WO2015092634A1 - Composés et compositions de 1,2,3,4-tétrahydroisoquinoléine en tant qu'antagonistes et agents de dégradation sélectifs des récepteurs des œstrogènes - Google Patents

Composés et compositions de 1,2,3,4-tétrahydroisoquinoléine en tant qu'antagonistes et agents de dégradation sélectifs des récepteurs des œstrogènes Download PDF

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WO2015092634A1
WO2015092634A1 PCT/IB2014/066813 IB2014066813W WO2015092634A1 WO 2015092634 A1 WO2015092634 A1 WO 2015092634A1 IB 2014066813 W IB2014066813 W IB 2014066813W WO 2015092634 A1 WO2015092634 A1 WO 2015092634A1
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substituted
methyl
4alkyl
mmol
halo
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PCT/IB2014/066813
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English (en)
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Heather Elizabeth BURKS
Rajeshri Ganesh Karki
Christina Ann KIRBY
Jill NUNEZ
Stefan Peukert
Clayton SPRINGER
Yingchuan Sun
Noel Marie-France THOMSEN
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Novartis Ag
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Publication of WO2015092634A1 publication Critical patent/WO2015092634A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/10—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 aromatic rings

Definitions

  • the present invention relates to compounds and compositions that are potent antagonists of estrogen receptor signaling and selective estrogen receptor degraders (SERDs).
  • SESDs selective estrogen receptor degraders
  • the invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with aberrant estrogen receptor activity.
  • estrogen receptor diseases or disorders such as breast, ovarian, colon, prostate, endometrial and uterine cancers.
  • Estrogen receptor (ERoc)-positive diseases such as breast cancer are usually treated with a selective estrogen receptor modulator (SERM) or an aromatase inhibitor (AI). While these therapies have proven effective at reducing the incidence of progression of breast cancer, some patients exhibit treatment resistance and progress to advanced metastatic breast cancer.
  • SERM selective estrogen receptor modulator
  • AI aromatase inhibitor
  • Treatment resistance results, in part, from the evolution of tumors to a state of hypersensitivity to low estrogen levels (AI treatment) or development of dependence upon the antiestrogen for activation of transcription (SERM treatment).
  • SERDs degrade the receptor, effectively eliminating ERoc expression and in so doing circumvent the underlying mechanisms of resistance that develop to antiendocrine monotherapy.
  • clinical and preclinical data show that a significant number of the resistance pathways can be circumvented by the use of an antiestrogen that exhibits SERD activity.
  • the compounds of the present invention can be used as therapies for the treatment of estrogen receptor diseases or disorders, for example, ovulatory dysfunction, uterine cancer, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor (ERoc)-positive breast cancer, in particular ERoc- positive breast cancer exhibiting denovo resistance to existing antiestrogens and aromatase inhibitors.
  • estrogen receptor diseases or disorders for example, ovulatory dysfunction, uterine cancer, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, estrogen receptor (ERoc)-positive breast cancer, in particular ERoc- positive breast cancer exhibiting denovo resistance to existing antiestrogens and aromatase inhibitors.
  • n is selected from 0, 1 and 2;
  • X is selected from N and CR6; wherein R6 is selected from hydrogen and Ci- 4alkyl;
  • Ri is hydrogen
  • R21S selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R3 is selected from -CH2CH2R8 and wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is selected from -C(0)ORsa, -
  • dotted line indicates the point of attachment with -CH2CH2 or - of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
  • R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy
  • R51S selected from C6-ioaryl, a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of Rs is unsubstituted or substituted where chemically available with 1 to 3 R11 groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo- substituted-Ci-4alkyl, cyano-substituted-Ci-4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted- Ci-4alkoxy, Ci-4alkoxy, -SFs, -NRi2aRi2b, -C(0)Ri2a, -S(0)o-2Ri2a, C3- 8 cycloalkyl-
  • the present invention provides a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, tautomer, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which a combined selective estrogen receptor anatagonist and estrogen receptor degarder can prevent, inhibit or ameliorate the pathology and/or symptom ology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • Formula I in the manufacture of a medicament for treating a disease in an animal in which estrogen receptor activity contributes to the pathology and/or symptomology of the disease.
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Ester/acid pairs exist in the examples where the esters basically serve as prodrugs of the acids.
  • the seter in example 3 is
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 7 carbon atoms (Ci -7 alkyl), or 1 to 4 carbon atoms (Ci -4 alkyl).
  • alkyl include, but are not limited to, methyl, ethyl, «-propyl, zso-propyl, «-butyl, sec- butyl, z ' sobutyl, ferr-butyl, «-pentyl, isopentyl, neopentyl, «-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, «-heptyl, «-octyl, «-nonyl, «-decyl and the like.
  • a substituted alkyl is an alkyl group containing one or more, such as one, two or three substituents selected from halogen, hydroxy or alkoxy groups.
  • Halo-substituted-alkyl and halo-substituted-alkoxy can be either straight-chained or branched and includes, methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl may be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl above where one or more of the ring members is a heteroatom.
  • C 5- ioheteroaryl is a minimum of 5 members as indicated by the carbon atoms but that these carbon atoms can be replaced by a heteroatom.
  • C 5- i 0 heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo-imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • C 3- i 0 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Heterocycloalkyl means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected
  • C 3-8 heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, pyrrolidinyl-2-one, piperazinyl, piperidinyl, piperidinylone, l,4-dioxa-8-aza-spiro[4.5]dec-8-yl, thiomorpholino, sulfanomorpholino, sulfonomo holino, etc.
  • Halogen (or halo) preferably represents chloro or fluoro, but may also be bromo or iodo.
  • Compounds of formula I may have different isomeric forms.
  • any asymmetric carbon atom may be present in the (R)-, (S)- or (R,S)-configuration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or preferably as pure isomers, preferably as pure diastereomers or pure enantiomers.
  • the plural form e.g. compounds, salts
  • a compound does not exclude that (e.g. in a pharmaceutical formulation) more than one compound of the formula I (or a salt thereof) is present, the "a” merely representing the indefinite article.
  • A can thus preferably be read as “one or more", less preferably alternatively as “one”.
  • the term "and/or an N-oxide thereof, a tautomer thereof and/or a (preferably pharmaceutically acceptable) salt thereof especially means that a compound of the formula I may be present as such or in mixture with its N-oxide, as tautomer (e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism) or in (e.g. equivalency reaction caused) mixture with its tautomer, or as a salt of the compound of the formula I and/or any of these forms or mixtures of two or more of such forms.
  • tautomer e.g. due to keto-enol, lactam-lactim, amide-imidic acid or enamine-imine tautomerism
  • equivalency reaction caused mixture with its tautomer
  • the present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof.
  • An isotopic variation of a compound of the invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of hydrogen, carbon, nitrogen and oxygen such as as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F, 36 C1 and 123 I.
  • isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • 3 H and 14 C isotopes may be used for their ease of preparation and detectability.
  • substitution with isotopes such as 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • Isotopic variations of the compounds of the invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • compounds of the invention can exist in a deutorated form as shown below:
  • the present invention relates to selective estrogen receptor degraders.
  • compounds of Formula I are compounds of Formula la:
  • n is selected from 0 and 1 ;
  • X is selected from N and CH;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl;
  • Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
  • Ri2a and Ri2b together with the nitrogen to which they are both attached form a 4 to 7 member saturated ring containing one heteroatom or group selected from O, N, NH, and S(0)o-2; wherein said C 3-8 cycloalkyl or 4-7 member ring of Rn can be unsubstituted or further substituted with a group selected from halo -substituted Ci -4 alkyl and Ci-4alkyl; or a pharmaceutically acceptable salt thereof.
  • R2 is selected from methyl, -
  • Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy-ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro-propyl, cyclobutyl, cyclopropyl-methyl, cyclopentyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro-ethoxy; or a pharmaceutically acceptable salt thereof.
  • n is selected from 0 and 1 ;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl; and
  • Rs is a 5-6 member heteroaryl or bicyclic ring selected from:
  • heteroaryl of Rs is unsubstituted or substituted with a group selected from methyl, isopropyl and methoxy; or a pharmaceutically acceptable salt thereof.
  • X is selected from N and CRJS; wherein R.6 is selected from hydrogen and Ci-4alkyl; Ri is hydrogen; R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ; R3 is selected from -CH2CH2R8 and wherein each R7 is independently selected from hydrogen, fluoro and Ci-4alkyl; and Rs is a 5-member heteroaryl selected from:
  • CR7 CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl; R 9 is selected from hydrogen, methyl, ethyl, trifluoro-ethyl, isobutyl, cyclopropyl, hydroxy-methyl and propyl; and Rio is selected from hydrogen and methyl;
  • Rs is selected from C6-ioaryl and a 5-6 member heteroaryl or bicyclic ring selected from:
  • n is selected from 0, 1 and 2;
  • X is selected from N and CR.6;
  • Rjds selected from hydrogen and Ci-4alkyl
  • Ri is hydrogen
  • R21S selected from methyl, -CH 2 F, - CHF 2 , CF 3 and CD 3
  • R3 is selected from -CfhCfbRs and wherein each R71S independently selected from hydrogen, fluoro and Ci-4alkyl
  • Rs is selected from -C(0)ORsa, - C(0)NR 8a R8b, -C(0)NHOR 8a , -C(0)YR 8a and a 5 -member heteroaryl selected from:
  • CR7 CR7 of R3; wherein Y is Ci-4alkylene; Rsa and Rsb are independently selected from hydrogen, Ci-4alkyl, hydroxy-substituted-Ci-4alkyl and halo-substituted-Ci-4alkyl; wherein said heteroaryl of Re is unsubstituted or substituted with a group selected from Ci-4alkyl and C3-8 cycloalkyl;
  • R41S selected from hydrogen, Ci-4alkyl, halo and Ci-3alkoxy; Rsis selected from
  • C6-ioaryl a 5-6 member heteroaryl containing 1 or 2 heteroatoms selected from O, S and N, and a partially saturated 9-10 member bicyclic ring containing 1 or two heteroatoms selected from O, S and N; wherein said C6-ioaryl, heteroaryl or bicyclic ring system of R5 is unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from hydroxy, amino, Ci-6alkyl, halo, nitro, cyano, halo-substituted-Ci-4alkyl, cyano-substituted-Ci- 4alkyl, hydroxy-substituted-Ci-4alkyl, halo-substituted-Ci-4alkoxy, Ci-4alkoxy, -SF5, -NRi2aRi2b, - C(0)Ri2a, -S(O) 0 -2Ri2a, C 3-8 cycloalkyl and
  • n is selected from 0 and 1;
  • X is selected from N and CH;
  • R2 is selected from methyl, -CH 2 F, -CHF 2 , CF 3 and CD 3 ;
  • R4 is methyl;
  • Rs is selected from Ce- and a 5-6 member heteroaryl or bicyclic ring selected from:
  • R2 is selected from -CH 2 F, -
  • Rs is selected from C6-ioaryl unsubstituted or substituted where chemically available with 1 to 3 Rn groups independently selected from fluoro, methyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, isopropoxy, trifluoromethyl, hydroxy, methoxy -ethyl, methyl substituted pyrazolyl, trifluoro-ethyl, trifluoro -propyl, cyclobutyl, l-(trifluoromethyl)cyclopropyl, trifluoromethoxy and trifluoro -ethoxy; or a pharmaceutically acceptable salt thereof.
  • the present invention relates to compounds of Formula I that diminish the effects of estrogen receptors and lower the concentrations of estrogen receptors, and therefore, are useful as agents for the treatment or prevention of diseases or conditions in which the actions of estrogens or estrogen receptors are involved in the etiology or pathology of the disease or condition or contribute to at least one symptom of the disease or condition and wherein such actions of estrogens or estrogen receptors are undesirable.
  • Compounds of the invention are both potent estrogen receptor antagonists and selective estrogen receptor degraders (SERDS).
  • the estrogen receptor (ER) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. In both females and males, estrogens play an important role in the regulation of a number of physiological processes. In humans, two different ER subtypes are known: ERoc and ER . Each subtype has a distinct tissue distribution and with different biological roles. For example, ERoc has high presence in endometrium, breast cancer cells, ovarian stroma cells and in the hypothalamus. The expression of the ER protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, bladder, ovary, testis, and endothelial cells.
  • Tamoxifen for example, behaves like an estrogen in bone and endometrium, whereas it behaves like an anti-estrogen in breast tissue.
  • Breast cancer is the predominant neoplastic disease in women.
  • ERoc is a major driver of breast cancer progression.
  • Multiple existing treatment approaches aim to reduce estrogen levels or block its binding to ERoc thereby minimizing tumor progression or even inducing tumor regression in ERoc -positive breast cancer.
  • Tamoxifen is a first-generation treatment for ERoc-positive breast cancer.
  • Fulvestrant is a pure ERoc antagonist without the partial agonist activity which is typical for the estrogen receptor modulators. It is the only marketed selective estrogen receptor degrader (SERD) and it is efficacious in second-line treatment of breast cancer. Fulvestrant both antagonizes estrogen receptors and effectively degrades or down-regulates ERoc protein levels in cells. This SERD activity inhibits ERoc -driven proliferation and tumor growth. Fulvestrant, when administered once a month at 250 mg is equally effective to tamoxifen in treatment of ERoc- positive advanced breast cancer.
  • SESD selective estrogen receptor degrader
  • fulvestrant In second-line treatment of ERoc -positive tamoxifen-resistant breast cancer, fulvestrant, when administered once a month at 250 mg, is equally effective to aromatase inhibitors, despite relatively poor bioavailability and/or target exposure which limits its clinical efficacy.
  • SERDs include "ICI 164,384", a structural analog of fulvestrant; "GW5638”, a structural analog of tamoxifen; and "GW7604", a structural analogue of 4-hydroxy -tamoxifen.
  • ERoc antagonists which would preferably have ER degrading or down-regulating activity in, for example, breast cancer cells without stimulating proliferation in ERoc -positive, hormone treatment-resistant breast cancer cells.
  • Such compounds would be orally administrable and be useful in the treatment of, amongst other things, ERoc -positive, hormone treatment-resistant breast cancer.
  • Estrogen receptor-related diseases or conditions include, but are not limited to, aberrant estrogen receptor activity associated with: cancer, for example, bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian and uterine cancer;
  • leiomyoma for example, uterine leiomyoma
  • central nervous system defects for example, alcoholism and migraine
  • cardiovascular system defects for example, aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease and hypertension
  • hematological system defects for example, deep vein thrombosis
  • immune and inflammation diseases for example, Graves' Disease, arthritis, mulitple sclerosis and cirrhosis
  • susceptibility to infection for example, hepatitis B and chronic liver disease
  • metabolic defects for example, bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia and osteoporosis
  • neurological defects for example, Alzheimer's disease, Parkinson's disease, migraine and vertigo
  • psychiatric defects for example, anorexia nervosa, attention deficity hyperactivity disorder, dementia, major depressive disorder and psychosis
  • reproductive defects for
  • the present invention relates to compounds that are both potent estrogen receptor anatagonists and selective estrogen receptor degraders.
  • the invention further provides a process for the preparation of compounds of the invention and pharmaceutical preparations comprising such compounds.
  • Another aspect of the present invention relates to a method of treating disorders mediated by estrogen receptors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as defined in the Summary of the Invention
  • compounds of the invention are used to treat cancer in a mammal.
  • the cancer is selected from breast, ovarian, endometrial, prostate, uterine, cervical and lung cancers.
  • the cancer is breast cancer.
  • the cancer is a hormone dependent cancer.
  • the cancer is an estrogen receptor dependent cancer.
  • the cancer is an estrogen-sensitive cancer.
  • the cancer is resistant to anti-hormonal treatment.
  • the cancer is an estrogen-sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormonal treatment.
  • the anti-hormonal treatment includes treatment with at least one agent selected from tamoxifen, fulvestrant, a steroidal aromatase inhibitor, and a nonsteroidal aromatase inhibitor.
  • compounds of the invention are used to treat hormone receptor positive metastatic breast cancer in a postmenopausal woman with disease progression following anti-estrogen therapy.
  • compounds of theinvention are used to treat a hormonal dependent benign or malignant disease of the breast or reproductive tract in a mammal.
  • the benign or malignant disease is breast cancer.
  • compounds of the invention are used to treat cancer in a mammal, wherein the mammal is chemotherapy -naive.
  • compounds of the invention are used to treat cancer in a mammal, wherein the mammal is being treated for cancer with at least one anti-cancer agent.
  • the cancer is a hormone refractory cancer.
  • compounds of the invention are used in the treatment of endometriosis in a mammal.
  • compounds of the invention are used in the treatment of leiomyoma in a mammal.
  • the leiomyoma is selected from uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma and small bowel leiomyoma.
  • compounds of the invention are used in the treatment of fibroids, for example, uterine fibroids, in a mammal.
  • Compounds of the present invention may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine, and other anticancer agents, e.g. cisplatin, 5-fluorouracil or 5-fluoro-2-4(l H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine.
  • chemotherapy agents for example, mitotic inhibitors such as a taxane, a vinca alkaloid, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine or vinflunine
  • the present invention relates to the aforementioned method, wherein said compound is administered parenterally.
  • the present invention relates to the aforementioned method, wherein said compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically or intranasally.
  • the present invention relates to the aforementioned method, wherein said compound is administered systemically.
  • the present invention relates to the aforementioned method, wherein said patient is a mammal.
  • the present invention relates to the aforementioned method, wherein said patient is a primate.
  • the present invention relates to the aforementioned method, wherein said patient is a human.
  • the present invention relates to a method of treating a disorder mediated by estrogen receptors, comprising the step of: administering to a patient in need thereof a therapeutically effective amount of a chemothereutic agent in combination with a therapeutically effective amount of a compound of formula I as defined in the Summary of the Invention.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin; (4) intravaginally or intrarect
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transport
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • a basic functional group such as amino or alkylamino
  • “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and
  • the pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids.
  • such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra)
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and poly anhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface -active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • peripheral administration and “administered peripherally” as used herein mean the
  • administration of a compound, drug or other material other than directly into the central nervous system such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • composition While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • the compounds according to the invention may be formulated for
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • treatment is intended to encompass also prophylaxis, therapy and cure.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • the compound of the invention can be administered as such or in admixtures with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides.
  • Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
  • Microemulsification technology can improve bioavailability of some lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic lipophilic
  • microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
  • amphiphilic carriers While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastrointestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate, PEG-mono- laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
  • Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include polyethylene glycol (PEG), polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • PEG polyethylene glycol
  • polylactic also termed polylactide
  • polyglycolic acid also termed polyglycolide
  • a polylactic-polyglycolic acid copolymer a polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons.
  • the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
  • hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline,
  • polyhydroxypropyl methacrylamide polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • Cyclodextrins are cyclic oligosaccharides, consisting of 6, 7 or 8 glucose units, designated by the Greek letter .alpha., .beta, or .gamma., respectively. Cyclodextrins with fewer than six glucose units are not known to exist. The glucose units are linked by alpha- 1,4- glucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (at C-2, C-3) are located on one side of the ring, while all the primary hydroxyl groups at C-6 are situated on the other side. As a result, the external faces are hydrophilic, making the cyclodextrins water-soluble.
  • the cavities of the cyclodextrins are hydrophobic, since they are lined by the hydrogen of atoms C-3 and C-5, and by ether-like oxygens.
  • These matrices allow complexation with a variety of relatively hydrophobic compounds, including, for instance, steroid compounds such as 17.beta. -estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)).
  • the complexation takes place by Van der Waals interactions and by hydrogen bond formation.
  • the physico-chemical properties of the cyclodextrin derivatives depend strongly on the kind and the degree of substitution. For example, their solubility in water ranges from insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of the cyclodextrins enable the control over solubility of various formulation components by increasing or decreasing their solubility.
  • cyclodextrin derivatives with anionic properties carboxylic acids, phosphorous acids, phosphinous acids, phosphonic acids, phosphoric acids, thiophosphonic acids, thiosulphinic acids, and sulfonic acids have been appended to the parent cyclodextrin [see, Parmeter (III), supra]. Furthermore, sulfoalkyl ether cyclodextrin derivatives have been described by Stella, et al. (U.S. Pat. No. 5,134,127).
  • Liposomes consist of at least one lipid bilayer membrane enclosing an aqueous internal compartment. Liposomes may be characterized by membrane type and by size. Small unilamellar vesicles (SUVs) have a single membrane and typically range between 0.02 and 0.05 ⁇ in diameter; large unilamellar vesicles (LUVS) are typically larger than 0.05 ⁇
  • Oligolamellar large vesicles and multilamellar vesicles have multiple, usually concentric, membrane layers and are typically larger than 0.1 ⁇ . Liposomes with several nonconcentric membranes, i.e., several smaller vesicles contained within a larger vesicle, are termed multivesicular vesicles.
  • One aspect of the present invention relates to formulations comprising liposomes containing a compound of the present invention, where the liposome membrane is formulated to provide a liposome with increased carrying capacity.
  • the compound of the present invention may be contained within, or adsorbed onto, the liposome bilayer of the liposome.
  • the compound of the present invention may be aggregated with a lipid surfactant and carried within the liposome's internal space; in these cases, the liposome membrane is formulated to resist the disruptive effects of the active agent-surfactant aggregate.
  • the lipid bilayer of a liposome contains lipids derivatized with polyethylene glycol (PEG), such that the PEG chains extend from the inner surface of the lipid bilayer into the interior space encapsulated by the liposome, and extend from the exterior of the lipid bilayer into the surrounding environment.
  • PEG polyethylene glycol
  • Active agents contained within liposomes of the present invention are in solubilized form. Aggregates of surfactant and active agent (such as emulsions or micelles containing the active agent of interest) may be entrapped within the interior space of liposomes according to the present invention.
  • a surfactant acts to disperse and solubilize the active agent, and may be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, including but not limited to biocompatible lysophosphatidylcholines (LPCs) of varying chain lengths (for example, from about C. sub.14 to about C.sub.20).
  • Polymer-derivatized lipids such as PEG-lipids may also be utilized for micelle formation as they will act to inhibit micelle/membrane fusion, and as the addition of a polymer to surfactant molecules decreases the CMC of the surfactant and aids in micelle formation.
  • Liposomes according to the present invention may be prepared by any of a variety of techniques that are known in the art. See, e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV, Amsterdam, 1993.
  • liposomes of the present invention may be prepared by diffusing a lipid derivatized with a hydrophilic polymer into preformed liposomes, such as by exposing preformed liposomes to micelles composed of lipid-grafted polymers, at lipid concentrations corresponding to the final mole percent of derivatized lipid which is desired in the liposome.
  • Liposomes containing a hydrophilic polymer can also be formed by homogenization, lipid-field hydration, or extrusion techniques, as are known in the art.
  • the liposomes are prepared to have substantially homogeneous sizes in a selected size range.
  • One effective sizing method involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size; the pore size of the membrane will correspond roughly with the largest sizes of liposomes produced by extrusion through that membrane. See e.g., U.S. Pat. No. 4,737,323 (Apr. 12, 1988).
  • the release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers.
  • release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine.
  • An enteric coating can be used to prevent release from occurring until after passage through the stomach.
  • Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine.
  • Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule.
  • Excipients which modify the solubility of the drug can also be used to control the release rate.
  • Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w polymer).
  • Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween® and Pluronic®.
  • Pore forming agents which add microstructure to the matrices i.e., water soluble compounds such as inorganic salts and sugars
  • the range should be between one and thirty percent (w/w polymer).
  • Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer.
  • a mucosal adhesive polymer examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).
  • the invention especially relates to the use of a compound of the formula I (or a pharmaceutical composition comprising a compound of the formula I) in the treatment of one or more of the diseases mentioned herein; wherein the response to treatment is beneficial as demonstrated, for example, by the partial or complete removal of one or more of the symptoms of the disease up to complete cure or remission.
  • compounds disclosed herein are useful in the treatment of breast cancer, either alone or in combination with other agents used to treat breast cancer, including but not limited to aromatase inhibitors, anthracylines, platins, nitrogen mustard alkylating agents and taxanes.
  • Agents used to treat breast cancer include, but are not limited to, paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab, pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine and ixabepilone.
  • compounds of the invention are useful in the treatment of breast cancer, either alone or in combination with other agents that modulate other critical pathways in breast cancer, including but not limited to those that target IGF1R, EGFR, erB-B2 and the PI3 K/AKT/mTOR axis, Rb axis including CDK4/6 and D-cyclins, HSP90, PARP and/or histone deacetylases.
  • a compound of the invention can, therefore, also be used in combination with the following:
  • VEGF receptor inhibitors Bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (N-methyl-2-[[3-[(£T)-2-pyridin-2- ylethenyl]-lH-indazol-6-yl]sulfanyl]benzamide, also known as AGO 13736, and described in PCT Publication No.
  • HER2 receptor inhibitors Trastuzumab (sold under the trademark Herceptin® by Genentech/Roche), neratinib (also known as HKI-272, (2iT)-N-[4-[[3-chloro-4-[(pyridin-2- yl)methoxy]phenyl] amino] -3 -cy ano-7-ethoxyquinolin-6-yl] -4-(dimethylamino)but-2-enamide, and described PCT Publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold under the trademark Tykerb® by Glaxo SmithKline);
  • CD20 antibodies Rituximab (sold under the trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);
  • Tyrosine kinase inhibitors Erlotinib hydrochloride (sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5- methylphenyl)urea, also known as ABT 869, available from Genentech), sunitinib malate (sold under the tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin-l-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No.
  • dasatinib (sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the tradenames Gilvec® and Gleevec® by Novartis);
  • Bcr/Abl kinase inhibitors nilotinib hydrochloride (sold under the tradename Tasigna® by Novartis);
  • DNA Synthesis inhibitors Capecitabine (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (sold under the trademark Gemzar® by Eli Lilly and Company), nelarabine ((2R,3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4- diol, sold under the tradenames Arranon® and Atriance® by GlaxoSmithKline);
  • Antineoplastic agents oxaliplatin (sold under the tradename Eloxatin® ay Sanofi- Aventis and described in US Patent No. 4,169,846);
  • Epidermal growth factor receptor (EGFR) inhibitors Gefitnib (sold under the tradename Iressa®), N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3- furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers
  • panitumumab sold under the tradename Vectibix® by Amgen
  • HER dimerization inhibitors Pertuzumab (sold under the trademark Omnitarg®, by
  • G-CSF modulators Filgrastim (sold under the tradename Neupogen® by Amgen);
  • Immunomodulators Afutuzumab (available from Roche®), pegfilgrastim (sold under the tradename Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the tradename Revlimid®), thalidomide (sold under the tradename Thalomid®);
  • CD40 inhibitors Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc);
  • Pro-apoptotic receptor agonists PARAs: Dulanermin (also known as AMG-951, available from Amgen/Genentech); [00174] Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4- (methylsulfonyl)- benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958);
  • PI3K inhibitors 4-[2-(lH-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l- yl]methyl]thieno[3,2-d]pyrimidin-4-yl]mo holine (also known as GDC 0941 and described in
  • Phospholipase A2 inhibitors Anagrelide (sold under the tradename Agrylin®);
  • BCL-2 inhibitors 4-[4-[[2-(4-chlorophenyl)-5 ,5 -dimethyl- 1 -cyclohexen- 1 -yl]methyl] - 1 - piperazinyl] -N- [ [4- [ [( 1 R)-3 -(4-morpholinyl)- 1 - [(phenylthio)methyl]propyl] amino] -3 -
  • Mitogen-activated protein kinase kinase (MEK) inhibitors XL-518 (Cas No. 1029872- 29-4, available from ACC Corp.);
  • Aromatase inhibitors Exemestane (sold under the trademark Aromasin® by Pfizer), letrozole (sold under the tradename Femara® by Novartis), anastrozole (sold under the tradename Arimidex®);
  • Topoisomerase I inhibitors Irinotecan (sold under the trademark Camptosar® by Pfizer), topotecan hydrochloride (sold under the tradename Hycamtin® by Glaxo SmithKline);
  • Topoisomerase II inhibitors also known as VP- 16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, sold under the tradename Vumon®);
  • mTOR inhibitors Temsirolimus (sold under the tradename Torisel® by Pfizer), ridaforolimus (formally known as deferolimus, (lR,2R,45)-4-[(2R)-2
  • CD33 Antibody Drug Conjugates Gemtuzumab ozogamicin (sold under the tradename Mylotarg® by Pfizer/Wyeth);
  • CD22 Antibody Drug Conjugates Inotuzumab ozogamicin (also referred to as CMC-
  • CD20 Antibody Drug Conjugates Ibritumomab tiuxetan (sold under the tradename
  • octreotide also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Sandostatin® also known as octreotide acetate, sold under the tradenames Sandostatin® and Sandostatin LAR®
  • Synthetic Interleukin-11 (IL-11): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);
  • Receptor Activator for Nuclear Factor ⁇ B (RANK) inhibitors Denosumab (sold under the tradename Prolia® by Amgen);
  • Thrombopoietin mimetic peptibodies Romiplostim (sold under the tradename Nplate® by Amgen;
  • Cell growth stimulators Palifermin (sold under the tradename Kepivance® by Amgen);
  • IGF-1R Anti-Insulin-like Growth Factor-1 receptor antibodies: Figitumumab (also known as CP-751,871, available from ACC Corp), robatumumab (CAS No. 934235-44-6);
  • Anti-CSl antibodies Elotuzumab (HuLuc63, CAS No. 915296-00-3);
  • CD52 antibodies Alemtuzumab (sold under the tradename Campath®);
  • CTLA-4 inhibitors Tremelimumab (IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206), ipilimumab (CTLA-4 antibody, also known as
  • Histone deacetylase inhibitors (HDI): Voninostat (sold under the tradename Zolinza® by Merck); [00198] Alkylating agents: Temozolomide (sold under the tradenames Temodar® and
  • Temodal® by Schering-Plough Merck dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclo
  • Biologic response modifiers bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), denileukin diftitox (sold under the tradename Ontak®);
  • Anti-tumor antibiotics doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), mitomycin C (sold under the tradename Mutamycin®);
  • Anti-microtubule agents Estramustine (sold under the tradename Emcyl®);
  • Cathepsin K inhibitors Odanacatib (also know as MK-0822, N-(l-cyanocyclopropyl)- 4-fluoro-N 2 - ⁇ (lS)-2,2,2-trifluoro-l-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl ⁇ -L-leucinamide, available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836);
  • Epothilone B analogs Ixabepilone (sold under the tradename Lxempra® by Bristol- Myers Squibb);
  • HSP Heat Shock Protein
  • TpoR agonists Eltrombopag (sold under the tradenames Promacta® and Revolade® by Glaxo SmithKline) ;
  • Anti-mitotic agents Docetaxel (sold under the tradename Taxotere® by Sanofi- Aventis);
  • Adrenal steroid inhibitors aminoglutethimide (sold under the tradename Cytadren®);
  • Anti -androgens Nilutamide (sold under the tradenames Nilandron® and Anandron®), bicalutamide (sold under tradename Casodex®), flutamide (sold under the tradename FulexinTM);
  • Androgens Fluoxymesterone (sold under the tradename Halotestin®);
  • CDK1 inhibitors Alvocidib (also known as flovopirdol or HMR-1275, 2-(2- chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-l-methyl-4-piperidinyl]-4-chromenone, and described in US Patent No. 5,621,002);
  • GnRH Gonadotropin-re leasing hormone receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);
  • Taxane anti -neoplastic agents Cabazitaxel (l -hydroxy-7 ,10 -dimethoxy-9-oxo-5 ,20- epoxytax-1 l-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3- ⁇ [(tert- butoxy)carbonyl]amino ⁇ -2-hydroxy-3-phenylpropanoate), larotaxel ((2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,7 ⁇ ,10 ⁇ ,13 ⁇ )- 4,10-bis(acetyloxy)-13-( ⁇ (2R,35)-3- [(fer?-butoxycarbonyl) amino]-2-hydroxy-3- phenylpropanoyl ⁇ oxy)-l- hydroxy -9-oxo-5, 20-epoxy-7, 19-cyclotax- 1 l-en-2-yl benzoate);
  • 5HTla receptor agonists Xaliproden (also known as SR57746, l-[2-(2-naphthyl)ethyl]- 4-[3-(trifluoromethyl)phenyl]-l,2,3,6-tetrahydropyridine, and described in US Patent No.
  • HPC vaccines Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck;
  • Iron Chelating agents Deferasinox (sold under the tradename Exjade® by Novartis);
  • Anti-metabolites Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and MylocelTM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorode
  • Demethylating agents 5-azacitidine (sold under the tradename Vidaza®), decitabine (sold under the tradename Dacogen®);
  • Plant Alkaloids Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), paclitaxel (sold under the tradenames Taxol and OnxalTM);
  • Retinoids Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cz ' s- retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®);
  • Glucocorticosteroids Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R, 1 OS, 1 IS, 135, 14S, 16R, 17R)-9-fluoro- 11 , 17-dihydroxy- 17-(2-hydroxy acetyl)- 10,13,16- trimethyl-6,7,8,9,10,11,12,13, 14,15, 16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone
  • Cytokines interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Pvoferon-A®);
  • LHRH Leutinizing hormone releasing hormone
  • megestrol also known as megestrol acetate, sold under the tradename
  • Trisenox® asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®);
  • a compound of formula (I) can also be used in combination with the following adjunct therapies:
  • Anti-nausea drugs NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and
  • Cytoprotective agents Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.
  • a compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable hydro lyzing agent (such as
  • ethanethiol/aluminum chloride and the like
  • a suitable solvent such as dichloromethane, or the like.
  • a compound of Formula I can be prepared by hydrolysing a compound of formula 2 in the presence of a suitable Lewis Acid (such as Boron tribromide, and the like) and a suitable solvent (such as dichloromethane, or the like) under a suitable pressure and atmosphere (such as -78°/Nitrogen, and the like). The reaction takes place at about 0°C from about 1 to about 4 hours to complete.
  • a suitable Lewis Acid such as Boron tribromide, and the like
  • a suitable solvent such as dichloromethane, or the like
  • a compound of Formula I can be prepared by reacting a compound of formula 3 with a compound of formula 4 in the presence of a suitable solvent (such as DMF and the like), a suitable catalyst (such as PdCl 2 (PPh 3 ) 2 , or the like), a suitable base (such as triethylamine, and the like). The reaction takes place at about 120 °C to about 200°C and can take from about 1 to about 18 hours to complete.
  • a suitable solvent such as DMF and the like
  • a suitable catalyst such as PdCl 2 (PPh 3 ) 2 , or the like
  • a suitable base such as triethylamine, and the like.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • Compounds of the formula I can also be modified by appending appropriate functionalities to enhance selective biological properties. Modifications of this kind are known in the art and include those that increase penetration into a given biological system (e.g. blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (e.g. injection, infusion), alter metabolism and/or alter the rate of secretion. Examples of this type of modifications include but are not limited to esterification, e.g. with polyethylene glycols, derivatisation with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution in aromatic rings.
  • esterification e.g. with polyethylene glycols, derivatisation with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings and heteroatom substitution in aromatic rings.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • any reference to the compounds or a compound of the formula I hereinbefore and hereinafter is to be understood as referring to the compound in free form and/or also to one or more salts thereof, as appropriate and expedient, as well as to one or more solvates, e.g. hydrates.
  • Salts are formed, for example, as acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom, especially the pharmaceutically acceptable salts.
  • Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxyethanesulfonic acid, ethane-
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80°C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985; Ferriz, J.M. et al., Current Pharmaceutical Design, 2010, 16, 2033-2052).
  • Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3 rd edition, John Wiley and Sons, Inc., 1999.
  • Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.
  • the compounds of Formula I can be made by a process, which involves:
  • Method I To a vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.5 g, 8.47 mmol) was dissolved in DMF (10 mL) and charged with l-fluoro-4-iodobenzene (3.76 g, 16.93 mmol) and potassium carbonate (1.170 g, 8.47 mmol). The reaction mixture was flushed with nitrogen, charged with copper(I) iodide (161 mg, 847 ⁇ ), and heated at 150 °C for 16 h at which point starting material remained. The reaction mixture was charged with additional copper(I) iodide (161 mg, 847 ⁇ ) and heated for an additional 16 h.
  • LC/MS indicated 50% consumption of starting material.
  • the reaction vial was charged with additional copper(I) iodide (215 mg, 1.129 mmol) and heated at 150 °C for an additional 16 h.
  • LC/MS indicated no addition conversion.
  • the reaction mixture was cooled to ambient temperature and was diluted with dichloromethane and water.
  • the organic layer was passed through a phase separator and concentrated.
  • the crude product was purified by silica gel chromatography (80 g, 0-100% ethyl acetate/heptanes) to afford 2-(4-fluoro-2-methylphenyl)-6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (1.1 g, 34% yield) as a beige solid.
  • Step 1 3-(4-bromophenyl)-lH-pyrazole (0.377 g, 1.690 mmol) was dissolved in THF (8.45 ml). 60% Sodium hydride in oil (0.101 g, 2.54 mmol) was added and the reaction was stirred at rt for 15 min. Methyl iodide (0.116 ml, 1.859 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.
  • Step 2 6-methoxy-2-(4-(l-methyl-lH-pyrazol-3-yl)phenyl)-3,4- dihydroisoquinolin-l(2H)-one compound and 6-methoxy-2-(4-(l-methyl-lH-pyrazol-5- yl)phenyl)-3, 4-dihydroisoquinolin- l(2H)-one were prepared using method I from above in combination with aryl bromide highlighted in above intermediate example (248 mg, 0.744 mmol, 71.3 % yield) as a white solid.
  • Step 1 To 2-(4-(benzyloxy)-3-fluorophenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.341 g, 0.904 mmol) was added ethanol (4.52 mL). The compound did not dissolve completely therefore THF (9 mL) was added until compound dissolved. A scoop of Pd(OH) 2 was added, then the reaction solution was purged with hydrogen and left with a hydrogen balloon at room temperature overnight. The reaction was filtered through a syringe filter and concentrated to afford product (0.341 g, 0.904 mmol) as a white solid.
  • Step 2 To a microwave vial, 2-(3-fluoro-4-hydroxyphenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.039 g, 0.136 mmol), N-phenyltrifluoromethanesulfonimide (0.058 g, 0.163 mmol), and potassium carbonate (0.056 g, 0.407 mmol) were suspended in THF (0.679 mL). The reaction was microwaved for 8 min at 120 °C. The reaction was done via LC/MS, so the reaction was filtered and concentrated.
  • Step 3 To 2-fluoro-4-(6-methoxy-l-oxo-3,4-dihydroisoquinolin-2(lH)- yl)phenyl trifluoromethanesulfonate (0.024 g, 0.057 mmol), potassium trifluoro(prop-l-en-2- yl)borate (0.017 g, 0.114 mmol), and triethylamine (0.024 ml, 0.172 mmol) were dissolved in THF (0.143 ml).
  • Step 4 To 2-(3-fluoro-4-(prop-l-en-2-yl)phenyl)-6-methoxy-3,4- dihydroisoquinolin-l(2H)-one (0.015 g, 0.048 mmol) was added methanol (1.5 mL). THF (0.5mL) was added until compound was dissolved. A scoop of 10% palladium on carbon was added and the reaction mixture was purged with hydrogen. The reaction stirred at room temperature for 1 h. The reaction was filtered through a syringe filter and concentrated to afford (13.7 mg, 0.044 mmol, 91 % yield) as a clear oil.
  • Step 1 To a 100 mL round-bottomed flask, 1 -(benzyloxy)-4-bromobenzene
  • Step 2 In a 100 mL round bottomed flask, the oven -dried iminium salt was dissolved in THF (20 mL) and the reaction flask was cooled to 0 °C. A 3 M solution of methylmagnesium bromide in diethyl ether (2.56 mL, 7.67 mmol) was added dropwise to the reaction mixture. Upon stirring at 0 °C for 30 min, LC MS analysis of an aliquot indicated partial conversion. The mixture was charged with an additional 1.5 mL of a 3 M solution of methylmagnesium bromide in diethyl ether and stirred for 1 h at 0 °C.
  • Step 3 In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluorophenyl)-6- methoxy-1 -methyl- 1, 2,3 ,4-tetrahydroisoquinoline (1.6 g, 3.53 mmol) dissolved in
  • Step 4 In a 30 mL vial, 4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenol (250 mg, 0.688 mmol) was dissolved in dichloromethane (3 mL). The vial was cooled to 0 °C and charged with triethylamine (115 ⁇ L, 825 ⁇ ) followed by trifluoromethanesulfonic anhydride (139 ⁇ L, 825 ⁇ ). The reaction mixture was warmed to room temperature and stirred for 2 h.
  • Step 1 To a 100 mL round bottomed flask was added l-(benzyloxy)-4- bromobenzene (1.522 g, 5.78 mmol) and tetrahydrofuran (20 mL). The reaction flask was cooled to -78 °C and charged with 1.6 M «-butyllithium in hexanes (3.98 mL, 6.36 mmol) over 10 min. The suspension was stirred at -78 °C for 40 min.
  • Step 2 In a 100 mL round bottomed flask, the iminium intermediate was dissolved in tetrahydrofuran (20 mL) and the reaction flask was cooled to 0 °C. The flask was charged with 3 M methymagnesium bromide in diethyl ether (2.056 mL, 6.17 mmol) dropwise. The reaction mixture stirred at 0 °C for 30 min at which time the reaction was monitored by LC MS, indicating 40% conversion. The reaction was charged with additional 3 M
  • Step 3 In a 30 mL vial, l-(4-(benzyloxy)phenyl)-2-(4-fluoro-2-methylphenyl)-
  • 6-methoxy-l -methyl- 1,2,3 ,4-tetrahydroisoquinoline (0.8 g, 1.711 mmol) was dissolved in dichloromethane (8 mL).
  • the reaction vial was charged with aluminum trichloride (684 mg, 5.13 mmol) and N,N-dimethylaniline (2.166 mL, 17.11 mmol) and stirred at room temperature for 2 h.
  • the reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (100 mL).
  • the mixture was treated with saturated sodium bicarbonate until pH 5 was obtained.
  • the layers were separated, the aqueous layer was extracted twice with dichloromethane.
  • Step 4 To a 30 mL vial, 4-(2-(4-fluoro-2-methylphenyl)-6-methoxy-l -methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenol (200 mg, 0.530 mmol), dichloromethane (2 mL), and triethylamine (89 ⁇ L, 636 ⁇ ) were added and the vial was cooled to 0 °C. The reaction mixture was charged with trifluoromethanesulfonic anhydride (107 ⁇ L, 0.636 mmol), warmed to room temperature and stirred for 2 h.
  • trifluoromethanesulfonic anhydride 107 ⁇ L, 0.636 mmol
  • Step 1 To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (22.0 mL) and cooled to 0 °C. The reaction was charged with a 1.6 M solution of methylmagnesium bromide in diethyl ether (3.16 mL, 9.48 mmol) and the reaction mixture was stirred at 0°C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude material.
  • Step 1 To a 40 mL vial was added l-bromo-4-iodo-2-methylbenzene (0.159 mL, 1.106 mmol) and pentanes (2.91 mL). The reaction vial was charged with a 2.5 M n- butyllithium in hexanes (444 ⁇ L, 1.110 mmol) and a white precipitate formed immediately.
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and cooled to 0 °C. To this, 1 M methylmagnesium bromide in tetrahydrofuran (0.132 g, 1.106 mmol) was added dropwise and the reaction stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride and extracted wth dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude product. Crude material was purified by silica gel chromatography (0-10% ethyl acetate/heptanes) to obtain product (157 mg, 97% yield) as a red-orange solid.
  • Step 1 To a 40 mL scintillation vial was added 5-bromo-2-iodopyridine (0.144 g, 0.508 mmol) and pentanes (1.335 mL). The reaction vial was charged with 2.5 M n- butyllithium (204 ⁇ L, 0.510 mmol) in hexanes and a precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C.
  • Step 2 To a cold solution of the iminium intermediate in tetrahydrofuran
  • Step 1 To a 40 mL scintillation vial was added 1 -bromo-4-iodobenzene (0.549 g, 1.939 mmol) and pentanes (2.55 mL). The reaction vial was charged with 2.5 M n-butyllithium (0.780 mL, 1.949 mmol) in hexanes and a white precipitate formed immediately. The lithiation reaction stirred at rt for 1 h at which time, the reaction mixture was cooled to -78 °C.
  • Step 2 Iminium intermediate was dissolved in tetrahydrofuran (2.094 ml) and cooled to 0 °C. The reaction was charged with a 1.4M solution of methylmagnesium bromide (0.693 ml, 0.970 mmol) in tetrahydrofuran and stirred at 0°C for 1 hour. The reaction appeared incomplete via LC/MS so the reaction was allowed to warm to room temperature overnight. The reaction was quenched with saturation ammonium chloride solution. The aqueous layer was separated and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated.
  • Step 1 To a 250 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 The crude material was suspended in tetrahydrofuran (54.8 mL) and cooled to 0°C (ice-water). The reaction mixture was charged with 3.0 M methylmagnesium bromide (6.77 mL, 20.31 mmol) in diethylether dropwise and left to stir for 2 h with warming to ambient temperature. The reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2 x with dichloromethane, the organic layers were pooled, washed with brine, passed through a phase separator, and condensed.
  • 3.0 M methylmagnesium bromide (6.77 mL, 20.31 mmol) in diethylether dropwise and left to stir for 2 h with warming to ambient temperature.
  • the reaction mixture was quenched with saturated ammonium chloride and diluted with dichloromethane. The layers were separated, the aqueous was washed 2
  • the reaction vial was flushed with nitrogen and heated at 80 °C for 16 h.
  • LC MS indicated partial conversion of starting material.
  • the reaction mixture was charged with additional methyl acrylate (160 ⁇ ,, 1776 ⁇ ) and Pd(PPh 3 ) 2 Cl 2 (15.58 mg, 0.022 mmol).
  • the vial was flushed with nitrogen and heated at 120 °C for 6 h.
  • the reaction mixture was cooled to ambient temperature and diluted with dichloromethane.
  • the organic layer was washed with water and brine then passed through phase separator and concentrated.
  • reaction mixture was heated for 1 h at 130 °C, LC MS indicated complete conversion to product.
  • the reaction mixture was quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.
  • the crude material was purified via silica gel chromatography using 0-50% ethyl acetate in heptanes to afford product (63 mg, 0.134 mmol, 52.8 % yield) as a yellow oil.
  • the crude reaction mixture was cooled to ambient temperature, diluted with dichloromethane and water. The layers were separated, the aqueous was washed 2 x with dichloromethane. The organic layers were pooled, washed with brine, passed through a phase separator, and condensed.
  • the crude material was purified by silica gel chromatography (0-70% ethyl acetate/heptanes) to afford the desired product as a pale yellow solid (1.18 g, 59% yield).
  • Step 1 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)-one.
  • Step 2 To a vial, 2-(4-fluorophenyl)-6-hydroxy-3,4-dihydroisoquinolin-l(2H)- one 420 mg, 1.633 mmol) was dissolved in dimethylformamide (3.27 mL). Tert- butylchlorodimethylsilane (369 mg, 2.449 mmol), N,N-dimethylpyridin-4-amine (40 mg, 0.327 mmol), and imidazole (500 mg, 7.35 mmol) were added and the reaction stirred at room temperature overnight. The reaction was quenched with water and extracted with
  • Step 1 To a 50 mL round bottomed flask was added l-bromo-4-iodobenzene
  • Step 2 To a cold solution of the iminium intermediate in tetrahydrofuran (6.50 mL) was added a 1.4 M solution of methylmagnesium bromide (2.140 mL, 3.00 mmol) in tetrahydrofuran. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was separated and extracted with
  • reaction mixture was cooled to -78 °C and quenched with methanol. Volatiles were removed and the pH of the resulting solution was adjusted with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator, and concentrated to afford the crude product.
  • Route B To a vial containing (£)-methyl 3-(4-(2-(4-fluorophenyl)-6-methoxy-
  • reaction mixture stirred at 0 °C for 1 h, the mixture was warmed to rt and stirred for 3 h.
  • the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride, and diluted with dichloromethane.
  • the organic phase was collected, dried (sodium sulfate), filtered, and concentrated to afford crude product.
  • Enantiomers were separated using analytical SFC with an IC column (20% methanol, 0.1% trifluoroacetic acid in carbon dioxide) - Analytical SFC, IC column, 2.37 min and 2.51 min. resulted in (S,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l-methyl-l,2,3,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid and (R,E)-3-(4-(2-(4-fluorophenyl)-6-hydroxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylic acid.
  • Iminium intermediate was dissolved in tetrahydrofuran (2.388 mL) and the reaction was cooled to 0 °C and a 1 M solution of l-methyl- 3 -magnesium iodide (1.106 mL, 1.106 mmol) in diethyl ether was added dropwise. The reaction stirred at 0 °C for 1 h at which time it was quenched with saturated ammonium chloride. The aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator, and concentrated.
  • the vial was charged with a mixture of l-methyl-4 -vinyl- lH-imidazole and 1 -methyl-5 -vinyl- 1H- imidazole (1.455 mL, 0.728 mmol) and Pd(PPh 3 ) 2 Cl 2 (26 mg, 0.036 mmol).
  • the system was flushed with nitrogen and heated at 150 °C for 1 h under microwave radiation.
  • the mixture was cooled to room temperature and quenched with saturated ammonium chloride.
  • the reaction mixture was extracted three times with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated to give crude material.
  • Example 20a LC MS (m/z, MH + ): 440.2 PI : 3 ⁇ 4 NMR (400 MHz,
  • Example 20b LC MS (m/z, MH + ): 440.2. P2: 3 ⁇ 4 NMR (400 MHz,
  • Step 1 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-l,2,3,4- tetrahydroisoquinolin- 1 -yl)phenyl)propanoic acid.
  • Step 2 To a 30 mL vial, 3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl- l,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)propanoic acid (0.036 g, 0.086 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0°C. Ethanethiol (118 ⁇ , 1.601 mmol) was added followed by aluminum trichloride (86 mg, 0.644 mmol). The reaction was warmed to rt and stirred for 3 h. The reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate.
  • the reaction mixture was stirred at 0 °C for 30 min, cooled at -78 °C and quenched with methanol and concentrated. Volatiles were removed and the solution was basified with saturated sodium bicarbonate to pH 9. The mixture was diluted with dichloromethane and the layers were separated. The organic layer was washed with water and brine, passed through phase separator and concentrated. The crude product was purified by reverse phase HPLC (15-95%
  • Step 1 In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)acrylic acid (Intermediate Fl) (40 mg, 0.096 mmol) was dissolved in dimethylformamide (958 ⁇ ). The reaction vial was charged with HATU (44 mg, 0.115 mmol), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.012 g, 0.105 mmol), and 4- methylmorpholine (53 ⁇ , 0.479 mmol) and stirred overnight at rt.
  • HATU 44 mg, 0.115 mmol
  • 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine 0.012 g, 0.105 mmol
  • 4- methylmorpholine 53 ⁇ , 0.479 mmol
  • Step 2 In a vial, (E)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l -methyl- 1,2,3 ,4- tetrahydroisoquinolin-l-yl)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (0.045 g, 0.087 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. Ethanethiol (120 ⁇ ⁇ , 1.625 mmol) and aluminum chloride (87 mg, 0.653 mmol) were added, the reaction vial was warmed to rt and stirred for 3 h.
  • the reaction was quenched with water and brought to pH 6 with saturated sodium bicarbonate.
  • the aqueous layer was extracted thrice with dichloromethane, the organic layers were combined, passed through a phase separator and concentrated but afforded no desired product.
  • the aqueous layer was acidified to pH 4 with 1 M hydrochloric acid and extracted thrice with dichloromethane.
  • the organic layers were combined, passed through a phase separator, and concentrated to give crude material.
  • the crude product was purified by reverse phase HPLC (5 mM NH 4 OH modifier, 15 -40% acetonitrile/water) the title compound as an orange solid (3 mg, 8% yield).
  • Step 1 To a 30 mL vial, (£)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l-methyl-
  • Step 2 To a 2 mL microwave vial, (iT)-3-(4-(2-(4-fluorophenyl)-6-methoxy-l- methyl-l ,2,3,4-tetrahydroisoquinolin-l-yl)phenyl)acrylamide (1.201 mL, 0.120 mmol) and dibutylstannanone (2.99 mg, 0.012 mmol) were suspended in 1,2-dimethoxyethane (1.201 mL). The vial was charged with azidotrimethylsilane (48 ⁇ ⁇ , 0.360 mmol) and the reaction was heated for 60 min at 180 °C under microwave radiation. LC MS showed partial conversion to product.
  • Step 3 To a vial containing, (£)-l-(4-(2-(2H-tetrazol-5-yl)vinyl)phenyl)-2-(4- fluorophenyl)-6-methoxy-l -methyl- 1, 2,3 ,4-tetrahydroisoquino line (3.2 mg, 7.25 ⁇ ) was dissolved in dichloromethane (72 ⁇ ) and cooled to 0 °C. Ethanethiol (1 ⁇ , 0.135 mmol) was added followed by the addition of aluminum chloride (7.25 mg, 0.054 mmol). The reaction was warmed to rt and stirred for 3 h.
  • Step 1 To a 40 mL scintallation vial was added l-bromo-4-iodobenzene (0.718 g, 2.54 mmol) and pentanes (6.68 mL, Ratio: 1.4). The reaction vial was charged with a 2.5 M n- butyllithium (1.019 mL, 2.55 mmol) solution in hexanes and a white precipitate formed immediately.
  • reaction mixture was then quenched with water (10 mL) and ethyl acetate (10 mL) and warmed to rt perchloric acid (0.219 ml, 3.64 mmol, 70% in water) was added and the reaction mixture stirred for 30 min at rt.
  • the reaction was then diluted with water and extracted with dichloromethane three times. The organic layers were combined, passed through a phase separator and concentrated to give crude iminium intermediate which was used crude in the next step.
  • Step 2 Iminium intermediate was dissolved in dimethylformamide (7 mL, 0.12
  • Step 3 Ethyl 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy-l,2,3,4- tetrahydroisoquinolin-l-yl)-2,2-difluoroacetate (0.362 g, 0.648 mmol) was dissolved in 1,4- dioxanes (6.48 mL). To this was added 1 M lithium hydroxide (1.621 mL, 1.621 mmol) and the reaction was heated to 40 °C for 2 h. LC MS showed the reaction was complete and the reaction was acidified to pH 1 with 1 N hydrochloric acid and extracted with DCM three times.
  • Step 4 In a vial, 2-(l-(4-bromophenyl)-2-(4-isopropylphenyl)-6-methoxy- l,2,3,4-tetrahydroisoquinolin-l-yl)-2,2-difluoroacetic acid (0.1 g, 0.189 mmol) was dissolved in l-methyl-2-pyrrolidinone (9.43 mL) and cesium fluoride (0.143 g, 0.943 mmol) was added. The reaction was put under nitrogen and heated to 192 °C for 24 h. After cooling to rt, water was added to the reaction and the reaction mixture was extracted with diethyl ether three times.
  • Step 5 To a 40 mL vial was added 1 -(4-bromophenyl)- l-(difluoromethyl)-2-
  • 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.011 g, 0.022 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 °C. To this was added aluminum chloride (0.024 g, 0.179 mmol) followed by the addition of ethanethiol (0.033 mL, 0.448 mmol). The reaction was warmed to rt and stirred for 2 h. The reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted three times with dichloromethane.
  • 1,2,3 ,4-tetrahydroisoquinolin-l-yl)phenyl)acrylate (0.009 g, 0.019 mmol) was dissolved in 1,4- dioxanes (1 mL) and lithium hydroxide (0.188 mL, 0.188 mmol) was added. The reaction was heated to rt for 3 h. The reaction was then quenched with aqueous 1 N hydrochloric acid and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated.

Abstract

La présente invention concerne des composés de formule (I) dans laquelle n, R1, R2, R3, R4 et R5 sont tels que définis dans les revendications; capables d'être tant des antagonistes que des agents de dégradation puissants des récepteurs des œstrogènes. L'invention concerne aussi un procédé de préparation de composés de l'invention, et l'invention concerne en outre des préparations pharmaceutiques comprenant ces composés et des procédés d'utilisation de ces composés et compositions pour la gestion de maladies ou de troubles associés à une activité aberrante des récepteurs des œstrogènes.
PCT/IB2014/066813 2013-12-16 2014-12-11 Composés et compositions de 1,2,3,4-tétrahydroisoquinoléine en tant qu'antagonistes et agents de dégradation sélectifs des récepteurs des œstrogènes WO2015092634A1 (fr)

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WO2017107754A1 (fr) 2015-12-22 2017-06-29 江苏恒瑞医药股份有限公司 Dérivé de benzopipéridine, son procédé de préparation et son utilisation médicale
WO2017182495A1 (fr) * 2016-04-20 2017-10-26 Astrazeneca Ab Dérivés d'indazole qui régulent négativement le récepteur d'œstrogène et possèdent une activité anticancéreuse
WO2017182493A1 (fr) * 2016-04-20 2017-10-26 Astrazeneca Ab Dérivés d'indazole destinés à être utilisés dans la régulation négative du récepteur d'œstrogène pour le traitement du cancer
US10118910B2 (en) 2015-12-09 2018-11-06 The Board Of Trustees Of The University Of Illinois Benzothiophene-based selective estrogen receptor downregulators
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US10149839B2 (en) 2016-07-25 2018-12-11 Astrazeneca Ab Chemical compounds
WO2018233591A1 (fr) * 2017-06-20 2018-12-27 江苏恒瑞医药股份有限公司 Sel de dérivé de benzopipéridine et forme cristalline de celui-ci, procédé de préparation du sel et de la forme cristalline de celui-ci
US10208011B2 (en) 2017-02-10 2019-02-19 G1 Therapeutics, Inc. Benzothiophene estrogen receptor modulators
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JP2019510799A (ja) * 2016-04-08 2019-04-18 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト テトラヒドロイソキノリン エストロゲン受容体モジュレーター及びその使用
CN109867659A (zh) * 2017-12-04 2019-06-11 江苏恒瑞医药股份有限公司 苯并哌啶类衍生物的制备方法
WO2019223715A1 (fr) * 2018-05-23 2019-11-28 江苏恒瑞医药股份有限公司 Dérivé de benzopipéridine ou d'hétéroarylpipéridine, son procédé de préparation et son utilisation médicale
US10703747B2 (en) 2016-10-24 2020-07-07 The Board of Directors of the University of Illinois Benzothiophene-based selective mixed estrogen receptor downregulators
CN112830919A (zh) * 2019-11-22 2021-05-25 江苏恒瑞医药股份有限公司 苯并哌啶衍生物可药用盐及其制备方法
WO2021139756A1 (fr) 2020-01-10 2021-07-15 江苏恒瑞医药股份有限公司 Dérivé tétrahydroisoquinoline tricyclique, son procédé de préparation et son application en médecine
US11364222B2 (en) 2017-01-06 2022-06-21 G1 Therapeutics, Inc. Combination therapy for treatment of cancer
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