Patent Grant
7550455
The present invention relates to novel substituted xanthines of the general formula
their tautomers, their enantiomers, their diastereomers, their mixtures, their prodrugs and their salts, in particular their physiologically tolerable salts with inorganic or organic acids, which have valuable pharmacological properties, in particular an inhibitory action on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), their preparation, their use for the prevention or treatment of illnesses or conditions which are connected with increased DPP-IV activity or can be prevented or alleviated by reduction of the DPP-IV activity, in particular of diabetes mellitus type I or type II, the medicaments comprising a compound of the general formula (I) or a physiologically tolerable salt thereof, and processes for their preparation.
Xanthines having a DPP-IV-inhibiting action are already known from WO 02/02560, WO 03/004496, WO 03/024965, EP 1 338 595 and WO 02/68420. These, however, differ markedly structurally from the compound according to the invention, in particular with respect to the substituents in position 7 and/or 8, or with respect to the group in the 1-position and the combination of groups in position 1 and 8.
In the above formula 1
Prodrugs are understood as meaning derivatives which are converted in vivo into the actually active compound. In the compounds according to the invention, the NH group of the piperazino or -[1,4]diazepan-1-yl group can in particular be substituted by a group which is cleavable in vivo. Groups of this type are described, for example, in WO 98/46576 and by N. M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
A group which can be cleaved in vivo by an imino or amino group is to be understood as meaning, for example, a hydroxyl group, an acyl group such as a phenylcarbonyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl groups or C1-3-alkyloxy groups, where the substituents can be identical or different, a pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichlorpropionyl or allyloxycarbonyl group, a C1-16-alkyloxycarbonyl or C1-16-alkylcarbonyloxy group, in which hydrogen atoms can be completely or partly replaced by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert-butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C1-6-alkyloxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-aminopropionyl group, in which the amino group can be mono- or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and the substituents can be identical or different, a C1-3-alkylsulfonyl-C2-4-alkyloxycarbonyl, C1-3-alkyloxy-C2-4-alkyloxy-C2-4-alkyloxycarbonyl, Rp—CO—O—(RqCRr)—O—CO, C1-6-alkyl-CO—NH—(RsCRt)—O—CO or C1-6-alkyl-CO—O—(RsCRt)—(RsCRt)—O—CO group, in which
Preferred compounds of the general formula I are those in which
Particularly preferred compounds of the general formula I are those in which
Very particularly preferred compounds are those in which
Those compounds of the general formula I form a preferred subgroup in which
Those compounds of the general formula I form a second subgroup in which
In particular, the following compounds may be mentioned:
According to the invention, the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
a) Reaction of a Compound of the Formula
in which
The reaction is expediently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulphoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulpholane optionally in the presence of an inorganic or tertiary organic base, e.g. sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base, e.g. triethylamine, or in the presence of N-ethyldiisopropylamine (Hüinig's base), where these organic bases can simultaneously also serve as solvents, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a catalyst based on palladium at temperatures between −20 and 180° C., but preferably at temperatures between −10 and 120° C. The reaction, however, can also be carried out without solvent or in an excess of piperazine or [1,4]diazepane.
b) Deprotection of a Compound of the Formula
in which R1, R2 and R3 are defined as mentioned at the outset.
The cleavage of the tert-butyloxycarbonyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80° C.
In the reactions described above, reactive groups optionally present such as amino, alkylamino or imino groups can be protected during the reaction by customary protective groups, which are cleaved again after the reaction.
For example, possible protective groups for an amino, alkylamino or imino group are the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group.
The optionally subsequent cleavage of a used protective group is carried out, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120° C., preferably at temperatures between 10 and 100° C.
The cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl group, however, is carried out, for example, hydrogenolytically, e.g. using hydrogen in the presence of a catalyst such as palladium/carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid optionally with addition of an acid such as hydrochloric acid at temperatures between 0 and 100° C., but preferably at room temperatures between 20 and 60° C., and at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar. The cleavage of a 2,4-dimethoxybenzyl group, however, is preferably carried out in trifluoroacetic acid in the presence of anisole.
The cleavage of a tert-butyl or tert-butyloxycarbonyl group is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
The cleavage of a trifluoroacetyl group is preferably carried out by treatment with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50° C.
The cleavage of a phthalyl group is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50° C.
Furthermore, the compounds of the general formula I obtained can be separated, as has been already mentioned at the outset, into their enantiomers and/or diastereomers. For example, cis/trans mixtures can thus be separated into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.
For example, the cis/trans mixtures thus obtained can be separated by chromatography into their cis and trans isomers, the compounds of the general formula I obtained, which occur as racemates, can be separated by methods known per se (see Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of the general formula I having at least 2 asymmetric carbon atoms can be separated on the basis of their physicochemical differences according to methods known per se, e.g. by chromatography and/or fractional crystallization, into their diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
The separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallizing from an optically active solvent or by reacting with an optically active substance, in particular acids and their activated derivatives or alcohols, forming salts or derivatives such as, for example, esters or amides, with the racemic compound and separating the diastereomeric salt mixture or derivative obtained in this way, e.g. on the basis of different solubilities, it being possible to liberate the free antipodes from the pure diastereomeric salts or derivatives by the action of suitable agents. Particularly common, optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyltartaric acid, di-O-p-toluoyl-tartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. A possible optically active alcohol is, for example, (+)- or (−)-menthol and an optically active acyl group in amides is, for example, (+)- or (−)-menthyloxycarbonyl.
In addition, the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical administration into their physiologically tolerable salts with inorganic or organic acids. Possible acids for this are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds of the general formulae II and III used as starting substances are either known from the literature or they are obtained by processes known per se from the literature (see Examples I to IV).
As already mentioned at the outset, the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the enzyme DPP-IV.
The biological properties of the novel compounds were tested as follows:
The ability of the substances and their corresponding salts to inhibit DPP-IV activity can be shown in a test set-up in which an extract of the human colon carcinoma cell line Caco-2 is utilized as the DPP-IV source. The differentiation of the cells, in order to induce the DPP-IV expression, was carried out according to the description of Reiher et al. in an article having the title “Increased expression of intestinal cell line Caco-2”, which appeared in Proc. Natl. Acad. Sci. Vol. 90, pages 5757-5761 (1993),. The cell extract was obtained from the cells solubilized in a buffer (10 mM tris HCl, 0.15 M NaCl, 0.04 t.i.u. aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35000 g for 30 minutes at 4° C. (for the removal of cell debris).
The DPP-IV assay was carried out as follows:
50 μl of substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μM, were introduced into black microtitre plates. 20 μl of assay buffer (final concentrations 50 mM tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) were pipetted in. The reaction was started by addition of 30 μl of solubilized Caco-2 protein (final concentration 0.14 μg of protein per well). The test substances to be investigated were typically added prediluted in 20 μl, the assay buffer volumes then being correspondingly reduced. The reaction was carried out at room temperature; the incubation period was 60 minutes. The fluorescence was then measured in a Victor 1420 multilabel counter, the excitation wavelength being at 405 nm and the emission wavelength at 535 nm. Blank values (corresponding to 0% activity) were obtained in batches without Caco-2 protein (volumes replaced by assay buffer), control values (corresponding to 100% activity) were obtained in batches without addition of substance. The potencies of the respective test substances, expressed as IC50 values, were calculated from dose-response curves, which consisted of 11 measurement points in each case. The following results were obtained thereby:
With respect to the ability to inhibit the DPP-IV activity, the compounds of the general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or illnesses which can be influenced by an inhibition of the DPP-IV activity. It is therefore to be expected that the compounds according to the invention are suitable for the prevention of illnesses or conditions such as diabetes mellitus type 1 and type 2, prediabetes, reduction of the glucose tolerance or changes in the fasting blood sugar, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycaemia, insulin resistance, metabolic syndrome, dyslipidaemias of all sorts of origin, arthritis, atherosclerosis and related diseases, adiposity, allograft transplantation and osteoporosis caused by calcitonin. Moreover, these substances are suitable for preventing B cell degeneration such as, for example, apoptosis or necrosis of pancreatic B cells. The substances are further suitable for improving or restoring the functionality of pancreatic cells, in addition for increasing the number and size of pancreatic B cells. Additionally and justified by the role of the glucagon-like peptides, such as, for example, GLP-1 and GLP-2 and their link with DPP-IV Inhibition, it is expected that the compounds according to the invention are suitable, inter alia, for achieving a sedating or anxiolytic effect, moreover of favourably influencing catabolic conditions after operations or hormonal stress responses or of being able to reduce the mortality and morbidity after myocardial infarct. Moreover, they are suitable for the treatment of all conditions which are connected with the abovementioned effects and are mediated by GLP-1 or GLP-2. The compounds according to the invention can likewise be employed as diuretics or antihypertensives and are suitable for the prevention and treatment of acute kidney failure. Furthermore, the compounds according to the invention can be employed for the treatment of inflammatory diseases of the airways. Likewise, they are suitable for the prevention and therapy of chronic inflammatory bowel diseases such as, for example, irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as in pancreatitis. In addition, it is expected that they can be employed in any type of injury or disturbance in the gastrointestinal tract and, for example, in cases of colitis and enteritis. Moreover, it is expected that DPP-IV inhibitors and thus also the compounds according to the invention can be used for the treatment of infertility or for the improvement of fertility in man or in the mammalian body, in particular if the infertility is connected with insulin resistance or with polycystic ovarian syndrome. On the other hand, these substances are suitable for influencing the motility of the sperm and and can thus be employed as contraceptives for use in man. Moreover, the substances are suitable for influencing growth hormone deficiency states, which are accompanied by low growth, and can be usefully employed in all indications in which growth hormone can be used. On account of their inhibitory action against DPP IV, the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, cases of thyroiditis and Basedow's disease etc. Moreover, they can be employed in viral diseases and, for example, in HIV infections, for the stimulation of haematopoiesis, in benign prostate hyperplasia, in cases of gingivitis, and for the treatment of neuronal defects and neurodegenerative diseases such as, for example, Alzheimer's disease. Compounds described are likewise to be used for the therapy of tumours, in particular for modifying tumour invasion and formation of metastases; examples here are use in T cell lymphomas, acute lymphoblastic leukaemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas. Further indications are stroke, cases of ischaemia of all sorts of origin, Parkinson's disease and migraine. Moreover, further indication areas are cases of follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, cases of encephalomyelitis, cases of glomerulonephritis, cases of lipodystrophy, and psychosomatic, depressive and neuropsychiatric diseases of all sorts of origin.
The compounds according to the invention can also be used in combination with other active compounds. The therapeutics suitable for such a combination include, for example, antidiabetics, such as, for example, metformin, sulphonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR gamma agonists (e.g. GI 262570) and antagonists, PPAR gamma/alpha modulators (e.g. KRP 297), PPAR gamma/alpha/delta modulators, AMPK activators, ACC1 and ACC2 inhibitors, DGAT inhibitors, SMT3 receptor agonists, 11β-HSD inhibitors, FGF19 agonists or mimetics, alpha-glucosidase inhibitors (e.g. acarbose, voglibose), other DPPIV inhibitors, alpha2 antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. In addition, SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as, for example, inhibitors of glucose 6-phosphatase, or of fructose 1,6-bisphosphatase, of glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, of glycogen synthase kinase or of pyruvate dehydrokinase, hypolipidaemics, such as, for example, HMG-CoA reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR alpha agonists, PPAR delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, colestyramine, inhibitors of ileal bile acid transport, HDL-increasing compounds such as, for example, inhibitors of CETP or regulators of ABC1 or LXRalpha antagonists, LXRbeta agonists or LXRalpha/beta regulators or active compounds for the treatment of obesity, such as, for example, sibutramine or tetrahydrolipstatin, dexfenfluramine, axokine, antagonists of the cannbinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.
In addition, a combination with medicaments for influencing high blood pressure such as, for example, All antagonists or ACE inhibitors, diuretics, β-blockers, Ca antagonists and others or combinations thereof is suitable.
The dose necessary to achieve an appropriate action is expediently, in the case of intravenous administration, 1 to 100 mg, preferably 1 to 30 mg, and in the case of oral administration 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4× daily. For this purpose, the compounds of the formula I prepared according to the invention, if appropriate in combination with other active substances, can be incorporated together with one or more inert customary vehicles and/or diluents, e.g. maize starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fat-containing substances such as hard fat or their suitable mixtures, in customary galenical preparations such as tablets, coated tablets, capsules, powders, suspensions or suppositories.
The following examples are intended to illustrate the invention in greater detail:
Preparation of the starting compounds:
A mixture of 28.91 g of 3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine, 20.00 g of 2-chloromethyl-4-methylquinazoline and 27.74 g of potassium carbonate in 235 ml of N-methylpyrrolidone is warmed to 75° C. and stirred at this temperature for six hours. Subsequently, the reaction mixture is slowly treated with 235 ml of water, a pale precipitate depositing. The suspension is cooled in an ice bath. The precipitate is filtered off with suction, washed with water and a little petroleum ether and dried at 50° C. in a circulating air drying oven.
Yield: 40.8 g (93% of theory) Mass spectrum (ESI+): m/z=453, 455 [M+H]+
The following compounds are obtained analogously to Example I:
Rf: 0.40 (silica gel, ethyl acetate/petroleum ether=1:1) Mass spectrum (ESI+): m/z=452, 454 [M+H]+
Rf: 0.50 (silica gel, cyclohexane/ethyl acetate=3:1) Mass spectrum (ESI+): m/z=488, 490 [M+H]+
Rf: 0.83 (silica gel, ethyl acetate/petroleum ether=4:1) Mass spectrum (ESI+): m/z=515, 517 [M+H]+
Rf: 0.50 (silica gel, ethyl acetate/petroleum ether=4:1) Mass spectrum (ESI+): m/z=467, 469 [M+H]+
Rf: 0.80 (silica gel, ethyl acetate/petroleum ether=4:1) Mass spectrum (ESI+): m/z=463, 465 [M+H]+
Rf: 0.75 (silica gel, ethyl acetate/petroleum ether=4:1) Mass spectrum (ESI+): m/z=463, 465 [M+H]+
Rf: 0.39 (silica gel, ethyl acetate) Mass spectrum (ESI+): m/z=439, 441 [M+H]+
A mixture of 40.00 g of 3-methyl-8-bromoxanthine, 36 ml of diisopropylethylamine and 23.00 g of 1-bromo-2-butyne in 500 ml of N,N-dimethylformamide is stirred at room temperature for three hours. 1 ml of 1-bromo-2-butyne is then added again and the mixture is stirred at room temperature for a further hour until the reaction is complete. For work-up, the reaction mixture is diluted with 400 ml of water. The resulting precipitate is filtered off with suction, washed with water, cold methanol and diethyl ether and dried.
Yield: 41.60 g (86% of theory) Mass spectrum (ESI+): m/z=297, 299 [M+H]+
Prepared by treatment of 2.95 g of 2-chloromethyl-4-methylquinazoline 3-oxide with 6 ml of phosphorus trichloride in 150 ml of chloroform under reflux.
Yield: 1.75 g (57% of theory) Rf: 0.81 (silica gel, methylene chloride/methanol=95:5) Mass spectrum (ESI+): m/z=193, 195 [M+H]+
Prepared by treatment of 2.40 g of 1-methyl-4-cyanoisoquinoline with 2.60 g of N-bromosuccinimide in the presence of 100 mg of azobisisobutyronitrile in carbon tetrachloride under reflux.
Yield: 704 mg (20% of theory) Rf: 0.58 (silica gel, methylene chloride) Mass spectrum (ESI+): m/z=247, 249 [M+H]+
The following compounds are obtained analogously to Example IV:
Rf: 0.62 (silica gel, methylene chloride)
Mass spectrum (ESI+): m/z=223, 225 [M+H]+Rf: 0.65 (silica gel, methylene chloride)
Preparation of the final compounds:
A mixture of 300 mg of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine and 290 mg of piperazine in 5 ml of N,N-dimethylformamide is heated at 200° C. for 5 min in a microwave oven. After cooling to room temperature, the reaction mixture is treated with water and saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The solid flask residue is triturated with diethyl ether, filtered off with suction and dried at 45° C. in a circulating air drying oven.
Yield: 200 mg (66% of theory) Melting point: 213-215° C. Mass spectrum (ESI+): m/z=459 [M+H]+
The following compounds are obtained analogously to Example 1:
Rf: 0.50 (reversed phase TLC ready-to-use plates (E. Merck), acetonitrile/water/trifluoroacetic acid=50:50:1) Mass spectrum (ESI+): m/z=458 [M+H]+
Melting point: 129-13 1° C. Mass spectrum (ESI+): m/z=472 [M+H]+
Melting point: 188-190° C. Mass spectrum (ESI+): m/z=473 [M+H]+
Rf: 0.50 (reversed phase TLC ready-to-use plate (E. Merck), acetonitrile/water/trifluoroacetic acid=50:50:1) Mass spectrum (ESI+): m/z=494 [M+H]+
Melting point: 223-225° C. Mass spectrum (ESI+): m/z=508 [M+H]+
Rf: 0.49 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1) Mass spectrum (ESI+): m/z=521 [M+H]+
Rf: 0.38 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1) Mass spectrum (ESI+): m/z=473 [M+H]+
Rf: 0.39 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90: 10:1) Mass spectrum (ESI+): m/z=469 [M+H]+
Rf: 0.34 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1) Mass spectrum (ESI+): m/z=469 [M+H]+
Rf: 0.46 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1) Mass spectrum (ESI+): m/z=445 [M+H]+
The following compounds can also be obtained analogously to the above examples and other processes known from the literature:
Coated Tablets Containing 75 mg of Active Substance
Preparation:
The active substance is mixed with calcium phosphate, maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the stated amount of magnesium stearate. Pressings having a diameter of about 13 mm are prepared on a tabletting machine; these are grated through a sieve having a mesh width of 1.5 mm on a suitable machine and blended with the remaining amount of magnesium stearate. These granules are pressed on a tabletting machine to give tablets having the desired shape.
The coated tablet cores thus prepared are coated with a film which consists essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are glazed with beeswax. Coated tablet weight: 245 mg.
Tablets Containing 100 mg of Active Substance
Composition:
Preparation Process:
Active compound, lactose and starch are mixed and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh width) and drying in a tray drying oven at 50° C., the mixture is sieved again (1.5 mm mesh width) and the lubricant is admixed. The press-ready mixture is compressed to give tablets.
Tablets Containing 150 mg of Active Substance
Composition:
Preparation:
The active substance mixed with lactose, maize starch and silicic acid is moistened with a 20% strength aqueous polyvinylpyrrolidone solution and pounded through a sieve having a mesh width of 1.5 mm.
The granules dried at 45° C. are again grated through the same sieve and mixed with the stated amount of magnesium stearate. Tablets are pressed from the mixture.
Hard Gelatine Capsules Containing 150 mg of Active Substance
Preparation:
The active compound is blended with the excipients, passed through a sieve of mesh width 0.75 mm and homogeneously mixed in a suitable apparatus.
The final mixture is filled into hard gelatine capsules of size 1.
Suppositories Containing 150 mg of Active Substance
1 Suppository Contains:
Preparation:
After melting the suppository mass, the active compound is homogeneously dispersed therein and the melt is poured into precooled moulds.
Suspension Containing 50 mg of Active Substance
100 ml of Suspension Contain:
Preparation:
Dist. water is heated to 70° C. Methyl and propyl p-hydroxybenzoate and also glycerol and carboxymethylcellulose sodium salt are dissolved therein with stirring. The mixture is cooled to room temperature and the active compound is added and homogeneously dispersed with stirring. After adding and dissolving the sugar, the sorbitol solution and the flavouring, the suspension is evacuated with stirring for deaeration. 5 ml of suspension contain 50 mg of active compound.
Ampoules Containing 10 mg of Active Substance
Composition:
Preparation:
The active substance is dissolved in the required amount of 0.01 N HCl, rendered isotonic using sodium chloride, sterile-filtered and filled into 2 ml ampoules.
Ampoules Containing 50 mg of Active Substance
Composition:
Preparation:
The active substance is dissolved in the required amount of 0.01 N HCl, rendered isotonic using sodium chloride, sterile-filtered and filled into 10 ml ampoules.
| Number | Date | Country | Kind |
|---|---|---|---|
| 103 55 304 | Nov 2003 | DE | national |
Benefit of U.S. Provisional Application Ser. No. 60/530,560, filed on Dec. 18, 2003, is hereby claimed, and which application is incorporated herein in its entirety.
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