Compositions and methods for the treatment of malaria

Patent metadata

Field	Value
Publication number	US-9353089-B2
Application number	US-201414226295-A
Country	US
Kind code	B2
Filing date	Mar 26, 2014
Priority date	Mar 26, 2013
Publication date	May 31, 2016
Grant date	May 31, 2016

Abstract

The present invention provides aminohydantoin anti-malarial agents. In some embodiments, these agents have the property of functions of targeting malarial aspartic proteases while at the same time having low activity against human BACE. Methods of employing such agents are also provided.

First claim

What is claimed is:

1. A compound of Formula I:

wherein:
R 1 is heterocycloalkyl (C3-7) or substituted heterocycloalkyl (C3-7) ;
R 2 is aryl (C6-10) , -arenediyl (C6-10) -alkoxy (C1-7) , -arenediyl (C6-10) -heteroaryl (C1-5) , or a substituted version of any of these groups;
R 3 is:
hydroxy, halo, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , or —CN; or
alkyl (C1-7) , haloalkyl (C1-7) , alkoxy (C1-7) , haloalkoxy (C1-7) , aryl (C6-10) , —O-aryl (C6-10) , heteroaryl (C1-9) , —O-heteroaryl (C1-9) , —O—CH 2 -aryl (C6-10) , -arenediyl (C6-C10) -alkynyl (C2-6) , substituted -arenediyl (C6-C10) -alkynyl (C2-6) , -heteroarenediyl (C6-C10) -alkynyl (C2-6) , substituted -heteroarenediyl (C6-C10) -alkynyl (C2-6) , —O—CH 2 -heteroaryl (C1-9) , substituted aryl (C6-10) , substituted —O-aryl (C6-10) , substituted heteroaryl (C1-9) , substituted —O-heteroaryl (C1-9) , substituted —O—CH 2 -aryl (C6-10) , or substituted —O—CH 2 -heteroaryl (C1-9) ; and

R 4 is:
H, halo, hydroxy, or —CN; or
alkyl (C1-7) , haloalkyl (C1-7) , alkoxy (C1-7) , or haloalkoxy (C1-7) ;

provided that when R 2 is cyclopropyl, R 3 is not 3-chlorophenyl;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is tetrahydropyranyl, piperidin-4-yl, 1-methylpiperidin-4-yl, N-Boc-piperidin-4-yl, 1-benzylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-benzoylpiperidin-4-yl, or 1-[3-(dimethylamino)propanoyl]piperidin-4-yl.

3. The compound of claim 1 , wherein R 3 is alkoxy (C1-7) .

4. The compound of claim 3 , wherein R 3 is methoxy, ethoxy or 2-methylpropoxy.

5. A compound of Formula III:

wherein:
R 9 is t-butyl, adamantanyl, aryl (C6-10) , heteroaryl (C1-6) or substituted versions of any of these groups;
R 10 is 3-methoxyphenyl or 4-methoxyphenyl;
R 11 is:
hydroxy, methoxy, methyl, trifluoromethyl, trifluoromethoxy, halo, or —CN; or
aryl (C6-10) , heteroaryl (C1-9) , substituted aryl (C6-10) , or substituted heteroaryl (C1-9) ; and

R 12 is H, halo, hydroxy, or —CN;
or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein R 9 is pyridyl or picolinyl.

7. The compound of claim 5 , wherein R 11 is 4-methoxy or 3-methoxy.

8. A compound further defined as:
3-cyclohexyl-2-imino-5,5-bis(4-methoxyphenyl)imidazolidin-4-one;
or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Saint Louis
• Guangzhou Inst Biomed & Health

Inventors

• Chen Xiaoping
• Ding Ke
• Meyers Marvin J
• Tortorella Micky D
• Xu Jing

Classifications

• C07D403/04

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

• C07D233/02

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title