HK1134079A

HK1134079A - Single enantiomer beta agonists method for production and use thereof as a medicament

Info

Publication number: HK1134079A
Application number: HK10100911.4A
Authority: HK
Inventors: Ingo Konetzki; Peter Sieger
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2006-08-22
Filing date: 2007-08-21
Publication date: 2010-04-16

Description

Enantiomers of beta agonists, methods for their preparation and use as medicaments

The present invention relates to enantiomerically pure compounds of the following formula 1:

wherein the radical R¹、R²、R³M and Y^m-Having the definitions as defined in the claims and the description, a process for their preparation and their use as medicaments, especially for the treatment of respiratory diseases.

Background

Beta mimetics (Betamimetics, beta-adrenergic substances) are known in the art. Reference is made in this respect to the disclosure of, for example, US4,341,778, which proposes beta mimetics for the treatment of various disorders.

In the case of medical treatment of diseases, it is often desirable to prepare a medicament with long-term efficacy. In general, this ensures that the in vivo concentration of the active substance required to achieve a therapeutic effect is maintained over a long period of time without the need for frequent re-administration of the drug. Furthermore, administration of the active substance at longer intervals may provide a higher degree of comfort to the patient.

It is particularly desirable to prepare a medicament which is therapeutically effective for once daily administration (single dose). The advantage of using once-a-day medications is that patients are relatively quickly accustomed to taking medications on a regular basis at specific times of day.

It is therefore an object of the present invention to provide a betamimetic agent which on the one hand provides therapeutic benefit in the treatment of respiratory diseases and which is also characterized by long-term efficacy and which can therefore be used for the preparation of a medicament with long-term efficacy. It is a particular object of the present invention to prepare beta mimetics which, due to their long-lasting effect, can be used to prepare medicaments for the treatment of asthma which are administered once a day. In addition to these objects, it is another object of the present invention to provide such betamimetics which not only have superior efficacy, but also are relatively beta₂The adrenergic receptors are characterized by a high degree of selectivity. It is a further object of the present invention to provide a betamimetic agent which, due to its physicochemical properties, is particularly useful for the preparation of pharmaceutical formulations particularly suitable for inhalation use. In particular, the present invention aims to provide a β mimetic agent which, in addition to having the above properties, is particularly suitable for the preparation of powders for inhalation and suspension aerosols.

Detailed Description

It has surprisingly been found that the above problems can be solved by the compounds of formula 1. The present invention relates to enantiomerically pure compounds of formula 1:

wherein

R¹And R²Independently of one another, H, halogen or C_1-4-alkyl, or together represent C_1-6-an alkylene group; and is

R³Represents H, halogen, OH, C_1-4Alkyl or O-C_1-4-an alkyl group;

Y^m-represents an anion having m negative charges, preferably selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, propanedisulfonate, benzoate and p-toluenesulfonate;

m represents 1 or 2;

optionally in the form of a tautomer, mixture of tautomers, hydrate or solvate thereof.

The compound of formula 1 is prepared from a molecule having a single positive charge and an anion Y having a single charge^m-Or an anion Y having a charge of m^m-Corresponding to the l/m portion of (a). Thus, for example, a bipartite molecule of the formula:

wherein the radical R¹、R²And R³Having the above-mentioned meaning, can be a double-charged anion Y^m-(wherein m is 2) for exampleThe ethanedisulfonate or propanedisulfonate radicals are present as crystalline units (crystaline units).

Preferred are the compounds of formula 1 as enantiomerically pure compounds as described above, but the R-enantiomer of the compounds of formula 1 according to the invention is of particular importance. The R-enantiomer of the compound of formula 1 may be represented by the general formula R-1:

wherein R is¹、R²、R³M and Y^m-May have the above-mentioned meaning. The (R) -and (S) -enantiomers can be obtained by methods commonly used in the art.

Preferred are enantiomerically pure compounds of formula 1, wherein

R¹And R²Which may be identical or different, represent 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;

Y^m-represents an anion having m negative charges, preferably an anion having m negative charges selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate;

m represents 1 or 2;

Preferred are enantiomerically pure compounds of formula 1, wherein

R¹And R²Which may be identical or different, represent 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;

m represents 1 or 2;

Preferred are enantiomerically pure compounds of formula 1, wherein

R¹And R²Which may be identical or different, represent 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;

Y^m-represents an anion having m negative charges, preferablyOptionally an anion having m negative charges selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate;

m represents 1 or 2;

Preferred are enantiomerically pure compounds of formula 1, wherein

R¹And R²Represents ethyl, propyl, or together represent-CH₂-CH₂-、-CH₂-CH₂-CH₂-、-CH₂-CH₂-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-CH₂-；

R³Represents hydrogen, fluorine, OH or methoxy;

m represents 1 or 2;

Preferred are enantiomerically pure compounds of the formula:

1.1: 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^*H(Ym-/m)

1.2: 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^*H(Y^m-/m)

1.3: 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^*H(Y^m-/m)

1.4: 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^*H(Y^m-/m)

1.5: 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^*H(Y^m-/m)

1.6: 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^*H(Y^m-/m)

1.7: 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^*H(Y^m-/m)

1.8: 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^*H(Y^m-/m)

1.9: 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^*H(Ym-/m)

1.10: 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^*H(Y^m-/m)

1.11: 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^*H(Y^m-/m)

1.12: 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^*H(Y^m-/m)

1.13: 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^*H(Y^m-/m)

1.14: 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^*H(Y^m-/m)

Wherein

m represents 1 or 2;

Most preferred are enantiomerically pure compounds of the formula:

1.9: 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^*H(Y^m-/m)

Wherein

m represents 1 or 2;

Particularly preferred are enantiomerically pure compounds of formula 1, wherein R is¹、R²And R³Have the above-mentioned meanings, and wherein Y^m-Represents chloride or bromide, optionally in the form of tautomers, mixtures of tautomers, hydrates or solvates thereof.

Particularly preferred are enantiomerically pure compounds of formula 1.1 to 1.14, wherein Y is^m-Represents chloride or bromide, optionally in the form of tautomers, mixtures of tautomers, hydrates or solvates thereof.

Particularly preferred are enantiomerically pure compounds of formulae 1.7 to 1.14, wherein Ym-represents chloride or bromide, optionally in the form of a tautomer, mixture of tautomers, hydrate or solvate thereof.

Also particularly preferred are enantiomerically pure compounds of formula 1 above in crystalline form, optionally in the form of their crystalline tautomers, crystalline hydrates or crystalline solvates. Particularly preferred are enantiomerically pure, crystalline compounds of formula 1 above, optionally in the form of their crystalline tautomers, crystalline hydrates or crystalline solvates, which are further characterized in that they are crystalline compounds which are present in the form of a single crystal.

The term "single crystal form" refers to a crystalline compound of formula 1 that does not constitute a mixture of any existing crystalline forms.

Another object of the present invention relates to enantiomerically pure, solvent-free, crystalline forms of the compounds of formula 1-base

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 is

R³Represents hydrogen, fluorine, chlorine, OH, methyl, ethyl, methoxy or ethoxy. Preference is given to enantiomerically pure, solvent-free, crystalline forms of the base compounds of the formula 1, in which

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-；

R³Represents hydrogen, fluorine, OH, methyl or methoxy, preferably hydrogen.

Most preferred are enantiomerically pure, solvent-free, crystalline forms of the compounds of the formula

1.7-base-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

1.8-base-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

1.9-base-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

1.10-base-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

1.11-base-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

1.12-base-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

1.13-base-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

1.14-base-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

Terms and definitions used

The term "C_1-4Alkyl "(including C as part of another group)_1-4-alkyl) refers to a branched or straight chain alkyl group having 1 to 4 carbon atoms. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu and the like may be optionally used for the above groups. Unless otherwise stated, it is to be understood that,the definition propyl and butyl includes all possible isomeric forms of the radicals in question. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, sec-butyl, tert-butyl, and the like.

The term "C_1-6Alkylene "(including C as part of another group)_1-6Alkylene) means a branched or straight chain alkylene group having up to 6 carbon atoms, and the term "C_1-4-alkylene "means a branched or straight chain alkylene having 1 to 4 carbon atoms. Preferably an alkylene group having 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1-dimethylpropylene, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless otherwise indicated, the definitions propylene, butylene, pentylene, and hexylene include all possible isomeric forms of the groups having the same number of carbons. Thus, for example, propylene also comprises 1-methylethylene and butylene comprises 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene.

Halogen in the context of the present invention represents fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are considered as preferred halogens.

The term enantiomerically pure (enantiomeric pure) is described in the context of the present invention as a compound of formula 1 which is present in an enantiomeric purity of at least 85% ee, preferably at least 90% ee, most preferably > 95% ee. The term ee (enantiomeric excess) is known in the art and describes the optical purity of chiral compounds.

The term solvent-free in the context of the present invention describes the base compound of formula 1 in a crystalline state, wherein no solvent in defined stoichiometric proportions enters the crystallization unit in the crystalline lattice positions.

Indications of

The compounds of formula 1 according to the invention are characterized by a wide variety of uses in the therapeutic field. Particular mention should be made of those which, according to the invention, can be used according to the invention which are preferably considered to be the pharmaceutical activity of the compounds of the invention of formula 1 as betamimetics.

Another object of the present invention correspondingly relates to enantiomerically pure compounds of the above formula 1 as medicaments. The invention further relates to the use of a compound of the general formula 1 as defined above for the preparation of a medicament for the treatment of respiratory diseases. The present invention preferably relates to the use of a compound of formula 1 as described above for the preparation of a medicament for the treatment of a respiratory disease selected from the group consisting of obstructive pulmonary diseases of diverse origin (obstructive pulmonary diseases of variable origins), emphysema of diverse origin (pulmonary emphysema of variable origins), restrictive pulmonary diseases, interstitial lung diseases, cystic fibrosis, bronchitis of diverse origin, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.

The compounds of formula 1 are preferably used for the preparation of a medicament for the treatment of a disease selected from the group consisting of: COPD (chronic obstructive pulmonary disease), bronchial asthma, pediatric asthma, severe asthma, acute asthma attack and chronic bronchitis, but is preferably used for the preparation of a medicament for the treatment of bronchial asthma according to the invention.

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of emphysema resulting from COPD (chronic obstructive pulmonary disease) or a deficiency in α 1-protease inhibitors.

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of a restrictive lung disease selected from: allergic alveolitis, restrictive lung diseases caused by work-related harmful substances, such as asbestosis or silicosis, and restrictive diseases caused by lung tumors, such as lymphangiosarcoma, bronchoalveolar tumor and lymphoma.

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of a pulmonary interstitial disorder selected from the group consisting of: pneumonia caused by infection (e.g., infection by viruses, bacteria, fungi, protozoa, worms, or other pathogens); pneumonia caused by various factors (e.g., inhalational and left cardiac insufficiency); radiation-induced pneumonia or fibrosis; collagenization (e.g., lupus erythematosus, systemic scleroderma, or sarcoidosis); granulomatosis (e.g., Burke's (Boeck) disease; idiopathic interstitial pneumonia or Idiopathic Pulmonary Fibrosis (IPF)).

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of cystic fibrosis or mucoviscidosis.

Also preferably, the compounds of formula 1 are 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.

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of bronchiectasis.

Also preferably, the compounds of formula 1 are used for the preparation of a medicament for the treatment of ARDS (adult respiratory distress syndrome).

Also preferably, the compound of formula 1 is used for the preparation of a medicament for the treatment of pulmonary edema, such as toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.

Preferably, the present invention relates to the use of a compound of formula 1 for the manufacture of a medicament for the treatment of asthma or COPD. Also of utmost importance is the above-mentioned use of a compound of formula 1 for the preparation of a medicament for the once-a-day treatment of inflammatory and obstructive respiratory diseases, in particular for the once-a-day treatment of asthma or COPD.

The invention also relates to a method for treating the above-mentioned diseases, characterized in that one or more compounds of the above-mentioned general formula 1 are administered in a therapeutically effective amount. The present invention also relates to a method of treating asthma or COPD characterized by administering one or more compounds of the above general formula 1 once daily in a therapeutically effective amount.

The compounds of the present invention may be prepared according to the methods illustrated in scheme 1.

Examples

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

Such compounds are known from EP 43940. The individual diastereomers of this embodiment may 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

Such compounds are known from EP 43940. The (R) -and (S) -enantiomers of this embodiment can be obtained by 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

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 synthetic examples described below are intended to illustrate the novel compounds of the invention in more detail. However, it is merely illustrative of the present invention as an example of a method and does not limit it to the subject matter described in the examples below.

HPLC method (method a): symmetry C18 (Waters): 3.5 microns; 4.6X 150 mm; column temperature: 20 ℃; gradient solution: acetonitrile/phosphate buffer (pH7)20:80 → 80:20, 30 min; flow rate: 1.0 ml/min; detection was at 220 and 254 nanometers.

Synthesis of intermediate products 1-8

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

a)4- (2-amino-phenyl) -heptan-4-ol:

90 ml (180.0 mmol) of propylmagnesium chloride (2M in ether) are added dropwise to a solution of 7.00 ml (54.0 mmol) of methyl anthranilate in dry THF (70 ml) at 0 ℃ over 30 minutes. The mixture was stirred at ambient temperature for 1 hour and then mixed with 100 ml of 3 molar aqueous ammonium chloride solution and ethyl acetate. The phases were separated and the aqueous phase was extracted thoroughly with ethyl acetate. The combined organic phases are 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 further purification.

Yield: 6.70 g (60%).

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

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

Yield: 6.00 g (yield, quantitative).

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

8.85 ml (16.81 mmol) of phosgene solution (20% by weight in toluene) are slowly added dropwise at 0 ℃ to a solution of 6.00 g (15.28 mmol) of {3- [2- (1-hydroxy-1-propyl-butyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester and 5.32 ml (38.21 mmol) 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 saturated aqueous ammonia solution. The aqueous phase was extracted thoroughly with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness in vacuo. Column chromatography (silica gel, cyclohexane/ethyl acetate ═ 6:1) gave the product as a yellow oil.

Yield: 4.57 g (71%).

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

a solution of 4.20 g (10.03 mmol) of tert-butyl [1, 1-dimethyl-3- (2-oxo-4, 4-dipropyl-4H-benzo [ d ] [1, 3] oxazin-1-yl) -propyl ] -carbamate in 35 ml of formic acid was stirred at ambient temperature for 24 hours 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 evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and mixed with 4 ml of a solution of hydrochloric acid in ethyl acetate (saturated). The solution was evaporated to dryness and mixed twice with a small amount of ethanol and evaporated to dryness in vacuo. The residue was triturated with diisopropyl ether to give the product as the hygroscopic hydrochloride salt.

Yield: 2.60 g (73%).

Intermediate product 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:

in analogy to intermediate product 1a, this product was 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: 4.1 g (99%).

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

the product was obtained in analogy to intermediate product 1b, starting from 3- (2-amino-4-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, dichloromethane/methanol 100:0 → 98: 2).

Yield: 7.70 g (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:

the product was obtained in analogy to intermediate product 1c, starting from {3- [2- (1-ethyl-1-hydroxy-propyl) -5-fluoro-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester.

Yield: 4.20 g (51%).

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

the product was prepared analogously to intermediate product 1d starting 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 as the free base.

Yield: 2.90 g (96%); ESI-MS: [ M + H ]]⁺＝309。

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

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

at ambient temperature, 2.45 ml (8.4 mmol) of tetraisopropyltitanyl (titanyl tetraisoproxide) are slowly added dropwise to a solution of 18.5 g (55.8 mmol) of methyl 2-dibenzylamino-benzoate in 150 ml of THF. After stirring for 1 hour, 40.9 ml (122.7 mmol) of ethylmagnesium bromide (3M in ether) were added. The mixture was stirred for 1 hour, 4 ml of a 3 molar solution of ethyl magnesium bromide were added and the mixture was stirred for 2 hours. The reaction mixture was mixed with a saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous phase was mixed with 1 molar 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 evaporated to dryness. The residue was purified by chromatography (hexane/ethyl acetate 20: 1). A yellow oil.

Yield: 10.0 g (54%).

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

9.90 g (30.1 mmol) of 1- (2-dibenzylamino-phenyl) -cyclopropanol are dissolved in 70 ml of methanol and hydrogenated in the presence of 1 g of palladium on charcoal (10%) under a hydrogen pressure of 3 bar. The catalyst was removed by suction filtration, the filtrate evaporated to dryness and the residue purified by chromatography (silica gel; cyclohexane/ethyl acetate 5: 1). A white solid.

Yield: 1.80 g (40%).

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

prepared in analogy to the procedure described for intermediate product 1b from 1.77 g (11.86 mmol) 1- (2-amino-phenyl) -cyclopropanol and 3.15 g (15.66 mmol) tert-butyl (1, 1-dimethyl-3-oxo-propyl) -carbamate. 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:

in analogy to intermediate product 1c, the product was obtained starting from 2.60 g (7.74 mmol) of {3- [2- (1-hydroxy-cyclopropyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester. The difference here is that no purification by column chromatography is carried out. A yellow oil.

Yield: 2.60 g.

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

obtained in analogy to the procedure described for intermediate product 1d by reacting 3.10 g (8.60 mmol) {1, 1-dimethyl-3- [ spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl ] -propyl } -carbamic acid tert-butyl ester with 30 ml formic acid. A yellow oil.

Yield: 2.10 g (94%).

Intermediate product 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:

100 ml of a 3 molar solution of ethylmagnesium bromide in ether are added dropwise at-40 ℃ to a solution of 7.77 ml (60 mmol) of 2-amino-methylbenzoic acid in 130 ml of THF. The mixture was stirred overnight, heated to ambient temperature, mixed with saturated ammonium chloride solution, acidified with 1 molar hydrochloric acid and extracted with ethyl acetate. The combined organic phases were extracted with water, dried over sodium sulfate and evaporated to dryness. A dark red oil which 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:

3.16 g (47.7 mmol) of sodium cyanoborohydride are added at ambient temperature to 5.70 g (31.8 mmol) of 3- (2-amino-phenyl) -pentan-3-ol and 2.63 ml (47.7 mmol) of acetic acid in 18 ml of methanol. A solution of 7.04 g (35 mmol) of (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester in 18 ml of methanol is then slowly added dropwise. After the addition was completed, the mixture was stirred for 4 hours, mixed with 1 molar hydrochloric acid (generated gas), and then made alkaline with an aqueous ammonia solution. It is extracted with ethyl acetate and the combined organic phases are washed with sodium chloride solution, dried over sodium sulfate and the solvent is removed. The residue was purified by column chromatography (silica gel, dichloromethane/methanol gradient containing 0.1% ammonia). A yellow oil.

Yield: 4.25 g (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:

2.91 g (9.6 mmol) of triphosgene are added to a solution of 3.50 g (9.6 mmol) of {3- [2- (1-ethyl-1-hydroxy-propyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester with 3.37 ml (24 mmol) of triethylamine in 35 ml of THF at 0 ℃ to 5 ℃. The mixture was left at ambient temperature and stirred overnight, and the precipitate formed was filtered off with suction. The filtrate was evaporated to dryness and the residual crude product was directly reacted further.

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:

25 ml of trifluoroacetic acid are added dropwise to a solution of 3.20 g of [3- (4, 4-diethyl-2-oxo-4H-benzo [ d ] [1, 3] oxazin-1-yl) -1, 1-dimethyl-propyl ] -carbamic acid tert-butyl ester (about 75%) in 25 ml of dichloromethane with cooling in an ice bath. The mixture was stirred at ambient temperature for 2 hours, the solvent was distilled off, and the acid residue was removed by repeated azeotropy with toluene. To liberate the free base, the residue is mixed with 1 molar sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated to dryness. The free base was dissolved in 8 ml of methanol and mixed with a solution of hydrochloric acid in ether. It was stirred overnight and the precipitate formed was filtered off with suction and washed with diethyl ether.

Yield: 2.15 g (hydrochloride salt); mass spectrum: [ M + H ]]⁺＝291。

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

a)1- (2-nitro-phenyl) -cyclohexanol:

40.16 ml (80.32 mmol) of phenylmagnesium chloride (2M in THF) are added dropwise to a solution of 20.0 g (80.32 mmol) of 2-nitro-iodobenzene in 150 ml of THF at-50 ℃ under nitrogen. After stirring for 15 minutes, 9.98 ml (96.30 mmol) of cyclohexanone were quickly added. The reaction mixture was heated to ambient temperature, stirred for two 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 evaporated to dryness. Column chromatography (silica gel, hexane/ethyl acetate ═ 20:1) afforded the product as a brown oil.

Yield: 5.20 g (29%); r_f0.26 (silica gel, hexane/ethyl acetate 10: 1); ESI-MS: [ M + H-H₂O]⁺＝204。

b)1- (2-amino-phenyl) -cyclohexanol:

5.20 g (16.45 mmol) of 1- (2-nitro-phenyl) -cyclohexanol in 70 ml of ethanol were hydrogenated in the presence of ni-ni and under a hydrogen pressure of 3 bar for 4 hours at ambient temperature. The catalyst was filtered off through celite and the filtrate was evaporated to dryness in vacuo. The residue was precipitated from hexane.

Yield: 1.53 g (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:

the compound was prepared from 1- (2-amino-phenyl) -cyclohexanol and (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester in analogy to intermediate product 1 b. Column chromatography (silica gel, hexane/ethyl acetate 7:1) afforded the product as a colorless oil.

Yield: 2.65 g (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:

prepared in analogy to intermediate product 1c from {3- [2- (1-hydroxy-cyclohexyl) -phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester.

Yield of the product: 2.60 g (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:

prepared from [1, 1-dimethyl-3- (spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -oxo-1-yl) -propyl ] -carbamic acid tert-butyl ester in analogy to intermediate product 1 d.

Yield: 1.80 g (92%); rf 0.10 (silica gel, dichloromethane/methanol/ammonia 95: 5: 0.5); ESI-MS: [ M + H ]]⁺＝303。

Intermediate product 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:

in analogy to intermediate product 1a, the product was obtained by reacting 2-amino-3-methoxy-benzoic acid methyl ester with ethylmagnesium bromide in dichloromethane at-78 ℃ → room temperature.

Yield: 5.20 g (92%); HPLC-MS: r_t12.85 minutes (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:

the product was obtained in analogy to intermediate product 1b, starting from 3- (2-amino-3-methoxy-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, cyclohexane/ethyl acetate 4: 1).

Yield: 4.60 g (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:

the product was obtained in analogy to intermediate product 1c, starting from {3- [2- (1-ethyl-1-hydroxy-propyl) -6-methoxy-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester.

Yield: 4.60 g (94%).

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

the product was obtained as the free base starting 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 analogously to intermediate product 1 d.

Yield: 3.00 g (93%); ESI-MS: [ M + H ]]⁺＝321。

Intermediate product 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:

prepared from 2-amino-5-fluoro-benzoic acid methyl ester and ethyl magnesium bromide in analogy to intermediate product 1 a. The resulting product was purified by chromatography (silica gel, cyclohexane/ethyl acetate ═ 8: 1).

Yield: 6.00 g (74%).

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

the product was obtained in analogy to intermediate product 1b, 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: 4.50 g (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:

prepared in analogy to intermediate product 1c from {3- [2- (1-ethyl-1-hydroxy-propyl) -4-fluoro-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester. The difference here is that no purification by column chromatography is carried out. 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:

the title compound was 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 as the free base in analogy to intermediate product 1 d.

Yield: 3.00 g (99%).

Intermediate product 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 by reacting 4.00 g (22 mmol) of methyl 2-amino-5-methoxy-benzoate with 5 equivalents of ethylmagnesium bromide at-78 deg.c-room temperature in dichloromethane. A brown oil.

Yield: 4.47 g (97%).

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

prepared in analogy to intermediate product 1b from 4.45 g (21 mmol) 3- (2-amino-5-methoxy-phenyl) -pentan-3-ol and 5.66 g (28 mmol) (1, 1-dimethyl-3-oxo-propyl) -carbamic acid tert-butyl ester. A brown oil.

Yield: 6.00 g (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:

in analogy to intermediate product 1c, the product was prepared from 6.00 g (15.2 mmol) of {3- [2- (1-ethyl-1-hydroxy-propyl) -4-methoxy-phenylamino ] -1, 1-dimethyl-propyl } -carbamic acid tert-butyl ester. A yellow oil.

Yield: 3.10 g (48%).

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

prepared in analogy to intermediate product 1d from 3.10 g (8.5 mmol) of [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 not converted to the hydrochloride salt. A yellow oil.

Yield: 2.20 g (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:

86 microliters (0.619 mmol) of triethylamine are added to a solution of 200mg (0.564 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-dipropyl-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one hydrochloride in 5ml of THF at ambient temperature under nitrogen atmosphere. The mixture was stirred for 30 minutes, 218 mg (0.575 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide were added and the mixture was stirred at ambient temperature for a further 2 hours. The mixture was cooled to 10 ℃, mixed with 51 mg (2.34 mmol) of lithium borohydride, heated to ambient temperature, and stirred for 1 hour. It was cooled again to 10 ℃ and diluted with 15 ml 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 evaporated to dryness in vacuo. The residue is dissolved in 8 ml of ethyl acetate and acidified to pH2 by addition of a saturated ethyl acetate solution of hydrochloric acid, the precipitate formed is filtered off, washed with ethyl acetate and evaporated to dryness.

Yield: 260 mg (67%, hydrochloride), HPLC: r_t19.8 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:

260 mg (0.386 mmol) of 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 hydrochloride in 8 ml of methanol was hydrogenated in the presence of 26 mg palladium on charcoal (10%) at ambient temperature. The catalyst was filtered off through celite and washed with methanol. The filtrate was evaporated in vacuo and the residue was stirred in ether.

Yield: 120 mg (53%, hydrochloride); mass spectrum: [ M + H ]]⁺＝548；HPLC：R_t14.7 minutes (method a).

The (R) -and (S) -enantiomers of this embodiment can be obtained by conventional methods known in the art. The (R) -enantiomer of this embodiment is of particular importance according to the invention.

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:

prepared in analogy to the procedure described for example 7a from 250 mg (0.66 mmol) N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide and 200mg (0.66 mmol) 1- (3-amino-3-methyl-butyl) -spiro (cyclohexane-1, 4 '-2H-3', 1 '-benzoxazine) -2' -one. The difference here is that the product obtained as the hydrochloride salt was also purified by chromatography (silica gel, dichloromethane/methanol ═ 50: 1).

Yield: 190mg (46%), HPLC: r_t17.8 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 (0.31 mmol) 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 ] -methanesulfonamide were hydrogenated. After separation of the catalyst, the filtrate was freed of solvent, mixed with 8 ml of ethyl acetate and acidified to pH2 by addition of a solution of hydrochloric acid in ethyl acetate. The solvent was distilled off, and the residue was stirred in ether and filtered.

Yield: 40mg (23%, hydrochloride); mass spectrum: [ M + H ]]⁺＝532；HPLC：R_t11.8 minutes (method a).

The (R) -and (S) -enantiomers of this embodiment can be obtained by conventional methods known in the art. Of particular importance is the (R) -enantiomer according to this embodiment of the invention.

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 ] -carboxylic acid sulfonamide

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 ] -carboxylic acid sulfonamide:

in analogy to example 7a, 292 mg (0.77 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide were reacted with 200mg (0.77 mmol) of 1- (3-amino-3-methyl-butyl) -spiro (cyclopropyl-1, 4 '-2H-3', 1 '-benzoxazine) -2' -one and worked up. The crude product was mixed with 8 ml of ethyl acetate and acidified to pH2 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: 400 mg (84%, hydrochloride), HPLC: r_t15.2 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 ] -carboxylic acid sulfonamide:

in analogy to example 1b, the product was prepared from 400 mg (0.65 mmol) 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.

Yield: 230 mg (67%, hydrochloride); mass spectrum: [ M + H ]]⁺＝490；HPLC：R_t8.9 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:

379 mg (1 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide and 290 mg (1 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one are 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 113 mg (3 mmol) of sodium borohydride, the mixture is stirred at ambient temperature for 3 hours, mixed with 0.7 ml of saturated potassium carbonate solution and stirred for a further 30 minutes. The mixture was filtered through alumina (basic), washed repeatedly with dichloromethane/methanol (15:1) and evaporated to dryness. The crude product thus obtained was purified by chromatography (dichloromethane containing 0-10% methanol/ammonia-9: 1). The benzyl ether thus obtained was dissolved in 10 ml of methanol and hydrogenated at 1 bar hydrogen pressure using palladium on charcoal as catalyst. The catalyst is then filtered off and the filtrate is evaporated to dryness. A white solid.

Yield 338 mg (65%, 2 steps); quality of foodSpectrum: [ M + H ]]⁺＝520。

The (R) -and (S) -enantiomers of this embodiment can be obtained by conventional methods known in the art. Of particular importance is the (R) -enantiomer according to this embodiment of the invention. The optical rotation 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 an acetone molecule) was-28.8 ° (c ═ 1% in methanol at 20 ℃).

N- (5- { (R) -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 (free base, crystals):

2.50 g (4.81 mmol) N- (5- { (R) -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 were heated in 250 ml methanol. Activated carbon was added and the mixture was hot filtered through celite (kieseguhr). The solution was then evaporated to 50 ml and slowly cooled. The precipitated solid is filtered off with suction and washed with methanol and diethyl ether.

Yield: 1.11 g; mass spectrum [ M + H]⁺520; melting point 168 ℃.

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, 246 mg (0.65 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide was reacted with 200mg (0.65 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one. One difference is that it omits the preparation of the hydrochloride salt. Instead, the free base was purified by chromatography (reverse phase, acetonitrile/water gradient solution, containing 0.1% trifluoroacetic acid).

Yield: 180 mg (trifluoroacetate), HPLC: r_t17.4 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:

175 mg of 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 trifluoroacetate in 9 ml of methanol were hydrogenated at ambient temperature in the presence of 40mg of Raney nickel and under a hydrogen pressure of 3 bar. The catalyst was filtered off and the filtrate was freed of solvent. A white solid.

Yield: 131 mg (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, 246 mg (0.65 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide were reacted with 200mg (0.65 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-7-fluoro-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one and worked up. Except that it omits the preparation of the hydrochloride salt, the free base was purified by chromatography (reverse phase, acetonitrile/water gradient solution, containing 0.1% trifluoroacetic acid).

Yield: 220 mg (trifluoroacetate), HPLC: r_t17.7 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:

prepared in analogy to example 11b from 210 mg 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. Grey solid.

Yield: 154 mg (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, 237 mg (0.625 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide was reacted with 200mg (0.624 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-8-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one. The crude product was dissolved in ethyl acetate and acidified to pH2 with an ethyl acetate solution of hydrochloric acid. The solvent was distilled off, and the residue was stirred in ether. The hydrochloride salt thus obtained (330 mg) was then further purified by chromatography.

Yield: 90mg (trifluoroacetate), HPLC: r_t17.6 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, 80mg (0.118 mmol) of 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 was hydrogenated. A beige solid.

Yield: 70 mg (trifluoroacetate salt); mass spectrometry: [ 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, 235 mg (0.619 mmol) of N- [ 2-benzyloxy-5- (2-ethoxy-2-hydroxy-acetyl) -phenyl ] -methanesulfonamide were reacted with 200mg (0.624 mmol) of 1- (3-amino-3-methyl-butyl) -4, 4-diethyl-6-methoxy-1, 4-dihydro-benzo [ d ] [1, 3] oxazin-2-one. One difference is that the crude product is not precipitated as the hydrochloride salt, but is purified by chromatography (reverse phase, acetonitrile/water gradient solution, containing 0.1% trifluoroacetic acid).

Yield: 150 mg (trifluoroacetate), HPLC: r_t16.9 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:

in analogy to example 11b, the title compound was prepared 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. Grey solid.

Mass spectrum: [ M + H ]]⁺＝550。

Synthesis of salts

The compounds of formula 1 can generally be prepared using the following methods.

a) And (3) a hydrobromide salt: 1.02 mmol of the free base of the compound of formula 1 are suspended in 3 ml of acetone and mixed with 170. mu.l (1.01 mmol) of 48% hydrobromic acid in 1 ml of acetone. Sufficient diethyl ether was added to the resulting solution to cause precipitation of a yellow oil. The oil was separated, dissolved in 2 ml of acetone, diluted with a small amount of ethyl acetate and mixed with a crystallization aid. The precipitated salt was filtered and washed with ethyl acetate and diethyl ether. The solid was then recrystallized from acetonitrile. Yield: about 75%, melting point: 145 +/-5 ℃.

b) Hydrochloride salt: 2.05 mmoles of the free base of the compound of formula 1 are suspended in 7 ml of acetone and mixed with 506 microliters (2.02 mmoles) of a solution of 4 molar hydrochloric acid in 550 microliters of acetone, at which time a clear solution is formed. After the addition of the crystallization aid, a total of 7 ml of diethyl ether was added dropwise. After 3 hours the precipitated solid was separated, washed with diethyl ether and dried at 40 ℃. The solid was then recrystallized from acetonitrile by adding a few drops of water, filtered and washed with diethyl ether. Yield: 46 percent. Melting point: 162 +/-3 ℃.

c) Hydrochloride salt: 1.92 mmol of the free base of the compound of formula 1 are suspended in 7 ml of acetone and mixed with 200. mu.l (1.76 mmol) of a 1 ml solution of 32% hydrochloric acid in acetone. A clear solution was formed. A solid precipitated after the addition of the crystallization aid. The solution was diluted with ether and filtered. The solid was washed with acetone/diethyl ether and recrystallized from acetonitrile. Yield: 73 percent.

The following compounds can be prepared by the methods described above:

EXAMPLE 1.1 a-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 hydrobromide salt

EXAMPLE 1.2a-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 hydrobromide

EXAMPLE 1.3 a-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 hydrobromide

EXAMPLE 1.4 a-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 hydrobromide salt

EXAMPLE 1.5 a-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 hydrobromide

EXAMPLE 1.6 a-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 hydrobromide

EXAMPLE 1.7 a-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 hydrobromide salt

EXAMPLE 1.8a-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 hydrobromide

EXAMPLE 1.9 a-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 hydrobromide

EXAMPLE 1.10 a-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 hydrobromide salt

EXAMPLE 1.11 a-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 hydrobromide

EXAMPLE 1.12 a-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 hydrobromide

EXAMPLE 1.13 a-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 hydrobromide

EXAMPLE 1.14 a-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 hydrobromide

EXAMPLE 1.1 b-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 hydrochloride

EXAMPLE 1.2 b-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 hydrochloride

EXAMPLE 1.3 b-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 hydrochloride

EXAMPLE 1.4 b-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 hydrochloride

EXAMPLE 1.5 b-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 hydrochloride

EXAMPLE 1.6 b-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 hydrochloride

EXAMPLE 1.7 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 hydrochloride

EXAMPLE 1.8 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 hydrochloride

EXAMPLE 1.9 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 hydrochloride

EXAMPLE 1.10 b-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

EXAMPLE 1.11 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 hydrochloride

EXAMPLE 1.12 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 hydrochloride

EXAMPLE 1.13 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 hydrochloride

EXAMPLE 1.14 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 hydrochloride

Preferred are the R-enantiomers of compounds 1.1a, 1.2a, 1.3a, 1.4a, 1.5a, 1.6a, 1.7a, 1.8a, 1.9a, 1.10a, 1.11a, 1.12a, 1.13a, 1.14a and 1.1b, 1.2b, 1.3b, 1.4b, 1.5b, 1.6b, 1.7b, 1.8b, 1.9b, 1.10b, 1.11b, 1.12b, 1.13b, 1.14 b.

X-ray powder diffractogram of example 10 and salts thereof

Parameters of the X-ray powder diffractometer used for measurement: STOE stii PX-ray powder diffractometer with position sensitive detector in transmission mode with curved germanium (111) primary monochromator; the wavelength used: CuK_α1λ 1.54098 angstroms; power absorption of X-ray tube: 40kV and 40 mA; absorption range: 3-40 degrees 2 theta.

The following table shows the characteristic X-ray diffraction in intensity (normalized, up to 40 ° 2 θ) for a particular example. Corresponding maps (fig. 1-3) can be seen in the attached drawing section.

FIG. 1: x-ray powder diffractogram of N- (5- { (R) -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 free base.

FIG. 2: x-ray powder diffractogram of N- (5- { (R) -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 monohydrochloride.

FIG. 3: x-ray powder diffractogram of N- (5- { (R) -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 monohydrobromide salt.

As known to those of ordinary skill in the art, the diffraction intensity varies with sample preparation. The specific intensities below are seen for the above example measurements and cannot be converted into any other measurements.

Table 1: x-ray diffraction (up to 30 ° 2 θ) of the free base of N- (5- [ (R) -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 expressed as intensity (normalized).

Table 2: x-ray diffraction in intensity (normalized) of N- (5- [ (R) -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 monohydrochloride (up to 30 ° 2 θ).

Table 3: x-ray diffraction in intensity (normalized) of N- (5- [ (R) -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 monohydrobromide salt (up to 30 ° 2 θ).

Example 10 thermal analysis (DSC/TG) of the salt thereof

With heat of useTechnical data relating to DSC devices: DSC 822 manufactured by Mettler Toledo; heating rate: 10K/min; crucible type: a porous aluminum crucible; atmosphere: n is a radical of₂80 mL/min throughput; general weight: 3-10 mg.

Technical data relating to the thermoanalytical TG devices used: TGA/SDTA 851 by Mettler Toledo in combination with IR (Nicolet FT-IR 4700) was used to analyze the separated volatile fraction; heating rate: 10K/min; crucible type: an open alumina crucible; atmosphere: n is a radical of₂20 mL/min throughput; general weight: 15-25 mg.

Melting points measured by DSC are listed in the examples. Corresponding maps (FIGS. 4-6) can be seen in the attached drawing section.

FIG. 4: DSC/TG profile of N- (5- { (R) -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 free base.

FIG. 5: DSC/TG plot of N- (5- { (R) -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 monohydrochloride.

FIG. 6: DSC/TG profile of N- (5- { (R) -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 monohydrobromide salt.

Combination of

The compounds of formula 1 may be used alone or in combination with other active substances of formula 1. If desired, the compounds of formula 1 may also be used in admixture with W, wherein W represents a pharmacologically active substance and is, for example, selected from the group consisting of beta mimetics, anticholinergics, corticosteroids, PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1-antihistamines, PAF antagonists and PI3 kinase inhibitors. Further, a double or triple combination of W may be combined with the compound of formula 1. The combination of W may be (for example):

w represents a beta mimetic in combination with an anticholinergic, a corticosteroid, a PDE4 inhibitor, an EGFR inhibitor or a LTD4 antagonist,

-W represents an anticholinergic in combination with a betamimetic, a corticosteroid, a PDE4 inhibitor, an EGFR inhibitor or an LTD4 antagonist,

-W represents a corticosteroid combined with a PDE4 inhibitor, an EGFR inhibitor or an LTD4 antagonist,

w represents a PDE4 inhibitor in combination with an EGFR inhibitor or LTD4 antagonist,

-W represents an EGFR inhibitor in combination with an LTD4 antagonist,

the compound used as a betamimetic agent is preferably a compound selected from: salbutamol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoproterenol, levalbuterol, mabuterol, meluadrin, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, soterel, salfentronol, terbutaline, tiaramide, tolobutarol, clenbuterol, CHF-1035, HOKU-81, KUL-8 and 1241035

-3- (4- {6- [ 2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino ] -hexyloxy } -butyl) -benzyl-sulphonamide

-5- [2- (5, 6-diethyl-indan-2-ylamino) -1-hydroxy-ethyl ] -8-hydroxy-1H-quinolin-2-one

-4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] -amino } ethyl ] -2(3H) -benzothiazolone

-1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol

-1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl ] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol

-1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol

-1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ] ethanol

-1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-n-butyloxyphenyl) -2-methyl-2-propylamino ] ethanol

-1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl ] -2-methyl-2-butylamino } ethanol

-5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoxazin-3- (4H) -one

-1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol

-6-hydroxy-8- { 1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1, 4] oxazin-3-one

-6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid ethyl ester) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1, 4] oxazin-3-one

-6-hydroxy-8- { 1-hydroxy-2- [2- (4-phenoxy-acetic acid) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1, 4] oxazin-3-one

-8- {2- [1, 1-dimethyl-2- (2, 4, 6-trimethylphenyl) -ethylamino ] -1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4] oxazin-3-one

-6-hydroxy-8- { 1-hydroxy-2- [2- (4-hydroxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1, 4] oxazin-3-one

-6-hydroxy-8- { 1-hydroxy-2- [2- (4-isopropyl-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1, 4] oxazin-3-one

-8- {2- [2- (4-ethyl-phenyl) -1, 1-dimethyl-ethylamino ] -1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4] oxazin-3-one

-8- {2- [2- (4-ethoxy-phenyl) -1, 1-dimethyl-ethylamino ] -1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4] oxazin-3-one

-4- (4- {2- [ 2-hydroxy-2- (6-hydroxy-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-8-yl) -ethylamino ] -2-methyl-propyl } -phenoxy) -butyric acid

-8- {2- [2- (3, 4-difluoro-phenyl) -1, 1-dimethyl-ethylamino ] -1-hydroxy-ethyl } -6-hydroxy-4H-benzo [1, 4] oxazin-3-one

-1- (4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol

Optionally in the form of its racemate, enantiomers, diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates or hydrates. According to the invention, the acid addition salts of betamimetics are preferably selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

The anticholinergic used is preferably a compound selected from the following: tiotropium salt (preferably bromide salt), oxitropium salt (preferably bromide salt), fluorotropium salt (preferably bromide salt), ipratropium salt (preferably bromide salt), glycopyrronium salt (preferably bromide salt), trospium salt (preferably chloride salt), tolterodine (tolterodine). In the above salts, the cation is a pharmacologically active component. As anions, the above-mentioned salts can preferably contain chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate, while as counter-ions preferably chloride, bromide, iodide, sulfate, methanesulfonate or p-toluenesulfonate. Of all salts, particular preference is given to chloride, bromide, iodide and methanesulfonate.

Other preferred anticholinergics are salts selected from the group consisting of formula AC-1:

wherein X^-Denotes an anion having a single negative charge, preferably an anion selected from the following ions: fluoride, chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate, preferably anions having a single negative charge, particularly preferably anions selected from the following: fluoride, chloride, bromide, methanesulfonate and p-toluenesulfonate, particularly preferably bromide, optionally in the form of its racemate, enantiomer or hydrate. Of particular interest are those pharmaceutical combinations containing enantiomers of the formula AC-1-ene.

Wherein X-may have the above-mentioned meaning. Other preferred anticholinergics are salts selected from the group consisting of formula AC-2:

wherein R represents methyl or ethyl and wherein X-may have the above-mentioned meaning. In an alternative embodiment, the compound of formula AC-2 may also be present as the free base AC-2-base,

other specific compounds are:

-tropinol 2, 2-diphenylpropionate methyl bromide;

-scopine 2, 2-diphenylpropionic acid methyl bromide;

-scopine 2-fluoro-2, 2-diphenylacetate methyl bromide;

-tropinol 2-fluoro-2, 2-diphenylacetate methyl bromide;

-tropinol 3, 3 ', 4, 4' -tetrafluorodiphenylglycolate methyl bromide;

-scopine 3, 3 ', 4, 4' -tetrafluorodiphenylglycolate methyl bromide;

-tropinol 4, 4' -difluorodiphenylglycolate methyl bromide;

-scopine 4, 4' -difluorodiphenylglycolate methyl bromide;

-tropinol 3, 3' -difluorodiphenylglycolate methyl bromide;

-scopine 3, 3' -difluorodiphenylglycolate methyl bromide;

-tropinol 9-hydroxy-fluorene-9-carboxylate methyl bromide;

-tropinol 9-fluoro-fluorene-9-carboxylate methyl bromide;

-scopine 9-hydroxy-fluorene-9-carboxylate methyl bromide;

-scopine 9-fluoro-fluorene-9-carboxylate methyl bromide;

-tropinol 9-methyl-fluorene-9-carboxylate methyl bromide;

-scopine 9-methyl-fluorene-9-carboxylate methyl bromide;

-cyclopropyl tropine diphenylglycolate methyl bromide;

-cyclopropyltropine 2, 2-diphenylpropionate methyl bromide;

-cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methyl bromide;

-cyclopropyltropine 9-methyl-fluorene-9-carboxylate methyl bromide;

-cyclopropyltropine 9-methyl-xanthene-9-carboxylate methyl bromide;

-cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methyl bromide;

-cyclopropyl tropine 4, 4' -difluoro benzilic acid methyl ester methyl bromide;

-tropinol 9-hydroxy-xanthene-9-carboxylate methyl bromide;

-scopine 9-hydroxy-xanthene-9-carboxylate methyl bromide;

-tropinol 9-methyl-xanthene-9-carboxylate methyl bromide;

-scopine 9-methyl-xanthene-9-carboxylate methyl bromide;

-tropinol 9-ethyl-xanthene-9-carboxylate methyl bromide;

-tropine 9-difluoromethyl-xanthene-9-carboxylate methyl bromide;

-scopine 9-hydroxymethyl-xanthene-9-carboxylate methyl bromide.

Within the scope of the present invention, the above-mentioned compounds can also be used as salts, where the salt methyl-X is used instead of methyl bromide, where X may have the above-mentioned administration of X^-The meaning of (a).

As corticosteroid, preferably a compound selected from the following is used: prednisolone, prednisone, butoxypropionate (butixocortpropionate), flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacorte (deflazacorte), RPR-106541, NS-126, ST-26, and

- (S) -6, 9-difluoro-17- [ (2-furylcarbonyl) oxy ] -11-hydroxy-16-methyl-3-oxo-androsta-1, 4-diene-17-carbothioic acid fluoromethyl ester

- (S) -6, 9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1, 4-diene-17-carbothioic acid (2-oxo-tetrahydro-furan-3S-yl) ester

-benhydroxol-dichloroacetate (etipirednol-dichloroacetate)

Optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of salts and derivatives thereof, solvates and/or hydrates thereof. Any reference to a steroid includes reference to any salt or derivative, hydrate or solvate that may be present. Examples of possible salts and derivatives of steroids may be: for example, an alkali metal salt of a sodium or potassium salt, a sulfonyl benzoate, a phosphate, an isonicotinate, an acetate, a propionate, a dihydrogen phosphate, a palmitate, a pivalate or a furoate.

PDE 4-inhibitors which can be used are preferably compounds selected from the following: amphetamine (enproffylin), theophylline, roflumilast, alisporol (ariflo) (cilomilast), tofacitrelate (tofacilarte), promastine (pumafentrin), liramilate (lirimalast), allofeline (arofylin) atizolam (atizoram), D-4418, Bay-198004, BY343, CP-325.366, D-4396(Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, and

-N- (3, 5-dichloro-1-oxo-pyridin-4-yl) -4-difluoromethoxy-3-cyclopropylmethoxybenzamide

-(-)p-[(4aR^*，10bS^*) -9-ethoxy-1, 2, 3, 4, 4a, 10 b-hexahydro-8-methoxy-2-methylbenzo [ s ]][1，6]Naphthyridin-6-yl]-N, N-diisopropylbenzamide

- (R) - (+) -1- (4-bromobenzyl) -4- [ (3-cyclopentyloxy) -4-methoxyphenyl ] -2-pyrrolidinone

-3- (cyclopentyloxy-4-methoxyphenyl) -1- (4-N' - [ N-2-cyano-S-methyl-isothioureido ] benzyl) -2-pyrrolidinone

-cis [ 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid ]

-2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxy-phenyl) cyclohexan-1-one

-cis [ 4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol ]

- (R) - (+) - [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene ] acetic acid ethyl ester

- (S) - (-) - [4- (3-cyclopentyloxy-4-methoxyphenyl) pyrrolidin-2-ylidene ] acetic acid ethyl ester

-9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-thienyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyridine

-9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (tert-butyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyridine

Optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention, the acid addition salts of betamimetics are preferably selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

The LTD4 antagonist used is preferably a compound selected from: montelukast, pranlukast, zafirlukast, MCC-847(ZD-3523), MN-001, MEN-91507(LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-1- (((R) - (3- (2- (6, 7-difluoro-2-quinolinyl) ethenyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) -methylcyclopropane-acetic acid

-1- ((1(R) -3(3- (2- (2, 3-dichlorothieno [3, 2-b ] pyridin-5-yl) - (E) -vinyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) -propyl) thio) methyl) cyclopropane-acetic acid

- [2- [ [2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl ] oxymethyl ] phenyl ] -acetic acid,

optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention, the acid addition salts of betamimetics are preferably selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate. Optionally salts or derivatives that may be capable of forming an LTD4 antagonist refer to (for example): for example, an alkali metal salt, an alkaline earth metal salt, a sulfonyl benzoate salt, a phosphate salt, an isonicotinate salt, an acetate salt, a propionate salt, a dihydrogen phosphate salt, a palmitate salt, a pivalate salt or a furoate salt of a sodium salt or a potassium salt.

EGFR inhibitors which may be used are preferably selected from the following compounds: cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-diethylamino) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy ] -quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopentyloxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7- [ (S) - (tetrahydrofuran-3-yl) oxy ] -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { [4- ((R) -2-methoxymethyl-6-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- ((S) -6-methyl-2-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopentyloxy-quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- (N, N-bis- (2-methoxy-ethyl) -amino) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopropylmethoxy-quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-ethyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- ({4- [ N- (tetrahydropyran-4-yl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopropylmethoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7- ((R) -tetrahydrofuran-3-yloxy) -quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7- ((S) -tetrahydrofuran-3-yloxy) -quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- [ N- (2-methoxy-ethyl) -N-methyl-amino ] -1-oxo-2-buten-1-yl } amino) -7-cyclopentyloxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N-cyclopropyl-N-methyl-amino) -1-oxo-2-buten-1-yl ] -amino } -7-cyclopentyloxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6, 7-bis- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -7- [3- (morpholin-4-yl) -propyloxy ] -6- [ (vinyl-carbonyl) amino ] -quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- (4-hydroxy-phenyl) -7H-pyrrolo [2, 3-d ] pyrimidine

-3-cyano-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (N, N-dimethylamino) -1-oxo-2-buten-1-yl ] -amino } -7-ethoxy-quinoline

-4- { [ 3-chloro-4- (3-fluoro-benzyloxy) -phenyl ] -amino } -6- (5- { [ (2-methanesulfonyl-ethyl) amino ] methyl } -furan-2-yl) quinazoline

-4- [ (R) - (1-phenyl-ethyl) amino ] -6- { [4- ((R) -6-methyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- { [4- (morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-chloro-4-fluorophenyl) amino ] -6- ({4- [ N, N-bis- (2-methoxy-ethyl) -amino ] -1-oxo-2-buten-1-yl } amino) -7- [ (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- { [4- (5, 5-dimethyl-2-oxo-morpholin-4-yl) -1-oxo-2-buten-1-yl ] -amino } -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (R) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -6- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {2- [4- (2-oxo-morpholin-4-yl) -piperidin-1-yl ] -ethoxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (tert-butoxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-amino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-3-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (methoxymethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (piperidin-3-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-acetylamino-ethyl) -piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-ethoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- ((S) -tetrahydrofuran-3-yloxy) -7-hydroxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (dimethylamino) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { trans-4- [ (morpholin-4-yl) sulfonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-acetylamino-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7- (2-methanesulfonylamino-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (piperidin-1-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-aminocarbonylmethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (tetrahydropyran-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (morpholin-4-yl) sulfonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-ethanesulfonylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-ethoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-acetylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- [1- (tert-butoxycarbonyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- (tetrahydropyran-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (piperidin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4- { N- [ (4-methyl-piperazin-1-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ (morpholin-4-yl) carbonylamino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [2- (2-oxopyrrolidin-1-yl) ethyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- (1-acetyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methyl-piperidin-4-yloxy) -7- (2-methoxy-ethoxy) -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-isopropoxycarbonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (cis-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- { cis-4- [ N- (2-methoxy-acetyl) -N-methyl-amino ] -cyclohexan-1-yloxy } -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- (piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- [1- (2-methoxy-acetyl) -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-ethynyl-phenyl) amino ] -6- {1- [ (morpholin-4-yl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (cis-2, 6-dimethyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methyl-morpholin-4-yl) carbonyl ] -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (S, S) - (2-oxa-5-aza-bicyclo [2, 2, 1] hept-5-yl) carbonyl ] -piperidin-4-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (N-methyl-N-2-methoxyethyl-amino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-ethyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (2-methoxyethyl) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- {1- [ (3-methoxypropyl-amino) carbonyl ] -piperidin-4-yloxy } -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ cis-4- (N-acetyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-methylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [ trans-4- (N-methanesulfonyl-N-methyl-amino) -cyclohexan-1-yloxy ] -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4-dimethylamino-cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (trans-4- { N- [ (morpholin-4-yl) carbonyl ] -N-methyl-amino } -cyclohexan-1-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- [2- (2, 2-dimethyl-6-oxo-morpholin-4-yl) -ethoxy ] -7- [ (S) - (tetrahydrofuran-2-yl) methoxy ] -quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-methanesulfonyl-piperidin-4-yloxy) -7-methoxy-quinazoline

-4- [ (3-chloro-4-fluoro-phenyl) amino ] -6- (1-cyano-piperidin-4-yloxy) -7-methoxy-quinazoline

Optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention, the preferred acid addition salts of the betamimetics are selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

The dopamine agonist used is preferably a compound selected from: bromocriptine (bromocriptine), cabergoline, α -dihydroergocriptine (alpha-dihydroergocryptine), lisuride, pergolide, pramipexol (pramipexol), roxylindole (roxindol), ropinirole (ropinarol), talipexol (talipexol), terguride and vezan (viozan), optionally in the form of the racemate, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof. According to the invention, the preferred acid addition salts of the betamimetics are selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

H1 antihistamines that can be used are preferably compounds selected from the following: epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedasine, dimetindine, clemastine, pamirine, dexchlorpheniramine, pheniramine, doxylamine, chlorphenxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratadine, and meclizine, optionally in the form of their racemates, enantiomers, or diastereomers, and optionally in the form of their pharmacologically acceptable acid addition salts, solvates, or hydrates thereof. According to the invention, preferred acid addition salts of betamimetics are selected from: hydrochloride, hydrobromide, hydroiodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate.

The PAF antagonist used is preferably a compound selected from:

-4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanon-1-yl]-6H-thieno- [3, 2-f]-[1，2，4]Triazolo [4, 3-a][1，4]Diaza derivatives

-6- (2-chlorophenyl) -8, 9-dihydro-1-methyl-8- [ (4-morpholinyl) carbonyl]-4H, 7H-cyclopenta- [4, 5]-thieno- [3, 2-f][1，2，4]Triazolo [4, 3-a][1，4]Diaza derivatives，

Optionally in the form of its racemate, enantiomers or diastereomers and optionally in the form of its pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention, preferred acid addition salts of betamimetics are selected from: hydrochloride, hydrobromide, hydroiodide, hydrogen sulphate, hydrogen phosphate, hydrogen methanesulphonate, hydrogen nitrate, hydrogen maleate, hydrogen acetate, hydrogen citrate, hydrogen fumarate, hydrogen tartrate, hydrogen oxalate, hydrogen succinate, hydrogen benzoate and hydrogen p-toluenesulphonate.

Preparation

Suitable formulations for administration of the compounds of formula 1 include, for example, tablets, capsules, suppositories, solutions, powders, and the like. The content of the pharmaceutically active compound should generally be in the range of 0.05 to 90% by weight, preferably 0.1 to 50% by weight of the composition. Suitable tablets may be obtained, for example, by mixing the active substance with known excipients, such as: for example calcium carbonate, calcium phosphate or lactose, disintegrating agents such as corn starch or alginic acid, binding agents such as starch or gelatin, lubricating agents such as magnesium stearate or talc and/or agents for delaying release such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

Thus, coated tablets may be prepared by coating cores manufactured analogously to tablets with substances conventionally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or to avoid incompatibilities the core may also consist of several layers. Similarly, the tablet coating may consist of several layers to achieve delayed release, in which case excipients as described above for the tablets may be used.

Syrups containing the active substances according to the invention or combinations thereof may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar; and flavoring agents, such as flavoring agents such as vanilla or citrus extract. It may also contain suspending or thickening agents such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide or preservatives such as p-hydroxybenzoates.

Solutions are prepared in a customary manner, for example with addition of isotonic agents, preservatives such as p-hydroxybenzoate or stabilizers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally with the use of emulsifiers and/or powders, while if water is used as diluent, for example optionally organic solvents can be used as solubilizers or dissolution aids and the solutions can be transferred into injection vials or ampoules or infusion bottles.

Capsules containing a compound of formula 1 according to the invention can be prepared, for example, by mixing the active substance with an inert carrier, for example lactose or sorbitol, and encapsulating it in gelatin capsules.

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

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

For oral use, the tablets may obviously contain, in addition to the specific carrier, additives such as sodium citrate, calcium carbonate and calcium hydrogen phosphate, as well as various other 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 in the manufacture of tablets. In the case of aqueous suspensions, the active substance may be mixed with various flavoring or coloring agents in addition to the excipients mentioned above.

In the use of the compounds of the formula 1, preferably for the treatment of respiratory diseases, formulations which can be administered by inhalation or pharmaceutical preparations are particularly preferably used according to the invention. Inhalable formulations include inhalable powders, propellant-containing metered aerosol 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.

The compounds of formula 1, which are particularly preferably used in crystalline form according to the invention, are preferably used for the preparation of inhalation powders. The inhalable powders which can be used according to the invention may contain the crystalline compound of formula 1, alone or in admixture with suitable physiologically acceptable excipients.

If the active substance is present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the preparation of these inhalable powders according to the invention: monosaccharides (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 mixtures of these excipients. Preferably a mono-or disaccharide is used, while preferably lactose or glucose is used, especially (but not exclusively) in the form of their hydrates. For the purposes of the present invention, lactose is a particularly preferred excipient, while lactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention, the excipient has a maximum average particle size of at most 250 μm, preferably between 10 μm and 150 μm, most preferably between 15 μm and 80 μm. In some cases, it may seem appropriate to add a finer excipient fraction having an average particle size of 1 μm to 9 μm to the above-mentioned excipient. These finer excipients are also selected from the possible excipients listed above. Finally, to prepare the inhalable powders according to the invention, the finely particulate active substance with a mean particle size preferably between 0.5 μm and 10 μm, more preferably between 1 μm and 5 μm, is added to the excipient mixture. The prior art is aware of processes for the manufacture of inhalable powders according to the invention by grinding and micronization and finally mixing these ingredients together.

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

The aerosol for inhalation comprising a propellant gas according to the invention may comprise a propellant gas in soluble form or in dispersed form. Propellant gases which can be used for the preparation of inhalation aerosols are known from the prior art. Suitable propellant gases are selected from hydrocarbons, such as n-propane, n-butane or isobutane; and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane, or cyclobutane. The propellant gases mentioned above may be used individually or in mixtures. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant-driven inhalation aerosol may also contain other ingredients such as co-solvents, stabilizers, surfactants, antioxidants, lubricants, and pH adjusters. All of these ingredients are known in the art.

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

The dosage of the compounds according to the invention naturally depends highly on the method of administration and on the disease to be treated. When administered by inhalation, the compounds of formula (la) are characterized by high potency even at doses in the microgram range. Compounds of this formula may also be used effectively in the microgram range or above. Then, for example, the dosage may be in the milligram range.

In another aspect, the present invention also relates to the above pharmaceutical preparations characterized by containing the compound of formula 1, particularly preferably to the above pharmaceutical preparations for administration by inhalation.

The following examples of formulations illustrate the invention without limiting the scope of the invention:

examples of pharmaceutical preparations

A) Each tablet of the tablet

Active substance 100mg

Lactose 140mg

Corn starch 240mg

Polyvinylpyrrolidone 15mg

Magnesium stearate5mg

500mg

The fine active substance, lactose and part of the corn starch are mixed together. The mixture was sieved, subsequently wetted with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.

B) Each tablet of the tablet

80mg of active substance

Corn starch 190mg

Lactose 55mg

Microcrystalline cellulose 35mg

Polyvinylpyrrolidone 15mg

Sodium carboxymethyl starch 23mg

Magnesium stearate2mg

The fine-grained active substance, part of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and granulated with the remaining corn starch and water, the granulate is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added and mixed and the mixture is compressed into tablets of appropriate size.

C) Coated tablet Each coated tablet

Active substance 5mg

Corn starch 41.5mg

Lactose 30mg

Polyvinylpyrrolidone 3mg

Magnesium stearate0.5mg

80mg

The active substance, corn starch, lactose and polyvinylpyrrolidone were thoroughly mixed and moistened with water. The wetted material was passed through a sieve of 1mm size, dried at about 45 ℃ and the granules were then passed through the same sieve. After mixing in the magnesium stearate, the tablet core with a diameter of 6mm was compressed in a tablet-making machine. The tablet cores thus produced are coated in a known manner with a covering layer consisting essentially of sugar and talc. The finished coated tablets were polished with wax.

D) Capsule per capsule

Active substance 50mg

Corn starch 268.5mg

Magnesium stearate1.5mg

320mg

The material and corn starch were mixed and moistened with water. The wet mass was sieved and dried. The dried granules are sieved and mixed with magnesium stearate. The finished mixture was encapsulated in size 1 hard gelatin capsules.

E) Ampoule solution

Active substance 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 to make it isotonic. The solution obtained is filtered free of pyrogens and the filtrate is transferred under sterile conditions into ampoules which are subsequently sterilized and sealed by melting. These ampoules contain 5mg, 25mg and 50mg of active substance.

F) Suppository

Active substance 50mg

Solid fat1650mg

1700mg

Melting the hard fat. The milled active was homogeneously dispersed therein at 40 ℃. It is cooled to 38 ℃ and poured into a slightly cooled suppository mold.

G) Oral suspension

Active substance 50mg

Hydroxyethyl cellulose 50mg

Sorbic acid 5mg

Sorbitol (70%) 600mg

Glycerol (200 mg)

Flavoring agent 15mg

Adding water to 5ml

Distilled water was heated to 70 ℃. Hydroxyethyl cellulose was dissolved therein with stirring. After addition of the sorbitol solution and glycerol, the formulation was cooled to ambient temperature. Sorbic acid, flavors and materials are added at ambient temperature. The suspension was evacuated under stirring to remove any air.

Claims

1. An enantiomerically pure compound of formula 1,

wherein

R¹And R²Independently of one another, H, halogen or C_1-4-alkyl, or together represent C_1-6-an alkylene group; and

R³represents H, halogen, OH, C_1-4Alkyl or O-C_1-4-an alkyl group;

Y^m-represents an anion having m negative charges, preferably an anion having m negative charges selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, propanedisulfonate, benzoate and p-toluenesulfonate;

m represents 1 or 2;

2. An enantiomerically pure compound of formula 1 according to claim 1, wherein

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

m represents 1 or 2;

3. An enantiomerically pure compound of formula 1 according to claim 1 or 2, wherein

R³Represents hydrogen, fluorine, OH, methyl or methoxy;

m represents 1 or 2;

4. An enantiomerically pure compound of formula 1 according to any one of claims 1 to 3, in which

R³Represents hydrogen, fluorine, OH, methyl or methoxy;

Y^m-represents an anion having m negative charges, preferably selected from chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, benzoate, citrateAnions having m negative charges of acid radicals, salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate, ethanedisulfonate, benzoate and p-toluenesulfonate;

m represents 1 or 2;

5. An enantiomerically pure compound of formula 1 according to any one of claims 1 to 4, in which

R³Represents hydrogen, fluorine, OH or methoxy;

m represents 1 or 2;

6. Enantiomerically pure compound of formula 1 according to any one of claims 1 to 5, characterised in that it is present in crystalline form, optionally in the form of its crystalline tautomer, crystalline hydrate or crystalline solvate.

7. An enantiomerically pure compound of formula 1 according to any one of claims 1 to 6 which is N- (5- { (R) -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 monohydrochloride.

8. The crystalline compound of claim 7, characterized by having a maximum endotherm at 162 ℃.

9. The crystalline compound of claim 7 or 8, having X-ray diffraction at d-5.82 angstroms, 5.78 angstroms, 5.43 angstroms, and 3.99 angstroms.

10. An enantiomerically pure compound of formula 1 according to any one of claims 1 to 6 which is N- (5- { (R) -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 monohydrobromide.

11. The crystalline compound of claim 10, having a maximum endotherm at 145 ℃.

12. A crystalline compound as claimed in claim 10 or 11, characterized by having X-ray diffraction at d-5.89 a, 5.81 a, 5.48 a, 4.59 a and 4.03 a.

13. An enantiomerically pure compound of formula 1 according to any one of claims 1 to 12 for use as a medicament.

14. Use of an enantiomerically pure compound of formula 1 according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of a respiratory disease.

15. Pharmaceutical preparation, characterized in that it contains a compound of formula 1 according to any one of claims 1 to 12.

16. Enantiomerically pure, solvent-free, crystalline forms of the compounds of the following formula 1-base,

1-base

Wherein

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

17. An enantiomerically pure, solvent-free, crystalline form of the compound of formula 1-according to claim 16, wherein

And is

R³Represents hydrogen, fluorine, OH, methyl or methoxy, preferably hydrogen.

18. The compound of claim 16 or 17 in enantiomerically pure, solvent-free crystalline form, which is a compound of the formula:

1.14-base-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.

19. The enantiomerically pure, solvent-free crystalline compound according to any one of claims 16 to 18 as a crystalline N- (5- { (R) -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.

20. The crystalline compound of claim 19, having a maximum endotherm at 168 ℃.

21. A crystalline compound as claimed in claim 19 or 20 having X-ray diffraction at d-18.56 angstroms, 8.14 angstroms and 6.31 angstroms.

22. An enantiomerically pure compound of the base of formula 1 as claimed in any one of claims 16 to 21 for use as a medicament.

23. Use of an enantiomerically pure compound of the formula 1-base according to any one of claims 16 to 21 in the manufacture of a medicament for the treatment of a respiratory disease.

24. Pharmaceutical preparation, characterized by containing a compound of the formula 1-base according to any one of claims 16 to 21.