HK1120030A

HK1120030A - Novel drugs for treating respiratory diseases

Info

Publication number: HK1120030A
Application number: HK08108806.9A
Authority: HK
Inventors: Ingo Konetzki; Thierry Bouyssou; Philipp Lustenberger; Andreas Schnapp
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2005-02-24
Filing date: 2006-02-16
Publication date: 2009-03-20

Description

Novel medicaments for the treatment of respiratory diseases

The invention relates to a compound of the general formula1In the preparation of compounds for the treatment of respiratory systemUse in medicine for treating systemic diseases, and novel formula1Compounds, processes for their preparation and pharmaceutical formulations containing them:

wherein the radical R¹、R²And R³Have the meaning as specified in the claims and the description.

Background

Beta-mimetics (Betamimetics) (beta-adrenergic agents) are known in the art. For example, reference may be made to the disclosure of, for example, US4,341,778 or EP43940, which suggest the use of β -mimetics for the treatment of various diseases.

In relation to the pharmacotherapy of diseases, it is often desirable to prepare medicaments having a longer duration of activity. Generally, this ensures that the concentration of the active substance in the body required to achieve a therapeutic effect is maintained over a longer period of time without the need for frequent re-administration of the drug. Furthermore, administering the active substance at longer time intervals helps to provide a high level of comfort to the patient.

It is particularly desirable to prepare a medicament for therapeutic use that can be administered once a day (single dose). The use of drugs once a day has the advantage that patients get used to them relatively quickly than taking them regularly at specific times of the day.

It is therefore an object of the present invention to prepare a β -mimetic which on the one hand provides therapeutic benefit in the treatment of respiratory diseases and is characterised by a longer duration of activity and can therefore be used for the preparation of a medicament with a longer duration of activity. It is a particular object of the present invention to prepare beta-mimetics which, by virtue of their long-lasting action, can be used to prepare a medicament which can be administered once a day for the treatment of asthma. Removing deviceIn addition to the stated objects, it is a further object of the invention to provide such beta mimetics which are not only particularly effective but which are characterized by a beta₂The adrenergic receptors are highly selective.

Detailed Description

Surprisingly, it has been found that1The compound of (4) can solve the above problems.

The present invention therefore relates to one or more, preferably one, of the formulae1For the manufacture of a medicament for the treatment of a respiratory disease:

wherein:

R¹and R²May be the same or different and represents hydrogen, halogen, C₁-C₄Alkyl or together represent C₁-C₆An alkylene group; and

R³represents hydrogen, halogen, OH, C₁-C₄Alkyl or-O-C₁-C₄An alkyl group;

these respiratory diseases are selected from the following diseases: obstructive pulmonary disease of various origins, emphysema of various origins, restrictive pulmonary disease (restrictive pulmonary disease), interstitial pulmonary disease (interstitial pulmonary disease), cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.

Preferred are compounds of the formula1The compound of (1) is used for the above purpose, wherein:

R¹and R²May be the same or different and represents hydrogen, fluorine, chlorine, methyl, ethyl, propyl, butyl or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-；

R³Represents hydrogen, fluorine, chlorine, OH, methyl, ethyl, methoxy or ethoxy.

Also preferred are compounds of the formula1The compound of (1) is used for the above purpose, wherein:

R¹and R²May be the same or different and represents hydrogen, methyl, ethyl, propyl or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-；

R³Represents hydrogen, fluorine, OH, methyl or methoxy.

General formula (VII)1The compounds of (1) are preferably used for the preparation of a medicament for the treatment of obstructive pulmonary diseases selected from the following diseases: bronchial asthma, pediatric asthma, severe asthma, acute asthmatic attacks, chronic bronchitis, and COPD (chronic obstructive pulmonary disease), and it is preferred according to the present invention to use it for the preparation of a medicament for the treatment of bronchial asthma or COPD.

General formula (VII)1Preferably also for the preparation of a medicament for the treatment of emphysema, caused by COPD or a deficiency in α 1-protease inhibitors.

General formula (VII)1Preferably also for the preparation of a medicament for the treatment of obstructive pulmonary disease selected from the following diseases: allergic alveolitis; restricted lung diseases caused by occupational-related harmful factors, such as asbestosis or silicosis; and restrictions caused by lung tumors, such as cancerous lymphangiopathy (lymphangiosis carinomatosa), bronchoalveolar carcinoma and lymphoma.

General formula (VII)1Preferably also for the preparation of a medicament for the treatment ofA medicament for treating an interstitial lung disease selected from the group consisting of: pneumonia caused by infection, such as infection by viruses, bacteria, fungi, protozoa, parasites, or other pathogens; pneumonia caused by various factors, such as aspiration (asparation) and left cardiac insufficiency; pneumonia or fibrosis caused by irradiation; collagen diseases; such as lupus erythematosus (lupuisythemates), systemic scleroderma (systemic scleroderma) or sarcoidosis (sarcoidosis); granulomatosis (granulomatoses), such as bueck's disease; idiopathic interstitial pneumonia or Idiopathic Pulmonary Fibrosis (IPF).

General formula (VII)1Preferably also for the preparation of a medicament for the treatment of cystic fibrosis or mucoviscidosis.

General formula (VII)1The compounds of (a) are preferably also used for the preparation of a medicament for the treatment of bronchitis, such as bronchitis caused by bacterial or viral infections, allergic bronchitis and toxic bronchitis.

General formula (VII)1The compounds of (a) are preferably also used for the preparation of a medicament for the treatment of bronchodilation.

General formula (VII)1The compounds of (a) are preferably also used for the preparation of a medicament for the treatment of ARDS (adult respiratory distress syndrome).

General formula (VII)1The compounds of (a) are preferably also used for the preparation of a medicament for the treatment of pulmonary edema, such as toxic pulmonary edema following inhalation (asparation) or inhalation (inhalation) of toxic substances or foreign bodies.

The invention particularly preferably relates to the general formula1The use of a compound of (a) for the preparation of a medicament for the treatment of asthma. General formula (VII)1The above use of the compounds of (a) for the preparation of a medicament suitable for the once-a-day treatment of inflammatory and obstructive respiratory diseases, in particular for the once-a-day treatment of asthma or COPD, is also of particular importance.

The invention also relates to a method for treating the above-mentioned diseases, characterized in that a therapeutically effective amount of one or more compounds of the above-mentioned general formula is administered1Of (2) to (b)A compound (I) is provided. The invention further relates to a method for treating asthma, characterized in that a therapeutically effective amount of one or more of the above formulae is administered once daily1The compound of (1). The invention further relates to a method for treating COPD, characterized in that a therapeutically effective amount of one or more of the above formulae is administered once daily1The compound of (1).

Preferred are compounds of formula (la) selected from1The use of the compound for the above-mentioned:

-N- (5- {2- [1, 1-dimethyl-3- (4-methyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [1, 1-dimethyl-3- (2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4-ethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (2-hydroxy-5- { 1-hydroxy-2- [3- (6-hydroxy-4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -ethyl } -phenyl) -methanesulfonamide;

-N- (2-hydroxy-5- { 1-hydroxy-2- [3- (6-methoxy-4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -ethyl } -phenyl) -methanesulfonamide.

Formula (II)1Compounds as defined above are known in the art as part of the explicitly named compounds. Reference is made here in particular to the disclosure of documents EP43940 and US 4341778.

The invention further relates to the novel formulae indicated herein1A compound is provided. These compounds are especially of the formula1The compound of (1), wherein:

R¹and R²Which may be identical or different, preferably identical, represent ethyl or propyl or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-; and wherein

R³May represent hydrogen, fluorine, chlorine, OH, methyl, ethyl, methoxy or ethoxy.

Particularly preferred are compounds of formula (II)1A compound, wherein:

R¹and R²Which may be identical or different, preferably identical, represent ethyl or propyl or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-; and wherein

R³May represent hydrogen, fluorine, OH, methyl or methoxy, preferably hydrogen.

Particularly preferred are compounds of formula (II)1The compound of (1), wherein:

R¹and R²Identical and represents ethyl or propyl; and wherein

Particularly preferred are compounds of formula (II)1A compound, wherein:

R¹and R²Together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-; and wherein

Particularly preferred are compounds of formula (II)1A compound of formula (I) wherein R³Represents hydrogen and R¹And R²Having the meaning given above.

Particularly preferred are compounds of formula (II)1Wherein R is³Represents fluorine and R¹And R²Having the meaning given above.

Particularly preferred are compounds of formula (II)1A compound, wherein: r¹And R²Both represent ethyl or propyl and wherein R³Having the meaning given above.

Particularly preferred are those selected from the following1A compound:

-N- (5- {2- [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide;

-N- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclopropane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide;

-N- (5- {2- [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide;

-N- (5- {2- [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide.

In another aspect, the invention relates to the above novel formula as a medicament1A compound is provided. The invention also relates to the above new formula1Use of a compound for the manufacture of a medicament for the treatment of a respiratory disorder selected from the group consisting of: obstructive pulmonary disease of various origins, emphysema of various origins, restrictive pulmonary disease, interstitial pulmonary disease, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.

In another aspect, the invention relates to the formula (I) in the form of individual optical isomers, mixtures of individual enantiomers, diastereomers or racemates1The above use of the compound. Particularly preferred are those in the form of enantiomerically or diastereomerically pure compounds1The above uses of the compounds, and according to the invention, the following formulaR-1The use of the R-enantiomer of the compound is of particular importance:

wherein the radical R¹、R²And R³Having the meaning given above.

In another aspect, the invention relates to the novel formulae described above in the form of the individual optical isomers, the individual enantiomers, mixtures of diastereomers or racemates1A compound is provided. Preference is given to the abovementioned in the form of enantiomerically or diastereomerically pure compoundsNovel formula1A compound according to the invention of the formulaR-1The R-enantiomer of the compound is of particular importance.

In a further aspect, the invention relates to a compound of formula (I) in free base form or in acid addition salt form with a pharmacologically acceptable acid and optionally in the form of a solvate and/or hydrate1The above use of the compound.

In a further aspect, the present invention relates to the novel formulae described above in the form of the free base or in the form of an acid addition salt with a pharmacologically acceptable acid and optionally in the form of solvates and/or hydrates1A compound is provided.

Acid addition salts with pharmacologically acceptable acids refer to, for example, salts selected from the following forms: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, benzoate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate.

Among the above acid addition salts, preferred according to the invention are the salts with hydrochloric acid, methanesulfonic acid, benzoic acid and acetic acid.

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

Unless otherwise specified, suitable alkylene groups are branched and straight chain doubly-linked alkyl bridges having from 1 to 6 carbon atoms. Examples thereof are mentioned: methylene, ethylene, n-propylene or n-butylene.

Examples of alkoxy (or also-O-alkyl) groups, unless otherwise stated, are branched and straight-chain alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom. Examples mentioned are: methoxy, ethoxy, propoxy or butoxy. The abbreviations MeO-, EtO-, PropO-or BuO-may also optionally be used to denote the radicals methoxy, ethoxy, propoxy or butoxy. Unless otherwise indicated, the definitions propoxy and butoxy 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 may optionally be used instead of the term alkoxy. The terms methoxy, ethoxy, propoxy or butoxy may optionally be used to denote the groups methoxy, ethoxy, propoxy or butoxy.

In the context of the present invention, halogen denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are considered to be preferred halogens.

The compounds of the invention may be prepared according to techniques known in the art or by analogous procedures. Suitable preparation processes are known, for example, from EP43940 or US4341778, which are incorporated herein in their entirety by reference.

The following examples further illustrate some of the compounds known from the prior art which, surprisingly, can be used for the treatment of the above-mentioned respiratory diseases.

Example 1: n- (5- {2- [1, 1-dimethyl-3- (4-methyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

This compound is known from EP 43940. The individual enantiomers of this example can be obtained by conventional methods known in the art.

Example 2: n- (5- {2- [1, 1-dimethyl-3- (2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

This compound is known from EP 43940. The (R) -enantiomer and the (S) -enantiomer of the present embodiment can be obtained according to conventional methods known in the art.

Example 3: n- (5- {2- [3- (4-ethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

This compound is known from EP 43940. The individual diastereomers of this example may be obtained in accordance with conventional methods known in the art.

Example 4: n- (5- {2- [3- (4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

Example 5: n- (2-hydroxy-5- { 1-hydroxy-2- [3- (6-hydroxy-4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -ethyl } -phenyl) -methanesulfonamide

Example 6: n- (2-hydroxy-5- { 1-hydroxy-2- [3- (6-methoxy-4, 4-dimethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -ethyl } -phenyl) -methanesulfonamide

The following synthetic examples serve to further illustrate the novel compounds according to the invention. However, it further illustrates the invention merely as an exemplary step and does not limit the invention to the subject matter exemplarily described below.

HPLC method (method a): symmetry C18 (Waters): 3.5 μm; 4.6X 150 mm; column temperature: 20 ℃; gradient: (within 30 minutes) acetonitrile/phosphate buffer (pH 7) 20: 80 → 80: 20; flow rate: 1.0 mL/min; detection was at 220 and 254 nm.

Intermediate product1Synthesis of (E) -8

Intermediate product1: 1- (3-amino-3-methyl-butyl) -4, 4-dipropyl-1, 4-dihydro-benzo [ d][1，3]Oxazin-2-ones

a)4- (2-amino-phenyl) -hept-4-ol

90mL (180.0mmol) of propylmagnesium chloride (2M in ether) was added dropwise to a solution of 7.00mL (54.0mmol) of methyl anthranilate in dry THF (70mL) over 30 minutes at 0 ℃. The mixture was stirred at ambient temperature for 1 hour and then mixed with 100mL of a 3M aqueous solution of ammonium chloride and ethyl acetate. The phases were separated and the aqueous phase was extracted completely with ethyl acetate. The combined organic phases were washed with potassium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. The crude product was used in the next reaction step without any further purification. Yield: 6.70g (60%).

b) {3- [2- (1-hydroxy-1-propyl-butyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

1.40g (22.27mmol) of sodium cyanoborohydride are added to a solution of 3.10g (14.05mmol) of 4- (2-amino-phenyl) -hept-4-ol and 3.60g (17.88mmol) of (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester in methanol (40mL) and acetic acid (6 mL). The mixture was stirred at ambient temperature for 16 h, diluted with ethyl acetate, washed with 0.5M potassium hydrogen sulfate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product was used in the next reaction step without any further purification. Yield: 6.00g (quantitative yield).

c) [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propyl ] -carbamic acid tert-butyl ester

8.85mL (16.81mmol) of phosgene solution (20% by weight in toluene) are slowly added dropwise at 0 ℃ to a solution of 6.00g (15.28mmol) of tert-butyl {3- [2- (1-hydroxy-1-propyl-butyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamate and 5.32mL (38.21mmol) of triethylamine in dry THF (80 mL). The mixture was stirred at ambient temperature for 2 hours, diluted with ethyl acetate, mixed with ice and made basic with a saturated aqueous ammonia solution. The aqueous phase was extracted completely with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. After column chromatography (silica gel, cyclohexane/ethyl acetate 6: 1), the product is obtained as a yellow oil. Yield: 4.57g (71%).

d)1- (3-amino-3-methyl-butyl) -4, 4-dipropyl-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

A solution of 4.20g (10.03mmol) of [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propyl ] -carbamic acid tert-butyl ester in 35mL of formic acid is stirred at ambient temperature for 24H and then poured onto ice. The aqueous phase was made basic with saturated aqueous ammonia and extracted thoroughly with ethyl acetate. The combined organic extracts were washed with sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was dissolved in ethyl acetate (50mL) and mixed (saturated) with 4mL of hydrochloric acid in ethyl acetate. The solution was concentrated by evaporation and mixed twice with a little ethanol and concentrated by evaporation in vacuo. Trituration of the residue with diisopropyl ether gives the product as a hygroscopic hydrochloride. Yield: 2.60g (73%).

Intermediate 2: 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-7-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

a)3- (2-amino-4-fluoro-phenyl) -pentan-3-ol

Like in the intermediate product1The product is obtained by reacting 2-amino-4-fluoro-benzoic acid methyl ester with ethyl magnesium bromide in dichloromethane at-78 ℃ and heating to ambient temperature. Yield: 4.1g (99%).

b) {3- [2- (1-Ethyl-1-hydroxy-propyl) -5-fluoro-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b, starting from 3- (2-amino-4-fluoro-phenyl) -pentan-3-ol and (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester to obtain the product. The crude product is purified by column chromatography (silica gel, dichloromethane/methanol 100: 0 → 98: 2). Yield: 7.70g (99%).

c) [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester

Like in the intermediate product1c, from {3- [2- (1-ethyl-1-hydroxy-propyl) -5-fluoro-phenylamino]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester to obtain the product. Yield: 4.20g (51%).

d)1- (3-amino-3-methyl-butyl) -4, 4-diethyl-7-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

Like in the intermediate product1d is prepared from [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d][1，3]Oxazin-1-yl) -1, 1-dimethyl-propyl]-carbamic acid tert-butyl ester to prepare the product as the free base. Yield: 2.90g (96%); ESI-MS: [ M + H ]]⁺＝309。

Intermediate 3: 1- (3-amino-3-methyl-butyl) -spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazin) -2' -one

a)1- (2-dibenzylamino-phenyl) -cyclopropanol

2.45mL (8.4mmol) of titanium tetraisopropoxide are slowly added dropwise at ambient temperature to a solution of 18.5g (55.8mmol) of methyl 2-dibenzylamino-benzoate in 150mL of THF. After stirring for 1 hour, 40.9mL (122.7mmol) of ethylmagnesium bromide (3M in ether) was added. The mixture was stirred for 1 hour, then 4mL of 3M ethyl magnesium bromide solution was added and stirred for 2 hours. The reaction mixture was mixed with saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous phase was mixed with 1M hydrochloric acid until a clear solution was obtained and extracted with ethyl acetate. The combined organic phases are washed with sodium bicarbonate solution and sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. The residue was purified by chromatography (hexane/ethyl acetate 20: 1). A yellow oil. Yield: 10.0g (54%).

b)1- (2-amino-phenyl) -cyclopropanol

9.90g (30.1mmol) of 1- (2-dibenzylamino-phenyl) -cyclopropane-alcohol are hydrogenated in 70mL of methanol and under a hydrogen pressure of 3bar in the presence of 1g of palladium-carbon (10%). The catalyst is filtered off with suction, the filtrate is concentrated by evaporation and the residue is purified by chromatography (silica gel; cyclohexane/ethyl acetate 5: 1). A white solid. Yield: 1.80g (40%).

c) {3- [2- (1-hydroxy-cyclopropyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b from 1.77g (11.86mmol) of 1- (2-amino-phenyl) -cyclopropanol and 3.15g (15.66mmol) of (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester. The crude product obtained is purified by column chromatography (silica gel, cyclohexane/ethyl acetate 4: 1). A yellow oil. Yield: 2.60 g.

d) {1, 1-dimethyl-3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1c, from 2.60g (7.74mmol) of {3- [2- (1-hydroxy-cyclopropyl) -phenylamino]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester to obtain the product. However, purification was not performed by column chromatography. A yellow oil. Yield: 2.60 g.

e)1- (3-amino-3-methyl-butyl) -spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazin) -2' -one

Obtained from 3.10g (8.60mmol) of {1, 1-dimethyl-3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazin) -2' -oxo-1-yl ] -propyl } -carbamic acid tert-butyl ester by reaction with 30mL of formic acid in analogy of the procedure described in intermediate step 1 d. A yellow oil. Yield: 2.10g (94%).

Intermediate 4: 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

a)3- (2-amino-phenyl) -pentan-3-ol

100mL of a 3M solution of ethylmagnesium bromide in ether was added dropwise to a solution of 7.77mL (60mmol) of 2-amino-benzoic acid in 130mL of THF at-40 ℃. The mixture was stirred overnight with heating to ambient temperature, mixed with saturated ammonium chloride solution, acidified with 1M hydrochloric acid and extracted with ethyl acetate. The combined organic phases are extracted with water, dried over sodium sulfate and concentrated by evaporation. A dark red oil crystallized out and reacted further directly. Yield: 10.9 g; mass spectrum: [ M + H ]]⁺＝180。

b) {3- [2- (1-Ethyl-1-hydroxy-propyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

3.16g (47.7mmol) of sodium cyanoborohydride are added at ambient temperature to 5.70g (31.8mmol) of 3- (2-amino-phenyl) -pentan-3-ol and 2.63mL (47.7mmol) of acetic acid in 18mL of methanol. A solution of 7.04g (35mmol) of (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester in 18mL of methanol is then slowly added dropwise. After the end of the addition, the mixture was stirred for 4 hours, mixed with 1M hydrochloric acid (gas generation), and then made basic with an aqueous ammonia solution. The mixture was extracted with ethyl acetate and the combined organic phases were washed with sodium chloride solution, dried over sodium sulfate and freed from solvent. The residue was purified by column chromatography (silica gel, dichloromethane/methanol gradient with 0.1% ammonia). A yellow oil. Yield: 4.25g (37%); mass spectrum: [ M +H]⁺＝365。

c) [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester

2.91g (9.6mmol) of triphosgene are added to 3.50g (9.6mmol) of {3- [2- (1-ethyl-1-hydroxy-propyl) -phenylamino ] at 0 to 5 deg.C]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester and 3.37mL (24mmol) triethylamine in 35mL THF. The mixture was stirred at ambient temperature overnight and the precipitate formed was suction filtered. The filtrate was concentrated by evaporation and the remaining oil was reacted further directly. Yield: 3.33 g; mass spectrum: [ M + H ]]⁺＝391。

d)1- (3-amino-3-methyl-butyl) -4, 4-diethyl-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

25mL of trifluoroacetic acid was added dropwise to 3.20g of [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] under ice-bath cooling][1，3]Oxazin-1-yl) -1, 1-dimethyl-propyl]-tert-butyl carbamate (about 75%) in 25mL of dichloromethane. The mixture was stirred at ambient temperature for 2 hours, the solvent was distilled off and the acid residue was removed by repeated co-distillation with toluene. To liberate the free base, the residue is mixed with 1M sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated by evaporation. The free base was dissolved in 8mL of methanol and mixed with an ether solution of hydrochloric acid. It was stirred overnight and the precipitate formed was filtered off with suction and washed with diethyl ether. Yield: 2.15g (hydrochloride salt); mass spectrum: [ M + H ]]⁺＝291。

Intermediate 5: 1- (3-amino-3-methyl-butyl) -spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -one

a)1- (2-nitro-phenyl) -cyclohexanols

40.16mL (80.32mmol) of phenylmagnesium chloride (2M in THF) are added dropwise to a solution of 20.0g (80.32mmol) of 2-nitro-iodobenzene in 150mL of THF under a nitrogen atmosphere at-50 ℃. After stirring for 15 minutes, 9.98mL (96.30mmol) of cyclohexanone were added quickly. The reaction mixture was heated to ambient temperature, stirred for 2 hours and mixed with ammonium chloride solution. The aqueous phase was separated and extracted thoroughly with ethyl acetate. The combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. Column chromatography (silica gel, hexane/ethyl acetate 20: 1) gave a brown oil. Yield: 5.20g (29%); r_f0.26 (silica gel, hexane/ethyl acetate 10: 1); ESI-MS: [ M + H-H₂O]⁺＝204。

b)1- (2-amino-phenyl) -cyclohexanols

5.20g (16.45mmol) of 1- (2-nitro-phenyl) -cyclohexanol in 70mL of ethanol are hydrogenated in the presence of Raney nickel (Raney nickel) at ambient temperature and a hydrogen pressure of 3bar for 4 hours. The catalyst was filtered off through Celite (Celite) and the filtrate was concentrated by evaporation in vacuo. The residue precipitated from hexane. Yield: 1.53g (49%); r_f0.38 (silica gel, hexane/ethyl acetate 4: 1); ESI-MS: [ M + H-H₂O]⁺＝174。

c) {3- [2- (1-hydroxy-cyclohexyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b, the compound was obtained from 1- (2-amino-phenyl) -cyclohexanol and (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester. Column chromatography (silica gel, hexane/ethyl acetate 7: 1) gave the product as a colourless oil. Yield: 2.65g (66%); r_f0.50 (silica gel, hexane/ethyl acetate 4: 1).

d) {1, 1-dimethyl-3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1c, from {3- [2- (1-hydroxy-cyclohexyl) -phenylamino]-1, 1-dimethyl-propaneTert-butyl phenyl } -carbamate. Yield: 2.60g (92%); r_f0.38 (silica gel, hexane/ethyl acetate 4: 1).

e)1- (3-amino-3-methyl-butyl) -spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -one

Analogously to intermediate 1d, starting from [1, 1-dimethyl-3- (spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl) -propyl]-carbamic acid tert-butyl ester. Yield: 1.80g (92%); r_f0.10 (silica gel, 95: 5: 0.5 dichloromethane/methanol/ammonia); ESI-MS: [ M + H ]]⁺＝303。

Intermediate 6: 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-8-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

a)3- (2-amino-3-methoxy-phenyl) -pentan-3-ol

Like in the intermediate product1The product was obtained by reacting 2-amino-3-methoxy-benzoic acid methyl ester with ethyl magnesium bromide in dichloromethane at-78 ℃→ RT. Yield: 5.20g (92%); HPLC-MS: r_f12.85 min. (method A); ESI-MS: [ M + H ]]⁺＝210。

b) {3- [2- (1-Ethyl-1-hydroxy-propyl) -6-methoxy-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b, starting from 3- (2-amino-3-methoxy-phenyl) -pentan-3-ol and (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester to obtain the product. The crude product was purified by column chromatography (silica gel, cyclohexane/ethyl acetate 4: 1). Yield: 4.60g (47%).

c) [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester

Like in the intermediate product1c, from {3- [2- (1-ethyl-1-hydroxy-propyl) -6-methoxy-phenylamino]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester to obtain the product. Yield: 4.60g (94%).

d)1- (3-amino-3-methyl-butyl) -4, 4-diethyl-8-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

Like in the intermediate product1d is prepared from [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d][1，3]Oxazin-1-yl) -1, 1-dimethyl-propyl]-carbamic acid tert-butyl ester gives the product as free base. Yield: 3.00g (93%); ESI-MS: [ M + H ]]⁺＝321。

Intermediate 7: 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

a)3- (2-amino-5-fluoro-phenyl) -pentan-3-ol

Like in the intermediate product1a, from 2-amino-5-fluoro-benzoic acid methyl ester and ethyl magnesium bromide. The product obtained is purified by chromatography (silica gel, cyclohexane/ethyl acetate 8: 1). Yield: 6.00g (74%);

b) {3- [2- (1-Ethyl-1-hydroxy-propyl) -4-fluoro-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b, starting from 3- (2-amino-5-fluoro-phenyl) -pentan-3-ol and (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate 6: 1 → 2: 1). Yield: 4.50g (41%).

c) [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester

Like in the intermediate product1c, from {3- [2- (1-ethyl-1-hydroxy-propyl) -4-fluoro-phenylamino]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester. However, purification by column chromatography was not performed. A colorless oil. Yield: 4.8 g.

d)1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

Like in the intermediate product1d is prepared from [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d][1，3]Oxazin-1-yl) -1, 1-dimethyl-propyl]-carbamic acid tert-butyl ester to prepare the target compound as a free base. Yield: 3.00g (99%).

Intermediate 8: 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

a)3- (2-amino-5-methoxy-phenyl) -pentan-3-ol

The product was obtained from the reaction of 4.00g (22mmol) of methyl 2-amino-5-methoxy-benzoate with 5 equivalents of ethylmagnesium bromide in dichloromethane at-78 ℃ → RT. Brown oil. Yield: 4.47g (97%).

b) {3- [2- (1-Ethyl-1-hydroxy-propyl) -4-methoxy-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester

Like in the intermediate product1b prepared from 4.45g (21mmol) of 3- (2-amino-5-methoxy-phenyl) -pentan-3-ol and 5.66g (28mmol) of (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester. Brown oil. Yield: 6.00g (72%).

c) [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester

Analogously to intermediate 1cFrom 6.00g (15.2mmol) {3- [2- (1-ethyl-1-hydroxy-propyl) -4-methoxy-phenylamino]-1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester. Yellow oil, yield: 3.10g (48%).

d)1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one

Like in the intermediate product1d from 3.10g (8.5mmol) [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ]][1，3]Oxazin-1-yl) -1, 1-dimethyl-propyl]-carbamic acid tert-butyl ester. The product was isolated as the free base and was not converted to the hydrochloride salt. A yellow oil. Yield: 2.20g (98%).

Example 7: n- (5- {2- [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

a) N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -phenyl) -methanesulfonamide

To 200mg (0.564mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-dipropyl-1, 4-dihydro-benzo [ d ] c-tylamine, 86 μ l (0.619mmol) of triethylamine are added under nitrogen at ambient temperature][1，3]Solution of oxazin-2-one hydrochloride in 5mL THF. The mixture was stirred for 30 min, 218mg (0.575mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -was added]Methanesulfonamide and stirred at ambient temperature for a further 2 hours. It was cooled to 10 deg.C, mixed with 51mg (2.34mmol) of lithium borohydride, heated to ambient temperature and stirred for 1 hour.It was again cooled to 10 ℃ and diluted with 15mL of water and 20mL of dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was dissolved in 8mL of ethyl acetate and acidified to pH 2 by addition of saturated hydrochloric acid in ethyl acetate. The precipitate formed was filtered off, washed with ethyl acetate and concentrated by evaporation. Yield: 260mg (67%, hydrochloride), HPLC: r_f19.8 minutes (method a).

b) N- (5- {2- [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

260mg (0.386mmol) of N- (2-benzyloxy-5- {2- [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] in 8mL of methanol at ambient temperature in the presence of 26mg of palladium-carbon (10%)][1，3]Oxazin-1-yl) -propylamino]-hydrogenation of 1-hydroxy-ethyl } -phenyl) -methanesulfonamide hydrochloride. The catalyst was filtered off through celite and washed with methanol. The filtrate was concentrated by evaporation in vacuo and the residue was triturated in ether. Yield: 120g (53%, hydrochloride); mass spectrum: [ M + H ]]⁺＝548；HPLC：R_f14.7 minutes (method a).

The (R) -enantiomer and the (S) -enantiomer of this example can be obtained in a conventional manner known from the prior art. According to the invention, the (R) -enantiomer of this example is of particular importance.

Example 8: n- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide

a) N- [ 2-benzyloxy-5- (2- {3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -1, 1-dimethyl-propylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide

In analogy to the procedure described in example 7a, starting from 250mg (0.66mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]-methanesulfonamide and 200mg (0.66mmol) of 1- (3-amino-3-methyl-butyl) -spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazin) -2' -one. However, except that the product obtained as the hydrochloride salt was also purified by chromatography (silica gel, dichloromethane/methanol 50: 1). Yield: 190mg (46%), HPLC: r_f17.8 minutes (method a).

b) N- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide

In analogy to example 7b, 190mg (0.31mmol) of N- [ 2-benzyloxy-5- (2- {3- [ spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl]-1, 1-dimethyl-propylamino } -1-hydroxy-ethyl) -phenyl]-hydrogenation of methanesulfonamides. After removal of the catalyst, the filtrate was freed from solvent, mixed with 8mL of ethyl acetate and acidified to pH 2 by addition of a solution of chlorous acid in ethyl acetate. The solvent was distilled off and the residue was stirred in ether and filtered. Yield: 40mg (23%, hydrochloride salt); mass spectrum: [ M + H ]]⁺＝532；HPLC：R_f11.8 minutes (method a).

Example 9: n- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide

a) N- [ 2-benzyloxy-5- (2- {3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -1, 1-dimethyl-propylamino } -1-hydroxy-ethyl) -phenyl ] -methanesulfonamide

In analogy to example 7a, 292mg (0.77mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide was reacted with 200mg (0.77mmol) of 1- (3-amino-3-methyl-butyl) -spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazin) -2' -one and worked up. The crude product was mixed with 8mL of ethyl acetate and acidified to pH 2 with a solution of hydrochloric acid in ethyl acetate. The solvent was distilled off and the residue was stirred in diethyl ether. A white solid. Yield: 400mg (84%, hydrochloride), HPLC: r_f15.2 min (method a).

b) N- [5- (2- {1, 1-dimethyl-3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propylamino } -1-hydroxy-ethyl) -2-hydroxy-phenyl ] -methanesulfonamide

In analogy to example 1b, from 400mg (0.65mmol) of N- [ 2-benzyloxy-5- (2- {3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl]-1, 1-dimethyl-propylamino } -1-hydroxy-ethyl) -phenyl]-methanesulfonamide hydrochloride to prepare the product. Yield: 230mg (67%, hydrochloride); mass spectrum: [ M + H ]]⁺＝490；HPLC：R_f8.9 minutes (method a).

Example 10: n- (5- {2- [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

379mg (1mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide and 290mg (1mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-1, 4-dihydro-benzo [ d][1，3]Oxazin-2-one was suspended in 5mL of ethanol and heated to 70 ℃. The resulting solution was stirred at 70 ℃ for 1 hour and then cooled to ambient temperature. After addition of 113mg (3mmol) of sodium borohydride, the mixture is stirred at ambient temperature for 3 hours, mixed with 0.7mL of saturated potassium carbonate solution and stirred for a further 30 minutes. The mixture is filtered through alumina (basic), washed repeatedly with dichloromethane/methanol (15: 1) and concentrated by evaporation. The crude product thus obtained was purified by chromatography (9: 1 dichloromethane/ammonia with 0-10% methanol). The benzyl ether thus obtained is dissolved in 10mL of methanol and hydrogenated over a palladium-carbon catalyst under a hydrogen pressure of 1 bar. The catalyst was then filtered off and the filtrate was concentrated by evaporation. A white solid. Yield: 338mg (65%, over 2 steps); mass spectrum: [ M + H ]]⁺＝520。

The (R) -enantiomer and the (S) -enantiomer of this example can be obtained in a conventional manner known from the prior art. According to the invention, the (R) -enantiomer of this example is of particular importance. The optical rotation (chiral value) of (R) -N- (5- {2- [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide hydrochloride (co-crystallized with 1M acetone) was-28.8 ° (c ═ 1% in methanol at 20 ℃).

Example 11: n- (5- {2- [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

a) N- (2-benzyloxy-5- {2- [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -phenyl) -methanesulfonamide

In analogy to example 7a, 246mg (0.65mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide with 200mg (0.65mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-fluoro-1, 4-dihydro-benzo [ D ]][1，3]Oxazin-2-one reaction. In contrast, the preparation of the hydrochloride was omitted. Instead of this, the free base was purified by chromatography (reverse phase, acetonitrile/water gradient containing 0.1% trifluoroacetic acid). Yield: 180mmg (trifluoroacetate), HPLC: r_f17.4 minutes (method a).

b) N- (5- {2- [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

175mg of N- [ 2-benzyloxy-5- {2- [3- (4, 4-diethyl-6-fluoro-2-oxo-4H-benzo [ d ] in 9mL of methanol in the presence of 40mg of Raney nickel at ambient temperature and a hydrogen pressure of 3bar][1，3]Oxazin-1-yl) -1, 1-dimethyl-propylamino]-1-hydroxy-ethyl } -phenyl) -methanesulfonamide trifluoroacetate salt is hydrogenated. The catalyst was filtered off and the filtrate was freed from solvent. A white solid. Yield: 131mg (trifluoroacetate salt); mass spectrum: [ M + H ]]⁺＝538。

Example 12: n- (5- {2- [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

a) N- (2-benzyloxy-5- {2- [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -phenyl) -methanesulfonamide

In analogy to example 7a, 246mg (0.65mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide with 200mg (0.65mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-7-fluoro-1, 4-dihydro-benzo [ D ]][1，3]Oxazin-2-ones are reacted and worked up. Except that the hydrochloride salt was omitted and the free base was purified by chromatography (reverse phase, acetonitrile/water gradient with 0.1% trifluoroacetic acid). Yield: 220mg (trifluoroacetate), HPLC: r_f17.7 minutes (method a).

b) N- (5- {2- [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

In analogy to example 11b, from 210mg of N- [ 2-benzyloxy-5- {2- [3- (4, 4-diethyl-7-fluoro-2-oxo-4H-benzo [ d ]][1，3]Oxazin-1-yl) -1, 1-dimethyl-propylamino]-1-hydroxy-ethyl } -phenyl) -methanesulfonamide trifluoroacetate salt. Grey solid. Yield: 154mg (trifluoroacetate salt); mass spectrum: [ M + H ]]⁺＝538。

Example 13: n- (5- {2- [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

a) N- (2-benzyloxy-5- {2- [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -phenyl) -methanesulfonamide

In analogy to example 7a, 237mg (0.625mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide with 200mg (0.624mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-8-methoxy-1, 4-dihydro-benzo [ d ]][1，3]Oxazin-2-one reaction. The crude product was dissolved in ethyl acetate and acidified to pH 2 with an ethyl acetate solution of hydrochloric acid. The solvent was distilled off and the residue was stirred in diethyl ether. The hydrochloride salt thus obtained (330mg) was then further purified by chromatography. Yield: 90mg (trifluoroacetate), HPLC: r_f17.6 minutes (method a).

b) N- (5- {2- [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

In analogy to example 11b, from 80mg (0.118mmol) N- [ 2-benzyloxy-5- {2- [3- (4, 4-diethyl-8-methoxy-2-oxo-4H-benzo [ d][1，3]Oxazin-1-yl) -1, 1-dimethyl-propylamino]-1-hydroxy-ethyl } -phenyl) -methanesulfonamide trifluoroacetate salt is hydrogenated. A beige solid. Yield: 70mg (trifluoroacetate salt); mass spectrum: [ M + H ]]⁺＝550。

Example 14: n- (5- {2- [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

a) N- (2-benzyloxy-5- {2- [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -phenyl) -methanesulfonamide

In analogy to example 7a, 235mg (0.619mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl]Methanesulfonamide with 200mg (0.624mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-methoxy-1, 4-dihydro-benzo [ d ]][1，3]Oxazin-2-one reaction. Except that the crude product was not precipitated as the hydrochloride salt but purified by chromatography (reverse phase, acetonitrile/water gradient containing 0.1% trifluoroacetic acid). Yield: 150mg (trifluoroacetate), HPLC: r_f16.9 minutes (method a).

b) N- (5- {2- [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propylamino ] -1-hydroxy-ethyl } -2-hydroxy-phenyl) -methanesulfonamide

Analogously to example 11b, from N- [ 2-benzyloxy-5- {2- [3- (4, 4-diethyl-6-methoxy-2-oxo-4H-benzo [ d][1，3]Oxazin-1-yl) -1, 1-dimethyl-propylamino]-1-hydroxy-ethyl } -phenyl) -methanesulfonamide trifluoroacetate salt the title compound is prepared. Grey solid (trifluoroacetate); mass spectrum: [ M + H ]]⁺＝550。

For administration of drugs1Suitable dosage forms of the compounds include, for example: tablets, capsules, suppositories, solutions, powders and the like. The content of the pharmaceutically active compound should be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight, of the total composition. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as: 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, e.g. magnesium stearate or talc, and/or delayed releaseAgents, for example, cellulose carboxyformate, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise multiple layers.

Thus, coated tablets may be prepared by coating the core, similarly manufactured to the tablet, with the substances usually used for tablet coating, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers for delayed release or to prevent incompatibilities. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, wherein the excipients mentioned above for the tablets may be used.

The syrups of active substances according to the invention may additionally contain sweetening agents, such as saccharin, cyclamate, glycerol or sugar, and flavor enhancers, such as aromatic substances, for example vanillin or citrus extract. It may also additionally contain suspension adjuvants or thickeners (e.g. sodium carboxymethylcellulose), wetting agents (e.g. condensation products of fatty alcohols with ethylene oxide) or preservatives (e.g. parabens).

Solutions are prepared in the usual manner, for example with addition of isotonic agents, preservatives (e.g. parabens) or stabilizers (e.g. alkali metal salts of ethylenediamine tetraacetic acid), optionally with the use of emulsifiers and/or dispersants, for example with the use of water as diluent, optionally with the use of organic solvents as solubilizers or cosolvents, and the solutions can be transferred into injection bottles or ampoules or infusion bottles.

For example, capsules containing one or more active substances can be prepared by mixing the active substances with inert carriers (e.g. lactose or sorbitol) and enclosing them in capsules.

For this purpose, suitable suppositories may be prepared, for example, by mixing with the carriers provided, for example, neutral fats or polyethylene glycols or derivatives thereof.

Useful excipients include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), monofunctional 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 (such as lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (such as magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

In the case of oral administration, it is clear that, in addition to the indicated carriers, the tablets may also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with 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 substances may be mixed with various taste-improving agents or colorants in addition to the abovementioned excipients.

Is of the same type1When the compounds are used according to the invention for the treatment of the above-mentioned respiratory diseases, formulations for inhalation or pharmaceutical preparations are particularly preferably used. Inhalable dosage forms include inhalable powders, propellant-containing metered aerosols or propellant-free inhalable solutions. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. Dosage forms that can be used within the scope of the present invention are described in detail in the next section of the specification.

The inhalable powders which can be used according to the invention may contain independently1Or comprises1In admixture with suitable physiologically acceptable excipients.

If active substances1In admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used for the preparation of such inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo-and polysaccharides (e.g. dextran), polyols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or these excipientsMixtures of sexual agents with each other. Preferably, mono-or disaccharides are used, whereas lactose or glucose are preferably used, especially (but not exclusively) in the form of their hydrates. For the purposes of the present invention, the use of lactose is particularly preferred, with lactose monohydrate being particularly preferred. Within the scope of the inhalable powders according to the invention, the excipient has a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, most preferably between 15 and 80 μm. In some cases, it may seem reasonable to incorporate into the above-mentioned excipients a finer excipient fraction having an average particle size of 1 to 9 μm. These finer excipients may also be selected from the excipients listed above that may be used. Finally, to prepare the inhalable powders according to the invention, the active substance is micronized1(preferably having an average particle size of 0.5 to 10 μm, more preferably 1 to 5 μm) is mixed into the excipient mixture. The process for the preparation of the inhalable powders according to the invention is known from the prior art by grinding and micronization and finally mixing the ingredients.

The inhalable powders according to the invention can be administered using inhalers known from the prior art.

The inhalable aerosols according to the invention containing propellant gas may contain a compound dissolved in propellant gas1Or compounds in dispersed form1. Compound (I)1May be included in separate dosage forms or in a common dosage form, wherein the compounds1Both dissolved, both dispersed or the next component only dissolved and the other dispersed.

Propellant gases which can be used for producing inhalation aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons (e.g. n-propane, n-butane or isobutane) and halogenated hydrocarbons (e.g. methane, ethane, propane, butane, cyclopropane or fluorinated derivatives of cyclobutane). The propellant gases mentioned above may be used alone or in mixtures thereof. Preferred propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

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

The above inhalation aerosols containing propellant gas can be administered using inhalers known in the art (MDI ═ metered dose inhalers).

Furthermore, the active substances according to the invention1Administration may be in the form of an inhalable solution or inhalable suspension without propellant gas. The solvent used may be an aqueous or alcoholic solution, preferably an alcoholic solution. The solvent can be water alone or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum proportion is preferably up to 70% by volume, more preferably up to 60% by volume and most preferably up to 30% by volume. The remaining volume was made up with water. Using a suitable acid will contain1Is adjusted to a pH value of 2 to 7, preferably 2 to 5. The pH can be adjusted using an acid selected from inorganic or organic acids. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, and the like. Preferred inorganic acids are hydrochloric acid and sulfuric acid. Acids which have formed an acid addition salt with one of the active substances may also be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferable. Mixtures of the above acids may be used if necessary, especially in the case of acids which have other properties in addition to their acidifying properties, for example for use as flavouring agents, antioxidants or complexing agents, for example citric acid or ascorbic acid. According to the invention, the use of hydrochloric acid for adjusting the pH is preferred.

If necessary, the addition of ethylenediaminetetraacetic acid (EDTA) or any of its known salts (sodium ethylenediaminetetraacetate) as a stabilizer or complexing agent can be omitted in such formulations. Other embodiments may contain such compounds or these compounds. In a preferred embodiment, the amount is as small as 100mg/100mL, preferably 50mg/100mL, more preferably 20mg/100mL, based on sodium edetate. Generally, inhalable solutions in which the sodium edetate is present in an amount of 0 to 10mg/100mL are preferred.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solution. Preferred cosolvents are solvents containing hydroxyl groups or other polar groups, such as alcohols (especially isopropanol), glycols (especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol), polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives herein denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with one or more active substances in a physiologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, such a substance has no significant pharmacological effect, or, when relevant to the intended treatment, no significant or at least no undesired pharmacological effect. Exemplary excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitol esters (e.g., polysorbates), polyvinylpyrrolidone; other stabilizers; a complexing agent; antioxidants and/or preservatives (which ensure or prolong shelf life of the finished pharmaceutical formulation); a flavoring agent; vitamins and/or other additives known in the art. Additives also include pharmacologically acceptable salts, such as sodium chloride as an isotonic agent.

Preferred excipients include antioxidants (e.g., ascorbic acid, provided it is not used to adjust pH), vitamin a, vitamin E, tocopherol, and the like, vitamins or provitamins present in the human body.

Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates, for example sodium benzoate, which are present in the concentrations known from the prior art. The preservative is preferably present in a concentration of up to 50mg/100mL, more preferably between 5 and 20mg/100mL, desolvated water and active substance1In addition, preferred formulations contain only benzalkonium chloride and sodium edetate。

In another preferred embodiment, sodium edetate is not present.

The dosage of the compounds according to the invention depends greatly on the method of administration and on the disease to be treated. When administered by inhalation, even at doses in the μ g range, formula (I)1The compounds are also characterized as being highly effective. Formula (II)1The compounds can also be used effectively in the μ g range. Thus the dosage may be in the milligram range, for example.

In another aspect, the invention relates to the above pharmaceutical preparation, characterized in that it contains a compound of formula1The above pharmaceutical preparations are particularly preferably administered by so-called inhalation.

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

examples of pharmaceutical preparations

A) Each tablet of the tablet

Active substance1 100mg

Lactose 140mg

Corn starch 240mg

Polyvinylpyrrolidone 15mg

Magnesium stearate5mg

500mg

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 suitable shape and size.

B) Each tablet of the tablet

Active substance1 80mg

Lactose 55mg

Corn starch 190mg

Microcrystalline cellulose 35mg

Polyvinylpyrrolidone 15mg

Sodium carboxymethylcellulose 23mg

Magnesium stearate2mg

400mg

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 processed with the remaining corn starch and water into granules, which are dried and sieved. Sodium carboxymethylcellulose and magnesium stearate are added and mixed. The mixture is compressed into tablets of suitable size.

C) Ampoule solution

Active substance1 50mg

50mg of sodium chloride

5ml 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 sodium chloride is added as an isotonic agent. The resulting solution is filtered free of pyrogens and the filtrate is transferred under aseptic conditions to an ampoule, which is then sterilized and hermetically sealed. Ampoules contain 5mg, 25mg and 50mg of active substance.

D) Metering aerosols

Active substance1 0.005

Sorbitan trioleate 0.1

Monofluorotrichloromethane and

TG134 a: TG 2272: 1 addition to 100

The suspension was transferred to a conventional aerosol container with a metering valve. Preferably, 50. mu.l of suspension is delivered per spray. If necessary, the active substance can also be metered in higher doses (e.g. 0.02% by weight).

E) Solutions (in mg/100 ml)

Active substance1 333.3mg

Benzalkonium chloride 10.0mg

EDTA 50.0mg

HCl (1n) added to pH 3.4

This solution can be prepared in a manner known in the art.

F) Powder for inhalation

Active substance1 12μg

Lactose monohydrate addition to 25mg

Powders for inhalation are produced in the usual manner by mixing the individual components.

Claims

1. General formula (VII)1The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of a respiratory disease:

wherein:

the respiratory disease is selected from: obstructive pulmonary disease of various origins, emphysema of various origins, restrictive pulmonary disease, interstitial pulmonary disease, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.

2. The general formula as claimed in claim 11The use of a compound of (1), wherein

3. The general formula as claimed in claim 11The use of a compound of (1), wherein

R³Represents hydrogen, fluorine, OH, methyl or methoxy.

4. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of an obstructive pulmonary disease selected from the group consisting of: bronchial asthma, infantile asthma, and severe asthmaSevere asthma, acute asthmatic attacks, chronic bronchitis and COPD, and it is particularly preferred according to the invention to use them for the preparation of a medicament for the treatment of bronchial asthma or COPD.

5. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of emphysema caused by COPD or deficiency of alpha 1-protease inhibitors.

6. The general formula as claimed in any of claims 1 to 31For the preparation of a pharmaceutical composition for the treatment of a restrictive lung disease selected from the group consisting of: allergic alveolitis; restricted lung diseases caused by occupational-related harmful factors, such as asbestosis or silicosis; and restrictions caused by lung tumors such as cancerous lymphangiopathy, bronchoalveolar carcinoma and lymphoma.

7. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of an interstitial lung disease selected from pneumonia caused by an infection, e.g. caused by a virus, bacterium, fungus, protozoa, parasite or other pathogen; pneumonia caused by various factors, such as aspiration and left cardiac insufficiency; pneumonia or fibrosis caused by irradiation; collagen diseases; such as lupus erythematosus, systemic scleroderma, or sarcoidosis; granulomatosis, such as burkholderia disease; idiopathic interstitial pneumonia or Idiopathic Pulmonary Fibrosis (IPF).

8. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis, bronchiectasis or ARDS (adult respiratory distress syndrome).

9. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) in the preparation of a pharmaceutical composition for the treatment of bronchitis, such as bronchitis caused by bacterial or viral infections, allergic bronchitis and toxic bronchitis.

10. The general formula as claimed in any of claims 1 to 31The use of a compound of (a) for the preparation of a pharmaceutical composition for the treatment of pulmonary edema, such as toxic pulmonary edema following inhalation or inhalation of toxic substances or foreign bodies.

11. The general formula as claimed in any of claims 1 to 101The use of a compound of (1), wherein the formula1The compounds are present as individual optical isomers, as mixtures or racemates of individual enantiomers or optionally diastereomers, preferably as enantiomerically pure compounds or optionally diastereomerically pure compounds.

12. The general formula as claimed in any of claims 1 to 101The use of a compound of (1), wherein the formula1The compounds are in the form of the free base or in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of solvates and/or hydrates.

13. Formula (II)1A compound:

wherein:

R¹and R²Which may be identical or different, preferably identical, represent ethyl or propyl or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-; and

14. A compound of claim 13 of the formula1A compound, wherein:

15. A compound of formula (la) as claimed in claim 13 or 141A compound selected from the following:

16. The general formula as claimed in any of claims 13 to 151Wherein the formula1The compounds are in the form of individual optical isomers, mixtures or racemates of individual enantiomers or optionally diastereomers, preferably in the form of enantiomerically pure compounds or optionally diastereomerically pure compounds.

17. The general formula as claimed in any of claims 13 to 151Wherein the formula1The compounds are in the form of the free base or in the form of an acid addition salt with a pharmacologically acceptable acid, and optionally in the form of solvates and/or hydrates.

18. The general formula as claimed in any of claims 13 to 171As a medicament.

19. Pharmaceutical preparation, characterized in that it contains a compound of formula (la) according to any one of claims 13 to 171A compound is provided.