CN1237176A - Tricyclic compounds useful as FPT inhibitors - Google Patents
Tricyclic compounds useful as FPT inhibitors Download PDFInfo
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- CN1237176A CN1237176A CN97199601A CN97199601A CN1237176A CN 1237176 A CN1237176 A CN 1237176A CN 97199601 A CN97199601 A CN 97199601A CN 97199601 A CN97199601 A CN 97199601A CN 1237176 A CN1237176 A CN 1237176A
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- 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
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- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
Novel tricyclic compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.
Description
Background
Patent Cooperation Treaty (PCT) down disclosed patent application WO 95/00497 (January 5 nineteen ninety-five) inhibitory enzyme is described, i.e. farnesyl-protein transferase (FPT or FTase), and therefore suppress the compound of oncogene protein Ras farnesylation.The protein ingredient of the frequent coded signal transduction pathway of oncogene, the stimulation that causes cell growth and mitotic division to take place.The expression of oncogene causes transformation in culturing cell, it is characterized by the intensive kitchen range growth of cell of the contact inhibition of the energy for growth of cell in soft agar and the performance of shortage non-transformed cell.Sudden change of some oncogenes and/or overexpression often with the mankind's related to cancer.
Be to obtain conversion capability, the method that the precursor of Ras oncoprotein must stand to be arranged in the cysteine residues of C-terminal tetrapeptide turns usefulness into.Thereby the inhibitor of the enzyme of this change of catalysis (being farnesyl-protein transferase) has been indicated as the carcinostatic agent of some tumour (promptly wherein Ras tumour that conversion is worked).The sudden change of Ras, the oncogene form usually is found in many human cancers, the most noticeable is (Kohl etc., Science, the 260th volume, 1834-1837 page or leaf, 1993) in surpassing 50% colorectal carcinoma and in the carcinoma of the pancreas.
In view of the realistic meaning of farnesyl protein transferase inhibitor, will be other compounds as farnesyl protein transferase inhibitor to the valuable contribution of this area.The present invention promptly provides this kind contribution.
The present invention's general introduction
Suppress farnesyl-protein transferase by tricyclic compounds of the present invention report is not arranged before this as yet.Therefore, the invention provides the method for using tricyclic compounds of the present invention to suppress farnesyl-protein transferase, described compound:, but do not suppress geranyl geranyl protein transferase I (ⅰ) at external effective inhibition farnesyl-protein transferase; (ⅱ) blocking-up is the conversion Ras form inductive phenotypic alternation of farnesyl acceptor, but do not block transformation be the conversion Ras form inductive phenotypic alternation of geranyl geranyl acceptor; (ⅲ) blocking-up is processing in the cell of the Ras of farnesyl acceptor, but does not block the processing in the cell of the Ras of geranyl geranyl acceptor that is of transformation; Reach (ⅳ) blocking-up by transforming the misgrowth of Ras inductive cell in culture.Verified several compounds of the present invention have anti-tumor activity in animal model.
The The compounds of this invention that the invention provides by giving significant quantity suppresses the excrescent method of cell (comprising cell transformed).The misgrowth of cell refers to not rely on the cell growth of normal regulating mechanism (as the forfeiture of contact inhibition).This comprises following misgrowth: (1) expresses the tumour cell (tumour) of activated Ras oncogene; (2) tumour cell that is activated because of the Cancer-causing mutation of another kind of gene of Ras albumen wherein; And the optimum and malignant cell of unusual other proliferative disease of Ras activated wherein appears in (3).
Tricyclic compound of the present invention comprises following compounds or its pharmacy acceptable salt or solvate:
4-[8-chloro-3,7-two bromos-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(4-thio-morpholinyl ethanoyl) piperidines
4-[8-chloro-3,7-two bromos-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(4-thio-morpholinyl ethanoyl) piperidines S-oxide compound
(+,-)-1-(3-bromo-8,10-dichloro--5-ethyl-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl)-4-(4-pyridyl ethanoyl) piperidines N4-oxide compound
(+,-)-4-(3-bromo-8,10-dichloro--6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl)-1-[2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1-oxoethyl] piperidines; With
(+,-)-4-(3,10-two bromos-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11 (R)-yl)-1-[(1-oxopropyl-4-piperidyl) ethanoyl] piperidines.In another embodiment, the present invention relates to suppress the medicinal compositions of abnormal growth of cells, it comprises the tricyclic compound and the pharmaceutically acceptable carrier of significant quantity.
In another embodiment, the present invention relates to suppress the excrescent method of cell (comprising transformant), this method comprises the tricyclic compound of Mammals (as the people) significant quantity that needs this kind treatment.The misgrowth of cell refers to not rely on the cell growth of normal regulating mechanism (as the forfeiture of contact inhibition).This comprises following misgrowth: (1) expresses the tumour cell (tumour) of activated Ras oncogene; (2) tumour cell that is activated because of the Cancer-causing mutation of another kind of gene of Ras albumen wherein; (3) the optimum and malignant cell of unusual other proliferative disease of Ras activated wherein occurs, and (4) are by being different from the optimum or malignant cell of the proteic machine-processed activated of Ras.Do not wish to be bound by theory, believe that these compounds can work by the function that blocking-up G-albumen isoprenylation suppresses G-albumen (as ras p21), thereby make them be used for the treatment of proliferative disease such as tumor growth and cancer, perhaps work, thereby make their anti-proliferative activities at the ras transformant by suppressing the ras farnesyl-protein transferase.
Repressed cell can be the tumour cell of expressing activated ras oncogene.For example, can comprise pancreas tumour cell, lung carcinoma cell, myelomatosis tumour cell, thyroid follicle tumour cell, myelodysplasia tumour cell, epidermal carcinoma tumour cell, bladder cancer tumour cell or colon tumor cell by repressed cell type.Thereby handle the misgrowth that can suppress cell with ras inhibition farnesyl-protein transferase by tricyclic compound.The tumour cell that wherein said Ras albumen Yin Jiyin (non-Ras gene) Cancer-causing mutation is activated also has restraining effect.In addition, tricyclic compound can also suppress by the proteic albumen activated of non-Ras tumour cell.
The present invention also provides the method that suppresses tumor growth by the tricyclic compound of the Mammals that needs this treatment (as the people) significant quantity.Specifically, the invention provides the method that suppresses to express the tumor growth of activated Ras oncogene by the above-claimed cpd that gives significant quantity.Example that can repressed tumour includes, but is not limited to lung cancer (as adenocarcinoma of lung), pancreas cancer (as the carcinoma of the pancreas of carcinoma of the pancreas as exocrinosity), colorectal carcinoma (as colorectal carcinoma as adenocarcinoma of colon and colorectal carcinoma), myelomatosis (as acute myelogenous leukemia (AML), thyroid follcular carcinoma, myelodysplastic syndrome (MDS), bladder cancer and epidermal carcinoma.
Believe that the present invention also provides the tricyclic compound of Mammals (as the people) significant quantity as herein described by needing this treatment to suppress some the optimum and method neoplasm disease, in these proliferative diseases, Ras albumen because of the Cancer-causing mutation of other gene by abnormal activation, promptly described Ras gene itself is not carcinogenic form by the sudden change activation.For example, can suppress hyperplasia of prostate sexual disorder neurofibromatosis or the tumour that is activated because of (as neu, src, abl, lck and the fyn) sudden change of Tyrosylprotein kinase oncogene or overexpression of Ras wherein by tricyclic compound as herein described.
In another embodiment, the present invention relates to by giving Mammals, especially the tricyclic compound of people's significant quantity suppresses the method for the farnesylation effect of ras farnesyl-protein transferase and oncogene protein Ras.Give patient's The compounds of this invention and can be used for treating above-mentioned cancer to suppress farnesyl-protein transferase.
The present invention describes in detail
As used in this, except that specializing, the following term of use is defined as follows:
M
+-represent the molion of molecule in the mass spectrum;
MH
+-represent the molion hydrogenation of molecule in the mass spectrum;
Bu-represents butyl;
Et-represents ethyl;
The Me-represent methylidene;
Ph-represents phenyl;
Following solvent and reagent are represented with abbreviation: tetrahydrofuran (THF) (THF); Ethanol (EtOH); Methyl alcohol (MeOH); Acetate (HOAc or AcOH); Ethyl acetate (EtOAc); N, dinethylformamide (DMF); Trifluoroacetic acid (TFA); Trifluoroacetic anhydride (TFAA); I-hydroxybenzotriazole (HOBT); M-chloro benzoic acid (MCPBA); Triethylamine (Et
3N); Ether (Et
2O); Chloro ethyl formate (ClCO
2Et) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (DEC).
Described substituent R
1, R
2, R
3And R
4The position carry out reference based on following numbering ring structure:
Can there be different isomer (as enantiomorph or diastereomer) in part compound of the present invention.This invention is intended to comprise the steric isomer of all these type of pure forms and mixture, comprise racemic mixture.For example the carbon atom of C-11 position can be S or R steric configuration.
The part tricyclic compound has acidity, and for example those have the tricyclic compound of carboxyl or phenolic hydroxyl group.These compounds can form pharmacy acceptable salt.The example of this type of salt comprises sodium salt, sylvite, calcium salt, aluminium salt, golden salt and silver salt.Also comprise the salt that forms with pharmaceutically acceptable amine such as ammonia, alkylamine, hydroxyalkyl amine, N-methylglucosamine etc.
The tricyclic compound of part alkalescence also can form pharmacy acceptable salt, as acid salt.For example, pyridine-nitrogen-atoms can form salt with strong acid, and the compound with alkali subtituent such as amino also can form salt with weak acid.The example that is fit to the salifiable acid of shape is hydrochloric acid, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid and other mineral acid well known in the art and carboxylic acid.Conventional method easily is to make free alkali form contact generation salt with the required acid of capacity to prepare described salt.By with suitable dilute alkaline aqueous solution, as described in handling as dilute sodium hydroxide, salt of wormwood, ammonia and sodium bicarbonate aqueous solution salt can regeneration as described in free alkali form.The form of these free alkalis is in some physical properties, and as some is different with their salt forms separately aspect the solubleness in polar solvent, but for purpose of the present invention, the salt of described bronsted lowry acids and bases bronsted lowry and they free alkali form separately but is equal to.
The salt of all these bronsted lowry acids and bases bronsted lowries can be used as the pharmacy acceptable salt in the scope of the invention, and for purpose of the present invention, thinks that the salt of all bronsted lowry acids and bases bronsted lowry and the free form of respective compound are equal to.
With the method for routine for example as with organic solvent from water extractive reaction mixture, evaporation organic solvent, then through silica gel or other suitable chromatography media chromatography, can be from reaction mixture the tricyclic compound of separate type 1.0.
Come the raw material of exemplary illustration The compounds of this invention and its preparation with the following examples, these embodiment should not constitute the restriction to disclosure scope.
Embodiment 1
4-[8-chloro-3,7-two bromos-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(4-thio-morpholinyl ethanoyl) piperidines
Steps A
In-5 ℃, with 4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-subunit)-(25.86g 55.9mmol) mixes with the 250ml vitriol oil 1-piperidines-1-ethyl formate, add 4.8g (56.4mmol) SODIUMNITRATE then, stirred 2 hours.This mixture is inclined to 600g ice, with dense ammonium hydroxide aqueous solution alkalization.Filter compound, use the 300ml water washing, use the 500ml dichloromethane extraction then.With 200ml water washing extract, use dried over mgso, filtering also then, vacuum concentration is a residue.Chromatography (silica gel, 10% ethyl acetate/dichloromethane) residue obtains 24.4g (productive rate 86%) product.M.p.=165-167 ℃, mass spectrum: MH
+=506,508 (CI).
Ultimate analysis: calculated value: C, 52.13; H, 4.17; N, 8.29
Measured value: C, 52.18; H, 4.51; N, 8.16.
Step B:
In 20 ℃, (20g 40.5mmol) mixes with the 200ml vitriol oil, then this mixture is cooled to 0 ℃ with the product of steps A.Add 7.12g (24.89mmol) 1 to this mixture, 3-two bromos-5,5-dimethyl-glycolylurea stirred 3 hours in 20 ℃.Be cooled to 0 ℃, (1.0g 3.5mmol), stirred 2 hours in 20 ℃ to add two bromo glycolylurea again.This mixture is inclined to 400g ice, alkalize with dense ammonium hydroxide aqueous solution, filter and collect the solid that produces in 0 ℃.With 300ml water washing solid, in 200ml acetone, make slurry, filter and obtain 19.79g (productive rate 85.6%) product.M.p.=236-237 ℃, mass spectrum: MH
+=586 (CI).
Ultimate analysis: calculated value: C, 45.11; H, 3.44; N, 7.17
Measured value: C, 44.95; H, 3.57; N, 7.16.
Step C:
In 50 ℃, the suspension of 90: 10 ethanol/waters of 700ml of the product of 25g (447mmol) iron filings, 10g (90mmol) calcium chloride and 20g (34.19mmol) step B is mixed.In refluxing down, this mixture heating up is spent the night, pass through Celite
Filter, with 2 * 200ml hot ethanol washing leaching cake.Merging filtrate and washings, vacuum concentration are residue.With 600ml dichloromethane extraction residue, use the 300ml water washing, through dried over mgso.Filtration and vacuum concentration are residue, and chromatography (silica gel, 30% ethyl acetate/dichloromethane) obtains 11.4g (productive rate 60%) then.M.p.=211-212 ℃, mass spectrum: MH
+=556 (CI).
Ultimate analysis: calculated value: C, 47.55; H, 3.99; N, 7.56
Measured value: C, 47.45; H, 4.31; N, 7.49.
Step D:
In-10 ℃, slowly (20g 35.9mmol) adds in the 120ml concentrated hydrochloric acid aqueous solution of (gradation) 8g (116mmol) Sodium Nitrite with the product of step C.In 0 ℃, 1 stirs the compound that produces 2 hours, then in 0 ℃, slowly added in (dropping) 150ml (1.44mol) 50% Hypophosporous Acid, 50 with 1 hour.In 0 ℃ of stirring 3 hours, incline then to 600g ice, with dense ammonium hydroxide aqueous solution alkalization.With 2 * 300ml dichloromethane extraction, through dried over mgso, simmer down to residue then.Residue chromatography (silica gel, 25% ethyl acetate/hexane) is obtained 13.67g (productive rate 70%).M.p.=163-165 ℃, mass spectrum: MH
+=541 (CI).
Ultimate analysis: calculated value: C, 48.97; H, 4.05; N, 5.22
Measured value: C, 48.86; H, 3.91; N, 5.18.
Step e:
With the product of step D (6.8g, 12.59mmol) and the 100ml concentrated hydrochloric acid aqueous solution merge, spend the night in 85 ℃ of stirrings.With this mixture cooling, incline to 300ml ice, with dense ammonium hydroxide aqueous solution alkalization.With 2 * 300ml dichloromethane extraction, use the dried over mgso extract then.Filtration and vacuum concentration are residue, and chromatography (silica gel, 10% methanol/ethyl acetate+2% ammonium hydroxide aqueous solution) obtains 5.4g (productive rate 92%) target compound then.M.p.=172-174 ℃, mass spectrum: MH
+=469 (FAB).
Ultimate analysis: calculated value: C, 48.69; H, 3.65; N, 5.97
Measured value: C, 48.83; H, 3.80; N, 5.97.
Step F:
In 20 ℃, (13g 33.3mmol) mixes with 300ml toluene, adds 32.5ml (32.5mmol) 1M DIBAL toluene solution then with the compound of embodiment 1 step e.In refluxing down with this mixture heating up 1 hour, be cooled to 20 ℃, add 32.5ml 1M DIBAL solution again, heated 1 hour down in refluxing.This mixture is cooled to 20 ℃, it is inclined to the mixture of 400g ice, 500ml ethyl acetate and 300ml 10% aqueous sodium hydroxide solution.(3 * 200ml) aqueous layer extracted are used the dried over mgso organic layer, and vacuum concentration is a residue then with methylene dichloride.Chromatography (silica gel, 12% methanol/ethyl acetate+4% ammonium hydroxide aqueous solution) obtains the 10.4g target compound, is racemoid.Mass spectrum: MH
+=469/471 (FAB).
Step G:
4-[8-chloro-3,7-two bromos-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(hydroxyacetyl) piperidines
Under room temperature, in 3ml anhydrous dimethyl formamide (DMF) solution of the material of 0.235g (0.5mmol) embodiment 1 step F, add the oxyacetic acid (glycolic acid) of the technical grade of 0.17ml N-methylmorpholine (NMM), 0.075g1-hydroxybenzotriazole (HOBT), 0.145g 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (DEC) and 0.06g 80%.The yellow solution that produces was stirred 24 hours, under high vacuum, evaporate then.Residue is allocated between methylene dichloride and the saturated salt solution, with methylene dichloride (3 * 25ml) aqueous layer extracted.Organic layer, filtration and concentrated through the dried over mgso merging.Residue with 60% ethyl acetate/hexane and 3% ethanol/methylene (each 0.5L) wash-out, obtains target compound (0.255g, productive rate 96.5%) through 30g flash chromatography on silica gel purifying.
MS:529(M+H)。
Step H
4-[8-chloro-3,7-two bromos-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(chloro ethanoyl) piperidines
Under room temperature, with the compound of embodiment 1 step G (0.11g, 0.2mmol) and the mixture of 1.5ml thionyl chloride stirred concentrating under reduced pressure then 18 hours.Residue is dissolved in the methylene dichloride, adds toluene and obtain muddy solution, it is concentrated once more, then dry under high vacuum, obtain target compound (0.11g), be yellow loose matter.
MS:547/549(M/M+2)。
Step 1
To about 0.11g 4-[8-chloro-3; 7-two bromos-5; 6-dihydro-11H-benzo [5; 6] cyclohepta-[1; 2-b] pyridine-11-yl]-add the 0.12ml thiomorpholine in the 5ml dichloromethane solution of 1-(chloro ethanoyl) piperidines; under room temperature, this mixture was stirred 24 hours, use the 20ml distilled water diluting.Separate each layer, return aqueous layer extracted with the 10ml methylene dichloride.With saturated salt solution the organic layer that merges is washed once, use dried over mgso, filter and be evaporated to brown residue.Through the 20g flash chromatography on silica gel, with 200ml 3% ethanol/methylene wash-out, obtain the 0.12g target compound, two step productive rates are 93.8%.MS:614.5(M+H)。
FPT?IC
50=0.0089μM。
Embodiment 2
4-[8-chloro-3,7-two bromos-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-1-(4-thio-morpholinyl ethanoyl) piperidines S-oxide compound
4-[8-chloro-3 to 0.09g (0.15mmol) embodiment 1 step 1,7-two bromos-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl]-add 123 μ l trifluoroacetic acids (TFA) and 121 μ l, 30% hydrogen peroxide in 10ml distilled tetrahydrofuran (THF) solution of 1-(4-thio-morpholinyl) piperidines.Under room temperature,, concentrate then the solution stirring that produces 20 hours.Methylene dichloride and 10ml distilled water extraction leftover with 2 * 10ml part.With saturated salt solution the organic layer that merges is washed once, use dried over mgso, filter and be evaporated to colourless residue.Preparation property TLC launches with 10% methyl alcohol (ammonia)/methylene dichloride, obtains the 0.03g target compound, is white solid.Productive rate: 32.6%.
MS:630(M)。
FPT?IC
50=0.0068μM。
Embodiment 3
(+,-)-1-(3-bromo-8,10-dichloro--5-ethyl-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl)-4-(4-pyridyl ethanoyl) piperidines N4-oxide compound
Steps A
In-78 ℃, on dry ice-propanone is bathed, ((2.8ml, (THF, distillatory is 20ml) in the solution for tetrahydrofuran (THF) 20.13mmol) 18.25mmol) to add to Diisopropylamine for 2.5M hexane solution, 7.3ml with n-Butyl Lithium.In 0 ℃ of stirring 30 minutes, be cooled to-78 ℃ then.(2.0g, THF 7.38mmol) (10ml) solution is-78 ℃ of purple solution restir half an hour with generation to add N-(1, the 1-dimethyl ethyl)-3-methyl-5-bromo-2-pyridine carboxamide in-78 ℃.Drip 3,5-dichlorobenzyl chloride (2.8g, tetrahydrofuran (THF) 14.32mmol) (10ml) solution in-78 ℃.Replace dry ice-propanone to bathe with ice/water-bath, reaction mixture was stirred 11/2 hour in 0 ℃.Thin-layer chromatography (the 3%V/V ethyl acetate: hexane) finish by assaying reaction.Water (100ml) makes the reaction mixture quenching, with ethyl acetate (2 * 200ml) extractions.Separate organic layer, water (100ml) washing, through dried over mgso, filter and evaporating solvent, obtain oily matter, with it through silica gel column chromatography (3%V/V ethyl acetate: hexane) obtain colorless oil, suction filtration under high vacuum (0.2mm), solidify and obtain white solid (2.7g, productive rate 96.7%).
Step B
In-78 ℃, ((0.82ml is in tetrahydrofuran (THF) 5.86mmol) (10ml the adds the sodium distillatory) solution 5.75mmol) to add to Diisopropylamine for 2.5M hexane solution, 2.3ml with n-Butyl Lithium.Stirred 20 minutes in-78 ℃.(1.0g 2.64mmol), stirs the purple solution that produce 1/2 hour in-78 ℃ to be added in the product of embodiment 3 steps A in the tetrahydrofuran (THF) (5ml).(0.7ml 9.37mmol), replaces the dry ice bath with ice/water-bath, in 0 ℃ reaction mixture is stirred 1 hour to add pure monobromoethane.(the 3%V/V ethyl acetate: hexane) assaying reaction is finished with silica gel thin-layer chromatography.In reaction mixture, add entry (50ml) and ethyl acetate (100ml).Separate organic layer, water (5ml) washing, through dried over sodium sulfate, filter and evaporating solvent, obtain faint yellow oily thing, (the 3%V/V ethyl acetate: hexane), suction filtration is 2 hours under high vacuum (0.2mm) through silica gel column chromatography with it, obtain colorless oil (0.95g, productive rate 88.7%).MS:CIMH?459。
Step C
(5ml, (0.9g in toluene 1.96mmol) (10ml) solution, stirred 5 hours down in refluxing then 53.6mmol) to add to embodiment 3 step B products with phosphoryl chloride.This reaction mixture is cooled to room temperature, solvent evaporated under reduced pressure.Add toluene (20ml), evaporating solvent once more.Order adds entry (30ml), ethyl acetate (100ml) and 10% sodium hydroxide (10ml) in residual oily matter.Separate organic layer, with salt solution (50ml) washing, through dried over mgso, filter and evaporating solvent, obtain oily matter, use it for next step reaction (0.8g, productive rate 100%) MS:CIMH 383/385.
Step D
In 20 ℃, (0.8g, 2.08mmol) (2.7g 20.2mmol) mixes, and stirs 10 minutes in 175 ℃ of oil baths in preheating then with aluminum chloride with the product of embodiment 3 step C.(1: 1 V/V ethyl acetate: hexane) finish with the silica gel thin-layer chromatography assaying reaction.Reactant is cooled to 0 ℃, adds entry (10ml), then add 2 normal hydrochloric acid (15ml).Under the ice bath cooling, add 20% sodium hydroxide alkalization mixture, use methylene dichloride (2 * 100ml) extractions then.Separate organic layer, through dried over mgso, filter and evaporating solvent, obtain white solid (0.6g, productive rate 75%).MS:CI?MH(383/385)。
Step e
Under reflux temperature, with product (0.3g, 7.79 * 10-4m) 6N hydrochloric acid (10ml) and methyl alcohol (5ml) solution stirring 24 hours of embodiment 3 step D.Reactant is cooled to 20 ℃, adds in the ice (100g), in 0 ℃ with 25% sodium hydroxide alkalize to pH be 14.Collection white solid precipitation, water (20ml) washing is dissolved in the methylene dichloride (100ml), uses dried over mgso, filters and evaporating solvent.Residual solids is through silica gel column chromatography (1: 1 V/V ethyl acetate: hexane) obtain white solid (200mg, productive rate 66%).MS:CI?MH(384/386)。
Step F
In 0 ℃, (100mg, (130mg in ethanol 0.338mmol) (5ml) solution, stirs this reaction mixture 5 minutes 2.66mmol) to add to embodiment 3 step e products with sodium borohydride.(silica gel, the 30%V/V ethyl acetate: hexane) assaying reaction is finished with thin-layer chromatography.Add entry (20ml) and methylene dichloride (30ml), separate organic layer, through dried over mgso, filter and evaporating solvent, obtain oily matter, with it through silica gel column chromatography (20%V/V ethyl acetate (ethylacelate): hexane), it is 70: 30 the mixture (130mg, productive rate 100%) of two diastereomers.MS:CI(MH?388)。
Step G
In 0 ℃, (0.15ml, (60mg is 0.155mmol) in toluene (3ml) solution 2.05mmol) to add to the product of embodiment 3 step F with thionyl chloride.In 0 ℃ this reaction mixture was stirred 1 hour, in 20 ℃ of restir 1 hour.Reactant is cooled to 0 ℃, and order adds entry (10ml), ethyl acetate (20ml) and 10% sodium hydroxide (5ml).Separate organic layer,,, filter and evaporating solvent, obtain oily matter (65mg) through dried over mgso with salt solution (5ml) washing.
Step H
In 0 ℃, (100mg, (60mg is in acetonitrile 0.155mmol) (5ml) solution 1.16mmol) to add to embodiment 3 step G products with piperazine.(0.2ml 1.43mmol), stirs this reaction mixture 2 hours in 20 ℃ to add triethylamine.Add entry (20ml) and methylene dichloride (50ml).Separate organic layer,,, filter and evaporating solvent, obtain the crude product product, be white solid (60mg) through dried over mgso with salt solution (20ml) washing.MS:CI?MH(456)。NMR is shown as 80/20 mixture of two diastereomers.
Step I
In 0 ℃, product (50mg to embodiment 3 step H, 0.109mmol) dimethyl formamide (5ml) solution in add I-hydroxybenzotriazole (40mg, 0.296mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (DEC1,50mg, 0.26mmol) and 4-pyridyl N-oxide compound acetate (40mg, 0.26mmol), (0.5ml 4.03mmol), stirs this reaction mixture 24 hours in 20 ℃ to add N-methylmorpholine.Solvent evaporated under reduced pressure, (40ml) extracts residual oily matter with methylene dichloride, water (20ml) and salt solution (20ml) washing, through dried over mgso, filtration and evaporating solvent, obtain oily matter, through silica gel column chromatography (10%V/V methyl alcohol: methylene dichloride) obtain product, at down dry 3 hours (50mg, the productive rate 78) of high vacuum (0.2mm) into white solid.
NMR: be 80: 20 mixture of diastereomer.
MS?FABS?MH?590.8/588.9
Accurate mass spectrum: C
27H
26N
4O
2BrCl
2Calculated value MH
+587.0616; Measured value 587.0612
Step 3J
The separation of diastereomer
With deriving from Chiral Technologies Inc., Exton, the Chiralpack AD post of Pennsylvania separate the mixture (200mg mixes at 80: 20) of two diastereomers, use ethanol as eluting solvent.Chiralpack AD is the amylose starch three (3,5-3,5-dimethylphenyl carbamate) of bag quilt on 10 μ m silica matrixes.
1) obtains main diastereomer (120mg), white solid into racemoid
FABS?MH?588.9/590.8
FABS MS MH
+C
27H
26N
4O
2BrCl
2Calculated value 587.0616; Measured value MH
+587.0612
FPT?IC
50=0.006μM。
2) obtain accessory diastereomer (20mg), white solid into racemoid
MS?FABS?588.9/590.8
Embodiment 4
(+)-4-(3-bromo-8,10-dichloro--6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-yl)-1-[2-(1,3-dihydro-1,3-dioxo-2H-isoindole-2-yl)-1-oxoethyl] piperidines
Steps A
(9.90g 18.9mmol) is dissolved in 150ml methylene dichloride and the 200ml acetonitrile and is heated to 60 ℃ with the product of embodiment 5 step B.Add 2.77g (20.8mmol) N-chlorosuccinimide, be heated to and refluxed 3 hours, with TLC (30% ethyl acetate/water) monitoring reaction.Add 2.35g (10.4mmol) N-chlorosuccinimide again, refluxed 45 minutes.This reaction mixture is cooled to room temperature, with 1N sodium hydroxide and dichloromethane extraction.Use the dried over mgso dichloromethane layer, filter and, obtain the required product of 6.24g through flash chromatography (the 1200ml purification on normal-phase silica gel is with 30% ethyl acetate/water elution).M.p.193-195.4℃。
Step B:
In-10 ℃, in the 160ml concentrated hydrochloric acid, add 2.07g (30.1mmol) Sodium Nitrite, stirred 10 minutes.Add embodiment 4 steps A product (5.18g, 10.1mmol), with this reaction mixture from-10 ℃ be heated to 0 ℃ 2 hours.Reactant is cooled to-10 ℃, adds the 100ml Hypophosporous Acid, 50, placement is spent the night.Be the extractive reaction mixture, it is inclined to trash ice, with 50% sodium hydroxide/methylene dichloride alkalization.Use the dried over mgso organic layer, filter and be concentrated into dried.Through flash chromatography (the 600ml purification on normal-phase silica gel is with 20% ethyl acetate/hexane wash-out) purifying, obtain the 3.98g product.Mass spectrum: MH
+497.2.
Step C:
Be dissolved in the product of 3.9g embodiment 4 step B in the 100ml concentrated hydrochloric acid and reflux and spend the night.Cool off this mixture, with the alkalization of 50%w/w sodium hydroxide, with the mixture of dichloromethane extraction generation.Use the dried over mgso dichloromethane layer, evaporating solvent, drying obtains the required product of 3.09g under vacuum.Mass spectrum: MH
+=424.9.
Step D:
With the method that is similar to embodiment 5 step F and G, obtain the required product of 1.73g, m.p.169.6-170.1 ℃; [α]
D 25+ 48.2 ° (c=1, MeOH).
Step e
Product (0.5g with embodiment 5 step D; 1.2mmol) be dissolved among the 10ml DMF, add 0.3g (1.5mmol) phthaloyl (pthaloyl) glycine, 0.29g (1.5mmol) DEC, 0.20g (1.5mmol) HOBT and 0.15g (1.5mmol) N-methylmorpholine in about 0 ℃.This reaction mixture stirring is spent the night, be warmed to room temperature.Remove volatile matter.It is allocated between water and the methylene dichloride.Use the dichloromethane extraction water.The combined dichloromethane component is through dried over mgso and concentrated.Through the flash chromatography purifying,, obtain target compound with 50% ethyl acetate-hexane wash-out.Mp=144-145 ℃ of mass spectrum MH+=614.
FPT?IC
50=0.0186μM。
Embodiment 5
(+)-4-(3,10-two bromos-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11 (R)-yl)-1-[(1-oxopropyl-4-piperidyl) ethanoyl] piperidines
Steps A:
In-5 ℃, with 4-(8-chloro-3-bromo-5,6-dihydro-11H-benzo [5,6] cyclohepta-[1,2-b] pyridine-11-subunit)-(15g 38.5mmol) mixes with the 150ml vitriol oil 1-piperidines-1-ethyl formate, add 3.89g (38.5mmol) saltpetre then, stirred 4 hours.This mixture is inclined to 3L ice, alkalize with the 50% concentrated sodium hydroxide aqueous solution.Use dichloromethane extraction, through dried over mgso, filter then, vacuum concentration is a residue.The recrystallization residue obtains the 6.69g product from acetone.
1H?NMR(CDCl
3,200MHz):8.5(s,1H)；7.75(s,1H)；7.6(s,1H)；7.35(s,1H)；4.15(q,2H)；3.8(m,2H)；3.5-3.1(m,4H)；3.0-2.8(m,2H)；2.6-2.2(m,4H)；1.25(t,3H)。
Step B
(6.69g 13.1mmol) merges with 100ml 85% ethanol/water, adds 0.66g (5.9mmol) calcium chloride and 6.56g (117.9mmol) iron then, under refluxing this mixture heating up is spent the night then with the product of steps A.Pass through celite
Filter the reaction mixture of heat, use the hot ethanol washing leaching cake.Vacuum concentrated filtrate obtains the 7.72g product.Mass spectrum MH
+=478.0.
Step C:
The product of 7.70g step B is mixed with 35ml acetate, add the acetic acid solution of 45ml bromine then, under room temperature, this mixture stirring is spent the night.Add 300ml 1N aqueous sodium hydroxide solution, add 75ml 50% aqueous sodium hydroxide solution then, use ethyl acetate extraction.Through the dried over mgso extract, vacuum concentration is a residue.Residue chromatography (silica gel, 20%-30% ethyl acetate/hexane) is obtained 3.47g product (and the partially purified product of 1.28g).Mass spectrum MH
+=555.9.
1H?NMR(CDCl
3,300MHz):8.5(s,1H)；7.5(s,1H)；7.15(s,1H),4.5(s,2H)；4.15(m,3H)；3.8(br?s,2H)；3.4-3.1(m,4H)；9-2.75(m,1H)；2.7-2.5(m,2H)；2.4-2.2(m,2H)；1.25(m,3H)。
Step D:
In 300ml HCl (being cooled to-10 ℃), add Sodium Nitrite (1.86g, 27mmol) and stirred 5 minutes.With in 10 fens these mixtures of clockwise by a compound that part adds embodiment 5 step C (5g, 9mmol).This reactant is warmed to 0-3 ℃, stirred 2 hours.Slowly add the 75ml Hypophosporous Acid, 50 to this mixture, this reaction mixture was kept in refrigerator about 16 hours.Mixture is inclined to ice, pH is transferred to 9-10 with 50% (v/v) sodium hydroxide.Use ethyl acetate extraction.Dry ethyl acetate layer and vacuum concentration are residue.Residue chromatography (silica gel, 10%-20% ethyl acetate/hexane) is obtained the 3.7g product.Mass spectrum MH
+=541.0.
1H?NMR(CDCl
3,200MHz):8.52(s,1H)；7.5(d,2H)；7.2(s,1H),4.15(q,2H)；3.9-3.7(m,2H)；3.5-3.1(m,4H)；3.0-2.5(m,2H)；2.4-2.2(m,2H)；2.1-1.9(m,2H)；1.26(t,3H)。
Step e:
(0.70g 1.4mmol) mixes with the 8ml concentrated hydrochloric acid aqueous solution, under refluxing this mixture heating up is spent the night with the product of step D.Add 30ml 1N aqueous sodium hydroxide solution, add 5ml 50% aqueous sodium hydroxide solution then, use dichloromethane extraction.Use the dried over mgso extract, vacuum concentration obtains the 0.59g target compound.Mass spectrum M
+=468.7.m.p.=123.9-124.2℃。
Step F:
Be prepared into toluene solution, add the toluene solution of 17.3ml 1M DIBAL from the compound (8.1g) of embodiment 5 step e.In this mixture of heating down that refluxes, with 40 minutes slow (dropping) 21ml 1M DIBAL/ toluene solutions that add.This reaction mixture is cooled to about 0 ℃, adds 700ml 1M aqueous hydrochloric acid.Separation also discards organic phase.Use the washed with dichloromethane water, discard extract, add 50% aqueous sodium hydroxide solution alkalization water then.Use dichloromethane extraction, through the dried over mgso extract, vacuum concentration obtains the 7.30g target compound, is the racemic mixture of enantiomorph.
Step G-Separation of Enantiomers
Separate the racemic target compound of embodiment 5 step F with preparation property chirality chromatography (Chiralpack AD, 5cm * 50cm post is with 20% isopropanol/hexane+0.2% diethylamine wash-out), obtain (+)-isomer and (-)-isomer of above-claimed cpd.
The physicochemical data of (+)-isomer: m.p.=148.8 ℃; Mass spectrum MH
+=472; [α]
D 25=+65.6 ° (12.9mg/2ml methyl alcohol)
The physicochemical data of (-)-isomer: m.p.=112 ℃; Mass spectrum MH
+=472; [α]
D 25=-65.2 ° (3.65mg/2ml methyl alcohol)
Step H:
(+)-isomer
With (+)-isomer products of embodiment 5 step G (3.21g, 6.80mmol) and the 150ml dry DMF mix.Make 1.33g (+)-isomer and 1.37g 1-N-tert-butoxycarbonyl piperidyl-4-acetate, 1.69g (8.8mmol) DEC, 1.19g (8.8mmol) HOBT and the reaction of 0.97ml (8.8mmol) 4-methylmorpholine, under room temperature, this mixture stirring is spent the night.Vacuum concentration is removed DMF, adds the saturated sodium bicarbonate aqueous solution of 50ml.(2 * 250ml) extractions are with 50ml salt water washing extract, through dried over mgso with methylene dichloride.Vacuum concentration is a residue, and chromatography (silica gel, 2% ethanol/methylene+10% ammonium hydroxide wash-out) obtains the 2.78g product.Mass spectrum MH
+=694.0 (FAB); [α]
D 25=+34.1 ° (5.45mg/2ml methyl alcohol).
Step I:
Handle compound and the 60ml methylene dichloride of 2.78g embodiment 5 step H, be cooled to 0 ℃ then, add 55ml TFA.In 0 ℃, this mixture was stirred 3 hours, add the 500ml1N aqueous sodium hydroxide solution, then add 30ml 50% aqueous sodium hydroxide solution.Use dichloromethane extraction, through dried over mgso, vacuum concentration obtains the 1.72g product.m.p.=104.1℃。Mass spectrum M
+=597; [α]
D 25=+53.4 ° (11.42mg/2ml methyl alcohol).
Step J:
The compound of embodiment 5 step I in being dissolved in anhydrous methylene chloride (6ml) (0.11g, 0.19mmol) and triethylamine (0.08ml, add in 0.57mmol) propionyl chloride (0.04ml, 2eq).After stirring under the room temperature is spent the night, add 1M hydrochloric acid, this mixture of jolting.Separate organic phase, with the washing of 1N sodium hydroxide, then through dried over mgso.Filter and vacuum concentration, obtain target compound (0.10g, productive rate 83%, mp106.4-109.3 ℃).
FPT?IC
50=0.0068μM。
The preparation of raw material
Embodiment by following preparation comes exemplary illustration to be used to prepare the raw material of The compounds of this invention, and these examples should not constitute the restriction to disclosure scope.This type of raw material can prepare with methods known in the art, as sees the Bioorganic ﹠amp of J.K.Wong etc.; MedicinalChemistry Letters (the 3rd volume, the 6th phase, the 1073-1078 page or leaf, (1993), U.S. patent 5089496,5151423,4454143,4355036, PCT/US94/11390 (WO95/10514), PCT/US94/11391 (WO95/10515), PCT/US94/11392 (WO95/10516); The OrganicFunctional Group Preparations of Stanley R.Sandler and Wolf Karo (the 2nd edition, Academic Press, Inc., SanDiego, California, 1-3 volume, (1983)) and J March, Advanced OrganicChemistry, Reactions ﹠amp; Mechanisms, and Structure, the 3rd edition, JohnWiley ﹠amp; Sons, New York, the 1346th page. the method for (1985) etc.Other mechanism approach and similar structures in the scope of the invention are apparent to those skilled in the art.
Measure
Vitro enzyme is measured: measure FPTIC according to WO/10515 or WO95/10516 disclosed method
50(inhibition of farnesyl-protein transferase, vitro enzyme is measured).Digital proof among embodiment compound of the present invention is the inhibitor of partially purified rat brain farnesyl-protein transferase (FPT) Ras-CVLS farnesylation.Data show that also compound of the present invention is effective inhibitor (IC of partially purified rat brain FPT Ras-CVLS farnesylation
50＜＜10 μ M).
By compound medicinal compositions of the present invention the time, inert, pharmaceutically acceptable carrier can be solid or liquid.Solid preparation comprises pulvis, tablet, dispersible granule, capsule, cachet and suppository.Pulvis and tablet can contain the active ingredient of the 5-that has an appointment about 70%.Suitable solid carrier is known in the art, as magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose.Tablet, pulvis, cachet and capsule are for being fit to the solid dosage of oral administration.
During preparation suppository, at first the mixture with low-melting wax such as glycerin fatty acid ester or theobroma oil melts, and stirs down with the active ingredient homodisperse wherein.Then the uniform mixture that melts is inclined to the mould of convenient size, therefore its cooling is also solidified.
Liquid preparation comprises solution, suspension and emulsion.The example that is fit to the parenteral injection is water or water-propylene glycol solution.
Liquid preparation also can comprise the solution for intranasal administration.
The aerosol formulation that be fit to suck can comprise the solid of solution and powder type, they can with pharmaceutically acceptable carrier for example the inertia pressurized gas mix.
Be also included within and face the solid form preparation that is translated into before the use for the liquid preparation of oral or parenteral admin.This type of liquid preparation comprises solution, suspension and emulsion.
Also can be with compound transdermal administration of the present invention.Transdermal composition can be paste, lotion, aerosol and/or emulsion, is included as the matrix type commonly used of this area purpose or the transdermal patch of Drug Storage type.
Preferred this compound oral administration.
Preferred this medicinal preparations is a unit dosage.During for this type of formulation, said preparation can be divided into the unitary dose of the active ingredient that contains the appropriate amount significant quantity of required purpose (as reach).
The amount of active compound can be according to concrete service condition in about 0.1mg-1000mg, more preferably variation or adjustment between about 1mg-300mg in the unit dosage of preparation.
Can change the actual dose of use according to the severity of patient's needs and disease to be treated.Those skilled in the art can easily determine suitable dose in particular cases.Generally speaking, treatment begins with the dosage lower slightly than the optimal dose of this compound.After this, increase dosage gradually to reaching best effect under specific circumstances.For simplicity, total dose every day can be separated, and gradation administration in whole day as required.
After the severity of the symptom of the age of having considered various factors such as patient, physical appearance and volume and treatment, adjust the dosage and the frequency of compound of the present invention and pharmacy acceptable salt thereof according to doctor's judgement.The recommended dose scheme of general oral administration be every day 10mg-2000mg, preferred every day 10-1000mg divide 2-4 administration to block tumor growth in whole day.When administration in this dosage range, described compound is avirulent.
Classify the embodiment of the pharmaceutical dosage form that contains The compounds of this invention down as.The restriction of the embodiment that provided is not provided the scope of medicinal compositions of the present invention aspect.
Pharmaceutical dosage form embodiment
Embodiment A-tablet
| Sequence number | Composition | The mg/ sheet | The mg/ sheet |
| ??1 | Activeconstituents | ?100 | ?500 |
| ??2 | Lactose USP | ?122 | ?113 |
| ??3 | W-Gum, food grade is 10% paste in the pure water | ?30 | ?40 |
| ??4 | W-Gum, food grade | ?45 | ?40 |
| ??5 | Magnesium Stearate | ?3 | ?7 |
| Add up to | ?300 | ?700 |
The preparation method
The composition of sequence number 1 and 2 was mixed 10-15 minute in the mixing tank that is fit to.To granulate with sequence number 3 mixture of ingredients.If desired can by scalping (as 1/4 ", 0.63cm) grind wet granular.Dry wet particle.If desired, sieve dry granules and make itself and the composition mixing of sequence number 4 10-15 minute.The composition of adding sequence number 5 also mixed 1-3 minute.On suitable tabletting machine, this mixture compressing tablet is become suitable size and weight.
Embodiment B-capsule
| Sequence number | Composition | The mg/ capsule | The mg/ capsule |
| ???1 | Activeconstituents | ????100 | ????500 |
| ???2 | Lactose | ????106 | ????123 |
| ???3 | W-Gum, food grade | ????40 | ????70 |
| ???4 | Magnesium Stearate NF | ????7 | ????7 |
| Add up to | ????253 | ????700 |
Manufacture method
The composition of sequence number 1,2 and 3 was mixed 10-15 minute in the mixing tank that is fit to.The composition of adding sequence number 4 also mixed 1-3 minute.On suitable packing machine, this mixture inserted two joints-hard gelatin capsule in.
Although introduced the present invention in conjunction with specific embodiment set forth above, its many other scheme, modifications and variations should be conspicuous for those of ordinary skills.All these selections, modifications and variations all will be thought within the spirit and scope of the present invention.
Claims (7)
1. be compound or its pharmacy acceptable salt of following formula structure:
2. suppress the medicinal compositions of abnormal growth of cells, it comprises the compound and the pharmaceutically acceptable carrier of the claim 1 of significant quantity.
3. suppress the method for abnormal growth of cells, this method comprises the compound of the claim 1 that gives significant quantity.
4. the method for claim 3, wherein repressed cell is for expressing the tumour cell of activated ras oncogene.
5. the method for claim 3, wherein repressed cell is pancreas tumour cell, lung carcinoma cell, myelomatosis tumour cell, thyroid follicle tumour cell, myelodysplasia tumour cell, epidermal carcinoma tumour cell, bladder cancer tumour cell and colon tumor cell.
6. the method for claim 3, wherein the inhibition of abnormal growth of cells produces by suppressing the ras farnesyl-protein transferase.
7. the method for claim 6, wherein said inhibition is the inhibition to tumour cell, wherein Ras albumen since other gene cancer sudden change of non-Ras gene be activated.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71390896A | 1996-09-13 | 1996-09-13 | |
| US08/713,908 | 1996-09-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1237176A true CN1237176A (en) | 1999-12-01 |
Family
ID=24868035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199601A Pending CN1237176A (en) | 1996-09-13 | 1997-09-11 | Tricyclic compounds useful as FPT inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0927181A1 (en) |
| JP (1) | JP2001500505A (en) |
| CN (1) | CN1237176A (en) |
| AU (1) | AU4337497A (en) |
| CA (1) | CA2265764A1 (en) |
| WO (1) | WO1998011106A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548297A (en) * | 2020-06-16 | 2020-08-18 | 大桐制药（中国）有限责任公司 | Synthetic method of vildagliptin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6228865B1 (en) * | 1997-06-17 | 2001-05-08 | Schering Corporation | Compounds useful for inhibition of farnesyl protein transferase |
| CA2319077A1 (en) | 1998-01-21 | 1999-07-29 | Yoshisuke Nakasato | Chemokine receptor antagonists and methods of use therefor |
| US6509346B2 (en) | 1998-01-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US6613905B1 (en) | 1998-01-21 | 2003-09-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US6433165B1 (en) | 1998-01-21 | 2002-08-13 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US7271176B2 (en) | 1998-09-04 | 2007-09-18 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use thereof |
| US6288083B1 (en) | 1998-09-04 | 2001-09-11 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US6503926B2 (en) | 1998-09-04 | 2003-01-07 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| US7342016B2 (en) * | 2000-08-30 | 2008-03-11 | Schering Corporation | Farnesyl protein transferase inhibitors as antitumor agents |
| US7541365B2 (en) | 2001-11-21 | 2009-06-02 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
| TWI291467B (en) | 2002-11-13 | 2007-12-21 | Millennium Pharm Inc | CCR1 antagonists and methods of use therefor |
| US7417026B2 (en) | 2003-08-13 | 2008-08-26 | Children's Hospital Medical Center | Mobilization of hematopoietic cells |
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| US5719148A (en) * | 1993-10-15 | 1998-02-17 | Schering Corporation | Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases |
| IL111235A (en) * | 1993-10-15 | 2001-03-19 | Schering Plough Corp | Pharmaceutical compositions for inhibition of g-protein function and for treatment of proliferative diseases containing tricyclic compounds some such compounds and process for preparing part of them |
| US5700806A (en) * | 1995-03-24 | 1997-12-23 | Schering Corporation | Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
| IL117798A (en) * | 1995-04-07 | 2001-11-25 | Schering Plough Corp | Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases and pharmaceutical compositions comprising them |
| SK86198A3 (en) * | 1995-12-22 | 1999-02-11 | Schering Corp | Tricyclic amides useful for inhibition of g-protein function and for treatment of proliferative diseases |
-
1997
- 1997-09-11 CA CA002265764A patent/CA2265764A1/en not_active Abandoned
- 1997-09-11 WO PCT/US1997/015901 patent/WO1998011106A1/en not_active Application Discontinuation
- 1997-09-11 AU AU43374/97A patent/AU4337497A/en not_active Abandoned
- 1997-09-11 JP JP10513760A patent/JP2001500505A/en active Pending
- 1997-09-11 EP EP97941475A patent/EP0927181A1/en not_active Withdrawn
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111548297A (en) * | 2020-06-16 | 2020-08-18 | 大桐制药（中国）有限责任公司 | Synthetic method of vildagliptin |
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|---|---|
| JP2001500505A (en) | 2001-01-16 |
| EP0927181A1 (en) | 1999-07-07 |
| AU4337497A (en) | 1998-04-02 |
| WO1998011106A1 (en) | 1998-03-19 |
| CA2265764A1 (en) | 1998-03-19 |
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