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Cortistatin analogues and syntheses thereof

a technology of cortistatin and analogues, which is applied in the field of cortistatin analogues and syntheses thereof, can solve the problems of high production cost and parenteral administration, and many currently available drugs are biologics, and achieve the effect of efficient carbon framework construction

Inactive Publication Date: 2011-08-04
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0014]There have been several previous syntheses of the B(9a)-homo-19-norsteroid skeleton, some of which have resulted in very efficient construction of the carbon framework (see the schemes below). Neef et al., New steroids by Simmons-Smith methylenation and subsequent rearrangement. Journal of Organic Chemistry 1987, 52, (18), 4143-4146; Neef et al., A radical approach to the synthesis of 9(10-19) abeosteroids. Tetrahedron 1993, 49, (4), 833-840; Kupchan et al., Buxus alkaloids 13. A synthetic approach to 9(10-19) abeo-pregnane system. Journal of the American Chemical Society 1967, 89, (24), 6327-6332; Abushanab et al., 9(10-19) abeosteroids—total synthesis of abeo-estradiol, abeo-estradiol 3-methyl ether, and 17-alpha-ethynyl abeo

Problems solved by technology

Furthermore, several of the currently available drugs are biologics and suffer the drawbacks of high production costs and required parenteral administration.

Method used

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  • Cortistatin analogues and syntheses thereof
  • Cortistatin analogues and syntheses thereof
  • Cortistatin analogues and syntheses thereof

Examples

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example 1

[0433]The synthesis plan was guided by a desire to produce 1 (cortistatin A), 2 (cortistatin C) and 3 (cortistatin J) for biological and medicinal studies and to generate diverse analogs to systematically determine the structural elements required for anti-angiogenic activity. Eventually, this may enable us to discover molecules less complex than 1 but that maintain its biological activity and that have improved drug properties. The synthesis a shown in the scheme below includes an aza-Prins cyclization via iminium ion 4 with transannular cyclization by a C8 tertiary carbinol. See Simth et al., Tetrahedron 1986, 42, 2957-2969. This reaction would simultaneously form the A ring and the oxabicyclo[3.2.1]octene as well as control the C3 N,N-dimethylamine and C5 tertiary ether stereocenters. Substructure matching of 4 suggested that it could be derived from enantiomerically pure Hajos-Parrish ketone. See Hajos et al., J. Org. Chem. 1974, 39, 1612-1615. Herein, we report achievement of t...

example 2

[0443]General Procedures. All reactions were performed in oven or flame-dried glassware under a positive pressure of argon unless noted otherwise. Flash column chromatography was performed as described by Still et al., J. Org. Chem. 1978, 43, 2923-2925, either employing E. Merck silica gel 60 (230-400 mesh ASTM) or using pre-packaged FLASH columns on a HPFC Biotage system (Biotage Inc.) unless noticed otherwise. Tetrahydrofuran, methylene chloride, toluene, acetonitrile, and dimethylformamide were degassed with argon and passed through a solvent purification system (designed by J.C. Meyer of Glass Contour) utilizing alumina columns. Anhydrous dimethylsulfoxide, 1,2-dichloroethane, and hexane were purchased at the highest quality from Aldrich and used without further purification. Triethylamine and pyridine were freshly distilled upon CaH2 before use. Pd(PPh3)4 was prepared following a literature procedure (See Coulson, Inorg. Synth. 1972, 13, 121-125) and stored under argon at −20° ...

example 3

[0566]Intermediate

[0567]To a solution of the TIPS phenol (4.39 g, 7.69 mmol) in THF / Ether (68 mL each) at 0° C. was added the TBAF (1.0 M in THF) (9.23 ml, 9.23 mmol) over 1 minute. The reaction mixture [rapidly bright golden, then orange] was stirred for 30 minutes at 0° C. 800 μL of TBAF were added, and the mixture further stirred 10 minutes. The 2,6-Lutidine (3.58 ml, 30.8 mmol) was then added, followed by the hexafluoroisopropanol (17 mL) and the BTIB (5.95 g, 13.84 mmol) as a solid in two portions over 5 minutes. The reaction mixture was stirred at 0° C. and monitored by TLC. After 30 minutes, the reaction mixture was diluted with ether (250 mL) and the organic layer washed with dilute aqueous acetic acid (50 mL). The aqueous layer was extracted with ether (2×50 mL), and the combined organic layers were washed with saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL), then dried over sodium sulfate, filtered, and concentrated. The organic residue was purifi...

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Abstract

The present invention relates to analogs of cortistatin A, J, K, and L, having the general formula: I and salts thereof, wherein R1, R2, R3, R4, n, and m are as defined herein; processes for preparing such compounds and intermediates thereto; pharmaceutical compositions comprising such compounds; methods for treating a proliferative disease; methods for treating a disease associated with aberrant angiogenesis; methods for inhibiting angiogenesis; and processes for preparing cortistatin A, J, K, and L, and analogs thereof.

Description

RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent applications, U.S. Ser. No. 61 / 092,492, filed Aug. 28, 2008, and U.S. Ser. No. 61 / 115,395, filed Nov. 17, 2008, each of which is incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Angiogenesis is the process of generating new capillary blood vessels from the pre-existing vasculature. After birth, angiogenesis contributes to organ growth, but in adulthood it is strictly regulated and occurs only during wound healing and in the female reproductive cycle. See Klagsbrun et al., Molecular angiogenesis. Chemistry &Biology 1999, 6 (8), R217-R224. Under normal physiological conditions, angiogenesis is tightly controlled by a series of pro-angiogenic and anti-angiogenic factors, which allow vascular growth for controlled periods of time. Ferrara, Vascular Endothelial Growth Factor as a Target for Anticancer Therapy. The Oncologist 2004, 9:2-10. Persistent, unreg...

Claims

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Application Information

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IPC IPC(8): A61K31/517C07D493/08C07D495/04A61K31/4725A61K31/35A61P35/00
CPCA61K31/34A61K31/4725A61P35/00C07D493/08
Inventor FLYER, ALEC NATHANSONLEE, HONG MYUNGMYERS, ANDREW G.NIETO-OBERHUBER, CRISTINA MONTSERRATSHAIR, MATTHEW D.SI, CHONG
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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