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WO2008077089A1 - Pyrrolidinanilines - Google Patents

Pyrrolidinanilines Download PDF

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Publication number
WO2008077089A1
WO2008077089A1 PCT/US2007/088066 US2007088066W WO2008077089A1 WO 2008077089 A1 WO2008077089 A1 WO 2008077089A1 US 2007088066 W US2007088066 W US 2007088066W WO 2008077089 A1 WO2008077089 A1 WO 2008077089A1
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WIPO (PCT)
Prior art keywords
alkyl
amino
chloro
methyl
benzonitrile
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Ceased
Application number
PCT/US2007/088066
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English (en)
Inventor
Linda S. Barton
James S. Frazee
Marlys Hammond
Patrick Stoy
Scott Kevin Thompson
David G. Washburn
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to JP2009543171A priority Critical patent/JP2010513568A/ja
Priority to EP07855260A priority patent/EP2094269A1/fr
Publication of WO2008077089A1 publication Critical patent/WO2008077089A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens
    • 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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to pyrrolidinanilines that are useful as progesterone receptor modulators.
  • Endometriosis is a disease characterized by the growth of endometrial tissue (called lesions) at extrauterine sites. This lesion attachment can result in pain, dysmenorrhea, dyspareunia, and infertility. It is estimated that greater than 80% of patients presenting with chronic pelvic pain are eventually diagnosed with endometriosis. The prevalence of the disease is about 7-10% of women of reproductive years with a familial association risk increase of 10-fold. Definitive diagnosis is only reached by laparoscopy, but typically there is about a ten year delay from disease onset to conclusive diagnosis.
  • uterine leiomyomas fibroids
  • Fibroids occur at rates of 20-25% and are the leading indication for hysterectomies.
  • the most common symptoms are menorrhagia, pelvic pain/discomfort, bladder and bowel compression symptoms, and possibly infertility.
  • Medical treatments for leiomyomas consist of those commonly prescribed for endometriosis, with treatments containing progesterone receptor modulators being most common due to safety, tolerability, ease of use and cost.
  • progestins are molecules that interact with progesterone receptor to activate or repress gene expression in target cells in a manner presumed to be progesterone-like.
  • progestins are used in oral contraception, hormone therapy, and treatment of reproductive disorders, such as endometriosis and leiomyomas, these agents cause a number of adverse effects, including breakthrough bleeding, mood altering, acne, weight gain, and breast tenderness.
  • progesterone receptor antagonists such as mifepristone have been suggested as potential therapies, but the data are limited with few patients and no placebo-controlled randomized trials. D. DeManno et al.
  • the present invention is a compound of the following formula I:
  • X is H, F, Cl, Br, or CF 3 ;
  • R 1 is Ci-C 6 -alkyl, CF 3 , Ci-C 6 -alkoxycarbonyl-Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, -heterocycloalkyl-(R 4 ) m , -heteroaryl-(R 5 ) n , -phenyl-(R 6 ) n , or -CH 2 R 7 ;
  • R 2 is Ci-C 5 -alkyl, Ci-C 6 -alkyloxy-Ci-C 5 -alkyl, C 3 -C 6 -cycloalkyl, -heterocycloalkyl-(R 4 ) m , C 2 -C 4 - alkenyl, naphthyl, -heteroaryl-(R 5 ) n , or -phenyl-(R 6 ) n ;
  • R 3 is H, Ci-C 5 -alkyl, or CF 3 ;
  • n 0, 1, or 2;
  • n 0, 1, 2, or 3;
  • R 4 is Ci-C 6 -alkyl, Q-Ce-alkyl-carbonyl, or -heteroaryl-(R 5 ) n
  • R 5 is independently C r C 6 -alkyl, F, Cl, Br, CF 3 , C r C 6 -alkoxy, C r C 6 -alkoxycarbonyl, C 1 -C 6 - alkylcarbonyloxy, dimethylamino, C 2 -C 4 -alkenyl, or CN, or, when n is 2 or 3, where 2 of the R 5 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
  • R 6 is independently Ci-C 6 -alkyl, F, Cl, Br, CF 3 , Ci-C 6 -alkoxy, dimethylamino, hydroxyethylmethylamino, amino, amido, C 2 -C/ralkenyl, nitro, -C(O)O-Ci-C6-alkyl, -C(O)-Ci-C 6 - alkyl, OH, COOH, CH 3 SO 2 -, -heterocycloalkyl-(R 4 ) m , or CN, or where 2 of the R 6 groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
  • R 7 is F, Cl, Br, C r C 6 -alkoxy, Ci-C 6 -alkoxy-C r C 6 -alkyl, CF 3 , CH 2 CF 3 , CN, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-Ci-C 5 -alkyl, COOH, Ci-Cg-alkylcarbonyl, -heterocycloalkyl-(R 4 ) m , C r C 6 -alkyl- heterocycloalkyl, heterocycloalkyl-CH 2 -, aminocarbonyl, aminocarbonyl-Ci-Ce-alkyl, di-Ci-C ⁇ - alkylamino, di-Ci-Ce-alkylaminocarbonyl, Ci-C 6 -alkylamino-Ci-C 6 -alkyl, di-Ci-C 6 -alkylamino- Ci-C 6
  • Compounds of the present invention are useful as progesterone receptor modulators.
  • compounds of the present invention can be combined with one or more exogenous estrogens prescribed for hormone therapy to reduce the risk of estrogen-dependent cancers such as endometrial cancer.
  • the present invention is a compound represented by the following formula I:
  • X is H, F, Cl, Br, or CF 3 ;
  • R 1 is H, Ci-C 6 -alkyl, -CR 3 -(OH)-C r C 5 -alkyl, -CR 3 - (NH 2 )-Ci-C 5 -alkyl CF 3 , hydroxymethyl, aminomethyl, Ci-Ce-alkoxycarbonyl-Ci-C ⁇ -alkyl, C 3 -C 6 - cycloalkyl, hydroxy-C 3 -C 6 -cycloalkyl, Ci-C 6 -alkyl-C 3 -C 6 -cycloalkyl, cyano-C 3 -C 6 -cycloalkyl, Ci- C 6 -alkoxy-C 3 -C 6 -cycloalkyl, -heterocycloalkyl-(R 4 ) m , -heteroaryl-(R 5 ) n , -phenyl-(R 6 )
  • R 1 is Ci-C 6 -alkyl, CF 3 , Ci-C 6 -alkoxycarbonyl-Ci-C 6 -alkyl, C 3 -C 6 -cycloalkyl, -heterocycloalkyl-(R 4 ) m , -heteroaryl-(R 5 ) n , -phenyl-(R 6 ) n , or -CH 2 R 7 ;
  • R 2 is C r C 5 -alkyl, d-Cg-alkyloxy-d-Cs-alkyl, C 3 -C 6 -cycloalkyl, -heterocycloalkyl-(R 4 ) m , C 2 -C 4 - alkenyl, naphthyl, -heteroaryl-(R 5 ) n , or -phenyl-(R 6 ) n ;
  • R 3 is H, Ci-C 5 -alkyl, or CF 3 ;
  • n 0, 1, or 2;
  • n 0, 1, 2, or 3;
  • R 4 is Ci-C ⁇ -alkyl, Ci-C ⁇ -alkyl-carbonyl, or -heteroaryl-(R 5 ) n
  • R 5 is independently C r C 6 -alkyl, F, Cl, Br, CF 3 , Ci-C 6 -alkoxy, Ci-Ce-alkoxycarbonyl, C r C 6 - alkylcarbonyloxy, dimethylamino, C 2 -C 4 -alkenyl, or CN, or, when n is 2 or 3, where 2 of the R 5 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
  • R 6 is independently Ci-C 6 -alkyl, F, Cl, Br, CF 3 , Ci-C 6 -alkoxy, dimethylamino, hydroxyethylmethylamino, amino, amido, C 2 -C 4 -alkenyl, nitro, -C(O)O-Ci-C 6 -alkyl, -C(O)-Cr C 6 alkyl, OH, COOH, CH 3 SO 2 -, -heterocycloalkyl-(R 4 ) m , or CN, or where 2 of the R 6 groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
  • R 7 is F, Cl, Br, C r C 6 -alkoxy, Ci-C 6 -alkoxy-Ci-C 6 -alkyl, CF 3 , CH 2 CF 3 , CN, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 5 -alkyl, COOH, C r C 6 -alkylcarbonyl, -heterocycloalkyl-(R 4 ) m , C r C 6 -alkyl- heterocycloalkyl, heterocycloalkyl-CH 2 -, aminocarbonyl, aminocarbonyl-Ci-Ce-alkyl, di-Ci-C 6 - alkylamino, di-Ci-Ce-alkylaminocarbonyl, Ci-C 6 -alkylamino-Ci-C 6 -alkyl, di-Ci-C 6 -alkylamino- Ci
  • R 1 is C r C 6 -alkyl, -CR 3 -(OH)-C r C 5 -alkyl, HO-C r C 6 -alkyl, or phenyl-(R 6 ) n , wherein R 6 is independently Ci-C ⁇ -alkyl, F, Cl, CF 3 , Ci-C ⁇ -alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
  • R 2 is phenyl-(R 6 ) n , where R 6 is independently CH 3 , F, Cl, Br, or CF 3 .
  • R 1 is Ci-C 6 -alkyl, -CR 3 -(OH)-Ci-C 5 -alkyl, or HO-Ci-Q-alkyl.
  • n is x + z, where x is 0 or 1 and z is 0, 1, or 2, with the proviso that when x is 0, z is 0.
  • the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof where y is 1 and R 1 is Ci-C ⁇ -alkyl or phenyl-(R 6 ) n , wherein R 6 is independently Ci-C ⁇ -alkyl, F, Cl, CF 3 , Ci-C ⁇ -alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
  • y is 1, X is Cl and R 2 is phenyl-(R 6 ) n , where R 6 is independently CH 3 , F, Cl, Br, or CF 3 .
  • n is x + z, where x is 0 or 1 and z is 0, 1 , or 2, with the proviso that when x is 0, z is 0.
  • the present invention is a compound or a pharmaceutically acceptable salt thereof, which compound is selected from the group consisting of: 2-chloro-4- ⁇ [(2-chloro-5-fluorophenyl)methyl] [(3 S)-I -(2-methylpropanoyl)-3- pyrrolidinyl] amino ⁇ benzonitrile;
  • Ci_ 6 -alkyl refers to a straight or branched chain radical of 1 to 6 carbon atoms, including, methyl, ethyl, w-propyl, isopropyl, n-butyl, isobutyl, ?-butyl, «-pentyl, isopentyl, neopentyl, and «-hexyl and isomers thereof.
  • Ci-C 6 -alkoxy groups include methoxy and ethoxy groups; examples of suitable Ci-C 6 -alkoxycarbonyl-Ci-C 6 -alkyl groups include -C(CHs) 2 C(O)OCH 2 CH 3 and -CH 2 CH 2 C(O)O- ?-butyl groups; an example of a suitable Ci-C6-alkoxy-Ci-C 6 -alkyl group is CH 3 OCH 2 - (methoxymethyl); examples of suitable Ci-C ⁇ -alkoxycarbonyl groups include -CO 2 CH 2 CH 3 and -CO 2 -?-butyl groups; examples of suitable C 3 -C 6 -cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
  • heterocycloalkyl refers to a 3-6-membered ring that contains at least one heteroatom selected from N, O, and S.
  • suitable heterocycloalkyl groups include piperidinyl, pyrrolidinyl, pyrazinyl, morpholino, pyrrolidinonyl, and l,3-dioxolan-2-yl groups.
  • Ci-C 6 -alkyl-heterocycloalkyl refers to a heterocycloalkyl group substituted with a Ci- C ⁇ -alkyl group.
  • Ci-C 6 -alkyl-heterocycloalkyl group is N-methylpiperidinyl.
  • heteroaryl is used herein to describe an aromatic group that contains at least one heteroatom selected from N, O, and S.
  • suitable heteroaryl groups include pyridinyl, oxidopyridinyl, furyl, thienyl, imidazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, and benzothiadiazolyl groups.
  • the heteroaryl and phenyl groups may also be substituted as described herein.
  • Heteroaryl also includes more than one heteroaryl groups, for example, pyridinylthienyl and methoxypyridinylthienyl groups.
  • R 2 is heteroaryl-(R 5 ) n or phenyl-(R 6 ) n and n is 2 or 3
  • two of the R 5 or R 6 groups can, together with the heteroaryl or phenyl groups respectively to which they are attached, form a fused bicyclic group.
  • fused bicyclic groups include benzodioxinyl and benzodioxolyl groups.
  • IC 5 o is used herein to refer to the molar concentration of a compound required to inhibit binding of 50% of Fluormone PL Red to the progesterone receptor. Furthermore, pIC 5 o refers to the negative log of the molar IC 5 O.
  • Pharmaceutically acceptable salts of the compounds of the present invention include salts formed by the addition of an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or by the addition of an organic acid such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, />-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, or tartaric acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid
  • an organic acid such as acetic acid, fumaric acid, succinic acid, maleic acid, citric acid, benzoic acid, />-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, or tartaric acid.
  • the compound and/or pharmaceutically acceptable salt of the present invention includes all of its manifestations including amorphous and crystalline forms or combinations thereof.
  • Crystalline forms include anhydrous forms as well as aqueous and nonaqueous solvate forms.
  • the compounds of the present invention may exist as optical isomers including diastereoisomers and enantiomers, and mixtures of isomers in all ratios including racemic mixtures.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier therefor.
  • the composition may be formulated for administration by any route, such as oral, topical or parenteral.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the present invention also relates to a method comprising administering to a patient in need thereof an effective amount of a compound of the present invention or a pharmaceutically- acceptable salt thereof to treat endometreosis or uterine fibroids.
  • Acquest/Biosystems is a multi-mode reader (FP reader); CHAPS refers to 3-cholamidopropyl- dimethylammonio- 1 -propanesulfonate; DTT refers to dithiothreitol.
  • PR Binding Assay - The assay was performed according to the manufacturers protocol (PR Competitor Assay Kit, Red - (Invitrogen - Product No. P2962)) with minor amendments. Briefly, 40 nM PR-Ligand Binding Domain, 2 nM Fluormone PL Red and ImM DTT were dissolved and mixed in Complete PR RED Buffer supplemented with 2 mM CHAPS. 10 ⁇ L of the mix was dispensed to each well of Greiner low volume plates, containing compounds at the required concentration. The plates were spun for 1 min at 200 g, covered to protect the reagents from light, and then incubated at room temperature for approximately 2 hours. Plates were read on an Acquest using a 530-25 nm excitation and 580-10 nm emission interference filter and a 561 nm Dichroic mirror.
  • the compounds of the present invention are useful as modulators of progesterone receptors and may be useful in the treatment of disease associated with endometreosis and uterine fibroids.
  • the present invention further relates to a method of treating a patient comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically-acceptable salt thereof to treat endometreosis or uterine fibroids.
  • the pyrrolidine 2b can also be functionalized by treatment with a carboxylic acid and different coupling reagents to yield 3a (Scheme 3).
  • the choloroformate 4c can be formed in situ by treatment of the corresponding alcohol (ROH) 4b with phosgene.
  • the pyrrolidine 2b can be further functionalized by treatment with a carboxylic acid 5a that was pretreated with NMM and isobutyl chloroformate to yield 5b (Scheme 5).
  • the substituent on the aniline nitrogen can be modified after installation. For example hydrogenation of 6a to form 6b which upon acidic deprotection of the Boc protecting group yields intermediate 6c. Furthermore, 6d can be hydrogenated to form 6e. Lastly, modification of the substitutent on the pyrrolidine nitrogen can also be achieved by removal of the Boc protecting group under acidic conditions to form 6g.
  • NMM N-Methylmorpholine
  • CDCI3 is deuteriochloroform
  • DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
  • CD3OD or dzj-Gr ⁇ OH is tetradeuteriomethanol.
  • Mass spectra were obtained using electrospray (ES) or atmospheric pressure chemical ionization (APCI) techniques.
  • ES electrospray
  • APCI atmospheric pressure chemical ionization
  • E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Flash chromatography was carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel or on an ISCO Combi-flash purification system using pre- filled silica gel cartridges.
  • Preparative HPLC was performed using Gilson chromatography systems using a 30 x 100 mm Xterra Prep RP column or 3O x 150 mm Sunfire prep column.
  • the solvent system used was a variable gradient of acetonitrile/water using either 0.1% TFA or ammonium hydroxide to adjust the pH to 10.
  • Celite® is a filter aid composed of acid- washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.
  • the reaction was diluted with 10% EtOAc/diethyl ether (150 mL). The organic layer was washed with saturated sodium chloride (50 mL, twice) and water (50 mL, twice). The organic layer was dried over Na 2 SOz I , filtered, and concentrated. The residue was purified via silica gel chromatography with 2% ethyl acetate in hexanes grading to 25% ethyl acetate in hexanes to afford the titled product (3.65 g, 78%) as a white foam.
  • the mixture was filtered through Celite, and the concentrated filtrate was purified via silica gel chromatography with 0% ethyl acetate in hexanes grading to 20% ethyl acetate in hexanes to afford the titled product (2.78 g, 76%) as a white foam.
  • Examples 1-12 are shown in detail, while Examples 13-810 are carried out substantially in the manner shown in the detailed examples.
  • Examples 811-819 are ?-butyl carbamates, which represent compounds of the present invention and which are also used as intermediates to make other intermediates.
  • E2campieJO 2-Chloro-4-[[(3S)-l-(2-methylpropanoyl)-3-pyrrolidinyl](2- methylpropyl)amino]benzonitrile
  • Methyl chloroformate (0.1 mL, 1.28 mmol) was to an ice cold solution of 2-chloro-4- ⁇ [(2,3- difluorophenyl)methyl][(3S)-3-pyrrolidinyl]amino ⁇ benzonitrile (100 mg, 0.288 mmol) in CH 2 Cl 2 (5 mL) and saturated aqueous NaHCO 3 (1 mL). After stirring at 0 0 C for 1 h, 10% solution of Na 2 CO 3 (3 mL) was added, the ice bath was removed, and the reaction was stirred for 30 min. CH 2 Cl 2 (5 mL) was added, the layers were separated, and the organic layer was concentrated. The residue was purified via silica gel chromatography to yield the desired compound (0.60 g, 51%).

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Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci où R1, R2, X et y sont définis ici. Les composés de la présente invention sont utiles comme modulateurs de récepteur de la progestérone.
PCT/US2007/088066 2006-12-19 2007-12-19 Pyrrolidinanilines Ceased WO2008077089A1 (fr)

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JP2009543171A JP2010513568A (ja) 2006-12-19 2007-12-19 ピロリジンアニリン類
EP07855260A EP2094269A1 (fr) 2006-12-19 2007-12-19 Pyrrolidinanilines

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7816395B2 (en) 2006-08-09 2010-10-19 Glaxosmithkline Llc Pyrrolidinone anilines as progesterone receptor modulators
WO2015046403A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
US9890139B2 (en) 2013-06-11 2018-02-13 Orion Corporation CYP17 inhibitors/antiandrogens
WO2023105387A1 (fr) * 2021-12-06 2023-06-15 Pfizer Inc. Antagonistes du récepteur 4 de la mélanocortine et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
US20030119811A1 (en) * 2001-04-03 2003-06-26 Liverton Nigel J. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
WO2006113552A2 (fr) * 2005-04-15 2006-10-26 Smithkline Beecham Corporation Cyanoarylamines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992022527A2 (fr) * 1991-06-17 1992-12-23 Smithkline Beecham Plc Derives de pyrrolidine 3-substitues comme antagonistes du calcium
US20030119811A1 (en) * 2001-04-03 2003-06-26 Liverton Nigel J. N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B Antagonists
WO2006113552A2 (fr) * 2005-04-15 2006-10-26 Smithkline Beecham Corporation Cyanoarylamines

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7816395B2 (en) 2006-08-09 2010-10-19 Glaxosmithkline Llc Pyrrolidinone anilines as progesterone receptor modulators
US9890139B2 (en) 2013-06-11 2018-02-13 Orion Corporation CYP17 inhibitors/antiandrogens
CN105555778B (zh) * 2013-09-26 2017-07-28 东丽株式会社 环状胺衍生物及其药物用途
KR20160060034A (ko) * 2013-09-26 2016-05-27 도레이 카부시키가이샤 환상 아민 유도체 및 그 의약 용도
US9505740B2 (en) 2013-09-26 2016-11-29 Toray Industries, Inc. Cyclic amine derivative and pharmaceutical use thereof
EP3050877A4 (fr) * 2013-09-26 2017-04-05 Toray Industries, Inc. Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
CN105555778A (zh) * 2013-09-26 2016-05-04 东丽株式会社 环状胺衍生物及其药物用途
RU2638549C2 (ru) * 2013-09-26 2017-12-14 Торэй Индастриз, Инк. Производное циклического амина и его фармацевтическое применение
WO2015046403A1 (fr) * 2013-09-26 2015-04-02 東レ株式会社 Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
EP3511003A1 (fr) * 2013-09-26 2019-07-17 Toray Industries, Inc. Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
EP3511002A1 (fr) * 2013-09-26 2019-07-17 Toray Industries, Inc. Dérivé d'amine cyclique et utilisation pharmaceutique de celui-ci
KR102276072B1 (ko) 2013-09-26 2021-07-12 도레이 카부시키가이샤 환상 아민 유도체 및 그 의약 용도
WO2023105387A1 (fr) * 2021-12-06 2023-06-15 Pfizer Inc. Antagonistes du récepteur 4 de la mélanocortine et leurs utilisations

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