EP4577534A1 - Nouveaux dérivés d'acide tétrahydroisoquinoléine-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques - Google Patents

Nouveaux dérivés d'acide tétrahydroisoquinoléine-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

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Publication number
EP4577534A1
EP4577534A1 EP23762378.0A EP23762378A EP4577534A1 EP 4577534 A1 EP4577534 A1 EP 4577534A1 EP 23762378 A EP23762378 A EP 23762378A EP 4577534 A1 EP4577534 A1 EP 4577534A1
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EP
European Patent Office
Prior art keywords
methyl
formula
compound
fluoropropyl
group
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.)
Pending
Application number
EP23762378.0A
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German (de)
English (en)
Inventor
Patrick Bernardelli
Youssef El-Ahmad
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.)
Sanofi SA
Original Assignee
Sanofi SA
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Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP4577534A1 publication Critical patent/EP4577534A1/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • ERs are in two forms: the estrogen receptor alpha (ER ⁇ ) and the estrogen receptor beta (ER ⁇ ) respectively encoded by the ESR1 and the ESR2 genes.
  • ER ⁇ and ER ⁇ are ligand- activated transcription factors which are activated by the hormone estrogen (the most potent estrogen produced in the body is 17 ⁇ -estradiol). In the absence of hormone, ERs are largely located in the cytosol of the cell. When the hormone estrogen binds to ERs, ERs migrate from the cytosol to the nucleus of the cell, form dimers and then bind to specific genomic sequences called Estrogen Response Elements (ERE). The DNA/ER complex interacts with co-regulators to modulate the transcription of target genes.
  • ER ⁇ is mainly expressed in reproductive tissues such as uterus, ovary, breast, bone and white adipose tissue.
  • Abnormal ER ⁇ signaling leads to development of a variety of diseases, such as cancers, metabolic and cardiovascular diseases, neurodegenerative diseases, inflammation diseases and osteoporosis.
  • ER ⁇ is expressed in not more than 10% of normal breast epithelium but approximately 50-80% of breast tumors.
  • Such breast tumors with high level of ER ⁇ are classified as ER ⁇ -positive breast tumors.
  • the etiological role of estrogen in breast cancer is well established and modulation of ER ⁇ signaling remains the mainstay of breast cancer treatment for the majority ER ⁇ -positive breast tumors.
  • ER ⁇ ER ⁇
  • LBD Ligand Binding Domain
  • - R1 and R2 independently represent a hydrogen atom or a deuterium atom
  • - R3’ and R3 independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group
  • - R4 represents a hydrogen atom or a fluorine atom
  • - R5 and R5’ independently represent a hydrogen atom or a fluorine atom
  • - represents a single bond or a double bond
  • - p is 0 or 1
  • the compounds of formula (I) can contain one or more asymmetric carbon atoms. They may therefore exist in the form of enantiomers.
  • the compounds of formula (I) may be present as well under tautomer forms.
  • the compounds of formula (I) may exist in the form of bases, acids, zwitterion or of addition salts with acids or bases.
  • compounds of formula (I) or pharmaceutically acceptable salts thereof may be prepared with pharmaceutically acceptable acids or bases, although the salts of other acids or bases useful, for example, for purifying or isolating the compounds of formula (I) are also provided.
  • hydrochloride may be cited.
  • halogen atom a fluorine, a chlorine, a bromine or an iodine atom, and in particular a fluorine and a chlorine atom
  • alkyl group a linear or branched saturated hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms (noted “(C1-C6)alkyl”).
  • the fluoroalkoxy group can be named perfluoroalkoxy group.
  • a zwitterion means: a globally neutral molecule with a positive and a negative electrical charge and having an acidic group and a basic group.
  • R1 and R2 are a hydrogen atom.
  • R3’ represents a hydrogen atom.
  • R3 represents a hydrogen atom.
  • R3’ and R3” both represent a hydrogen atom.
  • R4 represents a hydrogen atom.
  • R5 and R5’ both represent a hydrogen atom.
  • p is 0.
  • p is 1.
  • Y represents -CH 2 -.
  • R7 represents a fluorine atom and n is 1 or 2.
  • R8 represents a (C 1 -C 6 )alkyl group, and preferably represents a methyl group.
  • R6 represents a (C 1 -C 6 )alkyl group, said (C 1 -C 6 )alkyl group being optionally substituted with 1 to 3 fluorine atom, preferably said (C1-C6)alkyl group being substituted with 2 or 3 fluorine atom.
  • R6 represents a -CH2-CF3 group or a -CH2-CF2-CH3 group.
  • R6 represents a single bond.
  • p is equal to 1 when Y represents -CH2-, -O- or -NH-.
  • p is equal to 1.
  • Another embodiment is a method of treating ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
  • Another embodiment is a method of treating cancer, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound selected from the above list, or a pharmaceutically acceptable salt thereof.
  • Another embodiment is a pharmaceutical composition comprising as active principle an effective dose of a compound selected from the above list, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • Compound 1H can be converted in STEP 6 to compound 1J by carbonylation with carbon monoxide (CO), in solution in MeOH, in the presence of a palladium catalyst, for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM.
  • a palladium catalyst for example palladium acetate or [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (Pd(dppf)Cl 2 ), complex with DCM.
  • Compound 1J can be converted in STEP 7 to compound I by treatment with an aqueous solution of sodium hydroxide (NaOH) or lithium hydroxide (LiOH) in MeOH or THF. Extraction of the product could give the sodium or lithium salt of compound I.
  • Step 2 3-(4-Bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2-trifluoroacetic acid
  • Step 2 of Intermediate 8 was was prepared following a similar procedure to that of Step 2 of Intermediate 4 starting from tert-butyl 3-(3,5-difluoro-4-bromophenoxy)azetidine-1- carboxylate to give 2 g (crude) of 3-(4-bromo-3,5-difluoro-phenoxy)azetidine, 2,2,2- trifluoroacetic acid used as such in the next step.
  • Step 2 1-(3-Fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylene)azetidine
  • Step 2 of Intermediate 9 was prepared following a similar procedure to that of step 1 of Intermediate 3 from 3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine, 2,2,2-trifluoroacetic acid and 1-fluoro-3-iodopropane to give 1.05 g (60%) of 1-(3- fluoropropyl)-3-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)azetidine.
  • Step 2 3-((4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)pyrrolidine, hydrochloride, mixture of Z and E isomers
  • Step 3 Methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate
  • Step 3 of Example 4 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 34 mg (29%) of methyl (1S,3R)-1-(2,6-difluoro-4-(((S)
  • Step 4 (1S,3R)-1-(2,6-Difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 4 of Example 4 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyrrolidin-3- yl)oxy)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate to give 40 mg (34%) of (1S,3R)-1-(2,6-difluoro-4-(((S)-1-(3-fluoropropyl)pyr
  • Example 5 (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid Step 1: (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol Step 1 of Example 5 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and (S)-5-((1-(3- fluoropropyl
  • Step 2 (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate
  • Step 2 of Example 5 was prepared following a similar procedure to that of Step 2 of Example 4 from (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol and triflic anhydride to give 350 mg (crude) of (1S,3R)-1-(5-(((S)
  • Step 4 (1S,3R)-1-(5-(((S)-1-(3-Fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3-methyl- 2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 4 of Example 5 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxy)pyridin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate to give 12 mg (6%) of (1S,3R)-1-(5-(((S)-1-(3-fluoropropyl)pyrrol
  • Example 6 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylic acid
  • Step 1 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol
  • Step 1 of Example 6 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2,2-trifluoroethyl)amino)propyl)phenol (Intermediate 2) and 2,6-difluoro- 4-((
  • Step 2 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate
  • Step 2 of Example 6 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol to give 472 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoro
  • Step 3 Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate
  • Step 3 of Example 6 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 51 mg (21%) of methyl (1S,3R)-1-(2,6-difluoro-4-((1-(
  • Step 4 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 4 of Example 6 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate to give 25 mg (51%) of (1S,3R)-1-(2,6-difluoro-4-((1-(1-(1-(1-(2-fluoroprop
  • Example 7 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid Step 1: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol Step 1 of Example 7 was prepared following a similar procedure to that of Intermediate 11 from (R)-3-(2-((2,2-difluoropropyl)amino)propyl)phenol (Intermediate 1) and 2,6-difluoro- 4-((1-(3-fluoropropyl
  • Step 2 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate
  • Step 2 of Example 7 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-ol to give 509 mg (crude) of (1S,3R)-1-(2,6-difluoro-4-((1-(1-(1-(1-(1-(2-(
  • Step 3 Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Step 3 of Example 7 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2-(2,2- difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 146 mg (34%) of methyl (1S,3R)-1-(2,6-difluoro
  • Step 4 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)azetidin-3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 4 of Example 7 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3-yl)oxy)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylate to give 43 mg (52%) of (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoro)azetidin-3-ylidene
  • Step 2 (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate
  • Step 2 of Example 8 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol to give 140 mg (98%) of (1S,3R)- 1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino
  • Step 3 Methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate
  • Step 3 of Example 8 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate to give 117 mg (99%) of methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3
  • Step 4 (1S,3R)-1-(5-((1-(3-Fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3-methyl-2- (2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid
  • Step 4 of Example 8 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(5-((1-(3-fluoropropyl)azetidin-3-yl)amino)pyridin-2-yl)-3- methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate to give 40 mg (34%) of (1S,3R)-1-(5-((1-(3-fluoropropyl)azeti
  • Step 2 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6- yl trifluoromethanesulfonate, mixture of Z and E isomers
  • Step 2 of Example 9 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-ylidene)methyl)phenyl)- 3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol, mixture of Z and E isomers to give 1.43
  • Step 3 Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate
  • Step 3 of Example 9 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-6- yl trifluoromethanesulfonate, mixture of Z and E isomers to give methyl
  • Step 4 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylic acid
  • Step 4 of Example 9 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-3-methyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-6- carboxylate to give 51 mg (48%) of (1S,3R)-1-(2,6-difluoro-4
  • Step 1 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylic acid
  • Step 1 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6- ol, mixture of Z and E isomers
  • Step 1 of Example 10 was prepared following a similar procedure to that of Step 1 of Example 9 from (1S,3R)-1-(4-bromo-2,6-difluorophenyl)-2-(2,2-difluoro
  • Step 2 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, mixture of Z and E isomers
  • Step 2 of Example 10 was prepared following a similar procedure to that of Step 2 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6- ol, mixture of Z and E isomers to give 1.3
  • Step 3 Methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylate
  • Step 3 of Example 10 was prepared following a similar procedure to that of Step 3 of Example 1 from (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate, mixture of Z and E isomers to give methyl (1S,3R)-1-(2,6-difluoro-4-((
  • Step 4 (1S,3R)-1-(2,6-Difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylic acid
  • Step 4 of Example 10 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((Z)-(1-(3-fluoropropyl)pyrrolidin-3- ylidene)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylate to give 35 mg (15%) of (1S,3R)-1-(2,6-difluoro-4-(((Z)-(1-(3-fluoroprop
  • Method D 11: (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylic acid, 50/50 mixture of diastereomers
  • Step 1 Methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylate, 50/50 mixture of diastereomers
  • Step 2 (1S,3R)-1-(2,6-Difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3-yl)methyl)phenyl)-2- (2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 50/50 mixture of diastereomers
  • Step 2 of Example 11 was prepared following a similar procedure to that of Step 5 of Example 1 from methyl (1S,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)pyrrolidin-3- yl)methyl)phenyl)-2-(2,2-difluoropropyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-6- carboxylate, 50/50 mixture of diastereomers to give 44 mg (36%) of (1S,3R)-1-(2,6-Difluoro-4-((1-(
  • Estrogen receptor degradation activity Said test involves measuring the in vitro degradation activity of the compounds of the tables 1a and 1b. The measurements of the degradation activities were made using a breast cancer cell ER ⁇ in cell western assay as described hereunder.
  • MCF7 cells ATCC were seeded in 384 wells microplate (collagen coated) at a concentration of 10000 cells/ 30 ⁇ L per well in red phenol free MEM alpha medium (invitrogen) containing 5% charcoal dextran striped FBS.
  • LI-COR blocking buffer was removed and cells were incubated overnight at cold room with 50 ⁇ L anti-ER rabbit monoclonal antibody (Thermo scientific MA1-39540) diluted at 1:1000 in LI-COR blocking buffer containing 0.1% tween-20. Wells which were treated with blocking buffer but no antibody were used as background control. Wells were washed twice with PBS (0.1% tween-20) and incubated at 37 °C for 60 minutes in LI-COR (0.1% tween-20) containing goat anti-rabbit antibody Alexa 488 (1:1000) and Syto-64 a DNA dye (2 ⁇ M final concentration). Cells were then washed 3 times in PBS and scanned in ACUMEN explorer (TTP-Labtech).
  • Integrated intensities in the green fluorescence and red fluorescence were measured to determine the levels of ER ⁇ and DNA respectively.
  • the degradation activity with respect to estrogen receptors in this test is given by the concentration which degrades 50% of the estrogen receptor (or IC 50 ) in nM.
  • the Table 2 below indicates the estrogen receptor degradation activity results for the compounds of table 1 tested at 0.3 ⁇ M, and demonstrates that said compounds have a significant degradation activity on estrogen receptors. Table 2: % It is therefore apparent that the tested compounds have degradation activities for estrogen receptors, with IC50 less than 1 ⁇ M and with degradation levels greater than 50%.
  • the compounds of formula (I) can therefore be used for preparing medicaments, especially medicaments which are degraders of estrogen receptors. Accordingly, also provided herein are medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.
  • medicaments which comprise a compound of the formula (I), or a pharmaceutically acceptable salt thereof.
  • compounds of formula (I) defined above, or pharmaceutically acceptable salt thereof for use in therapy, especially as inhibitors and degraders of estrogen receptors.
  • a particular aspect is a compound of formula (I) defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • the cancer is a hormone dependent cancer.
  • the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor ⁇ dependent cancer.
  • the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancer, or a metastasis thereof.
  • the metastasis is a cerebral metastasis.
  • the cancer is breast cancer.
  • the breast cancer is an estrogen receptor positive breast cancer (ER ⁇ positive breast cancer).
  • the cancer is resistant to anti-hormonal treatment.
  • the compound of formula (I) is as used as single agent or in combination with other agents such as CDK4/6, mTOR or PI3K inhibitors.
  • a method of treating the pathological conditions indicated above comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the subject is a human.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in treating any of the pathological conditions indicated above, more particularly useful in treating cancer.
  • pharmaceutical compositions comprising as active principle a compound of formula (I).
  • compositions comprise an effective dose of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
  • compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intra-tracheal, intranasal, transdermal or rectal administration the active principle of formula (I) above, or its base, acid, zwitterion or salt thereof, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals and to human beings for the treatment of the above disorders or diseases.
  • the unit administration forms appropriate include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms, forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions
  • sublingual, buccal, intra-tracheal, intra-ocular and intra-nasal administration forms forms for inhalative, topical, transdermal, subcutaneous, intra-muscular or intravenous administration, rectal administration forms and implants.
  • topical application it is possible to use the compounds of formula (I) in creams, gels, ointments or lotions.
  • a unit administration form of a compound of formula (I) in tablet form may comprise the following components: Compound of formula (I) 50.0 mg Mannitol 223.75 mg Sodium croscarmellose 6.0 mg Corn starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg There may be particular cases in which higher or lower dosages are appropriate. According to usual practice, the dosage that is appropriate for each patient is determined by the doctor according to the mode of administration and the weight and response of the said patient.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Des composés de formule I, ou des sels pharmaceutiquement acceptables correspondants sont divulgués dans la présente invention. (I) dans laquelle R1 et R2 représentent indépendamment un atome d'hydrogène ou un atome de deutérium; R3' et R3" représentent indépendamment un atome d'hydrogène, un groupe méthyle, un groupe méthoxy, un atome de chlore, un atome de fluor ou un groupe cyano; R4 représente un atome d'hydrogène ou un atome de fluor; R5 et R5' représentent indépendamment un atome d'hydrogène ou un atome de fluor; Y représente -CH2-, -CH=, -CR9=, -O- ou -NH-, R9 représentant un atome de fluor ou un groupe alkyle en (C1-C3); représente une liaison simple ou une double liaison; p vaut 0 ou 1; X représente -CH=, -n= ou -CR"=, R" représentant un groupe alkyle en (C1-C3) ou un atome d'halogène, un groupe cyano, ou un groupe fluoroalkyle (C1-C3); R7 représente indépendamment un groupe alkyle en (C1-C3), un atome d'halogène, un groupe cyano, ou un groupe fluoroalkyle en (C1-C3); n vaut 0, 1 ou 2; et R6 représente un groupe alkyle en (C1-C6), ledit groupe alkyle étant éventuellement substitué; R8 représente un atome d'hydrogène, un groupe alkyle en (C1-C3), un groupe -CH2F, un groupe -CHF2, un groupe -CF3, ou un groupe cycloalkyle en (C3-C4). Sont divulgués en outre, un procédé de préparation de ceux-ci, des compositions pharmaceutiques les comprenant ainsi que lesdits composés de formule (I) pour une utilisation en tant qu'inhibiteur et agent de dégradation des récepteurs des œstrogènes, en particulier dans le traitement d'un dysfonctionnement ovulatoire, d'un cancer, d'une endométriose, d'une ostéoporose, d'une hypertrophie bénigne de la prostate ou d'une inflammation.
EP23762378.0A 2022-08-25 2023-08-24 Nouveaux dérivés d'acide tétrahydroisoquinoléine-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques Pending EP4577534A1 (fr)

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EP22306263 2022-08-25
PCT/EP2023/073275 WO2024042185A1 (fr) 2022-08-25 2023-08-24 Nouveaux dérivés d'acide tétrahydroisoquinoléine-6-carboxylique substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

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SG11201806829TA (en) 2016-02-15 2018-09-27 Sanofi Sa 6,7-dihydro-5h-benzo[7]annulene derivatives as estrogen receptor modulators
EP3440067B1 (fr) * 2016-04-08 2021-05-26 F. Hoffmann-La Roche AG Modulateurs des récepteurs d' estrogènes tétrahydroisoquinoléine et leurs utilisations
EP3541809B1 (fr) 2016-11-17 2025-06-25 Sanofi Composés n-(3-fluoropropyl)-pyrrolidine substitués, leurs procédés de préparation et leurs utilisations thérapeutiques

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