JPS62126179A - 4-acylresorcine ether, manufacture and drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula 8 is additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and/or halogen,
and Ring B may be additionally substituted with lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, carboxy, carbamyl, cyanide, halogen and/or trifluoromethyl]. and its salts.

Hydroxyalkylene radicals optionally interrupted by oxygen are, for example, in particular straight-chain hydroxy-lower alkylene radicals or hydroxy-(oxa)alkylene- or hydroxy-(dioxa)alkylene radicals, in which case the hydroxyl group has free valences (bonds). ) and higher than the β position for oxa members which are optionally present in positions higher than the α position and lower than the ω position and higher than the β position for free valences and lower than the (ω-1) position. connected in position. Such a group is, for example, represented by the formula %formula%() [wherein n8 and no independently represent 2.3 or 4, and 0 and p independently represent 0
or l], especially the group of the formula rb [wherein the exponents 0 and p are 0, one of the exponents 0 and p is 1 and the other is 0, and n and no are 2. be]
hydroxy lower alkylene J, (or hydroxy-
(oxa) is a lower alkylene group.

The "lower" organic compounds and groups derived therefrom, as mentioned above and below, are those having, for example, up to 7, and up to 4 carbon atoms (C-atoms).

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl, and also nibutyl or tertiary butyl, especially methyl in the case of R8 and especially propyl in the case of the lower alkyl substituent of ring A. .

Lower alkoxy is, for example, methoxy, ethoxy, propyloxy, isopropyloxy or butyl'oxy.

Halogen is, for example, 53 or less, especially 5 including 17 and 53.
Examples are fluorine, chlorine, bromine and iodine.

Lower alkenyl is, for example, allyl, metaallyl or 4-enyl (4-butenyl).

Lower alkynyl is, for example, propargyl.

Lower alkanoyl is, for example, formyl, acetyl, propionyl, butyryl,/hereroyl or piparoyl.

Hydroxy lower alkylene in which the hydroxy group is bonded in a position higher than the α-position and lower than the ω-position means, for example, 1,3-(2-hydroxy)propylene, and also 1,4-(2-hydroxy)propylene. -hydroxy)butylene or 1,5-(3-hydroxy)pentylene.

The hydroxy group is bonded in a position higher than the α-position relative to the free valence and lower than the ω-position and itself in a position higher than the β-position relative to the free valence and (
oxagl located lower than ω-1)
Hydroxy-(oxa) lower alkylene bonded at a position higher than the β-position to 1ed) is, for example, 1.
It means 7-(2-hydroxy-4-oxa)hebutylene, and may also be 1,1f-(2-hydroxy-decaoxa)hexylene.

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

Of particular interest as salts of the compounds of formula I are, for example, pharmaceutically usable salts, such as metal salts, ammonium salts or salts with organic bases. Metal salts include, for example, the corresponding alkali metal 12° alkaline earth metal salts, such as lithium, sodium, potassium, magnesium or calcium salts, and also pharmaceutically usable transition metal salts, such as zinc 1! ! or copper salts. Salts with organic bases are, for example, those of formula I [wherein R2 is carboxy or 5-
seven no from the compound [which is tetrazolyl].

di- or tri-substituted organic amines, such as the corresponding alkylamines, hydroxyalkylamines, heterocyclic compounds with at least one N-atom such as morpholine, thiomorpholine, piperidine or pyrrolidine, optionally N-substituted aminosaccharidenes 1 For example, tomethyl-〇-glucamine or basic amino acids such as lysine, arginine, histidine or ornisine (
In this case, the L-configuration is advantageous). An example of an alkylamine is 7-no.

Di- or tri-lower alkylamines such as ethyl-1-tert-butyl, diethyl, diisopropyl, trimethyl or triethylamine come into consideration. Hydroxyalkylamines are, for example, heptano, di- or trihydroxyalkylamines such as heptano, di-, triethanolamine or diisopropanolamine, or hydroxy lower alkyl-lower alkyl amines such as N.

N-dimethyl-, N,N-diethylaminoethanol or tri(hydroxymethyl)methylamine come into question.

Other salts include pharmaceutically usable acid addition salts such as formula I (
However, R2 in the formula is a hydrohalide salt, methanesulfonate salt, N
- Cyclohexylsulfamate, maleate or fumarate.

Compounds of the formula 1 having chiral carbon atoms, depending on the number of carbon atoms, exist in mutually enantiomeric or diastereomeric forms or as mixtures thereof, such as diastereomeric mixtures, racemates or racemic mixtures.

The compound according to the invention is characterized by valuable pharmaceutical properties. In particular, this compound has a pronounced antiallergic activity, which has a pronounced LTDa-antagonistic effect (Antag
enismus) and PAF antagonism (PAF-a
cether antagonism, antagonism, antagonism, and the reason for this is that the compound according to the present invention is capable of reacting with LiO2 in a range of about 0.005 to about 0.05 #mol/cross in vitro. Muscle contraction induced by Konstr.
This is because it prevents LTDa
- Antagonism can be demonstrated, for example, in isolated guinea pig ileum. For this purpose, organs are removed from guinea pigs weighing 300 to 400 g and placed in organ containers.
) in tyrodes solution (T7rodelliisung) (
Gas quenching with 85%02 and 5% CO2 at 38℃
Synthetic LTD for the ileal segment fixed in j′IB e g a s u n g ) and loaded with 1p, [
Muscle contraction (Konstraktion) by Leukotrien 04, potassium salt]
and record the amount. LTD4 of test substance
The extent of this muscle contraction inhibition attributable to antagonism is measured. LTD, the muscle contraction induced by the initial value of 50
%, the concentration of the test substance expressed as IC5o is obtained. In this experimental apparatus, for example, N-(3-
(3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy-propyloxy1-
0.0054 for the triethanolammonium salt of 4-bromo-8-methyl-phenyl)-1H-tetrazolyl-5-carboxamide. IC5o-value in moles/cross,
or N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy-propyl-oxy]-2-cyano-phenyl)-tetrazole-5-carboxamide triethanolammonium For the salt, an IC value of 0.03 umol/cross and N-(3-[3-(4-acetyl-3-
-propyl-phenoxy)-2-hydroxypropyloxy]-phenyl)-oxamic acid ethyl ester to N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy For the sodium salt of -propyloxy 1-2-cyano-phenyl)-oxamic acid (both U.S. Pat. No. 4,448
, 729) 0.087 #L mol/view I
C5o-values were obtained.

The new compound's t, to, -antagonistic action was observed in vivo (Roma1n
o) can also be demonstrated by the suppression of experimental LTD<--bronchial spasms in guinea pigs.

The present invention first relates to formula 1 [wherein R8 means lower alkyl, and alk is hydroxy(oxa)lower alkylene, hydroxy(oxa)lower alkylene or hydroxy(
dioxa) lower alkylene, in which the hydroxy group is higher than the α-position and lower than the ω-position relative to the free valence and higher than the β-position relative to the free valence and lower than the (ω-1)-position. It is bonded at a position higher than the β-position to an oxa member that is optionally present at a lower position. and R2 means 5-tetrazolyl, in which case term 8 is additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and/or halogen, and ring B is additionally lower alkyl, lower alkanoyl, lower alkoxy, lower and salts thereof, in particular pharmaceutically usable salts.

The invention particularly relates to compounds of the formula [wherein R1 is lower alkyl having up to 4 carbon atoms, such as methyl, R2 represents 5-tetrazolyl, and R3 is lower alkyl having up to 4 carbon atoms, such as propyl] , Ra is hydrogen, lower alkyl having up to 4 carbon atoms, such as methyl, 4
lower alkoxy having up to 4 carbon atoms such as methoxy or halogen with atomic number 35 such as chlorine or bromine, where RS is hydrogen, lower alkyl having up to 4 carbon atoms such as methyl, halogen with atomic number up to 35 such as chlorine. or bromine or trifluoromethyl, R6 being hydrogen, lower alkyl having up to 4 carbon atoms such as methyl, lower alkoxy having up to 4 carbon atoms such as methoxy, cya/or halogen with an atomic number of up to 35 For example, it represents chlorine or bromine, where R is hydrogen, lower alkyl having up to 4 carbon atoms, such as methyl, halogen with an atomic number of up to 35, such as chlorine or bromine, lower alkoxycarbonyl having up to 5 carbon atoms, such as ethoxy carbonyl, carboxy, cyano or lower alkanoyl having up to 7 carbon atoms, such as formyl, acetyl or pivaloyl, and alk in particular hydroxy lower alkylene having 3 or 4 carbon atoms attached at a linear end; In this case, the free valence is from the carbon atom at the β position relative to the hydroxyl group, for example 1,3-(2-hydroxy)propylene] and salts thereof, particularly pharmaceutically usable salts.

The present invention firstly relates to the formula Ia, in which R1 is lower alkyl having up to 4 carbon atoms, such as methyl;
R3 represents a straight-chain lower alkyl having up to 4 carbon atoms, such as propyl, R2 represents 5-tetrazolyl, R4 is hydrogen, R6 represents a lower alkyl having up to 4 carbon atoms, such as methyl, R6 is hydrogen; R, is a halogen of atomic number up to 35, such as chlorine or bromine;

or cyano and alk is a straight-chain terminally bonded hydroxy lower alkylene having 3 or 4 carbon atoms, in which case the free valence is from the carbon atom β to the hydroxy group, e.g. .3-(2-hydroxy)-propylene] and its salts, especially salts with pharmaceutically usable bases.

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

The invention furthermore relates to a process for the preparation of compounds of formula 1 and their salts, relying on methods known per se.

This process is characterized by either rearranging a compound of formula (a) or rearranging a compound of formula (b) (wherein x1 represents an optionally etherified hydroxy) by rearranging a compound of formula R1-x2 ( rv ) (wherein x2 is optionally functionally modified carboxy); or (c) (wherein x3 is a compound of formula R1-c(・0)-); In the compound (representing a group that is converted into a group), x3 is converted into this group, or.

(d) In the compound of formula (where x4 represents a group convertible to hydroxy), x4 is changed to hydroxy, or (e) in the compound of formula (wherein either group X or x6 is hydroxy optionally present in salt form and the other substituted by a reactive esterified hydroxy, optionally a hydroxyalkoxy group interrupted by oxygen or an epoxyalkoxy group interrupted by oxygen) The compounds may be reacted with each other, or the compounds of formula (f) (wherein alk' is a group that can be converted into a group alk)
convert alk' into the group alk in the compound of
Alternatively, the compound of formula (g) or a salt thereof may be added to a compound of formula or react with a compound of

(h) In the compound of the formula (wherein X6 is a group that can be converted to the desired group of the formula -NH-C(=O)-R2), x6 is changed to this group, and if desired, converting the compounds obtained by this method into other compounds of formula 1 and/or converting the free compounds obtained by this method into salts or the salts obtained by this method into MgI compounds or other salts.

Hydroquine optionally etherified in 2■
1 means, for example, M-isolated or aliphatically etherified hydroxy, such as hydroxy, or lower alkoxy, such as methoxy. but this is also an aromatic aliphatic (a
raliphatisch), cycloaliphatic or aromatic etherified hydroxy such as optionally substituted phenylalkoxy such as benzoyloxy, cycloalkoxy such as cyclohexyloxy or cyclopentyloxy, or even optionally substituted phenoxy good.

Optionally functionally converted carboxy×2 in formula ① is, for example, an esterified or anhydride carboxy of M, such as carboxy, lower alkoxycarbonyl, halogencarbonyl or formula -C(=O)-
0-C(-0)-J anhydride carboxy.

Group R1-C in formula V: can be changed to (=O)-, (x3 is, for example, formula R1-CH(X9)-(7)
(where x9 in the above formula is hydrogen or hydroxy optionally esterified with an organic carboxylic acid) or is also a group of the formula R1-(:(-N)I)- or further optionally a functional Carboxy groups which have been converted, for example 'M', are carboxy or cyano, present in salt form or esterified. Hydroxy esterified with an organic carboxylic acid may, for example, be lower alkanoyloxy, such as acetoxy, which may also be optionally substituted benzyloxy, carboxyx3
Examples of the salt form include alkali metal, alkaline earth metal, or ammonium salts, such as sodium f! 1 or in the form of ammonium monium or in the form of halogen magnesium salts. Esterified carboxy x3 is, for example, lower alkoxycarbonyl which may also be optionally substituted phenoxycarbonyl or phenyl lower alkoxycarbonyl such as benzyloxycarbonyl.

Group R that can be transferred to hydroxy in 2
4 is, for example, etherified or esterified hydrocarbon λ. Etherified hydroxy includes, for example, aliphatically etherified hydroxy, such as lower alkoxy, such as methoxy, or lower alkenyloxy, especially lower alkane-2-dynyloxy, such as allyloxy.

Phenyl lower alkoxy, especially optionally substituted phenyl lower alkoxy, such as benzyloxy, and also tetrahydropyran-2-yloxy or silyloxy, especially tri-lower alkylsilyloxy, such as trimethylsilyloxy, come into consideration. Esterified hydroxy x4 is, for example, hydroxy esterified by a carboxylic acid, such as an aliphatic or aromatic carboxylic acid, or by an aliphatic or aromatic half-ester of carbonic acid, such as lower alkanoyloxy, such as acetoxy, such as formula R1-
C(-0)-0- optionally substituted benzoyloxy, optionally halogenated lower alkoxycarbonyl such as methoxy-, ethoxy- or tert-butyloxycarbonyl, 2,2.2-) rhodoethoxy or 2,2.2-)lichloroethoxylponyl, optionally substituted phenyl lower alkoxycarbonyl, especially l-phenyl lower alkoxycarbonyl, such as benzyloxycarbonyl, or optionally substituted phenoxycarbonyl.

Hydroxy x5 in the formula (2) to x6 in the formula (2) to carboxy in the salt form (2) are in particular present in the form of an alkali metal salt, for example as a sodium or potassium salt.

A hydrodialkoxy group optionally interrupted by oxygen and substituted by a reactive esterifying hydroxy group or an epoxyalkoxy group optionally interrupted by oxygen in formula (1) x5 or x6 in formula (2) can be, for example, in particular a group of the formula +( CH2)n-0-)-CH2-X ' to X'-
CH2+ (CHz) #1 (wherein the Mg & hydroxy group is bonded to the free valence position higher than the alpha position and to the reactive esterified human mixi group) from epoxy lower alkyl to epoxy ( afternoon)
a lower alkyl group, a reactive monoesterified hydroxy lower alkyl group, or, for example, where X is a reactive esterified hydroxy group, X' is 1
．． 2-epoxyethyl, n and no are 2, 3 or 4
．． o represents O or 1 and p represents O or 1) is the corresponding reactive monoesterified dihydroxy (heptano or dioxa)alkyl group. In this case, reactive esterified and doxy groups can be, for example, halogens such as chlorine, bromine or iodine, or organic sulfonyloxys, such as lower alkanesulfonyloxys, such as methanesulfonyloxys, or optionally substituted benzenesulfonyloxys, such as benzene-1p-bromobenzene. - or P-) luenesulfonyloxy. Particularly preferably n or no is 2, 0 or p is 0, p
Preferably, 0 to 0 is 0 or the second one is 1.

Group -alk'- which can be converted into group -alk- in formula (■)
is, for example, a corresponding oxo-lower alkylene group or an oxo(neptano or dioxa)alkylene group, in particular a corresponding oxo-lower alkylene group or an oxo(neptano or dioxa) alkylene group, in which X'' is an etherified or esterified hydroxy, n and the correction are 2, 3 or 4, 0 is 0 or 1 and p is 0 or 1) is an etherified or esterified hydroxy-lower alkylene or hydroxy-(heptano or dioxa) alkylene group.

In this case, the etherified hydroxy x'' is, for example, α-
Hydroxy etherified by alkanols or silanols, such as optionally substituted benzyloxy or tri-lower alkylsilyloxy, such as trimethylsilyloxy.

Esterified hydroxy benzyloxycarbonyl such as carbobenzooxy.

optionally esterified, amidated or anhydride carboxy x7 is, for example, am carboxy, esterified carboxy R2 or carboxy esterified with an optionally substituted phenol, such as phenoxy-14-nitrophenoxy- or 2,4-
dinitrophenoxycarbonyl, amidated carboxy R2 or activated carbamyl, e.g. 1-imidazolyl- to 1-(2,5-dimethylimidazolyl)-carbonyl, or e.g. formula Hal-C (=0)
- (wherein Hal is chlorine, bromine or iodine, especially chlorine) carboxy, for example halogencarbonyl, anhydrified with hydrohalic acid.

The raw material
)-R2(XI b)(7) groups are considered. A 5-tetrazolyl group present in protected form is, for example, a 1-(α-furalkyl)-tetrazolyl-(5)-group substituted with an aryl moiety, such as a 1-benzyl-tetrazolyl-(5)-group.
) or 1-(p-methoxybenzyl)-tetrazolyl-(5). Formula in formula ■)1H-C: (=
The group x6 which can be converted into a group of O)-R2 is, for example, a group of the formula -N)I
-C: (=O)-CN group.

The reaction of the process according to the invention and the preparation of the new starting materials and intermediates are carried out analogously to known methods for reacting and forming starting materials and intermediates. In this case, customary auxiliary substances such as catalysts, condensing agents and solvolyzing agents and/or
Alternatively, solvents or diluents and reaction conditions, such as temperature and pressure conditions and optionally protective gases, are used.

The rearrangement of compound II according to process variant (a) is carried out, for example, photochemically or in the presence of an acidic condensing agent, preferably in an inert solvent. Suitable acidic condensing agents are, for example, Lewis acids, especially
(XIX) (However, in the formula, group II of the element periodicity
b, II [a, mb, IVb, Va or
n3 boron, aluminum, gallium m-IV
-V is a tin -, titanium, 7-tinymony - or iron atom, and Y is a composite metal halide, in particular a halogen atom having an atomic number of 35 or less, such as fluorine, chlorine or bromine. In particular, boron trifluoride, aluminum trichloride, gallium chloride, tin tetrachloride or zinc chloride may be used.
Further suitable acidic condensing agents are, in particular, complex oxygen acids of sulfur or phosphorus, such as sulfuric acid, pyroWL vinegar, pyrophosphoric acid or polyfillers. Suitable inert solvents are, for example, tetrachloromethane (carbon tetrachloride), tetrachloroethane, trichloroethylene, carbon disulfide or nitrobenzene. If necessary, it is operated with cooling or heating, for example at about -10°C to about 40°C, in particular from +5°C to +30°C.

The starting material can be prepared, for example, by the formula Groups of the formula %, for example, where X is a reactive esterified hydroxy such as a halogen and X' is epoxyethyl, are reacted with each other in a conventional manner to form is hydroxy) in a conventional manner, e.g.
1-X2(rV) (wherein X2 is, for example, halogen carbonyl or the formula -〇(=O)-0-C(-0)-R1
It can be produced by 0-acylation by reacting with a compound (which is an anhydride carboxy group). The preparation of compound (1) is as described in the section of variant (e).

The reaction of compounds m and (1) according to process variant (b) is usually carried out in the presence of an acidic condensing agent, preferably in an inert solvent, if necessary at a temperature of, for example, from -10°C to +100°C, especially +
It is carried out with cooling or heating at 5°C to +85°C. As acidic condensing agents and inert solvents, for example, modified methods (
A description of a) can be considered.

The starting material (2) may be, for example, a compound of the formula [where one of the groups x5 and x6 is optionally a hydroxy present in the form of a salt and the other is substituted by a reactive esterified hydroxy, optionally A hydroxyalkyl group interrupted by oxygen or an epoxyalkyl group optionally interrupted by oxygen, for example of the formula %, where X is a reactive esterified hydroxy such as a halogen and Xo is epoxyethyl. [meaning a group]] can be produced by reacting them with each other.

The starting material ■ is known.

The conversion of x3 into the group R1-C(・0)- by the modified method (C) is carried out in a usual manner by converting the compound V (in this case, x3 is of the formula R1-C
Starting from M(X9)-), for example by oxidation, a compound V (where x3 is a group of formula R1-C(-N)l
)-, for example by solvolysis and starting from compound V (in which case x3 is carboxy optionally functionally converted or present in salt form), the flammability lf formula R1-M(XV),
(However, in the formula Mka N engineering Jf type -M", -M /2 or M
``-)Ial, -MI metal radical, alkaline earth metal atom 1, e.g. lithium, MII is a super-alkali atom or earth metal atom e.g. magnesium, zinc or cadmium and Hal is a halogen atom e.g. chlorine, bromine or iodine It is carried out by reacting with a certain compound).

Suitable oxidizing agents for the oxidation of the group x3 of the formula R1-CH(X9)- are, for example, oxidizing heavy metal compounds such as Cr''-, CrvI
-1Mn■-, Fem-, 5nrV- or yV- compounds such as chromium dioxide, potassium chromate or potassium dichromate, manganese dioxide, potassium permanganate, iron trichloride, tin tetrachloride or vanadium pentoxide, as well as nitrogen, blue lead (bismuth), selenium or halogen oxidizing oxygen acids or salts or anhydrides 1 such as nitrogen dioxide, bismuth oxide, selenium dioxide, sodium hypozinc oxide, potassium chlorate or potassium periodate.

Particularly suitable for oxidizing the group x3 of the formula R1-C)I(X9)-1 (in which x9 is hydroxyte) are, for example, Jf potassium permanganate in aqueous pyridine or aqueous acetone to dichloromethane. It is pyridinium dichromate.

The solvolysis of 'l & Examples of this type include protic or mineral acids such as hydrochloric acid or sulfuric acid or organic sulfonic or carboxylic acids such as lower alkane- or optionally substituted benzenesulfonic acids or lower alkanoic acids such as 1fp-toluenesulfonic acid or acetic acid. is possible.

The reaction of the compound (in which x3 is a carboxy group optionally functionally converted or present in the form of a salt) with a metallized metallization agent, e.g. It is carried out in diethyl ether, tert-butyloxymethane, dioxane or tetrahydrofuran, if necessary, for example at -60 DEG to +40 DEG C., in particular from -20 DEG to +25 DEG C., with cooling and with mild warming.

The starting material V is prepared, for example, as follows: a compound of the formula [where one of the φ groups ×5 and ×6 is hydroxy, optionally present in the form of a salt, and the other is a reactive ester. a hydroxyalkyl group optionally interrupted by oxygen or an epoxyalkyl group optionally interrupted by oxygen, e.g. halogen and X' is epoxyethyl) are reacted with each other.

The starting material V in which x3 is the group R1-C:H(X9)- is reacted with the compounds XVI (X3 = formyl) and 1 with each other and the reaction product V (X3 = formyl) is further reacted with two metal compounds It can also be manufactured by

Furthermore, the starting material V in which X3 is the radical R1-0H(=NH)- can be prepared as follows: Compound 1 is converted into a Lewis acid such as 2M”Y
n(XIX) (However, in the formula, n and Y are modified (a
) having the meaning described in ) is present, especially in the presence of aluminum chloride, the formula R1-0N (
React with the nitrile of X■). In this case it is not necessary to isolate the intermediate; it is generally further reacted according to the invention under the processing conditions. This deformation is especially true for al
Suitable for the preparation of compounds V in which k is a hydroxyalkylene group optionally interrupted by oxygen and for the following reactions.

The conversion of group x4 to hydroxy by modified method (d) is carried out by a conventional method, for example, 2M"Yn(XIX) (However, in the formula, elements in periodic group 1Ia, rIb, ma, mb, ffb
, Va or vIb, e.g. magnesium-1 zinc 11-boron t3, aluminum, gallium ■-■- rV IV
V tin -, titanium -, antimony -
or iron m-■- or iron ion, Y represents a halogen atom with an atomic number of up to 35, e.g. fluorine or chlorine), such as aluminum trichloride or a tertiary organic ammonium salt, e.g. pyridinium halide or trichloride. This is carried out by treating the lower alkyl ammonium halides 1, for example with pyridinium chloride or pyridinium bromide or triethyl ammonium chloride, but this can also be done by solvolysis, especially by hydrolysis, preferably acidic if necessary. This can be carried out in the presence of a hydrolyzing agent. In addition to the usual basic hydrolyzing agents such as alkali metals that degrade water, acidic hydrolyzing agents include mineral acids such as hydrochloric acid,
Hydrobromic acid or hydriodic acid, sulfuric acid, phosphoric acid or polyphosphoric acid, as well as complex metal acids such as chloroantimonic acid, tetrafluoroboric acid, etc., in the case of hydroxy groups x4 esterified with organic carboxylic acids. Furthermore, lower alkanoic acids such as acetic acid are used. Solvents in the case of hydrolysis are, for example, organic solvents which are miscible with water. It is expedient to operate with cooling or heating, for example in the temperature range from about 0 to 120° C., in each case in the presence of a solvent or diluent or dissolution medium and/or under an inert gas.

The hydroxyl group thus etherified can be purified with e.g. aqueous hydriodic acid, pyridinium hydrochloride, e.g.
% acetic acid or by treatment with boron tribromide or aluminum trichloride. As a variation of this method, for example, the formula % formula % () (wherein X1 is an etherified hydroxy
x2 is an anhydride of hydroxy, e.g. can be treated with aluminum trichloride, in which case the compound vI (
In this case, x4 represents etherified hydroxyl) to form a hydroxy group. Yet another variation of this method involves the compound (where x4 is lower alkane-
2-enyloxy and term 8 is unsubstituted at the 〇-position relative to x4) at about 150 to 250°C1
Preferably at 190 DEG to 220 DEG C., advantageously in a solvent such as diphenyl ether or N,N-dimethyl-N,
The compound is processed by heating in N-diethylamine (
In this case, ring A can be converted into a compound substituted with lower alkane-2-enyl in the 0-position relative to the hydroxyl group.

In compounds (1) which have optionally substituted .alpha.-phenyl lower alkoxy groups or other conventionally reductively decomposable protected hydroxy groups as group x4, the hydroxy group is preferably liberated reductively. It is thus possible, for example, to hydrogenate, i.e. hydrogenate with hydrogen in the presence of a hydrogenation catalyst, such as a palladium-1-autonomous, nickel or rhodium catalyst, and reduce, for example with palladium on charcoal or with Raney nickel. .

Furthermore, starting from compound (1) (in which case x4 is a hydroxy esterified with an organic carboxylic acid), the hydroxy group can be removed by ester substitution, i.e. with an alcohol, such as a lower alkanol, with an acidic or basic agent, such as a mineral acid, such as sulfuric acid. Alternatively, 'M can be separated by treatment in the presence of an alkali metal hydroxide or an alkaline alkanolade such as sodium hydroxide or a sodium lower alkanolade.

Starting material (1) is produced, for example, as follows. i.e. a hydroxyalkyl group of the formula [where one of the groups x5 and x6 is hydroxy, optionally present in salt form, and the other is a hydroxyalkyl group substituted by a reactive esterified hydroxy and optionally interrupted by oxygen; or an epoxyalkyl group optionally interrupted by oxygen, such as a compound of the formula %, where X is a reactive esterified hydroxy group, such as a halogen, and Xo is epoxyethyl. or compound ■ (however, in this case x4 is etherified XI)
The corresponding compounds of the formula are prepared under mild conditions, e.g. -10 to +10 DEG C., or with mildly acting Lewis acids, e.g. I! Zinc monoxide is made to react with a compound of the formula R1-X2 [IX, X2 = halogen carbonyl or -0-C(=0)-Rt] using gallium judide.

The reaction of compounds (1) and (2) according to variant (e) can be carried out in a conventional manner using the starting materials (in which case XS to X6 are groups -0- substituted by a reactive esterified hydroxyl).
For example, starting from 11! Basic condensing agents, such as hydroxides or carbonates of alkaline total hydroxides or alkaline earth total hydroxides, such as sodium hydroxide or potassium hydroxide, potassium carbonate or calcium carbonate, are advantageously present. is a lower alcohol such as methanol or amyl alcohol, a di-lower alkyl keto/in which is e.g. acetone or diethyl ketone, or an N, N-di-lower alkyl lower alkanoic acid amide or an N-lower alkyl lower alkanoic acid lactam such as dimethylformamide or N - carried out in methylpyrrolidinone.

The starting material (i) is prepared, for example, as follows: a compound of formula R1-X2 [IV;
= halogen carbonyl or -o-C(-0)-J]
If desired, the resulting compound ■
(where x5 is hydroxy), R1-
hydroxyalkoxy groups substituted by halogens and optionally interrupted by oxygen by reacting the hydroxy group in p-position with respect to C(-0)- with dihalogenalkanols or halogenalkane epoxides optionally interrupted by oxygen; or converted into an epoxyalkoxy group.

Compound (I) can be obtained, for example, by reducing the nitro group to amino in a compound of formula with hydrogen, for example in the presence of Raney nickel, and converting the compound of formula with a base such as triethylamine or pyridine. In the presence of formula Mal-C(=O)-R2(X[b HH
al=halogen) and, if desired, the resulting compound (where x5 is hydroxy)
hydroxyalkoxy substituted by a halogen, optionally interrupted by oxygen, by reacting the hydroxy in the P-position relative to R1-C(-0)- with a dihalogenalkanol or a halogenalkane epoxide, optionally interrupted by oxygen. It is converted into a group or epoxyalkoxy.

In this case, the conversion of the hydroxys xs to x6 into hydroxyalkoxy groups, optionally interrupted by oxygen, or epoxyalkyl groups, optionally interrupted by oxygen, substituted by reactive esterified hydroxy is carried out in each case stepwise. can do. That is,
Compounds (1) to (2) having free hydroxy groups x5 to
) to form the corresponding compound ■ or ■ [where x5 or x6 is a group of the formula % formula % (however, 0 in the formula is l)] 0-order cono intermediate product a) with a compound of the formula Xi to x6 are groups of the formula a) -0-(-(CH2)icH2-X' mataha (in the formula, 0 and p are ])).

The Nimata formula X-CH2-CH(X”)-CH2X(X
XV) in which X is a reactive esterified hydroxy such as chlorine, bromine or iodine and X'' is a carboxylic acid esterified hydroxy such as lower alkanoyloxy such as acetoxy. Compound vri or VW (however, here-c x
, NaiL X, is the formula -(:H2-1cH(X")-C
H 2

The residue alk' of compound (1) is converted by modification f) into compound (1) (however, in this case, alk' is etherified by oxo with α-furkanol or by a mono-α-7ralkyl carbonate group) with the usual lt- starting from an alkylene group substituted by an esterified hydroxy, for example, reductively and from a compound (where alk
' is a residue alk substituted with an etherified or esterified hydroxy group other than the above-mentioned hydroxy group
is carried out solvolytically starting from

Residue a corresponding to residue alk' replaced by oxo
Reducing agents for the reduction to lk include, 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, such as impropatol. Or cyclohexanol in the presence of aluminum alcoholade is problematic, especially isopropanol in the presence of aluminum isopropanolade. The reaction of the alkali metal borohydrides is advantageously carried out in lower alkanols, di-lower alkyl ethers or lower alkylene ethers or mixtures of these solvents, for example in ethanol. In the case of the reaction with alcohol in the presence of aluminum alcoholade, it is effective to operate with an excess of the alcohol used as reducing agent.

The reductive decomposition of α-7 alkoxy to α-7 alkoxycarponyloxy to hydroxy is advantageously carried out by hydrogenolysis, i.e. using a hydrogenation catalyst 1 such as palladium on charcoal,
Platinum oxide or a palladium-1 platinum-, iridium- or nickel catalyst such as Raney nickel is present, advantageously in a lower alkanol, for example in methanol solution, optionally for example from about 1 to 10 bar and 20 The reaction is carried out at temperatures ranging from 60 DEG C. to 60 DEG C. under superatmospheric pressure and/or at elevated temperatures under the action of hydrogen.

The solvolytic release of hydroxy from etherified or esterified hydroxy groups different from those mentioned above, for example from silyloxy, lower alkanoyloxy or lower alkoxycarbonyl, can be carried out by e.g. hydrolysis (reaction with water), alcoholysis. (reaction with alcohol) or hydrolysis or amine decomposition (reaction with ammonia or amine with at least one 1# hydrogen)
, with the presence of an acidic or basic substance if necessary,
and/or carried out with heating, for example at 20° to 100°C. Suitable acidic agents include, for example, mineral acids [e.g.
Hydrohalogen acids, e.g. p-Toluenesulfonic acid or vinegar 1% F) 1. Basic hydrolyzing agents are, for example, alkali metal hydroxides or carbonates, such as potassium carbonate, sodium hydroxide or potassium hydroxide, and for alcoholylation, alcoholates such as alkali metal lower alkanolides, such as sodium methane. It's lard.

The starting material (2) can be obtained, for example, as follows: Group -0-alk' having hydroxy X
-X, i.e. a reactive esterified hydroxy and an alkoxy group optionally substituted by an oxo or etherified or esterified hydroxy and optionally interrupted by oxygen, are reacted with each other. .

For example, this is the following expression It is indicated by one of the following.

The reaction of the corresponding compounds (1) and (2) and their preparation are carried out, for example, analogously to the method described in the case of variant e).

The reaction of compound In the case of the reaction with protected 5-halogencarbonyltetrazoles, this is carried out, for example, in the presence of a basic condensing agent, such as a tertiary organic nitrogen base such as triethylamine or pyridine.

The 5-halogencarbonyltetrazole protected in the l-position is preferably treated with an alkali metal hydroxide or alkali metal carbide [e.g. sodium hydroxide or potassium hydroxide] in situ, e.g. optionally! It is prepared by reacting an alkali metal salt, such as the potassium salt of --protected tetrazole-5-carboxylic acid, with oxalyl chloride in the presence of pyridine.

The 1-position protecting group of the 5-tetrazolyl group R2 is
For example, treatment with trifluoro vinegar m/aninur,
It is decomposed by hydrogenolysis, especially using hydrogen and palladium-supported images.

Starting material X is produced, for example, as follows. That is, the formula [where one of the formula φ groups x5 and X6 is optionally a hydroxy+ present in salt form and the other is substituted by a reactive esterified hydroxy.

A hydroxyalkyl group optionally interrupted by oxygen or an epoxyalkyl group optionally interrupted by oxygen, such as the formula %, where X is a reactive esterified hydroxy such as a halogen and Xo is an epoxyethyl group. ) are reacted with each other.

In the resulting compound of formula, the nitro group can be replaced, for example, with a hydrogenation catalyst [
The amine is converted into an amine by reaction with hydrogen, for example in tetrahydrofuran, in the presence of, for example, a palladium-supported image or, in particular, a Raney-Nilakerko.

Variation of the group x8 in the compound h) Formula -NH-C
Conversion of (.0)-R2 into a group is carried out, for example, by reaction with hydronitridic acid.

The reaction of the radical xa of the formula -N)I-C(-0)-CM with hydronitride acid is advantageously carried out by treating the alkali metal azide with an acid such as hydrogen chloride, especially in toluene or a similar solvent. .

The starting material (2) is prepared, for example, as follows: a compound of the formula or an acid addition salt thereof is converted into a compound of the formula NG-COOH (XX
Cyanameisensi of Vlla)
ure) or particularly with its reactive derivatives. Reactive derivatives of acid XXa are in particular Wa derivatives containing esterified or anhydride carboxyl groups 1, such as lower alkoxycarbonyl or halogencarbonyl, such as chlorocarbonyl or bromocarbonyl.

Reactive derivatives of the acid X X W[a include, for example, cyanoformyl chloride or cyanogen.

The reaction of compound X with acid X carried out in the presence of a condensing agent [e.g. a mineral acid (e.g. hydrochloric acid or an alkali hydroxide (e.g. sodium hydroxide or potassium hydroxide) or an alkali metal carbonate] or an organic nitrogen base such as e.g. triethylamine or pyridine). In the case of reactions with anhydrides, for example acid chlorides, it is advantageous to use organic nitrogen bases as condensing agents.The reaction with carboxylic acids is advantageously carried out in the presence of dehydrating agents (ice binders), if desired. The process is carried out in closed containers with cooling or heating, in each case in an inert solvent at the customary temperatures or in the temperature range, for example from about θ° to 100° C., and/or in an inert gas, for example nitrogen.

The compounds of the general formula I obtainable according to the invention can be converted into other compounds of the general formula 1 in a manner known per se.

In this way, for example, free carboxyl groups can be converted in the usual manner, for example to diazo-lower alkanes or tri-lower alkyl oxonium salts, tri-lower alkylcarboxinium 31
1 or di-lower alkylcarbonium salts such as -hexachloroantimonate or -hexafluorophosphate, or in particular lower flukanols or their reactive derivatives [e.g. their carboxylic esters, phosphorous esters, sulfites]. esters or carbonates (e.g. lower alkane carboxylic esters, tri-lower alkyl phosphites or di-lower alkyl sulfites)] to form lower alkoxycarbonyls, or by reaction with ammonia. It can be converted into carbamyl or cyano by dehydration reaction of the carbamyl group.

Lower alkoxycarbonyls, carbamyl or cyano are added in the usual manner, for example as catalysts such as basic or intoxicating agents [e.g. strong bases (e.g. sodium hydroxide or potassium hydroxide) or mineral acids (e.g. hydrochloric acid, sulfuric acid or m%)].
MfllI carboxyl group can be obtained by hydrolysis in the presence of.

Furthermore, in the compounds obtained according to the present invention, substituents can be introduced into the phenyl terminus 8 and/or 1 and/or the existing substituents can be converted into other substituents. That is, lower alkyls are introduced into rings A and/or B by reaction with lower alkyl halides or lower alkanes or lower alkanoic acid halides or lower alkanoic acid anhydrides, in each case in the presence of a Lewis acid such as aluminum trichloride. Lower alkanoyl can be introduced into. Furthermore, halogen can be introduced, for example, by treatment with halogen in the presence of a Lewis acid such as ferric chloride or by reaction with N-chlorosuccinimide. Furthermore, lower alkenyl groups or lower alkynyl groups can be reduced to lower alkyl by treatment with hydrogen, for example in the presence of a hydrogenation catalyst such as palladium on charcoal. Furthermore, halogens such as iodine can be stirred up by trifluoromethyl by reaction with trifluoroiodomethane in the presence of copper or into cyano by reaction with alkali metal cyanides.

Depending on the choice of the starting materials and the method of operation, the novel compounds can be prepared in the form of one of the possible isomers or as a mixture thereof, e.g. as a pure isomer, e.g. as an antipode, depending on the number of asymmetric carbon atoms. Alternatively, it can be present as an isomeric mixture, for example a racemate, a diastereoisomer or a racemic mixture.

The resulting diastereomeric mixtures and racemic mixtures can be separated into pure isomers, diastereomers or racemates in known manner on the basis of the physicochemical differences of the components, for example by chromatography and/or fractional crystallization.

The resulting racemate is further fractionated into its optical counterpart by known methods, for example by recrystallization from an optically active solvent, by microorganisms, or by mixing an acidic crossroad with the racemic acid. By reacting with a salt-forming optically active base and separating the salts thus obtained, e.g. by their different solubility, the diastereomers (from which the enantiomers can be separated into TLl# by the action of suitable agents)
It is advantageous to isolate the more effective one of the two enantiomers that are separated into two groups.

The resulting separated gold compounds of the formula I, in which R2 is carboxy, can be converted into salts by methods known per se, for example with suitable salts of bases or carboxylic acids, usually in the presence of a solvent or diluent. It is made into salt by preparation.

The salts obtained can be converted into M-releasing compounds by methods known per se, for example by treatment with acidic reagents (eg mineral acids).

The compound may also be obtained in the form of its hydrate, including its salts, or may include the solvent used for crystallization.

Due to the close relationship between the new compound in its free form and its salt form, the free compound or its salt mentioned above or below in the specification of the present application may be referred to as the free compound or its salt. 11 also corresponds depending on the situation! 〜M Refers to a compound.

The invention also relates to process embodiments according to which, starting from the compounds obtained as intermediates at any stage of the process, the missing steps are carried out or the starting materials are converted into salts and / or used in racemic or enantiomer form or formed under particular reaction conditions.

The new starting materials and intermediate products occurring in the process according to the invention and its preliminary steps are also subject of the invention.

The compound described as particularly excellent in the above section is fy)
It is effective to use starting materials that are likely to leak and to select reaction conditions as described in "U.

The invention also relates to medicaments containing one of the compounds of formula I according to the invention or a pharmaceutically usable salt thereof. 0-actinic drugs intended for therapeutic or rectal as well as parenteral administration or for inhalation in warm-blooded animals and containing a pharmaceutically active substance alone or together with a pharmaceutically acceptable carrier material. The dosage of the substance depends on the type and age of the warm-blooded animal and on the individual condition and the application method.

The novel medicaments contain, for example, from about 10% to about 85% of the active substance, particularly preferably from about 20% to about 90%. Or in dosage unit form, e.g. sugar-coated tablet 1
It is a preparation in the form of tablets, capsules or herbal medicines as well as ampoules.

The medicaments according to the invention are manufactured in a manner known per se, for example using traditional mixing, granulation, sugar-coating, dissolution or freeze-drying methods. i.e. by combining the active substance with a solid carrier material, optionally granulating the resulting mixture and, if desired or necessary, processing the mixture or granules, after adding suitable auxiliary substances, into tablets or dragee cores. The drug can be obtained for oral use.

Suitable carrier materials are in particular fillers, such as sugars (
e.g. lactose, mannitol or sorbitol), cellulose preparations and/or calcium phosphates (e.g. tricalcium phosphate or calcium hydrogen phosphate)
, and also a binder [e.g. forge starch (e.g. corn-
1 wheat - 1 rice - and potato starch a), gelatin, tragaganth, methylcellulose and/or polyvinylpyrrolidone], and/or if desired disintegrants (Sprengmittel), such as the aforementioned starches, and also carboxymethyl Starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (
for example magnesium stearate or calcium stearate), and/or polyethylene glycol. Auxiliary agents include, first of all, lubricants or lubricants such as silicic acid, talc, stearic acid or salts thereof. Dragee cores are optionally coated with a gastric juice-resistant coating, in which case gum arabic, talc,
Concentrated sugar solutions containing polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures are used, or alternatively suitable cellulose preparations (e.g. acetate) are used to produce gastric fluid-resistant coatings. Dyestuffs or pigments may be added to the tablets or dragee coatings using cellulose phthalate or hydroxypropyl methylcellulose phthalate, for example for the purpose of identifying or characterizing the various active substances.

Still other orally common preparations are nested (hard) capsules made of gelatin and soft sealed capsules consisting of gelatin and a softening agent such as glycerin or sorbitol. Nested hole capsules contain the active substance in the form of granules, for example mixed with filler substances (for example lactose), binders (for example starches) and/or lubricants (for example talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oils or liquid polyethylene glycols, which may also contain stabilizers. You can leave it as is.

Medicaments which can be used rectally include, for example, suppositories, which consist of a combination of active substance and herbal base substance. Suitable as herbal base substances are, for example, natural or synthetic triglycerides, paraffinic hydrocarbons,
Polyethylene glycol or higher alcohol.

Furthermore, gelatin rectal capsules can also be used, which contain a combination of active substance and base substance; base substances include, for example, liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

IIX! For parenteral administration, first of all the active substances in water-soluble form, for example aqueous solutions of water-soluble salts, and also suspensions of the active substances, for example corresponding oily injection suspensions, are suitable. Lipophilic solvents or vehicles such as fatty oils (e.g. sesame oil) or synthetic fatty acid esters (e.g. ethyl oleate) or triglycerides are used, or also thickeners such as sodium-carboxymethylcellulose, sorbitol and/or Alternatively, aqueous injection suspensions containing dextran and optionally stabilizers are used.

Inhalation preparations for the treatment of the respiratory tract by nasal or oral administration are, for example, aerosols or sprays, which may disperse the pharmaceutical active substance in the form of a powder or in the form of droplets of a solution or suspension. can. Preparations with powder-dispersing properties usually contain, in addition to the active substance, a liquid gas with a boiling point below room temperature and, if desired, phase substances such as liquid or solid nonionic or anionic surfactants and/or diluents. Contains. Preparations in which the pharmaceutical active substance is contained in solution also contain suitable laxatives and, if desired, additional solvents and/or stabilizers. Compressed air can also be used instead of fuel gas. In this case, the compressed air can be generated, if necessary, by a suitable compression device and tension relief device.

Medications for topical and topical use are used, for example, for the treatment of skin lesions.
lotions and creams and ointments containing liquid or semi-solid oil-in-water emulsions or wood-in-oil emulsions (in which case they contain e.g. preservatives); or point II+ preparations contained in oily solutions and eye ointments, which are particularly good in the form of 17i-free formulations; for nasal treatments powders, aerosols and sprays (as mentioned above for the treatment of the respiratory tract) ) as well as for nasal sprays containing the active compound in an aqueous or oily solution or for topical treatments in the mouth, which are administered through the nasal passages by rapid inhalation, and the active compound is commonly formed from sugar and gum arabic or tragaganth. Chewable tablets, bonbons and oral tablets containing the active substance in an inert substance consisting of, for example, gelatin and glycerin or sugars and gum arabic, to which a tastant may be added.

The invention likewise relates to the pharmacological use of the novel compounds of formula 1 and their salts as active compounds, in particular allergy agents, in the form of medicaments. The daily dose administered to a warm-blooded animal weighing about 70 kg is about 200 B to about 1200 mg.

The examples described below are intended to illustrate the invention described above, but are not intended to limit the scope of the invention; temperatures are given in degrees Celsius.

1i: N-+3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-4-bromo-6-methyl-phenyl l-1(4- Methoxybenzyl)-Te) Love-
A solution of 12.8 g (19.1 mmol) of 5-carboxamide in trifluoroic acid % 250 st-J and anisole 25- was heated to reflux for 30 minutes. The reaction mixture was evaporated under reduced pressure to give about ether. 300- and petroleum ether 400- were mixed and the crystals were separated by furnace. The thus obtained N-(
3-(3-(4-acetyl-3-hydroxy-2-++
-propylphenoxy)=2-hydroxy-propyloxy1-4-bromo-6-methyl-phenyl)-1H
-Tetrazole-5-carboxamide; 1) 1-NMR
- Spectrum (δ for TMS.

DMSO-ds): 0.85 (triple line, 3H);
1.45 (multiple line.

2H); 2.25 (- double line, -3) 1); 2.55 (
Multiplet, 2H); 2.80 (single line, 3H); 4.
0-4.7 (multiplet, 4)1); 5.90 (multiplet,
1H): 8,65 (double line, 1H), 7.30
(- double line, I) I); 7.55 (- double line, 1H),
7.85 (double line.

1H); 10.75 (- double line, to); 12.8
0 (-double line, 1H): was dissolved in 7 setsone 100- and mixed with an equal volume of triethanolamine in 1 acetone. Crystal formation began after addition of ether. In this way, N-(3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy 1-4-bromo-6 -methyl-phenyl)-1H-tetrazole-5-
A triethanolammonium salt of carboxamide was obtained.

In a similar manner, N-(3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-4-chloro-6-methyl-
Starting from phenyl)-1-(4-methoxybenzyl)-tetrazole-5-carboxamide, N-(3-[3
-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-
4-chloro-6-methyl-phenyl)-1) 1-tetrazole-5-carboxamide, oil, 1H-N,M
R-spectrum (δ for TMS, 0M5O-ds
): 0.85 (triple line, 3H); 1.45 (
Multiplet, 2H); 2.25 (-multiplet, 3H);
2.55 (multiplet, 2H).

2.80 (-multiplet, 3H); 4.0-4.7 (multiplet, 4H).

5.90 (multiplet, 1H); 8.85 (doublet,
1)l), 7.25 (- double line, 1H), 7.35
(-double line, 1H), 7.85 (double line.

1H); 10.70 (- double line, 1H), 12.80 (
- heavy line, 1H) and its triethanol-ammonium salt were obtained.

The starting material is prepared, for example, as follows: 2-furomo 4-methyl-5-nitrophenol 1H
．． 2 g (70 mmol) of a solution in ethanol 130 are reacted with 0.32 g (7.4 mmol) of a 55% strength sodium hydride dispersion. This is followed by adding 4-(2,3-epoxypropoxy)-2-hydroxy-3-propyl-7cetophenone 1H. within 2 hours under reflux. 4g (73
, 539 mol) in 150 d of ethanol was added dropwise. The reaction mixture, which was then heated to reflux for an additional 8 hours, was cooled, concentrated in vacuo to about 1,000 ml, and poured onto ice. The aqueous phase was made acidic with dilute hydrochloric acid and extracted three times with dichloromethane. The combined organic phases were washed with water, dried over sodium sulphate and evaporated in vacuo.

Crystallization from ether gives 3-(3-(4-acetyl-3-hydroxy-2-n-
Propyl-phenoxy)-2-hydro-dipropyloxy]-4-bromo-6-methyl-nitrobenzene was obtained.

In a similar manner, 3-H-(4
-acetyl-3-hydroxy-2-n-propyl-phenoxy)=2-hydroxy-propyloxy]-4-chloro-6-meth/l/-nitrobenzene was obtained (
Starting from 2-di00-4-methyl-5-nitro-phenol).

3-[3-(4-acetyl-3-hydroxy-2-n-
Propyl-phenoxy)-2-hydroxy-propyloxy 1-4-bromo-6-methyl-nitrobenzene 23
．． 3 g (48.3 mmol) in tetrahydrofuran 24
The solution dissolved in 0- is mixed with 2.5 g of Raney nickel and hydrogenated at room temperature. The catalyst was separated in a furnace and washed with tetrahydrofuran. The collected liquid was concentrated in vacuo, reacted with ether, and precipitated crystals were separated in a furnace. Thus 3-13-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy) with melting point 78-80'
-2-hydroxy-propyloxy 1-4-bromo-6
-Methyl-aniline was 1').

Starting from 3-[3-(4-acetyl-3-hydroxy-2-n-7'ropyrufuenoxy)-2-hydroxy-propyloxy 1-4-chloro-6-methyl-nitrobenzene in a similar manner, 3-[3-
(4-acetyl-3-hydroxy-2-n-propyl-
Phenoxy)-2-hydroxy-propyloxy 1-tochloro6-methyl-aniline was obtained.

Potassium-[1-(4-methoxy-benzyl)-tetrazole]-5-carboxilade IO, 8 g (38,8
mmol) in benzene +70 wJ and pyridine 1.
Add oxalyl chloride to the suspension in 5ml at 0-5°3.
After adding 38 g (38.8 mmol) and stirring at room temperature for 30 minutes, the reaction mixture was evaporated and concentrated under reduced pressure, and the remaining liquid was dissolved in Zenzene and again evaporated and concentrated under reduced pressure. Dissolve the residual liquid in dichloromethane +35- and at O-5° within 10 minutes.

3-(3-(4-acetyl-3-hydrocy2-n-
Propyl-phenoxy)-2-hydroxy-propyloxy 1-4-bromo-6-methyl-aniline 12.8
5 g (28.4 mmol) and 2.7 J of pyridine (
3'3 mmol) was added dropwise to a solution in 100 al of dichloromethane.

The reaction mixture, which was then stirred at room temperature for 3 hours, was diluted with dichloromethane and washed three times with water. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The residue was purified with 400 g of silicic acid gel using dichloromethane/ethyl acetate (8:1).
Filtered through. The eluate is concentrated by evaporation and the residue is crystallized from ethanol. Thus melting point 114-11
6°N-(3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-4-bromo-6-methyl-phenyl)-1- (4-methoxybenzyl)-tetrazole-
5-carboxamide was obtained.

Starting from 3-[3-(4-acetyl-3-hydroxy-2-n-7'robirouphenoxy)-2-hydroxy-propyloxy 1-4-chloro-6-methyl-aniline in a similar manner, N-(3-(3-(4-acetyl-3
-Hydroxy-2-n-propyl-phenoxy)-2-
Hydroxy-propyloxy]-4-chloro-6-methyl-phenyl)-1-(4-methoxybenzyl)-tetrazole-5-carboxamide was obtained.

[: N-(3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-2-cyano-phenyl)-1-(
A solution of 1 g (11,8 mmol) of 4-methoxybenzyl)-tetrazole-5-carboxamidore in trifluoroacetic acid 150- and anisole 15-
The reaction mixture, heated to reflux for 0 minutes, was concentrated by evaporation under reduced pressure, mixed with about 200 g of ether and 300 g of petroleum ether, and the crystals were filtered out. The thus obtained N-(3-[3-(<-acetyl-3-hydroxy-2-n-propyl-phenoxy) with a melting point of 21G-213°
-2-hydroxy-propyloxy]-2-cyano-phenyl)-! H-tetrazole-5-carboxamide was hot dissolved in 50 wJ of acetone and mixed with equal amounts of triethanolamine and 20-acetone. Crystallization started after the addition of ether. In this way, N with a melting point of 80-82°
i3-[3-(4-acetyl-3-hydroxy-2-n
The triethanolammonium salt of -propyl-phenoxy)-2-hydroxy-propyloxy 1-2-cyano-phenyl)-1H-tetrazole-5-carpoxamide was obtained.

The starting material was obtained, for example, as follows: 34 g of 2-hydroxy-6-nitropenzonitrile (0,207
30 drops of Triton B were added to a solution of 60 g of 4-((2,3-epoxy)propyloxy]-2-hydroxy-3-propyl-7cetofonone in 450 T, l of dimethylformamide. The solution was heated to reflux for 1.5 hours to separate the solvent and the residue was dissolved in 500 ml of ethyl acetate. After washing with 500 ml of 0.5N caustic soda solution and 500 ml of water, it was washed over magnesium sulfate. Dry. The solvent is evaporated and the residue is chromatographed on silicic acid gel with methylene chloride/ethyl acetate (95:5). Melting point +17-
119° of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propoxy 1-6-nitropenzonitrile was obtained.

2-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy-propoxy]-
To a solution of 10 g (24.2 mmol) of 8-nitro-benzonitrile and 10 g of cyclohexene in 500 g of ethanol was added 2.5 g of 10% palladium on charcoal and heated under reflux for 30 minutes. After cooling to room temperature, the filtered solvent was evaporated. The residue was mixed with ether and precipitated.

The crystals were separated by furnace. 3-[3- with melting point 123-125°
(4-acetyl-3-hydroxy-2-11-7'robirufuenoxy)-2-hydroxy-propyloxy]
-2-cyano-aniline was obtained.

Potassium-[1-(4-methoxy-benzyl)-tetrazole]-5-carpoxylate) 5.8 g (21,
5 mmol) of benzene 1101IJ and pyridine 1
．． Oxalyl chloride at a temperature of 0-5° into suspension in 0d 1.
84. After addition of J (21.5 mmol) and stirring at room temperature for 30 minutes, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in benzene and concentrated again under reduced pressure. The residue was dissolved in 80°C of methylene chloride and heated at 0-5° for about 10°C.
Within minutes 3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
5.87 g of propyloxy 1-2-cyano-aniline (
17.2 mmol) and pyridine 1.72d (21
, 5 mmol) in methylene chloride, the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phases were combined, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in methylene chloride/ethyl acetate (8:
1) was subjected to chromatography using silicic acid gel as a developing solution. N-(3-[3-(4-acetyl-3-
hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-2-cyano-phenyl)
-1-(4-methoxybenzyl)-tetrazole-5-
The carboxamide was obtained as a colorless oil.

l: 2-fluoro-4-methyl-5-nitro-phenol, 4-methyl-5-nitro-phenol or 2-hydroxy-5-phenol in a similar manner to that described in Examples 1-2.
Starting from methyl-4-nitro-pentonitrile, N-
(3-(3-(4-acetyl-3-hydroxy-2-n
-propyl-phenoxy)-2-hydroxy-propyloxy]-4-fluoro-6-methyl-phenyl)-1
H-tetrazole-5-carboxamide; 1H-NM
R-spectrum (δ for TMS, DMSO-ds
): 0.85 (triple line, 3) 1); 1.45 (
Multiplet, 21(), 2.25(-multiplet, 3H).

2.55 (multiplet, 2H); 2.60 (-multiplet,
3H), 4.0-4.7 (multiperpendicular, 4H), 5.9
0 (multiple line, l), 6.85 (double line, 1H)
; 7.25 (-double line, 1H); 7.85 (-double line, 1H).

7.85 (double line, 1H); 10.70 (-double line,
1H), 12.80 (- double line, 1H); and its triethanolammonium salt, N-(3-[3"(4-
1H-NMR-spectrum (δ for TMS,
DMSO-da): 0.85 (triple line, 3H).

1.45 (multiplet, 2H): 2.25 (-multiplet,
3H); 2.55 (multiplet, 2H); 2.80(
- multiplet, 3H); 4.0-4.7 (multiplet.

4H), 5.90 (multiplet, 1)1); 8.80
(Multiplet, 2H).

7.10 (double line, 1H), 7.80 (multiple line,
2H); 10.70 (- double line, 1)I), 12.80
(- double line, 1H); and its triethanolammonium salt and N-(3-[3-(4-acetyl-3
-Hydroxy-2-n-propyl-phenoxy)-2-
hydroxy-propyloxy]-4-cyano-6-methyl-phenyl)-1H-tetrazole-5-carboxamide, 1H-NMR-spectrum (↑δ vs. MS
, DMS(lds): 0.85 (triple line, 3
H); 1.45 (multiplet, 2H); 2.25 (
- multiplet, 3H); 2.55 (multiplet, 2H); 2.
80 (-multiplet, 3H), 4.0-4.7 (multiplet,
4H); 5.90 (multiplet, 1H); 8.65 (
Double line, 1H), 7.30 (- double line, 1H);
7.45 (-double line, 1H), 7.85 (double line,
1H).

10.70 (-double line, 1)l), 12.80 (-double line, 1H); and its triethanolammonium salt were obtained.

[4: N-(3-[3-(4-7cetyl-3-hydroxy-2-n-propyl-phenoxy)-2-droxypropyloxy 1-6-methyl-phenyl 1-1H
4.9 g of -tetrazole-5-carboxamide was dissolved in A7TONE 45- and mixed with a solution of 1.0 g of jetanolamine in A7TONE 5-. Crystallization began upon addition of ethyl ether. Leave it at 5-10' for 30 minutes, then remove the suction and wash with diethyl ether. ? Dry in a 1L room. N-(3-[3-
(4-acetyl-3-hydroquine-2-n-propyl-
phenoxy)-2-hydroxy-propyloxy 1-8
-Methyl-phenyl)-1totitrazole-5-carboxamide was obtained.

In a similar manner its sodium and potassium salts.

Diethylammonium salt and tris(hydroxymethyl)-methylammonium salt could be produced.

Furthermore, in a similar manner, N-(3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy1-2-cyano-phenyl)-1) -tetrazole-5-carboxamide, N-(3-(3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-4-bromo-8-methyl-phenyl )-1H-tetrazole-5-carboxamide, N
-(3-[3-(4-acetyl-3-hydroxy-2-
n-propyl-phenoxy)-2-hydroxy-propyloxy-1-4-chloro-6-methyl-phenyl)-1
H-tetrazole-5-carboxamide, N-(3-[
3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy 1
-4-fluoro-6-methyl-phenyl)-1H-tetrazole-5-carboxamide and N-+3-[3
-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy1-
4-cyano-θ-methyl-phenyl}-1H-tetrazole-5-carboxamide sodium 31, potassium salt, jetanolammonium salt and tris(hydroxymethyl)methyl-ammonium I! 1 was fled.

L! : active substance e.g. N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-
Hydroxy-propyloxy 1-4-bromo-6-methyl-phenyl)-! Tablets containing triethanolammonium fix 25B of H-tetrazole-5-carboxamide could be prepared as follows (1000 tablets): Active substance 25.0 g lactose (
Lactose > 100.7g wheat starch 7.5g polyethylene glycol eooo 5. Og powder talc
5.0g Magnesium stearate
1.88 deionized water
Superfluid-L"L: All solid components are first mixed with a mesh size of 6-■
The active substance, lactose, powdered talcum, magnesium stearate and half of the starch were then mixed together. The other half of the starch was suspended in 4° of water, this suspension was added to a boiling solution of polyethylene glycol in 100° of water, and the mixture was granulated with addition of water if necessary. Dry the granules overnight at 35° until the mesh size is 1.2.
The mixture was filtered through a 11 sieve and compressed into tablets with a diameter of 8 m and concave on both sides.

In a similar manner it was also possible to prepare tablets each containing 25 mg of the other compounds of formula I mentioned in Examples 1 to 4.

active substance, e.g. N-+3- [3-(4-acetyl-3=hydroxy-2-n-propyl-phenoxy)
-2-hydroxy-propyloxy]-4-bromo-6
-Methyl-phenyl)-1) 1-tetrasol-5-carboxamide triethanolammonium 1130g
Chewable tablets containing the following can be manufactured, for example, as follows:
179.5g powder side (talc) 20.0g glycine
12.5g stearic acid
10.0g saccharin 1
．． 0g5χ gelatin solution appropriate amount m
First, sieve all the solid components through a sieve with a mesh size of 0.25 mm, mix mannitol and lactose, granulate it while adding gelatin solution, sieve through a 2 mm sieve, and dry again at 50 mm. Carefully mix the active ingredients, glycine and saccharin and add the mannitol, lactose, granules and powdered talc. Mix the whole thoroughly and reduce the diameter of the concave surfaces on both sides to about low.
It was pressed into a tablet having grooves on the upper surface.

In a similar manner it was also possible to prepare tablets each containing 30 mg of other compounds of the formula I as described in Table 4.

fLZ: agent e.g. N-(3-[3-(4-7-1
= thyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy-propyloxy 1-4-bromo-
8-Methyl-phenyl)-1H-tetrazole-5-carboxamide triethanolammonium salt 100+
Tablets containing sg can be manufactured as follows.

Issei-4 (1000 tablets): Active substance 100.0g lactose
248.5g corn starch 17.5g polyethylene glycol 6000 5. Ogg end talc
15.0 [Magnesium stearate
4.0 g deionized water Quantity - Preparation - L: The solid ingredients are first strained through a sieve with a mesh size of 0.6 mm. Then the active substance, lactose, powdered talc, magnesium stearate and starch are mixed intimately. The other half of the starch is suspended in 65° of water and this suspension is added to a boiling solution of polyethylene glycol in 260° of water.

Add the resulting paste to the powdered substance and mix the whole thing,
If it felt safe, granulation was carried out while adding water. The granules were dried at 35° overnight and filtered through a sieve with a mesh size of 1.2 mm, approximately 10 m in diameter.
Press I into a tablet with concave shapes on both sides and notches on the top surface.
li! Molded.

Other compounds 10 of formula I according to Examples 1 to 4 in a similar manner
Tablets containing 0 mg can also be manufactured.

[: To(3-(3-(4-7cetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxy-propyloxy1-4-bromo6-methyl-phenyl1-
A propellant-containing solid aerosol-forming inhalable suspension containing 1H-tetrazole-5-carboxamide (active substance) Q, 1% can be prepared, for example, as follows: ): Active substance (micronized) 0.111% “°
Sorbitan trioleate °' 0.5 beads 2a%h
'The active substance is removed using a Tingtong homogenizer (
The suspension is suspended in trichlorotrifluoroethane with the addition of sorbitan oleate using a homogenisator, the suspension is metered into an aerosol container, the container is closed and the dichlorodifluoromethane-dichlorotetrafluoroethane mixture is added under pressure. Fill it.

Inhalable suspensions containing other compounds of formula I according to Examples 1 to 7 can also be prepared in an analogous manner.

■ = N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-
An approximately 2% aqueous solution suitable for inhalation of the triethanolammonium salt of hydroxy-propyloxy 1-4-bromo-6-methyl-phenyl)-1H-tetrazole-5-carboxamide can be prepared, for example, with the following composition: Take-” = (1000 tablets): Active substance? ! 2000 ra
g Stabilizer 1 For example, ethylenediaminetetraacetic acid-dinatrium

I O 11g Preservative (preservative), such as 1! benzalkonium chloride 1011g water (
(freshly distilled) gold amount 1004 m: The active substance is dissolved in freshly distilled water. Stabilizers and preservatives are then added. After all the components have completely dissolved, the resulting solution is made into a 100% solution and is filled into a vial, which is closed airtight.

Containing other active substances of Examples 1 to 4 in a similar manner
A 2% inhalable solution can also be prepared.

fLL! 2: N-(3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)) suitable for blowing method
-2-hydroxy-propyloxy]-4-bromo-6
-Methyl-phenyl l-1H-tetrazole-5-carboxamide triethanolammonium 11! Approximately 25
Capsules containing 111 g as active substance can be produced, for example, with the following composition (1000 tablets): Active substance 25 g lactose (ground into a fine powder) 25 g Mix the substance and lactose intimately.

The resulting powder is then sieved and filled into 1000 gelatin capsules, each weighing 50 mg.

Insufflable capsules can also be produced in a similar manner, each containing an active substance according to any one of Examples 1 to 4.

Claims (1)

[Claims] 1. Formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I), [In the formula, R^1 means lower alkyl, and alk optionally represents a hydroxyalkylene group interrupted by oxygen. and R^2 represents 5-tetrazolyl, in which ring A is additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and/or halogen, and ring B is additionally lower alkyl, lower alkanoyl. , lower alkoxy, lower alkoxycarbonyl, carboxy, cyano, carbamyl, halogen and/or trifluoromethyl]
Novel 4-acyl resorcin ethers and salts thereof. 2. Formula I, [wherein R^1 represents lower alkyl,
alk represents hydroxy lower alkylene, hydroxy (oxa) lower alkylene, or hydroxy (dioxa) lower alkylene (in this case, the hydroxy group is higher than the α position and lower than the ω position with respect to the free valence (bond), and the free higher than the β-position relative to the valence and (ω-
1) bonded at a position higher than the β-position to an oxa member that is optionally present at a lower position), and R^2
represents 5-tetrazolyl, in which ring A is additionally represented by lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy and/or halogen, and ring B is additionally represented by lower alkyl, lower alkanoyl, lower alkoxy, lower The compound according to claim 1, which is optionally substituted with alkoxycarbonyl, carbamyl, carboxy, cyano, halogen and/or trifluoromethyl, and its salt. 3. Formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I a), or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I b), [However, in the formula, R_1 is lower alkyl having 4 or less carbon atoms. , R_2 means 5-tetrazolyl, R
_3 represents lower alkyl having up to 4 carbon atoms, R_4 is hydrogen, lower alkyl having up to 4 carbon atoms,
lower alkoxy with up to 4 carbon atoms or 35
Represents halogen with the following atomic numbers, R_5 represents hydrogen, lower alkyl with up to 4 carbon atoms, halogen or trifluoromethyl with atomic number up to 35, R_6 represents hydrogen, with up to 4 carbon atoms. R_7 represents hydrogen, lower alkyl with up to 4 carbon atoms, lower alkoxy with up to 4 carbon atoms, cyano or halogen with an atomic number of up to 35; represents lower alkoxycarbonyl, carboxy, cyano having up to 5 carbon atoms or lower alkanoyl having up to 7 carbon atoms, alk is a terminally attached hydroxy lower alkylene having 3 or 4 carbon atoms; 2. The compound according to claim 1, and its salt, wherein the free valence is emanating from a carbon atom located at the β position with respect to a hydroxyl group. 4, Formula I a (wherein R_1 represents a lower alkyl having up to 4 carbon atoms, R_3 represents a straight chain lower alkyl having up to 4 carbon atoms, R_2 represents 5-tetrazolyl, R_4 is hydrogen, R_5 means lower alkyl, R_6 represents hydrogen, R_7 is hydrogen,
represents a halogen or cyano having an atomic number of up to 35, alk being a straight-chain terminally attached hydroxy lower alkylene with 3 or 4 carbon atoms, in which the free valence is in the β position relative to the hydroxy group; The compound according to claim 1 and its salt with a base. 5, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
propyloxy]-4-bromo-6-methyl-phenyl}-1H-tetrazole-5-carboxamide or a salt thereof. 6, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
propyloxy]-2-cyano-phenyl}-1H-tetrazole-5-carboxamide or a salt thereof. 7, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
propyloxy]-6-methyl-phenyl}-1H-tetrazole-5-carboxamide or a salt thereof. 8, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
propyloxy]-4-chloro-6-methyl-phenyl}-1H-tetrazole-5-carboxamide or a salt thereof. 9, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-
propyloxy]-4-fluoro-6-methyl-phenyl}-tetrazole-5-carboxamide or a salt thereof. 10, N-{3-[3-(4-acetyl-3-hydroxy-2-n-propyl-phenoxy)-2-hydroxy-propyloxy]-4-cyano-6-methyl-phenyl}-tetrazole-5 - Carboxamide or its salt. 11. Compounds according to any one of claims 1 to 10 in the form of sodium, potassium, triethanolammonium, diethanolammonium or tris(hydroxymethyl)methylammonium salts. 12. A medicament containing a compound according to any one of claims 1 to 11 in addition to the customary auxiliaries and carrier substances. 13. Formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (However, in the formula, R_1 means lower alkyl, alk represents a hydroxyalkylene group optionally interrupted by oxygen, and R_2 represents 5-tetrazolyl. , in this case ring A
is additionally lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, and/or halogen, and Ring B is additionally lower alkyl, lower alkanoyl, lower alkoxy, lower alkoxycarbonyl, carboxy, cyano, carbamyl, halogen and A method for producing a new 4-resorcin ether and its salts (which may be substituted with / or trifluoromethyl), comprising: a) rearrangement (umlagern ), or b) a compound of the formula ▲mathematical formula, chemical formula, table, etc.▼(III), (wherein X_1 represents an optionally etherified hydroxy), or b) a compound of the formula R_1-X_2(IV) ( (However, X_2 in the formula means functionally converted carboxy as the case may be) or c) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. In the compound of the formula R_1-C (representing a group that can be changed to a group of =O)-, X_3 is changed to this group, or d) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI), (However, in the compound where X_4 represents a group that can be changed to hydroxy), X_4 is changed to hydroxy, or e) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) and ▲ Mathematical formulas, chemical formulas , tables, etc.▼(VIII) (However, among the groups X_5 and replaced,
or f) the formula ▲ is a mathematical formula, chemical formula, table, etc. ▼ (IX), (However, in the formula, the alk' group represents a group that can be changed to alk.) In the compound, alk' is changed to the group alk, or g) A compound of the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X) or reacting the salt thereof with a compound of the formula Or h) Compound of formula ▲ Numerical formula, chemical formula, table, etc. ▼ (XII) (wherein X_8 represents a group that can be converted into the desired group of formula -NH-C(=O)-R_2) In, X_
8 into this group and, if desired, convert the compounds obtained by the process of the invention into other compounds of formula I and/
or a salt of the compound obtained by the method according to the invention;
Alternatively, a production method characterized in that the salt obtained by the method according to the invention is converted into a free compound or into another salt.