# US 11,028,072 B2 · 2,4-diamino-6-ethylpyrimidine derivatives with antimalarial activities against Plasmodium falciparum

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- Number: US 11,028,072 B2
- Document ID: US11028072B2
- Status: Granted
- Kind: B2
- Application number: 15/762,530
- Filed: 2016-09-16
- Published: 2020-07-30
- Granted: 2021-06-08
- Earliest claimed: 2015-09-23
- Assignees: National Science and Technology Development Agency
- Applicants: National Science and Technology Development Agency
- Inventors: Sumalee Kamchonwongpaisan; Netnapa Charoensetakul; Krisana Peewasan; Jarunee Vanichtanankul; Roonglawan Rattanajak; Supannee Taweechai; Tosapol Anukunwithaya; Aphisit Yoomuang; Yongyuth Yuthavong; Tirayut Vilaivan
- Web page: https://patentgrep.com/patent/US11028072B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 33/06: Antimalarials
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to 2,4-diamino-6-ethylpyrimidine derivatives that are inhibitors of wild type and quadruple mutant dihydrofolate reductase (DHFR) of Plasmodium falciparum. They also show in vitro antimalarial activities against Plasmodium falciparum for both wild type and mutant that are comparable to or better than pyrimethamine. In addition, the compounds of the present invention show a good selectivity to Plasmodium falciparum and exhibit lower cytotoxicity than pyrimethamine.

## Claims

### Claim 1

Derivatives of 2,4-diamino-6-ethylpyrimidine of Formula (I):
Wherein X1, X2 are oxygen or absent, Y1, Y2 are (CH2)1-3alkyl or absent, Z is (1-substituted-1H-1,2,3-triazol-4-yl) ring, (3-(substituted(isoxazol-5-yl) ring, (2-(substituted(oxazol-4-yl) ring, (2-(substituted)thiazol-4-yl) ring; wherein Ar is an aromatic ring or substituted aromatic ring as below:
a. Z is a ring of (1-substituted-1H-1,2,3-triazol-4-yl); Ar is phenyl or carboxyl substituted phenyl; no group X1, X2, Y1 and Y2
b. Z is a ring of (1-substituted-1H-1,2,3-triazol-4-yl); Ar is phenyl, carboxymethyl substituted phenyl, carboxyl-substituted phenyl or diphenylcarbamoyl substituted phenyl; Y2 is C1-3 alkyl; no group X1, X2 and Y1
c. Z is a ring of (1-substituted-1H-1,2,3-triazol-4-yl); Ar is chloro-substituted phenyl or carboxymethyl-substituted phenyl; X2 is oxygen; Y2 is C2-3 alkyl; no group X1 and Y1
d. Z is a ring of (3-(substituted)isoxazol-5-yl); Ar is phenyl, fluoro-substituted phenyl, chloro-substituted phenyl, bromo-substituted phenyl, trifluoromethyl-substituted phenyl, methoxy-substituted phenyl, nitro-substituted phenyl, cyano substituted phenyl, carboxymethyl-substituted phenyl or carboxyl-substituted phenyl; X1 is oxygen; Y1 is C1-3 alkyl; no group X2 and Y2
e. Z is a ring of (2-(substituted)oxazol-4-yl); Ar is phenyl, chloro-substituted phenyl, methyl-substituted phenyl, nitro-substituted phenyl, alkoxy carbonylmethoxy substituted phenyl, carboxymethoxy-substituted phenyl, alkoxy carbonyl-substituted phenyl or carboxy-substituted phenyl; X1 is oxygen; Y1 is C1-2 alkyl; no group X2 and Y2
f. Z is a ring of (2-(substituted)thiazol-4-yl); Ar is phenyl, fluoro-substituted phenyl, chloro-substituted phenyl, bromo-substituted phenyl, methyl-substituted phenyl, m ethoxy-substituted phenyl, nitro-substituted phenyl, alkoxy carbonylmethoxy substituted phenyl, carboxymethoxy-substituted phenyl, alkoxy carbonyl-substituted phenyl or carboxyl-substituted phenyl; X1 is oxygen; Y1 is C1-2 alkyl; no group X2 and Y2.

### Claim 2 (depends on 1)

Formulations of compounds of Formula (I) for inhibition of Plasmodium falciparum comprise of one or more compounds according to claim 1 or their salts and pharmaceutically acceptable excipients.

### Claim 3 (depends on 2)

Formulations of compounds of Formula (I) for inhibition of Plasmodium falciparum according to claim 2, wherein the said salt is hydrochloride salt.

### Claim 4 (depends on 1)

The derivative compounds of 2,4-diamino-6-ethylpyrimidine of claim 1, wherein said compounds are compound 1 to compound 56 below:
(1) 2,4-diamino-6-ethyl-5-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrimidine
(2) 2,4-diamino-6-ethyl-5-(1-(3-(carboxy)phenyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(3) 2,4-diamino-6-ethyl-5-(1-benzyl-1H-1,2,3-triazol-4-yl)pyrimidine
(4) 2,4-diamino-6-ethyl-5-(1-((4-(carboxymethyl)phenyl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(5) 2,4-diamino-6-ethyl-5-(1-((4-(carboxy)phenyl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(6) 2,4-diamino-6-ethyl-5-(1-((4-(diphenylcarbamoyl)phenyl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(7) 2,4-diamino-6-ethyl-5-(1-(phenylethyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(8) 2,4-diamino-6-ethyl-5-(1-(3-phenylpropyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(9) 2,4-diamino-6-ethyl-5-(1-(2-(4-(chloro)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(10) 2,4-diamino-6-ethyl-5-(1-(2-(4-(carboxymethyl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(11) 2,4-diamino-6-ethyl-5-(1-(3-(4-(chloro)phenoxy)propyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(12) 2,4-diamino-6-ethyl-5-(1-(3-(4-(carboxymethyl)phenoxy)propyl)-1H-1,2,3-triazol-4-yl)pyrimidine
(13) 2,4-diamino-6-ethyl-5-((3-(phenyl)isoxazol-5-yl)methoxy)pyrimidine
(14) 2,4-diamino-6-ethyl-5-((3-(4-(fluoro)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(15) 2,4-diamino-6-ethyl-5-((3-(4-(chloro)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(16) 2,4-diamino-6-ethyl-5-((3-(4-(bromo)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(17) 2,4-diamino-6-ethyl-5-((3-(3-(trifluoromethyl)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(18) 2,4-diamino-6-ethyl-5-((3-(3-(methoxy)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(19) 2,4-diamino-6-ethyl-5-((3-(3-(nitro)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(20) 2,4-diamino-6-ethyl-5-((3-(3-(carboxy)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(21) 2,4-diamino-6-ethyl-5-((3-(4-(trifluoromethyl)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(22) 2,4-diamino-6-ethyl-5-((3-(4-(methoxy)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(23) 2,4-diamino-6-ethyl-5-((3-(4-(nitro)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(24) 2,4-diamino-6-ethyl-5-((3-(4-(carboxy)phenyl)isoxazol-5-yl)methoxy)pyrimidine
(25) 2,4-diamino-6-ethyl-5-(3-(3-(4-(chloro)phenyl)isoxazol-5-yl)propoxy)pyrimidine
(26) 2,4-diamino-6-ethyl-5-(3-(3-(3-(trifluoromethyl)phenyl)isoxazol-5-yl)propoxy)pyrimidine
(27) 2,4-diamino-6-ethyl-5-(3-(3-(3-(cyano)phenyl)isoxazol-5-yl)propoxy)pyrimidine
(28) 2,4-diamino-6-ethyl-5-(3-(3-(3-(carboxymethyl)phenyl)isoxazol-5-yl)propoxy)pyrimidine
(29) 2,4-diamino-6-ethyl-5-(3-(3-(3-(carboxy)phenyl)isoxazol-5-yl)propoxy)pyrimidine
(30) 2,4-diamino-6-ethyl-5-((2-(phenyl)oxazol-4-yl)methoxy)pyrimidine
(31) 2,4-diamino-6-ethyl-5-((2-(3-(methyl)phenyl)oxazol-4-yl)methoxy)pyrimidine
(32) 2,4-diamino-6-ethyl-5-((2-(3-(nitro)phenyl)oxazol-4-yl)methoxy)pyrimidine
(34) 2,4-diamino-6-ethyl-5-((2-(3-(carboxymethoxy)phenyl)oxazol-4-yl)methoxy)pyrimidine
(35) 2,4-diamino-6-ethyl-5-((2-(4-(chloro)phenyl)oxazol-4-yl)methoxy)pyrimidine
(37) 2,4-diamino-6-ethyl-5-((2-(4-(carboxymethoxy)phenyl)oxazol-4-yl)methoxy)pyrimidine
(38) 2,4-diamino-6-ethyl-5-(2-(2-(phenyl)oxazol-4-yl)ethoxy)pyrimidine
(39) 2,4-diamino-6-ethyl-5-(2-(2-(4-(carboxy)phenyl)oxazol-4-yl)ethoxy)pyrimidine
(40) 2,4-diamino-6-ethyl-5-((2-(phenyl)thiazol-4-yl)methoxy)pyrimidine
(41) 2,4-diamino-6-ethyl-5-((2-(3-(methyl)phenyl)thiazol-4-yl)methoxy)pyrimidine
(42) 2,4-diamino-6-ethyl-5-((2-(3-(nitro)phenyl)thiazol-4-yl)methoxy)pyrimidine
(44) 2,4-diamino-6-ethyl-5-((2-(3-(carboxymethoxy)phenyl)thiazol-4-yl)methoxy)pyrimidine
(45) 2,4-diamino-6-ethyl-5-((2-(3-(carboxymethyl)phenyl)thiazol-4-yl)methoxy)pyrimidine
(46) 2,4-diamino-6-ethyl-5-((2-(3-(carboxy)phenyl)thiazol-4-yl)methoxy)pyrimidine
(47) 2,4-diamino-6-ethyl-5-((2-(4-(methyl)phenyl)thiazol-4-yl)methoxy)pyrimidine
(48) 2,4-diamino-6-ethyl-5-((2-(4-(methoxy)phenyl)thiazol-4-yl)methoxy)pyrimidine
(49) 2,4-diamino-6-ethyl-5-((2-(4-(fluoro)phenyl)thiazol-4-yl)methoxy)pyrimidine
(50) 2,4-diamino-6-ethyl-5-((2-(4-(chloro)phenyl)thiazol-4-yl)methoxy)pyrimidine
(51) 2,4-diamino-6-ethyl-5-((2-(4-(bromo)phenyl)thiazol-4-yl)methoxy)pyrimidine
(53) 2,4-diamino-6-ethyl-5-((2-(4-(carboxymethoxy)phenyl)thiazol-4-yl)methoxy)pyrimidine
(54) 2,4-diamino-6-ethyl-5-((2-(4-(carboxymethyl)phenyl)thiazol-4-yl)methoxy)pyrimidine
(55) 2,4-diamino-6-ethyl-5-((2-(4-(carboxy)phenyl)thiazol-4-yl)methoxy)pyrimidine
(56) 2,4-diamino-6-ethyl-5-(2-(2-(phenyl)thiazol-4-yl)ethoxy)pyrimidine.