71

196 770

triethanolammonium salt of -phenyl} -1H-tetrazole-5-carboxamide. M.p. 80-82 °. .

The starting material is obtained as follows:

of a solution of 2-hydroxy-6-nitrobenzonitrile (207 mmol) and 4 - ((2,3-epoxy) propyloxy] -2-hydroxy-3-propylacetophenone (60 g) in dimethylformamide (450 mL). Triton B was added dropwise and the solution was refluxed for 1.5 hours, the solvent was removed and the residue was taken up in 500 ml of ethyl acetate, washed with 500 ml of 0.5 N sodium hydroxide solution and 500 ml of water, then dried over magnesium sulfate. the solvent was evaporated and the residue was chromatographed on silica gel with methylene chloride / ethyl acetate (9S: 5) to give 2- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propoxy] - 6-nitrobenzonitrile was obtained, m.p. 117-119 °.

2- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propoxy] -6-nitrobenzonitrile (24.2 mmol) and cyclohexane (10 g) were dissolved in ethanol (500 mL).

2.5 g of 10% palladium on activated carbon was heated at reflux for 30 minutes. After cooling to room temperature, the mixture is filtered and the solvent is evaporated. Ether was added to the residue and the precipitated crystals were filtered off.

3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy-2-cyanoaniline is obtained, m.p. 123-125 ° C.

5.8 g (21.5 mmol) of potassium 1 - (4-methoxybenzyl) - suspension of tetrazole-5-carboxylate in 110 ml of benzene and 1 ml of pyridine was added 1.84 mL (21.5 0-5 ⁰ oxalyl chloride and stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was taken up in benzene and evaporated again under reduced pressure. Dissolve the residue in 80 ml of methylene chloride at 0-5 ° C for approx. A solution of 5.87 g (17.2 mmol) of 3- (3- (4-aoethyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy) -2-cyanoaniline in 10 min. The reaction mixture was added dropwise to 40 ml of methylene chloride solution containing 72 ml (21.5 mmol) of pyridine, stirred at room temperature for 3 hours, diluted with methylene chloride and washed three times with water. The organic phases were combined, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with methylene chloride / ethyl acetate (6: 1) to give N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy] -propoxy] -2-cyanophenyl] -1- (4-methoxybenzyl) tetrazole-5-carboxamide was obtained as a colorless oil.

Example 3

In an analogous manner to those of Figs. EXAMPLE 2 is obtained from 2-fluoro-4-methyl-5-nitrophenol, 4-methyl-5-nitrophenol and the like. Starting from 2-hydroxy-5-methyl-4-nitrobenzonitrile, the following compounds were obtained.

N- {3- (3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-fluoro-6-methyl-phenyl} -1H-tetrazole-5 carboxamide, 1 H NMR spectra (δ against TMS, _DMSO-d6): 0.85 (triplet, 3H), 1.45 (m, 2H), 2.25 (s, 3H), 2 , 55 (multiplet, 2H), 2.60 (singlet, 3H) 4.0 - 4.7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.65 (doublet, 1H), 7.25 (singlet, 1H), 7.65 (singlet, 1H), $ 7 (doublet, 1H), 10.70 (singlet, 1H), 12.80 (singlet, 1H) and triethanolammonium salt of N- (3- [3- (4-acetyl-3-hydroxy-2-prop_ yl-phenoxy) -2-hydroxypropyl] -6-methyl-phenyl} -lH-tet ⁰ pyrazol-5-carboxamide, 1H NMR Spectrum (δ versus TMS, DMSO-d 6): 0.85 (triplet, 3H), 1.45 (multiplet, 2H), 2.25 (singlet, 3H), 2.55 (multiplet, 2H), 2 , 60 (singlet, 3H), 4.0 - 4.7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.60 (multiplet,

Q2H), 7.10 (doublet, 1H), 7.80 (multiplet, 2H), 10.70 (singlet, 1H), 12.80 (singlet, 1H), and the ammonium salt of triethanol and N- [3 - [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy] -2-hydroxy-propyloxy) - N 4 -cyano-6-methyl-phenyl-1H-tetrazole-5-carboxamide having 1 H-NMR spectrum (compared δ TMS, DMSO-d _e):

0.85 (triplet, 3H), 1.45 (multiplet, 2H), 2.25 (singlet, 3H), 2.55 (multiplet, 2H), 2.60 (singlet, 3H), 4.0-4 , 7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.65 (doublet, 1H), 7.30 (singlet, 1H), 7.45 (singlet, 1H), 7.85 (doublet, 1H), 10.70 (singlet, 1H) 12.80 (singlet, 1H), and triethanolammonium 20.

Example 4

4.9 g of N-; 3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-n-hydroxy-propyloxy] -6-methyl-phenyl] -1H-tetrazole-5- ⁰ Oxamides carboxylate 45 ml of acetone and 1.0 g of diethanolamine in 5 ml of acetone was added. After addition of diethyl ether, crystallization begins. The mixture was allowed to stand for 30 minutes at 5-10 ° C, filtered off with suction, rinsed with diethyl ether and allowed to air dry. N- [3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -6-methyl-phenyl} -1H-tetrazolecarboxamide was treated with diethyl ammonium. salt. Similarly, the sodium, potassium diethylammonium and tris (hydroxymethyl) methyl animonium salts can be prepared.

The following sodium, potassium, diethanolammonium, diethylammonium and tris (hydroxymethyl) methylammonium salts are also obtained analogously: N- {3- [3- (4-acetyl-3-hydroxy) 2-propylphenoxy) -2-hydroxypropyloxy] -2-cyanophenyl] -1H-tetrazole-5-carboxamide. N- {. 3- (3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-440-propyl-phenoxy) -2-hydroxy-propyloxy] - {4-bromo-6-methyl-phenyl} -1H-tetrazole-5-carboxamide, N- (3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl -phenyl] -1H-tetrazole-5-carboxylic acid, N- (3- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropylhoxy) ac-4-fluoro- 6-methylphenyl} -1H-tetrazole-5-carboxamide and N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4- cyano-6-methylphenyl-1H-tetrazole-5-carboxamide.

Example 5

2.2 g of N- [3- [3- (4-acetyl-3-methoxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H- To a solution of tetrazole-5-carboxamide in 20 ml of dichloromethane, cooled to -78 ° C, 3.0 g of boron tribromide are added dropwise over 5 minutes, and the reaction mixture is stirred at room temperature for 6 hours. Water (5 ml) was then added with cooling, and the organic layer was separated and concentrated under reduced pressure. After recrystallization from dichloromethane / ether, N- (3- (3- (4-acetH-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy) -4-bromo-6- methylphenyl} -1H-tetrazole-5-carboxamide, m.p. 155-158

They are at -8 ° C. The product obtained is dissolved in 100 ml of acetone and mixed with 1 equivalent of triethanolamine in 10 ml of acetone. After addition of ether, crystallization begins. Thus N- [3- (3- (4-acetyl-3H-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -44) -romo-6-methyl-phenyl} -1 The triethanolammonium salt of H-tetrazole-5-carboxamide is obtained, m.p. 76 DEG C. (with decomposition).

The starting material is e.g. can be prepared as follows:

A solution of 4.5 g of 4-bromo-5-hydroxy-2-methylnitrobenzene in 100 ml of tetrahydrofuran was mixed with 2.0 g of Raney-Nickel and hydrogenated at room temperature. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to give 4-bromo-5-hydroxy-2-methylaniline as a colorless oil.

To a suspension of 10.6 g of potassium [1- (4-methoxybenzyl) tetrazole] -5-carboxylate in 170 ml of benzene and 1.5 ml of pyridine is added 3.38 ml of oxalyl chloride at 0-5 ° C. and the reaction mixture is stirred at room temperature for 30 minutes and then concentrated under reduced pressure, the residue is taken up in benzene and concentrated again under reduced pressure. The residue was dissolved in dichloromethane (135 mL) and added dropwise at 0-5 C to a solution of 4-bromo-5-hydroxy-2-methylaniline (5.95 g) and pyridine (2.7 mL) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 3 hours, diluted with dichloromethane and washed three times with water. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was filtered through 300 g of silica gel with dichloromethane: ethyl acetate (6: 1). The eluate was evaporated and the residue was crystallized from ethanol. N- (4-Bromo-5-hydroxy-2-methyl-phenyl) -1- (4-methoxy-benzyl) -tetrazole-5-carboxamide is obtained.

A solution of 12.8 g of N- (4-bromo-5-hydroxy-2-methylphenyl) -1- (4-methoxybenzyl) tetrazole-5-carboxamide in 250 ml of trifluoroacetic acid and 25 ml of anisole was used under reflux. Boil for 30 minutes. The reaction mixture was concentrated under reduced pressure, mixed with about 300 mL of ether and 400 N petroleum ether and the crystals were filtered off. N- (4-bromo-5-hydroxy-2-methylphenyl) -1H-tetrazole-5-carboxamide is obtained.

22.3 g of N- (4-bromo-5-hydroxy-2-methylphenyl) -1H-tetrazole-5-carboxamide and 13.8 g of calcined potassium carbonate were prepared in 100 ml of ethyl methyl ketone. The slurry was mixed with spatula tip potassium iodide and 20.3 g of 4- (3-bromo-2-hydroxypropoxy) -2-methoxy-3-propylacetophenone, and the reaction mixture was refluxed for 20 hours, then cooled and poured into water. and extracted three times with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and finally evaporated to dryness under reduced pressure. Crystallization of the residue from a mixture of ether and hexane gave N- {3- [3- (4-acetyl-3-methoxy-2-propylphenoxy) -2-hydroxypyloxy] -4-bromo-6-methylphenyl} -1H-tetrazole-5-carboxamide is obtained.

Example 6

14.2 g of N-β- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -1-acetoxy-propyloxy] -4-bromo-6-methyl-phenyl-1H-tetrazol-5-one. A suspension of carboxamide in 80 ml of methanol and 100 ml of 1 N sodium hydroxide was heated under reflux for 1 hour. The reaction mixture was cooled, neutralized with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is concentrated under reduced pressure. After recrystallization from dichloromethane / ether, N- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-m.p. methyl-phenyl} -! H-tetrazole-5-carboxamide is obtained.

The product obtained is dissolved in 100 ml of acetone and mixed with 1 equivalent of triethanolamine in 10 ml of acetone. After addition of ether, crystallization begins. Thus, N-3- [3- (4-acetyl-3-hydroxy-2-propyl • phenoxy) -2-hydroxypropyloxy] 4-bromo-6-methylphenyl-1H-tetrazole-5-carboxamide triethanolammonium salt, m.p. 76 ° C (dec.).

For example, the starting material is prepared as follows:

A solution of 4.5 g of 4-bromo-5-hydroxy-2-methylnitrobenzene in 100 ml of tetrahydrofuran is mixed with 2.0 g of Raney-Nickel and hydrogenated at room temperature. The catalyst was filtered off and washed with tetrahydrofuran. Concentration of the filtrate under reduced pressure gave 4-bromo-5-hydroxy-2-methylaniline as a colorless oil.

To a suspension of 10.6 g of potassium [1- (4-methoxybenzyl) tetrazole] -5-carboxylate in 170 ml of benzene and 1.5 ml of pyridine at 0-5 ° C is added 3.38 ml of oxalyl chloride and the reaction mixture is stirred at room temperature for 30 minutes and then concentrated under reduced pressure, the residue is taken up in benzene and concentrated again under reduced pressure. The residue was dissolved in dichloromethane (135 ml) and added dropwise at 0-5 ° C to a solution of 4-bromo-5-hydroxy-2-methylaniline (5.95 g) and pyridine (2.7 ml) in dichloromethane (100 ml). The reaction mixture was then stirred at room temperature for 3 hours, diluted with dichloromethane and washed three times with water. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was filtered through 300 g of silica gel with dichloromethane: ethyl acetate (6: 1). The eluate was evaporated and the residue was crystallized from ethanol. There was thus obtained N- (4-bromo-5-hydroxy-2-methylphenyl) -1- (4-methoxybenzyl) -tetrazole-5-carboxamide.

12.8 g of N- (4-bromo-5-hydroxy-2-methylphenyl) -1- (4-methoxybenzyl) tetrazole-5-carboxamide in 250 ml of trifluoroacetic acid and. The yarn was spun for 30 minutes in 25 ml of anisole under reflux. The reaction mixture is concentrated under reduced pressure, mixed with about 300 ml of food and 400 ml of petroleum ether and the crystals are filtered off. N- (4-bromo-5-hydroxy-2-methylphenyl) -1H-tetrazole-5-carboxamide is obtained.

A suspension of 22.3 g of N- (4-bromo-5-hydroxy-2-methylphenyl) -1H-tetrazole-5-carboxamide and 13.8 g of calcined potassium carbonate in 100 ml of ethyl methyl ketone is mixed with a spatula tip with potassium iodide and

20.7 g of 4- (3-bromo-2-acetoxypropoxy) -2-hydroxy-3-propylacetophenone were added, and the reaction mixture was spun for 20 hours under reflux, cooled, poured into water and extracted three times with dichloromethane. . The organic layers were washed with water, combined, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from a mixture of ether and hexane to give N- (3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-acetoxy-propyloxy] -4-bromo-6-methylethyl-phenyl) - 1H-Tetrazole-5-carboxamide is obtained.

7..példa

A suspension of 2.1 g of 2,4-dihydroxy-3-propylacetophenone and 1.6 g of calcined potassium carbonate in 40 ml of ethyl methyl ketone is mixed with 1 spatula of potassium iodide and 4.2 g of N- [3- ( 3-Bromo-2-hydroxypropoxy) -4-bromo-6-methylphenyl] -1H-tetrazole-5-carboxamide, then the reaction mixture was refluxed for 8 hours, cooled, poured into water and dichloromethane. extracted three times with methane. The combined extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Recrystallization of the residue from dichloromethane / ether gave N- {3- [3- {4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -4-bromo-6-methylphenyl} -1H-tetrazolecarboxamide is obtained, m.p. 155-158 ° C.

The product obtained is dissolved in 100 ml of acetone and mixed with 1 equivalent of triethanolamine in 10 ml of acetone. After addition of ether, crystallization begins. Thus, N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -? 4-bromo-6-methyl-phenyl-1H-tetrazol-5-one. carboxamide triethanol ammonium salt is obtained, which melts at 76 ^e C (dec) ..

The starting material is e.g. can be prepared as follows:

To a suspension of potassium carbonate (g) and potassium iodide (0.5 g) in acetone (170 mL) was added 1-bromo-2,3-epoxypropane (52 mL) and the reaction mixture was heated to reflux. A solution of 29.2 g of 2-bromo-4-methyl-5-nitrophenol is then added dropwise over 2 hours and refluxed for a further 15 hours. The reaction mixture was stirred hot and evaporated. Chromatography of the residue on silica gel with toluene gave 2-methyl-4-bromo-5- (3-bromo-2-hydroxypropoxy) -nitrobenzene as a light yellow oil.

A solution of 2-methyl-4-bromo-5- (3-bromo-2-hydroxypropoxy) -nitrobenzene (g) in tetrahydrofuran (40 ml) was mixed with Raney-Nickel (1.0 g) and hydrogenated at room temperature. The catalyst was filtered off and washed with tetrahydrofuran. Concentration of the filtrate under reduced pressure gave 2-methyl-4-bromo-5- (3-bromo-2-hydroxypropoxy) aniline as a colorless oil.

10.6 g of potassium [1- (4-methoxybenzyl) tetrazole] -5-carboxylate are prepared with 170 ml of benzene and 15 ml of pyridine. 338 ml of oxalyl chloride were added to the slurry of it at 0-5 ° C, and the reaction mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, the residue was taken up in benzene and concentrated again under reduced pressure. The residue was dissolved in dichloromethane (135 mL) and added dropwise at 0-5 ° C over 10 minutes with 8.3 g of 2-methyl-4-bromo-5- (3-bromo-2-hydroxypropyloxy) aniline and 2 7 ml of pyridine in 100 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 3 hours, diluted with dichloromethane and washed three times with water. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue was filtered through 400 g of silica gel with dichloromethane: ethyl acetate (6: 1). The eluate was evaporated and the residue was crystallized from ethanol. N- [3- (3-bromo-2-hydroxypropoxy) -4-bromo-6-methylphenyl] -1- (4-methoxybenzyl) tetrazole-5-carboxamide is obtained.

12.8 g of N- [3- (3-bromo-2-hydroxypropoxy) -4-bromo-6-methylphenyl] -1- (4-methoxybenzyl) tetrazole-5-carboxamide are added in 250 ml of trifluoro in acetic acid and 25 ml of anisole under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, mixed with about 300 ml ether and 400 µl petroleum ether and the crystals were filtered off. There was thus obtained N- [3- (3-bromo-2-hydroxypropyloxy) -4-bromo-6-methylphenyl] -1H-tetrazole-5-carboxamide.

Example 8

To a suspension of 10.6 g of potassium [1- (4-methoxybenzyl) tetrazole] -5-carboxylate in 170 ml of benzene and 1.5 ml of pyridine is added 3.38 ml of oxalyl chloride at 0-5 ° C. and the reaction mixture is stirred at room temperature for 30 minutes and then concentrated under reduced pressure, the residue is taken up in benzene and concentrated again under reduced pressure. The residue was dissolved in dichloromethane (135 mL) and 3- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy) (12.85 g) at 0-5 ° C over 10 minutes. A solution of -4-bromo-6-methylaniline and 2.7 ml of pyridine in 100 ml of dichloromethane was added dropwise, the reaction mixture was stirred at room temperature for 3 hours, diluted with dichloromethane and washed three times with water. The residue was filtered through 400 g of silica gel with dichloromethane: ethyl acetate (6: 1), and the eluate was evaporated and the residue was crystallized from ethanol, m.p. 114-116 ° C. - (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl] -1- (4-methoxy-benzyl) -tetrazol-5-one. A solution of 12.8 g of this product is dissolved in 250 ml of trifluoroacetic acid and 25 ml of anisole and refluxed for 30 minutes. k) The reaction mixture is concentrated under reduced pressure, mixed with about 300 ml of food and 400 ml of petroleum ether and the crystals are filtered off. The resulting N- [3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H- tetrazole-5-carboxamide m.p. 155-158 ° C. This product is dissolved in 100 ml of acetone and mixed with 1 equivalent of triethanolamine in 10 ml of acetone. After addition of ether, crystallization begins. Thus, N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H-tetrazole- The 5-carboxamide triethanolammonium salt is obtained, m.p. 76 ° C (dec.).

The starting material is e.g. can be prepared as follows:

A solution of 2-bromo-4-methyl-5-nitrophenol (16.2 g) in ethanol (130 ml) was added to a solution of sodium hydride (55% in oil, 0.32 g). A solution of 18.4 g of 4- (2,3-epoxypropoxy) -2-hydroxy-3-propylacetophenone in 150 ml of ethanol was added dropwise over 2 hours under reflux, and the reaction mixture was refluxed for a further 8 hours. After cooling, concentrate in vacuo to about 100 ml and pour over ice. The aqueous phase is diluted with hydrogen chloride

-101

acid and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate and evaporated in vacuo. After crystallization from ether, 3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methyl · -nitro-, m.p. 104-106 ° C. benzene is obtained.

A solution of 23.3 g of 3- (3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy) -4-bromo-6-ethyl-nitrobenzene in 240 ml of tetrahydrofuran is stirred for 2 hours. The catalyst was filtered off and washed with tetrahydrofuran. The combined filtrates were concentrated in vacuo, mixed with ether and the precipitated crystals were filtered to give 3- [3- (4-acetyl-3) melting point 78-80 ° C. (hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-aniline is obtained.

Example 9

Tablets containing 25 mg of active ingredient, e.g. N-C 3- (3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methylphenyl-1 H-tetrazole; Containing 5-carboxamide, may be prepared as follows:

Ingredients (per 1000 tablets)

Active ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talcum 5.0 g

Magnesium stearate 1.8 g

Demineralized water qj.

manufacture:

All solid components are first sieved through a 6 mm mesh sieve. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water and granulated with water, if necessary. The granulate was dried overnight at 35 ° C, sieved through a 12 mm mesh sieve, and concave on both sides with ca. Compressed to 6 mm diameter tablets.

In an analogous manner, tablets of 25 mg, 1-8 can be prepared. containing the other compound of formula (I).

Example 10

Chewable tablets containing 30 mg of active ingredient, e.g. N- [3- [3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H-tetrazole Containing the triethanolammonium salt of -5-carboxamide, prepared as follows:

composition (per 1000 tablets):

Active ingredient 30.0 g

Man ni t 267.0 g

Lactose 179.5 g

Talcum 20.0 g

Glycine 12.5g

Stearic acid 10.0 g

Saccharin l, 0g

5% Gelatin solution qx

manufacture:

All solid components are first sieved through a 0.25 mm mesh sieve. The mannitol and lactose are mixed, granulated with the addition of gelatin oxide, passed through a sieve with a mesh size of 2 mm, dried at 50 ° C and again passed through a sieve with a mesh size of 1.7 mm. The active ingredient, glycine and saccharin are thoroughly mixed, the mannitol, the lactose granules, the stearic acid and the talc are added, the whole is thoroughly mixed and concave on both sides, ca. Compressed into 10 mm diameter tablets with a score on the top.

In an analogous manner, tablets of 30 mg, 1-8 may be prepared. containing another compound of the formula (I) as described in Example 3a.

Example 11

100 mg of active ingredient, e.g. N- {3- [3- (4-Acetyl-3-hydroxy-2-ptopyl-phenoxy] -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H-tetrazole-5 tablets containing the carboxamide triethanolammonium salt are prepared as follows:

composition (per 1000 tablets)

agent 100,0g Lactose 248.5 g corn starch 17.5g Polyethylene glycol 6000 5.0g talc 15.0 g Magnesium stearate 4.0 g Demineralized water qx

Preparation

The solid components are first screened through a 0.6 mm mesh screen. The active ingredient, lactose, talc, magnesium stearate and half of the starch are then thoroughly mixed, the other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 260 ml of water. The resulting chickpea is added to the powdered material, mixed and granulated with water if necessary. The granulate was dried overnight at 35 ° C, passed through a sieve with a mesh size of 1.2 mni and concave on both sides, ca. Compressed into 10 mm diameter tablets with a score on the top.

In an analogous manner, tablets may be prepared which contain 100 mg of the tablets of 1-8. containing the other compounds of formula (I).

Example 12

A propellant-containing solid aerosol inhalation suspension containing 0.1% by weight of N-J3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-. containing the active ingredient bromo-6-methylphenyl] -1H-tetrazole-5-carboxamide, prepared as follows:

Composition:

Active ingredient, micronized 0.1% by weight "Sorbitan trioleate" 0.5% by weight

Propellant (trichlorotrifluoroethane) 4.4% by weight

Propellant B qx (A mixture of 15 parts dichlorodifluoromethane and 80 parts sym dichlorotetrafluoroethane)

-111

manufacture:

The active ingredient is suspended in trichlorotrifluoroethane with the addition of sorbitan trioleate, using a standard homogenizer, with the exclusion of moisture, filled into a dispensing aerosol container and then filled under pressure with dichlorodifluoromethane and dichloroethane. mixture.

Analogously, inhalation suspensions may be prepared according to the method of FIGS. and other compounds of formula (1).

Example 13

For inhalation, the active ingredient is N- [3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl] -1H of the triethanolamine salt of -tetrazole-5-carboxamide. 2% aqueous solution, e.g. can be prepared in the following composition:

Composition:

agent Stabilizer, e.g. ethylene diamine tetra-acetic acid 2,000 mg disodium 10 mg Preservative, e.g. bezalkánium chloride 10 mg Freshly distilled water ad 100 ml manufacture:

The active ingredient is dissolved in freshly distilled water. The stabilizer and the preservative are then added. After all components have been completely dissolved, the resulting solution is made up to 100 ml, poured into a glass bottle and sealed with gas.

Analogously, 2% inhalation solutions can be prepared as described in Figures 1-8. containing the other active ingredient prepared according to example.

Example 14

Inhalable capsules containing about 25 mg of N- [3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl as active ingredient. -phenyl} -1H-tetrazole-5-carboxamide triethanolammonium salt, e.g. can be prepared in the following composition:

Composition:

Active ingredient 25 g

Lactose, finely ground 25 g

manufacture:

The active ingredient and the lactose are thoroughly mixed. The resulting powder is then sieved and filled in 50 mg portions into 1000 gelatin capsules.

Inhalation capsules analogous to those of claims 1-8 can be prepared analogously. containing the active ingredient prepared according to example.

Claims (11)

PATENT CLAIMS A process for the preparation of novel tetrazole-5-carboxamide derivatives of the formula (I) and their salts, wherein R 1 is C 1 -C 4 alkyl, alk is C 3 -C 4 hydroxyalkylene, where the hydroxy group is further away from the α-position relative to the free valences. R 1 is 5-tetrazolyl, wherein ring A is additionally substituted in the 2-position with C 1 -C 4 alkyl and ring B is additionally substituted in the 6-position by a C 1 -C 4 alkyl group and optionally in position 4 by a halogen atom or substituted at the 2-position with a cyano group, characterized in that (a) in a compound of Formula VI wherein X _{4 is an} etherified or esterified hydroxy group, R 1, A, B, alk and R ₂ are as defined herein, the X ₄ group is converted to a hydroxy group by treatment with a complex metal halide; or b) formula (VII) with a compound of formula basic condensing agent with a compound of formula (VIII), wherein X _s and X ₆ is optionally hydroxy and the other is in a metal salt form an ω-position with a reactive esterified hydroxy-substituted hydroxy- (3 -C 4 alkoxy) in which the free hydroxyl group is further away from the α-position and ω · of the alkoxy hydrogen, R 1, A, B and R ₂ are within the scope of the present invention, or c) a compound of formula IX wherein alk 'is an etherified or esterified hydroxy (C 3 -C 4) alkylene group in which the etherified or esterified hydroxyl group is attached at a position further away from the free valence, R 1, A , B and R ₂ are subjected to basic or acidic hydrolysis according to the invention, or d) reacting a compound of formula X wherein R ₁ , alk, A and B are as defined herein or a salt thereof in the presence of a basic condensing agent with a compound of formula XI wherein X ₇ is optionally esterified, is an amidated, anhydrated or carboxyl group at the base of a metal salt, R ₂ is as defined in the present invention, or a R ₂ protected in the 1-position, in which case the protecting group is finally removed, or e) a compound of Formula XII wherein Xg is -NH-C (= O) -R ' ₂ , wherein R' ₂ is a 5-tetrazolyl-protected in the 1-position with 4-methoxybenzyl; subjecting group and R alk _l, a and B are as defined above, to acid hydrolysis, and, if desired, (1) obtained free compound in a any of the above procedure is converted into a salt. A process for the preparation of a compound of formula (Ia) and salts thereof according to claim 1, wherein: R 1 is C 1-4 alkyl, R ₂ is 5-tetrazolyl R ₃ is C 1 -C 4 alkyl, R 1 is hydrogen, R _s and R ₇ is hydrogen and Rj represents a cyano group, or R _s is C 1-4 alkyl, R _e is hydrogen, and R ₇ is a halogen atom or a cyano group of up to 53, and alk is a terminal C 3 -C 4 hydroxyalkylene group in which the free valencies are carbon at position 0 relative to the hydroxy group. -121 496,770 mon are characterized by the use of appropriately substituted starting materials. 5 3. A method according to claim 1 for the preparation of (Ia) and salts and esters thereof, wherein R is alkyl of up to 4 carbon atoms, lower alkyl group, R ₃ is unbranched alkyl having up to 4 carbon atoms, lower alkyl group, R ₃ represents a 5- tetrazolyl, ^υ R4 is hydrogen, up to 4 carbon atoms lower alkyl, R _s hydrogen, _R6 is hydrogen, _R7 is a halogen atom, whose atomic number up to 53 or cyano and alk represents an unbranched, space 15 the gem a bonded C 3 or C 4 hydroxy (lower alkylene) group in which the free valencies are at the β-position of the hydroxy group, with the use of appropriately substituted starting materials. 20 The process according to claim 1, which is N-13- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl] - 1H-tetrazole-5-carboxamide or a salt thereof, wherein the appropriately substituted starting materials are used. The process according to claim 1, which is N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -3-hydroxy-propyloxy] -2-danophenyl] -1H-tetrazole -5-carboxamide or a salt thereof, characterized in that the corresponding substituted starting compounds are glazed. The process according to claim 1, which is N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -6-methyl-phenyl} -1H-tetrazole -5-carboxamide or a salt thereof, characterized in that the appropriately substituted starting compounds are used. * 7. A process according to claim 1) for N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy} -4-chloro-6-methyl-phenyl} The preparation of -1H-tetrazole-5-carboxylic acid or a salt thereof, wherein the appropriately substituted starting materials are used. 8. The process of claim 1, which is N- (3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-fluoro-6-methyl-phenyl) for the preparation of -1H-tetrazole-5-carboxamide or a salt thereof, wherein the appropriately substituted starting compounds are used. The process according to claim 1, which is N- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-dano-6-methylphenyl] - 1H-tetrazole-5-carboxamide or a salt thereof, wherein the appropriately substituted starting materials are used. The process of claim 1, wherein the process of claims 1-9 is as follows. A process for preparing the sodium, potassium, triethanolammonium, diethylammonium, diethanolammonium or tris (hydroxymethyl) methylammonium salts of the compounds of formula (I) according to any one of claims suitably substituted starting compounds. 11. A process for the preparation of an effective antiallergic pharmaceutical composition, characterized in that the method according to claims 1-10. A compound according to any one of claims 1 to 4 or a salt thereof, in combination with a carrier, excipient, lubricant, flavoring agent and other additives customarily used in the manufacture of medicaments, optionally in the form of tablets, pills, capsules, emulsions, or other items.