Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/04—Carbocyclic radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
  • C07D309/10—Oxygen atoms
• • 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
  • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
  • C07H7/06—Heterocyclic radicals

Definitions

• the invention relates to compounds of the formula
• 6-membered aromatic ring is mono- or disubstituted by Hal, OR 5 , NR 5 R 6 , CN, COOR 5 , CONR 5 R 6 , -OCOA,
• NR 5 COR 6 and / or NR 5 SO 2 A may be substituted
• R carb Ar or Het
• R 5 , R 6 are each independently H or A, carb is cycloalkyl of 3-7 C atoms, Ar is unsubstituted or mono-, di-, tri-, tetra- or quintuplet of Hal, A, benzyl, OR °, NR 5 ° rR-, 6 °, NO 2 , CN, CONR j5 0 D R6 0 , NR 5 COA, OCOA, NR 5 CONR 5 R 6 , NR 5 SO 2 A, CHO, COA, SO 2 NR 5 R 6 , S (O) P A and / or - (CR 5 R 6 ) m -COOR 5 substituted phenyl, naphthyl or biphenyl,
• Carbonyl oxygen may be substituted
• Hal is F, Cl, Br or I
• m is O, 1, 2 or 3
• p is O, 1 or 2
• the invention had the object of finding new compounds with valuable properties, in particular those that can be used for the production of medicaments.
• the compounds of the formula I and their salts possess very valuable pharmacological properties with good compatibility. They show SGLT1 and SGLT2 (sodium dependent glucose co-transporter) inhibiting properties and can therefore be used for To combat and prevent type 1 and type 2 diabetes.
• SGLT1 and SGLT2 sodium dependent glucose co-transporter
• SGLTs epithelial sodium-dependent glucose cotransporters
• SGLT1 e.g., Lee WS et al., (1994) The high-affinity Na + / glucose co-transporter: reevaluation of function and distribution of expression., J. Biol. Chem , 12032-1203
• SGLT2 for example, Mackenzie B. et al., (1994) SAAT1 is a low-affinity Na + / glucose cotransporter and not an amino acid transporter J. Biol. Chem., 269, 22488-22491).
• SGLT1 is believed to be important for the absorption of glucose in the gut, whereas SGLT2 is likely to be responsible for the reabsorption of free filtered glucose in the kidney.
• diabetes mellitus The main change in diabetes mellitus is hyperglycemia.
• Aromatic glycoside derivatives are known from WO 2004/052902 and WO
• WO 0280935 JP 2000080041 and EP 850948.
• Glucopyranoslyoxybenzylbenzenes are described in WO 0244192, WO 0228872 and WO 0168660.
• Glucopyranosyloxy-pyrazoles are known from WO 0268440,
• the compounds of the invention exhibit high splitting relative to the desired affinity of SGLT 2 for SGLT 1 .
• the compounds of the formula I are distinguished by favorable effects on the glucose metabolism, in particular they lower the blood sugar level and are suitable for the treatment of type 1 and type 2 diabetes.
• the compounds can therefore be used alone or in combination with other blood sugar-lowering agents (antidiabetics).
• the compounds of the formula I are furthermore suitable for the prevention and treatment of diabetic late damage, such as, for example, nephropathy, retinopathy, neuropathy and syndrome X, obesity, myocardial infarction, myocardial infarction, peripheral arterial occlusive diseases, thrombosis, arteriosclerosis, inflammation, immune diseases, autoimmune diseases such as AIDS, asthma, osteoporosis, cancer,
• diabetic late damage such as, for example, nephropathy, retinopathy, neuropathy and syndrome X, obesity, myocardial infarction, myocardial infarction, peripheral arterial occlusive diseases, thrombosis, arteriosclerosis, inflammation, immune diseases, autoimmune diseases such as AIDS, asthma, osteoporosis, cancer,
• Psoriasis Alzheimer's disease, schizophrenia and infectious diseases
• the treatment of type 1 and type 2 diabetes is preferred as well as for the prevention and treatment of late diabetic damage, syndrome X and obesity.
• the compounds of the formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the treatment and prevention of type 1 and type 2 diabetes.
• the invention relates to the compounds of formula I and their salts and to a process for the preparation of compounds of formula I and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, characterized in that starting from a compound of formula II
• R 1 splits off, and / or converting a base or acid of the formula I into one of its salts.
• the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate the optically active forms (stereoisomers),
• Solvates are e.g. Mono or dihydrate or alcoholates.
• Sugars or oligopeptides modified compounds of formula I which are rapidly cleaved in the organism to the active compounds of the invention.
• These include biodegradable polymer derivatives of the compounds of the invention, as z. In Int. J. Pharm. 115, 61-67 (1995).
• the invention also provides mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000th These are particularly preferably mixtures of stereoisomeric compounds.
• the compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the scope of the invention and are a further aspect of the invention.
• A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms.
• A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methyl-butyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,
• Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
• Ar means e.g. Phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p- tert
• Ar is particularly preferably unsubstituted phenyl, furthermore preferably mono-, di- or trisubstituted phenyl, for example by A, Hal, OA and / or OH. Het, irrespective of further substitutions, for example 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, A- or 5-imidazolyl, 1-, 3-, A- or 5-pyrazolyl, 2-, A- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or
• Pyrimidinyl furthermore preferably 1, 2,3-triazole-1, -A- or -5-yl, 1, 2,4-triazol-1, -3- or 5-yl, 1- or 5- Tetrazolyl, 1, 2,3-oxadiazol-4 or 5-yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1, 2,4-thiadiazol-3 or -5-yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or A-pyridazinyl, pyrazinyl, 1, 2, 3, A, 5-, 6- or 7-indolyl, A- or 5-
• the heterocyclic radicals may also be partially or completely hydrogenated.
• Het can thus z.
• Dihydro-2H-1, 5-benzodioxepin-6 or -7-yl furthermore preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl, 3,4-dihydro-2-oxo 1 / - / - quinazolinyl, 2,3-dihydrobenzoxazolyl, 2-oxo-2,3-dihydrobenzoxazolyl, 10 2,3-dihydrobenzimidazolyl, 1,3-dihydroindole, 2-oxo-1, 3 dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.
• Het more preferably denotes pyridyl, pyrimidinyl, furyl, thienyl, C 1 -tetrahydrofuranyl, tetrahydropyranyl, dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, which may also be monosubstituted by Hal, A and / or OO (carbonyl oxygen).
• R 5 , R 6 are preferably each independently, H or
• Hal preferably denotes F, Cl or Br, but also I.
• the compounds of formula I may possess one or more chiral centers 25 and therefore exist in different stereoisomeric forms.
• Formula I encompasses all these forms.
• the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given above.
• Some preferred groups of compounds can be expressed by the following partial formulas Ia to If which correspond to the formula I and the unspecified radicals reside in the formula 5 indicated in formula I.
• R are each independently H or methyl; in Ib R means Ar;
• R are each independently H or CH 3 - in Ic R;
• HHiaI, A and / or OR 5 is substituted phenyl
• Ie A is unbranched or branched alkyl having 1-6 C atoms, wherein 1-7 H atoms may be replaced by F and / or Cl;
• R Ar, R 5 H or A Ar unsubstituted or mono-, di- or trisubstituted by Hal, A and / or OR 5 phenyl,
• A is unbranched or branched alkyl having 1-6 C atoms, in which 1-7 H atoms may be replaced by F and / or Cl,
• Hal is F, Cl 1 is Br or I;
• the compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (eg in the standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart), under reaction conditions which are known and suitable for the reactions mentioned.
• the starting materials may, if desired, also be formed in situ, so that they are not isolated from the reaction mixture, but immediately further reacted to the compounds of formula I.
• hydroxy protecting group is well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or
• hydroxy-protecting groups are not critical, as they depend on the desired chemical Reaction or reaction sequence are removed again; preferred are groups having 1-20, in particular 1-10 C-atoms.
• examples of hydroxy-protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl or silyl protecting groups, with benzyl and tert-butyl being particularly preferred.
• SiIyI is generally trimethyl, triethyl, triisopropyl, tert-butyl-dimethyl or t-butyl-diphenylsilyl, in particular trimethyl or tert-butyl-dimethylsilyl.
• Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1.
• the reaction temperatures for the cleavage are suitably between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
• R 1 denotes a hydroxy-protecting group and R 2 denotes H or methyl
• M is a metal, preferably lithium or magnesium, and X is as defined in claim 1 meaning n at >.
• the reaction is carried out in an inert solvent under standard conditions.
• a metal preferably magnesium, or organometallic, preferably magnesium or lithium organyl.
• Magnesium or lithium organyl are generally methyl, ethyl or Isopropylmagnesiumchlorid, diethyl or Diisopropylmagnesium, n-butyl, sec-butyl or tert-butyllithium, especially isopropyl magnesium chloride or tert-butyllithium.
• M is a metal, preferably Mg or Li, and R has the meaning given in claim 1,
• R is as defined in claim 1 and W is Cl, Br or I,
• Compounds of formula VII are preferably obtainable by intramolecular acylation or alkylation according to standard methods.
• reaction times of the methods described are between a few minutes and 14 days depending on the conditions used, the reaction temperature between about 0 ° and 150 °, usually between 5 ° and 90 °, particularly preferably between 10 ° and 7O 0 C.
• Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as
• Position such as this e.g. occur in formulas III, IX or X, z.
• a catalyst e.g., a noble metal catalyst such as palladium, conveniently on a support such as carbon.
• Suitable solvents are those given above, in particular z.
• alcohols such as methanol or
• Ethanol or amides such as DMF.
• the hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar.
• Hydrogenolysis of the CBZ group succeeds z.
• Position as occur for example in formulas III, IX or X; can continue z. B. by treatment with a trialkylsilane such as triethyl or Triisopropylsilane and an acid such as trifluoroacetic acid or a Lewis acid such as BF 3 -Etherat usually be removed at temperatures between about -40 0C and 100 ° in an inert solvent.
• a trialkylsilane such as triethyl or Triisopropylsilane and an acid such as trifluoroacetic acid or a Lewis acid such as BF 3 -Etherat usually be removed at temperatures between about -40 0C and 100 ° in an inert solvent.
• Compounds of formula II can preferably be obtained by reacting from compounds of formula III the OR 2 group by means of a trialkylsilane such as triethyl or triisopropylsilane and a Lewis acid such as BF ß -etherate in an inert solvent such as methylene chloride at 10 temperatures between - 5O 0 C and 5O 0 C removed.
• a trialkylsilane such as triethyl or triisopropylsilane
• a Lewis acid such as BF ß -etherate
• an inert solvent such as methylene chloride
• Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as ⁇ c trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;
• hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
• chlorinated hydrocarbons such as ⁇ c trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride,
• Glycol ethers such as ethylene glycol monomethyl or monoethyl ether
• Ketones such as acetone or butanone; Amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); Carbon disulphide; 5 carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents.
• Q esters can e.g. be saponified with acetic acid or with NaOH or KOH in water, water-THF, water-dioxane or potassium carbonate in methanol at temperatures between 0 and 100 °
• Silyl ethers may be e.g. with fluoride-containing reagents such as HF in pyridine 5 or tetrabutylammonium fluoride in an inert solvent such as
• Tetrahydrofuran, or with inorganic carbonates such as potassium carbonate be cleaved in an alcohol such as methanol at temperatures between 0 and 100 °.
• the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts derived from various organic and
• Each one of their suitable salts are formed by reacting the compound with a suitable base to the corresponding base addition salt.
• bases include, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali
• alcoholates e.g. Potassium ethanolate and sodium propanolate
• organic bases such as piperidine, diethanolamine and N-methylglutamine.
• acid addition salts can be formed by reacting these compounds with pharmaceutically acceptable organic and inorganic acids, e.g.
• Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding Q salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, Maleate, succinate, citrate, benzoate, salicylate,
• acid addition salts of the compounds of formula I include the following: acetate, adipate, alginate, arginate, aspartate, Benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentaneproprionate, digluconate, dihydrogenphosphate, dinitrobenzoate,
• Preferred among the above salts are ammonium; the alkali metal salts sodium and
• Salts of compounds of formula I 1 derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, eg arginine, betaine, Caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, Iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine,
• Triethanolamine triethylamine, trimethylamine, tripropylamine and tris (Hydroxymethyl) -methylamine (tromethamine), but this is not intended to be limiting.
• Compounds of formula I of the present invention containing basic nitrogen-containing groups can be reacted with agents such as (C 1 -C 4 ) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (C 1 -C 4 ) alkyl sulfates, eg dimethyl, diethyl and diamylsulfate; (Ci 0 -Ci 8 ) alkyl halides, eg decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (Ci-C 4 ) alkyl halides, eg benzyl chloride and phenethyl bromide, quaternize. With such salts, both water-soluble and oil-soluble compounds of the formula I can be prepared.
• agents such as (C 1 -
• Preferred pharmaceutical salts include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate,
• the acid addition salts of basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner.
• the free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
• the free base forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; however, in the context of the invention, the salts otherwise correspond to their respective free base forms.
• the pharmaceutically acceptable base addition salts of the compounds of formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium.
• Preferred organic amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.
• the base addition salts of acidic compounds of formula I are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner.
• the free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
• the free acid forms in some sense differ from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; However, in the context of the invention, the salts otherwise correspond to their respective free acid forms.
• formula I also encompasses multiple salts.
• Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, but this is not intended to be limiting.
• the term "pharmaceutically acceptable salt” in the present context means an active ingredient which contains a compound of the formula I in the form of one of its salts, especially if this salt form is the active ingredient in the Imparts improved pharmacokinetic properties to the free form of the active ingredient or any other salt form of the active ingredient which has previously been used.
• the pharmaceutically acceptable salt form of the active ingredient may also be this It is possible to give the active substance only a desired pharmacokinetic property, which it has not previously possessed, and may even determine the pharmacodynamics of this active ingredient in terms of its therapeutic activity in the
• Compounds of the formula I according to the invention may be chiral due to their molecular structure and may accordingly occur in different enantiomeric forms. They may therefore be in racemic or optically active form.
• the pharmaceutical activity of the racemates or stereoisomers of the compounds of the invention may differ, it may be desirable to use the enantiomers.
• the end product or else the intermediates may already be separated into enantiomeric compounds, chemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.
• diastereomers are formed from the mixture by reaction with an optically active release agent.
• Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
• an optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or others
• Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures such. Hexane / isopropanol /
• the invention furthermore relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of a medicament (pharmaceutical preparation), in particular by a non-chemical route.
• a medicament pharmaceutical preparation
• they can together with at least one solid, liquid and / or semi-liquid carrier or
• Excipient and optionally in combination with one or more other active ingredients in a suitable dosage form.
• the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or pharmaceutically usable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and / or adjuvants.
• compositions may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• a moiety may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the invention, depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose.
• Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient.
• such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.
• compositions may be administered by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways, adapt.
• Such formulations can be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient together with the carrier (s) or excipient (s).
• compositions adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
• the active ingredient component in the case of oral administration in the form of a tablet or capsule, can be mixed with an oral, non-toxic and pharmaceutically acceptable inert carrier, e.g. Ethanol, glycerin, water and the like. combine. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol. A flavor, preservative, dispersant and dye may also be present.
• an oral, non-toxic and pharmaceutically acceptable inert carrier e.g. Ethanol, glycerin, water and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical excipient, e.g. an edible carbohydrate such as starch or mannitol.
• a flavor, preservative, dispersant and dye may also be present.
• Capsules are made by preparing a powder mix as described above and filling shaped gelatin casings therewith.
• Lubricants such as e.g. fumed silica, talc,
• Magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process.
• a disintegrants or solubilizers such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.
• suitable binding, lubricating and disintegrants as well as dyes can also be incorporated into the mixture.
• suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
• the lubricating agents used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• the disintegrating agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the tablets are formulated by, for example, preparing a powder mixture, granulating or dry-pressing, adding a lubricant and a disintegrating agent and pressing the whole into tablets.
• a powder mixture is prepared by dissolving the appropriately comminuted compound with a diluent or a base as described above, and optionally with a binder, e.g. Carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution reducer, such as e.g.
• Paraffin Paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, e.g. Bentonite, kaolin or dicalcium phosphate is mixed.
• the powder mixture can be granulated by mixing it with a binder, e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
• a binder e.g. Syrup, starch paste, Acadia slime or solutions of cellulosic or polymer materials is wetted and pressed through a sieve.
• Granulation can be run through the powder mixture through a tabletting machine, resulting in irregularly shaped lumps, which in
• Granules are broken up.
• the granules can be added by adding of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds.
• the greased mixture is then compressed into tablets.
• the active compounds may also be combined with a free-flowing inert carrier and then compressed directly into tablets without performing the granulation or dry-pressing steps.
• a transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosage units.
• Oral fluids e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compounds.
• Syrups can be prepared by dissolving the compounds in an aqueous solution of suitable taste while removing elixirs
• Suspensions can be formulated by dispersing the compounds in a non-toxic vehicle.
• Solubilizers and emulsifiers e.g. ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, i.a. can also be added.
• the unit dosage formulations for oral administration may optionally be encapsulated in microcapsules.
• the formulation can also be prepared so that the release is prolonged or retarded, such as by coating or embedding particulate material in polymers, wax and others.
• the compounds of the formula I and their salts, tautomers and stereoisomers, as well as the other active compounds can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. 5
• Liposomes can be prepared from various phospholipids, such as e.g.
• Cholesterol, stearylamine or phosphatidylcholines Cholesterol, stearylamine or phosphatidylcholines.
• the compounds of formula I as well as the salts, tautomers and stereoisomers, as well as the other active compounds can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds can also be coupled with soluble polymers as targetable drug carriers ⁇ c.
• Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals.
• the compounds can be attached to a class of biodegradable polymers which are capable of achieving a controlled biodegradability
• compositions adapted for transdermal administration may be presented as discrete patches for prolonged, intimate contact with the epidermis of the recipient.
• Q may be delivered to the drug from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).
• Pharmaceutical compounds 5 adapted for topical administration may be used as ointments, creams, suspensions, lotions, powders, solutions,
• the formulations are preferably applied as a topical ointment or cream.
• the active ingredient can be used with either a paraffinic or water miscible cream base.
• the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.
• eye drops wherein the active ingredient in a suitable carrier, especially an aqueous solvent, is dissolved or suspended 5.
• compositions adapted for topical application in the mouth include lozenges, troches and mouthwashes.
• compositions adapted for rectal administration may be presented in the form of suppositories or enemas.
• compositions adapted for nasal administration in which the vehicle is a solid contain a coarse powder having a particle size, for example in the range of 20-500 microns, which is administered in the manner in which snuff is taken up, ie by rapid inhalation via the nasal passages Q from a container held close to the nose with the powder.
• Suitable formulations for administration as a nasal spray or nasal drops with a liquid carrier include drug solutions in water or oil.
• Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or nebulas containing various types of pressurized dosing dispensers
• Aerosols, nebulizers or insufflators can be generated. 5
• compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
• compositions adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes, by the
• Recipient is included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners.
• the formulations may be administered in single or multiple dose containers, e.g. sealed ampoules and vials, presented
• Injectable solutions and suspensions prepared by formulation may be prepared from sterile powders, granules and tablets.
• formulations in addition to the above-mentioned particularly mentioned ingredients, may include other conventional art-known agents with reference to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.
• a therapeutically effective amount of a compound of formula I and 5 of the other active substance depends on a number of factors, including for example, the age and weight of the animal, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, and is ultimately determined by the attending physician or veterinarian.
• an effective amount of a compound is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day.
• the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same.
• An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound per se.
• the invention further provides the use of compounds of the formula I, in combination with at least one further active pharmaceutical ingredient, preferably for the treatment of type 1 and type 2 diabetes, in particular for lowering blood sugar.
• antidiabetics include insulin and insulin derivatives such as, for example, Lantus ® (see www.lantus.com) or HMR 1964 insulins, fast-acting (see US 6,221, 633), GLP-1 derivatives such as those described in WO 98/08871 of Novo Nordisk A / S, as well as orally active hypoglycemic agents.
• the orally active hypoglycemic agents preferably include sulphonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, e.g.
• the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
• an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.
• the compounds of formula I are administered in combination with a cholesterol resorption inhibitor, e.g.
• Formula I in combination with a PPAR gamma agonist such as rosiglitazone, pioglitazone, JTT-501, Gl 262570 administered.
• a PPAR gamma agonist such as rosiglitazone, pioglitazone, JTT-501, Gl 262570 administered.
• the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for example, GW 9578, GW 7647.
• Formula I in combination with a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, AVE 0897 or as described in WO 00/64888, WO 00/64876, WO 03/20269.
• a mixed PPAR alpha / gamma agonist e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, AVE 0897 or as described in WO 00/64888, WO 00/64876, WO 03/20269.
• the compounds of formula I are used in combination with a filtrate, e.g. Fenofibrate, clofibrate, bezafibrate.
• a filtrate e.g. Fenofibrate, clofibrate, bezafibrate.
• the compounds of formula I are administered in combination with an MTP inhibitor, e.g. Implitapide, BMS-201038, R-103757.
• the compounds of formula I are used in combination with bile acid resorption inhibitor (see, e.g., U.S. 6,245,744 or U.S. 6,221,897), e.g. HMR 1741 administered.
• the compounds of formula I are administered in combination with a CETP inhibitor, e.g. JTT-705.
• a CETP inhibitor e.g. JTT-705.
• the compounds of formula I are used in combination with a polymeric bile acid adsorber, e.g. Cholestyramine, colesevelam.
• a polymeric bile acid adsorber e.g. Cholestyramine, colesevelam.
• Formula I in combination with an LDL receptor inducer see US 6,342,512, such as HMR1171, HMR1586.
• the compounds of the formula I are administered in combination with an ACAT inhibitor, such as avasimibe.
• Formula I in combination with an antioxidant, e.g. OPC-14117 administered.
• the compounds of Formula I are used in combination with a lipoprotein lipase inhibitor, e.g. NO-1886, administered.
• a lipoprotein lipase inhibitor e.g. NO-1886
• the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB- 15 204990.
• the compounds of formula I are administered in combination with a squalene synthetase inhibitor, e.g.
• Lipoprotein (a) antagonist e.g. CI-1027 or nicotinic acid.
• the compounds of formula I are administered in combination with a lipase inhibitor, e.g. Orlistat, 25 administered.
• the compounds of the formula I are administered in combination with insulin.
• a sulphonylurea e.g. Tolbutamide, glibenclamide, glipizide or glimepiride.
• the compounds of Formula I are administered in combination with a biguanide, such as metformin. In another embodiment, the compounds of formula I are administered in combination with a meglitinide, such as repaglinide.
• the compounds of formula I are used in combination with a thiazolidinedione, e.g. Troglitazone, ciglitazone,
• Pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. med. Reddy's Research Foundation disclosed compounds, particularly 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy) phenyl] methyl] -2,4-thiazolidinedione.
• the compounds of formula I are used in combination with an ⁇ -glucosidase inhibitor, e.g. Miglitol or acarbose, administered.
• an ⁇ -glucosidase inhibitor e.g. Miglitol or acarbose
• Combination with an agent which acts on the ATP-dependent potassium channel of the beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• an agent which acts on the ATP-dependent potassium channel of the beta cells e.g. Tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.
• Combination with more than one of the aforementioned compounds e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.
• the compounds of formula I are used in combination with CART modulators (see “cocaine-amphetamine-regulated transcript-influenced energy metabolism, anxiety and gastric emptying in mice" Asakawa, A., et al., M.: Hormones and Metaboly Research (2001), 33 (9), 554-558), NPY antagonists eg naphthalene-1-sulfonic acid ⁇ 4 - [(4-amino-quinazolin-2-ylamino) -methyl] -cyclohexylmethyl ⁇ -amide; hydrochloride (CGP 71683A)), MC4 agonists (eg, 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo) 2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chloro-phen
• H3 agonists (3-cyclohexyl-1- (4,4-dimethyl-1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) -propane 1-one oxalic acid salt (WO 00 /
• TNF agonists TNF agonists
• CRF antagonists eg, [2-methyl-9- (2,4,6-trimethyl-phenyl) -9H-1, 3,9-triaza-fluoren-4-yl] -dipropyl-amine (WO 00/66585)
• CRF BP antagonists eg, urocortin
• urocortin agonists eg, urocortin
• urocortin agonists eg, ⁇ 3 agonists (eg, 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3-dimethyl- 1H-indol-6-yloxy) ethylamino] -ethanol; hydrochloride (WO 01/83451))
• MSH melanocyte-stimulating hormone
• CCK-A agonists eg, ⁇ 2- [4- (4-chloro) 2,5-dimethoxy
• Trifluoroacetic acid salt (WO 99/15525)); Serotonin reuptake inhibitors (e.g., dexfenfluramines), mixed serotonin and noradrenergic compounds (e.g., WO 10 00/71549), 5HT agonists, e.g. 1- (3-ethylbenzofuran-7-yl) -piperazine oxalic acid salt (WO 01/09111), Bombesin
• Agonists galanin antagonists, growth hormone (e.g., human
• growth hormone growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (See eg EP 0 462 884) decoupling protein 2- or 3-modulators, leptin agonists (see eg Lee, Daniel W., Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia.
• Leptin agonists as a Potential approach to the Treatment of obesity, Drugs of the Future (2001), 26 (9), 873-881), DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (eg WO 00/40569), PPAR modulators (eg WO 00/78312), RXR modulators or TR- ⁇ agonists.
• the further active ingredient is leptin; see eg "Perspectives in the Therapeutic Use of Leptin", Salvador, Javier; Gomez Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
• the further active ingredient is dexamphatamine or amphetamine.
• the other active ingredient is fenfluramine or dexfenfluramine.
• the other active ingredient is sibutramine.
• the other active ingredient is orlistat.
• the other active ingredient is mazindol or phentermine.
• Caromax is a carob containing product of the Fa.
• Caromax ® is possible in one preparation or by separate administration of compounds of the formula I and Caromax ®.
• Caromax ® can also be administered in the form of food, such as in baked goods or muesli bars.
• the invention is also a set (kit), consisting of separate
• the kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
• the set may e.g. containing separate ampoules in each of which an effective amount of a compound of formula I and / or its pharmaceutically acceptable salts, tautomers and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.
• the compounds can be tested for their SGLT-inhibitory properties by BHK cells expressing SGLT1 and SGLT2.
• the preparation of the cells and the examination can be carried out as described below.
• the SLC5A1 gene (homologous to NM_000343) from a cDNA library was amplified by standard PCR technology and cloned into the pcDNA3.1 expression vector (Invitrogen) via Nhel / Xhol sites, which neomycin as Selection marker contained.
• transcription uses the human cytomegalovirus enhancer / promoter.
• the final vector KL225 was introduced into cells together with an additional vector containing a dihydrofolate reductase gene as a selection marker.
• Transfection into BHK21 cells (ATCC CCL-10) cultured in DMEM medium (GIBCO / BRL) supplemented with 10% fetal calf serum (FCS) and 20 mM glutamine was done with calcium phosphate transfections according to Graham, F.L. and van der Ebb, AJ. (1973),
• Stable transfectants were selected in medium containing 1 mg / ml G418 (GIBCO / BRL) and 20-5000 nM methotrexate as the final concentration, whereby only cells expressing the neomycin gene and overexpressing the dhfr gene could grow. After 2-3 weeks of growth, the cells were cloned (0.5 cells / well) and the clones were analyzed for SGLT expression in radioactivity uptake assays.
• the SLC5A2 gene (homologous to NM_003041) from a cDNA library was amplified by standard PCR technology and cloned into PCIneo expression vector (Promega), the neomycin, via Nhel / Xhol sites when
• Selection marker contained.
• transcription uses the human cytomegalovirus enhancer / promoter and SV40 polyadenylation signal.
• the final vector KL224 was introduced into cells together with an additional vector containing a dihydrofolate reductase gene as a selection marker.
• AMG 14 C- ⁇ -methyl-D-glucopyranoside
• BHK cells (transfected with SGLT1 or SGLT2) were transfected into
• 96 well microtiter plates (Cultureplates, Perkin Elmer) inoculated. After at least 24 h, the medium was harvested and the cell layer was adjusted to pH with assay buffer (140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 5 mM Tris, 1 M KOH) 7.4 set) washed. After addition of 40 ⁇ l assay buffer 50 ⁇ l AMG (50 ⁇ M for SGLT1 or 2 mM for SGLT2) in the presence or absence of compounds, the cells were incubated in a total volume of 100 ⁇ l at 37 ° C for 90 min. incubated.
• assay buffer 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 5 mM Tris, 1 M KOH
• the supernatant was sucked off and discarded.
• the cells were washed and lysed by addition of 50 ⁇ l of water. After 10 minutes at room temperature, 200 ⁇ l of Micrsoscint 40 (Perkin Elmer) were added. The radioactivity was counted in a Topcount microplate scintillation counter (Perkin Elmer). The unspecific
• “usual workup” means adding water if necessary, adjusting to pH values between 2 and 10, if necessary, depending on the constitution of the final product, extracting with ethyl acetate or dichloromethane, separating, drying organic phase over sodium sulfate, evaporated and purified by chromatography
• Hewlett Packard HP 1100 series system with the following features: ion source: electrospray (positive mode); Scan: 100-1000 m / z; Fragmentation voltage: 60 V; Gas temperature: 300 ° C, DAD: 220 nm.
• reaction solution is warmed to room temperature, stirred for four hours at room temperature and then washed successively with 20 ml of saturated sodium bicarbonate and 20 ml of saturated 5 ter sodium chloride solution. After drying the methylene chloride solution over sodium sulfate and stripping off the solvent, the crude product is purified by column chromatography on silica gel (petroleum ether / ethyl acetate 95: 5).
• Bromphenetol in 35 ml of tetrahydrofuran is added under nitrogen with 4.95 ml (15% solution in n-hexane) of n-butyllithium and stirred at -78 0 C for one hour. Then a solution of 1.4 g (6.6 mmol) is added dropwise.
• Example A Injection glasses
• a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 2 l of bidistilled water with 2N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and closed under sterile conditions. Each injection jar contains 5 mg of active ingredient.
• a mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.
• a solution of 1 g of an active compound of the formula I, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzalkonium chloride in 940 is prepared ml of double distilled water. Adjust to pH 6.8, make up to 1 liter and sterilize by irradiation. This solution can be used in the form of eye drops.
• a mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is in the usual
• Tablets are pressed analogously to Example E, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dye.
• a solution of 1 kg of active compound of the formula I in 60 l of bidistilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

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