HK1077818A1 - Anticholinergic agents, method for producing the same and use thereof as medicaments - Google Patents

Abstract

The invention relates to novel anticholinergic agents of general formula (1), in which X - and the groups A, B, R, R1, R2, R3, R3', R4, R4', Rx and Rx' can be defined as per the claims and the description. The invention also relates to a method for producing said agents and to the use thereof as medicaments.

Description

Anticholinergic agents, method for the production thereof and use thereof as medicaments

Technical Field

The invention relates to the general formula1Novel anticholinergic agents

Wherein X^-And A, B, R, R¹、R²、R³、R^3′、R⁴、R^4′，R^XAnd R^X′The radicals have the meanings given in the claims and the description, processes for their preparation and their use as medicaments.

Disclosure of Invention

The invention relates to the general formula1Compound (I)

Wherein

X^-An anion having a single negative charge, preferably an anion selected from the group consisting of: chloride ion, bromide ion, iodide ion, sulfate radical, phosphate radical, methane sulfonate radical, nitrate radical, maleate radical, acetate radical and citrate radicalCitrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate;

a and B, which may be the same or different, preferably the same, represent-O, -S, -NH, -CH₂-CH-or-N (C)₁-C₄-alkyl) -;

r represents hydrogen, hydroxy, -C₁-C₄-alkyl, -C₁-C₄-alkoxy, -C₁-C₄Alkylene-halogen, -O-C₁-C₄Alkylene-halogen, -C₁-C₄alkylene-OH, -CF₃、CHF₂、-C₁-C₄alkylene-C₁-C₄-alkoxy, -O-COC₁-C₄-alkyl, -O-COC₁-C₄Alkylene-halogen, -C₁-C₄alkylene-C₃-C₆-cycloalkyl-, -O-COCF₃Or halogen;

R¹or R²May be the same or different and represents C₁-C₅-alkyl, which may optionally be substituted by C₃-C₆-cycloalkyl, hydroxy or halogen substitution;

or

R¹And R²Together represent-C₃-C₅-an alkylene bridge;

R³、R⁴、R^3′and R^4′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Or halogen;

R^Xand R^X′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Or halogen;

or

R^XAnd R^X′Together represent a single bond or a bridging group selected from: -O, -S, -NH, -CH₂、-CH₂-CH₂-、-N(C₁-C₄-alkyl) -, -CH (C)₁-C₄-alkyl) -, and-C (C)₁-C₄-alkyl groups)₂。

Preferred general formula1The compound is

X^-Is an anion having a single negative charge selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide;

a and B may be the same or different, preferably the same, and represent-O, -S, -NH or-CH ═ CH-;

r represents hydrogen, hydroxy, -C₁-C₄-alkyl, -C₁-C₄-alkoxy, -CF₃、-CHF₂Fluorine, chlorine or bromine;

R¹and R²May be the same or different and represents C₁-C₄Alkyl, which may optionally be substituted by hydroxy, fluorine, chlorine or bromine,

or

R¹And R²Together represent-C₃-C₄-an alkylene bridge;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Fluorine, chlorine or bromine;

R^Xand R^X′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Fluorine, chlorine or bromine;

or

R^XAnd R^X′Together represent a single bond or a bridging group selected from: -O, -S, -NH-, and-CH₂-。

Particularly preferred compounds of the formula1The compound is

X^-Represents an anion having a single negative charge selected from chloride, bromide and methanesulfonate, preferably bromide;

a and B, which may be the same or different, preferably the same, represent-S or-CH ═ CH-;

r represents hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, -CF₃Or fluorine;

R¹and R²May be the same or different and represents methyl, ethyl, -CH₂F or-CH₂-CH₂F, preferably methyl or ethyl;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, methyl, methoxy, -CF₃Or fluorine;

R^Xand R^X′May be the same or different and represents hydrogen, methyl, methoxy, -CF₃Or fluorine;

or

R^XAnd R^X′Together represent a single bond or a bridging group-O-.

Of particular interest according to the invention are the formulae1The compound is

X^-Represents an anion having a single negative charge selected from chloride, bromide and methanesulfonate, preferably bromide;

a and B, which may be the same or different, preferably the same, represent-S or-CH ═ CH-;

r represents hydrogen, hydroxy or methyl;

R¹and R²May be the same or different and represents a methyl group or an ethyl group;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, -CF₃Or fluorine, preferably hydrogen;

R^Xand R^X′May be the same or different and represents hydrogen, -CF₃Or fluorine, preferably hydrogen;

or

R^XAnd R^X′Together represent a single bond or a bridged group-O-.

Also preferred according to the invention are those of the formula1A compound of which

X^-Represents a bromide ion;

a and B represent-CH ═ CH —;

r represents hydrogen, hydroxy or methyl;

R¹and R²Represents a methyl group;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen or fluorine, preferably hydrogen;

R^Xand R^X′May be the same or different and represents hydrogen or fluorine, preferably hydrogen;

or

R^XAnd R^X′Together represent a single bond or a bridging group-O-.

The invention relates to the formula optionally in the form of individual optical isomers, mixtures or racemates of the individual enantiomers and optionally in the form of their pharmaceutically acceptable acid addition salts1A compound is provided.

In the general formula1In the compound, R³，R⁴，R^3′And R^4′When the radicals are other than hydrogen, in each caseCan be arranged in ortho, meta or para position relative to the "-C-R" group. If R is³，R⁴，R^3′And R^4′When none of the radicals represents hydrogen, R³And R^3′Preferably in para position and R⁴And R^4′Preferably in ortho or meta position, most preferably in meta position. If R is³And R⁴And R is^3′And R^4′One of the radicals represents hydrogen, the other radical is preferably bonded in each case in the meta or para position, preferably in the para position. If R is³，R⁴，R^3′And R^4′When none of the radicals represents hydrogen, then wherein R³，R⁴，R^3′And R^4′Radicals having the same meaning as1Compounds are particularly preferred according to the invention.

Of particular interest according to the invention are compounds of the formula1Wherein the two rings containing A and B are arranged such that A and B are in the ortho configuration, respectively, relative to the linkage of the "-C-R" carbon. This preferred configuration is particularly important when a and B do not represent-CH ═ CH-. These compounds correspond to the general formulaOrtho-1

Of particular interest according to the invention are compounds of the formula1Wherein a represents-CH ═ CH-and B represents-CH ═ CH-. These compounds correspond to the general formula1

Of particular interest according to the invention are compounds of the formula1Wherein the ester substituent on the azabicyclo is a compound in the alpha configuration. These compounds correspond to the general formula1-α

Preferred formulae according to the invention1Wherein the two rings containing A and B are arranged such that the bonds of A and B with respect to the carbon "-C-R" are each in the ortho configuration and wherein the ester substituent on the azabicyclo group is in the alpha configuration corresponds to the general formulaOrtho-1-alpha

Particularly preferred formulae according to the invention1Compounds in which a represents-CH ═ CH-and B represents-CH ═ CH-, and in which the ester substituents on the azabicyclic ring are in the alpha configuration correspond to the general formula1-α

The following compounds are of particular interest according to the invention:

-cyclopropylscopolamine (cyclopropyraponine) benzhydrylacetate methyl bromide;

-cyclopropyl scopolamine methyl bromide 2, 2-diphenylpropionate;

-9-hydroxy-xanthene-9-carboxylic acid cyclopropylhyoscyamine ester methyl bromide;

-9-methyl-fluorene-9-carboxylic acid cyclopropylscopolamine ester methyl bromide;

-4, 4' -Difluorodiphenyl glycolic acid methyl ester cyclopropyl scopolamine ester methyl bromide.

The alkyl groups used, unless otherwise specified, are branched or straight chain alkyl groups having from 1 to 4 carbon atoms. Examples thereof include: methyl, ethyl, propyl or butyl. The radicals methyl, ethyl, propyl or butyl and the like may optionally also be abbreviated as Me, Et, Prop or Bu. Unless otherwise indicated, the definition of propyl and butyl also includes all possible isomeric forms of the radicals mentioned. Thus, for example, propyl includes n-propyl and isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl, and the like.

The cycloalkyl groups used, unless otherwise specified, are alicyclic groups having 3 to 6 carbon atoms. These are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. According to the invention, cyclopropyl is of particular importance within the scope of the invention.

The alkylene groups used, unless otherwise specified, are branched or straight chain two-bonded alkyl bridges having from 1 to 4 carbon atoms. Examples thereof include: methylene, ethylene, propylene or butylene.

The alkylene-halogen radicals used, unless otherwise stated, are branched or unbranched two-bonded alkyl bridges of 1 to 4 carbon atoms which may be substituted by one, two or three, preferably two, halogens. Accordingly, unless otherwise indicated, the term alkylene-OH group denotes a branched or unbranched two-bonded alkyl bridge having 1 to 4 carbon atoms which may be mono-, di-or trisubstituted, preferably monosubstituted, by hydroxy.

The alkoxy groups used, unless otherwise stated, are branched or straight-chain alkyl groups having from 1 to 4 carbon atoms, bonded via oxygen atoms. The following are examples that may be mentioned: methoxy, ethoxy, propoxy or butoxy. Methoxy, ethoxy, propoxy or butoxy groups and the like are also optionally abbreviated as MeO-, EtO-, PropO-or BuO-. Unless otherwise indicated, propoxy and butoxy groups also include all possible isomeric forms of the groups described. Thus, for example, propoxy includes n-propoxy and isopropoxy, and butoxy includes isobutoxy, sec-butoxy and tert-butoxy, and the like. In the context of the present invention, the term alkoxy (alkoxy) may also be used instead of alkyloxy (alkoxy). The methyl, ethyl, propyl, or butyl oxy group may also be optionally referred to as methoxy, ethoxy, propoxy, or butoxy.

The alkylene-alkoxy radicals used, unless stated otherwise, are branched or unbranched two-bonded alkyl bridges of 1 to 4 carbon atoms which may be mono-, di-or trisubstituted, preferably monosubstituted, by alkoxy radicals.

the-O-CO-alkyl groups used, unless otherwise stated, are branched or straight-chain alkyl groups having from 1 to 4 carbon atoms, bonded via ester groups. The alkyl group may be bonded directly to the carbonyl carbon of the ester group. The term-O-CO-alkyl-halogen should also be understood analogously. -O-CO-CF₃Represents trifluoroacetate.

In the context of the present invention, halogen is fluorine, chlorine, bromine or iodine. Fluorine and bromine are preferred halogens unless otherwise indicated. The CO group represents a carbonyl group.

As explained hereinafter, the compounds of the invention can be prepared by methods which are in part analogous to those known in the art (scheme 1). Formula (II)3The carboxylic acid derivatives of (a) are known in the art or can be obtained by synthetic methods known in the art. If only appropriately substituted carboxylic acids are known in the art, the formula3The compounds can also be obtained directly by acid-or base-catalyzed esterification using the corresponding alcohols or by halogenation with the corresponding halogenating agents.

Slave type2Starting from compounds of the general formula4Can be prepared by reaction with an ester of formula (II)3Wherein R' represents, for example, chlorine or C₁-C₄-alkoxy groups. When R' is equal to C₁-C₄Alkoxy, this reaction may be carried out, for example, in a sodium melt at an elevated temperature, preferably from about 50 to 150 ℃ and more preferably from about 90 to 100 ℃ and at a reduced pressure, preferably below 500 mbar and most preferably below 75 mbar. In addition, in place of wherein R represents C₁-C₄Alkoxy derivatives 3, the corresponding acid chlorides (R ═ Cl) may also be used

Scheme 1:

thus obtained formula4The compounds can be prepared by reacting with a compound R²-X (wherein R²And X may have the abovementioned meaning) to the formula1The subject compound of (1). This synthesis can also be carried out using synthesis examples similar to those disclosed in WO 92/16528. At R¹And R²In the case where they together form an alkylene bridge, as will be appreciated by those skilled in the art, no further addition of reagent R is required²-X. In this case, formula (II)4The compound containing an appropriately substituted R according to the above definition¹Radical (e.g. C)₃-C₅Alkylene-halogen) and of formula1The compounds may be prepared by intramolecular quaternization of amines.

Or, formula (la) wherein R represents halogen4The compounds may also be prepared by the method shown in scheme 2.

For this purpose, the compounds of the formula (I) in which R represents a hydroxyl group are halogenated using suitable halogenating agents4Conversion of a compound to a compound of formula (la) wherein R represents halogen4A compound is provided. The methods used for the halogenation reaction carried out according to scheme 2 are well known in the art.

Scheme 2:

as understood in scheme 1, of the general formula4The intermediate products are of major importance. Thus, in another aspect, the invention relates to formula (la)4Intermediates

Wherein A, B, R¹，R³，R^3′，R⁴，R^4′，R^XAnd R^X′May be as defined above, optionally in the form of an acid addition salt thereof.

By acid addition salt is meant a salt selected from: hydrochloride, hydrobromide, hydroiodide, hydrogen sulphate, hydrogen phosphate, hydrogen methanesulphonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate, and p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrogen sulphate, hydrogen phosphate, hydrogen fumarate and hydrogen methanesulphonate.

As in the general formula1In the compound of formula (II)4In the compound, R³，R⁴，R^3′And R^4′When the radicals do not represent hydrogen, they may be arranged in each case in ortho, meta or para position relative to the bond of the "-C-R" group. R³，R⁴，R^3′And R^4′When none of the radicals represents hydrogen, then R³And R^3′Preferably in the para position and R⁴And R^4′Preferably in the ortho-or meta-position, particularly preferably in the meta-position. Such as R³And R⁴One of the two radicals and R^3′And R^4′One of the two radicals represents hydrogen, the other radical is preferably each bonded in the meta or para position, preferably in the para position. Such as R³，R⁴，R^3′And R^4′When none of the groups represents hydrogen, the general formula is particularly preferred for the present invention4The compound is wherein R³，R⁴，R^3′And R^4′The radicals have the same meaning.

As can be seen from scheme 1, the formula2The compound is used as a starting material to prepare the compound of formula1A compound is provided. These compounds are not known in the prior art. Thus, in another aspect, the invention also relates to compounds of the general formula2Compound (I)

Wherein

R¹Represents hydrogen or-C₁-C₅-alkyl, which may optionally be-C₃-C₆-cycloalkyl, hydroxy or halogen substituted, optionally in the form of an acid addition salt thereof.

By acid addition salt is meant a salt selected from: hydrochloride, hydrobromide, sulfate, phosphate, fumarate and methanesulfonate.

Preferred general formula2The compound is a compound of formula (I) wherein,

R¹represents hydrogen or-C₁-C₄-alkyl, which may be optionally substituted by hydroxy, fluoro, chloro or bromo, optionally in the form of an acid addition salt thereof.

Particularly preferred compounds of the formula2A compound of which

R¹Represents hydrogen, methyl, ethyl, -CH₂F or-CH₂-CH₂F, preferably methyl or ethyl, optionally in the form of its acid addition salts.

Of particular interest according to the invention are the formulae2The compound is

R¹Represents hydrogen, methyl or ethyl, optionally in the form of their acid addition salts.

Are also preferred according to the invention of the general formula2The compound is

R¹Represents hydrogen or methyl, optionally in the form of an acid addition salt thereof.

Preference is given according to the invention to using the formula in the alpha configuration2The compound is used as a starting material. The alpha-configuration compounds are therefore of particular importance according to the invention and correspond to the general formula2-α

R in the general formula 2-alpha¹The compound of the group methyl is hereinafter referred to as cyclopropylscopolamine. The alcohol group is considered to be that in the alpha position where the cyclopropyl group has the exo (exo) -configuration (cyclopropylscopine-exo-cyclopropyl-alpha-scopolamine), the alpha-configured compound is optionally also referred to as pseudocyclopropylscopolamine and the endo (endo) isomer is referred to as endo-cyclopropylscopolamine.

In another aspect, the invention relates to compounds of the formula2The compound is prepared by the following general formula4The use of the compounds. Furthermore, the present invention relates to the general formula2The compound is used for preparing the general formula1Use of a compound starting material.

General formula (VII)2The compounds can be prepared from the corresponding Tropenol derivatives in analogy to the methods known from the prior art. Suitable cyclopropylating agents include, for example, diazomethane.

The following synthetic examples are presented to further illustrate the invention. However, they are only to be regarded as examples of the method for further illustration of the invention, and do not limit the invention to the description set out below.

Preparation of compounds of general formula 2:

cyclopropyl scopolamine 2 a:

100 ml of diethyl ether were covered with 35 ml (0.35 mol) of 40% aqueous potassium hydroxide solution and cooled in an ice bath. To this, 23.64 g (0.101 mol) of N-methyl-N-nitrosourea was added in portions, and the mixture was stirred for about 10 minutes. The ether phase was decanted off and the resulting solution was used in the next step.

25 ml of the diazomethane solution prepared above were added to a solution of 4.01 g (0.028 mol) of scopoletin in 25 ml of ether and 5 ml of methanol while cooling with an ice bath. Then 53.4 mg (0.000139 mol) of bis (benzonitrile) dichloro-palladium (II) were added. Then 28 ml of diazomethane solution are added in portions. After about 1.5 hours, the solvent was distilled off in vacuo, the residue was extracted, the solution was filtered and the solvent was distilled off.

Yield: 4.25 g of yellowish crystals 2a (═ 96% of theory)

Example 1: methyl bromide cyclopropyl scopolamine Diphenyl Ethanolamine:

1.1: methyl benzilate 3 a:

90 g (0.394 mol) of diphenylethanolic acid are dissolved in 900 ml of acetonitrile and 109.6 g (0.72 mol) of DBU are added dropwise at 5 ℃. After addition of 204.4 g (1.44 mol) of methyl iodide, the mixture was stirred at ambient temperature (about 20-23 ℃ C.) for 24 hours. The solution was evaporated to dryness to a residue, which was dissolved in ether and washed with water. The organic phase was washed with 5% aqueous sodium carbonate solution and water in that order, dried and the solvent distilled off. Recrystallization from cyclohexane purified the product. Yield: 77.19 g of white crystals (═ 81% of theory). Melting point: 74-76 deg.C

1.2: 4a of cyclopropyl hyoscyamine diphenoxylate:

5.34 g (0.022 mol) of methyl benzilate3a1.53 g (0.01 mol) 2a and 0.25 g (0.01 mol) sodium were heated in the melt for 1 hour on a 75 mbar boiling water bath with occasional stirring. After cooling, the sodium residue was dissolved with acetonitrile, the solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The organic phase is washed with 10% sodium hydrogensulfate solution, the aqueous phase is made alkaline and extracted with dichloromethane. The organic phase is separated off, dried and evaporated to dryness. The product was purified by recrystallization from acetonitrile. Yield: 2.41 g of white crystals (═ 66% of theory).

1.3: benzhydrylacetic acid cyclopropyl scopolamine ester methyl bromide:

0.46 g (0.0013 mol)4aDissolved in 5 ml of acetonitrile and stirred with 1.53 g (0.0082 mol) of a 50% solution of methyl bromide in acetonitrile in a pressurized reaction vessel at 80 ℃. After 2 days, the solution was evaporated to dryness and the residue was dissolved in acetonitrile and filtered hot. After cooling, the precipitated crystals were separated off, dried and recrystallized from acetonitrile.

Yield: 0.066 g white crystals (═ 11% of theory); melting point: 208 ℃ to 209 DEG C

Elemental analysis: calculated values: c (62.89) H (6.16) N (3.06)

Measured value: c (62.98) H (6.20) N (3.03)

Example 2: cyclopropyl scopolamine methyl 2, 2-diphenylpropionate bromide:

2.1: 2, 2-diphenylpropanoyl chloride 3 b:

52.08 g (0.33 mol) of oxalyl chloride are slowly added dropwise at 20 ℃ to a suspension of 25.0 g (0.11 mol) of 2, 2-diphenylpropanoic acid, 100 ml of dichloromethane and 4 drops of dimethylformamide. It was stirred at 20 ℃ for 1 hour and then at 50 ℃ for 0.5 hour. The solvent was distilled off and the remaining residue was used in the next step without further purification.

2.2: 2, 2-Cyclopropylscopolamine Diphenyl propionate 4 b:

2.3 g (0.015 mol)2aAnd 2.13 g (0.016 mol) of diisopropylethylamine in 30 ml of dichloromethane are combined over a period of 15 minutes with the acid chloride 3b solution prepared in step 2.1 in dichloromethane. The mixture was then stirred at ambient temperature for 2 hours and then at 40 ℃ for 72 hours. For further treatment, washing with waterMgSO₄The solvent was dehydrated and distilled off. The product was converted to its hydrochloride salt using HCl in ether. For purification, the precipitated hydrochloride salt was dissolved in water and extracted with diethyl ether. The aqueous phase was made basic using 10% aqueous sodium carbonate and extracted with dichloromethane. The organic phase is washed with MgSO 2₄The solvent was dehydrated and distilled off.

Yield: 2.15 g of yellow oil (═ 36% of theory)

2.3: cyclopropyl scopolamine ester methyl bromide 2, 2-diphenylpropionate

1.8 g (0.005 mol) of the free base are added4bIn a manner analogous to that of step 1.3. It was recrystallized from acetonitrile/ether for purification.

Yield: 1.53 g of white crystals (═ 67% of theory); melting point: 208 ℃ to 209 DEG C

Elemental analysis: calculated values: c (65.79) H (6.63) N (3.07)

Measured value: c (65.47) H (6.77) N (3.03)

Example 3: 9-hydroxy-xanthene-9-carboxylic acid cyclopropyl scopolamine ester methyl bromide

3.1: 9-hydroxy-xanthene-9-carboxylic acid methyl ester 3 c:

a) xanthene-9-carboxylic acid methyl ester

A solution of sodium ethoxide was produced with 21.75 g (0.95 mol) of sodium and 1500 ml of ethanol. To this solution 214 g (0.95 mol) of xanthene-9-carboxylic acid are added in portions and the resulting suspension is stirred for 1 hour at ambient temperature. The solid is then separated off, washed with 1500 ml of diethyl ether, the precipitated crystals are suspended in 1500 ml of dimethylformamide and 126.73 ml (2.0 mol) of methyl iodide are added with stirring. The resulting solution was allowed to stand at ambient temperature for 24 hours, then diluted with water to a total volume of 6 liters, crystallized, filtered with suction, washed with water and dried.

Yield: 167 g of white crystals 7(═ 74% of theory)

Melting point: 82 deg.C

b) 9-hydroxy-xanthene-9-carboxylic acid methyl ester3c：

48.05 g (0.2 mol) of methyl xanthene-9-carboxylate are dissolved in 1200 ml of tetrahydrofuran and combined at 0 ℃ with 23.63 g (0.2 mol) of potassium tert-butoxide. Oxygen was then bubbled through the tube at-10 ℃ to-5 ℃ for 2 hours, followed by acidification of the mixture with 2N aqueous hydrochloric acid and distillation to remove most of the solvent. The remaining residue was extracted with ethyl acetate and water, and Na was added₂S₂O₅The organic phase is extracted with an aqueous solution, washed with water, dehydrated and the solvent is distilled off, and the product is purified by crystallization from isopropyl ether and cyclohexane.

Yield: 11.10 g of white crystals (═ 22% of theory).

3.2: 9-hydroxy-xanthene-9-carboxylic acid cyclopropyl hyoscyamine ester 4 c:

mixing 6.0 g (0.023 mol)3c3.065 g (0.02 mol)2aAnd 0.02 g of sodium in a manner analogous to that of step 1.24c. Yield: 2.2 g white crystals (═ 25% of theory) melting point: 115 ℃ and 116 DEG C

3.3: 9-hydroxy-xanthene-9-carboxylic acid cyclopropyl hyoscyamine ester methyl bromide:

2.1 g (0.006 mol) of the free base4cIn a manner analogous to that of step 1.3. Purification was performed by recrystallization from isopropanol.

Yield: 1.05 g of light brown crystals (═ 37% of theory); melting point: 218 deg.C

Elemental analysis: calculated values: c (61.02) H (5.55) N (2.97)

Measured value: c (60.40) H (5.72) N (2.96)

Example 4: 9-methyl-fluorene-9-carboxylic acid cyclopropylhyoscyamine ester methyl bromide:

4.1: 9-methyl-fluorene-9-carboxylic acid 3 d:

a) 9-methyl-fluorene-9-carboxylic acid methyl ester:

a sodium ethoxide solution was prepared from 7.6 g (0.33 mol) of sodium and 300 ml of ethanol, to which solution 69.6 g (0.33 mol) of 9-fluorene-carboxylic acid was added in portions. After the addition was completed, it was stirred at ambient temperature for 2.5 hours. It is then evaporated to dryness, the residue is suspended in 600 ml of dimethylformamide and 93.96 g (0662 mol) of methyl iodide are added dropwise. The resulting mixture was stirred at constant temperature for 3 hours. The cloudy solution is stirred with cooling into 500 ml of water and 300 ml of diethyl ether and extracted, the organic phase is washed with water and 10% sodium carbonate solution, dehydrated and evaporated to dryness. The residue was purified by column chromatography, eluent: cyclohexane/Ethyl acetate 96: 4.

Yield: 12.61 g white crystals (═ 16% of theory); melting point: 108 ℃ and 109 ℃.

b) 9-methyl-fluorene-9-carboxylic acid 3 d:

12.6 g (0.053 mol) of methyl 9-methyl-fluorene-9-carboxylate and 53 ml of 2M aqueous sodium hydroxide solution are stirred in 120 ml of 1, 4-dioxane at ambient temperature for 24 hours. The dioxane was distilled off, brought to a total volume of 300 ml with water and extracted with diethyl ether. The aqueous phase was acidified with 3M aqueous HCl, crystallized and filtered.

Yield: 11.25 g white crystals (═ 95% of theory); melting point: 168 ℃ and 169 ℃.

4.2: 9-methyl-fluorene-9-carboxylic acid cyclopropyl scopolamine ester 4 d:

from 4.0 g (0.018 mole)3d4.53 g (0.036 mol) of oxalyl chloride and 4 drops of dimethylformamide are taken in 40 ml of dichloromethane to prepare the acid chloride. Will be provided with24.8 g (0.016 mol)2aAnd 1.91 g (0.019 mol triethylamine suspended in 30 ml dichloromethane, the acid chloride was added dropwise to 30 ml dichloroethane at 30 ℃ over 15 minutes and stirred at 40 ℃ for 24 hours, the suspension was extracted with dichloromethane and water, the organic phase was washed with aqueous acetic acid, dehydrated and the solvent was distilled off.

The product was converted to its hydrochloride salt. The precipitated hydrochloride salt was dissolved in water and extracted with diethyl ether for purification. The aqueous phase was made basic and extracted with dichloromethane. The organic phase is washed with MgSO 2₄The solvent was dehydrated and distilled off. Recrystallization from acetonitrile purified the crude product. Yield: 1.81 g of brownish crystals (═ 30% of theory); melting point: 138-139 deg.C

4.3: 9-methyl-fluorene-9-carboxylic acid cyclopropylhyoscyamine ester methyl bromide:

1.81 g (0.005 mol) of the free base4dThe reaction is carried out in a manner analogous to that of step 1.3. Purification was performed by recrystallization from acetonitrile. Yield: 1.26 g white crystals (═ 56% of theory); melting point: 228 ℃ and 229 ℃.

Elemental analysis: calculated values: c (66.09) H (6.21) N (3.08)

Measured value: c (66.26) H (6.26) N (3.11)

Example 5: 9-methyl-xanthene-9-carboxylic acid cyclopropyl scopolamine ester methyl bromide

5.1: 9-methyl-xanthene-9-carboxylic acid 3 e:

a) 9-methyl-xanthene-9-carboxylic acid methyl ester:

the reaction was carried out in analogy to step 4.1.a, starting from 9.61 g (0.04 mol of methyl 9-xanthenecarboxylate (obtained according to step 3.1. a) to give the title compound.

Yield: 6.05 g of white crystals (═ 60% of theory); melting point: 91-92 ℃.

b) 9-methyl-xanthene-9-carboxylic acid3e：

The reaction was carried out in analogy to step 4.1.b, starting from 20.34 g (0.08 mol) of 9-methyl-xanthene-9-carboxylic acid methyl ester to give the title compound.

Yield: 14.15 g white crystals (═ 74% of theory); melting point: 207-208 ℃.

5.2: 9-methyl-xanthene-9-carboxylic acid cyclopropyl scopolamine ester 4 e:

from 5.0 g (0.021 mol)3eAcid chloride was prepared from 5.53 g (0.042 mol) of oxalyl chloride and 4 drops of dimethylformamide in 50 ml of dichloromethane. 3.06 g (0.02 mol)2aAnd the acid chloride prepared above in analogy to step 4.2.

Yield: 1.95 g of pale brown crystals (═ 26% of theory); melting point: 87-88 ℃.

53: 9-methyl-xanthene-9-carboxylic acid cyclopropyl scopolamine ester methyl bromide

1.95 g (0.005 mol) of the free base are added4eThe reaction is carried out in a similar manner to that in step 1.3. Purification was performed by recrystallization from acetonitrile.

Yield: 0.54 g white crystals (═ 23% of theory); melting point: 193 ℃ and 194 ℃.

Elemental analysis: calculated values: c (63.83) H (6.00) N (2.98)

Measured value: c (61.42) H (6.24) N (2.97)

Example 6: 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl scopolamine ester methyl bromide

6.1: 9-hydroxy-fluorene-9-carboxylic acid methyl ester 3 f:

50.4 g (0.223 mol) of 9-hydroxy-fluorene-9-carboxylic acid are dissolved in 500 ml of methanol, mixed with 5 ml (0.089 mol) of concentrated sulfuric acid and refluxed for 1 hour. After cooling, 100 ml of sodium bicarbonate solution (about pH 8) were added and most of the methanol was evaporated. The mixture was extracted with dichloromethane and water, the organic phase was dehydrated and evaporated to dryness. Purification was performed by recrystallization from ethyl acetate.

Yield: 50.0 g of white crystals (═ 93% of theory).

6.2: 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl scopolamine ester 4 f:

mixing 6.0 g (0.025 mol)3f3.45 g (0.023 mole)2aAnd 0.03 g of sodium in a manner analogous to that of step 1.24f. Purification was performed by recrystallization from acetonitrile.

Yield: 3.46 g of white crystals (═ 38% of theory); melting point: 131 ℃ and 132 ℃.

6.3: 9-hydroxy-fluorene-9-carboxylic acid cyclopropyl scopolamine ester methyl bromide:

3.36 g (0.009 mol) of the free base were added4fThe reaction is carried out in a similar manner to that in step 1.3. Purification was performed by recrystallization from isopropanol.

Yield: 3.32 g white crystals (═ 79% of theory); melting point: 219 ℃ 220 ℃

Elemental analysis: calculated values: c (63.19) H (5.74) N (3.07)

Measured value: c (62.93) H (5.93) N (3.10)

Example 7: methyl 4, 4' -difluorodiphenylglycolate cyclopropyl scopolamine ester methyl bromide:

7.1: methyl 4, 4' -difluorodiphenylglycolate 3 g:

a)4, 4' -difluorodiphenylglycolic acid:

a solution of 24.62 g (0.1 mol) of 4, 4' -difluorobenzil in 250 ml of dioxane was added dropwise to a solution of 49.99 g (125 mol) of NaOH flakes in 300 ml of water at about 100 ℃ and stirred for 2 hours. Most of the dioxane was distilled off and the remaining aqueous solution was extracted with dichloromethane. When the aqueous solution is acidified with sulfuric acid, a precipitate is formed which is filtered off with suction, washed and dried. The filtrate was extracted with dichloromethane and the organic phase was washed with Na₂SO₄Dehydrating and evaporating to dryness.

Yield: 25.01 g (═ 95% of theory); melting point: 133 ℃ C. & 136 ℃ C. (B.)

b)4, 4' -Difluorodiphenylglycolic acid methyl ester3g：

25.0 g (0.095 mol) of 4, 4' -difluorodiphenylglycolic acid was added at 20 ℃ to a sodium ethoxide solution freshly prepared from 2.17 g (0.095 mol) of sodium and 200 ml of ethanol and stirred for 3 hours. The solution was evaporated to dryness, the residue was dissolved in DMF, 22.57 g (0.16 mol) of methyl iodide was added dropwise at 20 ℃ and the mixture was stirred for 24 hours. 300 ml of water were added dropwise to the suspension formed under ice cooling, the mixture was extracted with diethyl ether, the organic phase was washed with water and then with Na₂SO₄Dehydrating and evaporating to dryness.

Yield: 21.06 g (═ 80% of theory).

7.2: 4, 4' -Difluorodiphenylglycolic acid methyl ester cyclopropyl scopolamine ester 4 g:

mixing 6.2 g- (0.022 mol)3g3.37 g (0.022 mol)2aAnd 0.051 g of sodium in a manner similar to that of step 1.24g. Purification was performed by recrystallization from acetonitrile.

Yield: 4.15 g white crystals (═ 47% of theory); melting point: 120 ℃ to 121 DEG C

7.3: 4, 4' -Difluorodiphenylglycolic acid methyl ester cyclopropyl scopolamine ester methyl bromide

2.0 g (0.005 mol) of the free base4gThe reaction is carried out in a similar manner to that in step 1.3. Purification was performed by recrystallization from ethanol/diethyl ether.

Yield: 1.8 g white crystals (═ 73% of theory); melting point: 206- & ltD & gt 207 & deg.C

Elemental analysis: calculated values: c (58.31) H (5.30) N (2.83)

Measured value: c (58.15) H (5.42) N (2.84)

The invention is found in1The compounds are antagonists of the M3 receptor (subtype 3 muscarinic receptor). The compounds of the invention have Ki values of less than 10nM with respect to their affinity for the M3 receptor. These values were measured in the following manner.

Chemical product

3H-NMS was obtained from Firma Amersham, Braunschweig, and had a specific radioactivity of 3071GBq/mmol (83 Ci/mmol). All other reagents were obtained from Serva, Heidelberg and Merck, Darmstadt.

Cell membrane:

we used cell membranes from CHO (chinese hamster ovary) cells transfected with the corresponding genes using the receptor subtypes hm1 to hm5 (boroner) of human muscarinic. The cell membranes of the desired subtype were thawed, resuspended by hand using a glass homogenizer and diluted to a final concentration of 20-30 mg protein/ml with HEPES buffer.

Receptor binding studies:

the binding assay was performed in a final volume of 1 ml and included 100. mu.l of unlabelled material at various concentrations, 100. mu.l of radioactive ligand (3H-N-methylacetanilide 2 nmol/l (3H-NMS), 200. mu.l of membrane preparation and 600. mu.l of HEPES buffer (20 mmol/l)HEPES, 10 mmol/l MgCl₂100 mmol/l NaCl, adjusted to pH7.4 with 1 mol/l NaOH). Nonspecific binding was determined using 10. mu.M atropine (atropine). The formulations were incubated in a 96-well microtiter plate (Beckman, polystyrene, No.267001) for 45 minutes at 37 ℃ in a dual measurement format. The incubation was terminated by filtration through Whatman G-7 filter paper using Inotech Cell Harvester (IH model 110). The filter paper was washed with 3 ml of ice-cooled HEPES buffer and dried before measurement.

And (3) radioactivity determination:

the radioactivity of the filter paper sheets was measured simultaneously using a two-dimensional digital autoradiograph (Berthold, Wildbad model 3052).

Evaluation:

ki values were calculated using an implicit equation (implicit equalisation) derived directly from the law of mass action, using a model of the 1 receptor 2 ligand response (SysFit-software, SCHITTKOWSKI).

The literature:

BONNER，TI，New subtypes of muscarinic acetylcholine receptors TrendsPharmacol.Sci.10，Suppl.：11-15(1989)；SCHITTKOWSKI K Parameterestimation in systems of nonlinear equations Numer Math.68：129-142(1994)。

the invention is of1The compounds show a range of utility in the therapeutic field. Of particular mention are those of the formula1The compounds are preferably used in view of their pharmaceutical activity as anticholinergics.

Examples of such uses are the treatment of asthma or COPD (chronic obstructive pulmonary disease). General formula (VII)1The compounds may also be used in the treatment of vagally induced sinus bradycardia (sinus bradikardie) and in the treatment of cardiac rhythm disorders. In general, the compounds of the invention may also be used to treat spasticity in a therapeutic manner, for example, in the gastrointestinal tract. They may also be used for the treatment of spasticity in the urinary tract and for the treatment of, for example, dysmenorrhea. At the upper partOf particular importance in the context of the indications mentioned is the use of the formula of the invention1The compounds treat asthma or COPD.

General formula (VII)1The compounds may be as such or in combination with other formulae1The active substance is used. General formula (VII)1The compounds may also be used in combination with other pharmaceutically active substances. These active substances can be, in particular, beta-mimetics (betamimetics), antiallergic agents, Platelet Activating Factor (PAF) antagonists, phosphodiesterase-IV (PDE-IV) inhibitors, leukotriene antagonists, p38 kinase inhibitors, Epidermal Growth Factor Receptor (EGFR) -kinase inhibitors and corticosteroids and combinations of these active substances.

Can be fitted according to the invention1Examples of beta-mimetics for use with the compounds include compounds selected from the group consisting of: mexican-hydroxy-albuterol (bambuterol), tolbutadine (bitolterol), albuterol (carbutarol), clenbuterol (clenbuterol), phenoprotamine (fenoterol), formoterol (formoterol), ipratropium (hexoprenaline), albuterol (ibuterol), pirbuterol (pirbuterol), salbutamol (procaterol), lipterol (reproterol), salmeterol (salmeterol), thiaarrol (sulphonterol), terbutaline (terbutaline), tolbutamol (tolbutamol), 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] propanal (carbutaline)]Sulfonyl } ethyl]-amino } ethyl]-2(3H) -benzothiazolone, 1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [3- (4-methoxybenzylamino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl]-2-methyl-2-butylamino } ethanol, 5-hydroxy-8- (1-hydroxy-2-isopropylamino)Butyl) -2H-1, 4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of their racemates, enantiomers, diastereomers and optionally pharmaceutically acceptable acid addition salts, solvates and/or hydrates thereof. Particularly preferred are compounds of the formula1Compounds the combination of beta-mimetics as active substance is a compound selected from the group consisting of: phenolprobutamol, formoterol, salmeterol, 1- [3- (4-methoxybenzyl methylamino) -4-hydroxyphenyl]-2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino]Ethanol, 1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl]-2- [4- (3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl)]-2-methyl-2-butylamino } ethanol, optionally in the form of its racemate, its enantiomers, its diastereoisomers and optionally pharmaceutically acceptable acid addition salts and the like, and hydrates thereof. Of the above β -mimetics, particularly preferred are the compounds formoterol and salmeterol, optionally in the form of their racemates, their enantiomers, their diastereomers and optionally pharmaceutically acceptable acid addition salts thereof, and the like, and hydrates thereof. According to the invention, the acid addition salts of the β -mimetics are salts selected from the following: hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate. Particularly preferred salts for salmeterol are those selected from the group consisting of the hydrochloride, sulfate, and xinafeng salts, with the xinafeng salt being most preferred. Particularly preferred salts for formoterol are those selected from: hydrochloride, sulfate and fumarate salts, with hydrochloride and fumarate salts being particularly preferred. According to the present invention formoterol fumarate is of exceptional importance.

In the hairWithin the clear range, optionally in combination1The corticosteroid used in the compound may be a compound selected from the group consisting of: 9-Defluorodermatan (flunoside), beclomethasone propionate (beclomethasone), triamcinolone (triamcinolone), budesonide (budesonide), fluticasone (fluticasone), mometasone (mometasone), ciclesonide (ciclesonide), Roflufenide (rofleponide), GW 215864, KSR 592, ST-126 and dexamethasone (dexamethasone). Preferred corticosteroids within the scope of the invention are those selected from: 9-Defluorodermatan (flunisolide), beclomethasone dipropionate, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, of which budesonide, fluticasone, mometasone and ciclesonide are important and budesonide and fluticasone are particularly important. In some cases, the term steroid may be used in place of the term corticosteroid within the scope of this patent application. Within the scope of the present invention, any reference to steroids includes salts or derivatives which may be formed from steroids. Examples of possible salts or derivatives include: sodium salt, sulfobenzoate, phosphate, isonicotinate, acetate, propionate, dihydrogen phosphate, palmitate, pivalate or furoate. In some cases, the corticosteroid may also be in its hydrate form.

According to the invention can be combined1Examples of PDE-IV inhibitors for use in combination with the compounds include compounds selected from the group consisting of: enprophylline (enpropylline), roflumilast (roflumilast), Arifluoro (ariflo), Bay-198004, CP-325366, BY343, D-4396(Sch-351591), V-11294A and AWD-12-281. Preferred PDE-IV inhibitors are selected from the following compounds: enprophylline, roflumilast, aclofloridol and AWD-12-281, wherein AWD-12-281 is of the formula1The combination of the compounds is particularly preferred. Any reference to the above PDE-IV inhibitors also includes, within the scope of the present invention, reference to any pharmaceutically acceptable acid addition salt which may be present. Physiologically acceptable acid addition salts which can be formed by the above-mentioned PDE-IV inhibitors are, for example, pharmaceutically acceptable salts formed from acids selected from the group consisting ofSalt: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, and maleic acids. According to the invention, it is preferably selected from: salts of acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate.

Within the scope of the invention, can be selected from1Compound the dopamine agonist used in combination is a compound selected from the group consisting of: bromocriptine (bromocriptine), cabergoline (cabergolin), α -dihydroergocriptine (alpha-dihydroergocryptine), lisuride (lisuride), pergolide (pergolide), pamidrol (pramipexol), rochenode (roxindol), ropinirole (ropinarol), talipexole (talipexol), tergulid (tergurid) and vozan (viozan). Within the scope of the invention as an and1preferred dopamine agonists of the combination partners of the compounds are selected from the group consisting of paisumi, talipexin, and voxas, of which paisumi is of particular importance. Also included within the scope of the present invention are any pharmaceutically acceptable acid addition salts and hydrates thereof which may be present in relation to any of the aforementioned dopamine agonists. Physiologically acceptable acid addition salts which can be formed from the aforementioned dopamine agonists refer, for example, to pharmaceutically acceptable salts formed from acids selected from the group consisting of: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, and maleic acids.

Can be according to the invention and1examples of antiallergic agents to be used in combination of the compounds include the following: epinastine (epinastine), cetirizine (cetirizin), azo * statin (azelastin), fexofenadine (fexofenadine), levocabastine (levocabastin), loratadine (loratadine), mizolastine (mizolastin), ketotifen (ketotifen), emedasine (emedasin), difindine (dimetinden), clemastine (clemastine), benemidine (bamine), cyprohexanilide (cexchloropheniramine), dimiton (pheniramine), benzethopamine (doxylamine), kresoximine (chlorothenoxamine), dimenhydrinamine (dimexylamine), dimenhydrinate (dimehydrinamine)te), diphenhydramine (diphenhydramine), promethazine (promethazine), abamectin (ebastin), but delocaline (desmodine), clobenzazine (meclizine). Within the scope of the present invention, preferred antiallergic agents which can be used in combination with the compound of formula 1 of the present invention are selected from the group consisting of: epinastine, cetirizine, nitrogen * statin, fexofenadine, levocabastine, loratadine, desloratidine (desloratidine) and mizolastine (mizolastine), with epinastine and desloratidine (desloratidine) being particularly preferred. Any reference to the above anti-allergic agents also includes, within the scope of the present invention, any pharmaceutically acceptable acid addition salt which may be present.

According to the invention can be combined1Examples of PAF antagonists for use in combination of compounds include 4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanon-1-yl]-6H-thieno- [3, 2-f][1，2，4]Triazolo [4, 3-a][1，4]Diaza * and 6- (2-chlorophenyl) -8, 9-dihydro-1-methyl-8- [ (4-morpholinyl) carbonyl]-4H, 7H-cyclopentane [4, 5 ]]Thieno- [3, 2-f]1，2，4]Triazolo [4, 3-a][1，4]Diaza *.

Can be combined with the invention1Examples of EGFR-kinase inhibitors for use in combination of compounds include, inter alia, 4- [ (3-chloro-4-fluoro-phenyl) amino]-7- [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]-6- [ (vinylcarbonyl) amino group]Quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino]-7- [4- ((S) -6-methyl-2-oxo-morpholin-4-yl) -butyloxy]-6- [ (vinylcarbonyl) amino group]Quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino]-7- (2- {4- [ (S) - (2-oxo-tetrahydrofuran-5-yl) -carbonyl]-piperazin-1-yl } -ethoxy) -6- [ (vinylcarbonyl) amino group]Quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino]-7- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy]-6- [ (vinylcarbonyl) amino group]Quinazoline, 4- [ (3-chloro-4-fluoro-phenyl) amino]-6- [4- { N- [2- (ethoxycarbonyl) ethyl]-N- [ (ethoxycarbonyl) methyl group]Amino } -1-oxo-2-buten-1-yl) amino]-7-cyclopropylmethoxy-quinazoline, 4- [ (R) - (1-phenyl-ethyl) amino]-6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl) amino } -7-cyclopropylmethoxy-quinazoline and 4- [ (3-chloro-4-fluoro-phenyl)) Amino group]-6- [3- (morpholin-4-yl) -propyloxy]-7-methoxy-quinazoline. Any reference to the above-mentioned EGFR-kinase inhibitors also includes, within the scope of the present invention, any pharmaceutically acceptable acid addition salt for which it is possible. Which is a physiologically or pharmaceutically acceptable acid addition salt which can be formed from an EGFR-kinase inhibitor, a pharmaceutically acceptable salt according to the invention, selected from the group consisting of the salts formed from the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, and maleic acids. Preferred salts of EGFR-kinase inhibitors according to the invention are salts selected from the following acids: acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

Can be combined with the invention1Particularly preferred examples of p 38-kinase inhibitors for use in combination of compounds include 1- [ 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl]Urea; 1- [ 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3- [4- (2- (1-oxothiomorpholin-4-yl) -ethoxy) naphthalen-1-yl]Urea; 1- [ 5-tert-butyl-2- (2-methyl-pyridin-5-yl) -2H-pyrazol-3-yl]-3- [4- (2-pyridin-4-yl-ethoxy) naphthalen-1-yl]Urea; 1- [ 5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl]-3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl]Urea or 1- [ 5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3- [4- (2-morpholin-4-yl-ethoxy) naphthalen-1-yl]Urea. Any reference to the above p 38-kinase inhibitors also includes, within the scope of the invention, any pharmaceutically acceptable acid addition salt thereof which may be present. Physiologically or pharmaceutically acceptable acid addition salts which can be formed by p 38-kinase inhibitors refer, for example, to pharmaceutically acceptable salts formed from acids selected from the group consisting of: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric, and maleic acids.

Is of type1When the compounds are used in combination with other active substances, particular preference is given to combinations of the above-mentioned compounds with steroids, PDE IV inhibitors or beta-mimetics. With beta-mimetics, especially long-acting beta-mimeticsThe combination is particularly important. The invention is of1The combination of the compound with salmeterol or formoterol is particularly preferred.

In the formula1Suitable formulations for administration of the salts include, for example, tablets, capsules, suppositories, solutions and the like. The compounds of the invention for administration by inhalation are of particular importance according to the invention (in particular for the treatment of asthma or COPD patients). The content of the pharmaceutically active compound must be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight, of the total composition. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrating agents such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or sustained-release agents such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

Coated tablets may accordingly be produced by means of tablet cores which are produced analogously to substances customarily used for tablet coatings, for example collidone (colladone) or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also comprise several layers in order to achieve sustained release or to prevent incompatibilities. Also, the tablet coating may comprise several layers to achieve sustained release, and excipients as described above for the tablets may be used.

Syrups containing the active substance or composition of the invention may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar, and taste-enhancing agents, for example flavours such as vanillin or orange extract. They may also contain suspension auxiliaries or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoic acid esters.

Solutions are prepared in a customary manner, for example with the addition of isotonic agents, preservatives such as p-hydroxybenzoic acid esters or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, if desired emulsifiers and/or dispersants, for example using water as diluent, if desired organic solvents can be used as solubilizers or dissolution aids, and the solutions can be transferred into injection vials or ampoules or infusion bottles.

Capsules containing one or more active substances or compositions of active substances can be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and filling gelatin capsules with them.

Suitable suppositories may be made, for example, by mixing with carriers provided for this purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut or sesame oil), mono-or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersible silicic acid and silicates), sugars (e.g. sucrose, lactose and glucose), emulsifiers (e.g. lignin, waste sulphite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

For oral use, the tablets may obviously contain, in addition to the carrier, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, as well as various additional substances such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may also be used to make tablets. In the case of aqueous suspensions, the active substance may be combined with various taste-enhancing agents or colorants in addition to the excipients mentioned above.

Is of the same type1Where the compounds are for use in the treatment of asthma or COPD, it is preferred according to the invention to administer the compounds in a formulation or pharmaceutical formulation suitable for inhalation. Administration as inhalation may be in the form of an inhalable powder, a metered aerosol with a propellant or an inhalable solution without a propellant. Propellant-free inhalable solutions within the scope of the invention also include the concentrated solutions or sterile solutions that can be usedThe solution may be inhaled. Formulations which can be used within the scope of the invention are described in detail in the next part of the description of the invention.

The inhalable powders which can be used according to the invention may contain compound 1 as such or in a mixture with suitable physiologically acceptable excipients.

If the active substance 1 is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the preparation of these inhalable powders according to the invention: monosaccharides (such as glucose or arabinose), disaccharides (such as lactose, sucrose, maltose), oligo-or polysaccharides (such as polydextrose), polyols (such as sorbitol, mannitol, xylitol), salts (such as sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono-or disaccharides are used, whereas lactose or glucose are preferred, in particular, but not exclusively, in the form of their hydrates. For the purposes of the present invention, lactose is a particularly preferred excipient, and lactose monohydrate is most particularly preferred.

Within the framework of the inhalable powders according to the invention, the excipient has a mean particle size of up to 250 microns, preferably between 10 and 150 microns, most preferably between 15 and 80 microns. It sometimes seems expedient to add a finer excipient fraction having an average particle size of 1 to 9 μm to the above-mentioned excipients. These finer excipients are also selected from the list of useful excipients above. Finally, for the preparation of the inhalable powders according to the invention, it is possible to add to the excipient mixture a micronized active substance 1, preferably having an average particle size of 0.5 to 10 microns, more preferably 1 to 5 microns. The inhalable powders according to the invention are prepared by methods known in the art and can be prepared by grinding and micronization and finally mixing the ingredients together. The inhalable powders according to the invention can be administered using inhalers known in the art.

The aerosol for inhalation comprising propellant gas to be used according to the invention can contain a plurality of compounds 1 dissolved in the propellant gas or in dispersed form therein. The plurality of compounds 1 may be contained in separate formulations or in a combined formulation, wherein the plurality of compounds 1 may be dissolved simultaneously, dispersed simultaneously or only one component dissolved while another component is dispersed. Propellant gases which can be used for the preparation of inhalation aerosols are known from the prior art. Suitable propellant gases are fluorinated derivatives selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used individually or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG134a and TG227 or mixtures thereof.

Inhalation aerosols containing propellant gas may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the prior art.

The propellant gas-containing inhalation aerosols of the invention described above can be administered using inhalers known in the art (MDIs ═ metered dose inhalers).

Furthermore, the active ingredient 1 according to the invention can be administered in the form of propellant-free inhalable solutions and suspensions. The solvent used may be aqueous or alcoholic, preferably ethanolic, and may be water itself or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited but can be up to 70% by volume, more preferably up to 60% by volume and most preferably up to 30% by volume. The remaining volume portion is made up of water. The solution or suspension containing 1 is adjusted to a pH of 2 to 7, preferably 2 to 5, using a suitable acid. The pH can be adjusted using a mineral acid or an organic acid. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid. Malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetoformic acid and/or propionic acid, etc. Preferred inorganic acids are hydrochloric acid and sulfuric acid, it also being possible to use acids which have formed an acid addition salt with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above-mentioned acids may be used, in particular acids which, in addition to their acidifying properties, also have other properties, for example as flavoring agents, antioxidants or complexing agents, etc., for example citric acid or ascorbic acid. According to the invention, it is particularly preferred to use hydrochloric acid for adjusting the pH.

In these formulations, acetic acid (EDTA) or its known salts, such as sodium acetate, are added as stabilizers or complexing agents, if necessary. Other embodiments may contain such compounds(s). In a preferred embodiment, the amount of sodium acetate based is less than 100 mg/100 ml, preferably less than 50 mg/100 ml, more preferably less than 20 mg/100 ml. Generally, the preferred inhalable solutions are those in which the sodium acetate content is between 0 and 10 mg/100 ml.

The propellant-free inhalable solutions of the present invention may be supplemented with co-solvents and/or other excipients. Preferred cosolvents are those containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropanol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipient and additive, as used herein, refer to any pharmaceutically acceptable material that is not an active substance, but that can be formulated with the active substance in a suitable solvent for the drug to improve the properties of the active substance formulation. Preferably, these substances have no therapeutic effect or no significant drug effect or at least no undesired drug effect in connection with the treatment. Such excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that ensure or prolong the shelf life of the finished pharmaceutical formulation, flavoring agents, vitamins and/or other additives known in the art. The additive also includes pharmaceutically acceptable salts such as sodium chloride as isotonic agents.

Preferred adjuvants include antioxidants such as ascorbic acid, provided that it is not already used for pH adjustment, vitamin a, vitamin E, tocopherols and similar vitamins or provitamins contained in the human body.

Preservatives may be used to protect the formulation from pathogenic contamination. Suitable preservatives are known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride, or benzoic acid or benzoates, for example sodium benzoate, in concentrations known from the prior art. The preservative is preferably present in a concentration of up to 50 mg/100 ml, more preferably between 5 and 20 mg/100 ml.

Preferably, the formulation contains only benzalkonium chloride and sodium acetate, in addition to the solvent water and the active substance 1. In another preferred embodiment, no sodium acetate is present.

The dosage of the compounds of the invention is of course highly dependent on the method of administration and the disease to be treated. When administered by inhalation, the formula1The compounds are characterized by high potency even at doses in the microgram range. Formula (II)1The compounds may also be used effectively in doses above the microgram range. For example, the dosage may be in the gram range. Higher doses of the compounds of the invention (e.g., without limitation, in the range of 1 to 1000 mg) may be used, particularly when administered by routes other than inhalation.

The following formulation examples are intended to illustrate the invention without limiting its scope:

examples of pharmaceutical preparations

A) Each tablet of the tablet

Active substance1100 mg of

Lactose 140 mg

Corn starch 240 mg

Polyvinylpyrrolidone 15 mg

Magnesium stearate 5 mg

500 mg of

The finely ground active substance, lactose and a portion of the corn starch are mixed with one another. The mixture was sieved, then wetted with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed with each other. The mixture is compressed into tablets of appropriate shape and size.

B) Each tablet of the tablet

Active substance180 mg of

Lactose 55 mg

Corn starch 190 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

Sodium carboxymethyl starch 23 mg

Magnesium stearate 2 mg

400 mg of

The finely ground active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed with one another, the mixture is sieved and then granulated with the remaining corn starch and water, dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed. The mixture is compressed to form tablets of appropriate size.

C) Ampoule solution

Active substance150 mg of

50 mg of sodium chloride

5 ml of water for injection

The active substance is dissolved in water at its own pH or optionally at a pH of 5.5 to 6.5 and is made isotonic by mixing with sodium chloride. The resulting solution is filtered to remove pyrogens and the filtrate is transferred under aseptic conditions to ampoules which are then sterilized and heat sealed and which contain 5 mg, 25 mg and 50 mg of active substance.

D) Metering aerosol

Active substance1 0.005

Sorbitan trioleate 0.1

Monochlorotrifluoromethane and

difluorodichloromethane 2: 3 to 100

The suspension is transferred into a conventional aerosol container equipped with a dosage valve. Preferably 50 microliters of suspension is released per actuation. Higher doses of active substance (e.g. 0.02 wt%) may also be released if desired.

E) Liquid agent (mg/100 ml)

Active substance1333.3 mg

333.3 mg formoterol fumarate

Benzalkonium chloride 10.0 mg

EDTA 50.0 mg

HCl (1n) is added to pH3.4

The solution is prepared in the usual manner.

F) Inhalable powders

Active substance16 microgram

Formoterol fumarate 6 microgram

Lactose monohydrate to 25 mg

Inhalable powders are prepared by mixing the ingredients in a conventional manner.

G) Inhalable powders

Active substance110 microgram of

Lactose monohydrate to 5 mg

The components are mixed in a conventional manner to produce an inhalable powder.

Claims (12)

1. General formula1Compound (I)

Wherein

X^-Is an anion having a single negative charge,

a and B may be the same or different and represent-O, -S, -NH, or-CH ═ CH;

r represents hydrogen, hydroxy, -C₁-C₄-alkyl, -C₁-C₄-alkanesOxy, -C₁-C₄Alkylene-halogen, -O-C₁-C₄Alkylene-halogen, -C₁-C₄alkylene-OH, -C₁-C₄alkylene-C₁-C₄-alkoxy, -O-COC₁-C₄-alkyl, -O-COC₁-C₄Alkylene-halogen, -C₁-C₄alkylene-C₃-C₆-cycloalkyl, or halogen;

R¹and R²May be the same or different and represents C₁-C₅-alkyl, optionally substituted by-C₃-C₆-cycloalkyl, hydroxy or halogen substitution;

or

R¹And R²Together represent-C₃-C₅-an alkylene bridge;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Or halogen;

R^Xand R^X′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Or halogen

Or

R^XAnd R^X′Together represent a single bond or a bridging group selected from: -O, -S, -NH-, -CH₂-。

2. A process according to claim 1 of the formula1A compound wherein R represents-CF₃、CHF₂or-O-COCF₃。

3. A process according to claim 1 of the formula1A compound of which

X^-Is a single negatively charged anion selected from chloride, bromide, 4-toluenesulfonate and methanesulfonate;

a and B, which may be the same or different, represent-O-, -S-, -NH-or-CH ═ CH-;

r represents hydrogen, hydroxy, -C₁-C₄-alkyl, -C₁-C₄-alkoxy, -CF₃、-CHF₂Fluorine, chlorine or bromine;

R¹and R²May be the same or different and represents C₁-C₄-alkyl, optionally substituted by hydroxy, fluoro, chloro or bromo,

or

R¹And R²Together represent-C₃-C₄-an alkylene bridge;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Fluorine, chlorine or bromine;

R^Xand R^X′May be the same or different and represents hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, hydroxy, -CF₃、-CHF₂、CN、NO₂Fluorine, chlorine or bromine;

or

R^XAnd R^X′Together represent a single bond or are selected from-O-, -S-, -NH-and-CH₂-bridging of.

4. A compound of the formula according to claim 1 or 31A compound of which

X^-Represents an anion having a single negative charge selected from the group consisting of chloride, bromide, and methanesulfonate;

a and B, which may be the same or different, represent-S-or-CH ═ CH-;

r represents hydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, -CF₃Or fluorine;

R¹and R²May be the same or different and represents methyl, ethyl, -CH₂F or-CH₂-CH₂F；

R³，R⁴，R^3′And R^4′May be the same or different and represents hydrogen, methyl, methoxy, -CF₃Or fluorine;

R^Xand R^X′May be the same or different and represents hydrogen, methyl, methoxy, -CF₃Or fluorine;

or

-R^XAnd R^X′Together represent a single bond or a bridging group-O-.

5. A compound of the formula according to claim 1 or 31A compound of which

X^-Represents an anion having a single negative charge selected from the group consisting of chloride, bromide, and methanesulfonate;

a and B, which may be the same or different, represent-S-or-CH ═ CH-;

r represents hydrogen, hydroxy or methyl;

R¹and R²May be the same or different and represents a methyl group or an ethyl group;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen, -CF₃Or fluorine;

R^Xand R^X′May be the same or different and represents hydrogen, -CF₃Or fluorine;

or

R^XAnd R^X′Together represent a single bond or a bridging group-O-.

6. A compound of the formula according to claim 1 or 31A compound of which

X^-Represents a bromide ion;

a and B represent-CH ═ CH —;

r represents hydrogen, hydroxy or methyl;

R¹and R²Represents a methyl group;

R³，R⁴，R^3′and R^4′May be the same or different and represents hydrogen or fluorine;

R^Xand R^X′Can be the same as orDifferent, represents hydrogen or fluorine; or R^XAnd R^X′Together represent a single bond or a bridging group-O-.

7. A compound of the formula according to claim 1 or 31A compound, which optionally may be in the form of a single optical isomer, a mixture of single enantiomers or a racemate thereof.

8. The compound of claim 1 to 71Use of a compound for the preparation of a pharmaceutical composition for the treatment of a disease in which an anticholinergic can develop a therapeutic benefit.

9. The compound of claim 1 to 71Use of a compound for the preparation of a pharmaceutical composition for the treatment of asthma, chronic obstructive pulmonary disease, vagally induced sinus bradycardia, arrhythmia, spasm in the gastrointestinal tract, spasm in the urinary tract, and dysmenorrhea.

10. Pharmaceutical preparation containing, as active substance, one or more compounds of the general formula according to one of claims 1 to 71The compounds, or physiologically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.

11. Pharmaceutical preparation according to claim 10, characterized by the fact that in addition to one or more of the formulae1In addition to the compound, it contains at least one further active substance selected from the group consisting of: beta-mimetics, antiallergic agents, platelet activating factor antagonists, phosphodiesterase-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, epidermal growth factor receptor-kinase inhibitors, and corticosteroids.

12. General formula4Intermediate of (2)

A, B, R, R therein¹、R³、R^3′、R⁴、R^4′、R^XAnd R^X′Has the meaning given in any one of claims 1 to 6, optionally in the form of an acid addition salt thereof.