Hydroxy-amino acid amides

• US 5,892,038 A
• Filed: 12/08/1997
• Issued: 04/06/1999
• Est. Priority Date: 12/08/1997
• Status: Expired due to Fees

• Current Assignee: Pharmacopeia LLC (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Pharmacopeia, Inc.
• Inventors: Patel, Hitesh K., Dolle, Roland Ellwood III
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): KEATING, DOMINIC J
• Application Number:
  US08/986,545
• Time in Patent Office: 484 Days
• Field of Search: 544/358, 544/390, 544/400, 546/343, 546/348, 548/579, 568/735, 585/409
• US Class Current: 544/358
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07D 207/06 with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compounds of Formula I ##STR1## are disclosed as inhibitors of plasmepsin and cathepsin D. The compounds are therefore useful to treat diseases such as malaria. In preferred compounds of formula I, Y is the residue of an N-acylated amino acid, a substituted 4-aminoproline or a substituted piperazinealkanoic acid. Intermediates in the solid phase synthesis of compounds of formula I, in which the compounds are attached to a solid support, are also disclosed.

Claims

1. A compound of Formula I

wherein:

R¹ and R³ are independently chosen from the group consisting of alkyl, alkoxyalkyl, 2-pyridinylmethyl, 3-pyridinylmethyl and arylalkyl;

R² is H; and

Y is --Aa--C(O)R⁴

wherein;

Aa is an amino acid attached via its carboxyl to the amine nitrogen of structure I;

R⁴ is chosen from the group consisting of alkyl, aryl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl ##STR31## and substituted heterocycloalkyl.

2. A compound according to claim 1 wherein

R¹ is chosen from the group consisting of butyl, 3-phenylpropyl and 3-methoxypropyl;

Aa is chosen from the group consisting of valine, leucine, phenylalanine, isoleucine β

-2-thienylalanine, t-butylglycine, cysteine and phenylglycine; and

R⁴ is chosen from the group consisting of ##STR32##

3. A compound according to claim 1 wherein R¹ is chosen from the group consisting of butyl, 3-phenylpropyl and 3-methoxypropyl;

Aa is chosen from the group consisting of valine, leucine, phenylalanine, isoleucine β

-2-thienylalanine, t-butylglycine, cysteine and phenylglycine; and

R⁴ is chosen from the group consisting of ##STR33##