Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention is concerned with the use of glycine transport inhibiting 4,4-b ⁇ s- (4-fluorophenyl)butyl]-l-(p ⁇ peraz ⁇ nyl and pipe ⁇ dinyl) de ⁇ vatives for the preparation of medicaments for treating disorders of the central and peripheral nervous system, m particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like
• the invention further comp ⁇ ses novel compounds, their preparation and their pharmaceutical forms
• the present invention is concerned with the use of glycine transport inhibiting compounds for the preparation of medicaments for treating disorders of the central and pe ⁇ pheral nervous system, said compounds having the formula
• n is 0 or 1
• m is 0 or 1
• Alk represents Ci 6 alkaned ⁇ yl
• A represents N or CH
• B 1 represents CH 2 or NH
• R represents Ci alkyl optionally substituted with Cj 4 alkyloxy, py ⁇ dmyl, aryl, arylcarbonyl, thienyl, furanyl, ⁇ m ⁇ dazo[l,2-a]py ⁇ d ⁇ nyl, thiazolyl, R 2 represents hydrogen or aryl,
• R 3 represents hydrogen, C ⁇ 6 alkyl or C 3 7 cycloalkyl
• R represents thienyl, furanyl, arylamino or a radical of formula
• R 5 is hydrogen or aryl
• aryl represents phenyl optionally substituted with 1 or 2 substituents selected from Ci 4 alkyl, halo, hydroxy, C] 4 alkyloxy
• the present invention also relates to a method of treating warm-blooded animals suffe ⁇ ng from disorders of the central and pe ⁇ pheral nervous system, in particular psychoses, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like
• Said method comprises the administration of a therapeutically effective amount of a compound of formula (I) or a N-oxide form, a pharmaceutically acceptable acid or base addition salt or a stereochemically isome ⁇ c form thereof in admixture with a pharmaceutical earner.
• halo is generic to fluoro, chloro, bromo and lodo
• C3-7cycloalkyl is gene ⁇ c to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl
• Ci-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like;
• Ci-6alkyl is meant to include C ⁇ _4alkyl and the higher homologues thereof having 5 or
• C ⁇ _6alkaned ⁇ yl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 2,3-butanediyl and the like.
• the pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base and acid addition salt forms which the compounds of formula (I) are able to form.
• the acid addition salt form of a compound of formula (I) that occurs in its free form as a base can be obtained by treating said free base form with an appropriate acid such as an inorganic acid, for example, hydrohalic acid, e.g.
• an organic acid such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic,
• the compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic base, i.e. metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases.
• Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
• salt forms can be converted into the free forms by treatment with an appropriate base or acid.
• addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form.
• solvates are for example hydrates, alcoholates and the like.
• N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
• stereochemically isomeric forms as used hereinbefore and hereinafter defines all the possible stereoisomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. Stereochemically isomeric forms of the compounds of formula (I) and mixtures of such forms are obviously intended to be encompassed by formula (I).
• the compounds of formula (I) and some of the intermediates hereinafter have at least one stereogenic center in their structure.
• This stereogenic center may be present in a R and a S configuration, said R and S notation is used in correspondance with the rules described in Pure Appl. Chem., 1976, 45, 11-30.
• L is a radical of formula (a) wherein B 1 is -CH 2 - and R 1 is pyridin-2- ylmethyl, thien-2-ylmethyl, furan-2-ylmethyl, benzyl or 4-fluorobenzyl, then
• the present invention also relates to the novel compounds of formula (I) as defined hereinabove for use as a medicine.
• An interesting group of compounds are those compounds of formula (I) wherein n is 0, m is 1; R 1 is C )-4 alkyl optionally substituted with C ⁇ -4 alkyloxy, arylcarbonyl or imidazo[l,2-a]pyridinyl and R 4 is thienyl, furanyl or a radical of formula (d-1).
• Preferred compounds are the compounds of formula (I) wherein L is a radical of formula (a) or (b).
• the compounds of formula (I) can be prepared according to reaction procedures described in EP-A-0, 151,826 and GB-1,055,100, more in particular, by i reacting an intermediate of formula (II) wherein W is an approp ⁇ ate leaving group such as, for example, a halogen, with an intermediate of formula (III)
• reaction-inert solvent such as, for example, methyhsobutyl keton, N,N-d ⁇ methylacetam ⁇ de or NN-dirnethylformamide
• a suitable base such as, for example, sodium carbonate, sodium bicarbonate or t ⁇ ethylamine, and optionally in the presence of potassium iodide
• reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, t ⁇ turation and chromatography
• the compounds of formula (I) can be prepared by reductive alkylation An intermediate of formula (IV) is then reacted with an intermediate of formula (III) m a reaction-inert solvent such as, for example, methanol, in the presence of a reducing agent such as, for example, hydrogen in the presence of a suitable catalyst, e.g palladium on activated charcoal, Conveniently, thiophene is added to the reaction mixture
• the compounds of formula (I) wherein X is ⁇ may be prepared by reacting an intermediate of formula (V) with an intermediate of formula (VI) wherein W 1 is a suitable leaving group such as for example, a halogen
• Said reaction may be performed in a reaction-inert solvent such as, for example, methylisobutyl keton, N,N-dimethylacetamide or N,N-dimethylformamide, in the presence of a suitable base such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and optionally in the presence of potassium iodide.
• a reaction-inert solvent such as, for example, methylisobutyl keton, N,N-dimethylacetamide or N,N-dimethylformamide
• a suitable base such as, for example, sodium carbonate, sodium bicarbonate or triethylamine, and optionally in the presence of potassium iodide.
• the compounds of formula (I) wherein L is a radical of formula (b), said compounds being represented by formula (I-b), may be prepared by reacting an intermediate of formula (VII) with an isocyanato derivative of formula (VIII).
• Said reaction may be performed in a reaction-inert solvent such as, for example, diisopropylether.
• the compounds of formula (I) can also be converted into each other followin ⁇ g art- known procedures of functional group transformation.
• the compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form.
• Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide.
• Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g.
• organic peroxides may comp ⁇ se peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxo ⁇ c acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide.
• Suitable solvents are, for example, water, lower alkanols, e g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents
• Some of the compounds of formula (I) and some of the intermediates in the present m- vention may contain an asymmetric carbon atom. Pure stereochemically isome ⁇ c forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e g.
• Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereome ⁇ c salts or compounds; then physically separating said mixtures of diastereome ⁇ c salts or compounds by, for example, selective crystallization or chromatographic techniques, e g. liquid chromatography and the like methods; and finally converting said separated diastereome ⁇ c salts or compounds into the corresponding enantiomers
• Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isome ⁇ c forms of the approp ⁇ ate intermediates and starting mate ⁇ als, provided that the intervening reactions occur stereospecifically.
• An alternative manner of separating the enantiome ⁇ c forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
• Glycine is an a ino acid neurotransmitter in the central and pe ⁇ pheral nervous system, both at inhibitory and excitatory synapses. These distinct functions of glycine are mediated by two types of receptor, each of which is associated with a different class of glycine transporter.
• glycine receptors that are sensitive to the convulsant alkaloid strychnine, and are therefore referred to as 'strychnine-sensitive.
• Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brainstem Glycine functions in excitatory transmission by modulating the actions of glutamate, the major excitatory neurotransmitter in the nervous system (Johnson and Ascher, Nature, 325, 529-531 (1987); Fletcher et al., Glvcme Transmission. (Otterson and Storm-Mathisen, eds., 1990), pp. 193-219).
• glycine is an obligatory co- agonist at the class of glutamate receptor termed N-methyl-D-aspartate (NMD A) receptor
• NMD A N-methyl-D-aspartate receptor
• NMDA receptors are widely dist ⁇ aded throughout the brain, with a particularly high density in the cerebral cortex and hippocampal formation
• Transporters take up neurotransmitter from the synapse, thereby regulating the concentration and term of neurotransmitter in the synapse, which together determine the magnitude of synaptic transmission
• transporters maintain the fidelity of synaptic transmission.
• transporters allow for transmitter reutihzation Neurotransmitter transport is dependent on extracellular sodium and the voltage difference across the membrane
• transporters can function in reverse, releasing neurotransmitter in a calciumindependent non-exocytotic manner (Attwell et al , Neuron, JU_, 401-407 (1993)) Modulation of neurotransmitter transporters thus provides a means for modifying synaptic activity, which provides useful therapy for the treatment of disturbances of the central and pe ⁇ pheral nervous system.
• GlyT-1 is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al , Neuron. 8, 927-935 (1992)).
• GlyT-la is found predominantly in the forebrain, and its distribution corresponds to that of glutamatergic pathways and NMDA receptors (Smith, et al , Neuron. 8, 927-935 (1992)).
• At least three splice va ⁇ ants of GlyT-1 are known, namely GlyT-la, GlyT-lb and GlyT-lc (Kim, et al., Molecular Pharmacology. 45, 608- 617 (1994)), each of which displays a unique distribution m the brain and pe ⁇ pheral tissues.
• GlyT-2 in contrast, is found predominantly in the brainstem and spinal cord, and its distribution corresponds closely to that of strychnine-sensitive glycine receptors (Liu et al , J Biological Chemistry. . 268, 22802-22808 (1993); Jursky and Nelson, Neurochemistrv. 64, 10261033 (1995))
• strychnine-sensitive glycine receptors Liu et al , J Biological Chemistry. . 268, 22802-22808 (1993); Jursky and Nelson, Neurochemistrv. 64, 10261033 (1995)
• GlyT-2 could be used to diminish the activity of neurons having strychnine-sensitive glycine receptors via increasing synaptic levels of glycine, and so diminish the transmission of pain-related (i.e., nociceptive) information in the spinal cord, which has been shown to be mediated by these receptors.
• enhancing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to decrease muscle hyperactivity, which is useful in treating diseases or conditions associated with increased muscle contraction, such as spasticity, myoclonus, and epilepsy (Truong et al., Movement Disorders. 3 , 77-87 (1988); Becker, FASEB J, 4 2767-2774 (1990)).
• Spasticity that can be treated via modulation of glycine receptors is associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of illness and injury of the nervous system.
• NMDA receptors are involved in memory and learning (Rison and Stanton, Neurosci. Biobehav. Rev.. 19, 533 552 (1995); Danysz at al., Behavioral Pharmacol., 6, 455-474 (1995)); and decreased function of NMDA-mediated neurotransmission appears to contribute to the symptoms of schizophrenia (Olney and Farber, Archives General Psychiatry. 52, 998-1007 (1996).
• agents that inhibit GlyT-1 and thereby increase glycine activation of NMDA receptors can be used as novel antipsychotics and anti -dementia agents, and to treat other diseases in which cognitive processes are impaired, such as attention deficit disorders and organic brain syndromes.
• NMDA receptors have been implicated in a number of disease states, in particular the neuronal death associated with stroke, head trauma and possibly neurodegenerative diseases, such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs.
• neurodegenerative diseases such as Alzheimer's disease, multi-infarct dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis or other conditions in which neuronal cell death occurs.
• Coyle & Puttfarcken Science, 262, 689-695 (1993); Lipton and Rosenberg, New Engl. J. of Medicine, 330. 613-622 (1993); Choi, Neuron I, 623-634 (1988).
• pharmacological agents that increase the activity of GlyT-1 will result in decreased glycine-activation of NMDA receptors, which activity can be used to treat these and related disease states.
• drugs that directly block the glycine site on the NMDA receptors can be used to treat these and related disease states.
• the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a novel compound of formula (I).
• a pharmaceutically acceptable carrier which may take a wide variety of forms depending on the form of preparation desired for administration.
• These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection.
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
• Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
• Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action.
• Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils.
• Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
• These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
• Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
• dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
• Example A 2 A mixture of 4-fluoro- ⁇ -(4-fluorophenyl)benzenebutanal (2.6 g), l-(4-fluorophenyl)-3- [2-(4-p ⁇ pe ⁇ d ⁇ nylmethyl)-lH-benz ⁇ m ⁇ dazol-l-yl]-l-propanone d ⁇ hydrobrom ⁇ de monohydrate (5 5 g), a solution of thiophene in ethanol 3% (1 g), potassium acetate (3 g) and methanol (200 ml) was hydrogenated at normal pressure and at 50°C with palladium-on-charcoal catalyst 10% (2 g).
• Example A.3 A mixture of l-[4,4-b ⁇ s(4-fluorophenyl]butyl]-p ⁇ peraz ⁇ ne (6 9 g), 4-chloro-l-(2-th ⁇ enyl)- butanone (4,1 g), sodium carbonate (3 18 g), a few crystals of potassium iodide in 4-methyl-2-pentanone (200 ml) was refluxed for 24 hours Then a second portion of 4-chloro-l-(2-th ⁇ enyl)butanone (4 1 g) was added and the whole was stirred and refluxed for an additional 36 hours After cooling, water was added (100 ml) The organic layer was separated, d ⁇ ed over potassium carbonate, filtered and evaporated The oily residue was dissolved in anhydrous ether (480 ml) The solution was filtered and gaseous hydrogen chlo ⁇ de was introduced into the filtrate The precipitated salt was filtered off and crystallized from 2-propanol (320 m
• Subconfluent HEK 293 -GlyTl cells i.e. a cell line which stably expresses human glycine transporter 1
• DMEM medium Dulbecco's Modified Eagle Medium supplemented with 10% foetal bovine serum, 1 mM Na-pyruvate, 2 mM glutamine, 100 U penicillin/ml and 0.1 mg/ml streptomycin.
• the cells were incubated for 48 hours at 37°C, 5% CO 2 , 95% humidity.
• the cells were washed using a Tecan PW96 microprocessor controlled washer designed to wash all 96 wells of a microplate simultaneously with uptake buffer (25 mM Hepes, 5.4 mM K-gluconate, 1.8 mM Ca-gluconate, 0.8 mM MgSO , 140 mM NaCl, 5 mM glucose, 5 mM alanine, adjusted to pH 7.5 with 2M Tris).
• the Tecan PW96 was programmed to wash the cells five times leaving 75 ⁇ l in each well.
• the test compounds were dissolved at different concentrations in the micromolar range in DMSO. 1 ⁇ l Test solution was added to each well and the cells were incubated for 5' to 10' at ambient temperature.
• Comp. 15 being 2-[[l-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-(2- pyridinylmethyl)-3H-imidazo[4,5-b]pyridine ethanedioate (1:2);
• comp. 16 being 2-[[l-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]methyl]-3-[(4-fluor- phenyl)methyl]-3H-imidazo[4,5-b]pyridine ethanedioate (1:2); comp.
• compositions suitable for systemic administration to animal and human subjects in accordance with the present invention exemplify typical pharmaceutical compositions suitable for systemic administration to animal and human subjects in accordance with the present invention.
• Active ingredient as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.
• Example C.l film-coated tablets
• Preparation of tablet core A mixture of 100 g of the A.I., 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.

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