DK161644B - Substituted N-(3-(omega-(4-acyl-3-hydroxy-2- alkylphenoxy)hydroxyalkoxy)phenyl)-1H-tetrazole-5- carboxamides and salts thereof having an antiallergic effect, pharmaceutical preparations which comprise these compounds, and a process for preparing them - Google Patents

Description

in

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This invention relates to novel substituted Ν- {3- [ω- (4-acyl-3-hydroxy-2-alkyl-phenoxy) -hydroxyalkoxy] -phenyl} -1H-tetrazole-5-carboxamides having antiallergic effect which are peculiar know that they have the general formula R1 «i« 1 h (I)

HOX Falcon-0 / X * X \ h-C — N

ft3 K4 0 H-N

wherein R 1 is C (1-4) alkyl, alk means straight chain hydroxy-C (3-7) alkyl, wherein the hydroxy group is bonded to the free valences at a higher position than the α position and 10 at a lower position than ω the position, R3 is C (1-4) alkyl, R4 is hydrogen or cyano, R5 is hydrogen, halogen having an atomic number not exceeding 53 or cyano, and Rg is hydrogen or C (1-4) alkyl, with at least one of the groups R4, R5 and Rg is different from hydrogen and salts thereof.

The compounds of the invention have antiallergic effect.

The term "low for organic compounds and derived groups hereinafter means those which contain at most 7, especially at most 4 carbon atoms, unless otherwise stated.

C (1-4) alkyl means, for example, methyl, ethyl, n-propyl, isopropyl or n-butyl, moreover sec- or tert-butyl, in the case of R 1 especially methyl and in the case of R 3 especially 25 n-propyl.

Halogen has an atomic number of no more than 53, especially from 17 to 53, and means fluorine, chlorine, bromine or iodine.

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Hydrc> xy-C (3-7) - alkylene in which the hydroxy group is bonded to the free valences at a higher position than the α position and at a lower position than the ω position means, for example, 5,3- (2-hydroxy) propylene, 1,4- (2-hydroxy) butylene or 1,5- (3-hydroxy) pentylene.

Salts of compounds of formula I are preferably pharmaceutically useful salts with bases such as metal salts, ammonium salts or salts with organic bases. As 10 examples of metal salts may be mentioned corresponding alkali metal salts and alkaline earth metal salts, e.g. lithium, sodium, potassium, magnesium or calcium salts, as well as pharmaceutically useful transition metal salts such as zinc or copper salts. Salts with organic bases are formed, for example, with mono-, di- or trisubstituted organic amines such as corresponding alkylamines, hydroxyalkylamines, suitable heterocyclic compounds containing at least one nitrogen atom such as morpholine, thiomorpholine, piperidine or pyrrolidine, optionally 20 N-substituted amino saccharides, e.g. N-methyl-D-glucamine, or basic amino acids such as lysine, arginine, histidine or ornithine, preferring amino acids of L configuration. As alkylamines, for example, mono-, di- or trilavalkylamines such as ethyl, tert-butyl, diethyl, diisopropyl, trimethyl or triethylamine can be used. Examples of hydroxyalkylamines include mono-, di- or trihydroxyalkylamines, such as mono-, di- or triethanolamine or diisopropanolamine, or hydroxylavalkyl-lower alkylamines such as N, N-dimethyl-30 or Ν, Ν-diethylaminoethanol or tris- (hydroxymethyl) methylamine.

Examples of other useful salts include pharmaceutically useful acid addition salts, such as hydrohalides, methanesulfonates, N-cyclohexyl sulfaminates, maleinates, maleate or fumarates, of compounds of formula I.

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The compounds of Formula I with chiral carbon atoms may, depending on their number, be in mutually enantiomeric or diastereomeric forms or as mixtures thereof, such as diastereomer mixtures, racemates or racemate mixtures.

From U.S. Patent No. 4,448,729 representing the prior art, compounds having antiallergic effect are known. However, with respect to basic structure 10, the known compounds are similar to the compounds of formula I. Instead of the 5-tetrazolyl group, the known compounds contain other substituents. EP A1 147,973 discloses, inter alia, compounds having antiallergic and anti-inflammatory effects as well as leukotriene synthesis-inhibiting effects. These known compounds also have a basic structure similar to the basic structure of the present compounds of formula I, but the known compounds differ substantially structurally from the compounds of the invention in that they contain instead of the hydroxyalkylene group alk between the two phenyl rings. alkylene group, and furthermore, the "right" phenyl ring of the known compounds differs in several respects from the "right" phenyl ring of the compounds of the invention of formula I with respect to the substitution pattern. Also known from EP A1 123,541 are other compounds having leukotriene-D4 antagonistic effects, the basic structure of which is somewhat similar to the basic structure of the compounds of the formula I. However, these known compounds differ substantially from the compounds of the invention in that they instead for the 1H-tetrazole-5-carboxamido group contains other substituents. Also, the substitution pattern of the "right" phenyl ring in the known compounds is in several respects different from the substitution pattern of the "right" phenyl ring in the compounds of the formula I invention.

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The compounds of the invention are characterized by valuable pharmacological properties. In particular, they have a surprisingly good antiallergic effect relative to those known from U.S. Patent No. 4,448,729 which can be deduced from a distinct LTD4 antagonism as well as a PAF antagonism (PAF acetether antagonism). , in vitro), since the subject compounds in vitro in the concentration range from ca. 0.003 to approx. 0.05 / imol / 1 inhibits 10 contractions induced by LTD4. For example, LTD4 antagonisms in vitro can be detected on isolated guinea pig ileum. For this purpose, ileum segments, extracted from guinea pigs weighing 300-400 g, are fixed in an organ bath in thyroid solution (38 ° C, aeration with a mixture of 95% O2 and 5% CO2) and loaded with lp , whereby contractions whose size is recorded are triggered by synthetic LTD4 (leukotriene D4, potassium salt). The magnitude of inhibition of these contractions, which can be traced back to the antagonistic activity of the test compound LTD4, is measured. The concentration of the test compound which reduces contractions induced by LTD4 is determined by 50% of the initial value. This concentration is referred to as the IC5Q value. In this experimental model, for example, for the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyl-oxy] -4'-bromo-6 is obtained. -methyl-phenyl} -IH-tetrazole-5-carboxamide of the invention has an IC 50 value of 0.0054 / nol / 1, for the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy) -2-propyl-phenoxy) -2-hydroxy-propyl-oxy] -2-cyano-phenyl} -tetrazole-5-carboxamide of the invention has an IC 50 value of 0.03 µχηοΐ / ΐ, for N- {3- [3- (4-Acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-cyano-6-methyl-phenyl} -1H-tetrazole-5-carboxamide of the invention an IC 50 value of 0.041 μιηοΐ / l, for N- {3- [3- (4- (3-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyl-oxy] -4- chloro-6-methyl-phenyl} -1H-tetrazole-5-carboxamide of the invention has an IC 50 value of 0.0027 μιηοΐ / ΐ, for N- {3- [3- (4-acetyl-3-hydroxy-2 n-propylphenoxy) -2-5

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hydroxy-propyloxy] -6-methyl-phenyl} -IH-tetrazole-5-carb-oxamide of the invention has an ICgg value of 0.04 µπιο1 / 1 and for N- {3- [3- (4-acetyl-3 -hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -phenyl} -oxamic acid ethyl ester and the sodium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) - 2-hydroxy-propyloxy] -2-cyano-phenyl) -oxamic acid, both known from U.S. Patent No. 4,448,729, has an ICsg value of 0.087 μιηοΐ / ΐ.

The LTD4 antagonistic effect of the subject compounds can also be demonstrated in vivo by the inhibition of experimental LTD4 bronchospasm in guinea pigs.

The invention relates primarily to compounds of formula I wherein C is (C 1-4) alkyl such as methyl, R 3 is C 1 -C 4 alkyl such as propyl, R 4 is hydrogen, R 5 is halogen having an atomic number of at most 53, such as chlorine or bromine, Rg represents C (1-4) alkyl, such as methyl, and alk means straight chain hydroxy-C (3-4) alkyl wherein the hydroxy group is bonded to the free valences of a higher positioning than the α position and in a lower position than the conversion such as 1,3- (2-hydroxy) propylene, as well as their salts, especially their pharmaceutical use salts with bases.

In particular, the invention relates to the compounds mentioned in the Examples of Formula I and their salts, in particular the pharmaceutically useful salts, with bases.

The invention further relates to a process for the preparation of compounds of formula I or salts thereof.

This method is based on methods known per se. The process of the invention is peculiar in that it a) rearranges a compound of formula 6

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κ \ R5 \ y \, ^ 6 «« 1 'in H (II)

O «3 ft4- ° * N-N

or b) translates a compound of the formula / \ R5 \ / \ i * i "into h (III)

1 k3 k, 8 J_J

wherein Χχ means optionally etherified hydroxy, with a compound of formula R1-X2 (IV), wherein X2 optionally represents functionally converted carboxy, or c) in a compound of formula x3 \ κ \ Rsw \

Il 1 II [„* - · * H Γνΐ κ \ / \ / \ / - \ / Nv.

HO * O-alK-O ·> H-C— <7 ΝΑ L fi 11 11

K 3 K4 U N-N

wherein X3 represents a group- which can be converted to the group of formula ^ -0 (= 0) -, X3 converts to this group, or d) in a compound of formula A Rsxy \ ./R6

Ri 'V 1 «1 ff --- (vx.) 7

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wherein X4 represents a group which can be converted to hydroxy, converts X4 to hydroxy, or e) interacts with compounds of the formulas «RS \ / * 6

Ri * * *

· * · 11 * and 11 1 H

<YNRrD

<VIIl (VIII) wherein one of the groups X5 and Xg optionally represents a hydroxy present in salt form, and the other means a terminally substituted with reactively etherified hydroxy 10 substituted straight chain hydroxyalkoxy group or a terminally substituted epoxy substituted straight chain alkoxy group, or f) in a compound of the formula

R1 l "l i Η \ H

H0 / X \ h-C-c / N ^

HO ^ O-alk'i-O ^ S

15 wherein alk * means a group which can be converted to alk, converts alk 'to alk, or g) converts a compound of formula 8

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/ \ / R5 \ / \

R 1 "/ 1 *, \ (X 2 HO 2" o-alk-c / 2 NHO K 2 R 4 "or a salt thereof having a compound of formula X7 - R 1 (XI) 5 wherein R the position is protected 5-tetrazolyl, and X7 means halogenocarbonyl, where halogen is chlorine, bromine or iodine, or, if R2 is in the 1-position protected 5-tetrazolyl, a salt-carboxyl group, and releases the 5-tetrazolyl group 10 from 1- position protected 5-tetrazolyl R2, or.

h) in a compound of the formula

Å Rs \ / \ A

Ri ίι; n 1 (xii)

p's. / \ / V

HO · O-alk-O * X.

wherein Xg represents a group which can be converted to a 1H-tetrazole-5-carboxamido group, Xg converts to this group and, if desired, converts a compound of formula I into another compound of formula I and / or converts a compound of formula I free compound of formula I to a salt thereof or a prepared salt of a compound of formula I to the free compound of formula I or to another salt.

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Optionally etherified hydroxy of formula III means, for example, free or aliphatic etherified hydroxy such as hydroxy or lower alkoxy, e.g. methoxy, but may also be araliphatic, cycloaliphatic or aromatic etherified hydroxy such as optionally substituted phenylalkoxy, e.g. benzyloxy, cycloalkoxy, e.g. cyclohexyloxy or cyclopentyloxy, or optionally substituted phenoxy.

Optionally, functionally converted carboxy X2 in Formula IV means, for example, free, esterified or anhydrided carboxy, such as carboxy, lower alkoxycarbonyl, halocarbonyl or anhydride carboxy of formula -O (= 0) -0-0 (= 0) - ^.

Groups X3 of formula V, which can be converted to the group 15 R 1 'C (= O) - are, for example, groups of the formula R 1 -CH (Xg) - wherein Xg represents hydrogen or optionally with an organic carboxylic acid esterified hydroxy, or groups having the formula R1 is C (= NH) -, further optionally optionally converted carboxy groups, such as free, saline or esterified carboxy or cyano. Hydroxy esterified with an organic carboxylic acid is, for example, low alkanoyloxy such as acetoxy, but may also be optionally substituted benzyloxy. As salt forms of carboxy X3 can be mentioned, for example, alkali metal, alkaline earth metal or ammonium salt forms, e.g. sodium or ammonium salt forms or halogen magnesium salts for worms. For example, esterified carboxy X3 is lower alkoxycarbonyl, but may also be optionally substituted phenoxycarbonyl or phenyllavalkoxycarbonyl such as benzyloxycarbonyl.

Groups X4 of formula VI which can be converted to hydroxy are, for example, etherified or esterified hydroxy groups.

As etherified hydroxy X4, for example, there may be mentioned aliphatic etherified hydroxy, e.g. low alkoxy such as methoxy or low alkenyloxy, especially low alkoxy-2-enyloxy, e.g. allyloxy, optionally substituted phenyllavalkoxy such as benzyloxy, 10

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in addition, tetrahydropyran-2-γΙοχγ and silyloxy, especially trilavalkylsilyloxy, e.g. -trimethylsilyloxy. For example, esterified hydroxy X 4 is hydroxy esterified with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid, or with an aliphatic or aromatic half ester of carbonic acid such as low alkanoyloxy, e.g. acetoxy, optionally substituted benzoyloxy, optionally halogenated lower alkoxycarbonyloxy, e.g. methoxy, ethoxy-10 or tert-butyloxycarbonyloxy, 2,2,2-triiodethoxy- or 2,2,2-trichloroethoxycarbonyloxy, optionally substituted phenyllavalkoxycarbonyloxy, especially 1-phenyllavalkoxycarbonyloxy, e.g. benzyloxycarbonyloxy, or optionally substituted phenoxycarbonyloxy.

Salt form hydroxy X5 of formula VII or Xg of formula XIII or salt form of X7 carboxy of formula XI is in particular in alkali metal salt form, e.g. such as sodium or potassium salt. With reactively esterified hydroxy terminally substituted saturated 20 hydroxyalkoxy groups or with epoxy terminally substituted straight chain alkoxy groups X5 of formula VII or Xg of formula VIII are similar straight chain epoxy C (3-7) alkoxy groups, e.g. of the formula X'-CK 2 -O, or terminally reactive, mono-esterified straight chain dihydroxy-C (3-7) alkoxy groups in which the free hydroxy group is bonded at a higher position than the α position. to the oxygen atom bearing the free valence and to the reactively esterified hydroxy group, e.g. with the formula -O-CH 2 -CH (OH) -CH 2 -X wherein X means reaction-capable esterified hydroxy and X 'represents epoxyethyl. Reactively esterified hydroxy X is, for example, halogen such as chlorine, bromine or iodine, or organic sulfonyloxy such as lower alkanesulfonyloxy, e.g. methanesulfonyloxy, or optionally substituted benzenesulfonyloxy, e.g. benzene, p-bromobenzene or p-toluene sulfonyloxy.

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Groups -alk'- of formula IX are, for example, similar straight chain oxo-C (3-7) alkylene groups of formula -CH2-CO-CH2- or similar straight chain etherified 5 or esterified hydroxy-C (3-7) alkylene groups, e.g. .g. with the formula -CH2 "CH (X") - CH2 ~, wherein X "means etherified or esterified hydroxy.

For example, etherified hydroxy X "is hydroxy etherified with an α-aralkanol or a silanol such as optionally substituted benzyloxy or trilavalkylsilyloxy, for example, trimethylsilyloxy.

Esterified hydroxy X "is, for example, hydroxy esterified with a carboxylic acid, such as a lower alkanoic acid, or a carbonic acid ester such as low alkanoyloxy, e.g., acetoxy or pivaloyloxy, lower alkoxycarbonyloxy, e.g., tert-butoxy-carbonyloxy, or optionally substituted benzyloxy -carbonyloxy, for example benzyloxycarbonyloxy.

For example, in the 1-position protected 5-tetrazolyl groups R 2 of formula XI are optionally substituted in the aryl moiety 1-20 (o; -aralkyl) -tetrazolyl (5) groups such as 1-benzyl-tetr-azolyl (5) or 1 - (p-methoxybenzyl) -tetrazolyl- (5) ^

For example, a group Xg of formula XII which can be converted to a group of formula -NH-C (= O) -5-tetrazolyl is the group of formula -NH-C (= O) -CN.

The execution of the present reactions and the preparation of novel starting compounds or intermediates are carried out analogously to the reaction and formation methods of known starting materials and intermediates. . Unless expressly stated otherwise, in these methods, the usual auxiliaries such as catalysts, condensing agents and solvents and / or solvents or diluents and reaction conditions such as temperature and temperature are used.

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pressure conditions, and possibly protective gases.

The rearrangement of compounds of formula II according to process a) is carried out, for example, photochemically or in the presence of an acidic condensing agent, preferably in an inert solvent. Suitable acidic condensing agents are, for example, Lewis acids, especially complex metal halides of the formula ΜηΥη (XIX), in which M means an n-valent, co-unsaturated metal atom from the groups 10 Ilb, Illa, Hib, IVb, Va or VHIb of the periodic system, e.g. . a zinc 1 *, boron * 11, aluminum ***, gallium ***, tin * v-, titanium * v-, antimony ^ or iron *** atom, and Y means a halogen atom, especially . with an atomic number not exceeding 35, such as fluorine, chlorine or bromine. Preferably boron trifluoride, aluminum trichloride, gallium chloride, tin tetrachloride or zinc chloride are used. Other suitable acidic condensing agents are. complex oxygen-containing acids, primarily of sulfur or phosphorus, such as sulfuric acid, pyrosulfuric acid, phosphoric acid, pyrophosphoric acid or polyphosphoric acid. Suitable inert solvents are, for example, tetrachloromethane, tetrachloroethane, trichloroethylene, carbon disulfide and nitrobenzene. If necessary, work during cooling or heating, e.g. in the temperature range from approx. -10 ° C to approx. 40 ° C, especially from 5 ° C to 30 ° C.

Starting compounds of formula II may be prepared, for example, by the usual reaction of compounds of formulas R5

U l H

['i (XIII) and / x / s.

"" Y "" <cΎίΛ R3 (VIII) 30 wherein Xg represents a terminal with reactive ability 13

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esterified hydroxy substituted straight chain hydroxyalkoxy group or a terminal substituted with epoxy substituted straight chain alkoxy group, e.g. a group of the formula 5 X'-CH 2 -O- or -X-CH 2 -CH (OH) -CH 2 -O- wherein X means reactively esterified hydroxy, e.g. halogen, and X 'represents epoxyethyl and O-acylates the reaction product of formula R ί1! h (III) xrr ° -aikVT ^ r ^ 10 wherein Χχ means hydroxy, in the usual manner, e.g. by reaction with a compound R1-X2 (IV), wherein X2, for example, means halocarbonyl or anhydride-carboxy of the formula -C (= O) -O-C (= O) -Rx. The preparation of compounds of formula VIII is described below. 15 e).

The reaction of compounds III and IV according to process b) is usually carried out in the presence of an acidic condensing agent, advantageously in an inert solvent, if necessary under cooling or heating, for example, at a temperature of from ca. -10 ° C to 100 ° C, preferably from 5-65 ° C. As acidic condensing agents and inert solvents, for example, those listed above in connection with process a) are used.

Starting compounds of formula III can be prepared, for example, by reacting compounds of formulas 14

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s \,. / \ Z * 6

»! <XIV> ° 9 i, i H

x'Y '5 - E3 6 4, 8 £ - (viir) wherein one of the groups X5 and Xg optionally represents hydroxy and the other a terminally substituted with 5 reactive esterified hydroxy substituted straight chain hydroxyalkoxy group or an terminated with epoxy substituted straight chain alkoxy group, e.g. a group of the formula X'-C1 -O- or X-CH2-CHCOH) -CH2-O-r in which X means reactively esterified hydroxy, e.g. halogen, and Xf means epoxy ethyl.

The starting compounds of formula IV are known compounds.

The conversion of X3 to the group R 1 -C (= O) - according to process c) is carried out in the usual manner, from compounds of formula V, wherein X 3 represents a group of formula R 2 -CH (X g) - e.g. by oxidation, from compounds of formula V, wherein X 3 represents a group of formula R 1 -C (= NH) -, for example, by solvolysis, and from compounds of formula V, wherein X 3 means optionally functionally converted carboxy, for example, by reaction with a compound of formula R 1 -M (XV) wherein M is a metal group, e.g. of the formula -M1, or M3 -Hal wherein -M1 means an alkali metal atom, e.g. lithium, M11 means an alkaline earth metal atom or an earth metal atom, e.g. magnesium, zinc or cadmium, and Hal means a halogen atom, e.g. chlorine, bromine or iodine.

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Oxidizing agents suitable for the oxidation of groups X3 of the formula R 1 -CH (X g) - are, for example, oxidizing heavy metal compounds such as Cr 11 .g. chromium trioxide, potassium chromate or dichromate, manganese dioxide, potassium permanganate, iron trichloride, tin tetrachloride or vanadium pentoxide; . For the oxidation of groups X3 of the formula R1-CH (Xg) - wherein Xg represents hydroxy is particularly suitable e.g. potassium permanganate in aqueous pyridine or aqueous acetone or pyridinium dichromate in dichloromethane.

The solvolysis of the group X3 of the formula R 1 -C (= NH) - is carried out, for example, by mild hydrolysis, ie. by the action of water, if necessary in the presence of a mild hydrolyzing agent. For example, as mild hydrolysis agents, protonic acids such as mineral acids, e.g. hydrochloric or sulfuric acid, or organic sulfonic acids or carboxylic acids such as lower alkanoic or optionally substituted benzenesulfonic acids or lower alkanoic acids, e.g. p-toluenesulfonic acid or acetic acid.

The reaction of compounds of formula V in which X or weak heating, e.g. at a temperature in the range of -60 ° C to 40 ° C, preferably from -20 ° C to 25 ° C.

Starting compounds of Formula V may be prepared, for example, by reacting 35 compounds of Formulas 16

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R5 \ / \ Z'6 x \ y \ «ihi] (XVI) and xx x / '\ hC — c ^ n« / y \ 5 6 k \ δ R3 (VIII) wherein one of the groups X5 and Xg optionally means on the salt form, hydroxy present, and the other means a terminally substituted with reactively esterified hydroxy substituted straight chain hydroxyalkoxy group or an terminally substituted epoxy substituted alkoxy group, e.g. a group of the formula X'-CH2 -O- or X-CH2rCH (OH) -CH2 -O- wherein X means reactively esterified hydroxy, e.g. halogen, and X 'means epoxyethyl.

In addition, starting compounds of formula V, wherein X3 represents a group R 1 -CH (Xg) - wherein Xg = OH, can be prepared by reacting compounds of formulas XVI (X3 = formyl) and VIII and further reacting the reaction product of formula V (X3 = formyl) having a metal compound of formula XV.

In addition, starting compounds of formula V, wherein X3 represents a group of formula R1-C (= NH) -, may be prepared by reacting a compound of formula R5W * \ / * 6 X1 λ λ δ 11 11 Η 2 κ4 υ Ν-Ν (III) 17

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wherein Xi has the meaning set forth above and e.g. is lower alkoxy, in the presence of a Lewis acid, e.g. a complex metal halide of the formula MnYn (XIX), wherein M, 5 n and Y have the meanings set forth above in connection with process a), especially aluminum chloride, with a nitrile of the formula R] - CN (XVII). It is not necessary to isolate the intermediate of formula V, since under the working conditions it usually reacts 10 according to the invention.

The conversion of groups X4 to hydroxy according to process d) is carried out in the usual manner, e.g. by treatment with a complex metal halide of the formula MnYn (XIX), wherein M is an n-valent, co-unsaturated metal cation from group Ila, Ilb, Illa, Hib, IVb, Va or VHIb in the periodic system, e.g. . a magnesium, zinc H, boron H, aluminum H, gallium H * -, tin ^ V, titanium IV, antimony or iron111 or ironVI ion, and Y means a halogen atom having an atomic number not exceeding 35, such as fluorine or chlorine, e.g. with aluminum trichloride, or with a tertiary organic ammonium salt such as a pyridinium or trilavalkylammonium halide, e.g. with pyridinium chloride or bromide or triethylammonium chloride, but it can also be carried out by solvolysis, especially by hydrolysis, if necessary in the presence of a, preferably acidic, hydrolyzing agent. In addition to conventional basic hydrolysing agents such as alkali metal hydroxides, hydrolysing agents are acidic hydrolysing agents such as e.g. mineral acids, e.g. hydrochloric acid, hydrogen bromic acid or hydrogen iodide acid, sulfuric acid, phosphoric acid or polyphosphoric acid, further complex metal acids, e.g. hexachloroanthimonic acid, tetrafluoroboronic acid and the like, in the case of hydroxy groups X4 esterified with carboxylic acids, and further lower alkanoic acids such as acetic acid.

35 In the hydrolysis, solvents are, for example, water-miscible organic solvents. Preferably, one is employed in the presence of a solvent or 18

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diluent or solvent-promoting agent, during cooling or heating, e.g. in a temperature range of approx. 0 ° C to approx. 120 ° C, and / or under an inert gas atmosphere.

Ethereal hydroxy groups X4 can be cleaved to hydroxy, e.g. by treatment with aqueous hydrogen iodide acid, pyridinium hydrochloride, for example, in di chl ormethane, or hydrobromic acid in highly concentrated, e.g. 98% acetic acid, or by treatment with boron tribromide or aluminum trichloride. For example, in one embodiment of this process, compounds of the formulas may be treated

RS \ / \ I

- U I - Il l U

/ \ / \ / \ (III)

x-O-alk-0 NH-C-C N

1 Å 1 Ϊ 11 11

K3 R / J υ N-N

and I 2 -X 2 (IV) 15 wherein etherified is hydroxy and X 2 represents anhydrided carboxy such as halocarbonyl or a group of formula R 1 -C (= O) -O-C (= O) - with a Lewis acid such as a complex metal halide of the formula MnYn (XIX), e.g. aluminum trichloride, whereby in the primarily formed compound of the form VI, wherein X4 represents etherified hydroxy, the hydroxy group is released.

Advantageously, in compounds of formula VI containing, as group X4, an optionally substituted α-phenyllavalkoxy group or other common hydroxy group cleavable protected cleavage group, the hydroxy group can be reductively released. Thus, for example, one can hydrogenate, i.e. with hydrogen in the presence of a hydrogenation catalyst, e.g. and palladium, platinum,

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19 nickel or rhodium catalyst, e.g. palladium on coal or Raney nickel.

Furthermore, from compounds of formula VI, wherein X 4 is hydroxy esterified with a carboxylic acid, the hydroxy group can be liberated by transesterification, i.e. in treatment with an alcohol, e.g. a low alkanol, in the presence of an acidic or basic agent such as a mineral acid, e.g. sulfuric acid or an alkali metal hydroxide or alcoholate, e.g. sodium hydroxide or a sodium low alkanolate.

Starting compounds of formula VI can be prepared, for example, by reacting compounds of formulas

Rs \ Y6

in? il in H

r / VX x / X- / XNH-r— C ^ N

II I (XVIII) 0g X6! li II II

χ / γ \ 5 5 N — N

R3 (VIII) wherein one of the groups X5 and Xg optionally represents a hydroxy present in salt form and the other a terminally substituted with a reactively esterified hydroxy substituted straight chain hydroxyalkoxy group or an terminally substituted with epoxy substituted alkoxy group, e.g. a group of the formula X'-CH 2 -O- or X-CH 2 -CH (OH) -CH 2 -O- wherein X means reactively esterified hydroxy, e.g.

halogen, and X 'represents epoxyethyl, or for the preparation of compounds of formula VI wherein X 4 represents etherified hydroxy X 2, a corresponding compound of formula 20

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r5 \ / \ y * 6 - i - - S (III) 'y w-o'y-w-c' "',

In ft3 H-4 0 N-N

under gentle conditions, e.g. at a temperature of from -10 ° C to 10 ° C or using a mild Lewis acid, e.g. zinc chloride or gallium chloride, having a compound of the formula R11 ~ X2 [IV, X.2 = balogen carbonyl or 1 ^ -0 (= 0) -0-0 (= 0) -].

The reaction of compounds of formulas VII and VIII according to process e) is carried out in the usual manner from starting materials, wherein X5 or Xg represents a terminally substituted with a reactively esterified hydroxy substituted straight chain hydroxyalkoxy group, for example in the presence of a basic condensing agent such as a hydroxide or carbonate of an alkali metal or alkaline earth metal, e.g. sodium or potassium hydroxide, potassium carbonate or calcium carbonate, advantageously in a low alkanol, e.g. methanol or amyl alcohol, dilavalkyl ketone, e.g. acetone or diethyl ketone, or Ν, Ν-dilavalkyllavalkanoic acid amide or N-lowalkyllavalkanoic acid lactam, e.g. Ν, Ν-dimethylformamide or N-methyl-pyrrolidone.

Starting compounds of formula VII are prepared, for example, by reacting a compound of formula A ~ l] I (XIII)

HO7 'Y *' \> H

21

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in the presence of a Lewis acid, e.g. aluminum trichloride or zinc chloride, having a compound of formula [IV, X2 = halocarbonyl or R2 ~ C (= O) -0-C (= O) -] and, if desired, in the compound of formula VII wherein X5 means hydroxy, converts the hydroxy group X5 to one which is desirably substituted alkoxy group X5.

Compounds of formula VIII can be prepared, for example, by reducing the nitro group in a compound of formula R5 v I [j (XX) X6 / x / NsNO2 R4.

to amino, e.g. with hydrogen in the presence of Raney nickel, and reacting the compound of the formula

Rc, R, 5µ / V "6 in tt (xxi) X6 / R4 in the presence of a base, for example, of triethylamine or pyridine, with a compound of the formula Hal-C (= O) -R2 (Xlb .

Hal = halogen) and, if desired, in the compound of formula VIII wherein X5 is hydroxy, the hydroxy group Xg converts to a as desired substituted alkoxy group Xg ·

Hydroxy X5 or Xg can be used if desired, e.g. by reaction with a compound of the formula X-CH2 ~ CH (X ") - CH2X

22

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(XXV) wherein X means reactively esterified hydroxy, such as chlorine, bromine or iodine, and X "means hydroxy esterified with a carboxylic acid such as low alkanoyloxy, e.g., acetoxy, converting to a group of the formula. CH (X + J-CHtOX, which by treatment with an alkali metal hydroxide, for example with sodium hydroxide in methanol) can be converted to the group of formula -O-CH2-X 'where X * = epoxyethyl.

The conversion of the group alk 'to alk in a compound of formula IX according to process f) is carried out in the usual manner, from compounds of formula IX, wherein alk' means a hydroxy substituted with oxo or an a-aralkanol ether or a carbonic acid monobenzyl ester. -15-substituted alkylene group, e.g. reductively and solvolytically from compounds of formula IX, wherein alk 'means a group of alk substituted by etherated or esterified hydroxy groups other than the above-mentioned alkyl group.

For example, as reducing agents for the reduction of oxo-substituted alkylene groups alk * to corresponding groups of alk, alkali metal borohydrides such as lithium borohydride, sodium borohydride or sodium cyanoborohydride, or secondary alcohols such as secondary lower alkanools or cyclolavalkanols, e.g. isopropanol or cyclohexanol, in the presence of an aluminum alcoholate, especially isopropanol in the presence of aluminum isopropanolate. The reaction with said alkali metal borohydrides is advantageously carried out in a low alkanol, a dilavalkyl ether or a low alkyl ether or mixtures of these solvents, e.g. in ethanol. When reacting with alcohols in the presence of an aluminum alcoholate, an excess of the alcohol used as a reducing agent is conveniently employed.

The reductive cleavage of cx-aralkoxy or benzyloxy

DK 161644B

Carbonyloxy to hydroxy is preferably carried out by hydrogenolysis, i.e. by the action of hydrogen in the presence of a hydrogenation catalyst such as a palladium, platinum, iridium or nickel catalyst, e.g. palladium on coal, platinum oxide or Raney nickel, advantageously in a low alkanol, e.g. in methanolic solution, if necessary under overpressure and / or under heating, e.g. at pressure of approx. 1 to approx. 10 bar and 10 a temperature of 20-60 ° C.

The solvolytic release of hydroxy from silyloxy, low alkanoyloxy and low alkoxycarbonyloxy is carried out, for example, by hydrolysis (reaction with water), alcoholysis (reaction with an alcohol) or ammonolysis or aminolysis 15 (reaction with ammonia or an amine containing at least one free hydrogen atom) , if necessary in the presence of an acidic or basic agent and / or during heating, e.g. at a temperature of approx. 20 ° C to approx. 100 ° C.

Suitable acidic agents are, for example, mineral acids, such as hydrogen halide acids, e.g. hydrochloric acid, or oxygen-containing acids derived from sulfur or phosphorus, e.g. sulfuric acid or phosphoric acid, or organic sulfonic acids or carboxylic acids such as lower alkanesulfonic acids or optionally substituted benzenesulfonic acids or lower alkanoic acids, e.g. p-toluenesulfonic acid or acetic acid. Basic hydrolyzing agents are, for example, hydroxides or carbonates of alkali metals, e.g. potassium carbonate, sodium hydroxide or potassium hydroxide, for the alcoholysis, furthermore, corresponding alcohols such as alkali metal avalkanolates, e.g.

Sodium methanolate.

Starting compounds of Formula IX can be prepared, for example, by interconnecting compounds of formulas 24

DK 161644 B

fl R / 'w * V Rsw \ y * 6

u 1 and ii f H

,, ο / 'Χ'Χχ5 <X D

(VII) (VIII) wherein one of the groups X5 and Xg optionally represents a hydroxy present in salt form and the other means a terminally substituted with reactively esterified hydroxy substituted group -O-alk'-H, e.g. with the formula -O-CH 2 -C (= °) -CH 2 -X or -O-CH 2 -CH (X ") - CH 2 -X, where X" means etherified or esterified hydroxy and X means reactively esterified hydroxy.

The reaction of the corresponding compounds of formulas VII and VIII as well as their preparation is carried out, for example, by analogy to process e).

Reaction of compounds of formulas X and XI according to - - process g) may be carried out in the usual manner, especially using analogous reactions known from the literature, if necessary in the presence of a condensing agent, by reacting with an the position protected 5-halo-carbonyltetrazole XI, for example in the presence of a basic condensing agent such as a · tertiary organic nitrogen base, e.g. triethylamine or pyridine.

5-Halocarbonyltetrazoles XI protected at the 1-position are preferably prepared in situ, e.g. by reacting an alkali metal salt, e.g. the potassium salt, protected by a 1-position, e.g. α-aralkylated tetrazole-5-carboxylic acid with oxalyl chloride in the presence of pyridine.

The 1-protecting group in 5-tetrazolyl groups R2 can then be cleaved e.g. by treatment with trifluoro-25

DK 161644 B

acetic acid / anisole or hydrogenolytic, especially by means of hydrogen and palladium on coal.

Starting compounds of formula X may be prepared, for example, by interconnecting compounds of formulas «r / Χ- / Λ- R5v, Rfi 1 µl i and \ .x 6 / \ / \ χ i 'Ϊ (XX ) in 3 X / Y 2 R 4 (VII) wherein one of the groups X5 and X5 optionally represents a hydroxy present in salt form, and the other a terminally substituted 10 'with reactively esterified hydroxy substituted straight chain hydroxyalkoxy group or an terminally substituted with epoxy substituted straight chain alkoxy group, f. eg. a group of formula X'-Cl 2 -O- or X-CH 2 -CH (OH) -CH 2 -O- wherein X means reactively esterified hydroxy, e.g.

15 is halogen, and X1 is epoxyethyl, and reduction of the nitro group in the compound of formula r / V \ R5 \ ./ 'V / R9 11'! Lr I (xxvi) hq / Y Vaik _ </ γ \ ο, K3 R4 2 to amino, e.g. by reaction with hydrogen in the presence of a hydrogenation catalyst such as palladium on coal 20 or, first of all, Raney nickel, for example in tetrahydrofuran.

26

DK 161644 B

The conversion of group Xg into compounds of formula XII into the group of formula -NH-C (= Q) -R2 (R2 = 5-terzolyl) according to process h) is carried out, for example, by reaction with hydrogen azide acid.

The reaction with hydrogen azide acid is preferably carried out to form this in situ by treating alkali metal azide with an acid such as hydrochloric acid, preferably in toluene or similar solvents.

The starting compounds of formula XII are prepared, for example, by reacting a compound of formula s "y \ 5 \ / \ Z'6 H ϋ i i! (X)

/ \ \ / \ / V

Or an acid addition salt thereof with cyanoic acid of formula NC-C00H (XXVIIa) or a preferably functional derivative thereof. Functional derivatives of acids of formula XXVIIa are primarily acid derivatives containing an esterified or anhydrided carboxy group such as low alkoxycarbonyl or halocarbonyl, e.g. chloro-20 or bromocarbonyl. As functional derivatives of acids of formula XXVIIa, for example, cyanformyl chloride or dicyan may be used.

The reaction of compounds of formula X with acids of formula XXVIIa or derivatives thereof may be carried out in the usual manner, for example in the presence of a water-binding agent such as an acid anhydride, e.g. phosphorus pentoxide, or dicyclohexylcarbodiimide, or a 27

DK 161644 B

eg. acidic or basic condensing agent, such as a mineral acid, e.g. hydrochloric acid, or an alkali metal hydroxide or carbonate, e.g. sodium or potassium hydroxide, or an organic nitrogen base, e.g. triethylamine or pyridine. In the reaction with an acid anhydride, such as an acid chloride, an organic nitrogen base is preferably used as a condensing agent. Reaction with carboxylic acids is preferably carried out in the presence of a water-binding agent. If necessary, the reactions are carried out in an inert solvent, at normal temperature or under cooling or heating, e.g. in a temperature range of approx. 0 ° C to approx. 100 ° C, in a closed container and / or under an inert gas atmosphere, e.g. in a nitrogen atmosphere.

A compound of general formula I can be converted into another compound of the general formula I.

In a prepared compound of formula I, e.g. in the phenyl ring bearing the 1H-5-tetrazolyl-carboxamido group introduce substituents and / or convert the substituents present to other substituents. Thus, e.g. by reacting with a lower alkyl halide or a low alkene, in each case in the presence of a Lewis acid such as aluminum trichloride, introduce lower alkyl. Furthermore, halogen may be introduced, e.g. by treatment with a halogen in the presence of a Lewis acid such as iron III chloride, or by reaction with 30 N-chlorosuccinimide. Furthermore, halogen, especially iodine, can be exchanged by reaction with an alkali metal cyanide with cyano.

The present compounds of formula I may, depending on the choice of starting compounds and the mode of action, be in the form of one of the possible isomers or as a mixture thereof, e.g. depending on the number of asymmetric carbon atoms, 28

DK 161644 B

as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomeric mixtures, or racemate mixtures.

Formed diastereomeric mixtures and racemate mixtures can, due to the physicochemical differences of the constituents, be separated in known manner into the pure isomers, diastereomers or racemates, e.g. by chromatography and / or fractional crystallization.

Furthermore, produced racemates can be separated into the optical antipodes in a manner known per se, e.g. by recrystallization from an optically active solvent, by microorganisms or by reacting an acidic end product with an optically active base which forms 15 salts with the racemic acid, and separating the salts thus formed, e.g. due to various solubilities, in the diastereomers from which the antipodes can be released by the action of suitable agents. Advantageously, one isolates the most effective of the two antipodes.

Prepared free compounds of formula I can be converted into a salt in a manner known per se, e.g. by treatment with a base or with a suitable salt of a carboxylic acid, usually in the presence of a solvent or diluent.

Formed salts of compounds of formula I can be converted to the free compounds of formula I in a manner known per se, e.g. by treatment with an acidic reagent such as a mineral acid.

The compounds of formula I and their salts may also be in the form of hydrates or they may contain the solvent used for crystallization.

29

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Due to the close relationship between the present compounds of formula I in free form and in salt form, the previous and subsequent free compounds or their salts may optionally also mean the corresponding salts or free compounds.

The invention also relates to such embodiments of the process in which starting from any intermediate compound-formed process and carrying out the missing steps or using a starting material in the form of a salt and / or a racemate or antipodes or, in particular, it forms under the reaction conditions.

Preferably, such starting compounds and reaction conditions are used which lead to the above-mentioned particularly preferred compounds of formula I.

The invention also relates to pharmaceutical compositions which are characterized in that they contain a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, and optionally conventional pharmaceutical adjuvants.

The pharmaceutical compositions are preparations for topical and topical as well as enteral, such as oral or rectal, as well as parenteral administration and for inhalation in humans and warm blooded animals, and which contain the pharmacologically active substance alone or together with a pharmaceutically useful carrier. The dosage of the active substance depends on the animal species, the age and the individual condition as well as the mode of application.

30

DK 161644 B

The pharmaceutical compositions contain e.g. from approx. 10% to about 95%, preferably about 10%. 20% to approx. 90% active substance. Pharmaceutical compositions of the invention are, for example, those in aerosol or spray form or in dosage unit forms such as dragees, tablets, capsules or suppositories, in addition, ampoules.

The pharmaceutical compositions are prepared in a manner known per se, e.g. by conventional mixing, granulation, drageering, dissolution or lyophilization methods. Pharmaceutical preparations for oral administration can thus be prepared by combining the active substance with solid carriers, optionally granulating a formed mixture and processing the mixture or granulate, if desired or if necessary after the addition of suitable excipients, to tablets or dragee cores.

Suitable carriers are in particular fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; further, binders such as starch adhesives, e.g. corn, wheat, rice or potato starch paste, gelatin, tragaganth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above starch types, in addition carboxymethyl starch, crosslinked polyvinylpyrrolidone, or crosslinked polyvinylpyrrolidone, or thereof, such as sodium alginate. Assistive products are primarily flow regulating agents and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores appear with suitable, possibly stomach-resistant coatings. uses concentrated sugar solutions optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, varnish solutions in suitable organic solvents or solvents or, to prepare gastric-resistant coatings, solutions of suitable cellulose preparations,

DK 161644 B

such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragee coatings may be added to dyes or pigments, e.g. for identifying or characterizing different doses of 5 active substance.

Other pharmaceutical compositions for oral use are gelatin socket capsules as well as soft closed capsules of gelatin and a plasticizer such as glycerol or sorbitol. The capsules may contain the active substance in the form of a granule, e.g. in admixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as fatty oils, paraffin oil or liquid polyethylene glycols, as stabilizers may also be added.

Pharmaceutical compositions for rectal use are e.g. suppositories, which consist of a combination of the active substance and a suppository matrix. As a suppository base mass, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols may be used. Furthermore, gelatin rectal capsules may be used which contain a combination of the active substance with a matrix. Liquid triglycerides, polyethylene glycols or paraffin hydrocarbons can be used as matrix materials, for example.

Suitable compositions for parenteral administration are primarily aqueous solutions of an active substance in water-soluble form, e.g. a water-soluble salt, further, suspensions of the active substance, such as similar oily injection suspensions, using suitable lipophilic solvents or carriers such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity enhancers, e.g. sodium carboxymethyl- 32

DK 161644 B

cellulose, sorbitol and / or dextran and optionally | stabilizers. | in

Inhalation preparations for treating the respiratory tract by nasal or buccal administration are, for example, aerosols or spray preparations which can disperse the pharmacologically active substance in the form of a powder or in the form of drops of a solution or suspension. Powder-distributing compositions generally contain, in addition to the active substance, a liquid propellant having a boiling point below room temperature, and, if desired, carriers such as liquid or solid nonionic or anionic surfactants and / or diluents. In addition, compositions in which the pharmacologically active substance is present in solution contain a suitable propellant, and, if necessary, an additional solvent and / or a stabilizer. Instead of the propellant gas, compressed air can also be used, which can be produced as needed by means of a suitable condensing and tensioning unit.

Pharmaceutical compositions for topical and topical use are e.g. for the treatment of skin lotions and creams containing a liquid or semi-solid oil-in-water emulsion or water-in-oil emulsion, and ointments (preferably containing a preservative), for the treatment of eye drops which contain the active compound in aqueous or oily solution, and eye ointments, preferably prepared in sterile form, for the treatment of nasal powders, aerosols and spray preparations (similar to those described above for the treatment of the respiratory tract), and coarse powder intended for rapid inhalation through the nostrils and nasal drops containing the active compound in aqueous or oily solution, or for topical treatment of the mouth suction cups containing the active compound in a mass usually composed of sugar and gum arabic or tragaganth, and which may be flavored, as well as 35 lozenges containing the active ingredient in an inert mass, e.g. of gelatin and glycerol or sugar and gum arabic.

DK 161644 B

-33

When using the novel compounds of formula I and their salts as pharmacologically active compounds, especially as antiallergics, preferably in the form of pharmaceutical preparations, the daily dose to a warm blooded animal or human with a body weight of about 5 70 kg from approx. 200 mg to approx. 1200 mg.

The invention is further illustrated in the following examples.

Example 1 A solution of 12.8 g (19.1 mmol) of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4 -Bromo-6-methyl-phenyl} -1- (4-methoxybenzyl) -1H-tetrazole-5-carboxamide in 250 ml of trifluoroacetic acid and 25 ml of anisole are heated under reflux for 30 minutes. The reaction mixture is evaporated under reduced pressure, adding approx. 300 ml of ether and 400 ml of petroleum ether and the crystals are filtered off. The N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) 2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -H tr a zo 1 - 5 -carboxamide with m.p. 155-158 ° C, 1 H-NMR spectrum (6 vs. TMS, 20 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), 6.65 (doublet, 1H), 7, (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 an equivalent of triethanolamine is added in 10 ml of acetone. After addition of ether, crystallization occurs. In this way, the triethanolammonium salt of N - {'3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} is obtained. -IH-tetra zo1-5-carboxamide 30 m.p. 76 ° C (dec.).

Analogous to the process described above is prepared from N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl phenyl} -1- (4-methoxybenzyl) -1H-tetrazole-5-carboxamide N- {3- [3- (4-acetyl-3-hydroxy-2-35 n-propylphenoxy) -2-hydroxy-propyloxy ] -4-chloro-6-methyl-34

DK 161644 B

phenyl} -1H-tetrazole-5-carboxamide, oil, 1 H-NMR spectrum (6 vs. TMS, DMSO-dg): 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 δ (doublet, 1H), 7.25 (singlet, 1H), 7.35 (singlet, 1H), 7.85 (doublet, 1H), 10.70 (singlet, 1H), 12.80 (singlet, 1H) , and its triethfranolammonium salt.

The starting material may be prepared, for example, as follows: To a solution of 16.2 g (70 mmol) of 2-bromo-4-methyl-5-nitro-phenol in 130 ml of ethanol is added 0.32 g (7.4 mmol) of 55 % sodium hydride dispersion in oil. Under reflux, a solution of 4- (2,3-epoxypropoxy) -2-hydroxy-3-propyl-aceto-phenone (18.4 g, 73.5 mmol) is then added dropwise in 150 ml of ethanol. Then, the mixture is heated for an additional 8 hours to reflux. The reaction mixture is cooled, evaporated in vacuo to ca. 100 ml and poured on ice.

The aqueous phase is acidified with dilute hydrochloric acid and extracted 3 times with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. Crystallization from ether gives 3- [3- C4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-nitrobenzene, m.p. 104-106 ° C ·

Analogously to the process described above, 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-ni-trobenzene is prepared with mp. 103-105 ° C (from 2-chloro-4-methyl-5-nitro-phenol).

To a solution of 23.3 g (48.3 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6- 30 g of methyl nitrobenzene in 240 ml of tetrahydrofuran are added 2.0 g

Raney nickel and hydrogenation at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The combined filtrates are evaporated in vacuo, ether is added and the precipitated crystals are filtered off.

H DK 161644 B

In this way, 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-aniline is obtained, m.p. 78-80 ° C.

Analogously to the process described above, 5 is prepared from 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl -nitrobenzene 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-aniline, m.p. 94-95 ° C.

To a suspension of 10.6 g (38.8 mmol) of potassium [1- (4-methoxybenzyl) -1H-tetrazole] -5-carboxylate in 170 ml of benzene and 1.5 ml of pyridine is added at 0-5 ° C 3.38 ml (38.8 mmol) of oxalyl chloride and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is evaporated under reduced pressure, the residue is taken up in benzene and evaporated again under reduced pressure. The residue is dissolved in 135 ml of dichloromethane, whereupon this solution is added dropwise over 10 minutes at a temperature of 0-5 ° C to a solution of 12.85 g (28.4 mmol) of 3- [3- (4-acetylacetamide)]. 3-hydroxy-2-n-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-aniline and 2.7 ml (33 mmol) of pyridine in 100 ml of dichloromethane. Then the mixture is stirred for 3 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed 3 times with water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue is filtered with dichloromethane / ethyl acetate (6: 1) over 400 g of silica gel. The eluate is evaporated and the residue is crystallized from ethanol. In this way, N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -

4-bromo-6-methyl-phenyl} -1- (4-methoxybenzyl) -1H-tetrazole-5-carboxamide, m.p. 114-116 ° C

Analogous to the process described above is prepared from 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-aniline N - {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-phenyl} -! - (4-methoxybenzyl) -LH-tetrazol-5-carboxamide.

36

DK 161644 B

Example 2

A solution of 7.1 g (11.8 mmol) of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyano phenyl} -1- (4-methoxybenzyl) -1H-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole are heated to reflux for 30 minutes. The reaction mixture 'is evaporated under reduced pressure, adding approx. 200 ml of ether and 300 ml of petroleum ether and the crystals are filtered off. The N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyano-phenyl} -1H-tetrazole-5-carboxamide with m.p. 210-213 ° C is dissolved hot in 50 ml of acetone, then an equivalent of triethanolamine is added in 20 ml of acetone. After addition of ether, crystallization occurs. In this way, the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyano-phenyl} -1H-tetrazole is obtained -5-carboxamide with m.p. 80-82 ° C.

For example, the starting materials are prepared as follows:

To a solution of 34 g (207 mmol) of 2-hydroxy-6-nitro-benzonitrile and 60 g of 4 - [(2,3-epoxy) propyloxy] -2-hydroxy-3-propyl-acetophenone in 450 30 drops of "TRITON B" are added in ml of dimethylformamide. The solution is heated to reflux for 1.5 hours, then the solvent is removed and the residue is taken up in 500 ml of ethyl acetate. After washing with 500 ml of 0.5 N sodium hydroxide solution and 500 ml of water, dry with magnesium sulfate.

The solvent is evaporated and the residue is chromatographed on methylene chloride / ethyl acetate (95: 5) on silica gel. 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propoxy] -6-nitro-benzonitrile is obtained. 117 "119 ° C.

To a solution of 10 g (24.2 mmol) of 2- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propoxy] -6-nitro-benzonitrile and 10 g of cyclohexene In 500 ml of ethanol, 2.5 g of 10% palladium is added to charcoal and the mixture is heated to reflux for 30 minutes. After cooling to room temperature, the mixture is filtered and the solvent is evaporated. To the residue is added ether, and 37

DK 161644 B

separated crystals are filtered off. There is obtained 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyanoaniline, m.p. 123-125 ° C.

To a suspension of 5.8 g (21.5 mmol) of potassium {1- (4-methoxybenzyl) -] E-tetrazole} -5-carboxylate in 110 ml of benzene and 1.0 ml of pyridine is added. at 0-5 ° C 1.84 ml (21.5 mmol) of oxalyl chloride and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is evaporated under reduced pressure, the residue is taken up in benzene and again evaporated under reduced pressure. The residue is dissolved in 80 ml of methylene chloride and added dropwise at 0-5 ° C over approx. 10 minutes to a solution of 5.87 g (17.2 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-n-propyl'-phenoxy) -2-hydroxy-propyloxy] -2 -cyanoaniline and 1.72 ml (21.5 mmol) of pyridine in 40 ml of methylene chloride. The mixture is then stirred for 3 hours at room temperature. The reaction mixture is diluted with methylene chloride and washed 3 times with water. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed with methylene chloride / ethyl acetate (6: 1) on silica gel. N - {. 3- [3- (4-Acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxypropoxy] -2-cyano-phenyl} -1- (4-methoxybenzyl) -1H -tetrazole-5-carboxamide in the form of a colorless oil.

Example 3

Analogous to the process described above in Examples 1 and 2, respectively, are prepared from 2-fluoro-4-methyl-5-nitro-phenol, 4-methyl-5-nitro-phenol and 2-hydroxy-5-methyl-phenol. 4-nitro-benzonitrile and N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-fluoro-6-methyl-phenyl} -one 1 H -Tetrazole-5-carboxamide, 1 H NMR Spectrum (δ vs. 30 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), 6.65 (doublet, 1H) , 7.25 (singlet, 1H), 7.65 (singlet, 1H), 7.85 (doublet, 1H), 10.70 (singlet, 1H), 12.80 (singlet, 1H), and its triethanolammonium salt, N- {3- [3- (4-acetyl-3-hydroxy-38)

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2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -6-methyl-phenyl} -1H-tetrazole-5-carboxamide, 1 H-NMR spectrum (δ vs. TMS, DMSO-dr): 0f85 (triplet, 3H) ,. 1.45 (multiplet, 2H), 2.25 (singlet)

ISLAND

light, 3H), 2.55 (multiplet, 2H), 2.60 (singlet, 3H), 4.0-4.7 (multiplet, 4H), 5.90 (multiplet, 1H), 6.60 ( multiplet, 2H), 7.10 (doubled, 1H), 7.80 (multiplet, 2H), 10.70 (singlet, 1H), 12.80 (singlet, 1H), and its triethanolammonium salt as well as N

J

{3- [3- (4-Acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-cyano-6-methyl-phenyl} -1H-tetrazo-5-carboxamide 10 H-NMR spectrum (6 vs. TMS, DMSO-d): 0.85 (triplet, 3H),

ISLAND

1.45 (multiplet, 2H), 2.25 (singlet, 3H), 2.55 (multiplet, in 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 its triethanolammonium salt.

Example 4 4.9 g of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy-2-hydroxy-propyloxy] -6-methyl-phenyl} -1H-tetrazole) Dissolve 5-carboxamide in 45 ml of acetone and add a solution of 1.0 g of diethanolamine in 5 ml of acetone. After addition of diethyl ether crystallization occurs. The mixture is left for 30 minutes at 5-10 ° C and the precipitate is suctioned off. , washed with diethyl ether and air dried to give the diethanol-ammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] 6-Methylphenyl} -1H-tetrazole-5-carboxamide Analogously, its sodium, potassium, diethylammonium and tris (hydroxymethyl) methylammonium salt can also be prepared.

In addition, the sodium, potassium, diethanolammonium, diethylammonium and tris (hydroxymethyl) methylammonium salt of the N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl) salt) phenoxy) -2-hydroxy-propyloxy] -2-cyano-phenyl} -1H-tetrazole-5-carboxamide, N - {3- [3- (4-acetyl-3-hydroxy-2-n-propyl) phenoxy) -2-hydroxy-propyl-oxy] -4-bromo-6-methyl-phenyl} -35H-tetrazole-5-carboxamide, N- {3- [3- (4-acetyl-3-hydroxy) 2-n- 39

DK 161644 B

propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-phenyl} -1H-tetrazole-5-carboxamide, N ~ {3- [3- (4-acetyl-3-hydroxy-2- n-propylphenoxy) -2-hydroxy-propyloxy] -4-fluoro-6-methyl-phenyl} -1H-tetrazole-5-carboxamide and N- {3- [3- (4-acetyl-3-hydroxy) 2-5 n-propylphenoxy) -2-hydroxy-propyloxy] -4-cyano-6-methyl-phenyl} -1H-tetrazole-5-carboxamide.

Example 5

Tablets containing 25 mg of active substance, e.g. the triethanol-ammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H -tetrazole-5-carboxamide, can be prepared as follows:

Ingredients (for 1000 tablets):

Active substance 25.0 g

Lactose 100.7 g 15 Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

Demineralized water e.g.

Preparation:

All solid components are first screened through a screen having a mesh width of 0.6 mm. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are mixed.

The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water, whereupon the mixture is granulated, if necessary, with the addition of water. The granulate is dried overnight at 35 ° C, pressed through a sieve with a mesh width of 1.2 mm and compressed into double concave tablets having a diameter of approx. 6 mm.

Analogously, tablets containing 25 mg of another of the compounds of Examples 1-4 may also be prepared.

40

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Example '6

Chewable tablets containing 30 mg of active substance, e.g. the tri-ethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4- & Γθπι-6-πιβΐ] ^ 1-ρ] ιβ For example, 1}-tet-5 tetrazole-5-carboxamide can be prepared as follows:

Composition (for 1000 tablets):

Active substance 30.0 g

Mannitol · 267.0 g Lactose 179.5 g

Talc 20.0 g

Glycine 12.5 g

Stearic acid 10.0 g

Saccharin 1.0 g of 5% gelatin solution q.s.

Preparation:

All solid components are first pressed through a sieve with a mesh width of 0.25 mm. The mannitol and lactose are mixed, the mixture is granulated with the addition of gelatin solution, the granulate is pressed through a sieve with a mesh width of 2 mm, dried at 50 ° C and then pressed through a sieve with a mesh size of 1.7 mm. The active substance, glycine and saccharin are thoroughly mixed, mannitol, lactose granulate, stearic acid and talc are added, and the whole mixture is thoroughly mixed and compressed into double concave tablets of approx. 10 mm and with split notch on the upper side.

Similarly, tablets containing 30 mg of another of the compounds of Examples 1-4 may also be prepared.

Example 7

Tablets containing 100 mg of active substance, e.g. the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H-41

DK 161644 B

tetrazole-5-carboxamide, can be prepared as follows:

Composition (for 1000 tablets):

Active substance 100.0 g

Lactose 248.5 g 5 Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium stearate 4.0 g

Demineralized water q.s.

Preparation:

The solid components are first pressed through a sieve with a mesh width of 0.6 mm. Then, thorough mixing of the active substance, lactose, talc, magnesium stearate and half of the starch is made. 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 formed adhesive is added to the powdered ingredients, the whole mixture mixed and granulated, if necessary, with the addition of water. The granulate is dried overnight at 20 ° C, pressed through a screen having a mesh width of 1.2 mm and compressed into double concave tablets with a diameter of about 10 mm with split notches on the top.

By analogy, tablets containing 100 mg of another compound prepared according to Examples 1-4 may also be prepared.

Example 8

A propellant-containing solid aerosol-forming inhalation suspension containing 0.1% by weight of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6 For example, -30 methyl-phenyl} -1H-tetrazole-5-carboxamide (active substance) can be prepared as follows:

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composition:

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

Fuel A

(Trichlorotrifluoroethane) 4.4% by weight

Fuel B

(mixture of 15 parts of dichlorodifluoro-methane and 80 parts of symmetrical dichloro-tetrafluoroethane) q.s.

Preparation;

The active substance is suspended under moisture exclusion by means of an ordinary homogenizer with the addition of sorbitan trioleate in trichlorotrifluoroethane, the suspension being charged to a dosing aerosol container which is closed and filled under pressure with the dichlorodifluoromethane-dichlorotetrafluoroethane mixture.

Similarly, inhalation suspensions may also be prepared containing another compound prepared according to Examples 1-4.

Example 9

One approx. 2% aqueous solution containing the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl phenyl} -1H-tetrazole-5-carboxamide as an active ingredient suitable for inhalation can be prepared, for example, with the following composition:

composition;

Active substance 2000 mg

Stabilizer, e.g. ethylene diamine tetraacetic acid disodium salt 10 mg 30 Preservative, e.g.

benzalkonium chloride 10 mg

Water, freshly distilled over 100 ml 43

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Preparation:

The active substance is dissolved in fresh distilled water. Then, the stabilizer and preservative are added. After complete dissolution of all the components, the resulting solution is adjusted to a volume of 100 ml, filled into small bottles which are sealed airtight.

By analogy, 2% inhalation solutions containing another active substance prepared according to one of Examples 1-4 can also be prepared.

1Q Example. 10

Capsules for insufflation, containing approx. 25 mg of triethanol-ammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl} -1H- For example, tetrazole-5-carboxamide as an active substance can be prepared with the following composition:

composition:

Active substance 25 g

Lactose, finely ground 25 g

Preparation ·:

The active substance and lactose are thoroughly mixed. The resulting 20 powder mixture is then sieved and then, in portions of 50 mg, filled into 1000 gelatin capsules.

Similarly, insufflation capsules containing another active ingredient prepared according to one of Examples 1-4 may also be prepared.

Claims (11)

1. Substituted N- {3- [c <> - (4-acyl-3-hydroxy-2-alkyl-phenoxy) -hydroxyalkoxy] -phenyl} -1H-tetrazole-5-carboxamides 5 having antiallergic effect, characterized by that they have the general formula? - / X / -6 R1 h \ «! "(I) k3 * 4 8 HN wherein C is (C 1-4) alkyl, alk means straight chain hydroxy-C (3-7) alkyl, wherein the hydroxy group is bonded to the free valences at a higher position than α- the position and in a lower position than the ω position, R3 means C (1-4) alkyl, R4 means hydrogen or cyano, R5 means hydrogen, halogen having an atomic number not exceeding 53 or cyano, and Rg means hydrogen or C (1) -4) -alkyl, wherein at least one of the groups R4, R5 and Rg is different from hydrogen and salts thereof. A compound according to claim 1, characterized in that R4 is hydrogen, R5 is halogen with an atomic number of not more than 53, Rg is C (1-4) alkyl, and alk is straight hydroxy-C (3-4) - the alkylene in which the hydroxy group is bound to the free valences at a higher position than the α position and at a lower position than the ω position. Compound according to claim 1, characterized in that it is N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo -6-methyl-phenyl} -1H-tetrazole-5-carboxamide or a salt thereof. Compound according to claim 1, characterized in that it is N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) - 2-hydroxy-propyloxy] -2 -cyano-phenyl} -1H-tetrazole-5-carboxamide or a salt thereof. Compound according to claim 1, characterized in that it is N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -6-methyl -phenyl} -1H-tetrazole-5-carboxamide or a salt thereof. Compound according to claim 1, characterized in that it is N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -10 2-hydroxy-propyloxy] -4-chloro ~ 6-methyl-phenyl} -1H-tetr-azole-5-carboxamide or a salt thereof. Compound according to claim 1, characterized in that it is N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-cyano-2 6-methyl-phenyl} -1H-tetrazole-5-carboxamide or a salt thereof. A compound according to any one of claims 1-7, characterized in that it is in the form of the sodium, potassium, tri-ethanolammonium, diethylammonium, diethanolammonium or tris (hydroxymethyl) methylammonium salt. Pharmaceutical preparations, characterized in that they contain a compound of formula I according to one of claims 1-8 in free form or in the form of a pharmaceutically useful salt, optionally together with conventional pharmaceutical excipients. 10. Analogous Process for Preparing Substituted N- {3- [3- (4-Acyl-3-hydroxy-2-alkyl-phenoxy) -hydroxyalkoxy] -phenyl} -IH-tetrazole-5-carboxamides formula DK 161644 B R1 u I ?! Η (Ι) "o7 Υ ValkV Y" HCf "ϊ ij» 4 6 * -Ν wherein R 1 is C (1-4) alkyl, alk means straight chain hydroxy-C (3-7) alkyl, wherein the hydroxy group is bound to 5 the free valences at a higher position than the or position and at a lower position than the ω position, R0 means C (1-4) -alkyl, R4 means hydrogen or cyano, R5 means hydrogen, halogen with an atomic number of at most 53 or cyano, and Rg is hydrogen or C (1-4) alkyl, wherein at least one of the groups R4, R5 and Rg is different from hydrogen, or salts thereof, characterized in that a) compound of the formula / \ R5w '\ / 6 H i *!! XX (XX) Vff "0" Y' o- »1 * -0 'Y" 1 {j, r3 k4 0 n-N or 15 b) converts a compound of the formula / V R5N / \ / 6 11. in jj (III) Y V. '- 0' 'Ϊ 1 K4 ^ NN wherein Χχ means optionally etherified hydroxy, with a compound of formula R1-X2 (IV) / wherein Xo optionally represents functionally converted carboxy, or c) in a compound of formula DK 161644 B X3V R5W \ / «ή > '1 H (v) "(/' Y'Vatk-i /" "k3 ^ 4 δ K-" wherein X3 means a group which can be converted to the group of formula R 1 -C (= O) -, X 3 to this group, or 5 d) in a compound of the formula / s "-sx / 's / 6 R1 .1 i»! H (vi) 4 k3 Η ΰ N- N wherein X4 means a group which can be converted to hydroxy, converting X4 to hydroxy, or e) mutually reacting compounds of the formulas in R v /% γ H Rl i1 1 g g A, /% / \ ^ \ YYV Vc-S b H0y X5 x6 S n- -N r3 (VII) (VIII) wherein one of the groups X5 and Xg optionally represents a hydroxy present in salt form and the other means a terminally substituted with a reactively etherified hydroxy substituted straight chain hydroxyalkoxy group or an terminated with epoxy substituted straight chain alkoxy group, or f) in a compound of formula DK 161644 BA / VV / V7 * 6 Rl * * (IX) / \ / \ / XA \ jh-C— CN »o · O-alk'V t ^ I J_S in K3 - -! wherein alk * means a group which can be converted to alk, j converts alk * to alk, or 5 g) converts a compound of formula j? . Rr. / v / ^ 6 / \ / ^ 5x / V R1 ii in "ί (X) H (/ y'Valk-o7 X; / Viffl2 k3 a4 or a salt thereof with a compound of formula X7 - R2 (XI) wherein R 2 optionally represents in the 1-position protected 5-tetrazolyl, and X 7 means halogenated carbonyl, wherein halogen is chlorine, bromine or iodine, or, if R 2 means in the 1-position, protected 5-tetrazolyl, a salt-carboxyl group and liberates 5 -tetrazolyl group protected from the 1-position 5-tetrazolyl R 2, or 15 h) in a compound of formula X / V v. Wherein Xg represents a group which can be converted to an IH-tetrazole-5-carboxamido group, Xg converts to this group and, if desired, , converting a prepared compound of formula I into another compound of formula I and / or converting a manufactured free compound of formula I into a salt thereof or a manufactured salt of a compound of formula I into the free compound of formula I or to another salt.