EP2094269A1 - Pyrrolidinanilines - Google Patents

Pyrrolidinanilines

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Publication number
EP2094269A1
EP2094269A1 EP07855260A EP07855260A EP2094269A1 EP 2094269 A1 EP2094269 A1 EP 2094269A1 EP 07855260 A EP07855260 A EP 07855260A EP 07855260 A EP07855260 A EP 07855260A EP 2094269 A1 EP2094269 A1 EP 2094269A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
amino
chloro
methyl
benzonitrile
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07855260A
Other languages
German (de)
French (fr)
Inventor
Linda S. BARTON
James S. Frazee
Marlys Hammond
Patrick Stoy
Scott Kevin Thompson
David G. Washburn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline LLC
Original Assignee
SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP2094269A1 publication Critical patent/EP2094269A1/en
Withdrawn legal-status Critical Current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

The present invention relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof where R1, R2, X, and y are defined herein. Compounds of the present invention are useful as progesterone receptor modulators.

Description

PYRROLIDINANILINES
BACKGROUND OF THE INVENTION
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. Consistent with their uterine origins, it is believed that the endometriotic lesions are hormonally dependent upon estrogen; consequently, therapies that functionally antagonize estrogen production or action, such as drugs containing progesterone receptor (PR) modulators, are efficacious in alleviating symptoms. Current therapeutic goals include reducing pain with anti-inflammatory agents and suspending the ovarian cycle using hormonal modulation drugs.
Another disease believed to be hormonally responsive to estrogen is uterine leiomyomas (fibroids), which appear as benign uterine smooth muscle tumors occurring primarily in women of reproductive age. 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.
Most drug development has focused on modulation by full agonism or antagonism of progesterone receptors. For example, 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. Though 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. Paradoxically, 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. (Steroids 68 (2003) 1019-1032), report that asoprisnil is a progesterone receptor modulator with mixed agonist/antagonistic activities. While the efficacy of the agent in treatment of endometriosis or fibroids is uncertain, early data from healthy female subjects indicate that the agent induces endometrial atrophy and amenorrhea, which suggests a predominantly progesterone receptor antagonist action in humans. Unfortunately, PR antagonists such as RU-486 tend to be abortifacient.
Accordingly, it would be desirable to discover a way to suppress estrogen-dependent endometriotic growth while reducing the systemic effects associated with current progesterone receptor modulating therapy.
SUMMARY OF THE INVENTION
In a first aspect, the present invention is a compound of the following formula I:
or a pharmaceutically acceptable salt thereof;
wherein X is H, F, Cl, Br, or CF3;
y is 0 or 1, with the proviso that when y is 0, R1 is H, Ci-C6-alkyl, -CR3-(OH)-CrC5-alkyl, -CR3- (NH2)-Ci-C5-alkyl CF3, hydroxymethyl, aminomethyl, Ci-C6-alkoxycarbonyl-Ci-C6-alkyl, C3-C6- cycloalkyl, hydroxy-C3-C6-cycloalkyl, Ci-C6-alkyl-C3-C6-cycloalkyl, cyano-C3-C6-cycloalkyl, Ci- C6-alkoxy-C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, -CR3-(OH)- phenyl-(R6)n, or -CH2R7, and;
when y is 1, R1 is Ci-C6-alkyl, CF3, Ci-C6-alkoxycarbonyl-Ci-C6-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, or -CH2R7; R2 is Ci-C5-alkyl, Ci-C6-alkyloxy-Ci-C5-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, C2-C4- alkenyl, naphthyl, -heteroaryl-(R5)n, or -phenyl-(R6)n;
R3 is H, Ci-C5-alkyl, or CF3;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
R4 is Ci-C6-alkyl, Q-Ce-alkyl-carbonyl, or -heteroaryl-(R5)n
R5 is independently CrC6-alkyl, F, Cl, Br, CF3, CrC6-alkoxy, CrC6-alkoxycarbonyl, C1-C6- alkylcarbonyloxy, dimethylamino, C2-C4-alkenyl, or CN, or, when n is 2 or 3, where 2 of the R5 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
R6 is independently Ci-C6-alkyl, F, Cl, Br, CF3, Ci-C6-alkoxy, dimethylamino, hydroxyethylmethylamino, amino, amido, C2-C/ralkenyl, nitro, -C(O)O-Ci-C6-alkyl, -C(O)-Ci-C6 - alkyl, OH, COOH, CH3SO2-, -heterocycloalkyl-(R4)m, or CN, or where 2 of the R6 groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
R7 is F, Cl, Br, CrC6-alkoxy, Ci-C6-alkoxy-CrC6-alkyl, CF3, CH2CF3, CN, C3-C6-cycloalkyl, C3-C6-cycloalkyl-Ci-C5-alkyl, COOH, Ci-Cg-alkylcarbonyl, -heterocycloalkyl-(R4)m, CrC6-alkyl- heterocycloalkyl, heterocycloalkyl-CH2-, aminocarbonyl, aminocarbonyl-Ci-Ce-alkyl, di-Ci-Cβ- alkylamino, di-Ci-Ce-alkylaminocarbonyl, Ci-C6-alkylamino-Ci-C6-alkyl, di-Ci-C6-alkylamino- Ci-C6-alkyl, C7-C8-bicycloalkyl, Ci-C6-alkylcarbonylamino-Ci-C6-alkyl, hydroxy-Ci-C6-alkyl, - SO2-Ci-C6-alkyl, Cio-tricycloalkyl, -CH2SO2-phenyl-(R6)n, -O-phenyl-(R6)n, Ci-Cβ-alkoxycarbonylamino, Ci-Ce-alkylcarbonylammo, naphthyl, -heteroaryl-(R5)n, -CH2-heteroaryl-(R5)n, -phenyl- (R6)n, -CH2-phenyl-(R6)n, or (R6)n-phenyl-carbonyl-Ci-C6-alkyl.
Compounds of the present invention are useful as progesterone receptor modulators. In addition 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.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a compound represented by the following formula I:
or a pharmaceutically acceptable salt thereof;
wherein X is H, F, Cl, Br, or CF3;
y is 0 or 1, with the proviso that when y is 0, R1 is H, Ci-C6-alkyl, -CR3-(OH)-CrC5-alkyl, -CR3- (NH2)-Ci-C5-alkyl CF3, hydroxymethyl, aminomethyl, Ci-Ce-alkoxycarbonyl-Ci-Cβ-alkyl, C3-C6- cycloalkyl, hydroxy-C3-C6-cycloalkyl, Ci-C6-alkyl-C3-C6-cycloalkyl, cyano-C3-C6-cycloalkyl, Ci- C6-alkoxy-C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, -CR3-(OH)- phenyl-(R6)n, or -CH2R7, and;
when y is 1, R1 is Ci-C6-alkyl, CF3, Ci-C6-alkoxycarbonyl-Ci-C6-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, or -CH2R7;
R2 is CrC5-alkyl, d-Cg-alkyloxy-d-Cs-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, C2-C4- alkenyl, naphthyl, -heteroaryl-(R5)n, or -phenyl-(R6)n;
R3 is H, Ci-C5-alkyl, or CF3;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
R4 is Ci-Cβ-alkyl, Ci-Cβ-alkyl-carbonyl, or -heteroaryl-(R5)n
R5 is independently CrC6-alkyl, F, Cl, Br, CF3, Ci-C6-alkoxy, Ci-Ce-alkoxycarbonyl, CrC6- alkylcarbonyloxy, dimethylamino, C2-C4-alkenyl, or CN, or, when n is 2 or 3, where 2 of the R5 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring;
R6 is independently Ci-C6-alkyl, F, Cl, Br, CF3, Ci-C6-alkoxy, dimethylamino, hydroxyethylmethylamino, amino, amido, C2-C4-alkenyl, nitro, -C(O)O-Ci-C6-alkyl, -C(O)-Cr C6alkyl, OH, COOH, CH3SO2-, -heterocycloalkyl-(R4)m, or CN, or where 2 of the R6 groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
R7 is F, Cl, Br, CrC6-alkoxy, Ci-C6-alkoxy-Ci-C6-alkyl, CF3, CH2CF3, CN, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C5-alkyl, COOH, CrC6-alkylcarbonyl, -heterocycloalkyl-(R4)m, CrC6-alkyl- heterocycloalkyl, heterocycloalkyl-CH2-, aminocarbonyl, aminocarbonyl-Ci-Ce-alkyl, di-Ci-C6- alkylamino, di-Ci-Ce-alkylaminocarbonyl, Ci-C6-alkylamino-Ci-C6-alkyl, di-Ci-C6-alkylamino- Ci-C6-alkyl, C7-C8-bicycloalkyl, Ci-C6-alkylcarbonylamino-Ci-C6-alkyl, hydroxy-CrC6-alkyl, - SOrCi-Ce-alkyl, Cio-tricycloalkyl, -CH2SO2-phenyl-(R6)n, -O-phenyl-(R6)n, Ci-Ce-alkoxycarbonylamino, Ci-Ce-alkylcarbonylammo, naphthyl, -heteroaryl-(R5)n, -CH2-heteroaryl-(R5)n, -phenyl- (R6)n, -CH2-phenyl-(R6)n, or (R6)n-phenyl-carbonyl-Ci-C6-alkyl.
In another aspect of the present invention, the compound is represented by the following formula Ia:
Ia
wherein X is Cl; y is O; and R1 is CrC6-alkyl, -CR3-(OH)-CrC5-alkyl, HO-CrC6-alkyl, or phenyl-(R6)n, wherein R6 is independently Ci-Cβ-alkyl, F, Cl, CF3, Ci-Cβ-alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
In another aspect of the present invention R2 is phenyl-(R6)n, where R6 is independently CH3, F, Cl, Br, or CF3.
In another aspect of the present invention, R1 is Ci-C6-alkyl, -CR3-(OH)-Ci-C5-alkyl, or HO-Ci-Q-alkyl.
In another aspect, the compound of the present invention is represented by formula II:
II
or a pharmaceutically acceptable salt thereof where 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.
In another aspect, the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof where y is 1 and R1 is Ci-Cβ-alkyl or phenyl-(R6)n, wherein R6 is independently Ci-Cβ-alkyl, F, Cl, CF3, Ci-Cβ-alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
In another aspect, y is 1, X is Cl and R2 is phenyl-(R6)n, where R6 is independently CH3, F, Cl, Br, or CF3.
In another aspect, the compound of the present invention is represented by formula III:
or a pharmaceutically acceptable salt thereof, where 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.
In another aspect, 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;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,3-difluorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4- { [(2-fluorophenyl)methyl] [(3S)-I -(2-hydroxy-2-methylpropanoyl)-3 - pyrrolidinyl] amino } benzonitrile;
2-chloro-4-({(3S)-l-[(2S)-2-hydroxypropanoyl]-3-pyrrolidinyl} {[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile;
2-chloro-4-([(2-fluorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,5-dichlorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4-([(2,5-dichlorophenyl)methyl] {(3S)-l-[(2R)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-((cyclohexylmethyl){(3S)-l-[(2R)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2,3-difluorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(5-fluoro-2-methylphenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,5-difluorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4-([(2,5-dichlorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4- { [(5-fluoro-2-methylphenyl)methyl] [(3S)-I -propanoyl-3 - pyrrolidinyl] amino } benzonitrile; 2-chloro-4-[[(3S)-l-(2-hydroxy-2-methylpropanoyl)-3- pyrrolidinyl](phenylmethyl)amino]benzonitrile;
2-chloro-4- { [(2,4-difluorophenyl)methyl] [(3 S)- 1 -(2-hydroxy-2-methylpropanoyl)-3- pyrrolidinyl] amino } benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(3-fluorophenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(3-methylphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-((cyclohexylmethyl){(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile; and
2-chloro-4-([(2,3-difluorophenyl)methyl] {(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile.
As used herein, "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.
Examples of suitable Ci-C6-alkoxy groups include methoxy and ethoxy groups; examples of suitable Ci-C6-alkoxycarbonyl-Ci-C6-alkyl groups include -C(CHs)2C(O)OCH2CH3 and -CH2CH2C(O)O- ?-butyl groups; an example of a suitable Ci-C6-alkoxy-Ci-C6-alkyl group is CH3OCH2- (methoxymethyl); examples of suitable Ci-Cβ-alkoxycarbonyl groups include -CO2CH2CH3 and -CO2-?-butyl groups; examples of suitable C3-C6-cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.
As used herein, "heterocycloalkyl" refers to a 3-6-membered ring that contains at least one heteroatom selected from N, O, and S. Examples of suitable heterocycloalkyl groups include piperidinyl, pyrrolidinyl, pyrazinyl, morpholino, pyrrolidinonyl, and l,3-dioxolan-2-yl groups. Similarly, "Ci-C6-alkyl-heterocycloalkyl" refers to a heterocycloalkyl group substituted with a Ci- Cβ-alkyl group. An example of a Ci-C6-alkyl-heterocycloalkyl group is N-methylpiperidinyl. The term "heteroaryl" is used herein to describe an aromatic group that contains at least one heteroatom selected from N, O, and S. Examples of 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.
When R2 is heteroaryl-(R5)n or phenyl-(R6)n and n is 2 or 3, two of the R5 or R6 groups can, together with the heteroaryl or phenyl groups respectively to which they are attached, form a fused bicyclic group. Examples of such fused bicyclic groups include benzodioxinyl and benzodioxolyl groups.
The term "IC5o" 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, pIC5o refers to the negative log of the molar IC5O.
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.
A skilled artisan will appreciate that 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 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.
Biological Assays
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 μL 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.
Data Analysis
All data was normalized to the mean of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following form was then applied
Where a is the minimum, b is the Hill slope, c is the XC50 and d is the maximum. Data is presented as the mean pIC5o with the standard deviation of the mean of n experiments.
Methods of Use
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. Thus, 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.
Synthetic Schemes In a first step, illustrated in Scheme 1, nucleophilic addition of pyrrolidine Ia to a phenyl fluoride forms aniline Ib. Removal of the Boc protecting group under acidic conditions yields compounds Ic. Treatment of Ic with either an acid chloride (R1 = alkyl, benzyl, phenyl, etc.) or a chloroformate (R1 = OR, where R = alkyl, benzyl, phenyl, etc.) yields Id which can be further functionalized via alkylation of the aniline nitrogen to form Ie.
Scheme 1
1d 1Θ
Treatment of the pyrrolidine Ib with alkyl or benzyl bromides (Scheme 2) under basic conditions can afford the desired pyrrolidines 2a. Subsequent acidic deprotection of the Boc protecting group yields 2b. The pyrrolidine nitrogen can be functionalized by heating with a lactone or an ester to form 2c or 2d, respectively.
Scheme 2
The pyrrolidine 2b can also be functionalized by treatment with a carboxylic acid and different coupling reagents to yield 3a (Scheme 3).
Scheme 3
The pyrrolidine 2b can also be functionalized by either an acid chloride or a chloroformate (R1 = OR) and different bases to yield 4a (Scheme 4). In some situations, the choloroformate 4c can be formed in situ by treatment of the corresponding alcohol (ROH) 4b with phosgene.
Scheme 4
in situ formation of chloroformate = OR toluene 4c
4b
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).
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.
Scheme 6
6d 6e
6f 6g
Abbreviations
EtOAc= Ethyl acetate
Et2O= Diethyl ether
DMSO= Dimethyl sulfoxide
DMF= N,N-Dimethylformamide
MeOH= Methanol
EtOH= Ethanol
TFA= Trifluoroacetic acid
MeCN= Acetonitrile TBAF= tetra-«-butylammonium flouride
TEA= Triethylamine
DIEA= N,N-Diisopropylethylamine
CMC= N-Cyclohexyl-N'-(2-morpholinoethyl)carbodiimide methyl-/>-toluenesulfonate
PyBOP= Benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate
NMM = N-Methylmorpholine
General
Proton nuclear magnetic resonance (^H NMR) spectra were recorded at 400 MHz, and chemical shifts are reported in parts per million (ppm) downfield from the internal standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethylsulfoxide, and CD3OD or dzj-Gr^OH is tetradeuteriomethanol. Mass spectra were obtained using electrospray (ES) or atmospheric pressure chemical ionization (APCI) techniques. 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 following general procedures relate to the preparation of intermediates that can be used to prepare compounds of the present invention, which are elucidated in the examples section. A particular class of intermediates, namely, the ?-butyl carbamates used to make intermediates, are also compounds of the present invention and can also be found in the table of examples.
General procedure #1 : 2-Chloro-4-{[(3£)-l-(2-methylpropanoyl)-3- pyrrolidinyl] amino } benzonitrile
a) 1 , 1 -Dimethylethyl (3S)-3- [(3-chloro-4-cyanophenyl)amino]- 1 -pyrrolidinecarboxylate
A mixture of 2-chloro-4-fluorobenzonitrile (4.26 g, 27.5 mmol), 1 , 1 -dimethylethyl (3S)-3-amino- 1 -pyrrolidinecarboxylate (5.11 g, 27.5 mmol), and NaHCO3 (4.62 g, 55 mmol) in DMSO (45 mL) and H2O (5 mL) was heated with stirring at 90 0C for 16 h. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3x). The organic extracts were washed with H2O (2x), dried over Na2SOzI, filtered, and concentrated. The residue was crystallized from Et2O/hexane to yield the titled compound (6.88 g, 78%). 1H NMR (400 MHz, CDCl3) δ :7.42 (d, IH), 6.65 (s, IH), 6.50 (d, IH), 4.08 (m, IH), 3.74 (m, IH), 3.50 (m, 2H), 3.30 (m, IH), 2.25 (m, IH), 1.95 (m, IH), 1.49 (s, 9H). LC-MS (ES) m/e 322 [M + H] +.
b) 2-Chloro-4-[(3S)-3-pyrrolidinylammo]benzonitrile
To a solution of 1 , 1 -dimethylethyl (3£)-3-[(3-chloro-4-cyanophenyl)amino]-l- pyrrolidinecarboxylate (6.0 g, 18.7 mmol) in CH2Cl2 (40 mL), TFA (9.2 mL, 148 mmol) was added and the reaction mixture was stirred for 5 h. Toluene (20 mL) was added and the reaction mixture was concentrated. Saturated NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (5 x 100 mL). The organic extracts were dried over MgSO/t, filtered, and concentrated to yield the crude product as a red-brown solid (6.8 g). LC-MS(ES) m/e 222.0
[M + H] +.
c) 2-Chloro-4-{[(3S)-l-(2-methylpropanoyl)-3-pyrrolidinyl]amino}benzonitrile
A solution of 2-methylpropanoyl chloride (0.735g, 6.89 mmol) in CH2Cl2 (3 mL) was added drop wise to a solution of 2-chloro-4-[(3S)-3-pyrroh'dinylammo]benzonitrile (1.70 g, 7.66 mmol) and Et3N (1 mL) in CH2Cl2 (50 mL) at 0 0C. The reaction was stirred at 0 0C for 1.5 h and then at room temperature for 1 h. The reaction was treated with saturated NaHCO3 and the layers were separated. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to yield the titled compound (1.5 g, 75%) as a yellow foam. LC-MS(ES) m/e 292.2 [M + H] +.
General procedure #2: 2-Chloro-4-((3S)-3-pyrrolidinyl{[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile
a) 1,1-Dimethylethyl (3£)-3-((3-chloro-4-cyanophenyl) {[2- (trifluoromethyl)phenyl]methyl} amino)- 1 -pyrrolidinecarboxylate
A solution of 1 , 1 -dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-l-pyrrolidinecarboxylate (10.43 g, 32.5 mmol) in DMF (40 mL) was added dropwise to an ice cold suspension of NaH (60% dispersion in mineral oil, 1.95 g, 48.7 mmol) (washed free of mineral oil with hexane) in DMF (100 mL) over 20 min. After stirring at 0 0C for 40 min, a solution of 1 -(bromomethyl)-2- (trifluoromethyl)benzene (11.65 g, 48.7 mmol) in DMF (25 mL) was rapidly added. The reaction mixture was stirred at 0 0C for 30 min and at room temperature for 30 min. The mixture was poured into a cold aqueous solution OfNH4Cl (200 mL) and extracted with Et2O (3x). The organic extracts were washed with H2O (2x), dried over NaSO4, filtered, and concentrated. The residue was purified by column chromatography (eluted with 25% EtOAc/hexane) to yield the titled compound (14.28 g, 92%). LC-MS (ES) m/e 480 [M + H]+.
b) 2-Chloro-4-((3S)-3-pyrrolidinyl{[2-(trifluoromethyl)phenyl]methyl}amino)benzonitrile
To a solution of 1 , 1 -dimethylethyl (3S)-3-((3-chloro-4-cyanophenyl){[2- (trifluoromethyl)phenyl]methyl} amino)- 1 -pyrrolidinecarboxylate (14.0 g, 29 mmol) in CH2Cl2 (16 mL), TFA (15 mL) was added and the reaction stirred for 1.5 h. The reaction mixture was concentrated and the residue was triturated with Et2O and MeOH to yield the trifluoroacetate salt as a white solid. The heterogeneous mixture was filtered, washed with Et2O, and dried. The trifluoroacetate salt was dissolved in MeOH (20 mL) and added to a stirred mixture of aqueous K2Cθ3 and Et2O. The Et2O was separated and the aqueous phase was extracted with Et2O (2x). The combined Et2O layers were washed with H2O and brine, dried over Na2SOzI, filtered, and concentrated to yield the titled compound (10.74 g, 98%). LC-MS (ES) m/e 380 [M + H]+.
General procedure #3: 2-chloro-4-{(2-methylpropyl)[(3S)-3-pyrrolidinyllamino}benzonitrile
a) 1 , 1 -dimethylethyl (3S)-3- [(3-chloro-4-cyanophenyl)(2-methyl-2-propen- 1 -yl)amino]- 1 - pyrrolidinecarboxylate
To a solution of 1 , 1 -dimethylethyl (3£)-3-[(3-chloro-4-cyanophenyl)amino]-l- pyrrolidinecarboxylate (4 g, 12.4 mmol) in DMF (25 mL) at 0 0C was added sodium hydride (60% dispersion in mineral oil, 0.75 g, 18.6 mmol) in two portions. The mixture was stirred for 30 minutes and then 3-bromo-2-methyl-l-propene (1.88 mL, 18.6 mmol) was added over five minutes. The reaction was stirred one hour and then quenched carefully with 5 mL of water. 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 Na2SOzI, 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. 1H-NMR (CDCl3) δ : 1.48 (9H, s), 1.79 (3H, s), 1.99 (IH, m), 2.20 (IH, m), 3.25 (IH, dd, J= 12, 8 Hz), 3.37 (IH, m), 3.55 (IH, m), 3.72 (3H, m), 4.44 (IH, quintet, J= 8 Hz), 4.71 (IH, s), 4.93 (IH, s), 6.58 (IH, d, J=8.8 Hz), 6.72 (IH, s), 7.43 (IH, d, J=
8.8 Hz). LC-MS (ES) m/e 376.3 (M+H)+.
b) 1 , 1 -dimethylethyl (3£)-3-[(3-chloro-4-cyanophenyl)(2-methylpropyl)amino]- 1 - pyrrolidinecarboxylate To a solution of 1 , 1 -dimethylethyl (3£)-3-[(3-chloro-4-cyanophenyl)(2-methyl-2-propen-l- yl)amino]-l-pyrrolidinecarboxylate (3.65 g, 9.71 mmol) in EtOH (97 mL) was added platinum oxide (0.365 g) and one drop of 0.6 N aqueous hydrochloric acid. The reaction was stirred under a hydrogen- filled balloon for two hours. 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. 1H-NMR (CDCl3) δ : 0.94 (6H, dJ= 6.8 Hz), 1.48 (9H, s), 2.06 (3H, m), 3.10 (2H, m), 3.32 (2H, m), 3.58 (IH, m), 3.66 (IH, m), 4.36 (IH, m), 6.70 (IH, d, J = 8.8 Hz), 6.83 (IH, s), 7.45 (IH, d, J
= 8.8 Hz). LC-MS (ES) m/e 377.8 (M+H)+.
c) 2-chloro-4-{(2-methylpropyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile
To a solution of 1 , 1 -dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(2-methylpropyl)amino]-l- pyrrolidinecarboxylate (2.75 g, 7.28 mmol) in CH2CI2 (36 mL) was added trifluoroacetic acid (9 mL). The reaction was stirred for two hours and then was concentrated. To this residue was added EtOAc (50 mL), 10% aqueous Na2CO3 (30 mL), and water (20 mL). The layers were separated, and the aqueous layer was extracted three times with EtOAc (10 mL). The combined organic extracts were dried over MgSO/t, filtered, and concentrated to afford the titled product (2.02 g, quantitative) as orange foam. 1H-NMR (methanol-cU) δ : 0.96 (6H, d, J = 6.4 Hz), 2.02 (2H, m), 2.22 (IH, m), 2.95 (IH, m), 3.23 (5H, m), 4.58 (IH, quintet, J= 8 Hz), 6.92 (IH, d, J= 9.2 Hz),
7.04 (IH, s), 7.54 (IH, d, J= 8.8 Hz). LC-MS (APCI) m/e 277.9 (M+H)+.
General procedure #4: 2-chloro-4-{(cyclopentylmethyl)[(3S)-3-pyrrolidinyllamino}benzonitrile
a) 1 , 1 -dimethylethyl (3 S)-3 - [(3 -chloro-4-cyanophenyl)( 1 -cyclopenten- 1 -ylmethyl)amino] - 1 - pyrrolidinecarboxylate
This compound was made according to general procedure #3 (part a) except substituting 1 - (bromomethyl)cyclopentene for 3-bromo-2-methyl-l-propene. LC-MS (ES) m/e 402.2 [M + H]+.
b) 1 , 1 -dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(cyclopentylmethyl)amino]- 1 - pyrrolidinecarboxylate
This compound was made according to general procedure #3 (part b) except substituting 1,1- dimethylethyl (3 S)-3 - [(3 -chloro-4-cyanophenyl)( 1 -cyclopenten- 1 -ylmethyl)amino] - 1 - pyrrolidinecarboxylate for 1 , 1 -dimethylethyl (3£)-3-[(3-chloro-4-cyanophenyl)(2-methyl-2- propen-l-yl)amino]-l -pyrrolidinecarboxylate. LC-MS (ES) m/e 404.3 [M + H]+.
c) 2-chloro-4- {(cyclopentylmethyl) [(3 S)-3 -pyrrolidinyl] amino } benzonitrile
This compound was made according to general procedure #3 (part c) except substituting 1,1- dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(cyclopentylmethyl)amino]-l- pyrrolidinecarboxylate for 1 , 1 -dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(2- methylpropyl)amino]-l -pyrrolidinecarboxylate. LC-MS (ES) m/e 304.3 [M + H]+.
General procedure #5: methyl (3£)-3-[(3-chloro-4-cyanophenyl)amino]- 1 -pyrrolidinecarboxylate
To an ice cold solution of 2-chloro-4-[(3S)-3-pyrrolidinylamino]benzonitrile (1.88 g, 8.48 mmol) in CH2Cl2 (50 mL) was added Et3N (2 mL, 12.7 mmol) followed by methyl chloroformate (0.76 g, 8.1 mmol). After stirring at 0 0C for 3 h, the reaction was washed with saturated NaHCO3, dried over Na2Sθ4 and concentrated. The residue was purified via flash chromatography to give the product as a white foam (2.12 g, 89%). LC-MS (ES) m/e 280.2 (M + H)+.
General Procedure #6: 2-chloro-4- {(2,2-dimethylpropyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile
a) 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(2,2-dimethylpropyl)amino]-l- pyrrolidinecarboxylate
This compound was made using a procedure similar general procedure #3 (part a) except substituting l-iodo-2,2-dimethylpropane (2 equivalents) for 3-bromo-2-methyl-l-propene. In addition, 2 equivalents of sodium hydride were used, and after beginning the reaction at 00C, it was heated at 95°C for 17 hours. LC-MS (ES) m/e 392.6 (M+H)+. b) 2-chloro-4-{(2,2-dimethylpropyl)[(3S)-3-pyrrolidinyl]amino}benzonitrile
This compound was made using a procedure similar to general procedure #3 (part c) except substituting 1 , 1 -dimethylethyl (3 S)-3 - [(3 -chloro-4-cyanophenyl)(2,2-dimethylpropyl)amino] - 1 - pyrrolidinecarboxylate for 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)(2- methylpropyl)amino]-l-pyrrolidinecarboxylate. LC-MS (ES) m/e 292.3 (M+H)+.
The following table illustrates intermediates (IMD) that were prepared in accordance with procedures as indicated (GP = general procedure followed). It is to be understood that there are some variations in the manner in which the reactions are carried out (reagents, temperatures, etc.) and in the way in which the intermediates are isolated. For example, intermediates analogous to Intermediate #5 can be isolated as the free base or as a salt, such as the HCl or TFA salt, and TFA salts can be concerted to the HCl salts for ease.
} -2-
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention. All of the compounds were found to have a p!C5o of > 5.5. 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.
Example 1 : 2-Chloro-4-{[(2-methylphenyl)methyl][(3S)-l-(2-methylpropanoyl)-3- pyrrolidinyl] amino } benzonitrile
To a solution of 2-chloro-4-{[(3S)-l-(2-methylpropanoyl)-3-pyrrolidinyl]amino}benzonitrile (0.098g, 0.34 mmol) in DMF (2 mL), NaH (60% in mineral oil, 0.020 g, 0.51 mmol) was added at 0 0C under a N2 atmosphere. After stirring for 10 min, 1 -(bromomethyl)-2-methylbenzene (0.062 g, 0.34 mmol) was added and the reaction was stirred at 0 0C for 1 h. The reaction mixture was quenched with H2O and then partitioned between EtOAc and H2O. The organic layer was dried over Na2SOzI, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% EtOAc in hexane grading to 100% EtOAc in hexane to yield the titled compound (0.105 g, 78%) as a white foam. LC-MS(ES) m/e 396.4 [M + H] +.
Example 2: 2-Chloro-4- { [(2-methylphenyl)methyl] [(35)- 1 -pentanoyl-3 - pyrrolidinyl] amino } benzonitrile
A solution of pentanoyl chloride (0.083 g, 0.69 mmol) in CH2Cl2 (2 mL) was added slowly to an ice cold solution of 2-chloro-4- {[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (0.150 g, 0.46 mmol) in CH2Cl2 (8 mL) and saturated aqueous NaHCO3 (2 mL). After stirring at 0 0C for 30 min, aqueous Na2CO3 (10%, 50 mL) was added, the ice bath was removed, and the reaction was stirred for additional 30 min. The layers were separated and the organic layer was washed with 10% Na2COs, dried over Na2SOzI, filtered, and concentrated. The residue was purified via silica gel chromatography with 20% EtOAc in hexane grading to 50% EtOAc in hexane to yield the titled compound (0.114 g, 61%) as a white solid. LC-MS(ES) m/e 410.4 [M +
H]+.
Example 3 : 2-Chloro-4-{[(2,5-dichlorophenyl)methyl] [(3S)-I -(3,3, 3-trifluoropropanoyl)-3- pyrrolidinyl] amino } benzonitrile
A mixture of 2-chloro-4-{[(2,5-dichlorophenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (0.136 g, 0.36 mmol), 3,3,3-trifluoropropanoic acid (0.046 g, 0.36 mmol) and N-cyclohexyl-N'-(2- morpholinoethyl)carbodiimide methyl-/>-toluenesulfonate (0.160 g, 0.38 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 15 h. The reaction mixture was then diluted with Et2O (50 mL), washed with H2O (2x) and aqueous Na2CO3, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 25% EtOAc in hexane grading to 100% EtOAc in hexane to afford the titled product (0.055 g, 31%) as a white foam. LC-MS (ES) m/e 490.4 [M + H]+.
Example 4: 2-Chloro-4- { [(3S)- 1 -(hydroxyacetyl)-3-pyrrolidinyl] [(2- methylphenyl)methyl] amino } benzonitrile
2-Chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (0.160 g, 0.49 mmol) and ethyl glycolate (1 mL, 10.6 mmol) was heated with stirring at 60 0C for 20 h. The reaction was diluted with EtOAc (3 mL) and Et2O (30 mL), washed with H2O (3x), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.122 g, 65%) as a white foam. LC-MS (ES) m/e 384.4 [M + H]+.
Example 5: 2-Chloro-4- { [(5-fluoro-2-methylphenyl)methyl] [(3 S)- 1 -(2-hydroxy-2- methylpropanoyl)-3 -pyrrolidinyl] amino } benzonitrile
A solution of 2-chloro-4-{[(5-fluoro-2-methylphenyl)methyl][(3£)-3- pyrrolidinyl] amino} benzonitrile hydrochloride salt (0.150 g, 0.40 mmol), 2-hydroxyisobutyric acid (0.045 g, 0.44 mmol), PyBOP (0.230 g, 0.44 mmol), and DIEA (0.212 g, 1.2 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 16 h. The reaction was concentrated and purified by preparative HPLC (Sunfire, 30 x 150 mm, 40 mL/min;: acetonitrile/water, 0.1% TFA, 30 to 60% over 12 min; UV detection at 214 nm) to give the titled product. LC-MS (ES) m/e 430.1 [M +
H]+.
Example 6: 2-Chloro-4- { {(3S>l-[(2S>2-hydroxypropanoyl]-3-pyrroridinyl} [(2- methylphenyl)methyl] amino } benzonitrile
A solution of (25)-2-{[(l,l-dimethylethyl)(dimethyl)silyl]oxy}propanoic acid (760 mg, 3.73 mmole) in 10 mL of THF at 0 0C was treated with N-methylmorpholine (414 mg, 4.1 mmole), and then a solution of /-butyl chloroformate (0.51 mL, 3.92 mmole) in 3 mL of THF. Stirring was continued at 0 0C for 30 minutes. A suspension of 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3- pyrrolidinyl] amino} benzonitrile hydrochloride (720 mg, 2.0 mmole) in 50 mL Of CH2Cl2 was treated with saturated aqueous NaHCθ3 (3 mL), and stirred until all the solids dissolved. The biphasic reaction mixture was cooled to 0 0C, treated with 9.0 mL of the above prepared mixed anhydride solution (~ 2.4 mmol), and stirred at 0 0C for 30 minutes. The reaction was washed with H2O, cold 0.05N HCl, aqueous NaHCO3, dried, and the solvent evaporated. The residual solid was dissolved in 10 mL of THF and treated with tetrabutylammonium fluoride (4.0 mL, IM in THF). After 30 minutes, the reaction was diluted with 50 mL Of H2O and extracted twice with Et2O. The extracts were washed with H2O, cold 0.02N HCl, dried and the solvent evaporated. The residue was purified by silica gel chromatography, and gave the desired product, 510 mg (64%). LC-MS
(ES) m/e 398 [M + H]+.
Example 7: 2-Chloro-4-([(3S)-l-(3-hydroxypropanoyl)-3-pyrroridinyl] {[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile
toluene, Δ
2-Chloro-4-([(3S>l-(3-hydroxypropanoyl)-3-pyrroridinyl] {[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile
A solution of β-propiolactone (0.1 mL, 1.6 mmol), 2-chloro-4-((3S)-3-pyrrolidinyl{[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile (0.166 mg, 0.44 mmol), and toluene (4 mL) was stirred at 105 0C for 15 min. The reaction was then concentrated, diluted with Et2O, washed with H2O (2x), dried over Na2SOzI, filtered, and concentrated. The residue was purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 3% MeOH in CH2Cl2 to yield the titled compound (0.115 g, 58%) as a white foam. LC-MS(ES) m/e 452.2 [M + H]+.
Example 8: 2-Chloro-4- { [(3S)- 1 -(4-hydroxybutanoyl)-3-pyrrolidinyl] [(2- methylphenyl)methyl] amino } benzonitrile
This compound was made according to general procedure of Example 7 except substituting γ- butyrolactone for β-propiolactone. LC-MS (ES) m/e 466.4 [M + H]+. Example 9: 2-Chloro-4-{[(2-methylphenyl)methyl][(3S)-l-(4-pyridinylcarbonyl)-3- pyrrolidinyl] amino } benzonitrile
A solution of 2-chloro-4-{[(2-methylphenyl)methyl][(3S)-3-pyrrolidinyl]amino}benzonitrile (0.074 g, 0.22 mmol), 4-pyridinecarbonyl chloride (0.042 g, 0.25 mmol) and DIEA (0.114 g, 0.88 mmol) in CH2CI2 (2 mL) was stirred at room temperature for 16 h. The reaction was concentrated and purified by preparative HPLC (X-bridge, 30 x 150 mm, 40 mL/min; A: acetonitrile B: water, pH= 10, A: 25 to 100% over 12 min; UV detection at 214 nm) to give the titled product. LC-MS
(ES) m/e 431.4 [M + H]+.
E2campieJO: 2-Chloro-4-[[(3S)-l-(2-methylpropanoyl)-3-pyrrolidinyl](2- methylpropyl)amino]benzonitrile
a) 2-Chloro-4-[[(3S)- 1 -(2-methylpropanoyl)-3-pyrrolidinyl](2-methyl-2-propen- 1 - yl)amino]benzonitrile
This compound was made according to general procedure of example 1, except substituting 3- bromo-2-methyl- 1 -propene for l-(bromomethyl)-2-methylbenzene. LC-MS (ES) m/e 348.3 [M +
H]+.
b) 2-Chloro-4-[[(31S)- 1 -(2-methylpropanoyl)-3-pyrrolidinyl](2-methylpropyl)amino]benzonitrile
To a solution of 2-chloro-4-[[(3S)-l-(2-methylpropanoyl)-3-pyrrolidinyl](2-methyl-2-propen-l- yl)amino]benzonitrile (0.060 g, 0.2 mmol) and 1 drop of IN HCl in EtOH (25 mL) under a N2 atmosphere, platinum oxide (0.01 g) was added. The reaction mixture was stirred under a H2 atmosphere for 1 h and then the H2 inlet was removed. The reaction was left undisturbed for 16 h and filtered through a pad of Celite. The filtrate was concentrated and purified by preparative HPLC to afford the titled product (0.016 g, 23%). LC-MS (ES) m/e 348.3 [M + H]+.
Example 11 : Methyl (3S)-3- {(3-chloro-4-cyanophenyl)[(2,3-difluorophenyl)methyl]amino}-l- pyrrolidinecarboxylate
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 CH2Cl2 (5 mL) and saturated aqueous NaHCO3 (1 mL). After stirring at 0 0C for 1 h, 10% solution of Na2CO3 (3 mL) was added, the ice bath was removed, and the reaction was stirred for 30 min. CH2Cl2 (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%).
LC-MS(ES) m/e 406.5 [M + H]+.
Example 12: 2-Chloro-4-([(3S)-l-glycyl-3-pyrrolidinyl] {[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile
A solution of 1 , 1 -dimethylethyl {2-[(3£)-3-((3-chloro-4-cyanophenyl){[2- (trifluoromethyl)phenyl]methyl}amino)-l-pyrrolidinyl]-2-oxoethyl}carbamate (0.07 g, 0.13 mmol) and TFA (0.5 mL) in CH2Cl2 (1 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated and the resultant TFA salt was stirred in a mixture of aqueous K2C03/Et0Ac. Layers were separated and the organic layer was dried over MgSOzt, filtered, and concentrated to give the titled product (0.047 g, 83%) as white foam. LC-MS (ES) m/e 437.6 [M +
H]+. The following table illustrates compounds that were prepared in accordance with procedures as indicated. (IMD = intermediate used; EN = detailed example number followed). As is the case for the intermediates, it is to be understood that there are some variations in the manner in which the reactions are carried out (reagents, temperatures, etc.) and in the way in which the compounds are isolated.
-2-
- { [4- -(3 - -(1 ,3- -3- -( 1 ,3 - -
-

Claims

Claims
1. A compound represented by the following formula:
or a pharmaceutically acceptable salt thereof;
wherein X is H, F, Cl, Br, or CF3;
y is 0 or 1, with the proviso that when y is 0, R1 is H, Ci-C6-alkyl, -CR3-(OH)-CrC5-alkyl, -CR3- (NH2)-Ci-C5-alkyl CF3, hydroxymethyl, aminomethyl, Ci-C6-alkoxycarbonyl-Ci-C6-alkyl, C3-C6- cycloalkyl, hydroxy-C3-C6-cycloalkyl, Ci-C6-alkyl-C3-C6-cycloalkyl, cyano-C3-C6-cycloalkyl, Ci- C6-alkoxy-C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, -CR3-(OH)- phenyl-(R6)n, or -CH2R7, and;
when y is 1, R1 is Ci-C6-alkyl, CF3, Ci-C6-alkoxycarbonyl-Ci-C6-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, -heteroaryl-(R5)n, -phenyl-(R6)n, or -CH2R7;
R2 is Ci-C5-alkyl, Ci-C6-alkyloxy-Ci-C5-alkyl, C3-C6-cycloalkyl, -heterocycloalkyl-(R4)m, C2-C4- alkenyl, naphthyl, -heteroaryl-(R5)n, or -phenyl-(R6)n;
R3 is H, CrC5-alkyl, or CF3;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
R4 is Ci-C6-alkyl, Ci-Cβ-alkyl-carbonyl, or -heteroaryl-(R5)n
R5 is independently Ci-Cβ-alkyl, F, Cl, Br, CF3, Ci-Cβ-alkoxy, Ci-Cβ-alkoxycarbonyl, Ci-Ce- alkylcarbonyloxy, dimethylamino, C2-C4-alkenyl, or CN, or, when n is 2 or 3, where 2 of the R5 groups, together with the heteroaryl ring to which they are attached form a fused bicyclic ring; R6 is independently Ci-C6-alkyl, F, Cl, Br, CF3, Ci-C6-alkoxy, dimethylamino, hydroxyethylmethylamino, amino, amido, C2-C4-alkenyl, nitro, -C(0)0-Ci-C6-alkyl, -C(O)-Ci-Ce - alkyl, OH, COOH, CH3SO2-, -heterocycloalkyl-(R4)m, or CN, or where 2 of the R6 groups, together with the phenyl ring to which they are attached form a fused bicyclic ring; and
R7 is F, Cl, Br, CrC6-alkoxy, Ci-C6-alkoxy-CrC6-alkyl, CF3, CH2CF3, CN, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C5-alkyl, COOH, CrC6-alkylcarbonyl, -heterocycloalkyl-(R4)m, CrC6-alkyl- heterocycloalkyl, heterocycloalkyl-CH2-, aminocarbonyl, aminocarbonyl-Ci-Ce-alkyl, di-Ci-C6- alkylamino, di-Ci-Ce-alkylaminocarbonyl, Ci-C6-alkylamino-Ci-C6-alkyl, di-Ci-C6-alkylamino- Ci-Cβ-alkyl, C7-C8-bicycloalkyl, Ci-C6-alkylcarbonylamino-Ci-C6-alkyl, hydroxy-Ci-Cβ-alkyl, - SOrCi-Ce-alkyl, Cio-tricycloalkyl, -CH2SO2-phenyl-(R6)n, -O-phenyl-(R6)n, Ci-Cβ-alkoxycarbonylamino, Ci-Ce-alkylcarbonylammo, naphthyl, -heteroaryl-(R5)n, -CH2-heteroaryl-(R5)n, -phenyl- (R6)n, -CH2-phenyl-(R6)n, or (R6)n-phenyl-carbonyl-Ci-C6-alkyl.
2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof which is represented by the following structure:
wherein X is Cl; y is O; and R1 is CrC6-alkyl, -CR3-(OH)-CrC5-alkyl, HO-CrC6-alkyl, or phenyl-(R6)n, wherein R6 is independently Ci-Cβ-alkyl, F, Cl, CF3, Ci-Cβ-alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
3. The compound of Claim 2 or a pharmaceutically acceptable salt thereof wherein R is phenyl-(R6)n, where R6 is independently CH3, F, Cl, Br, or CF3.
4. The compound of Claim 3 or a pharmaceutically acceptable salt thereof wherein R1 is Ci-Cβ- alkyl, -CR3-(OH)-CrC5-alkyl, or HO-CrC6-alkyl.
5. The compound of Claim 4 which is represented by the following structure:
or a pharmaceutically acceptable salt thereof where 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.
6. The compound of Claim 1 or a pharmaceutically acceptable salt thereof wherein y is 1 and R1 iiss CCii--CC6e--aallkkyyll oorr pphheennyyll--((RR66))nn,, wwhheerreeiinn RR66 iiss iinnddeeppeeindently Ci-C6-alkyl, F, Cl, CF3, Ci-Ce-alkoxy, dimethylamino, amino, amido, OH, COOH, or CN.
7. The compound of Claim 6 or a pharmaceutically acceptable salt thereof wherein X is Cl and R2 is phenyl-(R6)n, where R6 is independently CH3, F, Cl, Br, or CF3.
8. The compound of Claim 7 or a pharmaceutically acceptable salt thereof which is represented by the following structure:
or a pharmaceutically acceptable salt thereof, where 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.
9. 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;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,3-difluorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4- { [(2-fluorophenyl)methyl] [(3S)-I -(2-hydroxy-2-methylpropanoyl)-3 - pyrrolidinyl] amino } benzonitrile;
2-chloro-4-({(3S)-l-[(2S)-2-hydroxypropanoyl]-3-pyrrolidinyl} {[2- (trifluoromethyl)phenyl]methyl}amino)benzonitrile;
2-chloro-4-([(2-fluorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,5-dichlorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4-([(2,5-dichlorophenyl)methyl] {(3S)-l-[(2R)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-((cyclohexylmethyl){(3S)-l-[(2R)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2,3-difluorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(5-fluoro-2-methylphenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
methyl (3S)-3-{(3-chloro-4-cyanophenyl)[(2,5-difluorophenyl)methyl]amino}-l- pyrrolidinecarboxylate;
2-chloro-4-([(2,5-dichlorophenyl)methyl] {(3S)-l-[(2S)-2-hydroxypropanoyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4- { [(5-fluoro-2-methylphenyl)methyl] [(3S)-I -propanoyl-3 - pyrrolidinyl] amino } benzonitrile; 2-chloro-4-[[(3S)-l-(2-hydroxy-2-methylpropanoyl)-3- pyrrolidinyl](phenylmethyl)amino]benzonitrile;
2-chloro-4- { [(2,4-difluorophenyl)methyl] [(3 S)- 1 -(2-hydroxy-2-methylpropanoyl)-3- pyrrolidinyl] amino } benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(3-fluorophenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(3-methylphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-([(2-chlorophenyl)methyl] {(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile;
2-chloro-4-((cyclohexylmethyl){(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile; and
2-chloro-4-([(2,3-difluorophenyl)methyl] {(3S)-l-[(4-hydroxyphenyl)carbonyl]-3- pyrrolidinyl} amino)benzonitrile.
10. A pharmaceutical composition comprising the compound of Claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier therefor.
11. A method comprising administering to a patient in need thereof an effective amount of the compound of Claim 1 or a pharmaceutically-acceptable salt thereof to treat endometreosis or uterine fibroids.
EP07855260A 2006-12-19 2007-12-19 Pyrrolidinanilines Withdrawn EP2094269A1 (en)

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PCT/US2007/088066 WO2008077089A1 (en) 2006-12-19 2007-12-19 Pyrrolidinanilines

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MX2009001442A (en) 2006-08-09 2009-02-18 Smithkline Beecham Corp Pyrrolidinone anilines as progesterone receptor modulators.
TW201534586A (en) 2013-06-11 2015-09-16 Orion Corp Novel CYP17 inhibitors/antiandrogens
TWI652264B (en) * 2013-09-26 2019-03-01 東麗股份有限公司 Cyclic amine derivatives and their medical uses
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