EP1708714A1 - Use of substituted pyrimido pyrimido 5,4-d¨pyrimidines in the treatment of diseases of the respiratory tract - Google Patents

Abstract

The invention relates to the use of pyrimido[5,4-d]pyrimidines in the treatment of inflammatory and obstructive respiratory tract diseases, preferably asthma or COPD, and pharmaceutical compositions containing said compounds.

Description

 USE OF SUBSTITUTED PYRlMID0r5,4-D1PYRIMIDINES FOR THE TREATMENT OF RESPIRATORY DISEASES

The invention relates to the use of pyrimido [5,4-d] pyrimidines for the treatment of inflammatory and obstructive respiratory diseases, preferably asthma or COPD, and pharmaceutical compositions which contain these compounds.

BACKGROUND OF THE INVENTION

Inflammatory and obstructive respiratory diseases belong to the group of progressive respiratory diseases, which include characterized by breathing difficulties. These respiratory problems are usually associated with chronic inflammation of the airways, in which different cells play a role, especially macrophages, neutrophils and CD8 T lymphocytes.

The object of the present invention is to provide a medicament for the treatment of inflammatory and obstructive respiratory diseases. Furthermore, it is an object of the present invention to provide medicaments for the treatment of inflammatory and obstructive respiratory diseases which are characterized by fewer side effects, in particular emesis and nausea.

STATE OF THE ART

Pyrimido [5,4-dJρyrimidines are known from the prior art as active substances with an antiproliferative effect. DE 1151806 describes pyrimido [5,4-d] pyrimidines as corona dilators. EP 23559 describes 2- (perhydro-1,4-diazino) pyrimido [5,4-d] pyrimidines as having an inhibitory effect on the aggregation of cancer cells washed into the bloodstream. EP 55444 describes trisubstituted pyrimido [5,4-d] pyrimidines as

Compounds that have an antihypertensive and cardiotonic activity as well as an inhibitory effect on the aggregation of cancer cells that have been washed into the bloodstream. DESCRIPTION OF THE INVENTION

It has surprisingly been found that pyrimido [5,4-d] pyrimidines are suitable for the treatment of respiratory diseases, in particular inflammatory and obstructive respiratory diseases.

Surprisingly, it was also found that when using pyrimido [5,4-d] pyrimidines for the manufacture of a medicament for the treatment of respiratory diseases there are only minor side effects.

Preferred is the use of substituted pyrimido [5,4-d] pyrimidines for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, particularly preferably COPD or asthma.

The use of substituted pyrimido [5,4-d] pyrimidines is particularly preferred. for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, particularly preferably COPD or asthma with simultaneous reduction of the side effects, in particular emesis or nausea.

Preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases,

wherein

R ¹ and R ² is H or a residue selected from the group consisting of -Cι _-6 alkyl, -C _3-8 cycloalkyl and -Cι. ₆ -alkyl-O-Cι. _6- alkyl, which may be one or can be substituted several times by one or more radicals selected from the group consisting of aryl, -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, hetcycle, -NO ₂ , - NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ and -SR ⁴ or

R ¹ and R ² forms together with the nitrogen form a ring which optionally may be mono- or polysubstituted by one or more radicals selected from the group consisting of aryl, -Cι _-6 alkyl-OH ,, - CF _3, - CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, hetcycle, -NO ₂ , -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -O-Cι _-6- alkyl, -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ and -SR ⁴ ;

R ⁴ and R ⁵ independently of one another H, -Cι. ₆ alkyl;

R ⁶ H, -Cι. ₆ -alkyl, -C _1-6 -alkyl-CO-Cι _-6 -alkyl, hetaryl, hetcycle, -NR ⁴ R ⁵ ;

R ³ H or a radical selected from the group consisting of -Cι. ₈ -alkyl, -C _3-8 -cycloalkyl, -Cι _-6 -alkyl-R ⁷ and.phenyl which may optionally be annealed or substituted one or more times by one or more radicals selected from the group consisting of -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁴ , halogen, hetaryl, hetcycle, -NO ₂ , -NR ⁴ COR ⁴ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ and -SR ⁴ ;

R ⁷ hetaryl, hetaryl fused with hetcyclus, hetcyclus or phenyl, which may optionally be mono- or polysubstituted with one or more substituents selected from the group consisting of -Ci-e-alkyl, -OC _1-6 -alkyl, halogen, -NO ₂ and -CF ₃ ;

X -S-, -S (O) -, -S (O ₂ ) - and

-NR ⁴ -, -S-, -O- means; as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Particularly preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wherein

R ¹ and R ² H or a radical selected from the group consisting of -C _1-6 alkyl, -C ₃ . ₈ -cycloalkyl and -Cι. ₆ -alkyl-O-Cι- ₆ alkyl, which may optionally be mono- or polysubstituted by one or more radicals selected from the group consisting of -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, Hetcycle, -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ and -OR ⁴ or

R ¹ and R ² together with the nitrogen form a ring which can optionally be substituted one or more times by one or more radicals selected from the group consisting of. _6- alkyl-OH, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OC _1-6 -alkyl, -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ and -SR ⁴ ;

R ⁴ and R ^{5 are} independently H, -Cι _-6 -alkyl;

R ⁶ H, -de-alkyl, -C _1-6 -alkyl-CO-C ₁ . _{6 is} alkyl, hetaryl, hetcycle, NR ⁴ R ⁵ ;

R ³ H or a radical selected from the group consisting of -C _1-8 alkyl, -C _3-8 cycloalkyl, -C _1-6 alkyl R ⁷ and phenyl which may be annealed or substituted one or more times can be selected by one or more radicals from the group consisting of -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁴ , halogen, -NO ₂ , -NR ⁴ COR ⁴ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OR ⁴ and -SR ⁴ ;

R ⁷ hetaryl, hetaryl fused with hetcyclus, hetcyclus or phenyl, which may optionally be substituted one or more times with one or several substituents selected from the group consisting of -C _1-6 alkyl, -OC _1-6 alkyl, halogen, -NO and -CF ₃ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -NR ⁴ -, -S-, -O-; as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Also preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wori n

^• R ¹ and R ² H or a radical selected from the group consisting of -Cι. ₆ -a! Kyl, -C _3-8 -cycloalkyl and -Cι _-6 -alkyl-O-Cι. _6- alkyl, which may be mono- or polysubstituted by one or more radicals selected from the group consisting of -OH, -NR ⁴ R ⁵ , morpholinyl and ^■ pyridyl or

R ¹ and R ² together with the nitrogen form a ring selected from the group consisting of morpholinyl, thiomorpholinonyl, piperidyl and piperazinyl which may be substituted one or more times by one or more radicals selected from the group consisting of -OH, -de -alkyl-OH, -OC _1-6 -alkyl, -COOR ⁴ , -NR ⁴ R ⁵ , -CO-NR ⁴ R ⁵ , -COR ⁶ and -NH-COR ⁶ ;

R ⁴ and R ⁵ independently of one another H, -Cι. ₆ alkyl;

R ⁶ H, -C _1-6 -alkyl, -NR ⁴ R ⁵ , -d- ₆ -alkyl-CO-Cι _-6 -alkyl, furanyl, thiophenyi;

R ³ -Ci-s-alkyl, -C ₃ - ₈ -cycloalkyl, -Cι. _6- alkyl-R ⁷ or phenyl, which may optionally be annealed or substituted one or more times by one or more radicals selected from the group consisting of -CF ₃ , -COOR ⁴ , halogen, -NO ₂ , -NR ⁴ R ⁵ , -OR ⁴ and -SR ⁴ ;

R ⁷ furanyl, 2,3-dihydro-1H-inden-2-yl, naphthyl, 1, 3-benzodioxole or phenyl, which may optionally be substituted one or more times with one or more substituents selected from the group consisting of - d _-6 -alkyl, -O-Cι _-6 -alkyl, halogen, -NO ₂ and -CF ₃ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -NR ⁴ -, -S-, -O-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Most preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wherein

R ¹ Ci-β-alkyl, -C ₃ . ₈ -cycloalkyl or -Cι _-6 -alkyl-OC ₁ . _6- alkyl, which may optionally be mono- or polysubstituted by one or more radicals selected from the group consisting of -OH, -NR ⁴ R ⁵ , morpholinyl and pyridyl or

R ² H or -C _1-6 alkyl or

R ¹ and R ² together with the nitrogen form a piperazinyl ring;

R ⁴ and R ^{5 are} independently H, -d _-6 -alkyl;

-ds-alkyl, -C ₃ . ₈ -cycloalkyl, -de-alkyl-R ⁷ or phenyl, which may optionally be annealed or substituted one or more times by one or more radicals selected from the group consisting of -CF ₃ , -COOR ⁴ , halogen, -NO ₂ , -NR ⁴ R ⁵ , -OR ⁴ and -SR ⁴ ;

R ⁷ furanyl, 2,3-dihydro-1H-inden-2-yl, naphthyl, 1, 3-benzodioxole or phenyl, which may optionally be substituted one or more times with one or more substituents selected from the group consisting of - d _-6- alkyl, -OC _1-6 -alkyl, halogen, -NO ₂ and -CF ₃ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -S-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Of these, particular preference is given to compounds of numbers 2-17, the ^* indicating the point of attachment to pyrimidopyrimidine A.

Number OH Ό S = O "OH OH, OH * s' * NS = O OH * N

14 * SMe ^ N> OH 15 ^* SMe * NS = O OH

* N 16 ^* SMe NS = O ^

Also preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wherein

R ¹ d-β-alkyl, -C ₃ . ₈ -cycloalkyl or -d _-6 -alkyl-Od. _6- alkyl, which may optionally be mono- or polysubstituted by one or more radicals selected from the group consisting of -OH, -NR ⁴ R ⁵ , morpholinyl and pyridyl;

R ² H or -Cι _-6 -alkyl or

R and R ² together with the nitrogen form a piperazinyl ring;

R ⁴ and R ^{5 are} independently H, -C _1-6 alkyl;

R ³ benzyl;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -S-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof. Of these, particular preference is given to compounds of numbers 18-65, where the ^* indicates the point of attachment to pyrimidopyrimidine A.

Number R "

OH 27, ^ O * NS = O

Also preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wherein

R ¹ and R ² together with the nitrogen form a piperazinyl ring;

R ³ -ds-alkyl, -C ₃ - ₈ -cycloalkyl, -Cι _-6 -alkyl-R ⁷ or phenyl, which may optionally be annealed or substituted one or more times by one or more radicals selected from the group consisting of - CF ₃ , -COOR ⁴ , halogen, -NO ₂ , -NR ⁴ R ⁵ , -OR ⁴ and -SR ⁴ ;

R ⁷ furanyl, 2,3-dihydro-1H-inden-2-yl, naphthyl, 1, 3-benzodioxole or phenyl, which may optionally be substituted one or more times with one or more substituents selected from the group consisting of - Cι. ₆ -alkyl, -Od- ₆ -alkyl, halogen, -NO ₂ and -CF ₃ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -S-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Of these, particular preference is given to compounds of numbers 66-95, where the ^* indicates the point of attachment to pyrimidopyrimidine A. number

* N 67 ~ o NH

* N 68 S = O NH

69 <-o * N S = O NH

71, OH * S S = O NH

72 - * N S = O NH

89 * s— <(f ^ ^Bτ k ^ NH S = O

* 93 ^ J) S = O NH

* N 94 * SMe NH

* N 95 ^* SMe | IS = O NH

Also preferred is the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of the above. Respiratory diseases, wherein

R ¹ -CH ₂ -CH ₂ -OH;

R ² H;

R ³ -ds-alkyl, -C ₃ - ₈ -cycloalkyl, -d. ₆ -alkyl-R ⁷ or phenyl, which may optionally be annealed or substituted one or more times by one or more radicals selected from the group consisting of -CF ₃ , -COOR ⁴ , halogen, -NO ₂ , -NR ⁴ R ⁵ , -OR ⁴ and -SR ⁴ ;

R ⁷ furanyl, 2,3-dihydro-1H-inden-2-yl, naphthyl, 1, 3-benzodioxole or phenyl, which may optionally be substituted one or more times with one or more substituents selected from the group consisting of - C _1-6 alkyl, -OC _1-6 alkyl, halogen, -NO ₂ and -CF ₃ ; X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -S-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

Of these, particular preference is given to compounds of numbers 96-127, where the ^* indicates the point of attachment to pyrimidopyrimidine A.

Number R ⁷ * R ^{5 "}

97 / - * HN ^^ ° ^H S = O

98 ^{* S → *} HN ^^ ° ^HS = ^O

102 ^ ^"0 '* HN ^/ " ^ ° ^M S = O

OH

114 ₅ -H ^, * HN S = O

* s' 1 16 1 * HN S = O

1 17 OH, OH * HN S = O OH 1 18 ^ö > - II * HN ^^, OH ^π S = O

121 ^{* S} \ _ ^* HN ^^ ° ^H S = O

122 ^* S- - * H ^^ ° ^H S = O

123 ^* SH ^^ - 0 ^ * HN ^^ ° ^H S = O

124 * S— L λ / Λ / —— C ul ** HHNN ^^ ° ^H S = O

125 ^^ θ ^* HN ^^ ° ^H S = O

126 * s ^^ * HN ^^ ° ^H S = O 127 ^* SMe * HN ^^ ° ^H S = O

Another aspect of the invention form medicaments for the treatment of respiratory diseases, which contain one or more of the above-mentioned pyrimido [5,4-d] - pyrimidines of the general formula 1, which in combination with one or several additional active substances selected from the group of anticholinergics, steroids or β-agonists, together or in succession, can be used for simultaneous, sequential or separate administration.

Pharmaceutical formulations are therefore preferably characterized by the content of one or more compounds of the formula 1 according to the preferred embodiments above.

The present invention preferably relates to the use of compounds of general formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lungs, such as, for example, allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, asthma, COPD, idiopathic pulmonary fibrosis and fibrosing alveolitis.

The compounds of general formula 1 can be used alone or in combination with other compounds of general formula 1 according to the invention, optionally also in combination with other pharmacologically active substances. Anticholinergics (ipratropium, oxitropium, tiotropium), steroids or β ₂ agonists (albuterol, salmeterol, formoterol) may be mentioned as further pharmacologically active substances.

Suitable forms of use are, for example, tablets, capsules, solutions, juices, emulsions or inhalation powder or aerosols. The proportion of the pharmaceutically active compound (s) should in each case be in the range from 0.1 to 90% by weight, preferably 0.5 to 50% by weight, of the total composition, i.e. in amounts sufficient to reach the dosage range given below.

Oral administration can take the form of a tablet, a powder, a powder in a capsule (eg hard gelatin capsule), a solution or a suspension. In the case of inhalation administration, the active ingredient combination can be in the form of a powder, an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation. It is preferred if the compounds of the general formula 1 are administered orally, it is particularly preferred if the administration is carried out once or twice a day. Corresponding tablets can be obtained, for example, by mixing the active ingredient (s) with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with agents conventionally used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core can also consist of several layers to achieve a deposit effect or to avoid incompatibilities. The same can also

Drage cover to achieve a depot effect consist of several layers, wherein the excipients mentioned above for the tablets can be used.

Juices of the active substances or combinations of active substances according to the invention. A sweetener such as saccharin, cyclamate, glycerin or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending agents or thickening agents, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.

The capsules containing one or more active ingredients or combinations of active ingredients can be produced, for example, by mixing the active ingredients with inert carriers, such as milk sugar or sorbitol, and encapsulating them in gelatin capsules. Suitable suppositories can be produced, for example, by mixing them with carriers, such as neutral fats or polyethylene glycol or its derivatives. Examples of auxiliaries are water, pharmaceutically acceptable organic solvents such as paraffins (for example petroleum fractions), oils of vegetable origin (for example peanut or sesame oil), monofunctional or polyfunctional alcohols (for example ethanol or glycerol), carriers such as natural rock meal (for example kaolins, Clays, talc, chalk) synthetic rock flour (e.g. highly disperse silica and silicates), sugar (e.g. cane, milk and dextrose) emulsifiers (e.g. lignin, sufite liquor, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and Sodium lauryl sulfate) mentioned.

In the case of oral use, the tablets can of course also contain additives, such as e.g. Contain sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions, in addition to the auxiliaries mentioned above, the active ingredients can be mixed with various flavor enhancers or colorants.

It is also preferred if the compounds of general formula 1 are inhaled. are administered, it is particularly preferred if the administration takes place once or twice a day. For this purpose, the compounds of general formula 1 must be provided in inhalable dosage forms. Inhalable dosage forms are inhalable powders, metered-dose aerosols containing propellant gas, or propellant-free inhalation solutions, which are optionally present in a mixture with customary physiologically tolerable auxiliaries.

In the context of the present invention, the term propellant-free inhalation solutions also includes concentrates or sterile, ready-to-use inhalation solutions. The dosage forms which can be used in the context of the present invention are described in detail in the following part of the description.

inhalation powder

Are the compounds of general formula 1 contained in a mixture with physiologically acceptable auxiliaries, can be used to represent the invention Inhalation powder the following physiologically harmless adjuvants are used: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. Sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another. Mono- or disaccharides are preferred

Application, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as an auxiliary as particularly preferred in the sense of the invention. Processes for producing the inhalable powders according to the invention by grinding and micronizing and by finally mixing the constituents are known from the prior art.

Inhalation aerosols containing propellant gas

The inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can contain 1 dissolved in the propellant gas or in dispersed form. The propellant gases which can be used to produce the inhalation aerosols are known from the prior art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases can be used alone or in mixtures thereof. Particularly preferred propellants are fluorinated alkane derivatives selected from TG134a (1, 1, 1, 2-tetrafluoroethane), TG227 (1, 1, 1, 2,3,3,3-heptafluoropropane) and mixtures thereof. The inhalable aerosols containing propellant gas which can be used in the context of the use according to the invention can furthermore contain further constituents, such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these components are known in the art.

Propellant-free inhalation solutions The use of compounds of the general formula 1 according to the invention is preferably used for the production of propellant-free inhalation solutions and inhalation suspensions. Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic, solutions. The solvent can only be water or it is a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active ingredients. Among the organic acids are ascorbic acid,

Fumaric acid and citric acid preferred. If necessary, mixtures of the acids mentioned can also be used, especially in cases of acids which, in addition to their acidifying properties, also have other properties, e.g. as flavors, antioxidants or complexing agents, such as citric acid or ascorbic acid. According to the invention, hydrochloric acid is particularly preferably used to adjust the pH.

Co-solvents and / or other auxiliaries can be added to the propellant-free inhalation solutions which can be used in the context of the use according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, auxiliaries and additives are understood to mean any pharmacologically acceptable substance that is not an active ingredient, but together with the (the)

Active ingredient (s) can be formulated in the pharmacologically suitable solvent in order to improve the qualitative properties of the active ingredient formulation. These substances preferably have no or no significant or at least no undesirable pharmacological effect in the context of the desired therapy. The auxiliaries and additives include, for example, surface-active substances, such as, for example, soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which guarantee or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other known in the art Additives. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.

The preferred auxiliary substances include antioxidants, such as, for example, ascorbic acid, unless already used for adjusting the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human organism. Preservatives can be used to protect the formulation from contamination with germs. Suitable preservatives are those known from the prior art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.

Another aspect of the invention is a method for treating respiratory diseases using pyrimido [5,4-d] pyrimidines, in particular in which side effects such as emesis or nausea are reduced.

For this purpose, ready-to-use pack of a medicament for the treatment of respiratory diseases, including an enclosed description containing the words selected from the group respiratory disease, COPD or asthma, a pyrimido [5,4-d] pyrimidine and one or more combination partners selected from the group of anticholinergics , Steroids or ß-agonists.

TERMS AND DEFINITIONS USED

Pharmacologically compatible acid addition salts are understood to mean, for example, those salts which are selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrouccinate, hydrooxalate Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate. Unless otherwise stated, -d- ₆ -alkyl denotes branched and unbranched alkyl groups having 1 to 6 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. The abbreviations Me, Et, Pr or Bu may also be used to denote the groups methyl, ethyl, propyl or butyl. Unless otherwise described, the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and / so-propyl, butyl includes / so-butyl, sec-butyl and terf-butyl etc. Preferred are methyl, ethyl, π-propyl, / so-propyl, / so-butyl, seo -Butyl and tert-butyl.

As -C ₃ . ₈ -cycloalkyl with 3-8 carbon atoms are, for example, cyclopropyl,

Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopropyl and cyclohexyl are preferred.

Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorine and bromine are preferred halogens.

The term aryl stands for an aromatic ring system with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl or naphthyl, where the cycle can be substituted as indicated in the definitions.

In the context of the present invention, heteroaryl rings (also abbreviated to hetaryl) are understood to mean aromatic ring systems which contain one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and, as defined above, can optionally be substituted. For example, furan, thiophene, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, triazine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole and pyrazolidine are mentioned, where the heterocycle can be substituted as indicated in the definitions.

Furan, tetrahydrofuran, 2-methyltetrahydrofuran, for example, are used as 5- or 6-membered saturated or unsaturated heterocyclic rings (also abbreviated as heterocyclic), which can contain one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur as heteroatoms , 2-hydroxymethylfuran, tetrahydrofuranone, γ-butylrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane, Thiophene, dihydrothiophene, thiolan, dithiolan, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, oxyzoline, morpholine, tetrazine, morpholine, Isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine called, where the heterocycle can be substituted as indicated in the definitions.

Examples of 5-, 6- or 7-membered, saturated or unsaturated, heterocyclic rings which can be formed together with the nitrogen through the radicals R ¹ and R ² are: pyrrole, pyrroline, pyrrolidine, 2-ethylpyrrolidine, 3 -Methylpyrrolidine, piperidine, piperazine, Λ / -Methylpiperazine, Λ / -ethylpiperazine, Λ / - (n-propyl) -piperazine, N-benzylpiperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazoline, preferably pyrazoline , Λ / -benzylpiperazine, piperazine, and piperidine, where the heterocycles mentioned can be substituted as indicated in the definitions. In this context, the following are mentioned as particularly preferred rings: pyrrole, piperidine, piperazine, Λ / -methylpiperazine, Λ / -benzylpiperazine, morpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, N-benzylpiperazine, piperazine, and Piperidine, where the heterocycles mentioned can be substituted as indicated in the definitions.

In the context of the invention, respiratory diseases are understood to mean disorders which cause breathing difficulties, shortness of breath or pain in the respiratory tract in a patient, in particular inflammatory or obstructive respiratory diseases are mentioned here. Inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lungs, such as, for example, allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, asthma, COPD, idiopathic pulmonary fibrosis and fibrosing alveolitis are preferred. Asthma, chronic bronchitis or COPD are particularly preferred.

In the context of the invention, reduced side effects are understood to mean that a dose of a pharmaceutical composition can be administered without

Patients vomiting, preferably nausea, particularly preferred to cause malaise. It is highly preferred to administer a therapeutically effective amount of substance without triggering emesis or nausea at any stage in the course of the disease.

Claims

1. Use of substituted pyrimido [5,4-d] pyrimidines for the manufacture of a medicament for the treatment of respiratory diseases.

Use according to claim 1, wherein the respiratory disease is an inflammatory or obstructive respiratory disease.

Use according to one of claims 1 or 2, wherein the respiratory disease is COPD or asthma.

4. Use according to any one of claims 1-3, wherein side effects of the treatment are reduced.

5. Use according to any one of claims 1-4, wherein the reduced side effects are selected from the group emesis, nausea.

6. Use according to any one of claims 1 -5, wherein the pyrimido [5,4-d] pyrimidine is a compound of general formula 1,

wherein R ¹ and R ^{2 are} independently H, -Cι. ₆ -alkyl, -C ₃ . ₈ -cycloalkyl, -d-β-alkyl-ode-alkyl, each optionally substituted by one or more substituents selected from the group aryl, -CF _3> -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, hetcyclus, -NO ₂ , -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ or -SR ⁴ ; or

R and R ² together with the nitrogen form a ring, which may optionally be substituted, with one or more substituents selected from the group aryl, -C _{1 -6} -alkyl-OH, -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, hetcycle, -NO ₂ , -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -OC _1-6 -alkyl, -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ or -SR ⁴ ;

R ⁴ and R ^{5 are} independently H, -Cι _-6 -alkyl;

R ⁶ H, -Cι. ₆ -alkyl, -Cι. ₆ -alkyl-CO-Cι. _{6 is} alkyl, hetaryl, hetcycle, NR ⁴ R ⁵ ;

R ³ H, -ds-alkyl, -C ₃ . ₈ -cycloalkyl, -C _1-6 -alkyl-phenyl or phenyl, where each group may optionally be substituted or fused if possible, with one or more substituents selected from the group -d _-6 -alkyl-OH, -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁴ , halogen, hetaryl, hetcycle, -NO ₂ , -NR ⁴ COR ⁴ , -NR R ⁵ , -NR ⁴ SO ₂ R ⁴ , -O-Cι , _{6 is} alkyl, -OR ⁴ , -SO ₂ NR R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ or -SR ⁴ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -NR ⁴ -, -S-, -O-;

as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric

Forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

7. Use according to one of claims 1-6, wherein,

R ¹ and R ² independently of one another H, -Cι _-6 -alkyl, -C ₃ . ₈ -cycloalkyl, -Cι _-6 -alkyl-OC _1-6 -alkyl, each optionally substituted with one or more substituents selected from the group -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , halogen, hetaryl, hetcycle, -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -OR ⁴ ; or

R ¹ and R ² together with the nitrogen form a ring, which may optionally be substituted, with one or more substituents selected from the group -Cι _-6 -alkyl-OH, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁶ , -NR ⁴ COR ⁶ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -0-C _1-6 -alkyl, -OR ⁴ , -SO ₂ NR ⁴ R ⁵ , -SO ₂ R ⁴ , -SOR ⁴ or -SR ⁴ constitute; or - R ⁴ and R ^{5 are} independently H, -Cι- ₆ alkyl;

R ⁶ H, -d. _{6 is} -alkyl, -de-alkyl-CO-de-alkyl, hetaryl, hetcycle, -NR ⁴ R ⁵ ;

R ³ H, -ds-alkyl, -C ₃ . ₈ -cycloalkyl, -de-alkyl-R ⁷ or phenyl, optionally substituted with one or more substituents selected from the group -d _-6 -alkyl-OH, -CF ₃ , -CN, -CONR ⁴ R ⁵ , -COOR ⁴ , -COR ⁴ , halogen, -NO ₂ , -NR ⁴ COR ⁴ , -NR ⁴ R ⁵ , -NR ⁴ SO ₂ R ⁴ , -O-Cι. _{6 is} alkyl or -OR ⁴ ;

R ⁷ -OH, COOR ⁴ , -NR ⁴ R ⁵ , hetaryl, hetcyclus, hetaryl fused with hetcyclus, phenyl optionally substituted with one or more substituents selected from the group -Cι _-6 -alkyl, -ode-alkyl, halogen, - NO ₂ , -CF ₃ ;

X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -NR ⁴ -, -S-, -O-; as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

8. Use according to any one of claims 1-7, wherein,

R ¹ and R ² independently of one another H, -d. ₆ -alkyl, -C _3-8 -cycloalkyl, -Cι. ₆ -alkyl-O-Cι _-6 -alkyl, each optionally substituted with one or more substituents selected from the group -OH, - NR ⁴ R ⁵ , morpholinyl, pyridyl; or

R ¹ and R ² together with the nitrogen form a ring selected from the group morpholinyl, thiomorpholinonyl, piperidyl, piperazinyl, each optionally substituted by one or more substituents selected from the group -OH, -Cι _-6 -alkyl-OH, -Ode- form alkyl, -COOR ⁴ , -NR ⁴ R ⁵ , -CO-NR ⁴ R ⁵ , -COR ⁶ , -NH-COR ⁶ ; R ⁴ and R ^{5 are} independently H, -Cι _-6 -alkyl;

R ^{6 is} H, -de-alkyl, -NR ⁴ R ⁵ , -de-alkyl-CO-de-alkyl, furanyl, thiophenyl; R ³ -ds-alkyl, -C ₃ . ₈ -cycloalkyl, -C _1-6 -alkyl-R ⁷ , phenyl optionally substituted with one or more substituents selected from the group -C _1-6 -alkyl, -OC _1-6 -alkyl, -SC _1-6 -alkyl Is halogen, -NO ₂ , -CF ₃ ; R ⁷ -OH, COOR ⁴ , -NR ⁴ R ⁵ , furanyl, 2,3-dihydro-1H-inden-2-yl, naphthyl, 1, 3-benzodioxoI, phenyl optionally substituted with one or more substituents selected from the group Group is -C _1-6 alkyl, -OC _1-6 alkyl, halogen, -NO ₂ , -CF ₃ ; X is -S-, -S (O) -, -S (O ₂ ) -;

Y is -NR ⁴ -, -S-, -O-; as well as pharmacologically acceptable acid addition salts, tautomeric and isomeric forms or mixtures and individual geometric or optical isomers, in particular racemic or non-racemic mixtures of the isomers thereof.

9. Use according to any one of claims 1-8, wherein the medicament is administered once or twice a day.

10. Use according to any one of claims 1-9, wherein the medicament contains 1 to 200 mg of an active ingredient of the general formula 1, according to one of claims 5-8 or pharmacologically acceptable acid addition salts thereof.

11. Pharmaceutical composition for the treatment of respiratory diseases, characterized in that it contains one or more compounds of formula 1 according to any one of claims 5-8, which in combination with one or more additional active ingredients selected from the group of anticholinergics, steroids or ß- Agonists, together or sequentially, for simultaneous, sequential or separate administration.