DD240888A5 - METHOD FOR PRODUCING OTHER RESORCINAETHERS - Google Patents

Abstract

The invention relates to a process for the preparation of new 4-Acylresorcinaether for use as a medicament. The aim of the invention is the provision of new 4-Acylresorcinaether with antiallergic activity. According to the invention, new 4-acylresorcinol ethers of the formula wherein R1 is lower alkyl, alk is hydroxy optionally interrupted by oxygen and R2 is 5-tetrazolyl, ring A being additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and / or halogen and the ring B may additionally be substituted by lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, carboxy, cyano, carbamyl, halogen and / or trifluoromethyl, and their salts. Formula I

Description

^R 3 ^R 6

in which R, is lower alkyl with up to and with 4 C atoms, R _{2 is} 5-tetrazolyl, R _{3 is} lower alkyl with up to and with 4 C atoms, R _{4 is} hydrogen, lower alkyl with up to and with 4 C atoms, lower alkoxy having up to and including 4 carbon atoms or halogen having an atomic number is up to and including 35, R ₅ is hydrogen, lower alkyl having up to and including 4 carbon atoms, halogen having an atomic number of up to and including 35 or trifluoromethyl, R ₆ is hydrogen, lower alkyl bis and with 4C atoms, lower alkoxy with bis and with 4 C atoms, cyano or halogen of the atomic number up to and including 35 and R _{7 represents} hydrogen, lower alkyl with up to and with 4 C atoms, halogen of the atomic number up to and including 35, lower alkoxycarbonyl with bis and with 5 C atoms, carboxy, cyano or lower alkanoyl with up to and with 7 carbon atoms and alk for terminally bonded hydroxy-3-substituted lower alkylene, wherein the free valencies of the hydroxy group ß-C atoms go out, stand, or make their salts.

5. The method according to item 1 or 2, characterized in that one represents compounds of the formula Ia, wherein R _{1 is} lower alkyl having up to and with 4 C atoms, R _{3 is} straight-chain lower alkyl having up to and 4 C atoms, R _{2 represents} 5-tetrazolyl R ₄ is hydrogen, R 5 is lower alkyl, R _{6 is} hydrogen, R _{7 is} hydrogen, halogen of atomic number to and with 35 or cyano, and alk is straight-chain, terminally bound hydroxy-lower alkylene having 3 or 4 C atoms, wherein the free valencies from the hydroxy group ß-standing C-atoms, means, or produces their salts with bases.

6. The method according to item 1 or 2, characterized in that 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.

7. The method according to item 1 or 2, characterized in that 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.

8. The method according to item 1 or 2, characterized in that 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.

9. The method according to item 1 or 2, characterized in that N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro 6-methyl-phenyl} -1H-tetrazole-5-carboxamide or a salt thereof.

10. The method according to item 1 or 2, characterized in that N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-fluoro -6-methylphenyl} -tetrazole-5-carboxamide or a salt thereof.

11. The method according to item 1 or 2, characterized in that N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxyM-cyano-B methyl-phenyl-1-tetrazole-B-carboxamide or a salt thereof.

12. The method according to item 1 or 2, characterized in that one prepares a compound obtainable according to one of the items 1 to 11, in the form of the sodium, potassium, triethanolammonium, Diäthylammonium-, Diathanolammoniunvwder tris (hydroxymethyl) methylammonium salt.

Field of application of the invention

The invention relates to a process for the preparation of novel 4-acylresorcin ether with valuable pharmacological properties,

especially with pronounced antiallergic activity.

The compounds prepared according to the invention are used as medicaments, in particular as antiallergic agents.

Characteristic of the known technical solutions

There are no known data on compounds that have antiallergic activity. There are also no details known about processes for the preparation of 4-Acylresorcinäther.

The aim of the invention is the provision of new compounds, with valuable pharmacological properties, in particular with anti-allergic effect.

Explanation of the essence of the invention

"The invention has for its object to find new 4-Acylresorcinäther with the desired properties and processes for their preparation

 According to the invention, new 4-Acylresorcinäther the formula

l | _A j (j B -4 "- NH-CR ₂

alk is an optionally interrupted by oxygen hydroxyalkylene radical and R _{2 is} 5-tetrazolyl, wherein the ring A additionally by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and / or halogen and the ring B additionally by lower alkyl, lower alkanoyl, Lower alkoxy, lower alkoxycarbonyl, carboxy, carbamyl, cyano, halogen and / or trifluoromethyl and their salts.

Optionally interrupted by oxygen hydroxyalkylene are, for example, preferably geradkettige Hydroxyniederalkylenreste or hydroxy (oxa) alkylene or hydroxy (dioxa) alkylene radicals, wherein the hydroxy group in higher than the α- and lower than the ω-position to the free valencies and is bound in an oxo-member (s) which may be present in a position higher than the β-position relative to (m) and which is present in higher than the β- and lower than the (ω-1) -position relative to the free valencies. Such radicals are in particular radicals of the formula

wherein η and n 'are independently of each other 2,3 or 4 and ο and ρ are independently 0 or 1, before

Hydroxyniederalkylen- or hydroxy (oxa) lower alkylene radicals of the formula Ib, wherein the indices ο and ρ 0 and one of the indices ο and ρ is 1 and the other is 0 and η and n 'is 2.

Above and below, "lower" organic compounds and groups derived therefrom are, for example, those which have up to and including 7, in particular up to and including 4 carbon atoms (C atoms).

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl, furthermore secondary or tertiary butyl in the case of Ri, in particular methyl and in the case of a lower alkyl substituent of the ring A, in particular propyl.

Lower alkoxy means, for example, methoxy, ethoxy, propyloxy, isopropyloxy and butyloxy.

Halogen has, for example, the atomic number up to and including 53, in particular 17 to and 53, and denotes, for example, fluorine, chlorine, bromine and iodine.

Lower alkenyl is for example allyl, furthermore methallyl or but-4-enyl.

Lower alkynyl is, for example, propargyl.

Lower alkanoyl is, for example, formyl, acetyl, propionyl, butyryl, valeroyl or pivaloyl.

Hydroxyniederalkylen, wherein the hydroxy group is bonded in higher than the α- and lower than the ω-position, for example, 1,3- (2-hydroxy) propylene, but can also be 1,4- (2-hydroxy) butylene or 1 To be 5- (3-hydroxy) pentylene.

Hydroxy (oxa) lower alkylene, wherein the hydroxy group in higher than the α- and lower than the ω-position to the free valencies and in higher than the ß-position to the oxo, which in turn in higher than the ß- and in is lower than the ω-1! -location to the free valencies, is, for example, 1,7- (2-hydroxy-4 ^; oxa) heptylene, but may also be 1,6- (2-hydroxy-4-oxa ) hexylensein.

Lower alkoxycarbonyl is, for example, methoxy, ethoxy, propyloxy, isopropyloxy or butyloxycarbonyl.

Suitable salts of compounds of the formula I are preferably pharmaceutically acceptable salts, such as metal salts, ammonium salts or salts with organic bases. Metal salts are, for example, corresponding alkali, alkaline earth metal salts,

z. As lithium, sodium, potassium, magnesium or calcium salts, and pharmaceutically usable transition metal, such as zinc or copper salts. Salts with organic bases are exemplified by compounds of the formula I in which R _{2 is} carboxy or 5-tetrazolyl, with mono-, di- or trisubstituted organic amines, such as corresponding alkylamines, hydroxyalkylamines, suitable heterocycles having at least one N-atom, such as morpholine , Thiomorpholine, piperidine or pyrrolidine, optionally N-substituted amino-saccharides, e.g. With N-methyl-D-glucamine or basic amino acids such as lysine, arginine, histidine or ornithine, with those of L configuration being preferred. As alkylamines come z. As mono-, di- or Triniederalkylamine, such as ethyl, tert-butyl, diethyl, diisopropyl, trimethyl or triethylamine, into consideration. Hydroxyalkylamines are, for example, mono-, di- or trihydroxyalkylamines, such as mono-, di-, triethanolamine or diisopropanolamine, or hydroxy lower alkyl-lower alkylamines, such as Ν, Ν-dimethyl, Ν, Ν-Diäthylaminoäthanol or tri (hydroxymethyl) methylamine, into consideration.

Further salts which may be mentioned are pharmaceutically usable acid addition salts, such as hydrohalides, methanesulfonates, N-cyclohexylsufaminates, maleinates, maleates or fumarates of compounds of the formula I in which the radical R _{2 is} capable of forming corresponding salts.

Depending on their number, the compounds of the formula I with chiral C atoms can be present in enantiomeric or diastereomeric forms with respect to one another or as mixtures of the same, such as mixtures of diastereomers, racemates or racemic mixtures.

The compounds provided according to the invention are distinguished by valuable pharmacological properties. In particular, they have a pronounced antiallergic activity, which can be derived due to a marked LTD ₄ antagonism and a PAF antagonism (PAF-acether antagonism, in vitro), since the compounds of the invention in vitro in the range of about 0.005 to about 0.05μΜοΙ / Ι inhibit contractions induced by LTD ₄ . The LTD ₄ antagonism may be e.g. B. be detected on isolated guinea pig ileum. For this purpose, on ullage segments taken from guinea pigs of 300 to 400g body weight, in an organ bath in Tyrodelösung (38 ° C), gassing with 95% O ₂ and 5% CO ₂ ) attached and loaded with Ip, by synthetic LTD ₄ (leukotriene D ₄ , potassium salt) triggers contractions whose magnitude is registered. The extent of inhibition of these contractions due to the LTD ₄ antagonist activity of the test substance is measured. The IC ₅₀ concentration of the test substance is determined which reduces contractions induced by LTD ₄ to 50% of the original value. In this experiment, for example, for the triethanolammonium salt of N- {3 - [- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methylphenyl} -1H- tetrazolyl-5-carboxamide an IC ₅₀ of 0.0054μΜοΙ / Ι or for the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy] propyloxy] -2-cyano-phenyl} -tetrazole-5-carboxamide has an IC ₅₀ value of 0.03μΜοΙ / Ι and N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy ) -2-hydroxy-propyloxy] -phenyl} -oxaminsäureäthylester or the sodium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxypropyloxy] -2-cyano -phenyl} -oxamic acid, both according to US Patent No. 4448729 an IC ₅ o value of 0.087 μΜοΙ / Ι obtained. The LTD ₄ antagonist activity of the novel compounds can also be demonstrated in vivo by inhibition of guinea pig experimental LTD ₄ bronchospasm.

The invention relates primarily to the preparation of compounds of formula I, wherein Ri is lower alkyl, alk for hydroxy lower alkyl, hydroxy (oxa) lower alkylene or hydroxy (dioxa) lower alkylene, wherein the hydroxy group in higher than the α- and lower than the ω -Position to the free valences and in higher than the ß-position to (m) optionally present, in higher than the ß and in lower than the (ω-1! -Position to the free valencies oxaffie (n) bound and R _{2 is} 5-tetrazolyl, wherein ring A is additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and / or halogen and the remainder B is additionally lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, carbamyl, carboxy, cyano, halogen and / or trifluoromethyl, and their salts, especially pharmaceutically acceptable salts

 The invention relates above all to the preparation of compounds of the formulas

^ r YV

Y Y

further

wherein R ₁ is lower alkyl having bis and 4 C atoms, such as methyl, R _{2 is} 5-tetrazdyl, R _{3 is} lower alkyl having up to and containing 4 C atoms, such as propyl, R _{4 is} hydrogen, lower alkyl with bis and with 4 C atoms, such as methyl, lower alkoxy having up to and including 4 C atoms, such as methoxy or halogen of the atomic number up to and including 35, such as chlorine or bromine, R _{5 is} hydrogen, lower alkyl having up to and including 4 C Atoms, such as methyl, halogen of the atomic number up to and including 35, such as chlorine or bromine or trifluoromethyl, R _{6 is} hydrogen, lower alkyl with up to and with 4 C atoms, such as methyl, lower alkoxy with up to and with 4 C atoms vWe methoxy, cyano or halogen of the atomic number to and including 35, such as chlorine or bromine, and R _{7 is} hydrogen, lower alkyl having up to and including 4 C atoms, such as methyl, halogen of atomic number to and including 35, such as chlorine or bromine, lower alkoxycarbonyl with bis and with 5 C atoms, such as Aethoxycarbonyl, Catboxy, cyano or lower alkanoyl with up to and with 7 C atoms, such as form yl, acetyl or pivaloyl, and alk is in particular straight-chain, terminally bound Hydroxyniederalkylen having 3 or 4 carbon atoms, wherein the free valences of the hydroxy group ß-standing C-atoms emanate, such as 1,3- (2-hydroxy) propylene , and their salts, especially pharmaceutically acceptable salts.

The invention relates in the first place to the preparation of compounds of the formula Ia in which R _{1 is} lower alkyl having up to and including 4 C atoms, such as methyl, R _{3 is} straight-chain lower alkyl having up to and containing 4 C atoms, such as propyl, R ₂ 5-tetrazolyl, R _{4 is} hydrogen, R _{5 is} lower alkyl having up to and including 4 C atoms, such as methyl, R _{6 is} hydrogen, R _{7 is} halogen of atomic number up to and including 35, such as chlorine or bromine, or cyano and alk is a straight-chain, terminally bound hydroxy-3-substituted-lower alkylene, in which free valence proceeds from a C-terminal to the hydroxy group, such as 1,3- (2-hydroxy) -propylene, and its salts , In particular pharmaceutically acceptable salts with bases. The invention relates in particular to the preparation of the compounds of the formula I mentioned in the examples and their salts, in particular pharmaceutically usable salts, with bases.

The method based on methods known per se for the preparation of compounds of formula I and their salts is characterized in that a) a compound of formula

/ s / s

l'l Al Tl B 4 NH-CR ₂ (II)

rearranged or

b) a compound of the formula

/ s .A.

HAI HBH-NH-CR ₂ (HI),

χ / fulling / V

wherein Xi is optionally etherified hydroxy, with a compound of formula R1-X2 (IV) wherein X _{2 is} optionally functionally modified carboxy, reacting or c) in a compound of formula

Il A I

AI II B + -NH-CR ₂ (V),

yV <V ö

where X _{3 is} a radical which can be converted into the group of the formula R ₁ -Cf = O), X _{3 is converted} into this group or d) in a compound of the formula

ff

/ Vaik- / v '

ff τ

/ \ A A

^R i il AI il B + -NH-CR ₂ (VI),

' ^ö

wherein X _{4 is} a hydroxy-convertible radical, X _{4 converted} into hydroxy, or e) compounds of the formulas

ff

• • •%.

^RI SA i (VII) and i B 4 ^-NH -C-Rz (VIII)

in which one of the radicals X ₅ and X _{6 is} optionally present in salt form hydroxy and the other represents a hydroxy substituted by reactive esterified hydroxy optionally interrupted by oxygen hydroxyalkoxy or an interrupted by oxygen epoxyalkoxy, or f) in a compound of formula

"/ \ A A.

^R i Tl A ί HB H NH-CR ₂ (IX),

in which alk 'is a group convertible into a group alk, alk' is converted into a group alk, or

g) a compound of the formula

fl.

Ri Γ, Al il B f-NH ₂ (X)

or a salt thereof with a compound of the formula

X ₇ -R ₂ (XI)

in which X _{7 represents} an optionally esterified, amidated, anhydridized or in salt form carboxy group, or

h) in a compound of the formula

/ \ss ss

^R i it AJ - Il B + -Xa

where X _{8 is} a radical which can be converted into the desired group of the formula -NH-C f = O) -R ₂ , X _{8 is converted} into these and, if desired, a compound obtainable by the process is converted into another compound of the formula I and / or a compound obtainable by the process according to the invention into a salt or a salt obtainable according to the process into the free compound or into another salt.

Optionally etherified hydroxy X ₁ in formula III means, for example, free or aliphatic etherified hydroxy, such as hydroxy or lower alkoxy, z. As methoxy, but can also araliphatic, cycloaliphatic or aromatic etherified hydroxy, such as optionally substituted phenylalkoxy, z. B. benzyloxy, cycloalkoxy, z. B. cyclohexyloxy or cyclopentyloxy, or optionally substituted phenoxy.

Optionally, functionally modified carboxy X ₂ in formula IV means, for example, free, esterified or anhydridized carboxy, such as carboxy, lower alkoxycarbonyl, halocarbonyl or anhydridized carboxy of formula -CI = O) -O-CI = O) -R ₁ .

In the group R ₁ -CI = O) - convertible radicals X ₃ in formula V are, for example, groups of the formula R ₁ -CH (X ₉ ) -, wherein X _{9 is} hydrogen or optionally esterified with an organic carboxylic hydroxy, or groups of Formula R ₁ -CI = NH) -, further optionally functionally modified carboxy groups, such as free, present in salt form or esterified carboxy or cyano. For example, hydroxy esterified with an organic carboxylic acid is lower alkanoyloxy, such as acetoxy, but may also be optionally substituted benzyloxy. As a salt form of carboxy X ₃ are, for example, alkali metal, alkaline earth metal or ammonium salt forms into consideration, for. Sodium or ammonium salt forms or halomagnesium salt forms. Esterified carboxy X ₃ is, for example, lower alkoxycarbonyl, but may also be optionally substituted phenoxycarbonyl or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl.

Hydroxy-transferable radicals X ₄ in formula VI are, for example, etherified or esterified hydroxy groups. As etherified hydroxy X ₄ are, for example, aliphatic etherified hydroxy, ζ. B. lower alkoxy, such as methoxy, or lower alkenyloxy, in particular lower alk-2-enyloxy, z. Allyloxy, phenyl-lower alkoxy, especially optionally substituted phenyl-lower alkoxy, such as benzyloxy, furthermore tetrahydropyran-2-yloxy or silyloxy, in particular tetra-lower alkylsilyloxy, eg

Trimethylsilyloxy, into consideration. Esterified hydroxy X ₄ is, for example, 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 lower alkanoyloxy, ζ. Acetoxy, optionally substituted benzoyloxy, e.g. B. the formula R ₁ -CI = O) -O-, optionally halogenated lower alkoxycarbonyl, z. For example, methoxy, ethoxy or Tertiärbutyloxycarbonyl, 2,2,2-Trijodäthoxy- or 2,2,2-Trichloräthxycarbonyl, optionally substituted Phenylniederalkoxycarbonyl, in particular 1-Phenylniederalkoxycarbonyl, z. B. benzyloxycarbonyl, or optionally substituted phenoxycarbonyl.

La.Salzform present hydroxy X ₅ in formula VII or X ₆ in formula VIII or carboxy in formula XI is in particular in an alkali metal salt form, for. B. as sodium or potassium salt, before.

Optionally interrupted by oxygen, substituted by reactive esterified hydroxy hydroxyalkoxy or optionally interrupted by oxygen Epoxyalkoxyreste X ₅ in formula VII or X ₆ in formula VIII are, for example Epoxyniederalkyl- or epoxy (oxa) lower alkyl, especially the formula

-O-P- (CH ₂ ) -O-4-CH ₂ -X ¹ or X'-CH ₂ -fO- (CH ₂ ) -AO-, ' . η ^J ο ^u n ^J p

reactive mono-esterified Dihydroxyniederalkylreste in which the free hydroxy group is bonded in higher than the α-position to the free valence and the reactive esterified hydroxy group, or corresponding reactive monoesterified Dihydroxyfmono- or dioxa) alkyl radicals, in particular the formula

-Of- (CH ₂ ) -O ₃ -CH ₂ -CH (OH) -CH ₂ - [- O- (CH ₂ ) -η] -X or

-CH ₂ - £ -C- (CH ₂ ) ^ τ

wherein each X is reactive esterified hydroxy, X 'is 1,2-epoxyethyl, η and n' is 2,3 or 4, o is 0 or 1 and ρ is 0 or 1. Reactive esterified hydroxy is, for example, halogen, such as chlorine, bromine or iodine, or organic sulfonyloxy, such as Niederalkansulfonyloxy, z. Methanesufonyloxy, or optionally substituted benzenesulfonyloxy, Z..B. Benzene, p-bromobenzene or p-toluenesulfonyloxy. Preferably, η or n 'stands for 2, ο or ρ for 0 and ρ or ο for 0 or secondarily for 1.

In radicals -alk- transferable radicals -alk'- in formula IX are, for example, corresponding Oxoniederalkylenreste or 0xo (mono- or dioxa) alkylene radicals, in particular the formulas

- £ -CH ₂ ) _{; i} 0-4 ^ -CH ₂ -C (= O) -CH ₂ -EC- (CH ₂ ); ^

or etherified or esterified Hydroxyniederalkylen- or hydroxy (mono- or dioxa) alkylene radicals, in particular the formula

- £ -CH ₂ ) ^ 0-4 ^ -CH ₂ -CH (X ") -

wherein X "etherified or esterified hydroxy, η and η 'are 2,3 or 4, o is 0 or 1 and ρ is 0 or 1.

Etherified hydroxy X "is, for example, hydroxy etherified with a-aralkanol or a silanol, such as unsubstituted or substituted benzyloxy or tri-lower alkylsilyoxy, for example trimethylsilyloxy.

Esterified hydroxy X "is for example hydroxy-esterified with a carboxylic acid, such as a lower alkanoic acid or a monoester of carbonic acid, such as lower alkanoyloxy, for example acetoxy or pivaloyloxy, lower alkoxycarbonyloxy, for example

Tertiarybutoxycarbonyloxy, or optionally substituted benzyloxycarbonate, e.g. Carbobenzoxy.

Optionally esterified, amidated or anhydridized carboxy X ₇ in formula XI is, for example, free carboxy, esterified carboxy R ₂ or carboxy esterified with an optionally substituted phenol, such as phenoxy, 4-nitrophenoxy- or 2,4-dinitrophenoxycarbonyl, amidated carboxy R ₂ or activated carbamyl, such as 1-imidazolyl or 1- (2,5-dimethylimidazolyl) carbonyl, or carboxy anhydridised with a hydrohalic acid, such as halocarbonyl,

z. B. the formula HaI-Cf = O) -, wherein Hal is chlorine, bromine or iodine, especially chlorine.

As starting materials Xl come in particular in metal salt form, for. B. in potassium salt form, present carboxy groups or radicals of the formula Hal-CI = O) -R ₂ (XIb) into consideration. Protected form 5-tetrazolyl radicals are, for example, optionally substituted in the aryl part substituted 1- (a-aralkyl) -tetrazolyl- (5) radicals, such as 1-benzyl-tetrazolyl- (5) or i- (p-methoxybenzyl) -tetrazolyl- (5).

A ReStX ₈ in formula XII which can be converted into the group of the formula -NH-C- (= O) -R ₂ is, for example, the group of the formula -NH-Cf = O) -CN.

The implementation of the process according to the invention and the preparation of new starting materials or intermediates is carried out analogously to the reaction and formation of known starting materials or intermediates. In this case, although not expressly mentioned below, the customary auxiliaries, such as catalysts, condensation and Solvolysemittel and / or solvents or diluents, and reaction, such as temperature and pressure conditions, and optionally used protective gases.

The rearrangement of compounds II according to process variant a) takes place, for example, photochemically or in the presence of an acid condensing agent, preferably in an inert solvent. Suitable acid condensing agents are, for example, Lewis acids, in particular complex metal halides of the formula M ⁿ Y _n (XIX), where M is an n-valent, coordinately unsaturated metal atom of group II b. III a, III b, IVb, Va or VIII b of the Periodic Table of the Elements, z. As a zinc "-, boron ¹ " -, aluminum " ¹ -, gallium ¹ " -, tin ^iv -, titanium ^lv -, antimony ⁷ - or iron '"- atom and Y is a halogen atom, in particular the atomic number to and Preferably, boron trifluoride, aluminum trioride, gallium chloride, tin tetrachloride or zinc chloride are used Other suitable acid condensing agents are complex oxygen acids, especially sulfur or phosphorus such as sulfuric acid, pyrosulphuric acid, phosphoric acid, pyrophosphoric acid or polyphosphoric acid for example, carbon tetrachloride, tetrachloroethane, trichlorethylene, carbon disulfide or nitrobenzene. necessary, is carried out under cooling or heating, for example., at about -10 to about 4O ⁰ C, in particular at +5 to +30 ⁰ C.

Starting materials II can ζ. B. be prepared by reacting compounds of formulas Ii AI (XIII) and l'l B 4 NH-CR ₂ (VIII),

wherein X _{6 is} a hydroxy-substituted by reactive esterified, optionally interrupted by oxygen hydroxyalkyl or an optionally interrupted by oxygen epoxyalkyl, for. B. a group of the formula

X'-CH ₂ -OE- (CH ₂ ) - ^ jjO- or

Xf- (CH ₂ ) -rO-l-CH ₂ -CH (OH) -CH ₂ -O- (CH ₂ ) - * η ρ n

means in the X reactive esterified hydroxy, ζ. As halogen and X 'epoxy ethyl is usually reacted with each other and the reaction product of the formula

/ \ Λ

f, a I Il BH NH- (JR ₂ (HD,

wherein X, is hydroxy, in customary, for example by reaction with a compound R ₁ -X ₂ (IV) ₁ WoMnX ₂ Z ₁ B. halocarbonyl or anhydridized carboxy of the formula -C (= 0 JO-Cf = O) -R ₁ means, O-acylated. The preparation of compounds VIII is described under process variant e).

The reaction of compounds III and IV according to process variant b) is usually carried out in the presence of an acidic condensing agent, advantageously in an inert solvent, if necessary with cooling or heating, for example at about -10 to + 100 ⁰ C, especially at +5 to +65 ⁰ C. the acidic condensing agents and inert solvents are, for example, the meanings given for process variant a) into consideration.

Starting materials III can be prepared, for example, by reacting compounds of the formulas

IJ AI (XIV) and HB 4-NH-CR ₂ (VIII),

in which one of X ₅ and X ₆ optionally present in salt hydroxy and the other one substituted by reactive esterified hydroxy substituted, optionally interrupted by oxygen hydroxyalkyl or optionally interrupted by oxygen epoxyalkyl, z. B. a group of the formula

X'-CH ₂ -O

or

CH ₂ -CH (OH) -CH ₂ - ^ 0

means in the X reactive esterified hydroxy, ζ. As halogen and X 'is epoxyethyl. Starting materials IV are known.

The conversion of X ₃ into a group R ₁ -Cf = O) -according to process variant c) is carried out in customary manner, starting from compounds V, wherein X _{3 is} a group of the formula R ₁ -CH (X ₉ ) -, for example by Oxidation, starting from compounds V, wherein X _{3 is} a group of the formula R ₁ -Cf = NH) -, for example by solvolysis and starting from compounds V, wherein X _{3 is} optionally functionally modified or present in a salt form carboxy, for example by reaction with a compound of the formula R ₁ -M (XV) in which M is a metallic radical, for example of the formulas -M ⁱ , -M "/ 2 or M" -Hal, -M ^{1 is} an alkali metal atom, eg. As lithium, M "is an alkaline earth or earth metal atom, eg., Magnesium, zinc or cadmium, and a halogen atom, for example chlorine, bromine or iodine.

For the oxidation of groups X _{3 of} the formula R ₁ -CH (X ₉ ) - suitable Oxydationsmitel are, for example, oxidizing heavy metal compounds such as Cr '"-, Cr ^vl -, Mn ^iv -, Mn ^vn - Fe'" -, Sn ^lv - or V ^v compounds, eg chromium trioxide, potassium chromate or dichromate. Manganese dioxide, potassium permanganate, iron trichloride, tin tetrachloride or vanadium pentoxide, also oxidizing oxygen acids of nitrogen, bismuth, selenium or the halogens or their salts or anhydrides, such as nitrogen dioxide, bismuth oxide, selenium dioxide, sodium hypochlorite, potassium chlorate or potassium periodate. For the oxidation of groups X _{3 of} the formula R ₁ -CH (X ₉ ) -, wherein X _{9 is} hydroxy, is particularly suitable for. As potassium permanganate in aqueous pyridine or aqueous acetone or pyridinium dichromate in dichloromethane.

The solvolysis of groups X _{3 of} the formula R ₁ -Cf = NH) takes place in particular by mild hydrolysis, ie the action of water, if necessary in the presence of a mild hydrolysis agent. As such, for example, protic acids, such as mineral acids, for example hydrochloric acid or sulfuric acid, or organic sulfonic or carboxylic acids, such as lower alkane or optionally substituted benzenesulfonic or lower alkanoic acids, eg. As p-toluenesulfonic acid or acetic acid, into consideration.

The reaction of compounds V, wherein X _{3 is} an optionally functionally modified or present in a salt form carboxy, with a metal compound XV is carried out in the usual manner, for example in a di-lower alkyl or alkylene ether, such as diethyl ether, Tertiärbutloxymethan, dioxane or tetrahydrofuran, if necessary with cooling or gentle heating, for example at -60 to + 4O ⁰ C, especially at 20 to +25 ⁰ C.

 Starting materials V can be prepared, for example, by reacting compounds of the formulas

NH-CR ₂ (VIII),

^x \ .A. (XVI) and X ₆ ' .A Il A I Il B · H ₀ / ' ¹ v

in which one of the radicals X ₅ and X ₆ optionally present in salt hydroxy present and the other one by reactive esterified hydroxy-substituted, optionally interrupted by oxygen hydroxyalkyl radical or an optionally interrupted by oxygen epoxyalkyl, z. B. a group of the formula

X'-CH ₂ -O- - (CHa) _n - ^ O- or

Xf- (CH ₂ ) pO-3 CH ₂ -CHi OH) -CH ₂ - £ -O- (CH ₂ ) ^ - ^ O-

means in the X reactive esterified hydroxy, ζ. As halogen and X 'is epoxyethyl.

Starting materials V in which X _{3 is} a group R ₁ - (CH (X ₉ ) - can also be prepared by reacting compounds XVI (X ₃ = formyl) and VIII with each other and the reaction product V (X ₃ = formyl) with a metal compound XV continues.

Starting materials V in which X _{3 is} a group R ₁ - (C f = NH) - can be further prepared by reacting a compound of formula

^x l O ^N-aluminum 0

NH-CR ₂

wherein X _{1 has} the meaning given above and z. B. is lower alkoxy, in the presence of a Lewis acid, for. B. a complex metal halide of the formula M ⁿ X _n (XIX), wherein M, η and Y have the meanings given for the process variant a), in particular of aluminum chloride, with a nitrile of the formula R ₁ -CN (XVII). The intermediate V does not need to be isolated; it generally reacts further under the work-up conditions according to the invention. This variant is particularly suitable for the preparation and further reaction of compounds V, wherein alk represents an optionally interrupted by oxygen hydroxyalkylene radical.

The conversion of groups X ₄ in hydroxy according to process variant d) is carried out in customary manner, for example by treatment with a complex metal halide of the formula IVTY _n (XIX), where M is an n-valent, coordinatively unsaturated metal cation of the group Ha, lib, HIa, IHb, IVb, Va or VIIIb of the periodic system of elements, e.g. As magnesium, zinc "-, boron" ¹ -, aluminum ¹ "-, gallium" ¹ -, tin ^lv -, titanium ^lv -, antimony ⁷ - or iron ¹ "- or iron ^vi -ion, Y is a halogen atom the atomic number up to and including 35, such as fluorine or chlorine, for example aluminum trichloride or with a tertiary organic ammonium salt, such as a pyridinium or Triniederalkylammoniumhalogenid, eg with pyridinium chloride or bromine or triethylammonium chloride, but can also by solvolysis, Hydrolysis agents are, in addition to basic hydrolysis agents, such as alkali metal hydroxides, as acid hydrolysis agents, for example, mineral acids, eg complex metal acids, for example hexachloroantimonic acid, tetrafluoroboric acid and the like, in the case of hydroxyl groups X ₄ esterified with organic carboxylic acids, further Never deralkansäuren, such as acetic acid. Solvents are, for example, water-miscible organic solvents in the hydrolysis. Preferably, in each case in the presence of a solvent or diluent or a solubilizer, under cooling or heating, for. B. in the temperature range of about O to 12O ⁰ C, and / or under inert gas. So you can etherified hydroxy groups, for example, by treatment with aqueous hydriodic acid, pyridinium hydrochloride, z. In dichloromethane, with hydrobromic acid in highly concentrated, e.g. B. 98% acetic acid or by treatment with boron tribromide or aluminum trichloride to hydroxy. In a modification of this method can be z. B. Compounds of the formulas

• j Aj HB 4-NH-CR ₂ (III) and R _x -X ₂ (IV)

wherein X _{1 is} etherified hydroxy and X _{2 is} anhydrided hydroxy, such as halogen or a group of the formula R ₁ -Cf = O) -O-, with a Lewis acid, such as with a complex metal halide of the formula M ⁿ Y _n (XIX), e.g. , Example, aluminum trichloride treat, wherein from the primary formed compound Vl, wherein X _{4 is} etherified hydroxy, the hydroxy group is released. In another modification of this process variant can be a compound Vl, wherein X _{4 is} lower alk-2-enyloxy and the ring A is unsubstituted in the o-position to X ₄ , by heating to about 150 to 250 ^C C, preferably about 190 to 220 ⁰ C, advantageously in a solvent such as diphenyl ether or N, N-dimethyl-N, N-diethylamine, rearrange to a compound I, wherein the ring A is substituted in the o-position to the hydroxy group by lower alk-2-enyl.

In as group X ₄ an optionally substituted α-Phenylniederalkoxygruppe or another conventional by reduction cleavable protected hydroxy group-containing compounds Vl, the hydroxy group can be advantageously reductively released. Thus, for example, it is possible to hydrogenate, ie with hydrogen in the presence of a hydrogenation catalyst, for. As a palladium, platinum, nickel or rhodium catalyst, for example, from palladium on carbon or Raney nickel reduce. Furthermore, starting from compounds VI, wherein X _{4 is} esterified with an organic carboxylic acid hydroxy, the hydroxy group by transesterification, ie by treatment with an alcohol, for. As lower alkanol, in the presence of an acidic or basic agent, such as a mineral acid, ζ. For example, sulfuric acid or an alkali metal hydroxide or alcoholate, e.g. As sodium hydroxide or a Natriumniederalkanolates release

 Starting materials VI are prepared, for example, by reacting compounds of the formulas

Rx f | _A ^N | (XVIII) Tl B 4 NH-CR ₂ (VIII),

in which one of X ₅ and X ₆ optionally present in salt hydroxy and the other one substituted by reactive esterified hydroxy substituted, optionally interrupted by oxygen hydroxyalkyl or optionally interrupted by oxygen epoxyalkyl, z. B. a group of the formula

X'-CH ₂ -OF- (CH ₂ ) -4-0- or

^L η ο

XP- (CH ₂ ) -t <H CH ₂ -CH (OH) -CH ₂ - £ C- (CH ₂ ) -HO-

^L _ η ^J p _ _ ⁿ 9

means in the X reactive esterified hydroxy, ζ. B. halogen and X 'is epoxyethyl or for the preparation of compounds Vl, wherein X _{4 is} etherified hydroxy Xi, a corresponding compound of formula

|| A 1 ^v [1 BI-NH-CR ₂ (III),

Under mild conditions, ζ. B. at -10 to +10 ⁰ C or using a mildly effective Lewis acid, for. B. of zinc chloride or gallium chloride, with a compound of formula Ri-X ₂ [IV, X ₂ = halocarbonyl or-0-C (= 0) -Ri] brings to reaction.

The reaction of compounds VII and VIII according to process variant e) is carried out in customary manner, starting from starting materials in which X ₅ or X _{6 is} a reactive substituted by esterified hydroxy-substituted radical-O-alkH, for example in the presence of a basic condensing agent, such as a hydroxide or Carbonates of an alkali or alkaline earth metal, such as sodium or potassium hydroxide, potassium carbonate or calcium carbonate, advantageously in a lower alkanol, z. For example, methanol or amyl alcohol, Diniederalkylketon, z. In acetone or diethyl ketone, or N, N-di-lower alkyl-lower alkanoic acid amide or N, lower alkyl lower alkanoic acid lactam, e.g. In dimethylformamide or N-methylpyrrolidinone.

The starting materials VII are prepared, for example, by reacting a compound of the formula

(XIII)

HO

in the presence of a Lewis acid, e.g. Of aluminum trichloride or zinc chloride with a compound of formula R ₁ -X ₂ [IV; X ₂ = halocarbonyl-OdBr-OCI = O) -R ₁ ] and, if desired, in the resulting compound VII, wherein X _{5 is} hydroxy, the hydroxy group is p-position to Ri-C (= O) -by reaction with an optionally oxygen interrupted dihaloalkanol or haloalkane oxide into a halogen-substituted, optionally interrupted by oxygen hydroxy or epoxyalkoxy

 Compounds VIII can be obtained, for example, by reacting in a compound of the formula

IB 4-NO ₂ (XX)

x / V

the nitro group is reduced to amino, e.g. With hydrogen in the presence of Raney nickel, and the compound of the formula

IB -H-NH ₂ (XXI)

in the presence of a base, ζ. For example, triethylamine or pyridine, with a compound of formula HaI-Cf = O) -R ₂ (XIb; Hai = halogen) reacted and, if desired, in the resulting compound VII, wherein X _{5 is} hydroxy, the hydroxy group in p-position to R ₁ -Cf = O) - converted by reaction with an optionally interrupted by oxygen Dihalogenalkanol or Halogenalkanepoxid in a halogen-substituted, optionally interrupted by oxygen hydroxyalkoxy or epoxyalkoxy.

The conversion of hydroxy X ₅ or X ₆ into a hydroxy-substituted by reactive esterified, optionally interrupted by oxygen hydroxyalkoxy or an optionally interrupted by oxygen epoxyalkyl in each case can also be carried out stepwise. Thus, a compound VII or VIII with free hydroxy group X ₅ or X _{6 is} first reacted with a compound of the formula X- (CH ₂ I _n -OH (XXII) to give the corresponding compound VII or VIII, wherein X ₅ or X _{6 is} a group of the formula

and ο 1 means. This intermediate can then be reacted a) with a compound of the formula X-CH ₂ -X '(XXIV) or b) first with a compound XXIV and then with a compound XXIl to obtain a corresponding compound VII or VIII, wherein X ₅ or X _{6 is} a group of the formulas

a) -O-P- (CH ₂ ) -O - ^ - CH ₂ -X 'or

b) -Of- (CH ₂ ) - <H CH ₂ -CH (OH) -CH ₂ -Of- (CH ₂ ) -4-X

^u no η ρ

wherein ο and ρ are 1; means.

But one can also with a compound of formula X-CH ₂ -CH (X ¹¹ J-CH ₂ X (XXV), wherein X is reactive esterified hydroxy, such as chlorine, bromine or iodine, with X "esterified with a carboxylic acid hydroxy, such as . alkanoyloxy, for example acetoxy, means to give a compound VII or VIII, wherein X ₅ and X ₆ is a group of formula -CH ₂ -CH (X ") - CH ₂ X, implement and this group by treating with an alkali metal hydroxide, for example with sodium hydroxide in methanol, into a group of the formula -CH ₂ -X '.

The conversion of the radical alk'einer compound IX according to the process variant f) is carried out in a conventional manner, starting from compounds IX, wherein alk 'is a substituted by oxo, etherified with an a-alkanol or a carbonic acid mono-aralkyl radical esterified hydroxy alkylene radical, for example, reductively and starting from compounds IX, wherein alk 'means a ether etherified or esterified by other hydroxy groups than the abovementioned substituted alk, solvolytically.

As a reducing agent for the reduction of oxo-substituted radicals alk 'to the corresponding alk radicals, for example, alkali metal borohydrides, such as lithium borohydride, sodium borohydride or sodium cyanoborohydride, or secondary alcohols, such as secondary lower alkanols or Cycloniederalkanole, z. As isopropanol or cyclohexanol, in the presence of an aluminum alcoholate, in particular isopropanol in the presence of Aluiniumisopropanolat, into consideration. The reaction with the alkali metal borohydrides mentioned is advantageously carried out in a lower alkanol, a di-lower alkyl ether or lower alkylene ether or mixtures of these solvents, for example in ethanol. In the reaction with alcohols in the presence of an aluminum alcoholate is advantageously carried out in an excess of the alcohol used as the reducing agent. The reductive cleavage of a-aralkoxy or a-Aralkoxycarbonyloxy to hydroxy is preferably carried out by hydrogenolysis, ie exposure to hydrogen in the presence of a hydrogenation catalyst, such as a palladium, platinum, iridium or nickel catalyst, for. B. of palladium on carbon, platinum oxide or Raney nickel, advantageously in a lower alcohol, for. B. in methanolic solution, if necessary under pressure and / or heating, for. B. at about 1 to 10 bar and 20 ⁰ C to 60 ° C. The solvolytic release of hydroxy from other than the generten etherified or esterified hydroxy groups, such as from silyloxy, Niederalkanoyloxy or Niederalkoxycarbonyloxy, for example, by hydrolysis (reaction with water), alcoholysis (reaction with an alcohol) or ammonia or. Aminolysis (reaction with ammonia or an amine having at least one free hydrogen), if necessary in the presence of an acidic or basic agent and / or with heating, eg at about 20 ^° C. to 100 ^° C. Suitable acidic agents are, for example, mineral acids, such as hydrohalic acids, z. Hydrochloric acid, or oxygen acids of sulfur or phosphorus, e.g. As sulfuric or phosphoric acid, or organic sulfonic or carboxylic acids, such as lower alkanesulfonic acids or optionally substituted benzenesulfonic acids or lower alkanoic acids, eg. For example, p-toluenesulfonic acid or acetic acid. Basic hydrolysis agents include, for example, hydroxides or carbonates of alkali metals, e.g. As potassium carbonate, sodium hydroxide or potassium hydroxide, for the alcoholysis further corresponding alkoxides, such as Alkalimetallniederalkanolate, z. For example, sodium methoxide. Starting materials IX can be obtained, for example, by reacting compounds of the formulas

O ii a i N _x (VII) and X ii ¹ V. HO '

JVIII)

in which one of the radicals X ₅ and X ₆ optionally present in salt form hydroxy and the other a reactive esterified hydroxy X-containing radical O-alk'-X, ie a reactive esterified by hydroxy and additionally by oxo or etherified or esterified Hydroxy substituted, optionally interrupted by oxygen alkoxy. This has, for example, one of the formulas

0Η ₂ -0 (= 0) -0Η ₂ - £ -to-0Α ₂ ) _η -τ ^ X or

(CH ₂ ) _n - O

The reaction of the corresponding compounds VII and VIII and their preparation is carried out z. B. in an analogous manner as indicated for the process variant e).

The reaction of compounds X and XI according to process variant g) can be carried out in conventional manner, in particular in the manner known from the literature for analogous reactions, if necessary in the presence of a condensing agent, for example in the reaction with a optionally protected in 1-position 5-Halogencarbonyltetrazol a basic condensing agent, such as a tertiary organic nitrogen base, ζ. B. of triethylamine or pyridine. 1-position protected 5-halocarbonyltetrazoles are preferably prepared in situ, e.g. B. by reacting an alkali metal, z. Example, the potassium salt of a protected in the 1-position, for example, a-aralkylated tetrazole-S-carboxylic acid with Oxalylchlorid in the presence of pyridine. The 1-protecting group of 5-tetrazolyl radicals R ₂ can then be cleaved off, for example, by treatment with trifluoroacetic acid / antisol or hydrogenolytically, in particular by means of hydrogen and palladium on carbon. Starting materials X can be prepared, for example, by reacting compounds of the formulas

^RI HAI (VII) and ^8B 4-NO ₂ (XX),

h / V \ ₅ x / ^s · '.

in which one of the radicals X ₅ and X ₆ optionally present in salt hydroxy present and the other one by reactive esterified hydroxy-substituted, optionally interrupted by oxygen hydroxyalkyl radical or an optionally interrupted by oxygen epoxyalky, z. B. a group of the formula

X'-CH ₂ -OE- (CH ₂ ) -3-0- or

η ^J o

X £ - (CH ₂₎ -r0-3 CH ₂ -CH (OH) -CH ₂ -JF-O- (CH ₂₎ -

in the X, reactive esterified hydroxy, e.g. Halogen and X 'represents epoxyethyl, and in the resulting compound of the formula

iiV · + -NO ₂

_H0 / \

the nitro group is reduced to amino, for example by reaction with hydrogen in the presence of a hydrogenation catalyst, such as palladium on carbon or especially Raney nickel, for example in tetrahydrofuran.

The conversion of the group Xe into compounds XII into those of the formula -NH-Cf = O) -R ₂ according to process variant h) takes place, for example, by reaction with hydrazoic acid.

The reaction of groups X _{3 of} the formula -NH-Cf = O) -CN with hydrazoic acid is preferably carried out to form them in situ by treating an alkali metal azide with an acid such as hydrochloric acid, preferably in toluene or similar solvents.

The starting materials XII are prepared, for example, by reacting a compound of the formula

II

Η A j | j B_f ..- NH2 _(X)

or an acid addition salt thereof with cyanoformic acid of the formula NC-COOH (XXVII a) or a preferably functional derivative thereof. Functional derivatives of acids XXVII a are, above all, an esterified or anhydrided carboxy group, such as lower alkoxycarbonyl or halocarbonyl, eg. As chlorine or bromocarbonyl-containing acid derivatives. As functional derivatives of acids XXVII a are z. As cyanoformyl chloride or cyanogen.

The reaction of compounds X with acids XXVIIa or their derivatives can be carried out in the usual manner, for example in the presence of a water-binding agent such as an acid anhydride, for. As phosphorus pentoxide, or of dicyclohexylcarbodiimide, or a z. As acidic or basic condensing agent, such as a mineral acid, eg. Hydrochloric acid, or an alkali metal hydroxide or carbonate, ζ. As sodium or potassium hydroxide or an organic nitrogen base, ζ. B. of triethylamine or pyridine. In the reaction with an acid anhydride, such as acid chloride, it is preferable to use an organic nitrogen base as condensing agent 1. The reaction with carboxylic acids is preferably carried out in the presence of a water-binding agent. If necessary, one works in each case in an inert solvent, at normal temperature or under cooling or heating, for. B. in a temperature range of about ^{0 0} C to about 100 ⁰ C, in a closed vessel and / or under inert gas, for. Nitrogen.

A compound of the general formula I obtainable according to the invention can be converted in a manner known per se into another compound of the general formula I.

So you can, for example, a free carboxyl group in customary, z. Example by treating with a Diazoniederalkan or Triniederalkyloxonium-, Triniederalkylcarboxonium- or Diniederalkylcarboniumsalz, such as hexachloroantimonat or hexafluorophosphate, or especially by reaction with a lower alkanol or a reactive derivative, such as a carboxylic, phosphorous, sulfuric or carbonic acid ester thereof, z. Lower alkanecarboxylic acid ester, tri-lower alkyl phosphite or lower alkyl sulfite, in lower alkoxycarbonyl or by reaction with ammonia, dehydration of the primary ammonium salt form and, if desired, carbamyl group to carbamyl or cyano.

Lower alkoxycarbonyl, carbamyl or cyano can in the usual way, for. By hydrolysis in the presence of a catalyst, for example a basic or acidic agent such as a strong base, e.g. As sodium or potassium hydroxide, or a mineral acid, eg. As hydrochloric acid, sulfuric acid or phosphoric acid, are hydrolyzed to the free carboxyl group. In a compound obtainable according to the invention, it is further possible to introduce substituents into the phenyl ring A and / or B and / or to convert existing substituents into other substituents. Thus, by reaction with a lower alkyl halide or lower alkane or a Niederalkansäurehalogenid or anhydride, in each case in the presence of a Lewis acid such as aluminum trichloride, in the ring A and / or B lower alkyl or in the ring B lower alkanoyl introduce. Further, halogen may be introduced, for example, by treatment with a halogen in the presence of a Lewis acid, such as ferric chloride, or by reaction with N-chlorosuccinimide. Further, lower alkenyl or lower alkynyl groups may be reduced to lower alkyl, for example by treatment with hydrogen in the presence of a hydrogenation catalyst, e.g. from palladium on carbon. Furthermore, it is possible to replace halogen, in particular iodine, by reaction with trifluoromethane in the presence of copper by trifluoromethyl or by reaction with an alkali metal cyanide by cyano. The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as a mixture thereof, z. Example, depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes or mixtures of isomers, such as racemates, diastereoisomeric mixtures or racemate mixtures. Resulting diastereomer mixtures and mixtures of racemates can be separated in a known manner in the pure isomers, diastereomers or racemates due to the physicochemical differences of the constituents, for example by chromatography and / or fractional crystallization.

Racemates obtained can furthermore be decomposed by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms, or by reaction of an acidic end product with an optically active base forming salts with the racemic acid and separation of this way obtained salts, for. Due to their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. Advantageously, one isolates the more effective of the two antipodes.

Obtained free compounds of the formula I, e.g. those in which R represents carboxy can be converted into salts in a manner known per se, eg. By treatment with a base or with a suitable salt of a carboxylic acid, usually in the presence of a solvent or diluent.

Obtained salts can be converted in a conventional manner into the free compounds, for. By treating with an acidic reagent, such as a mineral acid.

The compounds, including their salts, may also be obtained in the form of their hydrates or include the solvent used for crystallization.

As a result of the close relationship between the novel compounds in free form and in the form of their salts, in the preceding and following among the free compounds or their salts, it will be understood, if appropriate, that they also include the appropriate salts or free compounds.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a salt and / or racemate or antipodes or forms in particular under the reaction conditions ,

The novel starting materials and intermediates occurring in the novel processes and their precursors likewise form the subject of the invention. ·

Preferably, such starting materials are used and the reaction conditions are selected so as to arrive at the compounds listed above as being particularly preferred.

The present invention also relates to pharmaceutical preparations containing one of the compounds of the formula I according to the invention or a pharmaceutically acceptable salt thereof. The pharmaceutical preparations according to the invention are those which are intended for topical and local as well as enteral, such as oral or rectal, as well as parenteral administration to and for inhalation by warm-blooded animals, and which contain the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier material. The dosage of the active substance depends on the species of warm-blooded animals, the age and the individual condition, as well as on the mode of administration. The new pharmaceutical preparations contain z. From about 10% to about 95%, preferably from about 20% to about 90% of the active ingredient. Inventive pharmaceutical preparations are, for. As such in aerosol or spray form or in dosage unit forms, such as dragees, tablets, capsules or suppositories, further ampoules.

The pharmaceutical preparations of the present invention are prepared in a manner known per se, for. B. by conventional mixing, granulation, coating, solution or lyophilization process. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or dragee cores ,

Suitable carriers are in particular fillers, such as sugars, for. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders such as starch paste, z. Corn, wheat, rice or potato starch paste, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof like sodium alginate. Auxiliaries are primarily flow regulators and lubricants, eg. For example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee - cores are provided with appropriate, possibly gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidones, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of granules, eg. In admixture with fillers such as lactose, binders such as starches, 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, it also being possible for stabilizers to be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a matrix may also be used; as basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. As a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvent or vehicle such as fatty oils, eg. As sesame oil, or synthetic fatty acid esters, eg. As ethyl oleate or triglycerides used, or aqueous injection suspensions, which viscosity-increasing substances, eg. B. sodium carboxymethylcellulose. Sorbitol and / or dextran and optionally also stabilizers. Inhalation preparations for the treatment of the respiratory tract by nasal or buccal administration are, for. As aerosols or sprays, which can distribute the pharmacological agent in the form of a powder or in the form of drops of a solution or suspension. Powder-dispersing agents generally contain, in addition to the active ingredient, a liquid propellant having a boiling point below room temperature and, if desired, carriers such as liquid or solid non-ionic or anionic surfactants and / or diluents. Preparations in which the pharmacologically active substance is in solution also contain a suitable propellant, and if necessary, an additional solvent and / or a stabilizer. Instead of the propellant gas and compressed air can be used, which can be generated by means of a suitable compression and expansion device as needed. Pharmaceutical preparations for topical and local use are e.g. For the treatment of the skin lotions and creams / containing a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative) for the treatment of the eyes eye drops, containing the active compound in aqueous or oily solution, and ointments, preferably prepared in sterile form, for the treatment of nasal powders, aerosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse powders produced by rapid Inhalation can be administered through the nostrils, and nasal drops containing the active compound in aqueous or oily solution, or for the local treatment of the mouth lollipop containing the active compound in a generally formed from sugar and gum arabic or Tragaganth mass, which flavors and lozenges containing the active ingredient in an inert Mass, z. As gelatin and glycerol or sugar and gum arabic included.

The invention also relates to the use of the novel compounds of the formula I and their salts as pharmacologically active compounds, in particular as antiallergic agents, preferably in the form of pharmaceutical preparations. The daily dose administered to a warm-blooded animal of about 70 kg is from about 200 mg to about 120 mg.

embodiment

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade.

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 -methylphenyl} -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 is concentrated under reduced pressure, treated with about 300 ml of ether and 400 ml of petroleum ether and the crystals are filtered off. The resulting N- {3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methylphenyl} -1H-tetrazole-5 carboxamide, mp. 155-158 ° C; 1 H NMR spectrum (δ vs TMS, DMSO-d ₆ ): 0.85 (triplet, 3H); 1.45 (multiple, 2H); 2.25 (singlet, 3H); 2.55 (multiple, 2H); 2.60 (singlet, 3H); 4.0-4.7 (multiple, 4H); 5.90 (multiple, 1 H); 6.65 (doublet, 1H);

7.30 (singlet, 1H); 7.55 (singlet, 1H); 7.85 (doublet, 1H), 10.75 (singlet, 1H); 12.80 (singlet, 1H); is dissolved in 100 ml of acetone and treated with one equivalent of triethanolamine in 10 ml of acetone. After adding ether, crystallization starts. The triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-N-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methylphenyl} is thus obtained. 1 H-tetrazole-5-carboxamide from SMp. 76 ⁰ C (Zers.).

In an analogous manner starting from N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methylphenyl} -1 - (4-methoxybenzyl) -tetrazole-5-carboxamide the N-f S -IS-acetyl-S-hydroxy-n-propyl-phenoxy-tert-hydroxypropyloxy-4-chloro-6-methyl-phenyl} -1 H- tetrazol-5-carboxamide; Oil; 1 H-NMR spectrum (δ to TMS, DMSOd ₆ ): 0.85 (triplet, 3H); 1.45 (multiple, 2H); 2.25 (singlet, 3H); 2.55 (multiple, 2H); 2.60 (singlet, 3H); 4.0-4.7 (multiple, 4H); 5.90 (multiple, 1 H); 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 can manz. B. produce as follows:

A solution of 16.2 g (7OmMoI) of 2-bromo-4-methyl-5-nitro-phenol in 130 ml of ethanol is treated with 0.32 g (7.4 mmol) of a 55% sodium hydride dispersion in oil. Under reflux, a solution of 18.4 g (73.5 mmol) of 4- (2,3-epoxypropoxy) -2-hydroxy-3-propyl-acetophenone in 150 ml of ethanol is then added dropwise within two hours. Thereafter, it is heated for a further 8 hours to reflux. The reaction mixture is cooled, concentrated in vacuo to about 100 ml and poured onto ice. The aqueous phase is acidified with dilute hydrochloric acid and extracted three times with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo.

Crystallization from ether gives the 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methylnitrobenzene, mp. 104 ° C-106 ° C.

In an analogous manner, 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-nitrobenzene of the mp. 103 ° C. -105 ° C (starting from 2-chloro-4-methyl-5-nitro-phenol).

A solution of 23.3 g (48.3 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methylnitrobenzene in 240 ml Tetrahydrofuran is mixed with 2.0 g of Raney nickel and hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The combined filtrates are concentrated in vacuo, ether is added and the precipitated crystals are filtered off. This gives 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxypropyloxy] -4-bromo-6-methyl-aniline, mp. 78 ° C-80 ° C. ,

In an analogous manner starting from 3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -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.

To a suspension of 10.6 g (38.8 mmol) of potassium [1- (4-methoxy-benzyl) -tetrazole] -5-carboxylate in 170 ml of benzene and 1.5 ml of pyridine is added at 0 ° C-5 ° C 3.38 ml (38.8 mmol) of oxychloride and allowed to stir for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure, the residue taken up in benzene and evaporated again under reduced pressure. The residue is dissolved in 135 ml of dichloromethane and added at 0 ° C.-5 ° C. within 10 minutes to a solution of 12.85 g (28.4 mmol) of 3- [3- (4-acetyl-3-hydroxy-2-n-one propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-aniline and 2.7 ml (33 mmol) of pyridine in 100 ml of dichloromethane.

The mixture is then stirred for 3 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed three 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 crystallized from ethanol. This gives N- {3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -2-hydroxypropyloxy] -4-bromo-6-methyl-phenyl} -1- (4 -methoxybenzyl) -tetrazole-5-carboxamide, m.p. 114 ° C-116 ° C.

In an analogous manner starting 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} -1- (4-methoxybenzyl) -tetrazol- 5-carboxamide.

Example 2: A solution of 7.1 g (11, SmMqI) of N-is-IS-f-1-acetyl-S-hydroxy-n-propyl-phenoxy-1-hydroxy-propyloxy-2-cyano-

phenylj-i-K-methoxybenzyO-tetrazole-B-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, treated with about 200 ml of ether and 300 ml of petroleum ether and the crystals filtered off. The thus obtained N- {3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -2-hydroxypropyloxy] -2-cyano-phenyl} -1H-tetrazole-5-carboxamide of Mp. 210 ° C-213 ° C is dissolved in 50 ml of acetone hot and with a

Equivalent triethanolamine in 20 ml of acetone. After adding ether, crystallization starts. This gives the triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propylphenoxy) -2-hydroxy-propyloxy] -2-cyano-phenyl} -1H-tetrazole -5-carboxamide, mp. 80 ° C-82 ° C.

The starting materials are obtained, for example, as follows:

To dissolve 34 g (207 mmol) of 2-hydroxy-6-nitro-benzonitrile and 60 g of 4 - [(2,3-epoxy) propyloxy] -2-hydroxy-3-propylacetophenone in 450 ml of dimethylformamide are added 30 drops of Triton B. The solution is heated to reflux for 1.5 hours, from

Solvent was removed and the residue was taken up in 500 ml of ethyl acetate. After washing with 500 ml of 0.5 N sodium hydroxide solution and with 500 ml of water is dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel with methylene chloride / ethyl acetate (95: 5). This gives 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propoxy] -6-nitro-benzonitrile, mp. 117 ° C-119 ° C.

To dissolve 10 g (24.2 mmol) of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -6-nitrobenzonitrile and 10 g of cyclohexane in 500 ml of ethanol are added 2, 5g 10% palladium on charcoal and heated to reflux for 30 minutes. After cooling to room temperature, the mixture is filtered and the solvent is evaporated off. The residue is treated with ether and the precipitated crystals are filtered off. This gives 3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -2-cyano-aniline, mp. 123 ° C-125 ° C.

To a suspension of 5.8 g (21.5 mmol) of potassium {1- (4-methoxybenzyl) -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 oxalic acid and allowed to stir for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure, the residue taken up in benzene and evaporated again under reduced pressure. The residue is dissolved in 80 ml of methylene chloride and added at 0-5 ⁰ C within about 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-cyano-aniline 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 three times with water. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with methylene chloride / ethyl acetate (6: 1). This gives N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxypropoxy] -2-cyano-phenyl} -1- (4-methoxybenzyl) -tetrazole. 5-carboxamide as a colorless oil.

Example 3: In an analogous manner as described in Examples 1 and 2, starting from 2-fluoro-4-methyl-5-nitro-phenol, 4-methyl-5-nitro-phenol or 2-hydroxy-5 Methyl 4-nitro-benzonitrile N- {3- [3- (4-Acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-fluoro-6-methyl-phenyl } -1 H-tetrazole-5-carboxamide 1 H NMR spectrum (δ vs TMS, DMSO-d ₆ ): 0.85 (triplet, 3H); 1.45 (multiple, 2H); 2.25 (singlet, 3H); 2.55 (multiple, 2H); 2.60 (singlet, 3H); 4.0-4.7 (multiple, 4H); 5.90 (multiple, 1 H); 6.65 (doublet, 1H); 7.25 (singlet, 1H); 7.85 (doublet, 1H), 10.70 (singlet, 1H) 12.80 (singlet, 1H); and its triethanolammonium salt, N-is-IS-1-acetyl-S-hydroxy-n-propylphenoxyl-hydroxy-propyloxyl-e-methylphenyl-iH-tetrazole-5-carboxamide 1 H-NMR spectrum (δ to TMS, DMSOd ₆ ): 0.85 (triplet, 3H); 1.45 (multiple, 2H); 2.25 (singlet, 3H); 2.55 (multiple, 2H); 2.60 (singlet, 3H); 4.0-4.7 (multiple, 4H); 5.90 (multiple, 1 H); 6,60 (multiple, 2H); 7.10 (doublet, 1H); 7.80 (multiple, 2H); 10.70 (singlet, 1H) 12.80 (singlet, 1H); and its triethanolammonium salt and N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) -2-hydroxy-propyloxy] -4-cyano-6-methylphenyl} -1H tetrazole-5-carboxamide-1 H-NMR spectrum (δ to TMS, DMSO-d ₆ ): 0.85 (triplet, 3H); 1.45 (multiple, 2H); 2.25 (singlet, 3H); 2.55 (multiple, 2H); 2.60 (singlet, 3H); 4.0-4.7 (multiple, 4H); 5.90 (multiple, 1 H); 6.65 (doublet, 1H); 7.30 (singlet, 1H); 7.45 (singlet, 1H); 7.65 (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} -1 H- Tetrazole-5-carboxamide are dissolved in 45 ml of acetone and treated with a solution of 1.0 g of diethanolamine in 5 ml of acetone. After addition of diethyl ether crystallization begins. It is allowed to stand for 30 minutes at 5-1O ⁰ C, filtered off, washed with diethyl ether and allowed to dry in the air. The diethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl) phenoxy) -2-hydroxypropyloxy] -6-methyl-phenyl} -1H-tetrazole-5 is obtained -carboxamide. In an analogous manner, it is also possible to prepare its sodium, potassium, diethylammonium and tris (hydroxymethyl) methylammonium salt.

The sodium, potassium, diethanolammonium, diethylammonium and tris (hydroxymethyl) methylammonium salts of N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) are also obtained in an analogous manner. 2-hydroxy-propyloxy] -2-cyano-phenyl} -1H-tetrazole-5-carboxamide, N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl-phenoxy) - 2-hydroxy-propyloxy] -4-bromo-6-methylphenyl} -1H-tetrazole-5-carboxamide, N- {3- [3- (4-acetyl-3-hydroxy-2-n-propyl) phenoxy) -2-hydroxy-propyloxy] -4-chloro-6-methyl-phenyl} -1H-tetrazole-5-carboxamide, N- {3- [3- (4-acetyl-3-hydroxy-2-n propyl-phenoxy) -2-hydroxypropyloxy] -4-fluoro-6-methyl-phenyl} -1H-tetrazole-5-carboxamide and N- {3- [3- (4-acetyl-3-hydroxy) 2-n-propylphenoxy) -2-hydroxy-propyloxy] -4-cyano-6-methyl-phenyl} -1H-tetrazole-5-carboxamide.

Example 5: Tablets containing 25 mg of active ingredient, e.g. B. Triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl-5-1H-tetrazole-5- carboxamide, can be prepared as follows:

ingredients (for 1000 tablets): active ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5 g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1,8g

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm mesh size. Then the active ingredient, the lactose, the talc, the 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, and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 ⁰ C dried through a sieve with 1.2 mm mesh size and pressed to both sides concave tablets of about 6 mm in diameter.

In an analogous manner, tablets containing in each case 25 mg of another of the compounds of the formula I mentioned in Examples 1 to 4 can also be prepared.

Example 6: Chewable tablets containing 30 mg of active ingredient, e.g. B. triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methylphenyl} -1H-tetrazole-5 carboxamide, for example, can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 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

5% gelatin solution q. s.

Preparation: All solid ingredients are first forced through a 0.25 mm mesh screen. The mannitol and the lactose are mixed, granulated with the addition of gelatin solution, forced through a sieve of 2 mm mesh width, dried at 50 ⁰ C and again forced through a sieve of 1.7 mm mesh size. The active ingredient, the glycine and the saccharin are mixed thoroughly, the mannitol, the lactose granules, the stearic acid and the talcum added, the whole thoroughly mixed and pressed into concave tablets of about 10mm diameter with scored groove on the top.

In an analogous manner, tablets containing in each case 30 mg of another of the compounds of the formula I mentioned in Examples 1 to 4 can also be prepared.

Example 7: Tablets containing 100 mg of active ingredient, e.g. B. triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methylphenyl} -1H-tetrazole-5 carboxamide, can be prepared as follows:

Composition (for 1000 tablets):

Active ingredient 100.0 g

Lactose 248.5 g

Corn starch 17.5 g

Polyethylene glycol 6000 5.0 g

Talc 15.0 g

Magnesium Stearate 4.0g

demineralised water q.s.

Preparation: The solid ingredients are first forced through a sieve of 0.6 mm mesh size. Then the active ingredient, lactose, talc, magnesium stearate and half of the starch are intimately mixed. The other half of the starch is suspended in 65 ml of water and this suspension added to a boiling solution of the polyethylene glycol in 260 ml of water. The resulting paste is added to the powdery substances, the whole is mixed and granulated, if necessary with the addition of water. The granules are dried overnight at 35 ⁰ C, driven through a sieve with 1.2 mm mesh size and pressed on both sides concave tablets of about 10 mm diameter with breaking notch on the top.

In an analogous manner, it is also possible to prepare tablets containing 100 mg of another compound of the formula I according to Examples 1 to 4.

Example 8: A propellant-containing, solid aerosol-forming inhalable suspension containing 0.1% by weight of N- {3- [3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -2-hydroxy-propyloxy] -4-bromo- 6-methyl-phenyl} -1H-tetrazole-5-carboxamide (active ingredient) can be prepared, for example, as follows.

Composition:

Active ingredient, micro-sized 0.1% by weight

"Sorbitan trioleates" 0.5% by weight -%

Propellant A

(Trichlorotrifluoroethane) 4.4% by weight

Propellant B (mixture of 15 parts of dichloromethane)

difluoromethane and 80 parts symm. Dichlortetra-

fluoroethane) q.s.

Preparation: The active ingredient is suspended with the exclusion of moisture with the aid of a conventional homogenizer with the addition of sorbitan trioleate in the Trichlortrifluoräthan, filled the suspension in a metered dose inhaler, this sealed and filled under pressure with the Dichloridifluormethan-Dichlortetrafluoräthan mixture.

In an analogous manner, inhalation suspensions containing another compound of the formula I according to Examples 1 to 4 can also be prepared.

EXAMPLE 9 An approximately 2% strength aqueous solution, suitable for inhalation, of 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 active ingredient, can, for example

be prepared in the following composition:

composition

Active ingredient 2000 mg

Stabilizer, z. Ethylenediaminetetraacetic acid

disodium salt 10 mg

Preservatives, for example. B. Benzalkonium chloride 10 mg

Water, freshly distilled ad 100 ml

Preparation: The active ingredient is dissolved in freshly distilled water. Then the stabilizer and the preservative are added. After complete dissolution of all components, the solution obtained is filled into 100 ml of filled vials and sealed gas-tight.

In an analogous manner, it is also possible to prepare 2% inhalable solutions containing another active compound of one of Examples 1 to 4.

Example 10: For insufflation, about 25 mg of triethanolammonium salt of N- {3- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxy-propyloxy] -4-bromo-6-methyl-phenyl } -1 H-tetrazole-5-carboxamide as active ingredient containing capsules can, for example be prepared in the following composition:

composition

Active ingredient 25 g

Lactose, finely ground 25g

Production: The active substance and the lactose are intimately mixed. The resulting powder is then sieved and bottled in portions of 50 mg each in 1000 gelatine capsules.

In an analogous manner, insufflation capsules containing in each case one active ingredient according to one of Examples 1 to 4 can also be prepared.

Claims (4)

Invention claim: 1. A process for the preparation of novel 'l-Acylresorcinäther the formula O -   u HO ^ fe ^ \ y ^ ¹ O-alk-0 (I). wherein Ri is lower alkyl, alk represents an optionally interrupted by oxygen hydroxyalkylene and R _{2 is} 5-tetrazolyl, wherein the ring A additionally by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, and / or halogen and the ring B additionally by lower alkyl, lower alkanoyl, lower alkoxy , Lower alkoxycarbonyl, carboxy, cyano, carbamyl, halogen and / or trifluoromethyl, and their salts, characterized in that a) a compound of the formula - NH-C-Rp R ₁ -COO-alk-0 rearranged or b) a compound of the formula j | B ^ f NH-CR ₂ χ O-alk-0 wherein X _{1 is} optionally etherified hydroxy, with a compound of formula R ₁ -X ₂ (IV), wherein X _{2 is} optionally substituted carboxy functional, reacting or
c) in a compound of the formula ^x \ / \ A H Al HB 4 -NH-CR ₂ (V), in which X _{3 is} a radical convertible into the group of the formula R _r C (= O), X _{3 is converted} into this group or d) in a compound of the formula " f " r / V \ s \ Il Al II B 4-NH-CR ₂ (VI), wherein X4 is a hydroxy-convertible radical, X _{4 converted} to hydroxy, or e) Compounds of the formulas ϊ
¹ 1 * 1 A! (VII) and ίB 4 NH-CR ₂ (VIII) in which one of X ₅ and X _{6 is} optionally present in salt hydroxy and the other represents a hydroxy substituted by reactive esterified, optionally interrupted by oxygen hydroxyalkoxy or an interrupted by oxygen epoxyoxy, or f) in a compound of the formula ft.. ¹ H Al II B · + -NH-CR ₂ (IX), HO '' ^ VaIk'-0 ⁷ V " ^Ö in which alk 'is a group convertible into a group alk, alk' is converted into a group alk, or g) a compound of the formula I / - Il AJ., HB - '"* ^(X) HO '^ ^ ⁴ O-alk-0 ~ or a salt thereof with a compound of the formula X ₇ -R ₂ (XI) in which X _{7 represents} an optionally esterified, amidated anhydridated or in salt form carboxy group, or
h) in a compound of the formula II- AI | j B 4- ^ X ₈ (XII). in which X _{8 is} a radical convertible into the desired group of the formula -NH-Cf = O) -R ₂ , X _{8 is converted} into these and, if desired, a compound obtainable by the process is converted into another compound of the formula I and / or a free process obtainable according to the process Converts the compound into a salt or a salt obtainable by the process into the free compound or into another salt. 2. The method according to item 1, characterized by proceeding from an intermediate obtainable at any stage of the process compound and performs the missing steps or uses a starting material in the form of a salt and / or racemate or antipodes or forms in particular under the reaction conditions , 3. The method according to item 1 or 2, characterized in that compounds of formula I, wherein RTNiederalkyl means alk for hydroxy lower alkyl, hydroxy (oxa) lower alkylene or hydroxy (dioxa) lower alkylene, wherein the hydroxy group in higher than the α and in lower as the ω-position to the free valences and in higher than the ß-position to (m) optionally present, located in higher than the ß- and in lower than the (ω-1! -position to the free valences, Oxaglied ( and R _{2 is} 5-tetrazolyl, ring A additionally being lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and / or halogen and B additionally being lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, carbamyl, carboxy, cyano , Halogen and / or trifluoromethyl, and their salts. 4. The method according to item 1 or 2, characterized by reacting compounds of the formulas _(I a) or. H Ra ρ NH-CR ₂ / '- V ^ -' ⁴ ^^ W ö (Ib) R ₁ Il I Μ 1 \\ VR HO I ^N O-alk-0 ί ^Κ 5