NO854221L - PROCEDURE FOR THE MANUFACTURE OF NEW FLUORED RESORCINETERS. - Google Patents

Abstract

4-acyl resorcinets of the formula. where R represents lower alkyl, R2 represents fluorinated lower alkyl, R represents hydrogen, lower alkoxy, trifluoromethyl or 'halogen, alk is an alkylene or hydroxyalkylene residue which is optionally interrupted by oxygen, one of the residues R., Rog R stands for |. a group of the formula -NH-C (= O) -Rg, one from this different residue R or R5 represents a residue g and one from this different residue represents a residue Rj_n # Rg is hydrogen, lower alkyl, trifluoromethyl, halogen, optionally etherified or amidated carboxy, cyano or lower alkanoyl, R 9 optionally represents etherified or amidated carboxy or 5-tetrazolyl, R 9 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R stands for hydrogen, lower alkyl, lower alkoxy, halogen. trifluoromethyl, cyano or optionally etherified or amidated carboxy, and their salts have antiallergic and anti-inflammatory properties. They are made e.g. The invention also relates to intermediates of the formula in which one of the radicals X1 and Xg is phydroxy which may be present in salt form and the other is an alkoxy radical which is substituted by reactive esterified hydroxy or epoxy. The invention also relates to intermediates of the formula. where R 1 represents fluorinated lower alkyl, means hydrogen, lower alkoxy, trifluoromethyl or halogen. and R 2 represents hydrogen or a group of the formula R 2 - O 1 - Q 1 -, wherein R 2 represents lower alkyl, and their

Description

The invention relates to a process for the production of new 2-fluoro-alkylated 4-acylresorcinethers with the formula

(IN)

where R\means lower alkyl, R2 is fluorinated lower alkyl, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene residue which is optionally interrupted by oxygen, one of the residues R4, R5 and R7 represents a group with the formula -NH-C( =0)-Rg, a residue R4 which is different from it, or R5 represents a residue R9 and a residue R7 which is different from it represents a residue Rjrj. fyj is hydrogen, lower alkyl, trifluoromethyl, halogen, optionally esterified or amidated carboxy, cyano or lower alkanoyl, Rg means an optionally esterified or amidated carboxy or 5-tetrazolyl, R9 means hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and R\ q stands for hydrogen , lower alkyl, lower alkoxy, halogen, trifluoromethyl, cyano or optionally esterified or amidated carboxy, and their salts.

Alkylene residues alk can have up to 9 chain links and are, for example, linear alkylene residues with the formula

(Ia)

where m means an integer from 2 to 9, but can also be alkylene residues which are branched, especially branched in the higher than a- and lower than the co-position, and are preferably lower alkylene residues (linear and branched) of the aforementioned type.

Alkylene residues which are interrupted by oxygen are, for example, mono-, di- or trioxaalkylene residues, e.g. with the formula

(Ib)

where n and n' independently of each other mean 2, 3 or 4 and k stands for 1, 2 or 3, and means in particular oxa- or dioxa-lower alkylene residues, e.g. with the formula Ib, where n and n' stand for 2 and k stands for 1 or 2.

Hydroxyalkylene residues which are optionally interrupted by oxygen are, for example, hydroxyalkylene, hydroxy(oxa)alkylene or hydroxy(dioxa)alkylene residues in which the hydroxy group is bound in a higher than a- and lower than the co-position, e.g. remainders with the formula

(Ic)

important information

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where 1 and T independently of each other mean 2 or 3 and o and p independently of each other stand for 0 or 1, and are particularly corresponding to hydroxy-lower alkylene residues, further hydroxy(oxa)lower alkylene residues.

Esterified carboxy is, for example, lower alkoxycarbonyl, but in the case of Rg can also be N,N-dilower alkylaminolower alkylcarbonyl, N,N-lower alkyleneaminolower alkylcarbonyl, optionally substituted N,N-(aza)-lower alkyleneaminolower alkylcarbonyl, N,N-(oxa)lower alkyleneaminolower alkylcarbonyl or N ,n-(thia)lower alkyleneaminolower alkoxycarbonyl.

Amidated carboxy is, for example, carbamyl, N-mono- or N,N-dilower alkylcarbamyl, further N,N-lower alkylene or N,N-(aza)lower alkylene, N,N-(oxa)lower alkylene or N,N-(thia)lower alkylenecarbamyl.

In the foregoing and following, "lower" organic compounds and groups derived from them shall be understood, for example, as having up to and including 7, especially up to and including 4, carbon atoms (C atoms).

Fluorinated lower alkyl has, for example, even 3, especially terminally bound fluorine atoms, and means, for example, mono-, di- or trifluoro-Ci-C4-alkyl, such as trifluoromethyl, 3-fluoropropyl, 3,3-difluoropropyl or 3,3,3- trifluoropropyl.

Lower alkyl means, for example, Ci-C4 alkyl such as methyl, ethyl, propyl, isopropyl or butyl, further secondary or tertiary butyl.

Lower oxy means, for example, C 1 -C 4 ~ alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy.

Halogen has, for example, atomic number up to and including 53, especially 17 up to and including 53, and means, for example, fluorine, chlorine, bromine or iodine.

Lower alkanoyl is, for example, Ci-Cy-alkanoyloxy, such as formyl, acetyl, propionyl, butyryl, valeroyl or pivaloyl.

Linear lower alkylene is, for example, linear C2-Cy alkylene such as ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,7-heptylene, but can also be 1,2 -propylene, 1,3-butylene or 2,4-pentylene.

Branched lower alkylene is, for example, branched C 1 -C 2 -alkylene, such as 1,3-(2-methyl)-propylene or 1,3-(2,2-dimethyl)propylene.

The oxalaverealkylene is, for example, 3- or 4-oxa-C5~C7-alkylene, such as 1,5-(3-oxa)pentylene or 1,7-(4-oxa)heptylene. The dioxalower alkylene is, for example, 1,7-(3,5-dioxa)heptylene.

The hydroxyl lower alkylene is, for example, 2-, 3- or 4-hydroxy-C3-C7-alkylene, such as 1,3-(2-hydroxy)propylene, 1,4-(2-hydroxy)butylene, 1,5-(3-hydroxy )pentylene, 1,6-(2-hydroxy)hexylene or 1,7-(4-hydroxy)heptylene. The hydroxy(oxa)lower alkylene is, for example, 2-hydroxy-4-oxo-Cft-Cy-alkylene, such as 1,6-(2-hydroxy-4-oxa)hexylene or 1,7-(2-hydroxy-4-oxa) heptylene.

Lower oxycarbonyl is, for example, C1-C4 alkoxycarbonyl, such as methoxy-, ethoxy-, propyloxy-, isopropyloxy- or butyloxycarbonyl.

N,N-dilower alkylaminolower oxycarbonyl is, for example, N,N-di-Ci-C4 - alkylamino - C2 - C4 - alkoxycarbonyl, such as 2 - (dimethylamino) ethoxy - carbonyl, 2-(diethylamino) ethoxycarbonyl or 3-(dimethylamino) propyloxycarbonyl .

N,N-lower alkyleneaminolower oxycarbonyl is, for example, 5- to 7-membered N,N-alkyleneamino-C2-C4-alkoxycarbonyl, such as 2-(pyrrolidino)-, 2-(piperidino)- or 2-(tetrahydroazepino)ethoxycarbonyl.

Optionally substituted N,N-(aza)lower alkyleneaminolower oxycarbonyl is, for example, 5- to 7-membered N,N-alkyleneamino-C2-C4-alkoxycarbonyl, such as 2-(piperazino)ethoxycarbonyl, 2-(4-methylpiperazino)ethoxycarbonyl.

N.N-(oxa)- or N,N-(thia)lower alkylaminolower oxycarbonyl is, for example, the 5- to 7-membered N.N-(oxa)- or N,N-(thia)-alkyleneamino-C2-

C4-Alkoxycarbonyl, as . 2-(morpholino)-■■■■.'respectively. 2-(thiomorpholino) ethoxy - carbonyl.

N-mono- or N,N-dilaverealkylcarbamoyl is, for example, N-Ci-Cy-alkyl-or N,N-di-Ci-C4-alk<y>lcarbamoyl>, as N-methyl-, N-ethyl- or N,N-dimethylcarbamyl.

N,N-lower alkylenecarbamyl or N.N-(aza)-, N.N-(oxa)- or N,N-(thia)lower alkylenecarbamyl are, for example, 5- to 7-membered N,N-alkylene-, N,N-(aza)alkylene-, N,N -(oxa)alkylene- or N,N-(thia)alkylenecarbamyl, such as pyrrolidino-, piperidino-, pyridazino-, (4-methyl)piperazino-, morpholino- or thiomorpholinocarbamyl.

Salts of compounds of formula I preferably include pharmaceutically usable salts, such as metal salts, ammonium salts or salts with organic bases. Metal salts are, for example, corresponding alkali, alkaline earth metal salts, e.g. lithium, sodium, potassium, magnesium or calcium salts, further pharmaceutically usable transition metal salts, such as zinc or copper salts. Salts with organic bases are formed, for example, by compounds of formula I, where R5 and/or R7 is carboxy and/or Rg is carboxy or 5-tetrazolyl, with mono-, di- or trisubstituted, organic amines, such as corresponding alkylamines, hydroxyalkylamines, heterocyclic compounds which are suitable and which have at least one N atom, such as morpholine, thiomorpholine, piperidine or pyrrolidine, possibly N-substituted amino-saccharides, e.g. with N-methyl-D-glucamine, or basic amino acids, such as lysine, arginine, histidine or ornithine, whereby those with L-configuration are preferred. As alkylamines, e.g. considering mono-, di- or tri-lower alkylamines, such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, trimethyl- or triethylamine. Hydroxyalkylamines are, for example, mono-, di- or trihydroxyalkylamines, such as mono-, di- or triethanolamine or diisopropanolamine, or hydroxyl lower alkyl lower alkyl amines, such as N,N-dimethyl or N,N-diethylamino-ethanol or tri-(hydroxymethyl)methylamine.

As additional salts, mention should be made of pharmaceutically usable acid addition salts, such as hydrohalides, methanesulfonates, N-cyclohexylsulfaminates, maleinates, fumarates, maleates or tartrates of compounds of formula I, where the residue R3 is capable of forming corresponding salts.

The compounds of formula I with chiral C atoms can, depending on the number of these, exist in enantiomers or diastereomeric forms or as mixtures thereof, as diastereomer mixtures, racemates or racemate mixtures.

The new compounds are distinguished by valuable pharmacological properties.

Thus, they exhibit a distinct antiallergic effect which is based on a distinct LTD4 (leukotriene-D4) as well as PAF (PAF acetate) antagonism. The LTD4-antagonistic properties of the compounds according to the invention can, for example, be demonstrated in vitro on the basis of their detectable inhibitory effect in concentrations from approx. 0.03 to approx. 0.10 umol/1 on contractions of isolated guinea pig ileum induced by LTD4, and in vivo on the basis of their detectable inhibitory effect by intravenous treatment in doses from approx. 0.08 mm/kg or in aerosol treatment with a content of active substances from approx. 0.025% by weight on bronchospasms in guinea pigs induced by LTD4. They also show a distinct inhibition of LTD4 synthesis, which can be demonstrated in vitro on the basis of inhibition of aggregation of peritoneal PMN in rats.

Compared to antiallergic compounds with a similar structure, the compounds according to the invention are characterized by a longer duration of action and, in addition to the aforementioned LTD4~antagonistic effect, exhibit phospholipase-inhibiting properties that are new for this compound class, and a pronounced anti-inflammatory or skin phlogistic effect as well as a pronounced inhibitory effect on leukotriene-134 biosynthesis which can be shown in vitro at concentrations from approx. 0.5 umol/1 which itself is already valuable and also complements the anti-allergic effect in a desirable way. The phospholipase-inhibiting properties can, for example, be demonstrated in vitro on the basis of the detectable inhibition of the activity of phospholipases A2 (from human leukocytes) and C (from human platelets) in concentrations from approx. 10 umol/1, and the anti-inflammatory resp. the skin phlogistic properties in vivo on the basis of the inhibitory effect on the experimental cronton oil ear edema in rats in concentrations from approx. 10 mg/ml.

The compounds according to the invention can therefore be used as anti-allergic agents, for example for the treatment of asthma, hay fever, rhinitis and skin allergies,

but especially as anti-inflammatory agents, above all for the treatment of inflammatory diseases in the rheumatic area, as well as as skin-

respectively mucous skin phlogistics, for the treatment of inflammatory dermatoses of various, but especially allergic, origins, for example for the treatment of skin irritations, contact dermatitis, exanthems, burns with inflammation and of mucous inflammations in the eyes, lips, mouth as well as genital or the anal region.

The inhibitory effect on the experimental ear edema in rats can be determined according to literature G. Tonelli and L. Thibault, Endocrinology 77^

625 (1965). For determining the other mentioned properties, e.g. the following experimental devices are used.

Inhibition of LTD^ induced contractions of guinea pig ileum.

Contractions are triggered on ileum segments taken from guinea pigs with a body weight of 300 to 400 g that are fixed in an organ bath in Tyrode's solution (38 °C, gassed with 95% O2 and 5% CO2) and loaded with lp with synthetic LTD4 (leukotriene D4 , potassium salt), as the extent of the contractions is recorded. The extent of the inhibition of these contractions which can be traced back to the test substance's LTD4-antagonistic action is measured. The concentration of the test substance is calculated, designated as IC50, which reduces the contractions induced by LTD4 to 50% of the initial value. In this experimental device, for example, the sodium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-propyl-phenyloxy)-propyloxy]-2-cyano-phenyl)-oxamic acid was obtained according to US patent 444,872 an _ICqi value of 0.087 umol/1 and for the sodium salt of N-{<3-{3-[4-acety 1-3- hydroxy -2-(3,3,3-trifluoropropyl)phe nyloxy] -propyloxy > -4-bromo-6-methyl-phenyl) >-1H-1,2,4-triazole-5-carboxamide according to the invention an IC5Q value of 0.012 umol/1.

In vitro test for the determination of the inhibition of phospholipase from human leukocytes,

Neutrophils, human leukocytes with polymorphous nuclei are isolated starting from "buffy coats" by multi-step fractional sedimentation and deep frozen. Phospholipase A2 is extracted from the cell suspension by homogenization with the addition of ice-cold 0.36N H2SO4 in 2 m NaCl and the supernatant obtained after centrifugation at 10,000 g is dialyzed against sodium acetate buffer pH 4.5.

To determine the enzyme activity, enzyme (10-30 ug protein) is incubated at 37°C for 1 hour in 0.1 M tris/HCl buffer pH 7 with the addition of 1 raM CaCl2 and substrate, consisting of phospholipids (2 uM) of Escherichia coli which is biosynthetically radioactively labeled with 14c -oleic acid. The reaction is stopped by the addition of Dole reagent (isopropanol/heptane/IN H2SO440:10:1, vol/vol) and the 14C -oleic acid that is released selectively with phospholipase A2 is extracted. Substrate that is co-extracted is also completely removed by filtering the extract through a column of silica gel. The determination of<I>^C-oleic acid in the eluate takes place by radiometry.

To determine an inhibitory effect of test substances on phospholipase A2, these are added to the incubation mixture as solutions in water, dimethyl sulfoxide (final concentration in the mixture to 5 vol-%) or ethanol (final concentration in the mixture to 2.5 vol-%). The effectiveness of the test substances is expressed by IC5Q, i.e. the concentration which causes an inhibition of 50% of the control activity. IC50 is calculated graphically by plotting the percentage inhibition on the ordinate against the logarithm of the concentration (>jM) on the abscissa.

In this test device, for example, the sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl-oxy>-4 -bromo-6-methyl-phenyl> >-1H-1,2,4-triazole-5-carboxamide an IC5Q value of 12 umol/1 and for N-{ {3-(3- [4-acetyl-3 -hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-chloro-6-methyl-phenyl}>-1H -1,2,4-triazole-5-carboxamide en K ^g value of 13 umol/1, whereas the sodium salt of N-{ 3- { 3-(4-ac ethyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propyloxy)-2-cyano-phenyl)- the oxamic acid according to US patent 4,448,729 also did not show any effect at 100 umol/1

Ca lsium ionophore-. induced synthesis of LTB4

Peritoneal exudate (neutrophil) of Wistar rats (RA 25, male rats) obtained 24 hours after i.p. injection of 12% sodium caseinate. Cells (lx 10^/ml) are stimulated for 4 minutes with calcium ionophore A 23187

(1 x 10~<6>M). Supernatant fluid is examined for its ability to trigger PMN aggregation in vitro. Inhibiting substances in DMSO are added 5 minutes before the addition of the ionophore.

The results are expressed in % inhibition of the control (without inhibitor) and as IC5Q.

The invention primarily applies to compounds of formula I, where Ri means lower alkyl, R2 means fluorinated lower alkyl with up to 3 fluorine atoms, R3 is hydrogen, lower alkoxy, trifluoromethyl or halogen, alk stands for the lower alkyl or the hydroxyl lower alkyl which is optionally interrupted by oxygen, in particular a residue with the formulas -(CH2)m-(Ia)>-(C<H>2)n, -[0-(CH2)n]k-(Ib) or

-[(CH2)r-0]sCH2-CH(OH)-CH2-<p->(CH2)i]p--(<Ic>)

where k stands for 1, 2 or 3, 1 and 1' independently of each other means 2 or 3, m means an integer from 2 up to and including 9, n and n' independently of each other means 2, 3 or 4 and 0 and p independently of each other stand for 0 or 1, one of the residues R4, R5 and R7 stands for a group with the formula -C(C=0)-Ra, one from this different residue R4 or R5 stands for a residue R9 and one from this different residue R7 stands for a residue Rig, Ré means hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxy, lower alkoxycarbonyl, cyano, carbamyl, N-mono- or N,N-dilower alkyl carbamyl, Rg on the one hand means carboxy, lower alkoxycarbonyl, N,N-dila veralkyl laminolower alkyl, N,N-lower alkyleneamino-lower alkyl, carbamyl, N-mono- or N,N-dilower alkylcarbamyl, N,N-lower alkylene- or N,N-(aza)lower alkylene-, N,N-(oxa) lower alkylene- or N,N-(thia)lower alkylenecarbamyl or on the other hand means 5-tetrazolyl, R9 means hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and Riq stands for hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, cyano, carbamyl, N-mono- or N,N-dilower alkylcarbamyl, and their salts, especially pharmaceutically usable salts.

The invention preferably relates to the preparation of compounds of formula I, where Ri is lower alkyl with up to and including 4 C atoms, such as methyl, R 2 means co-trifluoro-, to,00-difluoro- or co.co.to-trifluoro lower alkyl with, to and with 4 C atoms, such as trifluoromethyl, 3,3,3-trifluoro-3-fluoropropyl or 3,3-difluoropropyl, R3 is hydrogen, R4 is hydrogen, lower alkyl, such as methyl, trifluoromethyl or halogen with atomic number up to and including 35, which chlorine or bromine, R5 is oxaloamino, lower alkoxyoxalylamino with 3 to 6 C atoms, such as methoxy- or ethoxyoxalylamino or 5-tetrazolylcarbonylamino, R5 is hydrogen, lower alkyl with up to 4 C atoms, such as methyl, halogen with atomic numbers to and with 35, such as chlorine or bromine, trifluoromethyl, lower alkoxycarbonyl with up to and including 5 C atoms, such as ethoxycarbonyl, cyano or carboxy, R7 is hydrogen, lower alkyl with up to and including 4 C atoms, such as methyl, halogen with atomic number up to and including 35 , such as chlorine, carbamyl or cyano and alk means linear, termina lt bonded lower alkylene with 2 to 5 carbon atoms, such as 1,3-propylene, or hydroxy lower alkylene with 3 to 7 carbon atoms, in which the hydroxy group is bonded in a higher than a-position and in a lower than co-position , such as 1,3-(2-hydroxy)propylene, and their salts, especially pharmaceutically usable salts, with bases.

The invention relates in particular to compounds of formula I, where Ri means lower alkyl with up to and including 4 C atoms, such as methyl, R 2 means co-fluoro-, co.to-difluoro- or co,co,co-trifluorolower alkyl with up to and including 4 C -atoms, such as 3,3,3-trifluoropropyl, further 3-fluoropropyl or 3,3-difluoropropyl, R3 stands for hydrogen, R4 means hydrogen, lower alkyl, such as methyl, trifluoromethyl or halogen with atomic number up to and including 35, such as chlorine or bromine, R5 is oxaloamino, lower alkoxyoxalylamino of 3 to 6 C atoms, such as methoxy- or ethoxyoxalylamino or 5-tetrazolylcarbonylamino, R5 is hydrogen, lower alkyl of up to 4 C atoms, such as methyl, halogen of atomic number up to and including 35 such as chlorine or bromine, trifluoromethyl or cyano, R7 is hydrogen, lower alkyl of up to 4 C atoms, such as methyl, cyano or halogen of atomic number up to and including 35, such as chlorine or bromine, and alk means the linear, terminally bonded lower alkyl of 2 to and with 5 C atoms, such as 1,3-propylene, or the hydroxyl lower alkylene with 3 up to and including 7 C atoms, in which the hydroxy group is bound in a higher than a-position and in a lower than co-position, which

1,3-(2-hydroxy)propylene, and their salts, especially pharmaceutically usable salts, with bases.

The invention relates in particular to the preparation of compounds of formula I, where Ri means lower alkyl with up to and including 4 C atoms, such as methyl, R2 means co,co,co-trifluorolower alkyl with up to and including 3 C atoms, such as 3,3,3 -trifluoropropyl, R3 is hydrogen and R5 is oxaloamino, lower alkoxyoxalylamino with 3 up to and including 6 C atoms, such as methoxy- or ethoxyoxalylamino or 5-tetrazolylcarbonylamino, R4 stands for lower alkyl with 4 C atoms, such as methyl, R5 is halogen with atomic number up to and including 35 , such as chlorine or bromine, or cyano and R7 is hydrogen and alk means linear, terminally bonded lower alkylene of 2 to 5 carbon atoms, such as 1,3-propylene, further hydroxyl lower alkylene of 3 to 7 carbon atoms, in which the hydroxy group is bonded higher than the α-position and lower than the α-position, such as 1,3-(2-hydroxy)propylene, and their salts, especially pharmaceutically usable salts, with bases.

The invention relates primarily to the preparation of compounds of formula I, where Ri means lower alkyl with up to and including 4 C atoms, such as methyl, R2 means co-fluoro-, co.co-difluoro- or to.co.co-trifluorolower alkyl with up to and including 3 C atoms, such as 3,3,3-trifluoromethyl, R3 and R7 stand for hydrogen, one of the residues R3 and R5 means lower alkyl with up to and including 4 C atoms, such as methyl, and the other means halogen with atomic number up to 35, such as fluorine, chlorine or bromine, R5 means oxaloamino or 5-tetrazolylcarbonylamino and alk means linear, terminally bound lower alkylene with 2 up to and including 5 C atoms, such as 1,3-propylene, further hydroxyl lower alkylene with 3 up to and including 7 C- atoms, in which the hydroxy group is in the higher than a-position and lower than the co-position, such as 1,3-(2-hydroxy)-propylene, and their salts, especially pharmaceutically usable salts, with bases.

The invention relates in particular to the compounds of formula I mentioned in the examples, and their salts, especially pharmaceutically usable salts, with bases.

The invention further relates to a method for the preparation of compounds of formula I and their salts which is based on methods known per se. This is characterized by,

a) a compound with the formula

(II)

be re-stored or

b) a compound with the formula

(III)

where Xi means optionally etherified hydroxy, is reacted with a compound of the formula R1-X2(IV) where X2 means optionally converted carboxy, or

c) in connection with the formula

(V)

d) in connection with the formula

(WE)

where X4 means a residue that can be transferred to hydroxy, X4 is transferred to hydroxy or

e) compounds with the formulas

(VII) and (VIII)

are reacted with each other, where one of the residues X5 and X5 is hydroxy which is optionally present in salt form, and the other is a residue which is substituted with reactive, esterified hydroxy or epoxy -O-alkH, i.e. an alkoxy acid residue, mono-, di- or trioxaalkyl residue which corresponds to alk and which is substituted with reactive, esterified hydroxy, or is an alkoxy or mono- or dioxaalkylene residue which is substituted with epoxy, or

f) a compound with the formula

(IX)

where one of the residues R4', R5' and R7' is an amino group, one from this different residue R4' or R5' is a residue R9 and a residue different from this R7' is a residue Riq, or a salt thereof is reacted with a compound of the formula

(X)

where R3' means an optionally esterified or amidated carboxy group or

optionally in the 1-position protected 5-tetrazolyl and X7 means an optionally esterified, amidated, anhydridized or, if Rg' stands for 1-position protected 5-tetrazolyl, means a carboxy group present in salt form, and the protecting group in the 1-position is optionally cleaved from a tetrazolyl group Rg or

g) in connection with the formula

(XI)

where one of the residues R4", R5" and R7" means a residue Xg, one different from this residue R4" or R5" means a residue R9 and a residue different from this R7" is a residue Rig and Xg means a residue which can be transferred to the desired group with the formula -NH-C(=0)-Rg, Xg is transferred to this or

h) in connection with the formula

(s)

where alk' means a residue that can be transferred to a group of alk, alk' is transferred to a group of alk and, if desired, a compound obtainable according to the method is transferred to another compound of formula I, an isomer mixture obtainable according to the method is separated and the desired isomer(s) is isolated and/or a free compound which can be obtained according to the invention is converted into a salt or a salt which can be obtained according to the invention is converted into the free compound or into another salt.

Optionally etherified hydroxy X1 in formula III means, for example, lower alkoxy, such as methoxy.

Optionally functionally converted carboxy X2 in formula IV means, for example, free, esterified or anhydridized carboxy, such as carboxy, lower alkoxycarbonyl, e.g. methoxy or ethoxycarbonyl, halocarbonyl, e.g. chlorocarbonyl or anhydrided carboxy of the formula -C(=0)-0-C(=0)-Ri (IVa).

Residues X3 in formula V which can be transferred to fluorinated lower alkyl radicals R2 are, for example, fluorinated lower alkenyl radicals, such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-prop-1-enyl or 3-fluoro- or 3,3-difluoro-prop-2-enyl, fluorinated lower alkynyl radicals, such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-prop-1-inyl, further fluorinated hydroxyl lower alkyl radicals , such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-1-hydroxy-propyl, further halogen with atomic number 19 to 53 inclusive, such as bromine or iodine, further chlorine.

Residues X4 in formula VI which can be transferred to hydroxy are, for example, etherified or esterified hydroxy groups. As etherified hydroxy X4 comes, for example, aliphatic etherified hydroxy, e.g. lower alkyloxy, such as methoxy, or lower alkenyloxy, such as allyloxy, phenyl lower alkyloxy, especially optionally substituted phenyl lower alkyloxy, such as benzyloxy, further tetrahydropyran-2-yloxy or silyloxy, especially trilower alkylsilyloxy, e.g. trimethylsilyloxy. Esterified hydroxy X4 is, for example, hydroxy which is esterified with a carboxylic acid, such as an aliphatic or aromatic carboxylic acid or with an aliphatic or aromatic half-ester of carboxylic acid, such as lower alkanoyloxy, e.g. acetoxy, optionally substituted benzoyloxy, e.g. with the formula Ri-C(=0)-0-, optionally halogenated lower alkoxycarbonyl, e.g. methoxy-, ethoxy- or tertiary-butyloxycarbonyl, 2,2,2-triiodoethoxy- or 2,2,2-trichloroethoxycarbonyl, optionally substituted phenyl lavereal oxycarbonyl, especially 1-phenyl lavereal oxycarbonyl, e.g. benzyloxycarbonyl, or optionally substituted phenoxycarbonyl.

Hydroxy X5 in formula VII or X5i formula VIII or carboxy in formula

X which is present in salt form is particularly present in an alkali metal salt form, e.g. as sodium or potassium salt.

Alkoxy acid residue X5 in formula VII or X5 in formula VIII which is substituted with reactive, esterified hydroxy or epoxy are, for example, residues with the formulas -0-(CH2)m-X, [(CH2)fiO] -k(CH2)-ri'X, [(CH2)iO]{ j-CH2CH(OH)CH2-LO-(CH2)i']o<X>or.[(C<H>2)iO]pCH2-X,,where X is reactive, esterified hydroxy and X' is 1 ,2-epoxyethyl. Reactive, esterified hydroxy is thereby, for example, halogen, such as chlorine, bromine or iodine, or organic sulphonyloxy, such as lower alkanesulphonyloxy, e.g. methanesulfonyloxy, or optionally substituted benzenesulfonyloxy, e.g. benzene-, p-bromobenzene- or p-toluenesulfonyloxy.

Optionally esterified, amidated or anhydridized carboxy X7 in formula X is, for example, free carboxy, esterified carboxy R3 or carboxy which is esterified with an optionally substituted phenol, such as phenoxy-, 4-nitro-phenoxy- or 2,4-dinitrophenoxycarbonyl, amidated carboxy R3 or activated carbamyl, as 1-imidazolyl- or 1-(2,5-dimethylimidazolyl)-carbonyl, or carboxy which is anhydrided with a halohydrogen acid, such as halocarbonyl, e.g. with the formula Hal-C(=0)-, where Hal is chlorine, bromine or iodine, above all chlorine.

As starting materials X, in particular those with the formulas Rg^Rs" (Xa) where R3" means possibly esterified carboxy, or Hal-C(=O)-R3' come into consideration. 5-tetrazolyl residues R3' which are present in protected form are, for example, 1-(cx-aralkyl)-tetrazolyl-(5) residues which are optionally substituted in the aryl part, such as 1-benzyltetrazolyl-(5) or 1-(p-methoxybenzyl) )tetrazolyl-(5).

A residue X3 in formula XI that can be transferred to the group with the formula -NH-C(=0)-R3 is, for example, a residue that can be transferred to this by solvolysis, i.e. hydrolysis, alcoholysis (reaction with the alcohol corresponding to the desired, esterified carboxy group R3) and/or aminolysis (reaction with ammonia or an amine corresponding to the desired, amidated carboxy group R3), for example a group with the formula -NH-X^, where X^ means an oxalo group that is different from an optionally esterified or amidated oxalo group and which can be transferred to this functionally converted oxalo group. Such functionally converted oxalo groups are preferably those which, as functionally converted α-carbonyl grouping, exhibit thioxomethylene, iminomethylene or an esterified and/or etherified dihydroxymethylene grouping and/or as functionally converted carboxyl group a functionally converted carboxyl group that is different from an esterified or amidated carboxyl group. Esterified and/or etherified dihydroxymethylene groupings are, for example, dihydroxymethylene groups which are esterified with a hydrohalic acid, such as hydrochloric acid, and/or etherified with a lower alkanol, such as methanol or ethanol. As examples, above all, dihalogenomethylene groupings, such as dichloromethylene, lower alkoxyhalogenomethylene groupings, such as methoxy or ethoxychloromethylene, or dilavereal oxymethylene groupings, such as dimethoxy or diethoxymethylene, should be mentioned. Functionally converted carboxyl groups that are different from esterified or amidated carboxyl groups are, for example, the cyano group, anhydridized carboxyl groups, such as halogen, e.g. chlorocarbonyl, imino-ester-, as imide- or amine halide groups, e.g. iminochloro- or aminodichloromethyl, iminoether moieties, such as lower alkyl or lower alkylene iminoether moieties, e.g. methoxy- or ethoxyiminomethylene, 4,4- or 5,5-dimethyloxazolinyl-(2) or 4,4,6-trimethyl-dihydro-oxazinyl-(2), amidino groups, such as amidino or lower alkyl-, e.g. methylamidino, ortho acid groupings which are esterified with a halohydrogen acid, such as hydrochloric acid, and/or etherified with a lower alkanol, such as trilavereal oxy, lower alkoxyhalo or trihalomethyl groups, above all trimethoxy or triethoxymethyl, ethoxydichloromethyl or trichloromethyl, or optionally esterified thiocarboxyl groups, such as lower alkylthiocarbonyl groups , e.g. ethylthiocarbonyl.

A residue Xg which can be transferred to the group with the formula -NH-C(=0)-Rg where Rg means 5-tetrazolyl is, for example, the group with the formula -NH-C(=0)-CN or a group with the formula -NH- C(=O)-Rg', where Rg' is 5-tetrazolyl which is protected in the 1-position. 5-tetrazolyl residues Rg' which are present in protected form are, for example, 1-(oc-aralkyl)-tetrazolyl-(5)-residues, which are optionally substituted in the aryl part, such as 1-benzyltetrazolyl-(5), or 1-(p -methoxybenzyl)-tetrazolyl-(5).

Other residues Xg which can be transferred to groups with the formula

-NH-C(=0)-Rg, are for example groups with the formula -NH-Xg, which can be oxidatively transferred to these, where Xg means the possibly hydrated glyoxyl group which can be oxidatively transferred to the oxalo group with the formula -C(=0)- Rg, where Rg is carboxy. This can advantageously be set free during the oxidation reaction, e.g. from the acyl group of an optionally a, e-unsaturated or a,3-dihydroxylated, aliphatic or araliphatic carboxylic acid, a glycoloyl group which is optionally esterified on the hydroxy group or the glycyl group, formed in situ or from one of their functional derivatives, e.g. one of their acetals or imines. Acyl groups of optionally ot.p-unsaturated or a.p-dihydroxylated carboxyl-

acids are, for example, alkanoyl groups, such as lower alkanoyl, e.g. acetyl, acyl groups of oc,p-unsaturated, aliphatic mono- or dicarboxylic acids, e.g. acryloyl, crotonyl or the acyl group in the optionally functionally converted fumaric or maleic acid, acyl groups of oc.<p->unsaturated, araliphatic carboxylic acids, e.g. optionally substituted cinnamoyl, or acyl groups of aliphatic, α,β-dihydroxydicarboxylic acids such as tartaric acid, or monofunctional carboxy derivatives, such as esters or amides, thereof. Esterified glycoloyl groups are, for example, glycoloyl groups that are esterified at the hydroxy group with a mineral acid, such as a hydrohalic acid, e.g. with hydrochloric or hydrobromic acid, or with a carboxylic acid, for example with acetic acid or the optionally substituted benzoic acid. Acetalized glyoxyloyl groups are, for example, glyoxyloyl groups that are acetalized with lower alkanols or a lower alkane diol, such as dimethoxy-, diethoxy- or ethylenedioxyacetyl. Imines of glyoxyloyl groups are, for example, optionally substituted N-benzylimines or N-(2-benzothiazolyl)-imines thereof, or imines with 3,4-di-tert-butyl-o-quinone. Other residues that can be oxidatively transferred to the oxalo group are e.g. optionally substituted 2-furoyl groups which in the 5-position have an acetalized formyl group, such as diethoxymethyl. Groups that are oxidizable to esterified oxalo groups with the formula -C(=0)-Rg, where Rg stands for esterified carboxy, are esterified glycoloyl groups, such as lower alkoxyacetyl. Residues Xg which are oxidizable to optionally esterified or amidated oxaloamino groups are furthermore optionally hydrated or acetalized formylmethylamino groups or optionally functionally converted carboxymethylamino groups or carboxymethyleneimino groups, e.g. with the formula -NH-CH2-CH=0, -NH-CH2-Rg or -N=CH-Rg.

Groups that can be transferred to the alk residue are, for example, alk residues substituted with oxo or etherified or esterified hydroxy, such as oxoalkylene, oxo(oxa)alkylene or oxo(dioxa)alkylene residues, e.g. with the formula

(Ib')

respectively etherified or esterified hydroxy alkylene, hydroxy(oxa)alkylene or hydroxy(dioxa)alkylene radicals with the formula

(Ib")

where X" means etherified or esterified hydroxy.

Etherated hydroxy X" is thereby* for example hydroxy which is etherified with an α-aralkanol or a silanol, such as optionally substituted benzyloxy or trilaverealkylsilyloxy, e.g. trimethylsilyloxy.

Esterified hydroxy X" is, for example, hydroxy which is esterified with a carboxylic acid, such as a lower alkanoic acid or a half-ester of the carboxylic acid, such as lower alkanoyloxy, e.g. acetoxy or pivaloyloxy, lower alkoxycarbonyloxy, e.g. tertiary butoxycarbonyloxy, or optionally substituted benzyloxycarbonyl, e.g. .carbobenzoxy.

The carrying out of the reactions according to the method as well as the production of new starting materials or intermediate products take place analogously to the reaction and formation method of known starting substances or intermediate products. Thereby, although it is not expressly mentioned in the following, the usual aids are used, such as catalysts, condensation as well as solvolysis agents and/or solvents, respectively. diluents, and reaction conditions such as temperature and pressure, as well as possibly shielding gases.

The rearrangement of compound II according to method variant a) takes place, for example, photochemically or in the presence of an acidic condensation agent. Suitable acidic condensation agents are, for example, Lewis acids, especially complex metal halides with the formula M<n>Yn(XIX), where M is an n-valent, coordinatively unsaturated metal atom of the group Ilb, Illb, IVa, IVb, Va or VHIb in the periodic table the system, e.g. a zinc<H->, boron<UI->, aluminum<lll->, galliumHI-, tin<IV->, titanium^-, antimony^- or iron^H atom and Y a halogen atom, especially with atomic number to and with 35, as fluorine, chlorine or bromine. Ri fluoride, aluminum trichloride, gallium chloride, titanium tetrachloride or especially zinc chloride are preferably used. Other suitable acidic condensing agents are complex oxygen acids, above all of sulfur or phosphorus, such as sulfuric acid, pyrosulphuric acid, phosphoric acid, pyrophosphoric acid or polyphosphoric acid. Suitable inert solvents are, for example, tetrachloromethane, tetrachloroethane, trichloroethylene, carbon disulphur or nitrobenzene. If necessary, work during cooling or heating, e.g. at approx. -10 to approx. 40 °C, especially at +5 to +30 °C.

Output sto f f et II can e.g. produced, by connecting with the formulas

(XII) and (VIII)

where X5 is an <■alkoic acid residue which is substituted with reactive, esterified hydroxy or epoxy, e.g. with the formulas .0-(CH2)nX-, [(CH2)nO]k(CH2)n'-X, .[(CH2)10]pCH2CH(OH)CH2-[0-(CH2)r]5X or

^[(CH2)i<O>]pCH2-X'(where X means reactive, esterified hydroxy, e.g. halogen, and X' means 1,2-epoxyethyl, react with each other in the usual way and the reaction product with the formula

(XIII)

O-acylated in the usual way, e.g. by reaction with a compound R1-X1(IV), where X1 e.g. means halocarbonyl or anhydrided carboxy of the formula -C(=O)-O-C(=O)-Ri.

Compounds XII are obtained, for example, by compounds with the formulas

(XIV) and X10-<R>2(XV)

where the radicals R mean the same or different etherified hydroxy groups, R3' means hydrogen, lower alkoxy, trifluoromethyl, fluorine or nitro and one of the groups X9 and Xiq means a metallic residue, such as an alkali metal atom, e.g. sodium or lithium, further copper or a halogen alkaline earth metal group, e.g. with the formula -Mg-Hal, and the other stands for a group -Hal, which is halogen, e.g. bromine or iodine, react with each other, for example in a dilower alkyl or lower alkylene ether, such as diethyl ether, tertiary butoxymethane, dioxane or tetrahydrofuran, nitro R3' is reduced to amino and transferred to halogen R3 by treatment with sodium nitrite and a hydrohalic acid and the groups R, are cleaved to hydroxy , e.g. by treatment with hydrogen bromide in dichloromethane.

In a variation of this method, the organometallic components can be formed in situ, by starting from the corresponding halogen compound and carrying out the reaction, preferably under heating in the presence of the corresponding metal in finely divided form, e.g. of copper powder. In another transformation of this method, bisether derivatives of compounds XII are obtained by reacting a compound XIV, where X9 is one of the aforementioned metallic residues, preferably an alkali metal atom or a group -MHal, with a fluorinated lower real channel or lower alkanol, to the formed compound with the formula

(xvi)

where X3 is fluorinated hydroxyl lower alkyl, the hydroxyl lower alkyl group optionally after water removal, e.g. by acetylation and subsequent treatment with zinc and ammonium chloride, to the corresponding, fluorinated lower alkenyl group, is hydrogenated to the desired fluorinated residue R2, nitro is converted to halogen and R is cleaved to hydroxy.

In another variation of this method, a compound XIV, where X9 is bromine or iodine, can also be reacted in the presence of copper powder with trifluoroiodomethane to the corresponding compound with the formula

(XVII)

and then optionally converts nitro to halogen and the residue R to hydroxy.

Compounds XII, where R 2 is 3-fluoro- or 3,3-difluoropropyl, are obtained particularly elegantly, in that a compound of the formula

(XVIII)

where Xj means optionally etherified hydroxy and X3 a 1-fluoro- or 1,1-difluoroprop-2-enyl residue, which in turn can be obtained by reaction between the corresponding R3~resorcin or the corresponding resorcinol monoether and a 1-fluoro- or 1,1-difluorolower alkyl bromide are subjected to allyl rearrangement, for example by heating to approx. 150 to 250 °C, preferably to approx. 190

to 220 °C, advantageously in a solvent, such as diphenyl ether or N,N-dimethyl- or N,N-diethylaniline and in the reaction product of the formula

(XIX)

the formed 3-fluoro- or The 3,3-difluoroprop-2-enyl group of 3-fluoro- or 3,3-difluoro-propyl and, if necessary, etherified hydroxy X1 is cleaved to hydroxy.

Compounds XII, where R2 is 3,3,3-trifluoropropyl, are obtained particularly elegantly according to a new method, an aldehyde with the formula

(XX)

where R e.g. is methoxy, is reacted in the presence of dimethylformamide, with the compound of the formula CF3CCl2ZnCl(C2H5)20 (XXI) to the corresponding compound of the formula

(XXII)

this is acylated in the side chain, e.g. by reaction with acetic anhydride in the presence of pyridine, the reaction product with the formula

(XXIIa)

where Ac stands for acyl, e.g. acetyl, by treatment with a metallic reducing agent, e.g. with activated zinc dust in . presence of ammonium chloride, is transferred to the corresponding compound with the formula

(XXIII)

from. this splits off hydrogen chloride, e.g. by treatment with potassium tertiary butanolate, in the obtained compound of the formula

(XXIV)

the side chain is hydrated, e.g. in the presence of palladium charcoal, and in the obtained compound of the formula

(XXV)

the hydroxy groups are released, e.g. by treatment with hydrobromic acid in dichloromethane.

The production of compounds VIII is described under method variant e).

The reaction of compounds III and IV for which such are particularly suitable, in which X2 is carboxy, takes place according to method variant b) usually in the presence of an acidic condensation agent, advantageously in an inert solvent, if necessary during cooling or heating, for example at approx. +80 to +140 °C, above all at approx. 80 to approx. 120 °C. As acidic condensation agents, for example, those indicated for method variant e) are taken into consideration.

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

(XII) and (VIII)

react with each other, whereby the compound XII can also be present in monoether and/or salt form and Xq is a residue -O-alkH, which is substituted with reactive, esterified hydroxy, i.e. a reactive, esterified hydroxyalcolic acid residue or an epoxyalcolic acid residue, e.g. e.g. a group of the formulas -0-(CH2)nX-, [(CH2)nO]k(C<H>2)n<>>X, -[ (CH2)10]pCH2CH(OH)CH2-[0-( CH2)r] 0X resp.

-[(CH2)iO]pCH2-X'

where X means reactive, esterified hydroxy, such as halogen, and X' means 1,2-epoxyethyl. The turnover takes place e.g. in an analogous * way as indicated in the procedure variant e). ;-

The transfer of the residues X3, which exhibit the aforementioned fluorine, to groups R2 according to process variant c) takes place, for example, by reduction. As a reducing agent, for example, hydrogen comes into consideration in the presence of a hydrogenation catalyst, such as a platinum, palladium or rhodium catalyst, e.g. of platinum oxide. The treatment with catalytically activated hydrogen (hydration) takes place under normal or at most slightly elevated pressure and temperature conditions, e.g. at approx. 0 to 5 bar overpressure and/or in the temperature range from approx. 20 to approx. 80°C. The transfer of halogen to e.g. trifluoromethyl takes place, for example, by heating with trifluoroiodomethane and copper powder.

Starting substances V, where X3 means a mono- or difluorinated lower alkenyl radical, are obtained, for example, by a compound with the formula

(XXVI)

subjected to allyl rearrangement, for example by heating to approx. 150 to 250 °C, preferably to about 190 to 220 °C, advantageously in a solvent, such as diphenyl ether or N,N-dimethyl- or N,N-diethylaniline.

Compounds XXVI are obtained, in turn, by a corresponding compound with the formula

(XXVII)

is reacted with a fluorinated lower alkene of the formula X3-H (XXVIII) which is substituted in the allyl position of the double bond with chlorine, bromine or iodine, e.g. in the presence of a basic condensing agent, such as potassium carbonate.

The transfer of groups X4 to hydroxy according to process variant d) takes place in the usual way, for example by treatment with a complex metal halide with the formula M<n>Yn(XIX), where M means an n-valent, coordinatively unsaturated metal cation from group Ila, Hb, Illa, Illb, IVa, IVb, Va or VHIb in the periodic table, e.g. magnesium-, zinc^-, boron^<I->, aluminum^-, gallium^-, tin^<V->, titanium^-, antimony<V->or iron^I- respectively. iron<VI-> ion, Y means a halogen atom of atomic number up to and including 35, such as fluorine or chlorine, e.g. aluminum trichloride, or with a tertiary organic ammonium salt, such as a pyridinium or trilower alkyl ammonium halide, e.g. with pyridinium chloride or bromide or triethylammonium chloride, but can also take place by solvolysis, especially by hydrolysis, if necessary in the presence of a preferably acidic hydrolysis agent. Hydrolyzing agents are next to common, basic hydrolyzing agents, such as alkali metal hydroxides; as acidic hydrolysis agents, for example mineral acids, e.g. hydrochloric, bromic or hydroiodic acid, sulfuric acid, phosphoric acid or polyphosphoric acid,. similarly complex metal acids, e.g. hexachloroantimonic acid, tetrafluoroboric acid and the like, in the case of hydroxy groups X4 which are esterified with organic carboxylic acids, further lower alkane carboxylic acids, such as acetic acid. Solvents are organic solvents that are, for example, miscible with water during hydrolysis. Preferably work is done in the presence of a solvent or diluent or a solvent, during cooling or heating, e.g. in the temperature range from approx. 0 to 120 °C, and/or under inert gas.

In compounds VI which, as group X4, exhibit an optionally substituted oc-phenyl lower oxy group or a protected hydroxy group which is normally cleavable by reduction, the hydroxy group can advantageously be released reductively. Thus, for example, one can hydrate, i.e. reduce with hydrogen in the presence of a hydrogenation catalyst, e.g. a palladium, platinum, nickel or rhodium catalyst, e.g. of palladium-on-coal or of Raney nickel.

Furthermore, starting from compounds VI, where X4 is hydroxy which is esterified with an organic carboxylic acid, the hydroxy group can be released by transesterification, i.e. by treatment with an alcohol, e.g. lower alkanol, in the presence of an acidic or basic agent, such as a mineral acid, e.g. of sulfuric acid or an alkali metal hydroxide or alcoholate, e.g. of sodium hydroxide or a sodium laver alkanolate.

Starting materials VI are prepared, for example, by combining the formulas

(XXIX) and (VIII)

react with each other, where one of the residues X5 and X^ is hydroxy which is optionally present in salt form and the other a residue -O-alkH, which is

substituted with reactive, esterified hydroxy or epoxy, e.g.

a group with the formulas

-0-(CH2)nX-, -[(CH2)nO]k(CH2)n<>X,>-[(CH^iOlpCH^HCOH)^-^-^)!.]^ resp. - [(CH2)iO]<p>CH2-<X>\ where X means reactive, esterified hydroxy, e.g. halogen, and X' means 1,2-epoxyethyl.

The reaction of compounds VII and VIII according to process variant e) takes place in the usual way, for example in the presence of a basic condensation agent, such as a hydroxide or carbonate of an alkali or alkaline earth metal, such as sodium or potassium hydroxide, potassium carbonate or calcium carbonate, advantageously in a lower alkanol, e.g. methanol or amyl alcohol, dilave alkyl ketone, e.g. in acetone or diethyl ketone, or N,N-dilower 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 a compound with the formula

(XII)

in the presence of a Lewis acid, e.g. of zinc chloride, is reacted with a compound of the formula Ri-X2[IV; X2 = carboxy] and, if desired, is transferred in the obtained compound VII, where X5 is hydroxy, the hydroxy group in the p-position to Rj-C(=0)- by reaction with a dihaloalkane, epoxyalkane or a haloalkanol in an alkoxy acid residue which is substituted with a halogen or hydroxy, and optionally esterified hydroxyalkyloxy reactively, e.g. by treatment with thionyl chloride, phosphorus tribromide or a sulphonic acid chloride.

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

(XXX)

where one of the residues R4"\ R5'" and R7'" is the nitro group, one from this different residue R4"' or R5'" is a residue R9 and one from this different residue R7"' is a residue Riq, the nitro group is reduced to amino , e.g. with hydrogen in the presence of Raney nickel, and the compound of the formula

(XXXI)

where one of the residues R4V R5' and R7' means the amino group, one from this different residue R4' or R5' is a group R9 and one from this different residue R7' is a residue Rtq, is reacted in the presence of a base, e.g. of triethylamine or pyridine, with a compound of the formula Hal-C(=0)-R'3(Xb; Hal = halogen) and, if desired, transferred in the obtained compound VIII, where X5 is hydroxy, the hydroxy group of an carboxylic acid residue which is substituted with halogen, epoxy or hydroxy by reaction with a dihaloalkane, epoxyalkane or a haloalkanol, a dihalo-(hydroxy)alkane, halo(epoxy)alkane or a haloalkanediol, and optionally monoesterified hydroxyalkoxy or dihydroxy alkoxy reactive, e.g. by treatment with thionyl chloride, phosphorus tribromide or a sulphonic acid chloride.

The reaction of compounds IX and X according to process variant f) can take place in the usual way, in particular in the way known from the literature for analogous reactions, if necessary in the presence of a condensing agent, by reaction with an ester halide or amide halide of oxalic acid, for example a basic condensing agent , as a tertiary organic nitrogen base, e.g. of triethylamine or pyridine, or an alkali metal hydroxide or carbonate, e.g. of sodium or potassium hydroxide, or by reaction with oxalic acid, for example a condensation agent which causes dehydration of the primarily formed ammonium salt, as a water-binding agent, e.g. of dicyclohexylcarbodiimide or an isonitrile, such as of tertiary butyl isonitrile, or a mineral acid, e.g. of hydrochloric acid, or an acid anhydride, e.g. of phosphorus pentoxide, optionally in an inert solvent, such as a haloalkane, e.g. in dichloromethane, or an N,N-dialkylamide, e.g. in N,N-dimethylformamide or -acetamide.

The 1-protecting group from 5-tetrazolyl residues R'g can then be cleaved off, e.g. by acidolysis, i.e. treatment with an acid, e.g. with trifluoroacetic acid/anisole, or hydrogenolytically, especially using hydrogen and palladium on charcoal.

Starting substances IX can be prepared, for example, by compounds with the formulas

(VII) and (XXX) where one of the residues R4<1>" and R7"' is the nitro group, one from this different residue R4"' or R5'" is a residue R9 and one from this different i(residue R7"' is a residue Riq, are reacted with each other, where one of the residues X5 and X5 is hydroxy which is optionally present in salt form, and the other a residue O-alkH which is substituted with reactive, esterified hydroxy or epoxy, for example a group with the formulas

-0-(CH2)nX-, -[(CH2)n<O>]k(CH2)<3>133-'-X, -[(CH2)103pCH2CH(OH)CH2-[0-(CH2)1 .]5-X respectively.

-[-(CH2)-OJCH2-X\

where X means reactive, esterified hydroxy, e.g. halogen, and X' means 1,2-epoxyethyl, and in the obtained compound with the formula

(IXa)

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

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

The transfer of the group Xg in compounds XI to those of the formula

-NH-C(=0)-Rg according to process variant g) takes place, for example, by solvolysis or oxidation or starting from groups Xg with the formula - NH-C(=0)-CN by reaction with nitric acid respectively starting from groups Xg with the formula - NHC(=0)-Rg\ where Rg' means 5-tetrazolyl which is protected in the 1-position, by removal of the protecting group. Thus, the aforementioned groups X^ in residues Xg with the formula -Nr1-X^ can be transferred hydrolytically to the oxalo group. As functionally converted carboxy group a group X^ which, as functionally converted carboxy group exhibits an iminoether, orthoester or ester halide grouping and/or as functionally converted oc-carbonyl group exhibits thioxo- or iminomethylene or an esterified or etherified dihydroxymethylene group, can further hydrolyzed to esterified oxalo groups -C(=0)-Rg. Likewise, a group X^ which, as a functionally converted carboxy group, exhibits the cyano group, an amidino- or imide- or amide halide grouping and/or as functionally converted cx-carbonyl group exhibits thioxo- or iminomethylene or an etherified or esterified dihydroxymethylenemethylene group, are hydrolyzed to amidated oxalo groups -C(=0)-Rg. The hydrolysis can be carried out in the usual way, if necessary in the presence of a basic or preferably acidic hydrolysis agent, such as an alkali metal hydroxide, such as sodium or potassium hydroxide, or preferably in a protonic acid, preferably a mineral acid, e.g. a hydrohalic acid, such as hydrochloric acid or an organic carboxylic or sulphonic acid, e.g. of acetic acid or p-toluenesulfonic acid.

A functionally converted oxalo group X^ which as a functionally converted carboxy group exhibits an anhydridized carboxy group, such as halocarbonyl, e.g. chlorocarbonyl, cyanocarbonyl or a lower alkylenimine ether group, e.g. 4,4- or 5,5-dimethyl-oxazolinyl-(2), or 4,4,6-trimethyl-dihydro-oxazinyl-(2), can further by means of ordinary alcoholysis, i.e. reaction with the corresponding alcohol, are transferred to esterified oxalo groups -C(=0)-Rg. The alcoholysis of anhydridized carboxy groups is advantageously carried out in the presence of a basic condensation agent, e.g. of pyridine or triethylamine, while the alcoholysis of carboxy or a lower alkylene imino ether grouping is preferably carried out acidic, e.g. in the presence of hydrochloric acid, p-toluenesulfonic acid or acetic acid. In an analogous manner, a functionally converted oxalo group which exhibits an anhydridized carboxy group can also be transferred to an amidated oxalo group -C(=0)-Rg by ammono- or aminolysis, i.e. reaction with ammonia or a corresponding primary or secondary amine, preferably in the presence of a basic condensing agent, e.g. of sodium hydroxide, pyridine or triethylamine.

The transfer of the aforementioned groups Xg to those with the formula

-NH-C(=0)-Rg takes place, for example, oxidatively. The oxidation can normally take place by reaction with a suitable oxidizing agent. Suitable oxidizing agents are particularly oxidizing heavy metal compounds, such as silver compounds, e.g. silver nitrate or silver picolinate, oxygen acids of heavy metals, e.g. of manganese-IV, manganese-VII, chromium-VI and iron-III, or of halogens respectively their anhydrides or salts, such as chromic acid, chromium dioxide, potassium dichromate, potassium permanganate, manganese dioxide, potassium hexacyanoferrate, sodium chlorite in the presence of sulfamic acid, sodium hypochlorite in the presence of nickel chloride or sodium iodate, sodium periodate

or lead tetraacetate. The reaction with these oxidizing agents takes place in the usual way, for example in an inert solvent, such as acetone, acetic acid, pyridine or water, or a preferably aqueous, inert solvent mixture, at normal temperature or if necessary during cooling or heating, e.g. at approx. 0 to approx. 100 "C. The oxidation of optionally etherified glycoloyl groups to optionally esterified oxalo groups is advantageously carried out with potassium permanganate in aqueous pyridine or acetone at room temperature. Acetalized glyoxyl groups and iminoacetyl groups are preferably oxidized acidic, e.g. with potassium dichromate in sulfuric acid, acyl groups of oc,<p-> dihydroxylated, aliphatic carboxylic acids, such as the acyl residue of tartaric acid, are advantageously oxidized with periodic acid, while for the oxidation of the glycyl group potassium ferrate is preferably used in an alkaline environment, e.g. at pH 10-13, e.g. 11.5, or organic silver salts, as silver picolinate Groups of the formula -N=CH-Rg are preferably oxidized with an organic peracid, eg with peracetic acid or m-chloroperbenzoic acid, in an inert solvent, eg dichloromethane, chloroform or benzene.

The reaction of groups X3 with the formula -NH-C(=0)-CN with nitric acid preferably takes place during the formation of this in situ by treating an alkali metal azide with an acid, such as hydrochloric acid, preferably in toluene or similar solvents.

The removal of the protecting group from groups Xg with the formula -NH-C(=0)-Rg\ where Rg' is 5-tetrazolyl which is protected in the 1-position, takes place in the usual way, especially by acidolysis, i.e. treatment with an acid, e.g. with trifluoroacetic acid in an ether, such as anisole, or by catalytic hydrogenation, e.g. in the presence of palladium.

Starting materials XI are prepared, for example, by a compound with the formula

(IX)

where one of the residues R4', R5' and R7' is the amino group, a different residue R4' or R5' is a residue R9 and a residue different from this R7' is a residue Rig or an acid addition salt thereof is reacted with a corresponding acid, e.g. with the formula X^-OH (XXXIIa) or Xg-OH (XXXIIb) or Rg'-COOH (XXXIIc) or a functional derivative thereof. Functional derivatives of acids XXXIIa to XXXIIc are above all

acid derivatives containing an esterified, amidated or anhydridized carboxy group, such as - : lower alkoxycarbonyl', optionally substituted carbamyl, e.g. carbamyl or imidazolyl-1-carbonyl, or halocarbonyl, e.g. chloro- or bromocarbonyl, or a group of the formula -CON3 or -CON2+Ha<l>~. As examples of acids XXXIIa to XXXIIc and their functional derivatives should be mentioned in particular: As functional derivatives of acids XXXIIa oxalyl halides, such as oxalyl chloride or oxalyl bromide, trilavereal oxy- and dihalo-lavereal oxyacetic acid lower alkyl esters, such as oxalic acid tetraethyl ester or dichlorooxalic acid diethyl ester, oxalic acid imino-dialkyl ester, such as oxalic acid mono- or diiminodiethyl ester, oxalic acid- amidines, such as N-lower alkyloxalic acid ester amidines, oxalic acid dithiolower-alkyl-, such as -dimethyl ester, cyanoformyl chloride or cyan and as acids XXXIIb and their functional derivatives glycolic acids and their lower alkyl esters or the corresponding lactide, mono- or dilavereal oxyacetic acid lower alkyl-, as -ethyl ester, e.g. ethoxy or diethoxyacetic acid ethyl ester, haloacetic anhydrides, such as chloroacetic anhydride or chloroacetyl chloride and tartaric acid, respectively 2,3-diacetoxysuccinic anhydride, further cinnamoyl chloride, acetyl chloride and glycine. Functional derivatives of acids XXXIIc are especially their chlorides.

The reaction of compounds IX and XXXIIa to XXXIIc or their derivatives can take place in the usual way, for example in the presence of a water-binding agent, such as an acid anhydride, e.g. of phosphorus pentoxide, or of dicyclohexylcarbodiimide, or an e.g. acidic or basic condensing agent, such as a mineral acid, e.g. of hydrochloric acid, or an alkali metal hydroxide or carbonate, e.g. of sodium or potassium hydroxide, or an organic nitrogen base, e.g. of triethylamine or pyridine. In the reaction with an acid anhydride, such as acid chloride, an organic nitrogen base is preferably used as condensing agent 1. The reaction with carboxylic acids is preferably carried out in the presence of a water-binding agent. If necessary, work in an inert solvent, at normal temperature or during cooling or heating, e.g. in a temperature range from approx. 0 to approx. 100"C, in a closed vessel and/or under inert gas, eg nitrogen.

Analogously, compounds XI, where Xg means a group Rg-CH=N-, can be prepared by condensation of compounds IX with the optionally esterified or amidated glyoxylic acid.

Compounds XI, where Xg represents a group -NH-Xg and Xg represents glyoxyloyl, can further be prepared by heating a corresponding halogen, such as bromoacetyl compound, with hexamethylenetetramine, preferably in an aqueous alcohol, or oxidizing with silver tetrafluoroborate in dimethylsulfoxide. Analogously, a chloroacetyl compound can also be oxidized with potassium dichromate in hexamethylphosphoric acid triamide in the presence of the dicyclohexyl-18-crown-6-ether oxidizer. Compounds XI, where Xg means a group -NH-Xg and Xg means an iminoacetyl group, e.g. optionally substituted benzyliminoacetyl, can be prepared starting from the corresponding glycyl compounds, by reacting these with the corresponding carbonyl compound, e.g. with benzaldehyde, and the thus obtainable intermediate product, e.g. an N-benzylideneglycyl compound, is rearranged, preferably under the reaction conditions.

Functionally converted oxalo groups which, as a functionally converted carboxy group, exhibit an iminoether grouping, can be prepared starting from the corresponding cyanocarbonyl compound by reaction with the corresponding alcohol, e.g. lower alkane(di)ol or amino lower alkanol.

The transfer of the residue alk' in a compound I' according to method - variant h) takes place solvolytically in the usual way, starting from compound I', where alk' means a residue alk which is substituted with oxo and with hydroxy which is etherified with an oc- alkanol or esterified with a carbonic acid mono-oc-aralkyl residue, for example reductive and starting from compound IX, where alk' means a residue alk which is substituted with other, etherified or esterified hydroxy groups than those mentioned above.

As reducing agents for the reduction of residues alk' which are substituted with oxo, to the corresponding residues alk which are substituted with hydroxy, for example alkali metal borohydrides, such as lithium borohydride, sodium borohydride or sodium cyanoborohydride, or secondary alcohols, such as secondary lower alkanols or cyclolower alkanols, e.g. isopropanol or cyclohexanol, in the presence of an aluminum alcoholate, especially isopropanol in the presence of aluminum isopropanolate, in consideration. The reaction with the aforementioned alkali metal borohydrides is advantageously carried out in a lower alkanol, a dilower alkyl ether or lower alkylene ether or mixtures of these solvents, e.g. in ethanol. In the reaction with alcohols in the presence of an aluminum alcoholate, it is appropriate to work in an excess of the alcohol used as a reducing agent.

Residues alk' which are substituted by oxo can, however, also be reduced to the corresponding unsubstituted residues alk' by replacing the oxo group with two hydrogen atoms, reacting with hydrazine or semicarbazide and a base, e.g. an alkali metal low-alkanolate, or in a high-boiling alcohol, e.g. di- or triethylene glycol or diethylene glycol monomethyl ether, with hydrazine and an alkali metal hydroxide, such as potassium hydroxide, preferably under heating, e.g. by the cooking heat. Thereby, the corresponding hydrazones or semicarbazones are formed as intermediate products. However, it is also possible to react with a sulphonic acid hydrazide, e.g. with p-toluenesulfonic acid hydrazide, to the corresponding N'-sulfonylhydrazones, e.g. N'-(p-toluenesulfonyl)-hydrazones, and reducing these with an alkali metal borohydride, e.g. with lithium or sodium borohydride.

The reductive cleavage of α-aralkoxy or oc-aralkoxycarbonyloxy to hydroxy preferably takes place by hydrogenolysis, i.e. the action of hydrogen in the presence of a hydrogenation catalyst, such as a palladium, platinum, iridium or nickel catalyst, e.g. of palladium on carbon, platinum oxide or Raney nickel, advantageously in a lower alkanol, e.g. in methanolic solution, if necessary under overpressure and/or heating, e.g. at approx. 1 to 10 bar and 20 to 60 °C.

The solvolytic liberation of hydroxy from other than the aforementioned etherified or esterified hydroxy groups, such as from silyloxy, lower alkanoyloxy or lower alkoxycarbonyloxy, takes place for example by hydrolysis (reaction with water), alcoholysis (reaction with an alcohol) or ammono- or aminolysis (reaction with ammonia or an amine showing at least one free hydrogen atom), if necessary in the presence of an acidic or basic agent and/or under heating, e.g. at approx. 20 to 100 °C. Suitable acidic agents are, for example, mineral acids such as halogenated hydrogen acids, e.g. hydrochloric acid or oxygen acids of sulfur or phosphorus, e.g. sulfuric or phosphoric acid or organic sulphonic or carboxylic acids such as lower alkanesulphonic acids or optionally substituted benzenesulphonic acids or lower alkanesulphonic acids, e.g. p-toluenesulfonic acid or acetic acid. Basic hydrolysis agents are, for example, hydroxides or carbonates of alkali metals, e.g. potassium carbonate, sodium hydroxide or potassium hydroxide, for the alcoholysis further corresponding alcoholates, such as alkali metal low-area alcoholates, e.g. sodium methanolate.

Starting materials I' can be obtained, for example, by compounds with the formulas

(VII) and (VIII)

are reacted with each other, where one of the residues X5 and X5 means hydroxy which may be present in salt form, and the other means a residue

-O-alk'-X, i.e. a residue -O-alk-X, which is substituted with oxo or etherified or esterified hydroxy, such as an oxoalkylene-, oxo(oxa)-

alkylene, oxo(dioxa)alkylene residue which is substituted by X, or etherified or esterified hydroxy(oxa)alkylene or hydroxy(dioxa)alkylene residue, e.g. with the formulas -[(C<H>2)rO]sC<H>2C(=0)CH2-[0-(CH2)i]pX (Ib^) or

-C(CH2)1.O]0CH2CH(<X>")CH2-[O-(CH2)gpX (Ib™)

where X means reactive, esterified hydroxy, e.g. halogen.

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

Thus, for example, compounds of formula I, where there is a

free carboxyl group R5, R7 and/or R3 in the usual way, e.g. by treatment with a diazolaveralkane or triloweralkyloxonium, triloweralkylcarboxynium or diloweralkylcarbonium salt, such as hexachloroantimonate or hexafluorophosphate, or above all by reaction with the corresponding alcohol or a correspondingly reactive derivative, such as a carboxylic acid, phosphoric acid, sulfuric acid or carbonic acid ester thereof, e.g. a lower alkanol, N,N-dilower alkylamino-lower alkanol, N,N-lower alkyleneaminolower alkanol, optionally substituted N,N-(aza)-lower alkyleneaminolower alkanol, N,N-(oxa)lower alkyleneaminolower alkanol or N,N-(thia)lower alkyleneaminolower alkanol respectively. with a lower alkane carboxylic acid ester, tri-lower alkyl phosphite or di-lower alkyl-

sulphite, to compounds of the general formula I, where R 1 , R 7 and/or ■ R 8 is esterified carboxy. The reaction with the corresponding alcohol itself can advantageously take place in the presence of an acidic catalyst, such as a protonic acid, e.g. of chloric or bromohydrogen, sulphur, phosphoric, boric, benzenesulfonic and/or toluenesulfonic acid, in an inert solvent, in particular an excess of the alcohol used and if necessary in the presence of a water binding agent and/or under distilling, e.g. azeotrope, removal of reaction water and/or at elevated temperature. The reaction with a reactive derivative of the corresponding alcohol can be carried out in the usual way, starting from a carboxylic acid, phosphoric acid, sulfuric acid or carboxylic acid ester, for example in the presence of an acidic catalyst, such as one of the aforementioned, in an inert solvent, e.g. e.g. in toluene, or an excess of the alcohol derivative used or the corresponding alcohol, if necessary under, e.g. azeotropic distillation of the reaction water. Starting from a mineral acid or sulphonic acid ester, the acid to be esterified is advantageously used in the form of a salt, e.g. the sodium or potassium salt, and it is worked on if necessary in the presence of a basic condensing agent, such as an inorganic base, e.g. of sodium, potassium or calcium hydroxide or carbonate, or a tertiary organic nitrogen base, e.g. of triethylamine or pyridine, and/or in an inert solvent, such as one of the aforementioned tertiary nitrogen bases or a polar solvent, e.g. in dimethylformamide and/or at elevated temperature. The reaction with an olefin can, for example, take place in the presence of an acidic catalyst, e.g. one Lewis acid, e.g. of boron trifluoride, a sulphonic acid, e.g. of p-toluenesulfonic acid, or above all a basic catalyst, e.g. of sodium or potassium hydroxide, advantageously in an inert solvent, such as an ether, e.g. in diethyl ether or tetrahydrofuran. A free carboxyl group R5, R7 and/or Rg can further be transferred to an amidated carboxyl group by reaction with ammonia or an amine which has at least one hydrogen atom, in the usual way, during dehydration of the intermediately formed ammonium salt, e.g. by azeotropic distillation with benzene or toluene or dry heating.

However, the above-described conversions of carboxy into esterified or amidated carboxyl groups can also be carried out in such a way that a compound of formula I, where R5, R7 and/or Rg is carboxy, is first transferred in the usual way to a reactive derivative, for example by means of a halogenide of phosphorus or sulphur, e.g. by means of phosphorus trichloride or bromide, phosphorus pentachloride or thionyl chloride, to a fatty acid halide or by reaction with the corresponding alcohol or amine to a reactive ester, i.e. ester with electron-withdrawing structures, such as the ester with phenol, thiophenol, p-nitrophenol or cyanoethyl alcohol , or a reactive amide, e.g. the amide derived from imidazole or 3,5-dimethylpyrazole and the resulting reactive derivative are then reacted in the usual way, e.g. as described below for the transesterification, omamiderinwen or the mutual conversion of esterified and amidated carboxyl groups, with a corresponding alcohol, ammonia or the corresponding amine which has at least one hydrogen atom, to the desired group R4, R5 and/or Rg.

An esterified carboxyl group R 5 , R 7 and/or R 8 as well as cyano, R 5 and/or R 7 can be hydrolysed in the usual way, e.g. by hydrolysis in the presence of a catalyst, for example a basic or acidic agent, such as a strong base, e.g. of sodium or potassium hydroxide, or a mineral acid, e.g. of hydrochloric acid, sulfuric acid or phosphoric acid, to free carboxyl group, cyano R0 and/or R7 further to carbamyl. Likewise, esterified carboxy R5, R7 and/or Rg can be transferred to an amidated carboxyl group, e.g. by reaction with ammonia or the corresponding amine which exhibits at least one hydrogen atom.

An esterified carboxyl group R5, R7 and/or Rg can further be transesterified in the usual way to another esterified carboxyl group, e.g. by reaction with a metal salt, such as the sodium or potassium salt, a corresponding alcohol or with this even in the presence of a catalyst, for example a strong base, e.g. of sodium or potassium hydroxide, or a strong acid, such as a mineral acid, e.g. of hydrochloric, sulfuric or phosphoric acid, or an organic sulphonic acid, e.g. of p-toluenesulfonic acid, or a Lewis acid, e.g. of boron trifluoride etherate.

An amidated carboxyl group R0, R7 and/or Rg can be converted in the usual way to the free carboxyl group, e.g. by hydrolysis in the presence of a catalyst, for example a strong base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. of sodium or potassium hydroxide or carbonate, or a strong acid, such as a mineral acid, e.g. of hydrochloric, sulfuric or phosphoric acid.

In a compound that can be obtained according to the invention, substituents can further be introduced into one or both phenyl rings and/or substituents present can be converted into other substituents. Thus, by reacting with a lower alkyl halide or lower alkene or a lower alkanoic acid halide or anhydride, optionally in the presence of a Lewis acid, such as aluminum trichloride introducing a lower alkyl. Halogen can also be introduced, for example by treatment with a halogen in the presence of a Lewis acid such as iron III chloride or by reaction with N-chlorosuccinimide. Furthermore, halogen, especially iodine, can be replaced by reaction with trifluoroiodomethane in the presence of copper with trifluoromethyl.

As mentioned, the new compounds can, depending on the choice of starting materials and working methods, be in the form of one of the possible isomers or as a mixture of these, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, as antipodes or as isomer mixtures, as racemates, diastereomer mixtures or racemate mixtures.

Obtained diastereomer mixtures and racemate mixtures can, on the basis of the physico-chemical differences in the components, be divided into the pure isomers, diastereomers or racemates in a known manner, for example by chromatography and/or fractional crystallization.

Obtained racemates can be further divided into the optical antipodes according to known methods, for example by recrystallization from an optically active solvent, with the help of microorganisms, or by reacting an acidic final substance or with an optically active base that forms salts with the racemic acid and separation of the salts obtained in this way, e.g. owing to their different solubilities, in the diastereomers, from which the antipodes may be liberated by the action of suitable agents. Advantageously, the most effective of the two antipodes is isolated.

Obtained free compounds of formula I, e.g. such, where Rft and/or R7 stand for carboxy and/or R5 for carboxy or 5-tetrazolyl, can be transferred to salts 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.

Obtained salts can be converted in a manner known per se into the free compounds or obtained free compounds, where Rg is capable of forming acid addition salts, to their acid addition salts, e.g. by treatment with an acidic reagent, such as a mineral acid or one of the aforementioned salt-forming acids.

The compounds including their salts can 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 new compounds in free form and in the form of their salts, in the preceding and following the free compounds or their salts must also be understood as the corresponding salts or free connections.

The invention also applies to such embodiments of the method, according to which the starting point is a compound that is obtained as an intermediate at any step in the method and the missing steps are carried out or a starting substance is used in the form of a salt and/or racemate or antipodes or especially formed under the reaction conditions. The new starting materials and intermediate products that appear in the method according to the invention and its precursors as well as the method for their production also form part of the invention.

Such substances are preferably used and the reaction conditions are chosen so that the compounds which are listed above as particularly preferred are obtained.

According to this, the invention also applies to compounds with the formula

(XXXIII)

where R2 means fluorinated lower alkyl, R3 means hydrogen, lower alkoxy, trifluoromethyl or halogen and R11 means hydrogen or a group

Ri-C(=0)-, where Ri stands for lower alkyl, and their salts, a method for their preparation and their use as intermediates, - e.g. for the production of active pharmaceuticals.

Thereby, R1, R2 and R3, for example, have the meanings indicated for compound I. Similarly, salts of compounds XXXIII are preferably metal salts of the type indicated for compound I.

The invention concerns, for example, compounds with the formulas VII, where X5 is hydroxy, and/or compounds with the formula XII and possibly their salts, methods for their preparation and their use.

The invention applies above all to compounds of the formulas VII, XII or XXXIII, where Ri stands for lower alkyl with up to and including 4 C atoms, such as methyl, R 2 means two-fluoro, two.to-difluoro- or two.to.two-trifluorolower alkyl with even 4, e.g. 1 or 3, C atoms, such as trifluoromethyl or 3,3,3-trifluoropropyl, and R3 is hydrogen, and their salts, methods for their preparation and their use.

The invention preferably relates to compounds of the formulas VII, XII or XXXIII, where R 1 means lower alkyl with up to and including 4 C atoms, such as methyl, R 2 is to.to.to-trifluorolower alkyl with up to and including 4, e.g. 1 or 3, C atoms, such as 3,3,3-trifluoropropyl, and R3 means hydrogen and their salts, methods of their preparation and their use.

The invention relates in particular to 2-(3,3,3-trifluoropropyl)-resorcin of formula XII and 4-acetyl-2-(3,3,3-trifluoropropyl)-resorcin of formula VII in free form or in salt form, method for production of these and their application.

The invention further relates to a method for the preparation of compounds of formula XXXIII and their salts. This is characterized by, that

i) in connection with the formula

(XXIV)

where at least one of the residues X1 means etherified hydroxy R and a different residue X\ means free hydroxy and X11 is a group which can

is replaced with the desired residue R2 or can be transferred to this, X11 is replaced with the desired residue or transferred to this, etherified hydroxy R is cleaved to hydroxy and, if desired, it is transferred. compound obtained according to the invention to another compound of formula XXXIII, in particular a group with the formula Ri-C(=0)- is introduced instead of hydrogen Rij and/or a free compound obtained according to the invention is transferred to a salt or a salt obtained according to the invention is transferred to the free compound.

Groups X11 exchangeable with residues R2 are, for example, halogen atoms -Hal with atomic number 19 to 53, i.e. chlorine, bromine or iodine, above all bromine or iodine, or metallic residues, for example a group with the formulas -M<*>, or -M^- Hal, wherein MI means an alkali metal atom, e.g. lithium or sodium, or monovalent copper, mH means an alkaline earth metal atom e.g. magnesium, zinc, cadmium or divalent copper and -Hal means halogen with atomic number 19 to 53 inclusive.

The exchange of the aforementioned groups X11 against residues R2 takes place in the usual way, for example by reaction with a compound of the formula Xiq-R2(XV), where one of the residues Xiq and X11 means a metallic residue and the other halogen, respectively. by reaction with a compound of the formula Xiq-R2(XV), where both residues Xiq and X11 mean a halogen -Hal, in the presence of a metal, preferably one of those mentioned, especially of copper powder. The reaction of compounds XXXIV and XV, where Xiq or X11 represents a metallic residue, preferably takes place in the presence of an aliphatic or cycloaliphatic ether, such as a dilower alkyl ether, e.g. of diethyl ether or tertiary butoxymethane, or a 5- to 7-membered oxa- or dioxacycloalkene, e.g. of tetrahydrofuran or 1,4-dioxane, if necessary in the presence of a solvent or diluent, e.g. of dimethylformamide, advantageously under inert gas, such as argon. The reaction of compounds XXXIV and XV, where Xiq and X11 both mean halogen Hal, in the presence of a metal is preferably carried out under heating, e.g. to approx. 80 to 150°C in an inert, high-boiling solvent, such as dimethylformamide, 1,2-dimethoxyethane, 1,5-dimethoxy-(3-oxa)-butane or diphenyl ether, advantageously also under inert gas, such as argon.

Starting materials XV respectively, XXXIV, where Xiq respectively. X11 denotes a metallic residue, preferably formed by treatment of the corresponding compound XV or XXXIV, where Xjq or Xi 1 is a halogen Hal with the corresponding metal in situ and is used without insulation.

Starting from compounds XXXIV, where R 3 likewise means a halogen Hal, the aforementioned substitution reactions are disturbed by side reactions. These can be avoided by starting from a corresponding nitro compound and reducing the nitro group in the usual way to the amino group, e.g. with iron and hydrochloric acid, and this is replaced with the desired halogen atom, e.g. by means of sodium nitrite in a hydrohalic acid H-Hal. The condensation of compounds XV and XXXIV, where Xiq and X11 signifies a metallic residue, is furthermore not particularly suitable for the preparation of compound XXXIII, where X11 is an acyl group Ri-C(=0)-.

In a preferred embodiment, it is obtained, for example, by heating a compound XXXIV, where X^i stands for bromine or iodine, X1 stands for etherified hydroxy R and R11 stands for hydrogen, with trifluoromethyl iodide and copper powder in dimethylformamide to approx. 120 to 180 °C and subsequent transfer of etherified hydroxy R to hydroxy, compounds of formula XXXIII, where R 11 means hydrogen and R 2 means trifluoromethyl.

The group X11 which can be transferred to residues R2 are, for example, fluorinated lower alkenyl residues, such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-prop-1-enyl or 3-fluoro- or 3,3-difluoroprop-2-enyl, fluorinated lower alkynyl radicals, such as 3-fluoro-, 3,3-difluoro- or 3,3,3-trifluoroprop-1-inyl, further fluorinated hydroxyl lower alkyl radicals, such as 3- fluoro-, 3,3-difluoro- or 3,3,3-trifluoro-1-hydroxy-propyl.

The transfer of the aforementioned groups X11 to residues R2 takes place, for example, by reduction. As a reducing agent, for example, hydrogen in the presence of a hydrogenation catalyst, such as a platinum, palladium or rhodium catalyst, comes into consideration, e.g. of platinum oxide. The treatment with catalytically activated hydrogen (hydration) takes place under normal or at most moderately elevated pressure and/or temperature conditions, e.g. at approx. 0

to 5 bar overpressure and/or in the temperature range from approx. 20 to approx. 80°C.

Starting substances XXXIV where X11 is a fluorinated lower alk-1-enyl or 1-hydroxy lower alkyl radical and R11 is hydrogen, the radicals Xi stand for etherified hydroxy groups R and R3 are different from halogen Hal, obtained for example by a corresponding compound XXXIV^where X11 is a halogen Hal, is treated with a metal or the obtained compound XXXIV, where Xij is a group -MV2 or -MHal, is reacted with a fluorinated oxolave alkane and to produce compound XXXIV, where X11 means a fluorinated lower alk-1-enyl residue, water is split off from the primarily obtained fluorinated 1-hydroxyalkyl compound, e.g. by acetylation and subsequent acid treatment.

Starting substances XXXIV, where X11 means a mono- or difluorinated lower alk-2-enyl residue and at least one of the residues X1 means free hydroxy, is obtained, for example, by a compound with the formula

(XXXV)

subjected to allyl rearrangement, for example by heating to approx. 150 to 250 °C, preferably to about 190 to 220 °C, advantageously in a solvent,

such as diphenyl ether or N,N-dimethyl- or N,N-diethylaniline. Thereby the residue X3 is also rearranged so that from a 1-fluorine or 1,1-difluorolower alk-2-enyl residue results in the corresponding 3-fluoro- or 3,3-difluorolower alk-2-enyl residue.

Compounds XXXIV, where X11 means a fluorinated lower alk-1-inyl residue and R11 is hydrogen, are obtained, for example, by in a corresponding compound XXXIV, where Xn means a fluorinated lower alkenyl residue which at the doubly bonded C atoms has at least two hydrogen atoms, halogen is attached to X11 and on in the usual way, 2 moles of halogen hydrogen are split off.

Compounds of the formula XXXIII, where R 2 is 3,3,3-trifluoropropyl and R 3 and R 11 have the indicated meanings, and their salts are particularly easily obtained according to an overall and/or in important individual steps new process, in that a compound of the formula

(XX)

where R means etherified hydroxy, such as lower alkoxy, e.g. methoxy, in an inert solvent, e.g. in dimethylformamide, react with an etherate of 1,1-dichloro-2,2,2-trifluoroethylzinc chloride, e.g. with the formula CF3CCl2ZnCl(C2H5)20 (XXI) to the corresponding compound with the formula

(XXII)

this is acylated in the side chain, e.g. is acetylated, for example by means of acetic anhydride in pyridine, the reaction product with the formula

(XXIIa)

where the residue Ac stands for the introduced acyl group, e.g. acetyl, is transferred with a metallic reducing agent, for example a base metal, preferably with activated zinc dust in the presence of ammonium chloride, to the corresponding compound with the formula

(XXIII)

from this, hydrogen chloride is split off by treatment with a metal base, such as an alkali or alkaline earth metal alcoholate, e.g. with potassium tertiary butanolate, in the obtained compound of the formula

(XXIV)

the side chain is hydrated, e.g. in the presence of palladium charcoal, and the etherified hydroxy groups R are cleaved to hydroxy, for example by treatment with hydrobromic acid in dichloromethane, if desired a residue R11 is introduced with the formula Ri-C(=0)- and if desired the obtained free compound is converted into a salt or a the salt obtained is converted to the free compound.

The introduction of a residue R11 with the formula Rj-C(=0)-, which may subsequently be carried out, takes place, for example, as indicated under method variant a) or b), for example by reaction with a compound of the formula Ri-X2(IV), where X2 is functionally converted carboxy, such as carboxy, halocarbonyl with the formula -C(=0)-Hal or anhydridized carboxy, for example with the formula -C(=0)-0-C(=0)-Ri, in the presence of a Lewis acid , as defined under travel method variant b), e.g. by reaction with an acid of the formula (IV; X2=carboxy) in the presence of zinc chloride. The mutual transformation of the obtained acids and salts takes place in the same way as indicated for the compound of formula I.

The present invention likewise applies to pharmaceutical preparations, which contain one of the compounds of formula I according to the invention or a pharmaceutically usable salt thereof. Pharmaceutical preparations according to the invention are intended for local as well as enteral, as oral or rectal, as well as parenteral administration to and for inhalation of warm-blooded animals, and contain the pharmacological active substance alone or together with a pharmaceutically usable carrier material . The dosage of the active substance depends on the type of warm-blooded, the age and the individual condition, as well as the method of application.. They . the new pharmaceutical preparations contain e.g. from approx. 10 to approx. 95%, preferably from approx. 20 to approx. 90% of the active substance. Pharmaceutical preparations according to the invention are e.g. such in aerosol or spray form or in dosage unit form, such as dragees, tablets, capsules or suppositories, further ampoules.

The pharmaceutical preparations according to the present invention are produced on

in and of itself known way, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilizing methods. In this way, pharmaceutical preparations for oral use can be obtained, by combining the active substance with solid carriers, an obtained mixture possibly being granulated, and the mixture or the granulate, if desired or necessary, is processed into tablets or drag cores after adding suitable excipients.

Suitable carriers are especially 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 pastes, e.g. corn, wheat, rice or potato starch paste, gelatin, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, and/or if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof , such as sodium alginate. Aids are primarily flow control and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragon cores are equipped with suitable, possibly gastric juice-resistant covers, whereby it i.a. concentrated sugar solutions are used, which possibly contain gum arabic, talc, polyvinyl pyrrolidones, 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 acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragon coatings can be added with dyes or commercial pigments, e.g. for identification or to characterize different doses of active substance.

Other orally usable pharmaceutical preparations are gelatin suppositories, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can contain the active substance in the form of a granule, e.g. in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and possibly 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, whereby stabilizers can also be added.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, which consist of a combination of the active substance with a suppository base. As a suppository base material, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used, which contain a combination of the active substance with a base mass. As basic mass substances, e.g. namely liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration, aqueous solutions of an active substance in water-soluble form are primarily suitable, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents are used, such as fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or aqueous injection suspensions, which contain viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and optionally also stabilizers.

Inhalation preparations for treating the respiratory tract by nasal or buccal administration are e.g. aerosols or sprays, which can distribute the pharmacologically active substance in the form of a powder or in the form of drops of a solution or suspension. Preparations with powder-distributing properties usually contain, in addition to the active substance, a liquid propellant with a boiling point below room temperature, as well as, if desired, carrier substances, such as liquid or solid, non-ionic or anionic, surface-active agents and/or diluents. Preparations in which the pharmacological active substance is present in solution also contain a suitable propellant and, if necessary, an additional solvent and/or a stabilizer. Instead of the propellant gas, it can also be used: compressed air, whereby this can be obtained as needed with the help of a suitable densification and relaxation device.

Pharmaceutical preparations for 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 (whereas such preferably contain a preservative), for the treatment of the eyes, eye drops, containing the the active compound in aqueous or oil solution, and eye ointments, which are preferably prepared in sterile form, for the treatment of the nose powders, aerosols and sprays (similar to those described above for the treatment of the respiratory tract), as well as coarse powder, which can be administered by rapid inhalation through the nostrils, and nasal drops, which contain the active compound in aqueous or oil solution, or for the local treatment of the mouth lozenges, which contain the active compound in a mass usually formed from sugar and gum arabic or tragacanth, which may be flavored, as well as lozenges, which contain the active substance in an inert mass, e.g. of gelatin and glycerol or sugar and gum arabic.

The invention also applies to the use of the new compounds of formula I and their salts as pharmacologically active compounds, for example as anti-allergic or especially anti-inflammatory, preferably in the form of pharmaceutical preparations. The daily dose, which is given to a warm-blooded person of approx. 70 kg, amounts to approx. 200 mg to approx. 1200 mg.

The following examples illustrate the invention described above. However, they shall not in any way limit its scope. The temperatures are indicated in °C.

Example 1

A solution of 3 g (4.5 mmol) N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4- chloro-6-methyl-phenyl)>-1-(4-methoxy-benzyl)-tetrazole-5-carboxamide in 90 ml of trifluoroacetic acid and 9 ml of anisole is heated for 60 minutes at reflux. The reaction mixture is evaporated under reduced pressure, approx. 150 ml of ether as well as 3005 ml of petroleum ether and the crystals are filtered off. The thus obtained N-{ {3-{3-[4-acetyl-3-nydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-4-chloro-6-methyl-phenyl) ) -1H-tetrazole-5-carboxamide with melting point 236-238°

(cleavage) is dissolved in 50 ml of tetrahydrofuran and an equivalent of sodium dissolved in 5 ml of methanol is added. After adding ether, crystallization starts. In this way, the sodium salt of N-(<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-chloro is obtained -6-methyl-phenyl)>1H-tetrazole-5-carboxamide with melting point 90" (decomposition).

In an analogous manner, starting from N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-bromo-6-methyl- phenyl) >-1-(4-methoxybenzyl)-tetrazole-5-carboxamide with melting point 245-248°

(decomposition) and its sodium salt with a melting point of 120-130°C.

The starting material can e.g. produced in the following way:

Step A: 1,1-dichloro-2,2,2-trifluoroethylzinc chloride diethyl etherate,

CF3CCl2ZnCl(C2<H>5)0

In a 1 liter three-neck round flask, suspend under argon 65.4 g (1 mol) zinc dust (activated according to Fieser & Fieser) in 800 ml of diethyl ether and slowly add 188 g (1 mol) CF3CCI3. It is stirred for 20 hours at room temperature. The reaction mixture is then filtered through "Selecta" filter material, whereby the complex precipitates in crystalline form after cooling the filtrate. The complex is recrystallized for further purification from diethyl ether. Excess diethyl ether is decanted off and the colourless, crystalline residue is dried in a vacuum. 1,1-dichloro-2,2,2-trifluoroethylzinc chloride diethyl etherate with melting point 105°, yield 80% is obtained.

Step B: 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoropropyl)-benzene

In a three-necked round flask (1000 ml) with a thermometer, bubble counter and argon connection, after three times of vacuum/argon purging, 130.1 g (0.40 mol) of 1,1-dichloro-2,2,2-trifluoro-ethyl zinc chloride-diethyl etherate are placed in 700 ml of absolute dimethylformamide. Then 51.0 g (0.32 mol) of 2,6-dimethoxybenzaldehyde is added all at once. The yellow, clear reaction solution is stirred for 72 hours at room temperature and then poured onto a mixture of 600 g of ice and 600 ml of 10% hydrochloric acid. After decantation, washing with 2% hydrochloric acid, salt solution, drying over magnesium sulfate and evaporation, a dark red oil is obtained, from which red-brown crystals of 1,3-di me tok sy- 2- (1 - hyd rok sy -2,2-dichloro-3,3,3-trifluoro-propyl)-benzene, yield 99%. This does not need to be purified for further processing.

Step C: 1,3-dimethoxy-2-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)-benzene

In a 500 ml bulb flask, 97.6 g (0.30 mol) of 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoro-propyl)-benzene are added at room temperature 31 ml (0.33 mol) of acetic anhydride. Then, 30 ml (0.36 mol) of pyridine (weak exotherm) is added to the dark red solution. The reaction solution is stirred for 3 days at room temperature. The reaction mixture is then poured onto ice and acidified with 10% hydrochloric acid. It is extracted with ether, washed with water and saline, dried over magnesium sulfate and evaporated to dryness. The remaining 1,3-dimethoxy-2-(1-acetoxy-2,2-dichloro-3,3,3-trifluoropropyl)-benzene (yield 87%) is used in step D without further purification.

Step D: 1,3-dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzene

96.5 g (0.266 mol) of 1,3-dimethoxy-2-(1-hydroxy-2,2-dichloro-3,3,3-trifluoro-propyl) are dissolved in a 1.5 l flask with thermometer, cooler and bubble counter )-benzene in 1000 ml of ethanol and 30 g (0.56 mol) of ammonium chloride are added. Activated zinc according to Fieser & Fieser (36.9 g = 0.564 mol) is added to the obtained brownish suspension, whereby the reaction temperature rises to 42°. The mixture is stirred further overnight and then the grey-yellow reaction mixture is poured onto ice water, extracted with ether, washed with water (3x) and saline, dried over magnesium sulphate and evaporated. 1,3-Dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzene (Yield: 94%) is obtained as a reddish oil.

Step E: 1,3-dimethoxy-2-(3,3,3-trifluoroprop-1-ynyl)-benzene

30.7 g of potassium tertiary butanolate are placed in 900 ml of tertiary butanol in a 1.5 l flask with thermometer, cooler, bubble counter and dropping funnel. To this clear, colorless solution, 63.7 g (0.25 mol) of 1,3-dimethoxy-2-(2-chloro-3,3,3-trifluoroprop-1-enyl)-benzene in 100 ml of tertiary butanol (weak exothermic) and stirred for 24 hours at room temperature. The orange suspension is poured onto ice, extracted with ether, washed with water, n-bicarbonate solution and saline solution, dried over magnesium sulfate and evaporated until crystals precipitate. The crystal mass is cooled, filtered cold and washed with a little ice-cold petroleum ether. 1,3-dimethoxy-2-(3,3,3-trifluoroprop-1-inyl)-benzene is obtained in the form of light beige, fine crystals with melting point 110-111°, (yield 73%).

Step F: 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene

41.5 g (0.18 mol) 1,3-dimethoxy-2-(3,3,3-trifluoroprop-1-inyl)-benzene are dissolved in tetrahydrofuran and hydrated in the presence of palladium-on-charcoal at room temperature and normal pressure . The catalyst is filtered off with diatomaceous earth, washed with tetrahydrofuran and the filtrate is evaporated. After drying under reduced pressure, crystalline 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene is obtained (Yield 87%).

Step G: 2-(3,3,3-trifluoropropyl)-resorcinol

30.5 g (0.13 mol) of 1,3-dimethoxy-2-(3,3,3-trifluoropropyl)-benzene are placed in a 1.5 1 flask with thermometer, bubble counter, dropping funnel with cooling jacket, argon connection in 275 ml of dichloromethane and cooled to -75°. Then 340 ml of a pre-cooled 1-molar solution of boron tribromide in dichloromethane are added dropwise so that the reaction temperature does not exceed -70° (approx. 90 minutes). After 6 hours of stirring at room temperature, the red reaction solution is poured into 800 ml of ice water. The organic phase is separated, the aqueous phase is extracted once more, and the combined organic phases are washed with salt solution, dried over magnesium sulphate and evaporated. 2-(3,3,3-trifluoropropyl)-resorcinol is obtained in the form of red crystals with a melting point of 82-84° (yield 100%).

Step H: 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone

In a 100 ml three-neck round flask with cooler, bubble counter, thermometer attached

21.0 g (0.154 mol) of zinc chloride are added to 27 ml of glacial acetic acid and heated to 120°, whereby a clear, colorless solution is formed. At this temperature, 27.0 g (0.13 mol) of 2-(3,3,3-trifluoropropyl)-resorcinol are added, whereby the temperature drops to 82°. The red, clear solution is further heated for 4 hours to reflux (132°) and allowed to cool. A red suspension is obtained. This is poured onto 440 ml of semi-concentrated hydrochloric acid and extracted three times

times with ether. The organic phase is washed with saline solution, dried over magnesium sulfate and evaporated vigorously. The obtained, reddish crystals are suspended in pentane, suctioned off and washed with pentane. 2,4-Dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone is obtained, yield: 26.5 g of yellow crystals with melting point 180-184°, 82%.

Step I: 4-(3-bromopropyloxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone

To a solution of 2.45 ml of 1,3-dibromopropane in 30 ml of acetone, 3.32 g of potassium carbonate and 0.5 g of potassium iodide are added and heated to reflux. Over the course of 2 hours, a solution of 1.98 g of 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone in 10 ml of acetone is added dropwise and it is further heated to reflux for 3 hours. The reaction mixture is filtered and evaporated in vacuo. The residue is dissolved in 50 ml of dichloromethane and washed with 10 ml of water. The organic phase is dried over sodium sulphate, evaporated in vacuo and the residue chromatographed on 100 g of silica gel with dichloromethane as eluent.

In the first fraction, 4-(3-bromopropyloxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone is eluted, which after evaporation precipitates in the form of colorless crystals with a melting point of 70-72°C.

Step J: 3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -

propyloxy}-4-chloro or bromo-6-methyl-nitrobenzene.

A suspension of 1.87 g (10 mmol) of 2-chloro-4-methyl-5-nitro-phenol and 1.5 g (10.5 mmol) of calcined potassium carbonate in 30 ml of ethyl methyl ketone is added with a spatula tip of potassium iodide and 3.5 g (9.5 mmol) 4-(3-bromopropyloxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone and heated to reflux for 10 hours. The reaction mixture is cooled, poured onto water and extracted three times with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulfate and evaporated under reduced pressure to dryness. Crystallization of the residue from ether/petroleum ether gives 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-chloro-6-methyl-nitrobenzene with melting point 118-120° C.

In an analogous manner, starting from 2-bromo-4-methyl-5-nitrophenol 3-{3-[4-acety 1-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>- 4-bromo-6-methyl-nitrobenzene with melting point 106-109°C.

Step K: 3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -

propyloxy}-4-chloro or bromo-6-methyl-aniline.

A solution of 3.7 g of 3-[3-(4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy)-propyloxy]-4-chloro-6-methyl-nitrobenzene in 40 ml of tetrahydrofuran is added to 1.0 g of Raney nickel and hydrated at room temperature.: The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure and the residue is crystallized from ether/petroleum ether. In this way, 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-chloro-6-methylaniline with melting point 111-113- C.

In an analogous manner, starting from 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-bromo-6-methyl-nitrobenzene 3- {3-[4-acety 1-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-bromo-6-methyl-aniline with melting point 124-126°C.

Step L: N-{ (3-(3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy)-

propyloxy >-4-chloro or bromo-6-methyl-phenyl) >-1-(p-methoxy-benzyl)-tetrazole-5-carboxamide

To a suspension of 2.07 g (7.7 mmol) of potassium [1-(4-methoxy-benzyl)-tetrazole]-5-carboxylate in 30 ml of benzene and 0.5 ml of pyridine are added at 0-

5° 0.66 ml (7.7 mmol) 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 suspended in 200 ml of dichloromethane and added dropwise over 10 minutes to a solution of 2.6 g (5.8 mmol) 3-<3-[4-acetyl-3-hydroxy-2-(3,3,3- trifluoropropyl)-phenoxy]-propyloxy >-4-chloro-6-methyl-aniline and 0.61 ml of pyridine in 30 ml of dichloromethane. Then stir for 3 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed twice with water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from ether gives N-{ (3-<3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-4- chloro-6 -methyl-phenyl})-1-(4-methoxybenzyl)-tetrazole-5-carboxamide with melting point 148-150° C.

In an analogous manner, starting from 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-bromo-6-methylaniline N-{ (3 -{3-[4-acetyl-3-hydroxy-2-(3,3.3-trifluoropropyl)-phenoxy]-propyloxy )-4-bromo-6-methyl-phenyl) )-1-(4-methoxy-benzyl) -tetrazole-5-carboxamide with melting point 140-142°C.

Example 2

To a solution of 1.75 g (3.57 mmol) of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-bromo -6-methylaniline (Example 1) and 0.55 ml (3.57 mmol) of triethylamine in 25 ml of dichloromethane which has been cooled to 0° are added dropwise over the course of 5 minutes to a solution of 0.36 ml (3.57 mmol) of chlorooxalic acid methyl ester in 5 ml of dichloromethane. The mixture is stirred for 90 minutes at room temperature, the reaction mixture is poured onto ice water and the organic phase is separated. The organic phase is washed with water, dried over sodium sulphate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane/ether gives N-{ {3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-bromo-6 -methyl-phenyl))-oxamic acid methyl ester with melting point 139-140°C.

Example 3

A suspension of 1.75 g (3 mmol) of N-{(3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl ksy)-4-bromo-6-methyl-phenyl 1))-oxamic acid methyl ester (example 2) in 30 ml of methanol and 3.2 ml of n-sodium hydroxide solution is heated for 60 minutes to reflux. The reaction mixture is evaporated under reduced pressure, dissolved in acetone and dilute caustic soda and acidified with dilute hydrochloric acid. The precipitated product is filtered off and washed neutrally with water. In this way N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-bromo-6-methyl-phenyl ))-oxamic acid with melting point 207-209°C.

Example 4

1.55 g (2.76 mmol) N-{ { 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy )-4-bromo-6-methyl -phenyl))-oxamic acid (Example 3) is dissolved in 300 ml of hot acetone and a solution of 411 mg (2.8 mmol) of triethanolamine in 10 ml of acetone is added. The reaction solution is concentrated under reduced pressure to 50 ml. After adding ether, crystallization begins. The precipitated product is filtered off and washed with ether. In this way, the triethanolammonium salt of N-{ (3-{3-[4-acetyl-3-

hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-bromo~6-methyl-phenyl))-oxamic acid, melting point 133-135"C.

Example 5

To a solution cooled to 0° of 7.5 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-6-methyl- aniline and 3.0 g of triethylamine in 60 ml of dichloromethane are added dropwise over approx. 5 minutes a solution of 1.9 ml (21 mmol) of chlorooxalic acid methyl ester in 8 ml of dichloromethane. The mixture is stirred for 90 minutes at room temperature, the reaction mixture is poured onto ice water and the organic phase is separated. The dichloromethane phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from dichloromethane/ether gives N-{{3-{3-[4-acety 1-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-6-methyl -phenyl) ) -oxamic acid methyl ester.

In an analogous manner, starting from 3-{ 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-aniline N-{ {3-{3-[ 4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-phenyl ) )-oxamic acid methyl ester.

The starting material can, for example, be produced in the following way.

A suspension of 5.1 g of 4-methyl-3-nitro-phenol and 4.6 g of calcined potassium carbonate in 100 ml of ethyl enm ethyl ketone is added with a spatula tip of potassium iodide and 9.5 g of 4-(3-bromopropoxy)-2-hydroxy -3-(3,3,3-trifluoropropyl)-acetophenone and heated to reflux for 14 hours. The reaction mixture is cooled, poured onto water and extracted three times with ether. The organic phase is washed with water, combined, dried over sodium sulfate and combined under reduced pressure to dryness. Crystallization of the residue gives 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-6-methyl-nitrobenzene.

In an analogous manner, starting from m-nitrophenol, 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-nitrobenzene is obtained.

A solution of 9.1 g (23.5 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-propyloxy]-6-methyl-nitrobenzene in 90 ml of tetrahydrofuran is added 1 .0 g of Raney nickel and is hydrated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure. In this way, 3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-6-methylaniline is obtained.

In an analogous manner, starting from 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-nitrobenzene 3- (3- [4-acetyl-3 -hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-aniline (ether/petroleum ether).

Example 6

A suspension of 8.60 g (19.4 mmol) N-{ (3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -6-methyl-phenyl)}-oxamic acid methyl ester in 60 ml of methanol and 20 ml of water is added to 20 ml of IN sodium hydroxide solution and heated for 10 minutes at reflux. The reaction mixture is cooled and the precipitated product is filtered off. In this way the sodium salt of N-{ <3 -{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-6-methyl-phenyl>}-oxamic acid.

In an analogous manner, the sodium salt of N-{(3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-phenyl>>-oxamic acid can be prepared.

Example 7

In an analogous way as described in example 2, the following is achieved:

N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-2-methyl-phenyl}>-oxamic acid methyl ester;

N-{(3-{5-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-pentyl-oxy}-phenyl)>-oxamic acid methyl ester;

N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-3-methoxy-phenyl}>-oxamic acid methyl ester;

N-{ (4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-2-methyl-phenyl}>-oxamic acid methyl ester;

N-{{2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-phenyl >)-oxamic acid methyl ester; N-{ (4-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-phenyl >}-oxamic acid methyl ester; N-{ { 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-chloro-6-trifluoromethyl-phenyl)-oxamic acid methyl ester; N-{ (3-(3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy > -2,4,6-trichloro-phenyl }> -oxamic acid methyl ester as oil and N-{(3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy > -4,6-dimethyl- phenyl))-oxamic acid methyl ester.

The starting materials can e.g. is produced in an analogous way as described in example 1:

Example 8

In an analogous manner as described in example 3, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)- 2-methyl-f enyl} oxamic acid and its triethanolammonium salt as well as

N-{{3-{5-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-2-methyl-phenyl))-oxamic acid as well as its triethanolammonium salt, N-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-chloro-6-tri luormethyl-phenyl)>-oxamic acid and its triethanolammonium salt,

N-{ {3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy )-2,4,6-trichloro-phenyl )> -oxamic acid and its triethanolammonium salt and N-{ (3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-4,6-dimethyl -phenyl >)-oxamic acid and its triethanolammonium salt.

Example 9

A solution of 7.95 g of N-{{4-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-3-methoxy-phenyl)) -oxamic acid methyl ester in 100 ml of methanol is added to 18 ml of an n-sodium hydroxide solution and heated to reflux for one hour. The hot solution is then poured into 200 ml of 0.1N hydrochloric acid. The precipitated product is filtered off, washed with water and dried in a drying cabinet over phosphorus pentoxide. The N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-3-methoxy-phenyl > )-oxamic acid thus obtained is dissolved in again in 100 ml of hot methanol and an equivalent of triethanolamine in 100 ml of methanol is added. After adding 400 ml of ether

: starts the crystallization. In this way, the triethanolammonium salt is obtained

of N-{(4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy ■}.-.3-methoxy-phenyl > }-oxamic acid .

Analogously, this is achieved:

N-{<4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-2-methyl-phenyl)>-oxamic acid and its triethanolammonium salt,

N-{<2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-phenyl }>-oxamic acid and its triethanolammonium salt.

Example 10

In an analogous way as described in example 1, the following is achieved:

N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-phenyl>>-1H-tetrazole-5-carboxamide and its triethanolammonium salt.

Example 11

To a solution cooled to 0°C of 43.6 g of 3-{3-[4-acetyl-3-hydroxy-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -4-bromo-6 -methylaniline and 15.3 ml of triethylamine in 400 ml of dichloromethane are added dropwise over approx. 5 minutes a solution of 12.3 ml chlorooxalic acid ethyl ester in 30 ml dichloromethane and the mixture is then stirred for 90 minutes at room temperature. The reaction mixture is poured onto ice water and the organic phase is separated, washed with water, dried over sodium sulphate and evaporated under reduced pressure. Crystallization from ethyl acetate/ether/petroleum ether gives N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-bromo-6- the methyl-phenyl >}-oxamic acid methyl ester.

Example 12

A suspension of 4.0 g of N-{ (3-{3-[3-(4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -4-bromo- 6-methyl-phenyl})-oxamic acid methyl ester in 400 ml of ethanol, 448 mg (7.5 mmol) of potassium hydroxide are added and heated for 4 hours at reflux. The reaction mixture is cooled and the precipitated product is filtered off. In this way, the potassium salt of N-

The {{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-bromo-6-methyl-phenyl>}-oxamic acid.

In an analogous way, the sodium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3.3-trifluoropropyl)-phenoxy]-propyloxy >-4-bromo-6 -methyl-phenyl)>-oxamic acid is prepared. >!;. ■ -%

Example 13

4.06 g N-'{(3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-bromo-6-methyl-phenyl ) >-oxamic acid is dissolved in 40 ml of acetone and a solution of 840 mg of diethanolamine in 5 ml of acetone is added. After the addition of ether, crystallization begins. The precipitated product is filtered off and washed with ether. In this way, the diethanolammonium salt of N-{ ( 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-bromo-6-methyl-phenyl))-oxamic acid.

In an analogous way, the tris(hydroxymethyl)-methylammonium salt of N-

{ {3-{3- [ 4-acetyl -3-hydroxy-2-n-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy)-4-bromo-6-methyl-phenyl)) -oxamic acid is produced.

Example 14

A solution of 7.05 g of N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy )-2-cyano-phenyl) )-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is heated to reflux for 30 minutes. The reaction mixture is evaporated under reduced pressure, approx. 200 ml of ether as well as 300 ml of petroleum ether and the crystals are filtered off. Thus obtained N-{(3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-2-cyano-phenyl))- 1H-tetrazole-5-carboxamide with melting point 206-208° is dissolved in

50 ml of hot acetone and add the calculated amount of triethanolamine in 30

ml of acetone. After adding ether, crystallization starts. In this way, the triethanolammonium salt of N-{ <3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluorp ropyl) - f enok sy ] -p ropy lok sy )-2 is obtained -cyano-phenyl))-1H-tet razole-5-carboxamide.

Analogously, it can be produced:

N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy )-4-cyano-6-methyl-phenyl)) -1 -H-tetrazole-5-carboxamide, N-( {3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy )- 4-Fluoro-6-methyl-phenyl)-1-H-tetrazole-5-carboxamide.

ing The starting material can e.g. produced in the following way:

A suspension of 13.1 g of 2-cyano-3-nitro-phenol and 13.8 g of annealed potassium carbonate in 100 ml of ethyl methyl ketone is added with a spatula tip of potassium iodide and 31.5 g of 4-(3-bromopropoxy)-2-hydroxy-3- (3,3,3-trifluoropropyl)-acetophenone and heated for 20; hours to return. The reaction mixture is cooled, poured onto water and extracted three times with dichloromethane. The organic phases are washed with water, combined, dried over sodium sulfate and evaporated under reduced pressure to dryness. Crystallization of the residue from ether/hexane gives 2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-6-nitro-benzonitrile.

To the solution of 10 g of 2-<3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-6-nitro-benzonitrile and 10 g of cyclohexane in 500 ml of ethanol 2.5 g of 10% Pd on charcoal is added and it is heated to reflux for 30 minutes. After cooling to room temperature, it is filtered and freed from solvent. The residue is added to ether and the separated crystals are filtered off. 2-Amino-6-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-benzonitrile is obtained.

To a suspension of 5.8 g of potassium (1-(4-methoxybenzyl)-tetrazole)-5-carboxylate in 110 ml of benzene and 1.0 ml of pyridine is added at 0-5° 1.84 ml (21.5 mmol ) 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 80 ml of dichloromethane and added dropwise at 0-5° over approx. 10 minutes to a solution of 6.3 g of 2-amino-6-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-benzonitrile and 1, 72 ml of pyridine in 40 ml of dichloromethane. Then stir for 3 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed three times with water. The organic phases are combined, dried over sodium sulphate and evaporated under reduced pressure. Crystallization of the residue from ethyl acetate/hexane gives N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-2-cyano- phenyl)-1-(4-methoxybenzyl)-tetrazole-5-carboxamide.

Example 15

In an analogous way as described in examples 1-14, the following is achieved:

N- { { 3- { 3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy }-4-methyl-6-chloro-phenyl) > -oxamic acid methyl ester,

N-{ {3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-methyl-6-chloro-phenyl >> -oxamic acid methyl ester, N-{ {3-(3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-4-methyl-6-chloro- phenyl) >-oxamic acid and its triethanolammonium salt, N-{ (3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy)-4 -methyl-6-chloro-phenyl) )-1H-tetrazole-5-carboxamide and its triethanolammonium salt, N-{ <3-{3 - [4-acetyl-3-hydroxy-2- (3,3,3- trifluoropropyl)-phenoxy] -propyloxy >-4-methyl-6-bromo-phenyl) >-1H-tetrazole-5-carboxamide and its triethanolammonium salt, N-{ { 3-< 3 - [4-acetyl-3 -hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -2-cyano-phenyl >)-oxamic acid ethyl ester,

N-{ (3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-2-cyano-phenyl) >-oxamic acid and its triethanolammonium salt.

Example 16

To a solution cooled to -78°C of 2.2 g of N-{<3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl { -phenyl) )-oxamic acid methyl ester in 20 ml of dichloromethane is added dropwise over the course of 5 minutes to 3.0 g of boron tribromide. The mixture is then stirred for 6 hours at room temperature. While cooling, 5 ml of water is added, the organic phase is separated and evaporated under reduced pressure. After recrystallization from dichloromethane/ether the N-{(3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy)-phenyl))-oxamic acid methyl ester is obtained.

The starting material can e.g. produced as follows:

To a solution of 7.46 g of N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-nitrobenzene in 75 ml of dimethylformamide is added 5530 mg of sodium hydride and the reaction mixture is heated to 40°. During 15 minutes, 5.7 g of methyl iodide are added dropwise. The reaction mixture is then kept for another hour at 40°. After cooling, the mixture is poured onto dilute hydrochloric acid and extracted with methylene chloride and evaporated. After recrystallization from ether/hexane, 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-nitrobenzene is obtained.

A solution of 10 g of 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-nitrobenzene in 100 ml of tetrahydrofuran is added to 2.0 g of Raney nickel and hydrated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. After evaporation of the filtrate under reduced pressure, 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-aniline is obtained as a colorless oil.

To a solution of 9.2 g of 3-)3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-aniline and 4.3 ml of triethanolamine in 90 ml dichloromethane is added dropwise over 10 minutes to the solution of 3.45 ml of chlorooxalic acid methyl ester in 10 ml of dichloromethane. After stirring for 5 hours at room temperature, pour on water and extract with dichloromethane. Evaporation of the extract and recrystallization of the residue from ether gives N-{ {3-(3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropy1)-phenoxy]-propoxy) -fe nyl) ) -ok co-acidify the methyl ester.

Example 17

A suspension of 2.3 g of 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone and 1.6 g of calcined potassium carbonate in 40 ml of ethyl methyl ketone is added with a slit tip of potassium iodide and 3.2 g of N-[3 -(3-bromopropoxy)-phenyl)-oxamic acid methyl ester and heated for 8 hours at reflux. The reaction mixture is cooled, poured onto water and extracted three times with dichloromethane. The combined extracts are washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from ether gives the N-{(3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy)-phenyl))-oxamic acid methyl ester.

The starting material can e.g. produced as follows:

To a suspension of 29 g of potassium carbonate and 0.5 g of potassium iodide in 170 ml of acetone, 43 ml of 1,3-dibromopropane are added and the mixture is heated to reflux. A solution of 19.4 g of 3-nitrophenol is then added dropwise over the course of 2 hours and the mixture is heated for a further 15 hours at reflux. The reaction mixture is filtered hot and evaporated. After chromatography of e and the residue on silica gel with toluene, 3-(3-bromopropoxy)-nitrobenzene is obtained as a pale yellow oil.

A solution of 4 g of 3-(3-bromopropoxy)-nitrobenzene in 40 ml of tetrahydrofuran is added to 1 g of Raney nickel and hydrated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. After evaporation of the filtrate, 3-(3-bromopropoxy)aniline is obtained as a colorless oil.

To a solution of 3.5 ml of 3-(3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of dichloromethane, the solution of 1.5 ml of oxalic acid monomethyl ester chloride in 10 ml of methylene chloride is added dropwise over the course of 10 minutes. After stirring for 2 hours at room temperature, the mixture is poured onto water and extracted with dichloromethane. The combined extracts are evaporated and the residue is chromatographed with dichloromethane/ethyl acetate (10:1) on silica gel. The eluate is evaporated and the residue is crystallized from ether/hexane. The N-[3-(3-bromopropoxy)-phenyl]-oxamic acid methyl ester with melting point 90-91° is obtained.

Example 18

A suspension of 1.8 g of N-(3-hydroxyphenyl)-oxamic acid methyl ester and 1.38 g of calcined potassium carbonate in 20 ml of ethyl methyl ketone is added with a spatula tip of potassium iodide and 3.15 g of 4-(3-bromopropoxy)-2-hydroxy-3- (3,3,3-trifluoropropyl)-acetophenone and heated at reflux for 12 hours. The reaction mixture is cooled, poured onto water and extracted three times with dichloromethane. The combined extracts are washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from methylene chloride/ether gives the N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy>-phenyl>>-oxamic acid methyl ester.

The starting material is obtained, e.g. as follows:

To a solution of 2.5 g of 3-aminoanisole and 1.5 ml of pyridine in 40 ml of dichloromethane, the solution of 1.9 ml of chlorooxalic acid methyl ester in 10 ml of dichloromethane is added dropwise over the course of 10 minutes. After stirring for 3 hours at room temperature, the mixture is poured onto water and extracted with dichloromethane. The extracts are dried over sodium sulphate, evaporated and crystallized from ether/hexane. N-(3-methoxyphenyl)-oxamic acid methyl ester is obtained.

To a solution that has been cooled to -78° C. of 2 g of N-(3-methoxyphenyl)-oxamic acid methyl ester in 20 ml of dichloromethane, 5 g of boron tribromide are added dropwise over the course of 5 minutes. It is stirred for 5 hours at room temperature, 5 ml of water is added while cooling and the organic phase is separated. After drying over sodium sulfate and evaporation, N-(3-hydroxy-phenyl)-oxamic acid methyl ester is obtained.

Example 19

In an analogous manner as described in examples 1 to 14 and 16 to 18, the following is obtained: N-{ { 3-{3-[4-acetyl-3-hydroxy-(3,3.3-trifluoropropyl)-phenoxy]-propyloxy >-4-methoxycarbonyl-phenyl))-oxamic acid and its triethanolammonium salt as well as

N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-carboxy-phenyl))-oxamic acid and its mono- and disodium salt.

Example 20

A suspension of 10.0 g of N-{ (3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propyloxy)-6-methyl -phenyl))-oxamic acid methyl ester in 60 ml of methanol and 100 ml of n-sodium hydroxide solution is heated for one hour at reflux. The reaction mixture is cooled, acidified with dilute hydrochloric acid and the precipitated N-{ (3- { 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy )- The 6-methyl-phenyl)-oxamic acid is filtered off and washed with water. For purification, the product is dissolved in 200 ml of boiling methanol, 22 ml of n-sodium lye is added and evaporated under reduced pressure to approx. 100 ml. After adding acetone and ether, crystallization starts. The product is filtered off and washed with ether. In this way, the sodium salt of N-{(3-<3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy)-6-methyl- the phenyl))-oxamic acid.

In an analogous way, starting from N-{ (4-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propoxy)- 3-Methoxy-phenyl))-ocamic acid methyl ester is prepared N-{ {4-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2 -hydroxy-propyl oxy)-3-methoxy-pheny 1))-oxamic acid.

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

A solution of 18.4 g of 4-methyl-3-nitro-phenol in 180 ml of ethanol is added to 440 mg of a 55% sodium hydride suspension in mineral oil. A solution of 25.0 g of 4-(2,3-epoxypropoxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone, which can be obtained by reaction of 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)-acetophenone and epichlorohydrin in 150 ml of ethanol and stirred for 6 hours under reflux. The reaction mixture is cooled, evaporated to approx. 150 ml under reduced pressure and poured over ice. The aqueous phase is acidified with dilute hydrochloric acid and extracted three times with methylene chloride. The organic phases are washed with water, combined, dried over sodium sulfate and evaporated under reduced pressure. Crystallization of the residue from ether gives 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy>-6- methyl-nitrobenzene.

In an analogous manner, starting from 4-hydroxy-3-methoxy-nitrobenzene and 4-(2,3-epoxypropoxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone, 4-{3- [4 - acetyl-3-hydroxy γ-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy > -3-methoxy-nitrobenzene.

A suspension of 10.0 g of 3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy}-6-methyl-nitrobenzene in 100 ml of acetic anhydride and 1 ml of pyridine are stirred for one hour at 60°. The reaction mixture is then evaporated to dryness under reduced pressure and the crude 3-(3-[4-acetyl-3-hydroxy-2-(3,3,3- trifluoropropyl-phenoxy]-2-acetoxy-propyloxy>-6-methyl-nitrobenzene is hydrogenated with Raney nickel in tetrahydrofuran to give 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3- trifluoropropyl) - phenoxy] -2-acetoxy-propyloxy > -6-methyl-aniline.

In an analogous manner, starting from 4-{ 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy}-3-methoxy-nitrobenzene 4- { 3- [4- acetyl-3 -hydroxy y-2-(3,3,3-trif 1 uorpropyl 1)-phenoxy]-2-ace ethoxy - propyloxy >-3-methoxy-aniline as an oil with Rf- value = 0.10 (silica gel, toluene/ethyl acetate = 6:1).

To a solution cooled to 0°, of 8.3 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propyloxy> -6-methylaniline and 2.9 ml of triethylamine in 70 ml of methylene chloride are added dropwise over approx. 5 minutes a solution of 1.9 ml chlorooxalic acid methyl ester in 8 ml methylene chloride and is then stirred for 2 hours at room temperature. The reaction mixture is poured onto ice water and the organic phase is separated. The methyl enchlorid phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. In this way N-{ {3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-acetoxy-propyloxy > -6-methyl-phenyl > > - the oxamic acid ethyl ester as an oil with Rf value = 0.13 (silica gel, toluene/ethyl acetate = 6:1).

In an analogous manner, starting from 4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-2-acetoxy-propyloxy)-3-methoxyaniline N-{4 - The [3-(4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy)-2-acetoxy-propyloxy > -3-methoxy-phenyl) )-oxamic acid methyl ester.

Example 21

To a solution cooled to 0° of 5.5 g of 3-{ 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy- propyloxy>-4-bromo-6-methyl-aniline in 60 ml of dichloromethane is added dropwise with rapid stirring 1.45 ml of chlorooxalic acid ethyl ester. It is stirred for 40 minutes at 0° and 5 hours at room temperature, the reaction mixture is poured onto ice water and the organic phase is separated. The dichloromethane phase is washed three times with 10 ml of water each time, dried over sodium sulphate and evaporated under reduced pressure. The residue is crystallized from ether/petroleum ether. N-{ {3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy > -4-bromo-6-methyl-phenyl The > >-oxoamic acid ethyl ester melts at 113-115°C.

The starting material can be prepared as follows:

A mixture of 10.0 g of 2,4-dihydroxy-3-(3,3,3-trifluoropropyl)acetophenone and 16.4 g of epibromohydrin in 20 ml of ethanol is heated to reflux and a solution of 2.46 g of potassium hydroxide in 20 ml of ethanol and 0.5 ml of water. The suspension is heated for 2 hours under reflux, cooled, diluted with 150 ml of water and extracted with 200 ml of dichloromethane. The dichloromethane phase is washed with 40 ml of water, dried over sodium sulphate and evaporated to dryness under reduced pressure. 4-(2,3-epoxypropoxy)-2-hydroxy-3-(3,3,3-trifluoropropyl)-acetophenone is obtained as a yellow oil.

To a solution of 3.8 g of 2-bromo-4-methyl-5-nitro-phenol in 50 ml of anhydrous ethanol is added 0.1 g of sodium hydride mineral oil dispersion (55%). The red solution is heated to reflux and a solution of 5.0 g of 4-(2,3-epoxypropyl-oxy)-2-hydroxy-3-(3,3, 3-trifluoropropyl)-acetophenone in 50 ml of anhydrous ethanol. The mixture is heated for 7 hours under reflux, cooled, 200 ml of water and 200 ml of dichloromethane are added and acidified with 2N hydrochloric acid. The dichloromethane phase is separated and the aqueous suspension is extracted again with 100 ml of dichloromethane. The combined dichloromethane phases are washed with 50 ml of water, dried over sodium sulphate and evaporated to dryness under reduced pressure. Crystallization of the residue from ether/petroleum ether gives 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy)-4-bromo-6 -methyl-nitrobenzene as pale yellow crystals with melting point 127-129°.

A solution of 6.5 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy>-4-bromo-6-methyl -nitrobenzene in 65 ml of tetrahydrofuran is added to 1.0 g of Raney nickel and hydrated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure and the residue is crystallized from ether/petroleum ether. 3-{ 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy>-4-bromo-6-methyl-aniline melts at 118- 120°.

Example 22

A mixture of 3.3 g of N-{(3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy>-4-bromo -6-methyl-phenyl >}-oxamic acid ethyl ester in 40 ml of ethanol and 12.5 ml of n-sodium hydroxide solution is heated for 2 hours at reflux. The reaction mixture is evaporated under reduced pressure, 50 ml of water is added and acidified with 2N hydrochloric acid. The suspension is extracted with 100 ml The ethyl acetate solution is separated, washed with 20

ml of water, dried with sodium sulphate and evaporated under reduced pressure. The residue is crystallized from ethyl acetate-petroleum ether. N-{ <3-{3-[4-Acetyl-3-hydroxy -2- (3,3,3-tri if lu or pr opyl) -ph e nox y] -2 - hydr o x y -pr opyl oxy > The -4-bromo-6-methyl-phenyl)-oxamic acid melts at 195-196°.

Example 23

2.6 g of N-{ {3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy }-4-bromo-6- methyl-phenyl)>-oxamic acid is dissolved in 250 ml of acetone and a solution of 1 ml of diethylamine in 10 ml of acetone is added. The reaction solution is evaporated under reduced pressure to 30 ml and ether is added, whereby the diethylammonium salt of N-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] The -2-hydroxy-propyloxy > -4-bromo-6-methyl-phenyl}}-oxamic acid crystallizes out. Melting point 160-162°.

Example 24

A solution of 6.2 g of N-{ (3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy- p ropylox y > -4-brom-6-methyl 1-phenyl > } -1-(4-methoxybenzyl-tetrazole-5-carboxamide in 130 ml of trifluoroacetic acid and 14 ml of anisole are heated for 30 minutes at reflux. The reaction mixture is evaporated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. N-{ (3-{3-[4-acetyl-3-hydroxy -2- (3,3,3-tri if lu orpropyl)-phe noxy]-2-hydroxy-propylo xy}-4-bromo-6-methyl-phenyl >}-1H-tetrazole-5-carboxamide.

The starting material can e.g. produced as follows:

To a suspension of 3.0 g of potassium [1-(4-methoxy-benzyl)-tetrazole]-5-carboxylate in 40 ml of benzene and 0.7 ml of pyridine is added at 0-5° 1.0 ml of oxalyl chloride and the mixture 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 rest are suspended

in 300 ml of dichloromethane and added dropwise at 0-5° over 10 minutes to a solution of 4.2 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)- phenoxy]-2-hydroxypropyloxy)-4-bromo-6-methylaniline and 0.92 ml of pyridine in 40 ml of dichloromethane. Then stir for 3 hours at room temperature. The reaction mixture is diluted with dichloromethane and washed twice with water. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoro-propyl)-phenoxy]-2-hydroxy-propyloxy > -4- brom-6-methyl 1-phenyl > > -1-(4-methoxybenzyl)-tetrazole-5-carboxamide is present as a yellow oil.

In an analogous way, it can be prepared: N-{ {3- <3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2- f hydroxy-propyloxy>-4- chloro-6-methyl-phenyl> }-1H-tetrazole-5-carboxamide, N-{ {3- <3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -2-hydroxy-propyloxy > -4-cyano-6-methyl-phenyl> )-1H-tetrazole-5-carboxamide, N-{ <3- <3-[4-acetyl-3-hydroxy-2- (3 ,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propyloxy>-4-fluoro-6-methyl-phenyl>>-1H-tetrazole-5-carboxamide.

Example 25

In an analogous manner as described in example 2, reaction of 3[-{ 3- [4-ac ethyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -4-chloro- 6-methyl-aniline, 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-fluoro-6-methyl-aniline or 2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy > -4-amino-5-methyl-benzonitrile with chlorooxalic acid methyl ester or chlorooxalic acid ethyl ester,

N-{ (3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy > -4-chloro-6-methyl-phenyl > > -oxamic acid methyl ester,

N-<<3-<3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-chloro-6-methyl-phenyl}> -oxamic acid ethyl ester,

N-{ {3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy )-4-fluoro-6-methyl-phenyl} > -oxamic acid methyl ester,

N-{ {3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy >-4-fluoro-6-methyl-phenyl> > -oxamic acid ethyl ester,

N-{ (3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy > -4-cyano-6-methyl-phenyl)) -oxamic acid methyl ester,

N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-cyano-6-methyl-phenyl ) }-oxamic acid ethyl ester.

Example 26

In an analogous way as described in example 3, 6 or 12 is obtained by hydrolysis of N-{ {3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] --propyloxy)-4-chloro-6-methyl- phenyl))-oxamic acid methyl ester or r-ethyl ester, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propyloxy > -4-fluoro-6-methyl-f enyl>)-oxamic acid methyl ester or -ethyl ester or N-{ {3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-cyano-6-methyl-phenyl) )-oxamic acid methyl ester respectively . -ethyl ester: N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy >-4-chloro-6-methyl -phenyl) >-oxamic acid and its sodium and potassium salts, N-{ {3-{3 - [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy] -propyloxy )-4-fluoro-6-methyl-phenyl>)-oxamic acid and its sodium and potassium salts as well as N-{ {3-{3- [4-acetyl-3-hydroxy-2-(3,3,3 -trifluoropropyl)-phenoxy]-propyloxy)-4-cyano-6-methyl-phenyl))-oxamic acid and its sodium and potassium salts.

Example 27

In an analogous way as described in examples 13 and 23, another can also

of the oxamic acid resp. The 5-tetrazolecarboxamide compounds in the preceding examples are transferred to their diethanolammonium, tris(hydroxymethyl)methylammonium, or diethylammonium salts.

Example 28

Tablets containing 25 mg of active substance, e.g. The triethanolammonium salt of N-{ (3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4-chloro-6-methyl-phenyl))- oxamic acid, can be prepared in the following way:

Preparation: All solid ingredients are first pressed through a sieve with a mesh size of 0.6 mm. Then mix the active substance, lactose, talc, magnesium stearate and half of the starch. 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, if necessary with the addition of water, is granulated. The granulate is dried overnight at 35°, pressed through a sieve with a mesh size of 1.2 mm and pressed into two-sided concave tablets with approx. 6 mm diameter.

In an analogous manner, tablets each containing 25 mg of another of the compounds of formula I mentioned in examples 1 to 27 can also be prepared, whereby compounds, where Rg is carboxy or 5-tetrazolyl, can be present in the form of salts with bases, e.g. as sodium salt or triethanolammonium salt, or in free form.

Example 29

Chewable tablets, which contain 30 mg of active substance, e.g. the triethanolammonium salt of N-{ { 3-{ 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy>-4-chloro-6-methyl-phenyl)>- oxamic acid, can e.g. produced as follows:

Preparation: All solid ingredients are first pressed through a sieve with a mesh size of 0.25 mm. The mannitol and lactose are mixed, granulated while adding gelatin solution, pressed through a sieve with a mesh size of 2 mm, dried at 50° and pressed again through a sieve with a mesh size of 1.7 mm. The active substance, glycine and saccharin are thoroughly mixed, the mannitol, lactose granules, stearic acid and talc are added, the whole is thoroughly mixed and pressed into two-sided concave tablets with approx. 10 mm diameter with fracture marks on the upper side.

In an analogous manner, tablets each containing 30 mg of another of the compounds of formula I mentioned in examples 1 to 27 can also be prepared, whereby compounds where Rg is carboxy or 5-tetrazolyl can be present in free form or in the form of salts with bases, e.g. as * sodium salt or triethanolammonium salt.

Example 30

Tablets containing 100 mg of active substance, e.g. The triethanolammonium salt of N-{ { 3-{ 3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy )-4-chloro-6-methyl-phenyl))- oxamic acid, can be prepared in the following way:

Preparation: The solid ingredients are first pressed through a sieve with a mesh size of 0.6 mm. Then mix the active substance, lactose, the talc, the magnesium stearate and half of the starch well. The other half of the starch is suspended in 65 ml of water and this suspension is added to a boiling solution of the polyethylene glycol in 260 ml of water. The paste obtained is added to the powdery substances, the whole is mixed and granulated, if necessary with the addition of water. The granulate is dried overnight at 35°, pressed through a sieve with a mesh size of 1.2 mm and pressed into two-sided concave tablets with approx. 10 mm diameter with fracture marks on the upper side.

In an analogous manner, tablets can also be prepared, which contain 100 mg of another compound of formula I according to examples 1 to 27, whereby compounds, where Rg is carboxy or 5-tetrazolyl, can be present in free form or in the form of salts with bases, e.g. as sodium salt, or triethanolammonium salt.

Example 31

A propellant-containing solid aerosol-forming inhalation suspension containing 0.1% by weight of N-{ (3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy)-4 -chloro-6-methyl-phenyl) >-oxamic acid methyl ester (active substance) can e.g. produced as follows:

Preparation: The active substance is suspended under moisture exclusion using a normal homogenizer in the trichlorotrifluoroethane while adding the sorbitan trioleate, the suspension is filled in a dosing aerosol container, which is closed and filled under pressure with the mixture of dichlorodifluoromethane and dichlorotetrafluoroethane.

In an analogous way, inhalation suspensions containing another compound of formula I according to examples 1 to 27 can also be prepared, whereby compounds, where Rg is carboxy or 5-tetrazolyl, can be present in free form or in the form of salts with bases, e.g. . such as sodium salt or triethanolammonium salt.

Example 32

An approx. 2% aqueous solution of the triethanolammonium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4- chloro-6-methylphenyl)}-oxamic acid as an active substance suitable for inhalation can e.g. produced with the following composition:

Preparation: The active substance is dissolved in freshly distilled water. Stabilizer and preservative are then added. After complete dissolution of all the components, the resulting solution is made up to 100 ml, filled into bottles and these are sealed gas-tight.

In an analogous way, 2% inhalation solutions containing another active substance from one of examples 1 to 27 can also be prepared.

Example 33

Capsules that are suitable for insufflation and that contain approx. 25 mg of N-

{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyloxy}-4-chloro-6-methyl-phenyl>)-oxamic acid methyl ester as active substance , can e.g. produced with the following composition:

Preparation: The active substance and the lactose are mixed well. The powder obtained is then sieved and filled in portions of 50 mg each into 1000 gelatin capsules.

In an analogous way, insufflation capsules containing another active substance according to one of examples 1 to 27 can also be produced.

Claims (10)

1. Process for the preparation of 2-fluoroalkylated 4-acylresorcinethers with the formula where Ri means lower alkyl, R2 is fluorinated lower alkyl, R3 means hydrogen, lower alkoxy, trifluoromethyl or halogen, alk is an alkylene or hydroxyalkylene residue which is optionally interrupted by oxygen, one of the residues R4, R5 and R7 stands for a group with the formula -NH -C(=0)-Rg, one from this different residue R4 or R5 represents a residue R9 and one from this different residue R7 represents a residue Riq, R5 is hydrogen, lower alkyl, trifluoromethyl, halogen, optionally esterified or amidated carboxy , cyano or lower alkanoyl, Rg means optionally esterified or amidated carboxy or 5-tetrazolyl, R9 means hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and Riq stands for hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, cyano or optionally esterified or amidated carboxy, and their salts, characterized by ata) a compound of the formula be rearranged orb) a compound with the formula where Xi means optionally etherified hydroxy, is reacted with a compound of the formula R1 -X2 (IV), where X2 means optionally functionally converted carboxy, or c) a compound of the formula where X3 means a residue which_Jcan_o <y> .is_before.es__to the fluorinated lower alkyl residue R2 , or in a salt thereof X3 is transferred to fluorinated lower alkyl, ord) in a compound with the formula where X4 means a residue that can be transferred to hydroxy, X4 is transferred to hydroxy-"silier) compounds with the formulas are reacted with each other, where one of the residues X5 and X5 is hydroxy which is optionally present in salt form, and the other a residue -O-alkH, which is substituted with reactive, esterified hydroxy or epoxy, i.e. an alkoc acid residue or mono-, di- or trioxaalkyl radical which is substituted with reactive, esterified hydroxy, or an alkoxy or mono- or dioxaalkylene radical which is substituted with epoxy, orf) a compound of the formula where one of the residues R4', R5' and R7' is the amino group, one from this different residue R4' or R5' is a residue R9 and a residue different from this R7' is a residue Riq, or a salt thereof is reacted with a compound of the formula r X7 - Rg' (X) where Rg' means an optionally esterified or amidated carboxy group or optionally 5-tetrazolyl protected in the 1-position and Xy means an optionally esterified, amidated, anhydridized or, if Rg' stands for 5-tetrazolyl protected in the I-position, a carboxy group that is present in salt form, and optionally the protecting group in the 1-position is removed in a tetrazolyl group <R> g org) in a compound with the formula in in where one of the residues R4 ", R5 " and R7 " is a residue Xg, one from this different residue R4 " or R5" is a residue R9 and a residue different from this R7" is a residue Rig, and Xg means a residue that can be transferred to the desired group with the formula -NH-C(=Oj^Rg, transferred Xg~tir~this " ""orh) in connection with the formula in which alk' means a residue that can be transferred to a group of alk, alk' is transferred to a group of alk and, if desired, a compound that can be obtained according to the method is transferred to another compound of formula (I), an isomer mixture that can be obtained according to the invention -divided—and the or the desired isomers are isolated and/or a free compound that can be obtained according to the invention is converted into a salt or a salt that can be obtained according to the invention is converted to the free compound or to another salt. 2. Method according to claim 1 for the preparation of compounds of formula (I), characterized in that Ri means lower alkyl, R2 means fluorinated lower alkyl with up to and including 3 fluorine atoms, R3 means hydrogen, lower alkoxy, trifluoromethyl or halogen, alk stands for the lower alkyl or the hydroxyl lower alkylene which is optionally interrupted by oxygen, especially a residue with the formulas -(CH2 )m - (Ia), -(C <H> 2)n ,_[0-(CH2 )n] _k (Ib) or -[ ( CH2 ) 1 » -0] 0CH2-CH( OH )-CH2_[0- ( CH2 ) i3-p ( Ic ) where k stands for 1, 2 or 3, 1 and 1' independently of each other means 2 or 3, m means an integer from 2 up to and including 9, n and n' independently of each other means 2, 3 or 4 and 0 and p independently of each other stand for 0 or 1, a the residues R4 , R5 and R7 stand for a group with the formula-C(C=0)-Rg, one from this different residue R4 or R5 represents a residue R9 and one from this different residue R7 represents a residue Riq, R5 means hydrogen, lower alkyl, trifluoromethyl, halogen, lower alkanoyl, carboxy, lower alkoxycarbonyl, cyano, carbamyl, N-mono- or N,N-diloweralkylcarbamyl, Rg on one side carboxy, lower alkoxycarbonyl, N,N-diloweralkylaminolower oxycarbonyl, N,N-lower alkyleneaminolower alkoxycarbonyl, carbamyl, N-mono- or N,N-dilower alkylcarbamyl, N,N-lower alkylene- or N,N-di(aza)lower alkylene-, N,N-(oxa)lower alkylene- or N,N-(thia)lower alkylenecarbamyl or on the other hand 5-tetrazolyl, R9 is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl and Riq stands for hydrogen, lower alkyl, lower alkoxy, halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, cyano, carbamyl, N-mono- or N,N-dilower alkylcarbamyl, and their salts. 3. Method according to claim 1 for the preparation of compounds of formula (I), characterized in that R1 means lower alkyl with up to and including 4 C atoms, R2 means co.co.co trifluorolower alkyl with up to and including 3 C atoms, R3 means hydrogen and R5 is oxaloamino, lower alkoxy, lower alkoxyoxalylamino with 3 up to and including 6 C atoms or 5-tetrazolylcarbonylamino, R4 stands for lower alkyl with up to and including 4 C atoms, R5 is halogen with atomic number up to and including 35 or cyano, and R 7 is hydrogen and alk is linear, terminally bound lower alkylene of 2 to 5 carbon atoms or hydroxy lower alkylene of 3 to 7 carbon atoms, in which the hydroxy group is bonded in a higher than cx position and in a lower than co- position, and their salts. 4. Method according to claim 1, characterized in that N-< (3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl; phenoxy]-propyloxy)-4-chloro- 6-methyl-phenyl 1 > > -1H-tetrazol-5-carboxam or a salt thereof, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop}oxy >-4-bromo-6-methyl-phenyl > >-1H-tetrazole-5-carboxamide or a derivative thereof, N-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop: oxy > -4-bromo-6-methyl-phenyl} > -oxamic acid methyl ester, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop: oxy}-4-bromo-6-methyl-phenyl)-oxamic acid or a salt thereof, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop: oxy}-6-methyl-phenyl)-oxamic acid or a salt thereof, N-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop: oxy)-4-cyano-6-methyl-phenyl)-1-H-tetrazole-5-carboxamide or a derivative thereof, N-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop; oxy >-4-fluoro-6-methyl-phenyl> >-1-H-tetrazole-5-carboxamide or a Si thereof, N-{ {3- {3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-hydroxy-propoxy)-4-bromo-6-methyl-phenyl) >- oxamic acid or a sa: hence, N-{ {3-(3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-hydroxy-propoxy)-4-bromo-6-methyl--phenyl } )-1H -tetrazole-5-carboxame or a salt thereof, N-{ (3- (3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy ]-hydroxy - propoxy)-4-chloro-6-methyl-phenyl)>-1H-tetrazole-5-carboxam or a salt thereof, N-{ {3- {3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-hydroxy -propyloxy)-4-cyano-6-methyl-phenyl > >-1H-tetrazole-5-carboxame or a salt thereof, 3-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl}chloro-6-methyl-phenyl}>-oxamic acid or a salt thereof , 3-{ {3-(3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl) fluoro-6-methyl-phenyl} >-oxamic acid or a salt thereof or 3-{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl)cyano-6-methyl-phenyl)>-oxamic acid or a salt thereof. 5. Method according to claim 1, characterized in that N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propyloxy>-4-bromo-6 -methyl-phenyl > > -oxamic acid ethyl ester, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop}oxy)-2-cyano-phenyl>>-lH -tetrazole-5-carboxamide or a salt thereof, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop}oxy ) -2-cyano-phenyl > > -oxamic acid ethyl ester, N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-prop}oxy >-2-cyano-phenyl >>-oxamic acid or a salt thereof, N-{ <3- <3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-hydroxy-propyloxy}-6-methyl-phenyl>>-oxamic acid methyl ester, N-{ (3- {3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-hydroxy-propoxy > -4-bromo-6-methyl-phenyl >} -oxamic acid ethyl ester, 3-{ { 3-{3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl > chloro-6-methyl-phenyl))-oxamic acid methyl ester, 3-{ { 3-{ 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl > fluoro-6-methyl-phenyl))-oxamic acid methyl ester, 3-{ { 3-{ 3- [4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl > cyano-6-methyl-phenyl} > -oxamic acid methyl ester, 3-{<?3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl)4--chloro-6-methyl-phenyl}}-oxamic acid ethyl ester , 3-<<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl )4-fluoro-6-methyl-phenyl}>-oxamic acid ethyl ester or 3 -{<3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propyl)4-cyano-6-methyl-phenyl))-oxamic acid ethyl ester. 6. Method according to claim 1 for the production of a salt-forming compound, which can be obtained according to one of claims 1-5 in the form of the sodium, potassium, triethanolammonium, diethanolammonium, tris(hydroxymethyl)methylammonium or diethylammonium salt. 7. Procedure for the preparation of compounds of the formula where R2 means fluorinated lower alkyl, R3 means hydrogen, lower alkoxy, trifluoromethyl or halogen and R11 means hydrogen or a group with the formula Ri-0-(=0)-, where Ri stands for lower alkyl, and their salts, characterized in that in a compound with the formula where at least one of the radicals Xi represents v etherified hydroxy R and a different radical from this Xi represents free hydroxy and Xi \ is a group that can be exchanged for the desired radical R2 or can be transferred to this, X11 is replaced with the desired radical or transferred to this, etherified hydroxy R is cleaved to hydroxy and, if desired, the compound obtained according to the invention is transferred to another compound of formula (XXXIII), in particular a group of the formula Ri-C(=0)-and/ is introduced instead of hydrogen R11 or a free compound that can be obtained according to the invention is transferred to a salt, respectively a salt that can be obtained according to the invention is transferred to the free compound. 8. Procedure for the preparation of compounds of the formula where R2 means 3,3,3-trifluoropropyl, R3 means hydrogen, lower alkoxy, trifluoromethyl or halogen and R11 means hydrogen or a group with the formula Ri-0-(=0)-, where Ri stands for lower alkyl, and their salts, characterized in that a connection with the formula where R means etherified hydroxy, such as lower alkoxy, e.g. methoxy, is reacted in an inert solvent, with an etherate of 3,3,3-trifluoro-2,2-dichloro-ethylzinc chloride of the formula CF^ CC^ZnCb^^Hs^O (XXI) to the corresponding compound of the formula this is acylated in the side chain, the reaction product with the formula where the residue Ac stands for the introduced acyl group, on treatment with a metallic reducing agent is transferred to the corresponding compound with the formula when treating this with a metal base, hydrogen chloride is split off, in the obtained compound with the formula the side chain is hydrogenated and the etherified hydroxy groups R are cleaved to hydroxy, if desired a residue R11 is introduced with the formula Ri~ C-(=0)- and if desired a free compound obtained is converted to a salt or a salt obtained is converted to the free compound. 9. Process according to claim 7 for the preparation of compounds of formula (XXXIII), characterized in that Ri, if present, means lower alkyl with up to and including 4 C atoms, R2 is co.oj.co trifluorolower alkyl with up to and including 4 C- atoms and R 3 means hydrogen, and their salts, e.g. 2-(3,3,3-trifluoropropyl)-resorcinol or a salt thereof or 4-acetyl-2-(3,3,3-trifluoropropyl)-resorcinol or a salt thereof. 10. Method according to claim 8, characterized in that 2-(3,3,3-trifluoropropyl)-resorcinol or 4-acetyl-2-(3,3,3-trifluoropropyl)-resorcinol is produced, either in free form or in salt form.