Hydroxy-amino acid amides

• US 5,872,262 A
• Filed: 12/08/1997
• Issued: 02/16/1999
• Est. Priority Date: 11/05/1996
• Status: Expired due to Fees

• Current Assignee: Pharmacopeia, Inc.
• Original Assignee: Pharmacopeia, Inc.
• Inventors: Johnson, Theodore O. Jr., Patel, Hitesh K., Dolle, Roland Ellwood III, Carroll, Carolyn DiIanni, Tao, Shiwei
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US08/986,559
• Time in Patent Office: 435 Days
• Field of Search: 548/530, 548/537, 544/390, 544/400, 546/281, 564/153
• US Class Current: 548/537
• CPC Class Codes: C07C 237/12 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• 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 or S--C(O)--L--;

wherein;

S is a solid support; and

--L-- is a linker of Formula(a) ##STR31## wherein the left-hand bond is the point of attachment to --C(O)-- and the right-hand bond is the point of attachment to the amide nitrogen of Formula I;

Y is --C(O)R⁵

wherein;

R⁵ is ##STR32## wherein R⁶ and R⁷ are independently chosen from the group consisting of substituted alkyl, alkylcarbonyl and substituted alkylcarbonyl; and

R⁸ is alkyl.

2. A compound according to claim 1 wherein R² is hydrogen.

3. A compound according to claim 2 wherein:

R¹ is chosen from the group consisting of methyl, benzyl, butyl, 3-phenylpropyl, 3-methoxypropyl, 2-pyridinylmethyl and 3-pyridinylmethyl;

R⁶ is chosen from the group consisting of

3-pyridinylmethyl, phenylethoxyethyl,

3,4,5-trimethoxybenzyl, 4-acetamidobenzyl,

4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl,

3-phenylpropyl, ethyl adipoyl,

3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl, isobutyl, propionyl and

3,5-di(trifluoromethyl)phenylacetyl; and

R⁷ is chosen from the group consisting of

4-isopropoxybenzoyl,

3,4,5-trimethoxybenzoyl,

3-phenoxybenzoyl, 3-(2-methoxyphenyl)propyl,

3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, phenylacetyl, 3,4-dichlorophenylacetyl and ethyl adipoyl.

4. A compound according to claim 3 wherein:

R¹ is chosen from the group consisting of butyl, 2-pyridinylmethyl and 3-pyridinylmethyl;

R⁶ is chosen from the group consisting of 4-phenylbenzyl, isobutyl, propionyl and 3,5-di(trifluoromethyl)phenylacetyl;

R⁷ is chosen from the group consisting of phenylacetyl, 3-phenoxybenzoyl and 3,3-diphenylpropionyl; and

R⁸ is ethyl.

5. A compound according to claim 1 wherein R² is _S--C(O)--L--.

6. A compound according to claim 5 wherein:

R¹ is chosen from the group consisting of methyl, benzyl, butyl, 3-phenylpropyl, 3-methoxypropyl, 2-pyridinylmethyl and 3-pyridinylmethyl;

R⁶ is chosen from the group consisting of

3-pyridinylmethyl, phenylethoxyethyl,

3,4,5-trimethoxybenzyl, 4-acetamidobenzyl,

4-phenylbutyl, 3,4-dichlorobenzyl, 4-phenylbenzyl,

3-phenylpropyl, ethyl adipoyl,

3,5-bis(trifluoromethyl)benzyl, 3-phenylpropionyl, isobutyl, propionyl and

3,5-di(trifluoromethyl)phenylacetyl; and

R⁷ is chosen from the group consisting of

4-isopropoxybenzoyl, nicotinoyl,

3,4,5-trimethoxybenzoyl, 3-phenoxybenzoyl,

3-(2-methoxyphenyl)propyl,

3,4,5-trimethoxyphenylpropionyl, 3,3-diphenylpropionyl, phenylacetyl, 3,4-dichlorophenylacetyl and ethyl adipoyl.

7. A compound according to claim 6 wherein:

R¹ is chosen from the group consisting of butyl, 2-pyridinylmethyl and 3-pyridinylmethyl;

R⁶ is chosen from the group consisting of 4-phenylbenzyl, isobutyl, propionyl and 3,5-di(trifluoromethyl)phenylacetyl;

R⁷ is chosen from the group consisting of 3-phenoxybenzoyl, 3,3-diphenylpropionyl and phenylacetyl; and

R⁸ is ethyl.