WO2018148576A1 - Benzothiophene estrogen receptor modulators - Google Patents

Benzothiophene estrogen receptor modulators Download PDF

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Publication number
WO2018148576A1
WO2018148576A1 PCT/US2018/017668 US2018017668W WO2018148576A1 WO 2018148576 A1 WO2018148576 A1 WO 2018148576A1 US 2018017668 W US2018017668 W US 2018017668W WO 2018148576 A1 WO2018148576 A1 WO 2018148576A1
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Prior art keywords
compound
pharmaceutically acceptable
alkyl
formula
acceptable salt
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PCT/US2018/017668
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English (en)
French (fr)
Inventor
Jay Copeland Strum
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G1 Therapeutics Inc
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G1 Therapeutics Inc
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Priority to JP2019542672A priority Critical patent/JP2020507566A/ja
Priority to EP18751944.2A priority patent/EP3580223A4/en
Priority to CA3052810A priority patent/CA3052810A1/en
Priority to KR1020197026068A priority patent/KR20190117582A/ko
Priority to CN201880020916.XA priority patent/CN110461853A/zh
Priority to AU2018217809A priority patent/AU2018217809A1/en
Publication of WO2018148576A1 publication Critical patent/WO2018148576A1/en
Priority to IL268319A priority patent/IL268319A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/64—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Fulvestrant a complete estrogen receptor antagonist with no agonist activity, was disclosed by Imperial Chemical Industries (ICI) in U.S. Patent No. 4,659,516 and is sold by Astra Zeneca under the name Faslodex. It is indicated for the treatment of hormone receptor positive metastatic breast cancer in post-menopausal women with disease progression following anti-estrogen therapy. Fulvestrant has limited water solubility and requires monthly intramuscular (IM) injections. Fulvestrant's aqueous insolubility creates a challenge to achieve and maintain efficacious serum concentrations.
  • IM intramuscular
  • Z is selected from -0-, -C(R 3 )2-, -CHR 3 -, -CH2-, -CHF-, -CF2-, and -S-;
  • R 4 and R 5 are independently selected from hydrogen, halogen (for example F), C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
  • each R 1 is independently selected from C 1 -C 3 alkyl, halogen, and C 1 -C 3 haloalkyl; and R 3 is independently selected from -F, -CI, -Br, -CH3, -CH2F, -CHF2, and -CF3.
  • a method of treating or preventing hormone receptor positive metastatic breast cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from Formula I, II, ⁇ , or IV or its pharmaceutically acceptable salt or prodrug thereof, optionally in a pharmaceutically acceptable carrier;
  • heteroarylalkyl groups include:
  • a “prodrug” as used herein means a compound which when administered to a host in vivo is converted into a parent drug.
  • the term "parent drug” means any of the presently described chemical compounds described herein.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent.
  • Prodrug strategies exist which provide choices in modulating the conditions for in vivo generation of the parent drug, all of which are deemed included herein.
  • the present invention includes compounds of Formula I, ⁇ , ⁇ , and IV with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • Z is selected from -0-, -C(R 3 ) 2 - -CHR 3 -, -CH2-, -CHF-, -CF2-, and -S-;
  • each R 1 is independently selected from C 1 -C 3 alkyl, halogen, and C 1 -C 3 haloalkyl;
  • n 0, 1, or 2;
  • each R 1 is independently selected from C 1 -C 3 alkyl (for example methyl), halogen (for example F), and C 1 -C 3 haloalkyl (typically F substituted alkyl);
  • R 2 is -NH-(CH2)ni-NH2
  • the compound of Formula II is of Formula ⁇ - ⁇ :
  • the compound of Formula HI is of Formula ⁇ - ⁇ :
  • R 1 s there are 2, 3, 4, or 5, R 1 s and at least one R 1 is chloro.
  • aryl is a 6 carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring.
  • aryl include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring.
  • heteroaryl is a 6 membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e. pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
  • arylalkyr' include:
  • A is selected from:
  • A is selected from:
  • A is selected from:
  • A is selected from:
  • X is selected from:
  • m3 is 1, 2, 3, or 4.
  • R 12 is
  • the active agent can be combined with any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • the pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent, in a ratio that achieves the desired results.
  • anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
  • pimasertib/AS703026/MSC1935369 ((,S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l-( ⁇ 3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]phenyl ⁇ carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol),
  • RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
  • ALK inhibitors include but are not limited to Crizotinib, AP26113, and LDK378.
  • HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/US2018/017668 2017-02-10 2018-02-09 Benzothiophene estrogen receptor modulators Ceased WO2018148576A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2019542672A JP2020507566A (ja) 2017-02-10 2018-02-09 ベンゾチオフェンエストロゲン受容体モジュレーター
EP18751944.2A EP3580223A4 (en) 2017-02-10 2018-02-09 Benzothiophene estrogen receptor modulators
CA3052810A CA3052810A1 (en) 2017-02-10 2018-02-09 Benzothiophene estrogen receptor modulators
KR1020197026068A KR20190117582A (ko) 2017-02-10 2018-02-09 벤조티오펜 에스트로겐 수용체 조정제
CN201880020916.XA CN110461853A (zh) 2017-02-10 2018-02-09 苯并噻吩雌激素受体调节剂
AU2018217809A AU2018217809A1 (en) 2017-02-10 2018-02-09 Benzothiophene estrogen receptor modulators
IL268319A IL268319A (en) 2017-02-10 2019-07-29 Benzothiophene estrogen receptor modulators

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201762457643P 2017-02-10 2017-02-10
US62/457,643 2017-02-10
US201762460358P 2017-02-17 2017-02-17
US62/460,358 2017-02-17
US201862614279P 2018-01-05 2018-01-05
US62/614,279 2018-01-05

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WO2018148576A1 true WO2018148576A1 (en) 2018-08-16

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PCT/US2018/017668 Ceased WO2018148576A1 (en) 2017-02-10 2018-02-09 Benzothiophene estrogen receptor modulators

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US (3) US10208011B2 (https=)
EP (1) EP3580223A4 (https=)
JP (1) JP2020507566A (https=)
KR (1) KR20190117582A (https=)
CN (1) CN110461853A (https=)
AU (1) AU2018217809A1 (https=)
CA (1) CA3052810A1 (https=)
IL (1) IL268319A (https=)
TW (1) TW201835064A (https=)
WO (1) WO2018148576A1 (https=)

Cited By (3)

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WO2021065898A1 (ja) 2019-09-30 2021-04-08 日本ケミファ株式会社 アゼパン誘導体
JP2021512955A (ja) * 2018-02-06 2021-05-20 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ 選択的エストロゲン受容体分解剤としての置換ベンゾチオフェン類似体
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IL303038B2 (en) 2016-12-05 2024-08-01 G1 Therapeutics Inc Preservation of immune response during chemotherapy regimens
EP3565558B1 (en) 2017-01-06 2023-12-06 G1 Therapeutics, Inc. Combination therapy with a serd compound and a cdk4/6 inhibitor for the treatment of cancer
CN108203404A (zh) * 2018-03-02 2018-06-26 上海博邦医药科技有限公司 (r)-3-苯基哌啶或/和(s)-3-苯基哌啶以及尼拉帕尼的手性中间体的合成方法
CN112839646A (zh) * 2018-08-16 2021-05-25 G1治疗公司 用于治疗医学疾病的苯并噻吩雌激素受体调节剂
CN113816892A (zh) * 2021-08-27 2021-12-21 安徽鼎旺医药有限公司 一种醋酸巴多昔芬的合成方法
CN113801094A (zh) * 2021-10-29 2021-12-17 中国药科大学 一种2-羰基苯并噻吩类化合物及其制备方法和用途
TW202543650A (zh) 2024-03-08 2025-11-16 美商海爾達醫療運營公司 異雙官能化合物及其在治療疾病中之用途

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