Small molecule compounds that control mammal-pathogenic nematodes

Patent metadata

Field	Value
Publication number	US-9487551-B2
Application number	US-201214237800-A
Country	US
Kind code	B2
Filing date	Aug 8, 2012
Priority date	Aug 8, 2011
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention relates to methods of modifying nematode behavior using certain isolated modulator compounds. Also disclosed are methods of promoting or inhibiting reproduction in a nematode population, methods of promoting or inhibiting nematode aggregation at a mammal, and methods of treating or preventing parasite infection of a mammal.

First claim

The invention claimed is:

1. A method of modifying nematode behavior, comprising:
providing a composition comprising a compound of the formula:

or a salt thereof;
wherein:
R 1 is H, —C(R) 3 , —OR, —N(R) 2 halogen, an alkyl, a haloalkyl, an alkenyl, or a haloalkenyl; wherein each R is independently H, halogen, an alkyl, or an alkenyl;
R 1″ is absent, H, —C(R) 3 , —OR, —N(R) 2 , halogen, an alkyl, a haloalkyl, an alkenyl, or a haloalkenyl; wherein each R is independently H, halogen, an alkyl, or an alkenyl;
R 2 is a moiety of the formula:

R 3 is H, —CR 6 R 7 R 8 , —C(O)R 8 , an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 5 of another unit of Formula I;
R 4 is H, —CR 6 R 7 R 8 , —C(O)R 8 , an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 5 of another unit of Formula I;
R 5 is H, —OH, —OR 6 , —OCR 6 R 7 R 8 , —CR 6 R 7 R 8 , —NH 2 , —NHR 6 , —NR 6 R 7 , halogen, an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, an arylalkyl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 3 or R 4 of another unit of Formula I;
R 6 and R 7 are each independently H, —CR 3 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl is optionally substituted with one or more substituents independently selected from —OR 8 , —C(O)R 8 , —NHC(O)R 8 , alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl;
R 8 is H, —C(R) 3 , —[C(R) 2 ] n4 NHC(O)R 9 , —[C(R) 2 ] n4 C(O)(NH)R 9 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or a monosaccharide having 5 or 6 carbon atoms, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or monosaccharide is optionally substituted with one or more substituents independently selected from —C(R) 3 , —OR 9 , —C(O)R 9 , —NHC(O)R 9 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and a monosaccharide having 5 or 6 carbon atoms;
R 9 is H, —C(R) 3 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or a monosaccharide having 5 or 6 carbon atoms, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or monosaccharide is optionally substituted with one or more substituents independently selected from —C(R) 3 , —OR, —C(O)R, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl;
each R is independently H, halogen, alkyl, or alkenyl;
n 1 , n 2 , and n 3 are each independently an integer of 0 to 30;
n 4 is an integer of 1 to 30; and
the sum of n 1 , each n 2 , and each n 3 is 1 to 30; and
administering an effective dosage of the composition to the nematode;
wherein the nematode is in contact with a mammal; and
further wherein the nematode is not a Caenorhabditis species.

2. A method of promoting or inhibiting reproduction of a nematode in contact with a mammal, comprising:
providing a composition comprising a compound of the formula:

or a salt thereof;
wherein:
R 1 is H, —C(R) 3 , —OR, —N(R) 2 , halogen, an alkyl, a haloalkyl, an alkenyl, or a haloalkenyl; wherein each R is independently H, halogen, an alkyl, or an alkenyl;
R 1′ is absent, H, —C(R) 3 , —OR, —N(R) 2 , halogen, an alkyl, a haloalkyl, an alkenyl, or a haloalkenyl; wherein each R is independently H, halogen, an alkyl, or an alkenyl;
R 2 is a moiety of the formula:

R 3 is H, —CR 6 R 7 R 8 , —C(O)R 8 , an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 5 of another unit of Formula I;
R 4 is H, —CR 6 R 7 R 8 , —C(O)R 8 , an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 5 of another unit of Formula I;
R 5 is H, —OH, —OR 6 , —OCR 6 R 7 R 8 , —CR 6 R 7 R 8 , —NH 2 , —NHR 6 , —NR 6 R 7 , halogen, an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an aryl, a heteroaryl, an arylalkyl, a heterocyclyl, a cycloalkyl, a cycloalkenyl, an acyl, an amino acid, a nucleoside, a monosaccharide having 5 or 6 carbon atoms, or a bond connecting to R 3 or R 4 of another unit of Formula I;
R 6 and R 7 are each independently H, —CR 3 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, or cycloalkenyl is optionally substituted with one or more substituents independently selected from —OR 8 , —C(O)R 8 , —NHC(O)R 8 , alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl;
R 8 is H, —C(R) 3 , —[C(R) 2 ] n4 NHC(O)R 9 , —[C(R) 2 ] n4 C(O)(NH)R 9 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or a monosaccharide having 5 or 6 carbon atoms, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or monosaccharide is optionally substituted with one or more substituents independently selected from —C(R) 3 , —OR 9 , —C(O)R 9 , —NHC(O)R 9 , halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, and a monosaccharide having 5 or 6 carbon atoms;
R 9 is H, —C(R) 3 , —OR, —N(R) 2 , halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or a monosaccharide having 5 or 6 carbon atoms, where the alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, purine, pyrimidine, or monosaccharide is optionally substituted with one or more substituents independently selected from —C(R) 3 , —OR, —C(O)R, halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl;
each R is independently H, halogen, alkyl, or alkenyl;
n 1 , n 2 , and n 3 are each independently an integer of 0 to 30;
n 4 is an integer of 1 to 30; and
the sum of n 1 , each n 2 , and each n 3 is 1 to 30; and
administering an effective dosage of the composition to the nematode in contact with the mammal; and
further wherein the nematode is not a Caenorhabditis species.

3. The method of claim 2 , wherein the composition comprises one or more compounds selected from ascr#7, ascr#8, ascr#9, ascr#10, ascr#11, ascr#12, ascr#14, ascr#16, ascr#18, ascr#20, ascr#22, ascr#24, ascr#26

Assignees

• Choe Andrea
• Sternberg Paul W
• Schroeder Frank C
• Von Reuss Stephan H
• Aroian Raffi V
• California Inst Of Techn
• Boyce Thompson Inst For Plant Res
• Univ California

Inventors

• Choe Andrea
• Sternberg Paul W
• Schroeder Frank C
• Von Reuss Stephan H
• Aroian Raffi V

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title