Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
  • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
• • 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
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to new positive allosteric AMPA receptor modulators, processes for preparing them and their use as pharmaceutical compositions.
• WO 9967242 describes carbapenem derivatives with an antibacterial activity, wherein naphtho[1 ,8-de]-2,3-dihydro-1 , 1 -dioxide-1 ,2-thiazine is used as a synthesis component.
• the compounds according to the invention are compounds of general formula (I)
• R 1 denotes a group selected from among hydrogen, a d-C 6 -alkyl group optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 -C ⁇ -C 6 -alkyl,
• R 2 , R 3 which may be identical or different, denote a group selected from among hydrogen, a d-C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, -NO 2 , -SO 2 H, -SO 2 -CrC 6 -alkyl, -SO-C ⁇ -C 6 -alkyl, -CO-
• R 1 and R 2 together denote a C 4 -C 6 -alkylene bridge
• R 6 , R 7 which may be identical or different, denote hydrogen, C ⁇ -C 4 -alkyl or -CO-C ⁇ -C 4 -alkyl ,
• R 8 , R 9 which may be identical or different, denote hydrogen or C ⁇ -C -alkyl
• R 4 which may be identical or different, denotes a group selected from among a Ci-Ce-alkyl group optionally substituted by one or more halogen atoms, phenyl-d-C 4 -alkyl, halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -SO 2 -d-C 6 -alkyl, -SO- d-Ce-alkyl, -SO 2 -NR 6 R 7 , -COOH, -CO-d-C 6 -alkyl, -O-CO-d-C 4 -alkyl, -CO-O- d-C 4 -alkyl, -O-CO-O-d-C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-d-C 6 -alkyl,
• R 5 which may be identical or different, denotes a group selected from among a C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, phenyl-d-C 4 -alkyl, halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -SO 2 -d-C 6 -alkyl, -SO- C ⁇ -C 6 -alkyl, -SO 2 -NR 6 R 7 , -COOH, -CO-d-C 6 -alkyl, -O-CO-d-C 4 -alkyl, -CO-O- C ⁇ -C 4 -alkyl, -O-CO-O-C C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-Ci-C ⁇ -alkyI, -S-d-C 6 - alkyl, -NR 6 R 7 and an aryl group
• Preferred compounds are the compounds of general formula (I), wherein R 1 denotes a group selected from among hydrogen, a C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, -SO 2 H, -SO 2 -C ⁇ -C 6 -alkyl,
• R 2 , R 3 which may be identical or different, denote a group selected from among hydrogen, a C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, -NO 2 , -SO 2 H, -SO 2 -d-C 6 -alkyl, -SO-d-C ⁇ -alkyl, -CO- Ci-C ⁇ -alkyl, -OH, -O-d-C 6 -alkyl, -S-C ⁇ -C 6 -alkyl, -C ⁇ -C 4 -alkyl-NR 6 R 7 and -C ⁇ -C 4
• R 1 and R 2 together denote a C 4 -C 6 -alkylene bridge
• R 6 , R 7 which may be identical or different, denote hydrogen, C ⁇ -C 4 -alkyl or -CO-C ⁇ -C 2 -alkyl, and
• R 4 which may be identical or different, denotes a group selected from among a d-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -COOH, -CO-d-C 6 -alkyl, -O-CO-d-C 4 - alkyl, -CO-O-C ⁇ -C 4 -alkyl, -O-CO-O-C ⁇ -C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-Ci-Ce- alkyl, -S-C C 6 -alkyl and -NR 6 R 7 ,
• R 5 which may be identical or different, denotes a group selected from among a C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO 2 , -SO 2 H, -SO 3 H, -COOH, -CO-d-C 6 -alkyl, -O-CO-d-C 4 - alkyl, -CO-O-d-C 4 -alkyl, -O-CO-O-d-C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-d-C 6 - alkyl, -S-Ci-d-alkyl and -NR 6 R 7 , and n, m which may be identical or different represent 0,1 or 2,
• R 1 denotes hydrogen, C ⁇ -C -alkyl or benzyl
• R 2 , R 3 which may be identical or different, denote hydrogen or d-C 4 -alkyl, or R 1 and R 2 together denote a butylene bridge, and
• R 4 which may be identical or different, denotes a group selected from among a Ci-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO 2 , -COOH, -CO-Ci-Ce-alkyl, -O-CO-d-C 4 -alkyl, -CO-O-C 1 - C 4 -alkyl, -O-CO-O-C ⁇ -C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-Ci-Cs-alkyl, -S-d-C 6 -alkyl and -NR 6 R 7 ,
• R 5 which may be identical or different, denotes a group selected from among a Ci-Ce-alkyl group optionally substituted by one or more halogen atoms, halogen, -CN, -NO 2 , -COOH, -CO-d-C 6 -alkyl, -O-CO-d-C 4 -alkyl, -CO-O-d- C 4 -alkyl, -O-CO-O-C ⁇ -C 4 -alkyl, -CO-NR 6 R 7 , -OH, -O-C ⁇ -C 6 -alkyl, -S-C C 6 -alkyl and -NR 6 R 7 , and n, m which may be identical or different represent 0,1 or 2,
• R 1 , R 2 , R 3 which may be identical or different, denote hydrogen or d-C 4 -alkyl
• R 4 which may be identical or different, denotes a group selected from among a C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, -NO 2 , -O-CO-C ⁇ -C 4 -alkyl, -O-CO-O-d-C 4 -alkyl, -O-C C 6 -alkyl, and -NR 6 R 7 , R 5 , which may be identical or different, denotes a group selected from among a
• C ⁇ -C 6 -alkyl group optionally substituted by one or more halogen atoms, halogen, -NO 2 , -O-CO-C ⁇ -C 4 -alkyl, -O-CO-O-C ⁇ -C 4 -alkyl, -O-d-C 6 -alkyl, and -NR 6 R 7 , and n, m which may be identical or different represent 0,1 or 2,
• R 1 denotes methyl, ethyl, i-propyl, n-butyl or benzyl, optionally in the form of the various enantiomers and diastereomers thereof, as well as the pharmacologically acceptable salts thereof.
• R 1 denotes methyl, optionally in the form of the pharmacologically acceptable salts thereof. Also particularly preferred are compounds of general formula (I), wherein
• R 1 denotes methyl
• R 2 , R 3 denote hydrogen
• R 4 , R 5 which may be identical or different, denote halogen, preferably fluorine, chlorine, bromine, most preferably fluorine or chlorine, and n, m which may be identical or different represent 0,1 or 2, preferably 0 or 1 , optionally in the form of the pharmacologically acceptable salts thereof.
• alkyl groups used are branched and unbranched alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl and hexyl.
• the groups methyl, ethyl, propyl or butyl may optionally also be referred to by the abbreviations Me, Et, Pr or Bu.
• the definitions propyl, butyl, pentyl and hexyl also include all possible isomeric forms of the groups in question.
• propyl includes n-propyl and iso-propyl
• butyl includes iso-butyl, sec. butyl and tert- butyl, etc.
• one or more hydrogen atoms may optionally be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
• the substituents fluorine and chlorine are preferred.
• the substituent fluorine is particularly preferred. If desired, all the hydrogen atoms of the alkyl group may be replaced.
• alkyl group mentioned in the group phenyl-C ⁇ -C 4 -alkyl may be in branched or unbranched form. Unless otherwise stated benzyl and phenylethyl are preferred phenyl-CrC 4 -alkyl groups. Benzyl is particularly preferred.
• alkyl groups mentioned in the groups -SO 2 -d-C 6 -alkyl, -SO-C C 6 -alkyl, -CO- C ⁇ -C 6 -alkyl, -CO-C ⁇ -C 4 -alkyl, -d-C 4 -alkyl-NR 6 R 7 , -C ⁇ -C 4 -alkyl-O- C C 4 -alkyl, -O- C ⁇ -C 6 -alkyl, -S-d-C 6 -alkyl, -O-CO-d-C -alkyl, -CO-O-C ⁇ -C 4 -alkyl or -O-CO-O-d-C 4 - alkyl may be in branched or unbranched form with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, particularly preferably with 1 to 3 carbon atoms, most preferably with 1 to 2 carbon atoms.
• the C 4 -C 6 -alkylene bridge may, unless otherwise stated, be branched and unbranched alkylene groups having 4 to 6 carbon atoms, for example n-butylene, 1- methylpropylene, 2-methylpropylene, 1.1-dimethylethylene, 1.2-dimethylethylene etc. n-Butylene bridges are particularly preferred.
• the aryl group is an aromatic ring system having 6 to 10 carbon atoms, preferably phenyl.
• one or more hydrogen atoms may optionally be substituted by halogen atoms, -NO 2 , -SO 2 H or -d-C 4 -alkyl, preferably fluorine, chlorine , -NO 2 , ethyl or methyl, most preferably fluorine or methyl.
• C 3 -C 6 -cycloalkyl denotes saturated cyclic hydrocarbon groups having 3 - 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
• halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine, most preferably fluorine and chlorine, most preferably fluorine.
• the compounds of formula (I) or the various enantiomers and diastereomers thereof may be converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof.
• These salts may on the one hand take the form of physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids.
• the compound of formula (I) where R 1 is hydrogen may be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ions.
• the acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above acids.
• R 1 denotes hydrogen
• the compounds according to the invention may be prepared in a manner known per se.
• the following general methods of synthesis 1 and 2 shown in Diagrams 1 and 2 below are meant to illustrate the invention without restricting it to their content.
• naphthalene derivative (II) About 10 mmol of the naphthalene derivative (II) are taken up in 2 - 100 ml, preferably 3 - 80 ml, most preferably about 4 ml, of acetic anhydride and 10 - 100 mmol, preferably 11 - 80 mmol, particularly preferably 11 mmol or cone, sulphuric acid are added at 0 - 50°C, preferably 5 - 20°C, particularly preferably about 18 °C. After 2 - 16 h, preferably about 5 h, stirring at 20 - 100°C, preferably about 25 C°, the mixture is poured onto a saturated NaCI solution. The crystals formed are isolated.
• Methylene chloride, diisopropylether, ethyl acetate, trichloromethane, toluene, benzene or 1 ,4-dioxin may be used instead of acetic acid anhydride, while fuming sulphuric acid, sulphur trioxide, chlorine sulphates or combinations thereof may be used as an alternative to cone, sulphuric acid.
• naphthalene-1-sulphonic acids are combined successively with 10 - 500 mmol, preferably about 90 mmol, of phosphorus oxytrichloride and 8 - 50 mmol, preferably about 10 mmol, of phosphorus pentachloride and heated for 2 - 16 h, preferably about 5 h, at 20 - 100°C, preferably by refluxing. Then the reaction mixture is evaporated down and combined with water. After extraction with organic diluent the combined organic extracts are dried and freed from solvent. The crude product obtained is used in the subsequent steps without being purified.
• phosphorus oxytrichloride/phosphorus pentachloride mixture thionyl chloride, phosphorus pentachloride, a phosphoric acid/chlorine mixture or phosgene may be used.
• the reaction may alternatively be carried out in the diluents ethyl acetate, water, acetonitrile, N,N-dimethylacetamide, sulpholane, DMF, hexane or dichloroethane.
• Triethylamine, potassium carbonate, sodium hydrogen carbonate or sodium hydride may be used instead of sodium hydroxide, while tetrahydrofuran, diethylether, dichloromethane, trichloromethane, dioxin, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile may be used instead of toluene.
• Cvclisation of the naphthalene-1-sulphonyl-amino-acetic acids (IV): About 10 mmol of the naphthalene-1-sulphonyl-amino-acetic acids are combined with 10 - 200 g, preferably about 40 g, of polyphosphoric acid and stirred for 2 - 16 h, preferably about 5 h, at 20 - 110°C, preferably 75 - 95°C, most preferably at about 80°C . Then the reaction mixture is poured onto water and extracted. The combined organic extracts are dried and evaporated down. The residue is purified.
• R 1 and R 2 represent hydrogen
• methanesulphonic acid, trifluoroacetic acid, sulphuric acid, phosphoric acid or polyphosphoric acid may be used as strong acids.
• naphthalene-1-sulphonamides are added to 0 - 100 ml, preferably 20 - 80 ml, most preferably about 40 ml of methanesulphonic acid and combined with a solution of 3 - 50 mmol, preferably 4 - 30 mmol, most preferably 5 mmol of trioxane in 0 - 100 ml, preferably about 12 ml, of trifluoroacetic acid.
• the reaction mixture is stirred for 2 - 16 h, preferably 5 h, at 20 - 100 C°, preferably 30 -
• trioxane it is possible to use paraformaldehyde or formalin, while instead of trifluoroacetic acid it is possible to use boron trifluoride * diethylether, acetic acid, polyphosphoric acid, phosphoric acid or sulphuric acid. Acetic anhydride or dichloromethane may be used as possible diluents.
• the new compounds of general formula (I) may be synthesised analogously to the following Examples of synthesis. These Examples are, however, intended solely as examples of procedure to illustrate the invention further without restricting it to the subject matter thereof.
• Naphthalene-1-sulphonic acid tert-butylamide; 8 ml of tert. butylamine are placed in 50 ml of chloroform, cooled to 0° C and 5.75 g of 1-naphthalenic acid chloride in 45 ml of chloroform are added dropwise. Then the mixture is stirred for 24 h at ambient temperature. After concentration by evaporation in vacuo the residue obtained is dissolved in dichloromethane and washed with 2 N hydrochloric acid. The organic extracts collected are dried with sodium sulphate and evaporated down in vacuo. Yield: 5.48 g.
• 5-acetylamino-naphthalene-1-sulphonylchloride 1.40 g of 5-acetylamino-naphthalene-1 -sulphonic acid and 2.23 g of phosphorus pentachloride are combined and stirred for 4 h at 60° C. Then the solution is poured onto ice water and extracted with dichloromethane. The organic extracts collected are dried with sodium sulphate and evaporated down in vacuo. Yield: 1.10 g.
• 8-tert-butylsulphamoyl-naphthalene-1 -carboxylic acid 4.36 g of naphthalene-1 -sulphonic acid te/ -butylamide are placed in 80 ml tetrahydrofuran, cooled to -10° C and 29 ml of N-butyl lithium (1.6 molar solution in hexane) are cautiously added dropwise. The mixture is stirred first for 0.5 h at - 10°C, then for 3 h at ambient temperature. It is then cooled to -5°C and CO 2 obtained from dry ice is piped in within 0.25 h. The reaction mixture is stirred for 2.5 h at ambient temperature and then combined with water.
• reaction mixture is combined with 1.5 ml of 2 N hydrochloric acid and 2 ml of methanol, then stirred for 2 h at reflux temperature. 2 ml of ammonia are added and any crystals formed are filtered off. The filtrate is extracted with ethyl acetate, the organic extracts collected are dried with sodium sulphate and evaporated down in vacuo. Yield: 0.06 g.
• the test was carried out at concentrations of between 0.3 ⁇ mol and 300 ⁇ mol.
• the new compounds can also be used to treat illnesses or conditions in which neuronal networks which require AMPA receptors in order to function are damaged or limited in their function.
• the compounds of general formula (I) can thus be used in dementias, in neurodegenerative or psychotic illnesses and in neurodegenerative disorders and cerebral ischaemias of various origins, preferably in schizophrenia or learning and memory disorders.
• epilepsy hypoglycaemia, hypoxia, anoxia, cerebral trauma, brain oedema, amyotropic lateral sclerosis, Huntington's Disease, Alzheimer's disease, sexual dysfunction, disorders of sensory/motor function, memory formation, hyperkinetic behavioural changes (particularly in children), hypotension, cardiac infarct, cerebral pressure (increased intracranial pressure), ischaemic and haemorrhagic stroke, global cerebral ischaemia on stoppage of the heart, acute and chronic neuropathic pain, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, Parkinson's disease and depression, and related anxiety states.
• the new compounds may also be given in conjunction with other active substances, such as those used for the same indications, or for example with neuroleptics, nootropics, psychostimulants, etc. They may be administered topically, orally, transdermally, nasally, parenterally or by inhalation. Moreover, the compounds of general formula I or the salts thereof may also be combined with active substances of other kinds.
• the compounds of general formula (I) may be given on their own or in conjunction with other active substances according to the invention, and possibly also in conjunction with other pharmacologically active substances.
• suitable preparations include for example tablets, capsules, suppositories, solutions, - particularly solutions for injection (s.o, i.v., i.m.) and infusion - elixirs, emulsions or dispersible powders.
• the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
• Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, 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 gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients 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 gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• excipients for example inert dilu
• Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core may also consist of a number of layers.
• the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
• Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• a sweetener such as saccharine, cyclamate, glycerol or sugar
• a flavour enhancer e.g. a flavouring such as vanilline or orange extract.
• They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
• Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
• isotonic agents e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aid
• Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g.
• kaolins kaolins, clays, talc, chalk
• synthetic mineral powders e.g. highly dispersed silicic acid and silicates
• sugars e.g. cane sugar, lactose and glucose
• emulsifiers e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
• lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
• the preparations are administered by the usual methods, preferably by oral or transdermal route, particularly orally.
• the tablets may of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
• lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
• the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
• solutions of the active substances with suitable liquid carriers may be used.
• the dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and 500 mg per hour.
• the finely-ground active substance, lactose and some of the maize starch are mixed together.
• the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
• the granules, the remaining maize starch and the magnesium stearate are screened and mixed together.
• the mixture is compressed to produce tablets of suitable shape and size.
• lactose 55 mg maize starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg
• the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
• the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
• the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
• the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
• the ampoules contain 5 mg, 25 mg and 50 mg of active substance.

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