Complex and structurally diverse compounds

Patent metadata

Field	Value
Publication number	US-10800730-B2
Application number	US-201816136830-A
Country	US
Kind code	B2
Filing date	Sep 20, 2018
Priority date	Mar 23, 2012
Publication date	Oct 13, 2020
Grant date	Oct 13, 2020

Abstract

The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.

First claim

What is claimed is:

1. A compound that is a ring cleaved derivative of quinine wherein the C—N bond between the nitrogen atom and the —CH 2 CH(allyl) bridge of the quinuclidine moiety of quinine is cleaved, the compound has a molecular weight of at least 375 Daltons, and comprises at least one additional heteroatom compared to quinine or two additional stereogenic carbons compared to quinine.

2. The compound of claim 1 wherein the ring cleaved derivative of quinine is:

3. The compound of claim 1 wherein the ring cleaved derivative of quinine is an amide compound selected from:

4. The compound of claim 1 wherein the ring cleaved quinine derivative is a triazole compound selected from:

5. The compound of claim 1 wherein the ring cleaved quinine derivative is a sulfonamide compound selected from:

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.

7. A method of treating cancer comprising administering to a subject in need thereof an effective anti-cancer amount of a compound of claim 1 , thereby treating the cancer, wherein the cancer is selected from cervical cancer or lung cancer.

8. A compound of Formula X1 or X2:

wherein
R 1 is Cl, N 3 , NH 2 , NH(C═O)Me, NH(C═O)Ph, NH(C═O)CH 2 O(C═O)Me, NH(C═O)N(CH 2 CH 2 ) 2 O, NH(C═O)CH 2 OCH 2 Ph, NH(C═O)(2-chloropyridin-5-yl), NHS(O) 2 R a , or

R a is 4-methylphenyl, 4-acetanilide, 1-naphthyl, 2-benzofuran, 2-phenoxypyridin-5-yl, or

 and
R b is phenyl, 4-bromophenyl, 4-phenoxyphenyl, —(CH 2 ) 3 OH, 1-hydroxycyclopentyl-1-yl, benzhydrol-1-yl, or —CH 2 O(N-phthalimide); or
R 2 is N 3 , NH 2 , NH(C═O)Me, NH(C═O)(2-chloropyridin-5-yl), NH(C═O)(2-chloropyridin-5-yl), NH(C═O)CH 2 O(C═O)Me, NH(C═O)CH 2 OCH 2 Ph, NHS(O) 2 R c , or

R c is 4-methylphenyl, 4-acetanilide, 1-naphthyl, 2-benzofuran, or 2-phenoxypyridin-5-yl; and
R d is phenyl, 4-N,N-dimethylaminophenyl, 1-hydroxycyclopentyl-1-yl, benzhydrol-1-yl, or —CH 2 O(N-phthalimide).

Assignees

• Univ Illinois

Inventors

• Hergenrother Paul J
• Huigens Iii Robert W
• Morrison Karen C
• Hicklin Ii Robert W
• Flood Jr Timothy A

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D303/10

  in which the oxirane rings are condensed with a carbocyclic ring system having three or more relevant rings · CPC title

• C07J71/001

  Oxiranes · CPC title