WO2012035078A1 - 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS - Google Patents

17α-HYDROXYLASE/C17,20-LYASE INHIBITORS Download PDF

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Publication number
WO2012035078A1
WO2012035078A1 PCT/EP2011/065965 EP2011065965W WO2012035078A1 WO 2012035078 A1 WO2012035078 A1 WO 2012035078A1 EP 2011065965 W EP2011065965 W EP 2011065965W WO 2012035078 A1 WO2012035078 A1 WO 2012035078A1
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Prior art keywords
alkyl
pyridin
methyl
preparation
dihydro
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PCT/EP2011/065965
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English (en)
French (fr)
Inventor
Mark G. Bock
Christoph Gaul
Venkateshwar Rao Gummadi
Henrik Moebitz
Saumitra Sengupta
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Novartis AG
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Novartis AG
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Priority to CN201180044494.8A priority Critical patent/CN103108871B/zh
Priority to US13/823,792 priority patent/US8946260B2/en
Priority to EP11761540.1A priority patent/EP2627648A1/en
Priority to JP2013528663A priority patent/JP2013537210A/ja
Publication of WO2012035078A1 publication Critical patent/WO2012035078A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Cancer is characterized by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (i.e., metastasis).
  • Non-steroidal small molecule inhibitors have been described for example in BMC 2004,12,(4313), YM116, 2-(lH-imidazol-4-ylmethyl) -9H-carbazole, and their effects in decreasing adrenal androgen synthesis by inhibiting CI 7-20 lyase activity in NCI-H295 human adrenocortical carcinoma cells has_been described by Ideyama Y, Kudoh M, Tanimoto K, Susaki Y, Nanya T, Nakahara T, Ishikawa H, Fujikura T, Akaza H, Shikama H in 2(213-20)".
  • the present invention provides compounds of formula (I) which have been shown to be inhibitors of
  • R 6 is a group of Formula (6) where R 6 is H; R 6b is H, halo, methyl, trifluoromethyl, methoxy, or -C(0)OCH 3 ; and R 6c is halo, - CN, methyl, ethyl, methoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropan-2-yl, difluoromethyl, trifluoromethyl, dimethoxymethyl, cyclopropyl, where said cyclopropyl is optionally substituted with hydroxy, -NH 2 , or -NHC(0)CH 3 ; or a pharmaceutically acceptable salt thereof.
  • R 6a is H; R 6b is H; and R 6c is methyl or cyclopropyl. In one particular embodiment, R 6c is methyl. In another particular embodiment, R 6c is cyclopropyl.
  • a compound of Formula (II) is provided where R 6c is d 3 -methyl; or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease, disorder, or syndrome mediated by Cypl7 inhibition comprises administering to a subject in need of such treatment a Compound of Formula (I) (including compounds of Formulae (I-A), (I-B), (I-C), (I-D) and (I-E)) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the Compound of Formula (I) (including compounds of Formulae (I-A), (I-B), (I-C), (I-D) and (I-E)) or Formula (II), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • fused heteroaryl refers to a heteroaryl group fused to another ring, such as another heteroaryl (e.g. purinyl, thieno[3,2-c]pyridinyl, imidazo[l,2- a]pyridinyl, benzo[b]thiophenyl, quinolinyl, benzooxazolyl, benzothiazolyl, indolyl, isoquinolinyl, benzofuranyl, indazolyl, benzimidazolyl, etc.).
  • the fused heteroaryl can be substituted on any of the atoms within the fused system.
  • an imidazo[l,2-a]pyridinyl group may be substituted on the imidazole or pyridine portion of the fused system.
  • phrases "pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the terms “treating”, “treat”, or “treatment” embrace both preventative, i.e., prophylactic, and palliative treatment.
  • the present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders modulated by the inhibition of 17a-hydroxylase/Cn j2 o-lyase.
  • Scheme II below provides an alternative synthetic route for making compounds of the present invention, especially where R 2 and R 3 are other than hydrogen.
  • Scheme IV illustrates how to prepare compounds of the present invention where R 2 or R 3 is taken together with R 4 or R 5 to form a double bond.
  • the acrylic acid intermediate (4b) is accessible by condensing a
  • the acrylic acid intermediate (5a) can be prepared from a dersired aldehyde (SM-5) and malonic acid using a standard aldo condensation reaction in pyridine (optionally, in the presence of piperidine) at elevated temperatures. Although intermediate 5 a is depicted above in the cis configuration, it is mostly likely trans or a cis/trans mixture. The acrylic acid unsaturation can then be reduced to the
  • isotopes suitable for inclusion in the compounds of the invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and ,4 C, chlorine, such as 3 C1, fluorine, such as 18 F, iodine, such as 123 I and ,25 I, nitrogen, such as l3 N and 15 N, oxygen, such as 15 0, ,7 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • hydrogen such as 2 H and 3 H
  • carbon such as n C, 13 C and ,4 C
  • chlorine such as 3 C1
  • fluorine such as 18 F
  • iodine such as 123 I and ,25 I
  • nitrogen such as l3 N and 15 N
  • oxygen such as 15 0, ,7 0 and 18 0, phosphorus, such as 32 P
  • sulphur such as 35 S.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • GRAS solvents recognized by persons skilled in the art as safe
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark
  • aminopeptidase Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are e.g. bengamide or a derivative thereof.
  • Implants containing corticosteroids refers to compounds, such as e.g. fluocinolone, dexamethasone.
  • Nitro methane (1.156mL, 0.02135mmol) was added to a stirred solution of 4- chloro-benzaldehyde (3g, 0.02135mmol) in ethanol (lOOmL) at 0°C, followed by dropwise addition of ION NaOH solution (896mg, 0.0224mmol) over a period of 10 minutes.
  • the resulting mixture was stirred at room temperature for 1 hour.
  • the reaction was monitored by TLC (20% ethylacetate in hexane).
  • the reaction mixture was quenched with HCl (50mL) and water (50mL) followed by stirring for an additional 1 hour at room temperature.
  • the solid formed was collected and dried under reduced pressure to afford 3.4g of the product (87% yield).
  • step 2 l-bromo-4-(2-nitro-vinyl)-benzene fl-3a: 10.5g, 0.046055mmol) in dry THF (1 OOmL) was reacted with LAH (3.4g, 0.0921 Ommol) in dry THF (1 OOmL) to afford 7.5g of the crude product which was used in the next step without further purification.
  • step 3 2-(4-trifluoromethyl-phenyl)-ethylamine (Mb: 1.5g, 7.94mmol) in chloroform (1 OmL) was reacted with chloro ethyl formate (1.097g, 9.5mmol) and 2N Na 2 C0 3 solution (5mL) at 0°C. The resulting mixture was stirred at room temperature for 1 hour to afford the crude product. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 700mg of the product (33.78% yield).
  • step 4 (2-thiophen-2-yl-ethyl)-carbamic acid ethyl ester (I-7c: 800mg, 3.50887mmol) in POCI3 (lOmL) was reacted with P 2 0 5 (996mg, 7.0175mmol). The resulting mixture was stirred at 110°C for 4 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCI3) afforded 180mg of the product (33.5% yield).
  • step 2 2-(2-nitro-vinyl)-naphthalene (I- 10a: 3g, 15.00mmol) in dry THF (15mL) was reacted with LAH (1.14g, 30.00mmol) in dry THF (15mL) to afford 3.2g of the crude product which was used in the next step without further purification.
  • step 4 (2-naphthalen-2-yl-ethyl)-carbamic acid ethyl ester (I-10c: 1.3g, 5.349mmol) in
  • step 1 3-methoxy-benzaldehyde (16.0g, 118.518mmol) in ethanol (160mL) was reacted with nitro methane (7.0mL, 1 18.518mmol) and 10N NaOH (4.7g,
  • step 2 l-methoxy-3-(2-nitro-vinyl)-benzene (I- 11 a: 10.5g, 58.659mmol) in dry THF (1 lOmL) was reacted with LAH (6.68g, 175.97mmol) to afford 6.5g of the product (73% yield).
  • step 3 2-(3-methoxy-phenyl)-ethylamine (I-l lb: 6.5g, 43.046mmol) in chloroform (65mL) was reacted with chloro ethyl formate (4.91mL, 51.655mmol) and 2N Na 2 C0 3 solution (65mL) at 0°C. The resulting mixture was stirred at room temperature for 3 hours to afford the crude product. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 6.2g of the product (68% yield).
  • step 4 [2-(3-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-l lc: 6.2g, 29.5238mmol) in POCl 3 (62mL) was reacted with P 2 0 5 (8.38g, 59.047mmol). The resulting mixture was stirred at 120°C for 1 hour to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 0.400g of the product (7.6% yield).
  • step 1 2-chloro-benzaldehyde (5g, 35.7142mmol) in ethanol (161mL) was reacted with nitro methane (1.93mL, 35.7142mmol) and ION NaOH (1.35g, 33.9607mmol). The resulting mixture was stirred at 0°C for lhr to afford 4.5g of the product (75.73% yield).
  • step 1 4-bromo-thiophene-2-carbaldehyde (5g, 0.02617mmol) in ethanol ( 1 OOmL) was reacted with nitro methane (1.7mL, 0.0327mmol) and 10N NaOH (1.09g, 0.274mmol) to afford 5g of the product (81.9% yield).
  • Step 2 Preparation of Intermediate 2-(4-Bromo-thiophen-2-yl) ⁇ ethylamine (I-15b) (I- 15b)
  • step 2 4-bromo-2-(2-nitro-vinyl)-thiophene (5g, 21.367mmol) in dry THF (150mL) was reacted with L1BH4 (1.86g, 85.470mmol), chloro trimethyl silane (21.6mL, 170.576mmol) to afford 4.4g of the crude product which was used in the next step without further purification.
  • step 3 2-(4- bromo-thiophen-2-yl)-ethylamine d-1 b: 4.4g, 0.02125mmol) in chloroform (50mL) was reacted with chloro ethyl formate (2.1mL, 0.0265mmol) and 2N Na 2 C03 solution (50mL). The resulting mixture was stirred at room temperature for 4 hours to afford the crude product. Purification by column chromatography on silica gel (10% ethylacetate in hexane) afforded 5.5g of the product (93% yield).
  • step 4 [2-(4-bromo-thiophen-2-yl)-ethyl]-carbamic acid ethyl ester (I- 15c: 6g, 21.73mmol) in POCl 3 (60mL) was reacted with P 2 0 5 (6.217g, 43.782mmol) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHC1 3 ) afforded 2.6g of the product (52% yield).
  • Step 5 Preparation of Intermediate 3-(4-Fl oro-phenyl)-6, 7-dihvdro-5H-thieno[3,2- c]pyridin-4-one (I-15c)
  • step 3 2-(4- trifluoromethyl-phenyl)-ethylamine (I- 16a: 2g, 10.58mmol) in chloroform (20mL) was reacted with chloro ethyl formate (1.37g, 12.698mmol) and 2N Na 2 C0 3 solution (20mL) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes to afford 2.7g of the product (97.79% yield).
  • step 1 2- methyl-2-(4-trifluoromethyl-phenyl)-propionitrile (I-20a: 1.2g, 5.6338mmol) in methanolic ammonia (lOmL) was reacted with to Raney nickel (200mg) to afford 1.3 g of the crude product which was used in the next step without further purification.
  • Step 3 Preparation of Intermediate [2-Methyl-2-i4-trifluoromethyI-phenvI)-propyl]- carbamic acid ethyl ester I-20c)
  • Step 4 Preparation of Intermediate 4,4-Dimethv 7-trifluoromethyl-3,4-dihvdro-2H- isoq inolin-l-one (I-20d)
  • step 4 [2- methyl-2-(4-trifluoromethyl-phenyl)-propyl]-carbamic acid ethyl ester (I-20c: 1. lg, 3.8062mmol) in POCl 3 (8mL) was reacted with P 2 0 5 (1.08g, 7.6162mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in DCM) afforded 360mg of the product (33.3% yield).
  • step 3 2-(2- trifluoromethyl-phenyl)-ethylamine (l .lg, 5.820mmol) in chloroform (1 ImL) was reacted with chloro ethyl formate (0.66mL, 6.984mmol) and 2N Na 2 C0 3 solution (1 ImL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours to afford 1.2g of the product (79% yield).
  • step 4 [2- (2-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester fl-22c: 1.2g, 4.5977mmol) in POCl 3 (13mL) was reacted with P 2 0 5 (1.3g, 9.195mmol). The resulting mixture was stirred at 115°C for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090g of the product (9.1% yield).
  • step 3 2-(4- methoxy-phenyl)-ethylamine (5g, 33.1 lmmol) in chloroform (64mL) was reacted with chloro ethyl formate (4.3 lg, 39.73mmol) and 2N Na 2 C0 3 solution (64mL) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes to afford 6.5g of the product (94% yield).
  • step 4 [2- (4-methoxy-phenyl)-ethyl]-carbamic acid ethyl ester (I-26a: 3g, 13.452mmol) in POCI3 (30mL) was reacted with P 2 0 5 (3.793g, 26.905mmol). The resulting mixture was stirred at 110°C for 1 hour to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 400mg of the product (16.8% yield).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/EP2011/065965 2010-09-16 2011-09-14 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS Ceased WO2012035078A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201180044494.8A CN103108871B (zh) 2010-09-16 2011-09-14 17α-羟化酶/C17,20-裂合酶抑制剂
US13/823,792 US8946260B2 (en) 2010-09-16 2011-09-14 17α-hydroxylase/C17,20-lyase inhibitors
EP11761540.1A EP2627648A1 (en) 2010-09-16 2011-09-14 17aHYDROXYLASE/C17,20-LYASE INHIBITORS
JP2013528663A JP2013537210A (ja) 2010-09-16 2011-09-14 １７α−ヒドロキシラーゼ／Ｃ１７，２０−リアーゼ阻害剤

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IN2719CH2010 2010-09-16
IN2719/CHE/2010 2010-09-16

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WO2012035078A1 true WO2012035078A1 (en) 2012-03-22

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