US 2017/0291886 A1Published application

Methods for treating protozoan infections

AssigneeNeoculi Pty Ltd

InventorsStephen Page, Andrew Stevens, Adam McCluskey, Martine Keenan, Rebecca Abraham

Life of this patent

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Abstract

The invention provides compounds of Formula (I), and their use in methods for treating or preventing a protozoan infection in a subject using a compound of Formula (I). The invention also provides the use of a compound of Formula (I) in the manufacture of a medicament for the treatment of a protozoan infection in a subject. The invention further provides a medical device when used in a method of treating or preventing a protozoan infection in a subject and to a medical device comprising the composition of the invention.

Claims41

Dependent claims

A method of treating or preventing a protozoan colonisation or infection in a subject, the method comprising the step of administering a therapeutically effective amount of a compound of Formula I or stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof to the subject, wherein the protozoan infection is caused by a protozoan agent, wherein Formula I is:

wherein R1 is H, cycloalkyl, Formula II, or Formula III;
wherein R3 is selected from the group consisting of:
H;
NH2;
NHNH2;
O—CH2—CH3;
NH—C(O)-phenyl;
NH—CH-chlorophenyl;
NH-chlorophenyl;
NH—CH2-chlorophenyl;
NH—N—CH-cycloalkyl;
N and R4 is CH—N—CH—CCl— and R4 is bonded to R3;
Formula IV;
Formula V;
and Formula VI;
wherein A0 is N, C, CH, or A0 is C and A0 is bonded to R4 to form a triazole ring;
wherein A1 is N, C, NH, —(CH)2—N—, —(C6H5)C—CH—N—, or Formula VII;
A2 is N, C, NH, N—C(O)-phenyl or Formula VII, or (CH2)n wherein n is an integer between 1 and 3, inclusive;
wherein A3, A4, A5, A6, A7, A8, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21 A23, A24, A25, A26 and A27 are independently C, O, N, NH, S;
wherein A9 is C, O, N, NH, N—C(O)—O—CH2—CH3, N—C(O)—O—CH(CH3)2, N—C(O)—NH—CH2—CH3, N—C(O)—NH—CH2-phenyl, N—C(O)—CH2—CH2—CH2—CH2—CH2—CH3, N—C(O)—CH2-furan-2-yl;
wherein A10 is C, NH, —N—(CH)2—, —N—CH—C(C6H5)—;
wherein A22 is —CH(CH3)—, —N—CH—, —N—C(CH3)—, N—C(CH2OH)—;
R2 is H, COOH, CH2NH2, CH2OH, CH2NHNH2, methyl, ethyl, propyl, butyl, pentyl, heptyl, cyclopentyl, CH2(Cyclohexyl), (CH2)2(cyclopentyl) or Formula VII and R2 are R4 are bonded together to form a pyrimidine, pyrazine or triazine ring, or R2 and R9 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R4 is H2, N, NH, O, S, or R4 and A0 are bonded together to form a triazole ring, or R4 is N and R4 and R2 are bonded together to form a pyrimidine ring;
wherein R7 is H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CCH, CF3, OCF3, SCF3, NO2, butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R7 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R6, R8, R14, R16, R25 and R27 are independently H, OH, Cl, F, Br, CH3, CN, OCH3, COOH, NO2, CF3, R8 and R7 bond together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring, or benzene ring, R14 and R15 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, R8 and R9 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R14 and R13 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R5, R9, R17, R24 and R28 are independently H, O, OH, Cl, F, Br, NH2, CH3, CF3, OCH3, CN, NO2, phenyl, —NH—CH(OH)—CH3, —NH—C(O)—CH3, or R9 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R13 and R14 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R10, R11, R19, R20, R22 and R23 are independently H, Cl, or Br, or R10 and R11 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R19 and R20 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R22 and R23 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R12, R18 and R21 are independently H, COOH, CH2NH2, CH2OH, methyl, ethyl, propyl, butyl, cyclopentyl, or R12 and R13 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R15 and R26 are independently H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CF3, OCF3, SCF3, NO2, CCH, n-butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R15 and R14 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
and
wherein “” is a double bond or a single bond.

29 more elements

An antiprotozoan pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a therapeutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient or carrier, wherein Formula I is:

wherein R1 is H, cycloalkyl, Formula II, or Formula III;
wherein R3 is selected from the group consisting of:
H;
NH2;
NHNH2;
O—CH2—CH3;
NH—C(O)-phenyl;
NH—CH-chlorophenyl;
NH-chlorophenyl;
NH—CH2-chlorophenyl;
NH—N—CH-cycloalkyl;
N and R4 is CH—N—CH—CCl— and R4 is bonded to R3;
Formula IV;
Formula V;
and Formula VI;
wherein A0 is N, C, CH, or A0 is C and A0 is bonded to R4 to form a triazole ring;
wherein A1 is N, C, NH, —(CH)2—N—, —(C6H5)C—CH—N—, or Formula VII;
A2 is N, C, NH, N—C(O)-phenyl or Formula VII, or (CH2)n wherein n is an integer between 1 and 3, inclusive;
wherein A3, A4, A5, A6, A7, A8, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21 A23, A24, A25, A26 and A27 are independently C, O, N, NH, S;
wherein A9 is C, O, N, NH, N—C(O)—O—CH2—CH3, N—C(O)—O—CH(CH3)2, N—C(O)—NH—CH2—CH3, N—C(O)—NH—CH2-phenyl, N—C(O)—CH2—CH2—CH2—CH2—CH2—CH3, N—C(O)—CH2-furan-2-yl;
wherein A10 is C, NH, —N—(CH)2—, —N—CH—C(C6H5)—;
wherein A22 is —CH(CH3)—, —N—CH—, —N—C(CH3)—, N—C(CH2OH)—;
R2 is H, COOH, CH2NH2, CH2OH, CH2NHNH2, methyl, ethyl, propyl, butyl, pentyl, heptyl, cyclopentyl, CH2(Cyclohexyl), (CH2)2(cyclopentyl) or Formula VII and R2 are R4 are bonded together to form a pyrimidine, pyrazine or triazine ring, or R2 and R9 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R4 is H2, N, NH, O, S, or R4 and A0 are bonded together to form a triazole ring, or R4 is N and R4 and R2 are bonded together to form a pyrimidine ring;
wherein R7 is H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CCH, CF3, OCF3, SCF3, NO2, butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R7 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R6, R8, R14, R16, R25 and R27 are independently H, OH, Cl, F, Br, CH3, CN, OCH3, COOH, NO2, CF3, R8 and R7 bond together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring, or benzene ring, R14 and R15 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, R8 and R9 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R14 and R13 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R8, R9, R17, R24 and R28 are independently H, O, OH, Cl, F, Br, NH2, CH3, CF3, OCH3, CN, NO2, phenyl, —NH—CH(OH)—CH3, —NH—C(O)—CH3, or R9 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R13 and R14 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R10, R11, R19, R20, R22 and R23 are independently H, Cl, or Br, or R10 and R11 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R19 and R20 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R22 and R23 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R12, R18 and R21 are independently H, COOH, CH2NH2, CH2OH, methyl, ethyl, propyl, butyl, cyclopentyl, or R12 and R13 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R15 and R26 are independently H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CF3, OCF3, SCF3, NO2, CCH, n-butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R15 and R14 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
and
wherein “” is a double bond or a single bond.

29 more elements

A compound selected from the list of compounds consisting of:

(E)-2-(1-(4-(tert-butyl)phenyl)ethylideneamino)guanidine (NCL231);
(E)-2-(4-(tert-butyl)benzylideneamino)guanidine (NCL232);
(E)-2-(1-(4-chlorophenyl)butylidene)hydrazine-1-carboximidamide hydrochloride (NCL233);
(E)-2-(1-(4-chlorophenyl)propylidene)hydrazine-1-carboximidamide (NCL234);
(E)-2-(4-chloro-2-fluorobenzylidene)hydrazine-1-carboximidamide (NCL235);
(E)-2-(1-(4-chloro-2-fluorophenyl)ethylidene)hydrazine-1-carboximidamide (NCL236);
(E)-2-(1-(4-chloro-2-hydroxyphenyl)-2-cyclohexylethylideneamino)guanidine (NCL237);
4,6-bis(2-((E)-(6-chloropyridin-3-yl)methylene)hydrazinyl)pyrimidin-2-amine (NCL238);
4,6-bis(2-((E)-pyridin-3-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL239);
4,6-bis(2-((E)-pyridin-2-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL240);
4,6-bis(2-((E)-pyridin-4-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL241);
4,6-bis(2-((E)-2,5-dihydroxybenzylidene)hydrazinyl)pyrimidin-2-aminium 2-formyl-4-hydroxyphenolate (NCL242);
4,6-bis(2-((E)-3,4-dihydroxybenzylidene)hydrazinyl)pyrimidin-2-amine (NCL243);
4,6-bis(2-((E)-2,3-dihydroxybenzylidene)hydrazinyl)pyrimidin-2-aminium 2-formyl-6-hydroxyphenolate (NCL244);
4,6-bis(2-((E)-naphthalen-1-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL245);
4,6-bis(2-((1E,2E)-3-phenylallylidene)hydrazinyl)pyrimidin-2-amine (NCL246);
4,6-bis(2-((E)-3,4,5-trihydroxybenzylidene)hydrazinyl)pyrimidin-2-amine (NCL247);
(E)-2-(naphthalen-1-ylmethylideneamino)guanidine (NCL248);
(E)-2-((E)-3-phenylallylideneamino)guanidine (NCL249);
(1E,1′E)-N,N′-(ethane-1,2-diyl)bis(1-(4-chlorophenyl)methanimine) (NCL250);
(1E,1′E)-N,N′-(butane-1,4-diyl)bis(1-(4-chlorophenyl)methanimine) (NCL251);
(1E,1′E)-N,N′-(propane-1,3-diyl)bis(1-(4-chlorophenyl)methanimine) (NCL252);
(E)-2-(4-(dimethylamino)benzylideneamino)guanidine (NCL253);
(E)-2-(1-(4-chlorophenyl)hexylidene)hydrazine-1-carboximidamide hydrochloride (NCL254);
4,6-bis(2-((E)-[1,1′-biphenyl]-4-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL255);
4,6-bis(2-((E)-2,4-dihydroxybenzylidene)hydrazinyl)pyrimidin-2-amine (NCL256);
(E)-2-((2-hydroxynaphthalen-1-yl)methylene)hydrazine-1-carboximidamide hydrochloride (NCL257);
N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine (NCL258);
(E)-2-(1-(4-chlorophenyl)-2-cyclohexylethylidene)hydrazine-1-carboximidamide hydrochloride (NCL259);
N1,N2-bis(4-chlorobenzyl)ethane-1,2-diamine (NCL260);
(E)-2-(naphthalen-2-ylmethylene)hydrazine-1-carboximidamide hydrochloride (NCL261);
4,6-bis(2-((E)-3-phenylpropylidene)hydrazinyl)pyrimidin-2-amine (NCL262);
(E)-2-(2-fluoro-4-(trifluoromethyl)benzylidene)hydrazine-1-carboximidamide hydrochloride (NCL263);
4,6-bis(2-((E)-naphthalen-2-ylmethylene)hydrazinyl)pyrimidin-2-amine (NCL264);
(E)-2-(1-(4-chlorophenyl)-octylideneamino)guanidine (NCL265);
(E)-2-(1-(4-chlorophenyl)-3-cyclopentylpropylideneamino)guanidine (NCL266);
(E)-4-chloro-6-(2-(4-chlorobenzylidene)hydrazinyl)pyrimidin-2-amine (NCL267);
(E)-4-chloro-6-(2-(4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine (NCL268);
(Z)-2-(1-(1H-indol-3-yl)ethylidene)hydrazinecarboximidamide (NCL269);
2,2′-Bis(1-(1H-indol-3-yl)ethylidine)hydrazidecarboximidamide (NCL270);
2,2′-Bis(1-(4-chlorophenyl)hexylidene)hydrazidecarboximidamide (NCL271);
2,2′-Bis(1-(4-chlorophenyl)octylidene)hydrazidecarboximidamide (NCL272);
2,2′-Bis(1-(4-chlorophenyl)-3-cyclopentylpropylidene)hydrazidecarboximidamide (NCL273);
2,2′-Bis((1H-indol-3-yl)methylene)hydrazine carboximidamide (NCL274);
and
2,2′-Bis(1-(4-chlorophenyl)-2-ethoxyethylidene)hydrazidecarboximidamide (NCL275).

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/508,266Filed 28 Aug 2015
Priority: AU 20149035032 Sep 2014
Published: 12 Oct 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification44 codes

C07D 333/58
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring: radicals…
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/0053
Galenical forms characterised by the site of application: mouth and digestive tract, i.e. intraoral and peroral administration

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US 10,392,363 B2Related patent
US 2017/0291886 A1This patent

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Abstract

wherein R1 is H, cycloalkyl, Formula II, or Formula III;
wherein R3 is selected from the group consisting of:
H;
NH2;
NHNH2;
O—CH2—CH3;
NH—C(O)-phenyl;
NH—CH-chlorophenyl;
NH-chlorophenyl;
NH—CH2-chlorophenyl;
NH—N—CH-cycloalkyl;
N and R4 is CH—N—CH—CCl— and R4 is bonded to R3;
Formula IV;
Formula V;
and Formula VI;
wherein A0 is N, C, CH, or A0 is C and A0 is bonded to R4 to form a triazole ring;
wherein A1 is N, C, NH, —(CH)2—N—, —(C6H5)C—CH—N—, or Formula VII;
A2 is N, C, NH, N—C(O)-phenyl or Formula VII, or (CH2)n wherein n is an integer between 1 and 3, inclusive;
wherein A3, A4, A5, A6, A7, A8, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21 A23, A24, A25, A26 and A27 are independently C, O, N, NH, S;
wherein A9 is C, O, N, NH, N—C(O)—O—CH2—CH3, N—C(O)—O—CH(CH3)2, N—C(O)—NH—CH2—CH3, N—C(O)—NH—CH2-phenyl, N—C(O)—CH2—CH2—CH2—CH2—CH2—CH3, N—C(O)—CH2-furan-2-yl;
wherein A10 is C, NH, —N—(CH)2—, —N—CH—C(C6H5)—;
wherein A22 is —CH(CH3)—, —N—CH—, —N—C(CH3)—, N—C(CH2OH)—;
R2 is H, COOH, CH2NH2, CH2OH, CH2NHNH2, methyl, ethyl, propyl, butyl, pentyl, heptyl, cyclopentyl, CH2(Cyclohexyl), (CH2)2(cyclopentyl) or Formula VII and R2 are R4 are bonded together to form a pyrimidine, pyrazine or triazine ring, or R2 and R9 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R4 is H2, N, NH, O, S, or R4 and A0 are bonded together to form a triazole ring, or R4 is N and R4 and R2 are bonded together to form a pyrimidine ring;
wherein R7 is H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CCH, CF3, OCF3, SCF3, NO2, butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R7 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R6, R8, R14, R16, R25 and R27 are independently H, OH, Cl, F, Br, CH3, CN, OCH3, COOH, NO2, CF3, R8 and R7 bond together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring, or benzene ring, R14 and R15 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, R8 and R9 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R14 and R13 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R5, R9, R17, R24 and R28 are independently H, O, OH, Cl, F, Br, NH2, CH3, CF3, OCH3, CN, NO2, phenyl, —NH—CH(OH)—CH3, —NH—C(O)—CH3, or R9 and R8 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R13 and R14 are bonded together to form a substituted or unsubstituted saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R10, R11, R19, R20, R22 and R23 are independently H, Cl, or Br, or R10 and R11 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R19 and R20 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring, or R22 and R23 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
wherein R12, R18 and R21 are independently H, COOH, CH2NH2, CH2OH, methyl, ethyl, propyl, butyl, cyclopentyl, or R12 and R13 are bonded together to form a pyrrolidinyl oxindole ring;
wherein R15 and R26 are independently H, Cl, Br, F, OH, CH3, OCH3, SCH3, CN, CF3, OCF3, SCF3, NO2, CCH, n-butyl, t-butyl, dimethylamino, phenyl, n-propyl, i-propyl, —NH—C(O)—CH3, —(CH)2—COOH, piperazin-1-yl, or R15 and R14 are bonded together to form a substituted or unsubstituted, saturated or unsaturated aliphatic ring, heterocyclic ring or benzene ring;
and
wherein “” is a double bond or a single bond.

29 more elements

Facts

Application

15/508,266Filed 28 Aug 2015

Priority

AU 20149035032 Sep 2014

Published

12 Oct 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification44 codes

C07D 333/58
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring: radicals…
A61K 9/0014
Galenical forms characterised by the site of application: skin, i.e. galenical aspects of topical compositions
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/0053
Galenical forms characterised by the site of application: mouth and digestive tract, i.e. intraoral and peroral administration