Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
• • 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
• • 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
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P11/02—Nasal agents, e.g. decongestants
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to quinazolines of the general formula
• R a is a benzyl or 1-phenylethyl group or a phenyl group substituted by the radicals R- L and R 2 , where
• R- L represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyan or ethynyl group and R 2 represents a hydrogen or fluorine atom,
• R b is a -N (CH 2 CO 2 R 3 ) 2 group, where
• R 3 represents a hydrogen atom, a methyl or ethyl group, an R 4 O-CO-CH 2 -N-CH 2 -CH 2 -OH group optionally substituted on the methylene groups by 1 or 2 methyl or ethyl groups, where
• R 4 represents a hydrogen atom or a C 1-4 alkyl group
• n is an integer from 2 to 4,
• Particularly preferred compounds are the compounds of the general formula I mentioned above in which
• R a is a 1-phenylethyl group or a phenyl group substituted by the radicals R x and R 2 , where
• R x represents a fluorine, chlorine or bromine atom, a methyl or ethinyl group and R 2 represents a hydrogen or fluorine atom,
• R b is a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl or ethyl groups, or
• n is an integer from the range from 2 to 4, their tautomers, their stereoisomers and their salts.
• R a is a 1-phenylethyl or 3-chloro-4-fluorophenyl group
• R b is a 2 -oxo-morpholin-4-yl group which is substituted by 1 or 2 methyl groups
• n is an integer from the range from 2 to 4,
• the compounds of the general formula I can be prepared, for example, by the following processes:
• R a , R b and n are defined as mentioned at the beginning, with a
• a leaving group such as a halogen atom, for example a chlorine or bromine atom, a vinylcarbonyloxy group or a hydroxyl group.
• the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane, if appropriate in the presence of an inorganic or organic base and, if appropriate, in the presence of a dehydrating agent at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane, if appropriate in the presence of an inorganic or organic base and, if appropriate, in the presence of a dehydrating agent at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80
• the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide preferably at temperatures between -80 and 150 ° C, preferably at temperatures between -60 and 80 ° C.
• a solvent or solvent mixture such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride / tetrahydrofuran or dioxane
• the reaction is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N, N ' -Dicyclohexylcarbodiimid, N, N '-Dicyclohexyl-carbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine, N, N' -carbonyldiimidazole or triphenylphosphine / tetra-chlorocarbon as appropriate in a carbon Methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl
• reaction is carried out particularly advantageously with acrylic acid and acrylic acid chloride in the presence of triethylamine.
• any reactive groups present such as hydroxyl, carboxy or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
• the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group
• the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert. butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-ethoxybenzyl group are considered.
• the subsequent subsequent splitting off of a protective radical used takes place, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, for example in Presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
• an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium
• a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
• a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
• a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
• a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
• the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
• ice / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
• the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol.
• the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
• a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
• (+) - or (-) menthol comes as optically active alcohol and as optically active
• the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
• acids for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
• the compounds of the general formula I according to the invention and their physiologically tolerated salts have valuable pharmacological properties, in particular an inhibitory effect on the signal transduction mediated by the epidermal growth factor receptor (EGF-R), this being achieved, for example, by inhibiting the Ligand binding, the receptor dimerization or the tyrosine kinase itself can be effected. It is also possible that the signal transmission on further downstream components may be blocked.
• EGF-R epidermal growth factor receptor
• EGF-R-mediated signal transmission can be demonstrated, for example, with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha.
• An interleukin-3 (IL-3) -dependent cell line of murine origin was used here which has been genetically modified in such a way that it expresses functional human EGF-R.
• the proliferation of these cells called F / L-HERc can therefore be stimulated either by murine IL-3 or by EGF (see von Rüden, T. et al. In EMBO J. 2, 2749-2756 (1988) and Pierce, JH et al. in Science 2__9_, 628-631 (1988)).
• the FDC-Pi ⁇ cell line was used as the starting material for the F / L-HERc cells. Their production by Dexter, TM et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth factor-dependent cells can also be used (see, for example, Pierce, JH et al. In Science 2.3.2, 628-631 (1988), Shibuya, H. et al. In Cell 2JQ_, 57-67 ( 1992) and Alexander, WS et al. In EMBO J. Lu, 3683-3691 (1991)). Recombinant retroviruses were used to express the human EGF-R cDNA (see Ullrich, A. et al.
• F / L-HERc cells were in RPMI / 1640 medium (BioWhittaker), supplemented with 10% fetal bovine serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng / ml human EGF (Promega), at 37 ° C and 5% CO 2 cultivated.
• FCS fetal bovine serum
• FCS Boehringer Mannheim
• 2 mM glutamine BioWhittaker
• standard antibiotics 20 ng / ml human EGF (Promega)
• 20 ng / ml human EGF Promega
• the compounds according to the invention were dissolved in 100% dimethyl sulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated at 37 ° C for 48 hours. To determine the inhibitory activity of the compounds according to the invention, the relative cell number was determined using the Cell
• the compounds of the general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as has been shown using the example of the human EGF receptor, and are therefore useful for the treatment of pathophysiological processes which are caused by overactive tyrosine kinases.
• tyrosine kinases e.g. benign or malignant tumors, in particular tumors of epithelial and neuroepithelial origin, metastasis and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
• the compounds of the invention are also useful for the prevention and treatment of respiratory and lung diseases associated with increased or altered mucus production caused by stimulation of tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, l-antitrypsin deficiency, or for cough, pulmonary emphysema, pulmonary fibrosis and hyperreactive respiratory tract.
• tyrosine kinases such as e.g. for inflammatory diseases of the respiratory tract such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, l-antitrypsin deficiency, or for cough, pulmonary em
• the compounds are also suitable for the treatment of diseases of the gastrointestinal tract and bile ducts and - bladder that is associated with impaired activity of the tyrosine kinases, such as those found in chronic inflammatory changes, such as cholecystitis, Crohn's disease, ulcerative colitis, and ulcers in the gastrointestinal tract or as in gastrointestinal disorders Tracts that are associated with increased secretion, such as M. Menetrier, secreting adenomas and protein loss syndromes,
• nasal polyps as well as of polyps of the gastrointestinal tract of different genesis such as e.g. villous or adenomatous polyps of the large intestine, but also of polyps in familial polyposis coli, in intestinal polyps as part of the Gardner syndrome, in polyps in the entire gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolypes, in juvenile polyps , with colitis cystica profunda and with Pneumatosis cystoides intestinales.
• different genesis such as e.g. villous or adenomatous polyps of the large intestine, but also of polyps in familial polyposis coli, in intestinal polyps as part of the Gardner syndrome, in polyps in the entire gastrointestinal tract in Peutz-Jeghers syndrome, in inflammatory pseudopolypes, in juvenile polyps , with colitis cystica profunda and with Pneumatosis cystoides intestinales.
• kidney diseases in particular in the case of cystic changes such as in cystic kidneys
• kidney cysts which may be of idiopathic origin or occur in the context of syndromes such as e.g. in tuberous sclerosis, in von Hippel-Lindau syndrome, in nephronophthisis and marrow sponge kidney as well as other diseases which are caused by aberrant function of tyrosine kinases, e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells etc.
• psoriasis epidermal hyperproliferation
• the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumor therapy in monotherapy or in combination with other anti-tumor therapeutic agents, for example in combination with topoisomerase inhibitors (for example etoposide) , Mitosis inhibitors (e.g. vinblastine), with nucleic acid interacting compounds (e.g. cis-platinum, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc), cytokines (e.g. interferons), antibodies etc.
• topoisomerase inhibitors for example etoposide
• Mitosis inhibitors e.g. vinblastine
• nucleic acid interacting compounds e.g. cis-platinum, cyclophosphamide, adriamycin
• hormone antagonists e.g. tamoxifen
• these compounds are used alone or in combination with other respiratory therapeutic agents such as secretolytic, broncholytic and / or anti-inflammatory substances.
• these compounds may also be used alone or in combination with moti- lticians- or secretion influencing or inflammatory ⁇ inhibiting substances are given. These combinations can be administered either simultaneously or sequentially.
• Combination with other active substances can take place intravenously, subcutaneously, intramuscularly, intrarectally, intraperitoneally, intranasally, by inhalation or transdermally or orally, aerosol formulations being particularly suitable for> inhalation.
• the compounds according to the invention are generally used in warm-blooded vertebrates, in particular in humans, in doses of 0.01-100 mg / kg body weight, preferably 0.1-15 mg / kg.
• these are mixed with one or more conventional inert carriers and / or diluents, e.g.
• the residue is stirred with plenty of ethyl acetate, washed with a little cold water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. Since a mixture of open-chain and already cyclized product is evidently formed, the resinous residue is refluxed with 0.08 ml of acetyl chloride in 40 ml of ethanol for about 30 minutes. The mixture is then concentrated and toluene is added to the residue. The solvent is distilled off and the flask residue is suspended in methylene chloride, mixed with a little ice water and made alkaline with 1 ml of 4N sodium hydroxide solution. The organic phase is separated off, dried over magnesium sulfate and concentrated.
• the organic phase is washed with water and saturated sodium chloride solution and remains overnight at room temperature, a yellow precipitate being formed. This is suctioned off, washed with ethyl acetate and dried. The filtrate is concentrated and the evaporation residue recrystallized from ethyl acetate. The crystals obtained in this way are combined with the precipitate which has been suctioned off and recrystallized again from ethyl acetate. The desired product is obtained in the form of pale yellow crystals.
• the substance is obtained in 65% yield by hydrogenation of 4- [(3-chloro-4-fluorophenyl) amino] -7- [3- (5, 5-dimethyl-2-oxomorpholin-4-yl) - propyloxy] -6-nitro-quinazoline in tetrahydrofuran in the presence of Raney nickel in a Parr apparatus at a hydrogen partial pressure of 50 psi.
• 1 coated tablet contains: Active substance 75.0 mg
• the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape.
• the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
• the finished film coated tablets are polished with beeswax. : Coated weight: 245 mg.
• Composition 1 tablet contains:
• Active ingredient, milk sugar and starch are mixed and moistened uniformly with an aqueous solution of the polyvinylpyrrolidone. After screening the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C, sieving is again carried out (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg
• Diameter 10 mm, biplane with facet on both sides and partial notch on one side.
• 1 tablet contains: active substance 150.0 mg
• the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a mesh size of 1.5 mm.
• 1 capsule contains:
• the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
• the final mix is filled into size 1 hard gelatin capsules.
• Capsule filling approx. 320 mg capsule shell: hard gelatin capsule size 1.
• 1 suppository contains:
• Polyethylene glycol 1500 550.0 mg
• the active ingredient is homogeneously distributed therein and the melt is poured into pre-cooled molds.
• the melt is poured into pre-cooled molds.
• Carboxymethylcellulose Na salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g cane sugar 10.00 g
• Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. According were to admit and ⁇ dissolving the sugar, the sorbitol solution and the flavoring, the suspension is evacuated with stirring for deaeration.
• 5 ml of suspension contain 50 mg of active ingredient.
• the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
• composition active ingredient 50.0 mg
• the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.
• 1 capsule contains:
• the active substance is mixed with lactose for inhalation purposes.
• the mixture is filled into capsules on a capsule machine (weight of the empty capsule approx. 50 mg).
• 1 hub includes:
• the active substance and benzalkonium chloride are dissolved in ethanol / water (50/50).
• the pH of the solution is adjusted with 1N hydrochloric acid.
• the adjusted solution is filtered and filled into containers (cartridges) suitable for the hand-held nebuliser.

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