EP1708715A1 - Utilisation de pteridines substituees pour traiter des maladies des voies respiratoires - Google Patents

Utilisation de pteridines substituees pour traiter des maladies des voies respiratoires

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Publication number
EP1708715A1
EP1708715A1 EP05700802A EP05700802A EP1708715A1 EP 1708715 A1 EP1708715 A1 EP 1708715A1 EP 05700802 A EP05700802 A EP 05700802A EP 05700802 A EP05700802 A EP 05700802A EP 1708715 A1 EP1708715 A1 EP 1708715A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
use according
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05700802A
Other languages
German (de)
English (en)
Inventor
Peter Nickolaus
Christopher J. Montague Meade
Horst Dollinger
Jürgen Mack
Georg Dahmann
Domnic Martyres
Birgit Jung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1708715A1 publication Critical patent/EP1708715A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the invention relates to the use of pteridine for the treatment of inflammatory and obstructive respiratory diseases, preferably asthma or COPD, and pharmaceutical compositions which contain these compounds.
  • 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.
  • Pteridines are known from the prior art as active ingredients with an antiproliferative effect. Merz et al. describe in the Journal of Medicinal Chemistry 1998, 41, 4733-4743 the preparation of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and derivatives thereof which are free of positional isomers. It has been shown that the compounds produced can inhibit the growth of tumor cells.
  • DE 3540952 describes 2-piperazino-pteridines which are substituted in the 6-position with a halogen atom selected from a fluorine, chlorine or bromine atom. These compounds have been shown to inhibit the activity of tumor cells and human platelets in vitro.
  • DE 3323932 discloses 2-piperazino Pteridines which carry a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group in the 4-position. These compounds have been shown to inhibit the activity of tumor cells and human platelets in vitro.
  • DE 3445298 describes pteridines with a large number of different substituents in the 2-, 4-, 6- and 7-position, compounds with a 2-piperazino group on the pteridine structure being suitable as inhibitors for tumor growth and also antithrombotic and Have metastatic inhibitory properties.
  • 2,940,972 discloses tri- and tetrasubstituted pteridine derivatives, with general statements being made that these pteridines have valuable pharmacological properties, namely coronary-expanding, sedative, antipyretic and analgesic effects.
  • pteridines are suitable for the treatment of respiratory diseases, in particular inflammatory and obstructive respiratory diseases.
  • Preferred is the use of substituted pteridines for the manufacture of a medicament for the treatment of inflammatory or obstructive respiratory diseases, particularly preferably COPD or asthma.
  • substituted pteridines 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 abovementioned respiratory diseases,
  • X is CH 2 , O, NR 1 , S, S (0), S (O 2 );
  • Y is CH, N, N (O), N (S);
  • Z is CH 2 , O, NR 1 , S, S (O), S (O 2 );
  • R 1 H, -C ⁇ . 6 is alkyl or -GOR 2 ;
  • R 2 is independently H or -C -6- alkyl;
  • R 3 and R 4 are independently H, -C ⁇ -6 alkyl-R 5, aryl, or R 3 and R 4 together with the nitrogen form a 5-, 6- or 7-gIiedrigen, saturated or unsaturated, heterocyclic rings, each optionally substituted with one or more substituents selected from the group COR 2 ;
  • X is CH 2 , O, NR ⁇ S, S (O), S (O 2 );
  • Y is CH, N, N (O), N (S);
  • Z is CH 2 , O, NR 1 , S, S (O), S (O 2 );
  • R 1 is H, -Ci-e-alkyl or -COR 2 ;
  • R 2 is independently H or -C 1-6 alkyl;
  • R 3 and R 4 are independently H, -C ⁇ -6 -alkyl, R 5 , phenyl, or
  • R 3 and R 4 together with the nitrogen represent a substituent selected from the group pyrrole, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, imidazole, irnidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, ⁇ / -oxydothiomorpholinyl, S-oxidothiomorph each optionally substituted with one or more substituents selected from the group COR 2 ; R 5 H, -OH, phenyl, optionally substituted with one or more substituents independently selected from the group halogen, -C ⁇ -6 -alkyl or -O-C ⁇ . 6 is alkyl;
  • R 6 is H, phenyl, halogen, -de-alkyl, -S-C ⁇ -6 -alkyl, -SC 1-6 -alkyl-R 5 ; and n is 1, 2, 3 or 4;
  • X is CH 2 , O, S, S (O);
  • Y is N, N (O), N (S); Z is NR 1 ;
  • R 1 is H or -COR 2 ;
  • R 2 is independently H or -C 1-6 alkyl
  • R 3 and R 4 are independently H, -C ⁇ . 6- alkyl-R 5 , phenyl, or R 3 and R 4 together with the nitrogen form a substituent selected from the group morpholine, thiomorpholine, ⁇ / -oxidothiomorpholine, S-oxidothiomorpholine, piperazine, each optionally substituted with one or more substituents selected from the group COR 2 ;
  • R 5 H, -OH, phenyl, optionally substituted with one or more substituents independently selected from the group halogen, -C ⁇ . 6 is alkyl or -OC -6 alkyl;
  • R 6 is H, phenyl, Cl, -OC 1-6 alkyl, -Sd- ⁇ -al yl, -SC 1-6 alkyl-R 5 ; and n is 1, 2, 3 or 4;
  • X is S
  • Y is N (O), N (S); Zz is NH;
  • R 2 is independently H or -d- ⁇ -alkyl
  • R 3 and R 4 are independently H, -C 1-6 alkyl-R 5 , phenyl, or
  • R 3 and R 4 together with the nitrogen form a substituent selected from the group morpholine, thiomorpholine, ⁇ -oxidothiomorpholine, S-oxidothiomorpholine, piperazine, each optionally substituted with one or more substituents selected from the group COR 2 ;
  • R 6 is H, phenyl; and n is 2;
  • X is S, S (O);
  • YN is; z is NR 1 ;
  • R 1 is H or -COR 2 ;
  • R 2 is H
  • R 3 and R 4 are independently H, -C ⁇ . 6- alkyl-R 5 , phenyl, or
  • R 3 and R 4 together with the nitrogen form a substituent selected from the group morpholine, thiomorpholine, ⁇ / -oxidothiomorpholine, S-oxidothiomorpholine, piperazine, each optionally substituted with one or more substituents selected from the group COR 2 ;
  • R 5 is H, -OH, phenyl;
  • R 6 is H, phenyl, Cl, -Od- ⁇ -alkyl » -Sd- 6 -alkyl, -Sd -6 -alkyl-R 5 ; and
  • n is 2; 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.
  • R 2 is independently H or -C -6- alkyl;
  • R 3 and R 4 are independently H, -C ⁇ . 6- alkyl-R 5 , phenyl, or
  • R 3 and R 4 together with the nitrogen form a substituent selected from the group morpholine, thiomorpholine, / V-oxidothiomorpholine, S-oxidothiomorpholine, piperazine, each optionally substituted with one or more substituents selected from the group COR 2 ;
  • R 6 is Cl; and n is 1, 2, 3 or 4;
  • Another aspect of the invention form medicaments for the treatment of respiratory diseases, which contain one or more of the above-mentioned pteridines of the general formula 1, which, in combination with one or more additional active substances selected from the group of anticholinergics, steroids or ⁇ -agonists, or sequentially, for simultaneous, sequential or separate administration.
  • compositions 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 the 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 ⁇ 2 agonists albuterol, salmeterol, formoterol
  • 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, powder, powder in a capsule (e.g. hard gelatin capsule), solution or suspension.
  • the combination of active substances can take the form of a powder, an aqueous or aqueous-ethanolic solution or a propellant gas formulation.
  • 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 can be obtained.
  • 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
  • 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 coated tablet shell can also consist of several layers in order to achieve a depot effect, wherein the auxiliaries mentioned above for the tablets can be used.
  • Juices of the active substances or combinations of active substances according to the invention can additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. Flavorings, such as vanillin or orange extract, contain. They can also contain suspending aids or bulking 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.
  • a sweetener such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g.
  • Flavorings such as vanillin or orange extract
  • suspending aids or bulking 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 carrier agents such as neutral fats or polyethylene glycol or its derivatives.
  • 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.
  • 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
  • the tablets can of course also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like, in addition to the carrier substances mentioned.
  • Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting.
  • the active ingredients can be mixed with various flavor enhancers or colorants.
  • the compounds of the general formula 1 are administered by inhalation, it is particularly preferred if the administration is carried out once or twice a day.
  • 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.
  • 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.
  • the compounds of general formula 1 are contained in a mixture with physiologically acceptable auxiliaries
  • the following physiologically acceptable auxiliaries can be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo and polysaccharides (for example dextrans), polyalcohols (for example sorbitol, mannitol, xylitol), salts (for example sodium chloride, calcium carbonate) or mixtures of these auxiliaries with one another.
  • monosaccharides e.g. glucose or arabinose
  • disaccharides e.g. lactose, sucrose, maltose
  • oligo and polysaccharides for example dextrans
  • polyalcohols for example sorbitol, mannitol, xylitol
  • salts for example sodium chloride, calcium carbonate
  • Mono- or disaccharides are preferably used, the use of lactose or glucose being preferred, in particular, 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 Application. 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.
  • 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.
  • 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.
  • 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.
  • organic acids examples include: 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 can also the acids are used which already form an acid addition salt with one of the active ingredients. Ascorbic acid, fumaric acid and citric acid are preferred among the organic acids.
  • mixtures of the acids mentioned can also be used, in particular in the case of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid.
  • hydrochloric acid is particularly preferably used to adjust the pH.
  • co-solvents can contain co-solvents and / or other auxiliary substances.
  • 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.
  • auxiliaries and additives include e.g.
  • surfactants such as Soy lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which ensure or extend the useful life of the finished pharmaceutical formulation, flavors, vitamins and / or other additives known in the prior art.
  • 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.
  • 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.
  • The are suitable as preservatives State of the 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 of treating
  • Respiratory diseases using pteridines especially where side effects such as emesis or nausea are reduced.
  • 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 pteridine and one or more combination partners selected from the group of anticholinergics, steroids or ⁇ -agonists.
  • 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.
  • -de-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.
  • the definitions propyl and butyl encompass all conceivable isomeric forms of the respective radicals.
  • propyl includes n-propyl and / so-propyl
  • butyl includes / so-butyl, seo-butyl and te / t-butyl etc.
  • Halogen in the context of the present invention is fluorine, chlorine, bromine or iodine. Unless stated otherwise, fluorine, chlorine and bromine are preferred halogens.
  • 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.
  • Examples of 5-, 6- or 7-membered, saturated or unsaturated, heterocyclic rings which can be formed by the radicals R 3 and R 4 together with the nitrogen are: pyrrole, pyrroline, pyrrolidine, 2, piperidine, piperazine , Morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, N-oxidothiomorpholinyl, S-oxidothiomorpholinyl, preferably morpholine, piperazine, N-oxidothiomorpholinyl, S-oxidothiomorpholinyl and piperidine, the substituted being as given in the heterocytes as mentioned in the definition of heterocytes can.
  • respiratory diseases are understood to mean disorders which trigger respiratory problems, shortness of breath or pain in the respiratory tract in a patient, in particular inflammatory or obstructive respiratory diseases.
  • 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.
  • Reduced side effects are understood in the context of the invention to be able to administer a dose of a pharmaceutical composition without inducing vomiting, preferably nausea, particularly preferably discomfort in the patient. 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.

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Abstract

Utilisation de pteridines pour traiter des maladies inflammatoires et obstructives des voies respiratoires, de préférence l'asthme ou la broncho-pneumopathie chronique obstructive, et compositions pharmaceutiques qui contiennent ces composés.
EP05700802A 2004-01-17 2005-01-11 Utilisation de pteridines substituees pour traiter des maladies des voies respiratoires Withdrawn EP1708715A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004002556 2004-01-17
PCT/EP2005/000164 WO2005067935A1 (fr) 2004-01-17 2005-01-11 Utilisation de pteridines substituees pour traiter des maladies des voies respiratoires

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AR (1) AR047386A1 (fr)
CA (1) CA2552540A1 (fr)
TW (1) TW200529855A (fr)
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DE102004029784A1 (de) 2004-06-21 2006-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue 2-Benzylaminodihydropteridinone, Verfahren zur deren Herstellung und deren Verwendung als Arzneimittel
DE102004033670A1 (de) 2004-07-09 2006-02-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Pyridodihydropyrazinone, Verfahren zu Ihrer Herstellung und Ihre Verwendung als Arzneimittel
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EP1630163A1 (fr) 2004-08-25 2006-03-01 Boehringer Ingelheim Pharma GmbH & Co.KG Dihydropteridinones, procédés de préparation et leur utilisation en tant que médicaments
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JP2007517828A (ja) 2007-07-05
AR047386A1 (es) 2006-01-18
US20070015749A1 (en) 2007-01-18
WO2005067935A1 (fr) 2005-07-28
TW200529855A (en) 2005-09-16
US20050165010A1 (en) 2005-07-28
UY28720A1 (es) 2005-08-31
CA2552540A1 (fr) 2005-07-28

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