US2018092898A1PendingUtilityA1
Processes of making and crystalline forms of a mdm2 inhibitor
Est. expiryJun 10, 2033(~6.9 yrs left)· nominal 20-yr term from priority
Inventors:Matthew BioSebastien CailleBrian CochranYuanqing FangBrian M. FoxBrian Stuart LucasLawrence R. McgeeFilisaty VounatsosSean H. WiedemannSarah Wortman
C07C 309/25C07D 498/04C07D 211/94C07D 211/76C07C 313/02C07B 2200/13A61K 31/451C07C 309/04C07C 309/35C07D 491/048A61P 35/00A61K 31/45A61P 43/00A61P 35/02
70
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Claims
Abstract
The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . Crystalline
2 . Crystalline anhydrous
3 . Crystalline anhydrous
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle 2 theta degrees at approximately 11.6, 12.4, 18.6, 19.0, 21.6 and 23.6.
4 . Crystalline anhydrous
in accordance with claim 3 having the X-ray diffraction pattern substantially shown in FIG. 1 .
5 . A pharmaceutical composition comprising: crystalline
in accordance with claim 2 or 3 ; and a pharmaceutically acceptable excipient.
6 . A method of treating bladder cancer, breast cancer, colon cancer, rectal cancer, kidney cancer, liver cancer, small cell lung cancer, non-small-cell lung cancer, esophagus cancer, gall-bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervix cancer, thyroid cancer, prostate cancer, squamous cell carcinoma, melanoma, acute lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute myelogenous leukemia, chronic myelogenous leukemia, endometrial cancer, head and neck cancer, glioblastoma, osteosarcoma, or rhabdomyosarcoma, the method comprising administering to a patient in need thereof, a therapeutically acceptable amount of a pharmaceutical composition comprising crystalline
in accordance with claim 2 or 3 .
7 . The compound
8 . The compound
9 . Crystalline
10 . Crystalline
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle 2 theta degrees at approximately 8.7, 18.5, 22.6 and 26.6.
11 . Crystalline
in accordance with claim 10 having the X-ray diffraction pattern substantially shown in FIG. 3 .
12 . The compound
13 . A process for making
the process comprising:
reacting
under dehydrating conditions with
to form
14 . The process of claim 13 wherein the dehydrating conditions are azeotropic distillation with toluene.
15 . A process of making
the process comprising:
reacting
to form
wherein X is CF 3 SO 3 − or
16 . A process of making
the process comprising:
reacting
with toluene to form
17 . A process of making
the process comprising:
reacting
with lutidine and
to form
18 . A process of making
the process comprising reacting
to form
which is oxidized to
which is further converted to
19 . The process of claim 18 wherein the oxidation is accomplished using ozone.
20 . The process of claim 18 wherein the oxidation is accomplished using ozone followed by Pinnick oxidation.
21 . The process of claim 18 wherein the conversion of
is accomplished using methanol and water.
22 . The process of claim 18 wherein the oxidation is accomplished using ozone followed by Pinnick oxidation, and the conversion of
is accomplished using methanol and water.
23 . A process of making
the process comprising reacting
to form
to form
which is further converted to
24 . The process of claim 23 wherein the
are reacted in the presence of a base.
25 . The process of claim 24 wherein the base is sodium tert-butoxide.
26 . The process of claim 23 wherein the oxidation is accomplished using RuCl 3 and NaIO 4 .
27 . The process of claim 23 wherein the conversion of
is accomplished using methanol and water.
28 . The process of claim 23 wherein the
are reacted in the presence of a base;
the oxidation is accomplished using RuCl 3 and NaIO 4 ; and
the conversion of
is accomplished using methanol and water.
29 . The compound
30 . Crystalline
31 . Crystalline
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle 2 theta degrees at approximately 10.5, 18.2, 20.3, 21, 21.9 and 24.2.
32 . Crystalline
in accordance with claim 31 having the X-ray diffraction pattern substantially shown in FIG. 6 .
33 . The compound
34 . Crystalline
35 . Crystalline
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle 2 theta degrees at approximately 11.5, 14.3, 15.8, 17.7, 19.5 and 20.7.
36 . Crystalline
in accordance with claim 35 having the X-ray diffraction pattern substantially shown in FIG. 12 .
37 . A process of making
the process comprising reacting
with an oxidizing agent and DABCO to form
and reacting
with an acid to form
38 . The process of claim 37 wherein the oxidizing agent is ozone and the acid is hydrochloric acid.Cited by (0)
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