Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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

• a dimerization of the receptor is induced, and the kinase domain is activated by a cascade of tyrosine autophosphorylation steps in the juxtamembrane region (Y1003), the activation loop of the kinase (Y1234 and Y1235) and the carboxy-terminal domain (Y1349 and Y1356).
• Phosphorylated Y1349 and Y1356 comprise the multi-substrate docking site for binding adapter proteins necessary for downstream c-Met signalling [C. Ponzetto et al., Cell 77: 261-71 (1994)].
• HGF is expressed by mesenchymal cells, and its binding to c-Met, which is widely expressed in particular in epithelial cells, results in pleiotropic effects in a variety of tissues including epithelial, endothelial, neuronal and hematopoetic cells.
• the effects generally include one or all of the following phenomena: i) stimulation of mitogenesis; HGF was identified by its mitogenic activity on hepatocytes; ii) stimulation of invasion and migration; in an independent experimental approach, HGF was identified as scatter factor based on its induction of cell motility ("scattering"); and iii) stimulation of morphogenesis (tubulogenesis). HGF induces the formation of branched tubules from canine kidney cells in a collagen matrix.
• the compounds according to this invention can also be present in the form of their salts, hydrates and/or solvates.
• the compounds of this invention may, either by nature of asymmetric centers or by restricted rotation, be present in the form of isomers (enantiomers, diastereomers). Any isomer may be present in which the asymmetric center is in the (R)-, (S)-, or (R, S) configuration.
• Monoalkylamino in general represents an amino radical having one alkyl residue attached to the nitrogen atom.
• Non-limiting examples include methylamino, ethylamino, n-propylamino, iso- propylamino, n-butylamino, tert.-butylamino.
• radicals such as monoalkyl- aminocarbonyl.
• Heteroaryl in general represents a mono- or bicyclic, aromatic heterocyclic radical having a total number of 5 to 10 ring atoms, including 2 to 9 carbon atoms and up to 3 heteroatoms independently selected from the group consisting of N, O and S, which ring system can be bonded via a ring carbon atom or, if possible, via a ring nitrogen atom.
• Halogen represents radicals of fluorine, chlorine, bromine and iodine. Preference is given to radicals of fluorine and chlorine.
• said (Ci-C 6 )-alkyl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, trifluoromethyl, hydroxy, (Ci-C 4 )-alkoxy, amino, mono-(Ci-C 4 )-alkylarnino, di-(Ci-C 4 )-alkyl- amino, mono-(Ci-C 4 )-alkylaminocarbonyl, di-(C r C 4 )-alkylaminocarbonyl, (C 3 -C 6 )-cycloalkyl, phenyl, 4- to 6-membered heterocycloalkyl and 5- or 6- membered heteroaryl,
• R 9 is (C-O-alkyl
• R 17A and R 17B are independently hydrogen or methyl
• R 4 is (Ci-C 4 )-alkyl optionally substituted with up to three fluoro atoms, or is amino,
• the present invention relates to compounds of general formula (T), wherein R 6 is hydrogen or methyl.
• R 9 is methyl or ethyl
• R 15 and R 16 are joined and, taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocycloalkyl ring, which may contain a second ring heteroatom selected from N and O, and which is optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, oxo, hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,
• R 3 is cyano
• the present invention relates to compounds of general formula (I), wherein
• said (C 3 -C 6 )-cycloalkyl and 5- or 6-membered heterocycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of fluoro, methyl, ethyl, oxo, hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino,
• R 4 is methyl, difluoromethyl or trifluoromethyl
• R 6 is hydrogen
• R 4 has the meaning described above
• R 2 , R 3 , R 4 , R 5 , R 11 and R 12 have the meanings described above,
• Process steps (II) + (EI) ⁇ (IV), (IV) + (V) ⁇ (I-A), (VI) + (HI) ⁇ (VII) and (VII) + (V) ⁇ (VIE) are generally carried out in an inert solvent at a temperature range from +20 0 C to the boiling point of the solvent under atmospheric pressure.
• the 3-aminoindazole formation in process step (VET) ⁇ (EX) is generally carried out employing an excess of hydrazine or hydrazine hydrate in an alcoholic solvent such as methanol, ethanol, M-propanol, isopropanol, w-butanol or tert-butanol, or in a mixture thereof with water at a tem- perature range from +20 0 C to the boiling point of the solvent under atmospheric pressure.
• Hydrazine salts may also be used for the conversion in the presence of an auxiliary amine base such as triethylamine, N-methylmorpholine, N-methylpiperidine or NN-diisopropylethylamine.
• Preferably used as protecting group in the above process is tert- butoxycarbonyl (Boc), 2-(trimethylsilyl)ethoxymethyl (SEM) or /7-methoxybenzyl (PMB).
• Boc tert- butoxycarbonyl
• SEM 2-(trimethylsilyl)ethoxymethyl
• PMB /7-methoxybenzyl
• the removal of these groups is preferably carried out by reacting with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as water, dioxane, dichloromethane or acetic acid; it is also possible, where appropriate, for the removal to be carried out without an additional inert solvent.
• the reactions (X) + (XI) ⁇ (XII-A) and (XII-A) + (Xffl) ⁇ (XII-B) are generally performed under atmospheric pressure in a temperature range from -20 0 C to +120 0 C, preferably at 0 0 C to +80 0 C.
• R , R , R , R and R have the meanings described above,
• R ⁇ >2 , R ⁇ > 3 , D R 4 , D R 5 and R ) 6A have the meanings described above,
• R 1B and R 2 have the meanings described above.
• disorders relating to or mediated by c-Met shall include diseases associated with or implicating c-Met activity, for example the hyperactivity of c-Met, and conditions that accompany with these diseases.
• disorders relating to or mediated by c-Met include disorders resulting from overstimulation of c-Met due to abnormally high amount of c-Met or mutations in c- Met, or disorders resulting from abnormally high amount of c-Met activity due to abnormally high amount of c-Met or mutations in c-Met.
• brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
• Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
• Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal and vulvar cancer, as well as sarcoma of the uterus.
• Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.
• the compounds of the present invention may also be used to prevent and treat diseases of the airways and the lung, diseases of the gastrointestinal tract as well as diseases of the bladder and bile duct.
• 17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone acetate, 5-alpha reductase inhibitors such as finasteride and epristeride, anti-estrogens such as tamoxifen citrate and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex, and anti-progesterones and com- binations thereof;
• Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity; such agents include, e.g., krestin, lentinan, sizofiran, picibanil,
• mTOR inhibitors such as, e.g. , temsirolimus, sirolimus/Rapamycin, and everolimus;
• Proteasome inhibitors such as bortezomib and carfilzomib;
• Integrin inhibitors including alpha5-betal integrin inhibitors such as, e.g., E7820, JSM 6425, volociximab, and endostatin;
• Androgen receptor antagonists including, e.g., nandrolone decanoate, fluoxymesterone, Android, Prost-aid, andromustine, bicalutamide, flutamide, apo-cyproterone, apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and nilutamide;
• Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
• An exemplary dose range is from 0.01 to 100 mg/kg per day or 0.1 to 150 mg/kg per day.
• Example 7A The product mixture obtained in Example 7A was dissolved in ethanol (4 ml), treated with 3 N hydrochloric acid (1 ml) and heated to 90 0 C for 4 h. After this time, 3 N hydrochloric acid (0.2 ml) was again added, and heating was continued for 3 h. The mixture was evaporated to dryness, and the crude product thus obtained was used in the next step without further purification.
• Example 9A The title compound was prepared from Example 9A in analogy to the procedure described in Example 8A. The crude product thus obtained was used in the next step without further purification.
• Example HA The title compound was prepared from Example HA in analogy to the procedure described in Example 8A. The crude product thus obtained was used in the next step without further purification.
• the title compound was prepared from 300 mg (0.672 mmol) 5-(l,3-dioxolan-2-yl)-3-iodo-l- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -lH-indazole (Example 6A) in analogy to the procedure described in Example 2 IA.
• the crude product was purified by preparative RP- ⁇ PLC (acetonitrile/water gradient) to afford 129 mg (48% of th.) of the title compound.
• the title compound was prepared from 300 mg (0.672 mmol) 5-(l,3-dioxolan-2-yl)-3-iodo-l- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ -lH-indazole (Example 6A) in analogy to the procedure described in Example 2 IA.
• the procedure was modified by using 5 equivalents of 2-(lH-pyrazol-l-yl)- ethanol as the alcohol reactant and by switching to toluene as solvent.
• the reaction mixture was heated to 140 0 C for 2 h using microwave irradiation, after which time the same amounts of catalyst and ligand were added again. This cycle was repeated one more time.
• the crude product thus obtained was purified by preparative RP- ⁇ PLC (acetonitrile/water gradient) to afford 153 mg (52% of th.) of the title compound.
• Example 41 A The title compound was prepared from Example 41 A in analogy to the procedure described in Example 8A. The crude product thus obtained was used in the next step without further purification.
• the aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
• the residue was dissolved in dichloromethane (4 ml), and to the solution were added 0.175 ml (2.27 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP- ⁇ PLC (acetonitrile/water gradient) to give 32 mg (30% of th.) of the title compound.
• Example 12A The title compound was prepared from Example 12A in analogy to the procedure described in Example 2 yielding 36 mg (65% of th.) after purification by RP-HPLC (acetonitrile/water + 0.05% TFA gradient).
• Example 3A The title compound was prepared following the procedure described for Example 1 using 100 mg (0.256 mmol) tert-butyl 3-arnmo-5-(3,5-dicyano-2,6-dimemyl-l,4-dmydropyridin-4-yl)-lH-inda- zole-1-carboxylate (Example 3A) and 173 mg (0.77 mmol) 2-(2,5-dioxopyrrolidin-l-yl)ethane- sulfonyl chloride. Yield: 20 mg (17% of th.).
• Example 3A The title compound was prepared following the procedure described for Example 6 starting from 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-l,4-dihydropyridin-4-yl)- lH-indazole-1-carboxylate (Example 3A) and 346 mg (1.54 mmol) (4-chlorophenyl)methane- sulfonyl chloride. Yield: 4 mg (3% of th.).
• Example 17A The title compound was prepared from Example 17A in close analogy to the procedure described in Example 2 yielding 18 mg (62% of th.) of product after RP- ⁇ PLC purification (acetonitrile/ water + 0.05% TFA gradient).
• Example 19A 41 mg (0.073 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-l,4-dmydropvridin-4-yl)-3- ⁇ [(3- ethoxy-3-oxopropyl)sulfonyl]amino ⁇ -lH-indazole-l-carboxylate (Example 19A) were dissolved in dichloromethane (4 ml) and treated with 0.062 ml (0.8 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution.
• Example 20A tert-butyl 5-(3,5-dicyano-2,6-dimethyl-l,4-dihydropyridin-4-yl)-3-[(propyl- sulfonyl)amino]-lH-indazole-l-carboxylate (Example 20A) were dissolved in dichloromethane (4 ml) and treated with 0.1 ml (1.28 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution.
• Example 22A The title compound was prepared from 277 mg (1.57 mmol) of Example 22A in analogy to the procedure described in Example 2 yielding 194 mg (40% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 24 A The title compound was prepared from 101 mg (0.495 mmol) of Example 24 A in analogy to the procedure described in Example 2 yielding 58 mg (35% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 28A The title compound was prepared from 151 mg (0.656 mmol) of Example 28A in analogy to the procedure described in Example 2 yielding 87 mg (37% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 30A The title compound was prepared from 141 mg (0.686 mmol) of Example 30A in analogy to the procedure described in Example 2 yielding 75 mg (32% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 32A The title compound was prepared from 150 mg (0.604 mmol) of Example 32A in analogy to the procedure described in Example 2 yielding 167 mg (72% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 34A The title compound was prepared from 98 mg (0.356 mmol) of Example 34A in analogy to the procedure described in Example 2 yielding 20 mg (13% of th.) after purification first by RP-HPLC (acetonitrile/water gradient) followed by silica gel chromatography (dichloromethane/methanol gradient).
• Example 36A The title compound was prepared from 278 mg (1.01 mmol) of Example 36A in analogy to the procedure described in Example 2 yielding 119 mg (29% of th.) after purification first by RP- HPLC (acetonitrile/water gradient) followed by silica gel chromatography (dichloromethane/ methanol gradient).
• Example 38A The title compound was prepared from 59 mg (0.230 mmol) of Example 38A in analogy to the procedure described in Example 2 yielding 30 mg (33% of th.) after purification by RP-HPLC (acetonitrile/water gradient).
• Example 48A The title compound was prepared from 136 mg (0.583 mmol) 3-[(2-methoxyethyl)(methyl)amino]- lH-indazole-5-carbaldehyde (Example 48A) in analogy to the procedure described in Example 2 yielding 39 mg (17% of th.) after purification by RP-HPLC (acetonitrile/water gradient, final mixture 90:10 v/v).
• Example 51A The title compound was prepared from 106 mg (0.429 mmol) 3-[(3-methoxypropyl)(methyl)- amino]-lH-indazole-5-carbaldehyde (Example 51A) in analogy to the procedure described in Example 2 yielding 17 mg (10% of th.) after purification by RP- ⁇ PLC (acetonitrile/water gradient, final mixture 90:10 v/v).
• Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.
• Recombinant human c-Met protein (Invitrogen, Carlsbad, California, USA) is used.
• substrate for the kinase reaction the peptide KKKSPGEYVNIEFG (JPT, Germany) is used.
• Assay 1 ⁇ L of a 51 -fold concentrated solution of the test compound in DMSO is pipetted into a white 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany).
• the kinase reaction is started by the addition of 25 ⁇ L of a solution of adenosine triphosphate (ATP, final concentration 30 ⁇ M), substrate (final concentration 100 ⁇ M), nicotinamide adenine dinucleotide ( ⁇ ADH, final concentration 50 ⁇ M) and dithiothreitol (DTT, final concentration 2 mM) in assay buffer, and the resulting mixture is incubated for a reaction time of 100 min at 32°C.
• ATP adenosine triphosphate
• substrate final concentration 100 ⁇ M
• ⁇ ADH nicotinamide adenine dinucleotide
• DTT dithiothreitol
• test compounds are tested on the same microtiter plate at 9 different concentrations in the range of 10 ⁇ M to 1 nM (10 ⁇ M, 3.1 ⁇ M, 1.0 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M; dilution series prepared before the assay at the level of the 51 -fold concentrated stock solutions by serial 1 :3 dilutions) in duplicate for each concentration, and IC 50 values are calculated using an inhouse software.
• the N-terminally His6-tagged recombinant kinase domain of the human c-Met (amino acids 960- 1390), expressed in insect cells (SF21) and purified by Ni-NTA affinity chromatography and consecutive size exclusion chromatography (Superdex 200), is used. Alternatively, commercially available c-Met (Millipore) can be used.
• substrate for the kinase reaction the biotinylated poly- Glu,Tyr (4:1) copolymer (# 6 IGTOBLC, Cis Biointernational, Marcoule, France) is used.
• a solution of c-Met in assay buffer [25 mM Hepes/NaOH, pH 7.5; 5 mM MgCl 2 ; 5 mM MnCl 2 ; 2 mM dithiothreitol; 0.1% (v/v) Tween 20 (Sigma); 0.1% (w/v) bovine serum albumin] are added, and the mixture is incubated for 15 min at 22°C to allow pre-binding of the test compound to the enzyme before the start of the kinase reaction.
• the kinase reaction is started by the addition of 3 ⁇ L of a solution of adenosine triphosphate (ATP, 16.7 ⁇ M; final concentration in the 5 ⁇ L assay volume is 10 ⁇ M) and substrate (2.27 ⁇ g/mL, final concentration in the 5 ⁇ L assay volume is 1.36 ⁇ g/mL ⁇ 30 nM) in assay buffer, and the resulting mixture is incubated for a reaction time of 30 min at 22°C.
• the concentration of c-Met in the assay is adjusted depending on the activity of the enzyme lot and is appropriately chosen to have the assay in the linear range; typical enzyme concentrations are in the range of about 0.03 nM (final concentration in the 5 ⁇ L assay volume).
• the reaction is stopped by the addition of 5 ⁇ L of a solution of HTRF detection reagents [40 nM streptavidine-XLent and 2.4 nM PT66-Eu-chelate, an europium-chelate labelled anti-phosphotyrosine antibody (Perkin-Elmer)] in an aqueous EDTA solution [100 mM EDTA, 0.2% (w/v) bovine serum albumin in 50 mM HEPES/NaOH, pH 7.5].
• the resulting mixture is incubated for 1 h at 22°C to allow the binding of the biotinylated phos- phorylated peptide to the streptavidine-XLent and the PT66-Eu-chelate.
• Human gastric adenocarcinoma cells (MKN45, purchased from ATCC) seeded on 384-well micro- titer plates (9000 cells/well) are incubated in 25 ⁇ l full growth media for 24 h at 37°C with 5% CO 2 .
• MKN45 Human gastric adenocarcinoma cells
• 384-well micro- titer plates (9000 cells/well) are incubated in 25 ⁇ l full growth media for 24 h at 37°C with 5% CO 2 .
• Lysates are transferred to BSA-blocked plates with prebound c-Met capture antibody [purchased from Mesoscale Discovery (MSD), Gaithersburg, MD, USA] for 1 hour with shaking, after washing once with Tris-buffered saline + 0.05% Tween 20 (TBST).
• the Sulfa-TAG anti-phospho-c-Met detection antibody is added at a final concentration of 5 nM in antibody dilution buffer to the plate for 1 hour with shaking at RT. After washing the wells with Tris buffer, Ix reading buffer is added, and the plates are measured on the Sector Imager 6000 (purchased from Mesoscale). IC 50 values are calculated from dose- response curves using Marquardt-Levenberg-Fit.
• the adherent tumor cell proliferation assay used to test the compounds of the present invention involves a read-out called Cell Titre-Glo developed by Promega [B.A. Cunningham, "A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth", The Engineer 2001, 15 (13), 26; S.P. Crouch et al., "The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity", Journal of Immunological Methods 1993, 160, 81-88].
• Generation of a luminescent signal corresponds to the amount of ATP present, which is directly proportional to the number of metabolically active (proliferating) cells.
• H460 cells lung carcinoma, purchased from ATCC
• 96-well plates at 3000 cells/well in complete media with 10% fetal calf serum and incubated 24 hours at 37°C.
• test compounds are added over a final concentration range of 10 nM to 20 ⁇ M in serial dilutions at a final DMSO concentration of 0.2%.
• Cells are incubated for 72 hours at 37°C in complete growth media after addition of the test compound.
• the cells are lysed, and 100 ⁇ l of substrate/buffer mixture is added to each well, mixed and incubated at room temperature for 8 minutes.
• the samples are read on a luminometer to measure the amount of ATP present in the cell lysates from each well, which corresponds to the number of viable cells in that well. Values read at 24-hour incubation are subtracted as Day 0.
• a linear regression analysis can be used to determine the drug concentration which results in a 50% inhibition of cell proliferation using this assay format.
• This protocol can be applied to different cell lines of interest, which include, but not limited to, CAKI-I, MNK-45, GTL-16, HCC2998, K562, H441, K812, MEGOl, SUPl 5 and HCTl 16.
• compositions according to the present invention can be illustrated as follows:
• a 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary.
• the solution is diluted for administration to 1-2 mg/ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.
• a sterile preparation can be prepared with (i) 100-1000 mg of the desired compound of this invention as a lyophilized powder, (ii) 32-327 mg/ml sodium citrate, and (///) 300-3000 mg Dextran 40.
• the formulation is reconstituted with sterile, injectable saline or 5% dextrose to a concentration of 10 to 20 mg/ml, which is further diluted with saline or 5% dextrose to 0.2 to 0.4 mg/ml, and is administered either as i.v. bolus or by i.v. infusion over 15-60 minutes.
• a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
• the capsules are washed and dried.
• the active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water-miscible medicine mix.
• a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose.
• Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability, or delay absorption.

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