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  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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  • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
  • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to new beta-agonists of general formula (I) wherein the groups R 1 to R 7 have the meanings given below in the specification, the tautomers, the enantiomers, the diastereomers, the mixtures thereof, the prodrugs thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, processes for preparing these compounds and their use as pharmaceutical compositions.
• type II diabetes and obesity are based primarily on reducing calorie intake and increasing physical activity. These methods are rarely successful in the longer term.
• beta-3 receptor agonists have a significant effect on lipolysis, thermogenesis and the serum glucose level in animal models of type II diabetes (Arch J R. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress, Eur J. Pharmacol. 2002 Apr. 12; 440(2-3):99-107).
• the aim of the present invention is to provide selective beta-3 agonists which can be used to prepare pharmaceutical compositions for the treatment of obesity and type II diabetes.
• compounds of general formula (I) wherein the groups R 1 to R 7 are defined as hereinafter are effective as selective beta-3 agonists.
• the compounds according to the invention may be used to treat diseases connected with the stimulation of beta-3-receptors.
• the present invention therefore relates to compounds of general formula (I) wherein
• the invention also relates to compounds of general formula (I) for use as pharmaceutical compositions.
• the invention also relates to compounds of general formula (I) for use as pharmaceutical compositions with a selective beta-3-agonistic activity.
• the invention also relates to compounds of general formula (I) for preparing a pharmaceutical composition for the treatment and/or prevention of diseases connected with the stimulation of beta-3-receptors.
• the invention further relates to a method for the treatment and/or prevention of diseases connected with the stimulation of beta-3-receptors, in which a patient is given an effective amount of a compound of general formula I.
• the invention further relates to a pharmaceutical composition containing as active substance one or more compounds of general formula (I), optionally combined with conventional excipients and/or carriers.
• the invention further relates to a pharmaceutical composition containing as active substance one or more compounds of general formula (I) or the physiologically acceptable salts thereof and one or more active substances selected from among antidiabetics, inhibitors of protein tyrosinephosphatase 1, substances which influence deregulated glucose production in the liver, lipid lowering agents, cholesterol absorption inhibitors, HDL-raising compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.
• active substances selected from among antidiabetics, inhibitors of protein tyrosinephosphatase 1, substances which influence deregulated glucose production in the liver, lipid lowering agents, cholesterol absorption inhibitors, HDL-raising compounds, active substances for the treatment of obesity and modulators or stimulators of the adrenergic system via alpha 1 and alpha 2 as well as beta 1, beta 2 and beta 3 receptors.
• the invention further relates to a process for preparing a compound of general formula (I), wherein
• alkyl groups including alkyl groups which are a part of other groups, denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms, while groups with 1 to 6 carbon atoms are preferred. Particularly preferred are alkyl groups with 1 to 4 carbon atoms, particularly those with 1 or 2 carbon atoms. Examples include: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl.
• propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all the possible isomeric forms.
• propyl includes the two isomeric groups n-propyl and iso-propyl
• butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl
• pentyl includes iso-pentyl, neopentyl, etc.
• one or more hydrogen atoms may optionally be replaced by other groups.
• these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
• the substituents are fluorine or chlorine.
• the substituent chlorine is most preferred. All the hydrogen atoms of the alkyl group may optionally also be replaced.
• one or more hydrogen atoms may optionally be replaced, for example, by OH, NO 2 , CN or an optionally substituted group selected from among —O—C 1 -C 5 -alkyl, preferably methoxy or ethoxy, —O—(C 6 -C 14 -aryl), preferably phenyloxy, —O-heteroaryl, preferably —O-thienyl, —O-thiazolyl, —O-imidazolyl, —O-pyridyl, —O-pyrimidyl or —O-pyrazinyl, saturated or unsaturated —O-heterocycloalkyl, preferably —O-pyrazolyl, —O-pyrrolidinyl, —O-piperidinyl, —O-piperazinyl or —O-tetrahydro-oxazinyl,
• Alkenyl groups as well as alkenyl groups which are a part of other groups denote branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1 to 6, particularly preferably 1 to 4 carbon atoms, which contain at least one carbon-carbon double bond. Examples include: ethenyl, propenyl, methylpropenyl, butenyl, pentenyl, hexenyl, heptenyl, methylheptenyl, octenyl, nonenyl and decenyl.
• propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl used above include all the possible isomeric forms.
• butenyl includes the isomeric groups but-1-enyl, but-2-enyl and but-3-enyl, etc.
• alkenyl groups one or more hydrogen atoms may optionally be replaced by other groups.
• these alkenyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
• the substituents fluorine or chlorine are preferred.
• the substituent fluorine is particularly preferred. It is also possible to replace all the hydrogen atoms of the alkenyl group.
• Alkynyl groups as well as alkynyl groups which are a part of other groups denote branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1 to 6, particularly preferably 1 to 4 carbon atoms which contain at least one carbon-carbon triple bond. Examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl.
• the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl used above include all the possible isomeric forms.
• butynyl includes the isomeric groups but-1-ynyl, but-2-ynyl and but-3-ynyl, etc.
• one or more hydrogen atoms may optionally be replaced by other groups.
• these alkynyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine.
• the substituents fluorine or chlorine are preferred.
• the substituent fluorine is particularly preferred. It is also possible to replace all the hydrogen atoms of the alkynyl group.
• aryl denotes an aromatic ring system with 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, most preferably phenyl, which may optionally be substituted and may preferably carry one or more of the following substituents: OH, NO 2 , CN, —OCHF 2 , —OCF 3 , —NH 2 , —NH-alkyl, —N(alkyl)-alkyl, —NH-aryl, —N(alkyl)-aryl, —NHCO-alkyl, —NHCO-aryl, —N(alkyl)-CO-alkyl, —N (alkyl)-CO-aryl, —NHSO 2 -alkyl, —NHSO 2 —N(alkyl) 2 , —NHSO 2 -aryl, —N(alkyl)-SO 2 -alkyl, —N (alkyl)-SO 2 -SO
• heteroaryl groups are 5 to 10-membered mono- or bicyclic heteroaryl rings wherein up to three C atoms may be replaced by one heteroatoms selected from among oxygen, nitrogen or sulphur, for example furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole, oxadiazole, while each of the above-mentioned heterocycles may optionally also be annellated to a benzene ring, such as benzimidazole, and these heterocycles may optionally be substituted and preferably carry one or more of the following substituents: OH, NO 2 , CN, —NH 2 , —NH-alkyl, —N(alkyl)-alkyl, —NH-aryl
• cycloalkyl groups are saturated or unsaturated cycloalkyl groups with 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the above-mentioned cycloalkyl groups may optionally also carry one or more substituents or be annellated to a benzene ring.
• heterocycloalkyl or heterocyclyl groups include 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulphur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranone, ⁇ -butyrolactone, ⁇ -pyran, ⁇ -pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolane, dithiolane, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl,
• prodrugs compounds of general formula I which contain a group that can be cleaved in-vivo are so-called prodrugs, and compounds of general formula I which contain two groups that can be cleaved in-vivo are so-called double prodrugs.
• Halogen generally denotes fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine, particularly preferably fluorine.
• the compounds according to the invention may be in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, prodrugs, double prodrugs and in the form of the tautomers, salts, solvates and hydrates as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic, formic, malic, benzoic, benzenesulphonic, camphorsulphonic, acetic, ethanesulphonic, glutamic, maleic, mandelic, lactic, phosphoric, nitric, sulphuric, succinic, para-toluenesulphonic, trifluoroacetic, tartaric, citric or methanesulphonic acid.
• the new compounds of formula I thus obtained contain a carboxy group or another acid group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
• Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
• the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
• the enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
• Optically active acids in common use are e.g.
• An optically active alcohol may be, for example, (+) or ( ⁇ )-menthol and an optically active acyl group in amides, for example, may be a (+)- or ( ⁇ )-menthyloxycarbonyl.
• the substituent R 1 may represent optionally substituted aryl or heteroaryl, preferably substituted phenyl. Particularly preferably, the substituent R 1 denotes phenyl.
• the substituent R 2 may represent a heteroaryl or heterocyclyl mono- or polysubstituted by R 10 , where R 2 contains at least one nitrogen atom. Particularly preferred is a triazole mono- or polysubstituted by R 10 , a 1,4-dioxo-3,4-dihydro-1H-phthalazine mono- or polysubstituted by R 10 , a 2-oxoimidazolidine mono- or polysubstituted by R 10 , a benzimidazole mono- or polysubstituted by R 10 or an imidazole mono- or polysubstituted by R 10 .
• R 2 are a 1H-[1,2,3]triazol-1-yl monosubstituted by R 10 , a 1,4-dioxo-3,4-dihydro-1H-phthalazin-2-yl monosubstituted by R 10 , a 2-oxo-imidazolidin-1-yl monosubstituted by R 10 , a benzimidazol-1-yl monosubstituted by R 10 or an imidazol-1-yl monosubstituted by R 10 .
• the substituents R 3 and R 4 may independently of one another represent hydrogen or an optionally substituted group selected from among C 3 -C 6 -cycloalkyl or C 1 -C 5 -alkyl, preferably C 1 -C 5 -alkyl, or R 3 and R 4 together represent a 2- to 7-membered alkylene bridge, preferably a 2- to 5-membered alkylene bridge, particularly an ethylene bridge.
• a substituted R 3 or R 4 is preferably substituted by C 1 -C 3 -alkyl.
• R 3 denotes methyl
• R 4 denotes methyl
• the substituents R 5 , R 6 and R 7 may independently of one another denote hydrogen or a group selected from among halogen, cyano, —NR 8 CO—(C 1 -C 5 -alkyl), —NR 8 CO-aryl, —NR 8 SO 2 —(C 1 -C 5 -alkyl), —NR 8 SO 2 -aryl, —CO 2 R 8 , —SO 2 R 8 , —CONHR 8 , —SO 2 NHR 8 , —OR 8 , optionally substituted C 3 -C 6 -cycloalkyl and optionally substituted C 1 -C 10 -alkyl, preferably hydrogen, halogen, cyano, methoxy, methanesulphonylamino, methanesulphonyl, difluoromethoxy, trifluoromethoxy, difluoromethyl or trifluoromethyl, particularly hydrogen, fluorine, chlorine or cyano.
• the substituent R 8 may represent hydrogen or C 1 -C 5 -alkyl, preferably methyl.
• the substituent R 9 may represent hydrogen, optionally substituted aryl or optionally substituted heteroaryl, preferably optionally substituted phenyl, pyridyl or thiophenyl.
• the substituent R 10 may represent OH, NO 2 , CN, —OCHF 2 , —OCF 3 , —NH 2 , —NH-alkyl, —N(-alkyl)-alkyl, —NH-aryl, —N(-alkyl)-aryl, —NHCO-alkyl, —NHCO-aryl, —N(-alkyl)CO-alkyl, —N(-alkyl)CO-aryl, —NHSO 2 -alkyl, —NHSO 2 -aryl, —N(-alkyl)SO 2 -alkyl, —N(-alkyl)-SO 2 -aryl, —CO 2 -alkyl, —SO 2 -alkyl, —SO 2 -aryl, —CONH-alkyl, —CONH-aryl, —CON(-alkyl)-alkyl, —CON(-alkyl)-aryl,
• R 10 denotes —OH, —NO 2 , —CN, —NH 2 , —I, —N(CH 3 ) 2 , —NHCO 2 CH 3 , —NHSO 2 CH 3 , —SO 2 N(C H 3 ) 2 , —CO 2 H, benzyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, —CONHOH, tetrazol-5-yl, pyridin-4-yl, pyridin-2-yl, 6-methoxy-pyridin-3-yl, phenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-methoxy-phenyl, 4-aminophenyl, 4-nitrophenyl, thiophen-2-yl, 5-methyl-thiophen-2-yl, 3,5-dimethyl-isoxazol-4-yl or 1-acetyl-2-amino-propenyl.
• the free base was prepared from the amine-bistrifluoroacetate obtained using known methods.
• racemic end compound obtained may be separated into the two enantiomers for example by chiral column chromatography or by recrystallisation with suitable chiral counter-ions.
• the aqueous phase was separated from the organic phase and extracted twice with 50 mL ethyl acetate.
• the combined organic phases were washed with 20 mL saturated, aqueous sodium chloride solution, dried over magnesium sulphate and freed from the solvent using the rotary evaporator.
• the residue was purified by flash column chromatography [methylene chloride/methanol/ammonia (90:10:1)]. 12.9 g (10.5 mmol, 45%) N-(3- ⁇ 1-hydroxy-2-[3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propylamino]-ethyl ⁇ -phenyl)-benzenesulphonamide were obtained as a colourless solid.
• Examples 4, 9, 16, 19, 20, 21, 23, 26, 27, 28 and 38 were synthesised analogously to the method described for Example 22.
• the following reagents were used instead of 5-methylthiophene-2-boric acid.
• the reaction mixture was stirred for 48 h at ambient temperature and then poured into 500 mL ice water/ethyl acetate 2:1. The phases were separated and the aqueous phase was extracted three times with 150 mL ethyl acetate. The combined organic phases were washed five times with 150 mL water, then once with 150 mL saturated, aqueous sodium chloride solution, dried over sodium sulphate and the solvent was eliminated using the rotary evaporator. The residue was purified by flash column chromatography [petroleum ether/ethyl acetate (70:30)].
• the free base was prepared from 0.34 g (0.90 mmol) 1-(3-amino-3-methyl-butyl)-3-(4-fluoro-phenyl)-imidazolidin-2-one bistrifluoroacetate by known methods. It was dissolved in 4 mL ethanol, combined with 0.20 g (0.60 mmol) N-[3-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-benzenesulphonamide and refluxed for 15 h. The reaction mixture was cooled to 0° C. and then combined with 0.34 g (9.00 mmol) sodium borohydride.
• Examples 1, 2, 3, 6, 7, 13, 15, 18, 24, 25, 29, 30, 31 and 37 were synthesised analogously to the method described in Example 5.
• the following reagents were used in the first reaction step instead of 1-(4-fluoro-phenyl)-imidazolidin-2-one:
• Examples 17, 32, 34 and 35 were synthesised analogously to the method described in Example 8. The following compounds were used instead of N-[3-(2- ⁇ 3-[4-(4-nitro-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino ⁇ -1-hydroxyethyl)-phenyl]-benzenesulphonamide:
• N,N-dimethylsulphamyl chloride was added at 0° C. to 0.208 g (0.400 mmol) N-[3-(2- ⁇ 3-[4-(4-amino-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino ⁇ -1-hydroxyethyl)-phenyl]-benzenesulphonamide in 4 mL pyridine and the mixture was stirred for 16 h at ambient temperature. The reaction mixture was poured into 50 ml hydrochloric acid (1M)/ethyl acetate 1:1.
• the (R)- and (S)-enantiomers of the Examples may be obtained from the racemate by chiral HPLC, for example (e.g. column: Chirobiotic T, 250 ⁇ 4.6 mm obtained from Messrs Astec).
• the mobile phase used may be methanol with 0.05% triethylamine and 0.05% acetic acid (eluant A) in acetonitrile.
• Silica gel with a particle size of 5 ⁇ m to which the glycoprotein teicoplanin is covalently bound may be used as the column material.
• the compounds of general formula (I) are characterised by their great versatility in the therapeutic field. Particular mention should be made of those applications in which the effects of beta-3-agonists, particularly selective beta-3-agonists play a part.
• Such diseases include for example:
• the beta-3 agonists according to the invention are particularly suitable for the treatment of obesity, insulin resistance, type 2 diabetes mellitus, urinary incontinence, irritable colon and other diseases with decreased intestinal motility or depression, particularly for the treatment of diabetes and obesity.
• the activity of the beta-3 agonists can be determined for example in a lipolysis test.
• the test procedure may be carried out as follows:
• Adipocytes were isolated from fatty tissue ex vivo by modifying a method according to Rodbell (Rodbell, M. Metabolism of isolated fat cells. I. Effects of hormones on glucose metabolism and lipolysis. J Biol Chem 239: 375-380. 1964).
• the excised fatty tissue was cut into small pieces and mixed with 1 mg/ml collagenase in Krebs Ringer Buffer (KRB) containing 6 mM glucose and 2% albumin by gently shaking for 30-40 min at 37° C.
• KRB Krebs Ringer Buffer
• the cells were filtered through a gauze, washed twice with KRB and in each case 50-150 g were centrifuged for 5 min.
• Glycerol is phosphorylated by ATP via glycerol kinase.
• the resulting glycerol-1-phosphate is oxidised by glycerolphosphate oxidase to form dihydroxyacetone phosphate and hydrogen peroxide.
• a quinonimine dye is produced by the peroxidase-catalysed coupling of sodium-N-ethyl-N-(3-sulphopropyl)m-ansidine and 4-aminoantipyrine.
• the dye has an absorption peak at 540 nm. The absorption is directly proportional to the glycerol concentration in the samples.
• the new compounds may be used for the prevention or short-term or long-term treatment of the above-mentioned diseases, and may also be used in conjunction with other active substances used for the same indications.
• active substances used for the same indications.
• antidiabetics such as metformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g. GI 262570), alpha-glucosidase inhibitors (e.g.
• acarbose voglibose
• alpha2 antagonists insulin and insulin analogues
• GLP-1 and GLP-1 analogues e.g. exendin-4
• amylin e.g., inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as e.g.
• lipid lowering agents such as HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g.
• nicotinic acid and its derivatives cholesterol absorption inhibitors such as for example ezetimibe, bile acid-binding substances such as for example cholestyramine, HDL-raising compounds such as for example inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesity, such as e.g. sibutramine or tetrahydrolipostatin.
• drugs for treating high blood pressure such as e.g. All antagonists or ACE inhibitors, diuretics, ⁇ -blockers, and other modulators of the adrenergic system or combinations thereof.
• combinations with stimulators of the adrenergic system via alpha 1 and alpha 2 and also beta 1, beta 2 and beta 3 receptors are particularly suitable.
• the compounds of general formula (I) may be used on their own or in conjunction with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances.
• suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., 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.
• the specified doses may be taken several times a day, if necessary.
• 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 or 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 vanillin 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 vanillin or orange extract.
• 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, optionally organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
• 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, 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.
• 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, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
• lignin 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, preferably oral.
• the tablets may, of course contain, apart from the above-mentioned 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 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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