US20150329482A1 - Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethoxy}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid - Google Patents
Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethoxy}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid Download PDFInfo
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- US20150329482A1 US20150329482A1 US14/810,783 US201514810783A US2015329482A1 US 20150329482 A1 US20150329482 A1 US 20150329482A1 US 201514810783 A US201514810783 A US 201514810783A US 2015329482 A1 US2015329482 A1 US 2015329482A1
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- HZZMSGKDRGRMFJ-UHFFFAOYSA-N COC1=CC2=C(C=C1)/C1=C(\C3CCCCC3)C3=CC=C(C(=O)O)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.COC1=CC2=C(C=C1)/C1=C(\C3CCCCC3)C3=CC=C(C(=O)OC(C)(C)C)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.O=CC(F)(F)F Chemical compound COC1=CC2=C(C=C1)/C1=C(\C3CCCCC3)C3=CC=C(C(=O)O)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.COC1=CC2=C(C=C1)/C1=C(\C3CCCCC3)C3=CC=C(C(=O)OC(C)(C)C)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.O=CC(F)(F)F HZZMSGKDRGRMFJ-UHFFFAOYSA-N 0.000 description 1
- BQTTUPATUONYDB-UHFFFAOYSA-N COC1=CC2=C(C=C1)C1=C(C3CCCCC3)C3=CC=C(C(=O)O)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.COC1=CC2=C(C=C1)C1=C(C3CCCCC3)C3=CC=C(C(=O)OC(C)(C)C)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(=O)(=O)NC(=O)OC(C)(C)C)=C2.II Chemical compound COC1=CC2=C(C=C1)C1=C(C3CCCCC3)C3=CC=C(C(=O)O)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(N)(=O)=O)=C2.COC1=CC2=C(C=C1)C1=C(C3CCCCC3)C3=CC=C(C(=O)OC(C)(C)C)C=C3N1CC(C(=O)N(C)CCOCCN(C)S(=O)(=O)NC(=O)OC(C)(C)C)=C2.II BQTTUPATUONYDB-UHFFFAOYSA-N 0.000 description 1
- KEQQONPVAQQBHG-UHFFFAOYSA-N C[N+](C)=C1C=CN(S(=O)(=O)[N-]C(=O)OC(C)(C)C)C=C1 Chemical compound C[N+](C)=C1C=CN(S(=O)(=O)[N-]C(=O)OC(C)(C)C)C=C1 KEQQONPVAQQBHG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C307/04—Diamides of sulfuric acids
- C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2- ⁇ 2-[methyl-(sulphamoyl)-amino]-ethoxy ⁇ -ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid.
- the present invention also relates to a new compound, namely tent-butyl (methyl- ⁇ 2-[2-(methylamino)-ethoxy]-ethyl ⁇ -sulphamoyl)-carbamate, used in this improved method.
- WO 2010 / 003658 describes some macrocyclic indoles that can be used as inhibitors of the hepatitis C virus.
- the aim of the present invention is to provide an improved method for the synthesis of 13-cyclohexyl-3-methoxy-6-[methyl-(2- ⁇ 2-[methyl-(sulphamoyl)-amino]-ethoxy ⁇ -ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid (Compound ‘A’) that is easier to carry out and is more efficient than the method known so far.
- the present invention achieves this aim by providing an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2- ⁇ 2-[methyl-(sulphamoyl)-amino]-ethoxy ⁇ -ethyl)-carbamoyl]-7H-indolo-[2, 1 -a]-[2]-benzazepine- 10-carboxylic acid (‘Compound A’), characterized in that it comprises the following steps:
- the coupling agent in Step a) is e.g. carbodiimidazole (CDI), dicyclohexylcarbodiimide (DCC), O-(7-azabenztriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), bromotri-(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), a combination of 1-hydroxybenztriazole hydrate (HOBt.H 2 O) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI).
- CDI carbodiimidazole
- DCC dicyclohexylcarbodiimide
- HATU O-(7-azabenztriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
- PyBrOP bromotri-
- a suitable solvent in Step a) is e.g. dichloromethane, 2-methyltetrahydrofuran, acetonitrile, acetone, 2-butanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate or toluene.
- the hydrolysis in Step b) can be carried out by using trifluoroacetic acid, methanesulphonic acid, hydrogen chloride, hydrogen bromide, para-toluenesulphonic acid, sulphuric acid or phosphoric acid.
- Steps a) and b) can be carried out as a two-step synthesis, in which Compound (II) is isolated in Step a) before carrying out Step b), or else Steps a) and b) are conducted as a one-vessel synthesis.
- the overall yield obtained in Steps a) and b) is between 86 and 91%, depending on which of the procedures described in Examples 3, 4 and 5 (Experiment B) is used to carry out the new method.
- the present invention also relates to a new compound (Compound ‘B’) with the following formula, and possible acid-addition salts thereof:
- the acid-addition salts of Compound ‘B’ include the salts that Compound ‘B’ can form with organic or inorganic acids, such as mineral acids, sulphonic acids, carboxylic acids and phosphorus-containing acids.
- organic or inorganic acids such as mineral acids, sulphonic acids, carboxylic acids and phosphorus-containing acids.
- salt-forming mineral acids are hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, nitric acid, chloric acid, perchloric acid and phosphoric acid.
- Salt-forming sulphonic acids are toluenesulphonic acid, benzenesulphonic acid, methanesulphonic acid and trifluormethanesulphonic acid.
- Salt-forming carboxylic acids are formic acid, acetic acid, propionic acid, butanoic acid and the like.
- Salt-forming dicarboxylic acids are oxalic acid, malonic acid, succinic acid, glutaric acid and the like.
- Salt-forming hydroxy-acids are glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and the like.
- Other salt-forming carboxylic acids are trifluoroacetic acid, benzoic acid, chloroacetic acid, phthalic acid, maleic acid and malonic acid.
- Phosphorus-containing acids are various phosphono-acids, phosphonic acids and phosphinic acids.
- This new Compound ‘B’ can be synthesized as follows:
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid. The present invention also relates to a new compound, namely tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate, used in this improved method.
Description
- The present invention relates to an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid. The present invention also relates to a new compound, namely tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate, used in this improved method.
- WO 2010 / 003658 describes some macrocyclic indoles that can be used as inhibitors of the hepatitis C virus. The synthesis of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1 -a]-[2]-benzazepine-10-carboxylic acid (Compound ‘A’) was described there on pages 38 and 39 (see Compound 1e) as a three-step synthesis, giving an overall yield of 62%.
- The aim of the present invention is to provide an improved method for the synthesis of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid (Compound ‘A’) that is easier to carry out and is more efficient than the method known so far.
- The present invention achieves this aim by providing an improved method for the preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2, 1 -a]-[2]-benzazepine- 10-carboxylic acid (‘Compound A’), characterized in that it comprises the following steps:
- a) 1 0-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo-[2,1 -a]-[2]-benzazepine-6-carboxylic acid (Compound I) is reacted with tent-butyl (methyl-{2-[2-(methylamino)-ethoxy]-ethyl}-sulphamoyl)-carbamate (‘Compound B’) in the presence of a coupling agent in a suitable solvent
- b) and Compound (II) thus obtained is hydrolysed with an acid to prepare Compound ‘A’.
- The coupling agent in Step a) is e.g. carbodiimidazole (CDI), dicyclohexylcarbodiimide (DCC), O-(7-azabenztriazolo-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), bromotri-(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), a combination of 1-hydroxybenztriazole hydrate (HOBt.H2O) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI).
- A suitable solvent in Step a) is e.g. dichloromethane, 2-methyltetrahydrofuran, acetonitrile, acetone, 2-butanone, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate or toluene.
- The hydrolysis in Step b) can be carried out by using trifluoroacetic acid, methanesulphonic acid, hydrogen chloride, hydrogen bromide, para-toluenesulphonic acid, sulphuric acid or phosphoric acid.
- Steps a) and b) can be carried out as a two-step synthesis, in which Compound (II) is isolated in Step a) before carrying out Step b), or else Steps a) and b) are conducted as a one-vessel synthesis.
- The overall yield obtained in Steps a) and b) is between 86 and 91%, depending on which of the procedures described in Examples 3, 4 and 5 (Experiment B) is used to carry out the new method.
- The present invention also relates to a new compound (Compound ‘B’) with the following formula, and possible acid-addition salts thereof:
- The acid-addition salts of Compound ‘B’ include the salts that Compound ‘B’ can form with organic or inorganic acids, such as mineral acids, sulphonic acids, carboxylic acids and phosphorus-containing acids. Examples of salt-forming mineral acids are hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, sulphuric acid, nitric acid, chloric acid, perchloric acid and phosphoric acid. Salt-forming sulphonic acids are toluenesulphonic acid, benzenesulphonic acid, methanesulphonic acid and trifluormethanesulphonic acid. Salt-forming carboxylic acids are formic acid, acetic acid, propionic acid, butanoic acid and the like. Salt-forming dicarboxylic acids are oxalic acid, malonic acid, succinic acid, glutaric acid and the like. Salt-forming hydroxy-acids are glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and the like. Other salt-forming carboxylic acids are trifluoroacetic acid, benzoic acid, chloroacetic acid, phthalic acid, maleic acid and malonic acid. Phosphorus-containing acids are various phosphono-acids, phosphonic acids and phosphinic acids.
- This new Compound ‘B’ can be synthesized as follows:
- The following abbreviations are used here:
- A/A: active yield
- CDI: carbonyldiimidazole
- CSI: chlorosulphonyl isocyanate
- DBU: 1,8-diaza-bicyclo-[5,4,0]-undecene-7
- DIPE: diisopropyl ether
- DMAP: 4-dimethylaminopyridine
- DME: 1,2-dimethoxyethane
- DMSO-d6: deuterated dimethylsulphoxide
- EDCI: 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
- F/F: physical yield
- HOBt: 1-hydroxybenzotriazole hydrate
- iPrOAc: isopropyl acetate
- LC: liquid chromatography
- MeCN: acetonitrile
- MEK: methyl ethyl ketone (2-butanone)
- MeTHF: 2-methyltetrahydrofuran
- MeSO3H: methanesulphonic acid
- MIK: methyl isopropyl ketone
- MTBE: methyl tent-butyl ether
- NMR: nuclear magnetic resonance
- tBuOH: tent-butanol
- tBOC: tert-butoxycarbonyl
- THF: tetrahydrofuran
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- A solution of 8.205 g of chlorosulphonyl isocyanate (58.0 mmol, 1 Eq) in 50 ml of acetonitrile (1 litre/mol) was cooled to −2° C. on an ice/salt bath under nitrogen, using a 500-ml four-neck flask fitted with a thermometer, a magnetic stirrer and a dropping (addition) funnel. A solution of 4.297 g of tent-butanol (58.0 mmol, 1 Eq) in 33 ml of acetonitrile (0.5 l/mol) was added dropwise over 20 minutes, with the temperature remaining below 4° C. Four minutes later (when the temperature had dropped to 1° C.), a solution of DMAP (116.0 mmol, 2 Eq) in 55 ml of acetonitrile (1 litre/mol) was added dropwise over 24 minutes, with the temperature remaining below 5° C.
- The solution was allowed to stand for 65 minutes to ensure the best crystallization, with the temperature remaining below 3° C. The white suspension was filtered on a Buchner funnel filter, giving a non-tacky white powder. The precipitate was dried overnight in a drying cabinet at 40° C. under vacuum, which gave 9.465 g of Intermediate (I).
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- 109.1 g (0.825 mol) of 1,5-bis-(methylamino)-3-oxapentane and 1.5 litres of acetonitrile were introduced into a reaction vessel with an inert atmosphere. The resulting solution was cooled to 0° C., and 226 g (0.75 mol) of Intermediate (1) was added to it. The mixture thus obtained was stirred first for 6 hours at 10° C., and then for 3 days at 0° C. The precipitate was filtered off and washed with acetonitrile. After drying at 25° C., Compound ‘B’ was obtained in a yield of 95 g (40.6%, corrected for purity) in the form of white crystals.
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- 0.400 g (0.82 mmol, 1 Eq) of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy- 7H-indolo-[2,1-a]-[2]-benzazepine-6-carboxylic acid (called Compound 1b on page 38 of WO 2010/003658), 0.164 g of HOBt (1.07 mmol, 1.3 Eq) and 0.201 g of EDCI (1.07 mmol, 1.3 Eq) were dissolved in 6.5 ml of MeTHF (8 l/mol) in a closed glass flask. The contents of the flask were stirred for 1 hour at room temperature. 0.469 g of Compound ‘B’ (64.3 wt-%, 0.98 mmol, 1.2 Eq) was then added to the reaction mixture, which was analysed after a reaction time of 18 hours. Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 93.1%.
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- 12.00 g (24.61 mmol, 1 Eq) of 10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy- 7H-indolo-[2,1-a]-[2]-benzazepine-6-carboxylic acid, 4.92 g of HOBt (31.99 mmol, 1.3 Eq) and 6.03 g of EDCI (31.99 mmol, 1.3 Eq) were introduced into a 100-ml flask and dissolved in 200 ml of MeTHF (8 l/mol). The contents of the flask were stirred for 1 hour at room temperature. Then 11.663 g of Compound ‘B’ (77.4 wt-%, 29.53 mmol, 1.2 Eq) was added, and the reaction mixture was analysed after a reaction time of 18 hours. Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 98.3%.
- The reaction mixture was then extracted and washed first with two 180-ml portions of H2O (15 l/mol), and then with two 180-ml portions of an NaHCO3 solution (15 l/mol). The organic layer was dried with 2.4 g of Na2SO4 and filtered, after which the volume of the filtrate obtained was determined. 60 ml of MeTHF was added to make up the volume to 200 ml (8 l/M). Analysis by LC indicated that Intermediate (2) had been obtained in a yield of 93.7%.
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- To 13.722 g of Intermediate (2) (16.4 wt-%, 1 Eq, 2.88 mmol) dissolved in MeTHF (8 l/mol) in a 100-ml flask without a nitrogen atmosphere(this solution contained 2.17 wt-% of water), 251 pl of water was added to bring the water content up to 4 wt-%. After the addition of 1.9 ml of MeSO3H (1 Eq, 28.8 mmol), the reaction mixture was placed on an oil bath heated to 50° C. A sample was taken and analysed after a reaction time of 5 hours. After a reaction time of 22 hours, the reaction mixture was brought to room temperature, and sampled again for analysis. The whole reaction mixture weighed 15.022 g.
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- After 5 hours: 90.1% of Compound ‘A’
- After 22 hours: 75.4% of Compound ‘A’
- 119.6 g of Intermediate (2) (10.27 wt-%, 15.7 mmol, 1 Eq) was dissolved in MeTHF (8 l/mol) in a reaction vessel with a nitrogen atmosphere. The solution contained 2.21 wt-% of water. 2.81 g of water were added to bring the water content up to 4 wt-%. After the addition of 10.31 ml of MeSO3H (157 mmol, 10 Eq), the reaction mixture was heated to 50° C. After a reaction time of 5 hours, the reaction mixture was cooled to room temperature, and a sample of it was analysed. The whole reaction mixture weighed 119.6 g.
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- 92.7% of Compound ‘A’
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/810,783 US20150329482A1 (en) | 2010-06-24 | 2015-07-28 | Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethoxy}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10167221 | 2010-06-24 | ||
US13/805,607 US9127010B2 (en) | 2010-06-24 | 2011-06-24 | Preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid |
PCT/EP2011/060606 WO2011161232A1 (en) | 2010-06-24 | 2011-06-24 | PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(SULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7H-INDOLO-[2,1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID |
US14/810,783 US20150329482A1 (en) | 2010-06-24 | 2015-07-28 | Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethoxy}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid |
Related Parent Applications (2)
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US13/806,607 Division US20130091758A1 (en) | 2010-06-24 | 2011-06-22 | Insect bait |
PCT/EP2011/060606 Division WO2011161232A1 (en) | 2010-06-24 | 2011-06-24 | PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(SULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7H-INDOLO-[2,1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID |
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US20150329482A1 true US20150329482A1 (en) | 2015-11-19 |
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US13/805,607 Expired - Fee Related US9127010B2 (en) | 2010-06-24 | 2011-06-24 | Preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid |
US14/810,783 Abandoned US20150329482A1 (en) | 2010-06-24 | 2015-07-28 | Preparation of 13-Cyclohexyl-3-Methoxy-6-[Methyl-(2-(2-[Methyl-(Sulphamoyl)-Amino]-Ethoxy}-Ethyl)-Carbamoyl]-7H-Indolo-{2,1-a]-[2]-Benzazepine-10-Carboxylic Acid |
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US13/805,607 Expired - Fee Related US9127010B2 (en) | 2010-06-24 | 2011-06-24 | Preparation of 13-cyclohexyl-3-methoxy-6-[methyl-(2-{2-[methyl-(sulphamoyl)-amino]-ethoxy}-ethyl)-carbamoyl]-7H-indolo-[2,1-a]-[2]-benzazepine-10-carboxylic acid |
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US (2) | US9127010B2 (en) |
EP (1) | EP2585438B1 (en) |
JP (1) | JP5870098B2 (en) |
CN (1) | CN103097356B (en) |
AU (1) | AU2011268922B2 (en) |
BR (1) | BR112012032889A2 (en) |
CA (1) | CA2801517C (en) |
IL (1) | IL223427A (en) |
MX (1) | MX2012015198A (en) |
RU (1) | RU2559886C2 (en) |
WO (1) | WO2011161232A1 (en) |
Cited By (1)
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US9427440B2 (en) | 2008-07-08 | 2016-08-30 | Janssen Sciences Ireland Uc | Macrocyclic indole derivatives useful as hepatitis C virus inhibitors |
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US20110105473A1 (en) * | 2008-07-08 | 2011-05-05 | Tibotec Pharmaceuticals | Macrocyclic indole derivatives useful as hepatitis c virus inhibitors |
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US6054472A (en) | 1996-04-23 | 2000-04-25 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
US5807876A (en) | 1996-04-23 | 1998-09-15 | Vertex Pharmaceuticals Incorporated | Inhibitors of IMPDH enzyme |
CZ298463B6 (en) | 1996-04-23 | 2007-10-10 | Vertex Pharmaceuticals Incorporated | Urea derivatives intended for use as IMPDH enzyme inhibitors and pharmaceutical compositions in which the derivatives are comprised |
DK0966465T3 (en) | 1997-03-14 | 2003-10-20 | Vertex Pharma | Inhibitors of IMPDH enzymes |
ES2405316T3 (en) | 1999-03-19 | 2013-05-30 | Vertex Pharmaceuticals Incorporated | IMPDH enzyme inhibitors |
WO2002019369A1 (en) | 2000-08-30 | 2002-03-07 | Matsushita Electric Industrial Co., Ltd. | Plasma display unit and production method thereof |
US7153848B2 (en) | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
KR20080040032A (en) | 2005-09-02 | 2008-05-07 | 티보텍 파마슈티칼즈 리미티드 | Benzodiazepines as hcv inhibitors |
US7399758B2 (en) | 2005-09-12 | 2008-07-15 | Meanwell Nicholas A | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
GB0522881D0 (en) | 2005-11-10 | 2005-12-21 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
WO2007092000A1 (en) | 2006-02-06 | 2007-08-16 | Bristol-Myers Squibb Company | Inhibitors of hcv replication |
US7456166B2 (en) | 2006-05-17 | 2008-11-25 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US7521443B2 (en) | 2006-05-17 | 2009-04-21 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US7521441B2 (en) | 2006-05-22 | 2009-04-21 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US7521442B2 (en) * | 2006-05-25 | 2009-04-21 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
AU2008277440A1 (en) | 2007-07-17 | 2009-01-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic indole derivatives for the treatment of hepatitis C infections |
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- 2011-06-24 US US13/805,607 patent/US9127010B2/en not_active Expired - Fee Related
- 2011-06-24 CA CA2801517A patent/CA2801517C/en not_active Expired - Fee Related
- 2011-06-24 RU RU2013103004/04A patent/RU2559886C2/en not_active IP Right Cessation
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- 2011-06-24 EP EP11727184.1A patent/EP2585438B1/en not_active Not-in-force
- 2011-06-24 WO PCT/EP2011/060606 patent/WO2011161232A1/en active Application Filing
- 2011-06-24 JP JP2013515907A patent/JP5870098B2/en not_active Expired - Fee Related
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- 2011-06-24 BR BR112012032889A patent/BR112012032889A2/en not_active IP Right Cessation
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US20110105473A1 (en) * | 2008-07-08 | 2011-05-05 | Tibotec Pharmaceuticals | Macrocyclic indole derivatives useful as hepatitis c virus inhibitors |
Non-Patent Citations (1)
Title |
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PubChem (see CID 56592562, âSCHEMBL12070859â, p. 1-11, downloaded on 1/31/2017 from <https://pubchem.ncbi.nlm.nih.gov/compound/56592562> with a public availability date of 1/30/2012). * |
Cited By (1)
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US9427440B2 (en) | 2008-07-08 | 2016-08-30 | Janssen Sciences Ireland Uc | Macrocyclic indole derivatives useful as hepatitis C virus inhibitors |
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BR112012032889A2 (en) | 2015-09-15 |
EP2585438B1 (en) | 2014-08-20 |
MX2012015198A (en) | 2013-02-11 |
US20130102777A1 (en) | 2013-04-25 |
WO2011161232A1 (en) | 2011-12-29 |
RU2013103004A (en) | 2014-07-27 |
JP2013530976A (en) | 2013-08-01 |
AU2011268922A1 (en) | 2013-01-10 |
CN103097356B (en) | 2016-01-13 |
RU2559886C2 (en) | 2015-08-20 |
US9127010B2 (en) | 2015-09-08 |
CA2801517C (en) | 2017-12-12 |
CN103097356A (en) | 2013-05-08 |
IL223427A (en) | 2015-04-30 |
CA2801517A1 (en) | 2011-12-29 |
JP5870098B2 (en) | 2016-02-24 |
AU2011268922B2 (en) | 2014-06-12 |
EP2585438A1 (en) | 2013-05-01 |
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