JP2006502207A - Novel beta mimetics with extended duration of action, methods for their preparation and their use as drugs - Google Patents

Abstract

The present invention relates to compounds of general formula 1 in which the radicals R ¹ , R ² and R ³ can have the meanings given in the claims and in the description, the process for their preparation And their use as medicaments, especially for the treatment of inflammatory and obstructive bronchial diseases.

Description

(式中、基R¹、R²及びR³は、特許請求の範囲及び本明細書中に記載の意味を有していてもよい)。 The present invention relates to the compounds of general formula 1, their preparation and their use as pharmaceutical compositions, in particular for the treatment of inflammatory and obstructive respiratory complaints;

(Wherein the groups R ¹ , R ² and R ³ may have the meanings set forth in the claims and herein).

Beta mimetics (β-adrenergic drugs) are known from the prior art. They may be used to work well in various therapeutic fields.
With respect to drug treatment of diseases, it is often desirable to produce a drug with a longer duration of action. In general, this ensures a long-term guarantee of the active substance concentration in the body required to achieve a therapeutic effect without having to re-administer the drug frequently. Furthermore, the administration of the active substance at longer intervals contributes to a high degree of patient satisfaction. Another major advantage of drugs with long-term activity is evident in the case of diseases or illnesses whose signs appear exclusively in the second half of the night. A single application of a drug with long-term activity before going to bed is thought to give the patient considerable convenience and represent an improvement in quality of life. It is particularly desirable to produce a pharmaceutical composition that can be used by treatment with once daily administration (single administration). The use of the drug once a day has the advantage that the patient can get used to it relatively quickly compared to taking the drug regularly a certain number of times a day.

Accordingly, an object of the present invention is to provide beta mimetics that are characterized by long-term activity and that can be used to produce pharmaceutical compositions having long-term activity. A particular object of the present invention is to produce beta mimetics that can be used to produce once-daily drugs due to their long-lasting action. A further object of the present invention is the novel beta mimetics that can be used to produce once-daily drugs for the treatment of inflammatory or obstructive respiratory complaints due to their long-lasting effects. Is to manufacture.
In addition to the above objects, the present invention also aims to provide beta mimetics that are not only very potent, but also characterized by a high degree of selectivity for the β ₂ -adrenergic receptors.

｛式中、R¹は、炭素数１〜４のアルキルを表し；
R²は、炭素数１〜４のアルキルを表し；
R³は、炭素数１〜４のアルキル又はフェニル(それらは所望により一置換又は多置換されていてもよい)を表し；又は
R²とR³は、一緒になって、-CH₂-CH₂-及び-CH₂-CH₂-CH₂-から選ばれる二重に結合する基(double-bonded group)を表す｝。 Surprisingly, it has been found that the above problems are solved by the compounds of general formula 1.
The present invention therefore relates to compounds of general formula 1;

{Wherein R ¹ represents alkyl having 1 to 4 carbon atoms;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ represents alkyl having 1 to 4 carbons or phenyl (which may be optionally mono- or polysubstituted); or
R ² and R ³ together represent a double-bonded group selected from —CH ₂ —CH ₂ — and —CH ₂ —CH ₂ —CH ₂ —.

Preferably, in the formula:
R ¹ represents alkyl having 1 to 4 carbons;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ is alkyl having 1 to 4 carbons or phenyl (they are optionally alkyl having 1 to 3 carbons, CF ₃ , methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, —OCF ₃ , —CHF ₂ , It may be mono-, di-, tri-, or tetra-substituted by one or more groups selected from -NHCOCH ₃ and -NHSO ₂ CH ₃ , or
R ² and R ³ are compounds of the general formula 1 in which R ² and R ³ together represent a double-bonded group selected from —CH ₂ —CH ₂ — and —CH ₂ —CH ₂ —CH ₂ —.

Also preferred are those in which
R ¹ represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ is alkyl or phenyl having 1 to 4 carbon atoms (which are optionally mono-substituted, di-substituted, tri-substituted, or one or more groups selected from methyl, ethyl, CF ₃ , methoxy, ethoxy and hydroxy) Which may be tetrasubstituted), or
R ² and R ³ are compounds of the general formula 1 in which R ² and R ³ together represent a double-bonded group selected from —CH ₂ —CH ₂ — and —CH ₂ —CH ₂ —CH ₂ —.

Also preferred are those in which
R ¹ represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ² represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ³ is alkyl having 1 to 4 carbon atoms, preferably methyl or phenyl (they are optionally mono-, di-, tri-substituted by one or more groups selected from methyl, CF ₃ , methoxy and hydroxy Or may be tetrasubstituted), or
A compound of the general formula 1 in which R ² and R ³ together represent a double bond group, —CH ₂ —CH ₂ —.

Preferred compounds of general formula 1 according to the invention are those in which
R ¹ represents methyl or ethyl, preferably methyl;
R ² represents methyl;
R ³ is methyl, ethyl or phenyl (which may be optionally mono-, di-, tri- or tetra-substituted by one or more groups selected from methyl, CF ₃ , methoxy and hydroxy) Or
R ² and R ³ together represent a double bond group, —CH ₂ —CH ₂ —.
Particularly preferred are:
R ¹ represents methyl;
R ² represents methyl;
R ³ represents methyl or phenyl (which may optionally be mono-, di- or tri-substituted by one or more groups selected from methyl, ethyl and hydroxy), or
A compound of the general formula 1 in which R ² and R ³ together represent a double bond group, —CH ₂ —CH ₂ —.

Also preferred according to the invention is
R ¹ represents methyl;
R ² represents methyl;
R ³ represents methyl or phenyl, or
A compound of the general formula 1 in which R ² and R ³ together represent a double bond group, —CH ₂ —CH ₂ —.

Examples of particular importance according to the invention include compounds of general formula 1 below:
4- [2- (1,1-dimethyl-propylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol;
4- [1-hydroxy-2- (1-methyl-cyclopentylamino) -ethyl] -3-methoxy-benzene-1,2-diol;
4- {2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol;
4- {2- [1,1-dimethyl-2-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol;
4- {2- [1,1-dimethyl-2- (2,3,5,6-tetra-methyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1, 2-diol;
4- [2- (1,1-dimethyl-2-o-tolyl-ethylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol.

The present invention relates to compounds of the general formula 1, optionally in the form of individual optical isomers, individual enantiomers or racemic mixtures, free bases or corresponding acid addition salts of pharmacologically acceptable acids. About.
The compounds of the general formula 1 according to the invention may optionally occur in the form of their individual optical isomers, individual enantiomers or racemic mixtures and may be purified using methods known from the literature. It may be separated into forms. The R-enantiomer is preferred if the compound is used in enantiomerically pure form.

Acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, nitric acid, maleic acid, acetic acid, benzoic acid, citric acid, fumaric acid, tartaric acid; oxalic acid, succinic acid and By p-toluenesulfonic acid, preferably a salt formed with a pharmacologically acceptable acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid and methanesulfonic acid.
Unless otherwise specified, the alkyl group is a linear or branched alkyl group having 1 to 4 carbon atoms. The following are mentioned by way of example: methyl, ethyl, propyl or butyl. In some cases, the abbreviations Me, Et, Prop or Bu are used to represent methyl, ethyl, propyl or butyl. Unless otherwise specified, the definitions of propyl and butyl include all possible isomeric forms of the group. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. Butyl, tert-butyl, and the like.

Of the acid addition salts, salts of hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid are particularly preferred according to the present invention.
The compounds according to the invention may be prepared analogously to methods already known in the art. Suitable manufacturing methods are known, for example, from US 3657244, the contents of which are incorporated herein.
The present invention is more fully illustrated using the synthetic examples described below. They are merely intended to be illustrative of methods without limiting the invention to the objects described below.

a) 2-(1,1-ジメチル-プロピルアミノ)-1-(4-メトキシ-2,2-ジフェニル-ベンゾ[1,3]ジオキソール-5-イル)-エタノン；
αブロモ-2-メトキシ-3,4-ジフェニルメチレンジオキシアセトフェノン(US 3657244により得られる)42.5gを、1,1-ジメチルプロピルアミン30gと、エタノール150ml中、攪拌しながら3時間還流した。溶媒を、減圧下で留去し、残渣をジエチルエーテルと合わせ、水で二回抽出した。溶媒を減圧下で留去した後、残っている残渣を酢酸エチルに溶解し、塩酸エーテル(ethereal hydrochloric acid)で酸性化した。沈殿した結晶を吸引ろ過し、酢酸エチル及びジエチルエーテルで洗った。
収量：26g(56％、ヒドロクロライド)；融点＝174〜176℃。 4- [2- (1,1-Dimethyl-propylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol

a) 2- (1,1-dimethyl-propylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone;
42.5 g of α-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone (obtained by US 3657244) was refluxed with stirring in 30 g of 1,1-dimethylpropylamine and 150 ml of ethanol for 3 hours. The solvent was removed under reduced pressure and the residue was combined with diethyl ether and extracted twice with water. After the solvent was distilled off under reduced pressure, the remaining residue was dissolved in ethyl acetate and acidified with ethereal hydrochloric acid. The precipitated crystals were suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 26 g (56%, hydrochloride); mp = 174-176 ° C.

b) 1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-propylamino) -ethanone:
2- (1,1-dimethyl-propylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone 25 g, 15% hydrochloric acid methanol 50 ml, The mixture was refluxed for 2 hours with stirring. The solvent was removed under reduced pressure and the residue was dissolved in acetonitrile and combined with ethyl acetate. The precipitated crystals were suction filtered and washed with acetonitrile and diethyl ether.
Yield: 15 g (92%) Compound as hydrochloride salt.
For further purification, the free base may be liberated from the hydrochloride salt under normal conditions and then suspended in methanol, combined with an equimolar amount of benzoic acid and heated. The crystals thus obtained were suction filtered and washed with diethyl ether.
Melting point = 151-154 ° C (benzoate).

c) 4- [2- (1,1-Dimethyl-propylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol:
6.5 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethylpropylamino) -ethanone was hydrogenated with 0.1 g of platinum oxide as catalyst in 125 ml of methanol. The catalyst was filtered off with suction, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the precipitated crystals were suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 5.5 g (85%; benzoate); mp = 172-174 ° C.

a) 1-メチル-シクロペンチルアミン：
シアン化ナトリウム66.5gを氷酢酸150mlに溶解した。硫酸300ml及び氷酢酸150mlの溶液を、5〜10℃で、シアン化ナトリウム溶液に滴下して加えた。1-メチル-シクロペンタノール 126gをこの混合物に加えた。得られた混合物を一晩静置した。その後、水210ml及び、氷で冷却しながら、水1.5リットル中に水酸化ナトリウム770gを含む溶液をそれらに加えた。混合物を4時間還流し、アミンを水蒸気蒸留により単離した。留出物を濃塩酸で酸性化し、ジエチルエーテルで抽出し、その後50％水酸化ナトリウム溶液でアルカリ性にした。残渣を分留した。(B_p 760mm＝114〜115℃)。
収量：45g(36％)。 4- [1-Hydroxy-2- (1-methyl-cyclopentylamino) -ethyl] -3-methoxy-benzene-1,2-diol

a) 1-methyl-cyclopentylamine:
66.5 g of sodium cyanide was dissolved in 150 ml of glacial acetic acid. A solution of 300 ml sulfuric acid and 150 ml glacial acetic acid was added dropwise to the sodium cyanide solution at 5-10 ° C. 126 g of 1-methyl-cyclopentanol was added to this mixture. The resulting mixture was allowed to stand overnight. Thereafter, 210 ml of water and a solution containing 770 g of sodium hydroxide in 1.5 liters of water was added to them while cooling with ice. The mixture was refluxed for 4 hours and the amine was isolated by steam distillation. The distillate was acidified with concentrated hydrochloric acid, extracted with diethyl ether and then made alkaline with 50% sodium hydroxide solution. The residue was fractionated. (B _p 760 mm = 114-115 ° C.).
Yield: 45 g (36%).

b) 1- (4-Methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -2- (1-methyl-cyclopentylamino) -ethanone:
35 g of α-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone was refluxed with 45 g of 1-methyl-cyclopentylamine in 150 ml of ethanol for 1 hour. The solvent was distilled off under reduced pressure, the residue was dissolved in diethyl ether and extracted with water, and the solvent was distilled off under reduced pressure. The remaining residue was dissolved in acetonitrile, acidified with hydrochloric acid, and the resulting crystals were isolated.
Yield: 19 g (48%; hydrochloride); melting point = 173 ° C. (decomposition)

c) 1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- (1-methyl-cyclopentyl-amino) -ethanone:
19 g of 1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -2- (1-methyl-cyclopentylamino) -ethanone was stirred in 190 ml of 15% hydrochloric acid methanol. The mixture was refluxed for 2 hours. The solvent was distilled off under reduced pressure and the remaining residue was dissolved in acetonitrile. The precipitated crystals were washed with diethyl ether.
Yield: 11 g (88%; hydrochloride); melting point = 187-189 ° C. (decomposition).

d) 4- [1-Hydroxy-2- (1-methyl-cyclopentylamino) -ethyl] -3-methoxy-benzene-1,2-diol:
5 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1-methyl-cyclopentyl-amino) -ethanone hydrochloride was hydrogenated with 0.2 g of PtO _{2 in} 200 ml of methanol. The catalyst was filtered off with suction, and the solvent was distilled off under reduced pressure. The remaining residue was dissolved in ethanol and combined with 5 g of sodium benzoate. The title compound was isolated in its benzoate form.
Yield: 4.5 g (70.5%; benzoate); melting point = 179-180 ° C.

a) 2-クロロメチル-1,3,5-トリメチル-ベンゼン：
メシチレン400gを、パラホルムアルデヒド130gと合わせ、塩酸2リットルを、60〜70℃で7時間以内にパイプで入れた。その後、その混合物をベンゼンで抽出し、その後、有機層を2N水酸化ナトリウム溶液で洗った。残渣を分留した。
収量：204g(36％)；bp₁₅ ＝130〜140℃ 4- {2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol

a) 2-Chloromethyl-1,3,5-trimethyl-benzene:
400 g of mesitylene was combined with 130 g of paraformaldehyde and 2 liters of hydrochloric acid were piped at 60-70 ° C. within 7 hours. The mixture was then extracted with benzene and then the organic layer was washed with 2N sodium hydroxide solution. The residue was fractionated.
Yield: 204 g (36%); bp ₁₅ = 130-140 ° C

b) (2,4,6-trimethyl-phenyl) -acetonitrile;
66 g of sodium cyanide was refluxed with stirring in 100 ml of water and 140 ml of ethanol until a clear solution was formed. 136 g of 2-chloromethyl-1,3,5-trimethyl-benzene was slowly added dropwise to this solution and the mixture was refluxed for 3 hours with stirring. It was diluted with 1 liter of water and extracted 3 times with 200 ml of benzene. The combined organic layers were washed with water and the solvent was removed under reduced pressure. The residue was fractionated.
Yield: 92 g (72%); bp ₁₅ = 145-153 ° C.

c) (2,4,6-Trimethyl-phenyl) -acetic acid:
155 g of (2,4,6-trimethyl-phenyl) -acetonitrile was added to a solution containing 1.1 liters of water and 915 ml of concentrated sulfuric acid heated to 50 ° C. The mixture was refluxed for 6 hours with stirring. The reaction mixture was then poured onto 3 kg of ice. The solid was filtered off with suction and washed with water.
Yield: 131 g (86%); melting point = 163-166 ° C.

d) Methyl (2,4,6-trimethyl-phenyl) -acetate:
173 g of (2,4,6-trimethyl-phenyl) -acetic acid was refluxed with stirring in 131 ml of concentrated hydrochloric acid and 1.1 l of methanol for 3 hours. The solvent was distilled off under reduced pressure, and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were extracted twice with a saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was fractionated.
Yield: 116 g (57%); bp ₁₅ = 140 ° C.

e) 2-Methyl-1- (2,4,6-trimethyl-phenyl) -propan-2-ol:
97 g (79%) of the title compound are prepared under standard conditions in a Grignard reaction from 38 g of magnesium and 222 g of methyl iodide and 116 g of methyl (2,4,6-trimethyl-phenyl) -acetate in 1.2 l of diethyl ether did. bp ₁₅ = 140 ° C.

f) N- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethyl] -formamide:
90 ml of glacial acetic acid and 33 g of potassium cyanide were combined while cooling with ice. Thereafter, 90 ml of sulfuric acid and 90 ml of glacial acetic acid were added dropwise at 20 ° C. 65 g of 2-methyl-1- (2,4,6-trimethyl-phenyl) -propan-2-ol was slowly added to the solution at a constant temperature. After the addition was complete, the mixture was stirred for an additional hour. The mixture was poured onto ice water, neutralized with sodium carbonate solution and extracted with diethyl ether. The solvent was distilled off under reduced pressure, and the residue was fractionated.
Yield: 55 g (74%); bp _0.1 = 155 ° C.

g) 1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamine:
61 g of N- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethyl] -formamide was refluxed for 9 hours with stirring in 35 g of potassium hydroxide and 155 ml of ethylene glycol. After the end of the mixture, the mixture was poured onto 1 kg of ice. The aqueous layer was extracted 3 times with diethyl ether, and the solvent was distilled off under reduced pressure. The residue was fractionated.
Yield: 48 g (89%); bp ₁₅ = 135-140 ° C.

h) 2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxole- 5-yl) -ethanone:
α-Bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone 42.5 g, 1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamine 22 g and potassium carbonate 17 g, ethanol The mixture was refluxed in 150 ml and 50 ml of acetonitrile with stirring for 3 hours. The solid was removed by filtration and the solvent was removed under reduced pressure. The residue was dissolved in a small amount of acetonitrile and combined with hydrochloric acid ether. The precipitated crystals were suction filtered and washed with acetonitrile and ethyl acetate.
Yield: 25 g (44%; hydrochloride); melting point = 240-250 ° C.

i) 1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -ethanone:
2- [1,1-Dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxole-5- Yl) -ethanone hydrochloride (17 g) was refluxed with 170 ml of 15% hydrochloric acid methanol for 90 minutes with stirring. Most of the solvent was distilled off under reduced pressure. The remaining residue was crystallized. The crystals were filtered and washed with diethyl ether.
Yield: 10 g (80%; hydrochloride), melting point = 199-201 ° C.

j) 4- {2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol :
9 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,4,6-trimethyl-phenyl) -ethylamino] -ethanone-hydrochloride, Hydrogenated with 0.4 g of platinum (IV) oxide in 125 ml of methanol. The catalyst was filtered and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, the precipitated crystals were suction filtered and washed with diethyl ether and ethyl acetate.
Yield: 6 g (67%, hydrochloride); melting point = 98-105 ° C.

a) 2-(1,1-ジメチル-フェニルエチルアミノ)-1-(4-メトキシ-2,2-ジフェニル-ベンゾ[1,3]ジオキソール-5-イル)-エタノン：
α-ブロモ-2-メトキシ-3,4-ジフェニルメチレンジオキシアセトフェノン 45gを、1,1-ジメチル-2-フェニルエチルアミン 39gと、エタノール200ml中、3時間還流した。反応混合物を濃塩酸で酸性化し、水と合わせた。沈殿した結晶を吸引ろ過し、水、トルエン及び酢酸エチルで連続的に洗った。
収量：34g(61％、ヒドロクロライド)；融点＝167〜170℃ 4- [2- (1,1-Dimethyl-2-phenyl-ethylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol

a) 2- (1,1-Dimethyl-phenylethylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone:
45 g of α-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone was refluxed with 39 g of 1,1-dimethyl-2-phenylethylamine in 200 ml of ethanol for 3 hours. The reaction mixture was acidified with concentrated hydrochloric acid and combined with water. The precipitated crystals were suction filtered and washed successively with water, toluene and ethyl acetate.
Yield: 34 g (61%, hydrochloride); melting point = 167-170 ° C

b) 1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-2-phenylethylamino) -ethanone:
34 g of HCl salt of 2- (1,1-dimethyl-2-phenylethylamino) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone The mixture was refluxed in 340 ml of% hydrochloric acid for 2 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The precipitated solid was suction filtered and washed with ethyl acetate and diethyl ether.
Yield: 18 g (77%, hydrochloride); mp 192-196 ° C.

c) 4- {2- [1,1-Dimethyl-2-phenyl-ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2-diol:
Hydrogenate 10 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-2-phenylethylamino) -ethanone hydrochloride with 0.5 g of PtO _{2 in} 200 ml of methanol did. The catalyst was filtered off with suction, and the solvent was distilled off under reduced pressure. The remaining residue was dissolved in 200 mL of acetonitrile, combined with 5 g of sodium benzoate and refluxed for 15 minutes. After excess sodium benzoate was filtered, the product precipitated in the filtrate was filtered and washed with acetonitrile and diethyl ether.
Yield: 64.5% (benzoate); mp 149-150 ° C.

a) 2-[1,1-ジメチル-2-(2,3,5,6-テトラメチル-フェニル)-エチルアミン]-1-(4-メトキシ-2,2-ジフェニル-ベンゾ[1,3]ジオキソール-5-イル)-エタノン：
α-ブロモ-2-メトキシ-3,4-ジフェニルメチレンジオキシアセトフェノン 28.5g、1,1-ジメチル-2-(2,3,5,6-テトラメチル-フェニル)-エチルアミン 11g及び炭酸ナトリウム8gを、エタノール100ml及びアセトニトリル10mlの溶液中、3時間還流した。その後、無機塩をろ過し、溶媒を留去した。残渣を酢酸エチルに溶解し、塩酸エーテルで酸性化し、ジエチルエーテルと合わせた。沈殿した固形物をろ過し、ジエチルエーテルで洗い、その後、水中で沸騰させた。ろ過及び乾燥後に生成物を得た。
収量11g(ヒドロクロライド)；融点194〜198℃。 4- {2- [1,1-dimethyl-2- (2,3,5,6-tetra-methyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1,2 -Diol

a) 2- [1,1-Dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine] -1- (4-methoxy-2,2-diphenyl-benzo [1,3] Dioxole-5-yl) -ethanone:
α-Bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone 28.5 g, 1,1-dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine 11 g and sodium carbonate 8 g The solution was refluxed for 3 hours in a solution of 100 ml of ethanol and 10 ml of acetonitrile. Thereafter, the inorganic salt was filtered and the solvent was distilled off. The residue was dissolved in ethyl acetate, acidified with hydrochloric acid ether and combined with diethyl ether. The precipitated solid was filtered, washed with diethyl ether and then boiled in water. The product was obtained after filtration and drying.
Yield 11 g (hydrochloride); mp 194-198 ° C.

b) Preparation of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine] -ethanone :
2- [1,1-Dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine] -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxole- 11 g of 5-yl) -ethanone-hydrochloride was refluxed in 110 ml of 15% hydrochloric acid for 1.5 hours. The crude product was filtered off with suction, washed with acetonitrile and then precipitated from methanol / diethyl ether.
Yield: 7 g (hydrochloride); mp 213-215 ° C. (decomposition).

c) 4- {2- [1,1-Dimethyl-2- (2,3,5,6-tetra-methyl-phenyl) -ethylamino] -1-hydroxy-ethyl} -3-methoxy-benzene-1 Production of 1,2-diol:
1- (3,4-Dihydroxy-2-methoxy-phenyl) -2- [1,1-dimethyl-2- (2,3,5,6-tetramethyl-phenyl) -ethylamine] -ethanone-hydrochloride 7g Was hydrogenated with 0.2 g of platinum (IV) oxide in 100 ml of methanol. Thereafter, the catalyst was filtered and the solvent was distilled off. The residue was dissolved in 20 ml of water and combined with 1N hydrochloric acid. After cooling, the precipitated crystals were filtered, washed with ice water, dried and recrystallized from ethyl acetate.
Yield: 5 g; mp 165-168 ° C.

a) 2-(1,1-ジメチル-2-o-トリル-エチルアミン)-1-(4-メトキシ-2,2-ジフェニル-ベンゾ[1,3]ジオキソール-5-イル)-エタノンの製造:
α-ブロモ-2-メトキシ-3,4-ジフェニルメチレンジオキシアセトフェノン 26g、1,1-ジメチル-2-o-トリル-エチルアミン 10g及び炭酸ナトリウム9.5gを、アセトニトリル中、3時間還流した。無機塩をろ過し、溶媒を留去した。残渣を酢酸エチルに溶解し、塩酸エーテルで酸性化し、そこで出発アミンを沈殿させ、吸引ろ過した。ろ液へのジエチルエーテルの添加の後、生成物を結晶化した。
収量10g(30％；ヒドロクロライド)；融点180〜184℃。 4- [2- (1,1-Dimethyl-2-o-tolyl-ethylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol

a) Preparation of 2- (1,1-dimethyl-2-o-tolyl-ethylamine) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone:
26 g of α-bromo-2-methoxy-3,4-diphenylmethylenedioxyacetophenone, 10 g of 1,1-dimethyl-2-o-tolyl-ethylamine and 9.5 g of sodium carbonate were refluxed in acetonitrile for 3 hours. The inorganic salt was filtered and the solvent was distilled off. The residue was dissolved in ethyl acetate and acidified with hydrochloric acid ether, whereupon the starting amine was precipitated and suction filtered. The product crystallized after addition of diethyl ether to the filtrate.
Yield 10 g (30%; hydrochloride); mp 180-184 ° C.

b) Preparation of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-2-o-tolyl-ethylamine) -ethanone:
10 g of 2- (1,1-dimethyl-2-o-tolyl-ethylamine) -1- (4-methoxy-2,2-diphenyl-benzo [1,3] dioxol-5-yl) -ethanone-hydrochloride The mixture was refluxed in 100 ml of 15% hydrochloric acid for 1.5 hours. The reaction mixture was evaporated and the residue was recrystallized from ethyl acetate. After filtration, the resulting solid was washed with diethyl ether.
Yield 6 g (85%; hydrochloride); mp 198-201 ° C. (decomposition).

c) Preparation of 4- [2- (1,1-dimethyl-2-o-tolyl-ethylamino) -1-hydroxy-ethyl] -3-methoxy-benzene-1,2-diol:
4 g of 1- (3,4-dihydroxy-2-methoxy-phenyl) -2- (1,1-dimethyl-2-o-tolyl-ethylamine) -ethanone-hydrochloride under normal conditions in 50 ml of methanol, Hydrogenated with 0.2 g of platinum (IV) oxide. Thereafter, the catalyst was filtered and the solvent was distilled off. The residue was combined with 100 ml acetonitrile and 3 g sodium benzoate. It was refluxed for 20 minutes and the inorganic material was filtered. The product crystallized from the filtrate was suction filtered and recrystallized from acetonitrile.
Yield 2.4 g (benzoate); mp 114 ° C.

It has been found that the compounds of general formula 1 are characterized by their versatility in the therapeutic field. Of particular note is their use in which the compounds of general formula 1 according to the invention are preferably used due to their pharmaceutical effectiveness as beta mimetics.
These include, for example, treatment of asthma, COPD (chronic obstructive pulmonary disease), prevention of early labor in midwifery (suppression of uterine contraction), recovery of cardiac sinus rhythm in atrioventricular block, and symptoms of bradycardiac heart rhythm Examples include elimination of bradycardic heart rhythm disorders (antiarrhythmia), cardiovascular shock treatment (vasodilation and increased cardiac output), and treatment of skin pruritus and inflammation.

  The compounds of general formula 1 may be used on their own or with other active substances of general formula 1. The compound of general formula 1 may also be used in combination with other pharmacologically active substances. They may in particular be anti-cholinergic drugs, anti-allergic drugs, PAF antagonists, PDE-IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids, and combinations of their active substances .

Examples of preferred anticholinergic agents that may be used with compounds of general formula 1 are tiotropium salts, ipratropium salts, oxitropium salts, salts of compounds known from WO 02/32899,
Tropenol-N-methyl-2,2-diphenylpropionate,
Scopine N-methyl-2,2-diphenylpropionate,
Scopine N-methyl-2-fluoro-2,2-diphenylacetate and tropenol N-methyl-2-fluoro-2,2-diphenylacetate and the salt of the compound known from WO 02/32899 Tropenol N-methyl-3, 3 ', 4,4'-tetrafluorobenzylate,
Scopine N-methyl-3,3 ', 4,4'-tetrafluorobenzylate;
Scopine N-methyl-4,4'-dichlorobenzylate,
Scopine N-methyl-4,4'-difluorobenzylate,
Tropenol N-methyl-3,3'-difluorobenzylate,
Scopine N-methyl-3,3′-difluorobenzilate and tropenol N-ethyl-4,4′-difluorobenzilate, optionally selected from those in the form of hydrates and solvates is there. The salt means those compounds containing, in addition to the cation, an anion having a single negative charge selected from chloride, bromide and methanesulfonate as a counter ion.

Particularly preferably, the active substance within the scope of the present invention is a bromide or methanesulfonate of the above structure.
Of particular interest within the scope of the present invention are, for example, the anticholinergic drugs tiotropium bromide, ipratropium bromide, oxitropium bromide, tropenol 2,2-diphenylpropionate-methobromide, scopine 2,2- Diphenylpropionate-methobromide, scopine 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 2-fluoro-2,2-diphenylacetate-methobromide, tropenol 3,3 ', 4,4'-tetrafluorobenzilate -Methobromide, scopine 3,3 ', 4,4'-tetra-fluorobenzilate-methobromide; scopine 4,4'-dichlorobenzylate-methobromide, scopine 4,4'-difluorobenzylate-methobromide, tropenol 3,3 '-Difluorobenzilate-Metobromide, Scopine 3,3'-Difluorobenzilate- Tobromide and tropenol 4,4'-difluorobenzilate-ethyl bromide, including tiotropium bromide, ipratropium bromide, tropenol 2,2-diphenylpropionate-methobromide, scopine 2,2-diphenylpropionate-methobromide, scopine 2 Of particular importance are -fluoro-2,2-diphenylacetate-methobromide and tropenol 2-fluoro-2,2-diphenylacetate-methobromide.

In addition to the compounds of the general formula 1 according to the invention, drug combinations containing tiotropium bromide as other active substance are particularly preferred according to the invention. This combination is particularly important for the treatment of asthma or COPD, in particular COPD. Particularly important are those containing tiotropium bromide in its crystalline monohydrate form known from WO 02/30928 or in its crystalline anhydride form known from WO 03/000265. It is a combination.
Within the scope of the present invention, corticosteroids that may optionally be used with the compound of general formula 1 are flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide. , GW 215864, KSR 592, ST-126, and a compound selected from dexamethasone. Preferably, within the scope of the present invention, the corticosteroid is selected from flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, with budesonide, fluticasone, mometasone and ciclesonide being important, budesonide and fluticasone Of particular importance. In some cases, within the scope of this patent application, the term steroid is used per se instead of the word corticosteroid. References to steroids within the scope of the present invention include references to salts or derivatives that may be formed from sterods. Examples of possible salts or derivatives are; sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Also, in some cases, corticosteroids may occur in their hydrate form.

  Examples of PDE-IV inhibitors that may be used according to the present invention as a combination with a compound of general formula 1 include enprofylline, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch- 351591), V-11294A, Z-15370 and AWD-12-281. Preferred PDE-IV inhibitors are selected from enprofylline, roflumilast, ariflo, Z15370 and AWD-12-281, with AWD-12-281 being particularly preferred as a combination partner with the compound of general formula 1 according to the invention. Also within the scope of the present invention, references to the above PDE-IV inhibitors include references to their pharmaceutically acceptable acid addition salts that may be present. Physiologically acceptable acid addition salts that may be formed by the PDE-IV inhibitors are according to the invention hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, It means a pharmaceutically acceptable salt selected from salts selected from lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, salts selected from acetates, hydrochlorides, hydrobromides, sulfates, phosphates and methanesulfonates are preferred herein.

  Within the scope of the present invention, the term dopamine agonist that may optionally be used with compounds of general formula 1 is bromocriptine, cabergoline, α-dihydroergocryptin, lisuride, pergolide, pramipexole, roxindol, ropinirole Represents a compound selected from talipexol, terguride and viozan. Within the scope of the present invention, it is preferred to use a dopamine agonist selected from pramipexole, talipexol and biozan as a combination partner with the compound of general formula 1, with pramipexole being particularly important. References to the above dopamine agonists include within the scope of the present invention references to their pharmaceutically acceptable acid addition salts and hydrates that may be present. Those physiologically acceptable acid addition salts that may be formed by the dopamine agonist are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid. Meaning a pharmaceutically acceptable salt selected from salts of citric acid, tartaric acid and maleic acid.

  Examples of antiallergic agents that may be used according to the present invention as combinations with compounds of general formula 1 include epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimethindene, clemastine, bamipin , Cexchloropheniramine, phenylamine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclizine. Preferred antiallergic agents that may be used within the scope of the present invention in combination with a compound of general formula 1 according to the present invention are from epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine Epinastine and desloratidine are particularly preferred. References to the above antiallergic agents also include references to their pharmaceutically acceptable acid addition salts that may be present within the scope of the present invention.

Examples of PAF antagonists that may be used according to the present invention as a combination with a compound of general formula 1 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] diazepine and 6- (2-chlorophenyl) -8, 9-Dihydro-1-methyl-8-[(4-morpholinyl) carbonyl] -4H, 7H-cyclo-penta- [4.5] thieno- [3,2-f] [1,2,4] triazolo [4, 3-a] [1,4] diazepine.
Examples of EGFR kinase inhibitors that may be used as a combination with a compound of general formula 1 according to the invention include in particular 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4- ( (R) -6-Methyl-2-oxo-morpholin-4-yl) -butyloxy] -6-[(vinylcarbonyl) amino] -quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [4-((S) -6-Methyl-2-oxo-morpholin-4-yl) -butyloxy] -6-[(vinylcarbonyl) amino] -quinazoline, 4-[(3-chloro-4 -Fluoro-phenyl) amino] -7- (2- {4-[(S)-(2-oxo-tetrahydrofuran-5-yl) carbonyl] -piperazin-1-yl} -ethoxy) -6-[(vinyl Carbonyl) amino] -quinazoline, 4-[(3-chloro-4-fluoro-phenyl) amino] -7- [2-((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy ] -6-[(vinylcarbonyl) amino] -quinazoline, 4-[(3-chloro-4-fluoro Phenyl) amino] -6-[(4- {N- [2- (ethoxycarbonyl) -ethyl] -N-[(ethoxycarbonyl) methyl] 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-butene-1 -Yl] amino} -7-cyclopropylmethoxy-quinazoline and 4-[(3-chloro-4-fluorophenyl) amino] -6- [3- (morpholin-4-yl) -propyloxy] -7-methoxy -Quinazoline. References to the above EGFR kinase inhibitors also include references to their pharmaceutically acceptable acid addition salts that may be present within the scope of the present invention. Physiologically or pharmacologically acceptable acid addition salts thereof that may be formed by EGFR kinase inhibitors are according to the invention hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid. A pharmaceutically acceptable salt selected from salts of succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Preferred according to the invention are salts of EGFR kinase inhibitors selected from the salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

  Particularly preferred examples of p38 kinase inhibitors that may be used in combination with compounds of general formula 1 according to the invention 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-methylpyridin-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. Reference to the p38 kinase inhibitor also includes reference to pharmaceutically acceptable acid addition salts thereof that may be present within the scope of the present invention. Physiologically or pharmacologically acceptable acid addition salts thereof which may be formed by p38 kinase inhibitors are according to the invention hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid. Means a pharmaceutically acceptable salt selected from salts of succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.

If a compound of general formula 1 is used with other active substances, a combination of the above classes of compounds with steroids, PDE IV inhibitors or anticholinergics is particularly preferred. Combinations with anticholinergic drugs are particularly important.
Suitable formulations for administering the compound of general formula 1 include, for example, tablets, capsules, suppositories and liquids. Inhalation administration of the compounds according to the invention is of particular importance according to the invention (especially for the treatment of asthma or COPD). The content of pharmaceutically active compound is considered as a whole from 0.05 to 90% by weight, preferably from 0.1 to 50% by weight of the composition. Suitable tablets are, for example, active substances, known excipients such as inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants. It may be obtained by mixing with an agent such as magnesium stearate or talc and / or a release-retarding agent such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. A tablet may contain several layers.

Coated tablets are prepared accordingly by coating a core made analogously to tablets with substances usually used for tablet coating, such as Kollidon or shellac, gum arabic, talc, titanium dioxide or sugar. Also good. In order to achieve delayed release or prevent incompatibility, the core may consist of multiple layers. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, optionally using the tablet excipients described above.
Syrups or elixirs containing the active substances according to the invention or combinations thereof further comprise sweeteners such as saccharin, cyclamate, glycerol or sugar and flavor enhancers such as flavors such as vanillin or orange extract. You may go out. They may also contain suspending aids or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as p-hydroxybenzoates.

The solution is prepared using conventional emulsifiers and / or dispersants as desired, for example by addition of isotonic agents, preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid. If water is used as a diluent, for example, an organic solvent may be used as a solubilizer or solubilizer, and the solution may be transferred to an infusion vial or ampoule or infusion bottle.
Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and filling them into gelatin capsules.

Suitable suppositories may be made by mixing with a carrier provided for this purpose, for example neutral fat or polyethylene glycol or derivatives thereof.
Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (eg petroleum fractions), vegetable oils (eg peanut oil or sesame oil), monofunctional or polyfunctional Alcohol (eg, ethanol or glycerol), carrier, eg, natural mineral powder (eg, kaolin, clay, talc, chalk), synthetic mineral powder (eg, highly disperse silicic acid and silicate), sugar (eg, sucrose, lactose) And glucose), emulsifiers (eg lignin, sulfite drainage, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

For oral use, tablets may contain, in addition to the specified carrier, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, and various additional substances such as starch, preferably potato starch, gelatin and the like. It may be clearly included with. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used to make tablets. In the case of aqueous suspensions, the active substances may be combined with various flavor enhancers or colorants in addition to the above excipients.
In the preferred use of the compound of general formula 1 for the treatment of asthma or COPD, it is particularly preferred according to the invention to use a formulation or pharmaceutical formulation suitable for inhalation. Examples of inhalation preparations include inhalation powders, propellant-containing quantitative aerosols or propellant-free inhalation solutions. Within the scope of the present invention, the term propellant-free inhalation solution also includes concentrates or sterile ready-to-use inhalation solutions. Formulations that may be used within the scope of the present invention are described in more detail in the following portions of the specification.

Inhalable powders that may be used according to the present invention may comprise 1 either on their own or in a mixture with suitable physiologically acceptable excipients.
If the active substance 1 is present in a mixture with physiologically acceptable excipients, the following physiologically acceptable excipients are used to produce these inhalable powders according to the invention. May be used: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose), oligosaccharides and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol) ), Salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably monosaccharides or disaccharides are used, the use of lactose or glucose being preferred, especially in the form of their hydrates, although not exclusively. For the purposes of the present invention, lactose is a particularly preferred excipient, with lactose monohydrate being most preferred.

  Within the inhalable powders according to the invention, the maximum average particle size of the excipient is not more than 250 μm, preferably 10 to 150 μm, most preferably 15 to 80 μm. In some cases, it may be considered suitable to add a finer excipient fraction with an average particle size of 1-9 μm to the excipient. These finer excipients are also selected from the group of possible excipients described above. Finally, to produce an inhalable powder according to the invention, micronized active substance 1, preferably having an average particle size of 0.5-10 μm, more preferably 1-5 μm, is added to the excipient mixture. Processes for producing inhalable powders according to the invention by grinding the ingredients, micronizing and finally mixing together are known from the prior art. The inhalable powder according to the invention may be administered using inhalers known from the prior art.

An inhalation aerosol containing an atomizing gas according to the present invention may comprise Compound 1 in a form dissolved or dispersed in the atomizing gas. Compound 1 is contained in separate or common formulations, where it is either dissolved together or dispersed together, or in each case only one component is dissolved and the other is dispersed. May be. Nebulizing gases that may be used to produce inhaled aerosols are known from the prior art. Suitable atomizing gases are selected from hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.
The spray inhalation aerosol may also contain other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All those components are known in the art.
The above nebulized inhalation aerosols according to the present invention may be administered using inhalers known in the art (MDI = metered dose inhalers).

  Furthermore, the active substance 1 according to the invention may be administered in the form of spray-free inhalable solutions and suspensions. The solvent used may be aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water alone or a mixture of water and ethanol. The relative ratio of ethanol compared to water is not limited but is preferably at most 70% by volume, more specifically 60% by volume or less, most preferably 30% by volume or less. The remainder of the volume is composed of water. The solution or suspension containing 1 is adjusted to pH 2-7, preferably 2-5, using a suitable acid. The pH may be adjusted using an acid selected from inorganic acids or organic acids. 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, acetic acid, formic acid and / or propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use an acid that has already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If necessary, in particular in the case of acids having other properties in addition to their acidifying properties, such as fragrances, antioxidants or complexing agents, such as citric acid or ascorbic acid, a mixture of said acids may be used. May be used. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

  If desired, the addition of edetic acid (EDTA) or one of their known salts, sodium edetate, as a stabilizer or complexing agent, is unnecessary for these formulations. Other embodiments may include this compound or these compounds. In a preferred embodiment, the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. In general, an inhalation solution having a sodium edetate content of 0 to 10 mg / 100 ml is preferred.

  Co-solvents and / or other excipients may be added to the propellant-free inhalation solution. Preferred cosolvents are those containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropyl alcohol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. It is. In this specification, the terms excipients and additives are not active substances, but are qualitatively formulated into active substance formulations in active substances (or active substances) in physiologically suitable solvents. Represents any pharmacologically acceptable substance that can improve properties. Preferably, these substances do not have a pharmacological action or, in connection with the desired treatment, the pharmacological action is undetectable or at least has no undesirable pharmacological action. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as polysorbate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives. Such as those that guarantee or postpone the shelf life of the finished pharmaceutical formulation, fragrances, vitamins and / or other additives known in the art. Examples of the additive include a pharmacologically acceptable salt, for example, sodium chloride as an isotonic agent.

Preferred excipients include antioxidants such as ascorbic acid (for example, if not already used to adjust pH), vitamin A, vitamin E, tocopherol and similar vitamins that occur in the human body. And provitamins.
Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates, such as sodium benzoate, at concentrations known from the prior art. . The preservative is preferably present at a concentration of 50 mg / 100 ml or less, more preferably 5-20 mg / 100 ml.
A preferred formulation contains only benzalkonium chloride and sodium edetate in addition to the solvent water and the active substance. In other preferred embodiments, sodium edetate is absent.
The dosage of the compounds according to the invention naturally depends considerably on the method of administration and the complaint to be treated. When administered by inhalation, compounds of general formula 1 are characterized by high potency, even in amounts in the μg range. Moreover, the compound of General formula 1 may be used effectively exceeding a microgram range. Thus, the dosage may be in the gram range, for example. In particular, when administered by routes other than inhalation, the compounds according to the invention may be administered in higher amounts (eg, but not limited to the range of 1-1000 mg).

The following formulation examples illustrate the invention without limiting the scope of the invention:
Examples of pharmaceutical formulations
A) Tablet
Per tablet

A portion of the fine active substance, lactose and corn starch were mixed together. The mixture was sieved and then wetted with aqueous polyvinylpyrrolidone solution, kneaded, wet granulated and dried. The granules, the remaining corn starch and magnesium stearate were screened and mixed together. The mixture was compressed into tablets of suitable shape and size.
B) Tablet
Per tablet

The fine active substance, a portion of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved, mixed with the remaining corn starch and water, formed into granules, dried and sieved It was. To these, carboxymethyl sodium starch and magnesium stearate were added, they were mixed together and the mixture was compressed into tablets of suitable shape and size.
C) Ampoule solution

The active substance was dissolved in water at its own pH or optionally at pH 5.5-6.5 and sodium chloride was added to make an isotonic solution. The resulting solution was filtered to remove pyrogens, and the filtrate was transferred to aseptic and heat-sealed ampoules under aseptic conditions. Ampoules contained 5 mg, 25 mg and 50 mg of active substance.

D) Weighing aerosol

The suspension was transferred to an aerosol container with a conventional metering valve. Preferably 50 μl of the suspension was released with each actuation. In addition, the active substance may be released in larger amounts as required (eg 0.02% by weight).
E) Liquid
(mg / 100ml)

You may manufacture this liquid agent by the conventional method.
F) Powder for inhalation

  Inhalable powders were prepared in a conventional manner by mixing the individual components.

Claims (14)

Compounds of general formula 1;

{Wherein R ¹ represents alkyl having 1 to 4 carbon atoms;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ represents alkyl having 1 to 4 carbons or phenyl (which may be optionally mono- or polysubstituted); or
R ² and R ³ together represent a double-bonded group selected from —CH ₂ —CH ₂ — and —CH ₂ —CH ₂ —CH ₂ —. Where
R ¹ represents alkyl having 1 to 4 carbons;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ is alkyl having 1 to 4 carbons or phenyl (they are optionally alkyl having 1 to 3 carbons, CF ₃ , methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, —OCF ₃ , —CHF ₂ , It may be mono-, di-, tri-, or tetra-substituted by one or more groups selected from -NHCOCH ₃ and -NHSO ₂ CH ₃ , or
Is R ² and R ^3, taken together, -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ - represents a bond to group doubly selected from the general formula of claim 1 1 compound. Where
R ¹ represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ² represents alkyl having 1 to 4 carbon atoms;
R ³ is alkyl or phenyl having 1 to 4 carbon atoms (which are optionally mono-substituted, di-substituted, tri-substituted, or one or more groups selected from methyl, ethyl, CF ₃ , methoxy, ethoxy and hydroxy) Which may be tetrasubstituted), or
R ² and R ^3, together, -CH ₂ -CH ₂ - and -CH ₂ -CH ₂ -CH ₂ - represents a bond to group doubly selected from, according to claim 1 or 2 A compound of general formula 1. Where
R ¹ represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ² represents alkyl having 1 to 4 carbon atoms, preferably methyl;
R ³ is alkyl having 1 to 4 carbon atoms, preferably methyl or phenyl (they are optionally mono-, di-, tri-substituted by one or more groups selected from methyl, CF ₃ , methoxy and hydroxy Or may be tetrasubstituted), or
The compound of general formula 1 according to any one of claims 1 to 3, wherein R ² and R ³ together represent a doubly bonded group, -CH ₂ -CH _2- . Where
R ¹ represents methyl or ethyl, preferably methyl;
R ² represents methyl;
R ³ is methyl, ethyl or phenyl (which may be optionally mono-, di-, tri- or tetra-substituted by one or more groups selected from methyl, CF ₃ , methoxy and hydroxy) Or
The compound of the general formula 1 according to any one of claims 1 to 4, wherein R ² and R ³ together represent a double-bonded group, -CH ₂ -CH _2- . Where
R ¹ represents methyl;
R ² represents methyl;
R ³ represents methyl or phenyl (which may optionally be mono-, di- or tri-substituted by one or more groups selected from methyl, ethyl and hydroxy), or
The compound of the general formula 1 according to any one of claims 1 to 5, wherein R ² and R ³ together represent a doubly bonded group, -CH ₂ -CH _2- . Where
R ¹ represents methyl;
R ² represents methyl;
R ³ represents methyl or phenyl, or
The compound of the general formula 1 according to any one of claims 1 to 6, wherein R ² and R ³ together represent a doubly bonded group, -CH ₂ -CH _2- .   8. Any one of claims 1 to 7 in the form of individual optical isomers, individual enantiomers or racemic mixtures, and the corresponding acid addition salts of free bases or pharmaceutically acceptable acids. A compound of general formula 1 as described in 1 above.   Use of a compound of general formula 1 according to any one of claims 1 to 8 as a pharmaceutical composition.   Use of a compound of general formula 1 according to any one of claims 1 to 8 for the manufacture of a pharmaceutical composition for the treatment of diseases for which beta mimetics can provide a therapeutic benefit.   Asthma, COPD, preterm delivery in midwifery (uterine contraction suppression), atrioventricular block, and bradycardiac rhythm symptoms (antiarrhythmia), cardiovascular shock (vasodilation and increased cardiac output), and skin pruritus And the use of a compound of general formula 1 according to any one of claims 1 to 8 for the manufacture of a pharmaceutical composition for the treatment of inflammation.   9. A pharmaceutical preparation comprising as active substance one or more compounds of general formula 1 according to any one of claims 1 to 8, optionally in combination with conventional excipients and / or carriers.   In addition to one or more compounds of general formula 1, at least one selected from anticholinergic drugs, antiallergic drugs, PAF antagonists, PDE IV inhibitors, leukotriene antagonists, p38 kinase inhibitors, EGFR kinase inhibitors and corticosteroids The pharmaceutical preparation according to claim 12, comprising other active substances or combinations of active substances.   14. Pharmaceutical formulation according to claim 13, which in addition to one or more compounds of general formula 1 also contains tiotropium bromide as active substance.