Heterocyclic-imidazole compounds, pharmaceutical compositions thereof, preparation method therefor and use thereof
Inventors
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Publication Number
US-10174023-B2
Publication Date
2019-01-08
Expiration Date
Abstract
The present invention relates to heterocyclic-imidazole derivatives, a preparation method therefor, and a medical use thereof, and particularly to new heterocyclic-imidazole derivatives as represented by general formula (I), a preparation method therefor, pharmaceutical compositions comprising same, and a use thereof as a therapeutic agent, particularly as a poly(ADP-ribose)polymerase (PARP) inhibitor.
Core Innovation
The invention relates to heterocyclic-imidazole PARP inhibitors of general Formula I, including a tautomer thereof and a pharmaceutically acceptable salt thereof. In Formula I, structural definition constrains the substituent R, the arrangement of nitrogen versus CH among X, Y, and Z, and the value of M as nitrogen or CR1, with R1 being hydrogen, oxo, alkyl, alkoxy, or haloalkyl. The disclosure also identifies intermediate construction leading to Intermediate V, which is used in a condensation approach to form the Formula I compounds.
The patent identifies a preparation concept in which a compound of Formula I is formed by condensation of Intermediate V with a phthalazinecarboxylic acid derivative of Formula VI. The document links this to intermediate construction and deprotection to obtain Intermediate V, which is then condensed with the Formula VI derivative to yield the Formula I compounds.
The invention also encompasses pharmaceutical compositions containing the Formula I compound or a pharmaceutically acceptable salt and therapeutic use for diseases ameliorated by PARP inhibition. The therapeutic context emphasized in the document is cancer treatment, including HR/BRCA-deficient tumor settings, tumor adjuvant use, and boosting effects in chemotherapy and radiotherapy contexts.
Claims Coverage
The independent claim coverage is directed to a compound of Formula I, including a tautomer thereof or a pharmaceutically acceptable salt. The coverage centers on the permitted substituent patterns and heteroatom placement, with additional coverage in dependent claims to preparation and treatment aspects. A total of four inventive features are explicitly identified across the merged claim set.
Heterocyclic-imidazole parp inhibitor structural definition of formula I
A compound of Formula I or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, halo, C1-C6 alkoxy or C1-C6 haloalkyl; one of X, Y, and Z is nitrogen and the others are CH, or one of X, Y, and Z is CH and the others are nitrogen; and M is nitrogen or CR1, in which R1 is hydrogen, oxo, alkyl, alkoxy or haloalkyl.
Condensation of intermediate V with a phthalazinecarboxylic acid derivative to form formula I
A method prepares the compound of claim 1 or a pharmaceutically acceptable salt by condensing Intermediate V with a compound of Formula VI to produce a compound of Formula I, where R, X, Y, Z, and M are defined in claim 1 and R2 is hydroxyl, halo, or biimidazol-1-yl.
Preparation using selected carboxyl-activation and condensation reagents
A method for preparing the compound includes a condensation reaction where the condensing agent is chosen from 1,1'-carbonyl diimidazole, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate.
Administration for breast or ovarian cancer treatment
A method for treating a subject’s breast or ovarian cancer by administering a compound of claim 1 or a pharmaceutically acceptable salt thereof.
Across the provided independent and related claims, the claim coverage is anchored in the Formula I heterocyclic-imidazole PARP inhibitor structural constraints, with further coverage that prepares the compounds via condensation of Intermediate V with Formula VI and covers method-of-use administration for breast or ovarian cancer.
Stated Advantages
Inhibits PARP activity.
Provides treatment for cancers, including HR-deficient/BRCA1/BRCA2-deficient tumors.
Acts as an adjuvant to chemotherapeutics and boosts cancer radiotherapy.
Inhibition of PARP-1 enzyme activity (IC50 values reported versus AZD2281).
Inhibition of cancer cell proliferation in MDA-MB-436 cells (ED50 values reported).
Anti-tumor activity in nude-mouse xenograft models, reported as tumor inhibition for Compound (4) versus AZD2281.
Documented Applications
Use of Formula (I) compounds as PARP inhibitors for treating cancers, including HR-deficient/BRCA1/BRCA2-deficient tumors.
Use of Formula (I) compounds for breast cancer treatment and ovarian cancer treatment.
Use of Formula (I) compounds as an adjuvant to chemotherapeutics and as an adjuvant to boost cancer radiotherapy.
Treatment of vascular diseases, septic shock, ischemic damage, neurotoxic symptoms, hemorrhagic shock, inflammatory disease, multiple sclerosis, neurodegenerative diseases, and diabetes.
PARP-1 inhibition activity of Compounds (1)-(21), with IC50 values reported versus AZD2281.
Cell proliferation inhibition in MDA-MB-436 triple-negative breast cancer cells, with ED50 values reported.
In vivo anti-tumor use in nude-mouse xenograft models using MDA-MB-436, MX-1, and CAPAN-1, with tumor inhibition data reported for Compound (4) compared to AZD2281.
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