# US 7,608,724 B2 · Antibacterial and/or antiprotozoal nitromidazole derivative compounds with urease inhibitor activity, process for preparing these compounds and use in pharmaceutical compositions and medicines

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- Number: US 7,608,724 B2
- Document ID: US7608724B2
- Status: Granted
- Kind: B2
- Application number: 10/577,331
- Filed: 2004-10-27
- Published: 2007-03-29
- Granted: 2009-10-27
- Earliest claimed: 2003-10-28
- Assignees: Ems S.A.
- Inventors: Antônio Silva; Andressa Munhoz; Jean Santos; Rodolfo Camargo; Lúcia Castro; Renato Menegon; Wagner Vilegas; Antonio Ferreira; Eliana Varanda; Man Chin Chung
- Web page: https://patentgrep.com/patent/US7608724B2

## CPC

- C07D 233/94: with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present application describes nitroimidazolic derivative compounds with antibacterial and/or antiprotozoal activity, which are potent urease inhibitors. It also describes the process for preparing those compounds and their use in pharmaceutical compositions and medicines.

## Claims

### Claim 1

A compound represented by the formula (I)
or its pharmaceutically acceptable salts, wherein:
R1═NO2, R2═CH3 and R3═CH2, CHCH3, CHCH2Cl OR
R1═H, R2═NO2 and R3═O(CH2)4, OCH2(CH2CH2, OCH2—C═C—CH2, CHCH2OCH3, CONH(CH2)1-2,
and
CH2CO, wherein n=1-6
R5═NHCONH2, NHCONHOH, ONHCONHOH, OCH2NHCONHCH2OH, NHCSNH2, NHCSNHOH, ONHCSNHOH, OCH2NHCSNHCH2OH, NHCNHNH2, NHCNHNHOH, ONHCNHNHOH, OCH2NHCNHNHCH2OH.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1═NO2, R2═CH3,
wherein n=1, and R5═NHCSNH2.

### Claim 3

A process for preparing a compound of the formula (I)
wherein:
R1═NO2, R2═CH3 and R3═CH2, CHCH3, CHCH2Cl
OR
R1═H, R2═NO2 and R3═O(CH2)4, OCH2(CH)2CH2, OCH2—C═C—CH2, CHCH2OCH3, CONH(CH2)1-2,
and
CH2CO, wherein n=1-6
R5═NHCONH2, NHCONHOH, ONHCONHOH, OCH2NHCONHCH2OH, NHCSNH2, NHCSNHOH, ONHCSNHOH, OCH2NHCSNHCH2OH, NHCNHNH2, NHCNHNHOH, ONHCNHNHOH, OCH2NHCNHNHCH2OH
which comprises reacting a compound of formula (III)
wherein R1, R2, R3, R4 are described above and X═OH or Cl, with an urease affinity compound selected from the group consisting of urea, N-hydroxyurea, N,N′-dihydroxyurea, bis-(hydroxymethil)urea, thiourea, N-hydroxythiourea, N,N′-dihydroxythiourea, bis-(hydroxymethyl)thiourea, guanidine, N-hydroxyguanidine, N,N′-dihydroxyguanidine and bis-(hydroxymethyl)guanidine.

### Claim 4 (depends on 3)

The process according to claim 3, wherein for X═OH the reaction with the urease affinity compound is done by using a coupling agent selected from the group consisting of N,N′-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and 1,3-diisopropyl carbodiimide (DCI).

### Claim 5 (depends on 1)

A pharmaceutical composition comprising:
a) a compound of claim 1 in an amount of at least 0.001% in weight of the final composition, and
b) at least one pharmaceutically acceptable excipient.

### Claim 6

A compound selected from the group consisting of:
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-[(aminocarbonothioyl)amino]-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-[(aminocarbonyl)amino]-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[amino(imino)methyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)carbonothioyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)carbonyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)(imino)methyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-[(aminocarbonothioyl)amino]-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-[(aminocarbonyl)amino]-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[amino(imino)methyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)carbonothioyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)carbonyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)(imino)methyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl {2-[(aminocarbonothioyl)amino]-2-oxoethoxy}acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl {2-[(aminocarbonyl)amino]-2-oxoethoxy}acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[amino(imino)methyl]amino}-2-oxoethoxy)acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)carbonothioyl]amino}-2-oxoethoxy)acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)carbonyl]amino}-2-oxoethoxy)acetate; and
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)(imino)methyl]amino}-2-oxoethoxy)acetate;
or their pharmaceutically acceptable salts.

### Claim 7 (depends on 6)

A pharmaceutical composition comprising as pharmaceutical active ingredient a compound according with claim 6, which is used in an amount of at least 0.001% in weight of the final composition, and at least a pharmaceutically acceptable ingredient.

### Claim 8

A method for treating a bacterial or parasitic infection comprising administering to a subject infected by a bacterium or parasite an effective amount of a pharmaceutical composition comprising a compound of the formula (I)
wherein:
R1═NO2, R2═CH3 and R3═CH2, CHCH3, CHCH2Cl
OR
R1═H, R2═NO2 and R3═O(CH2)4, OCH2(CH)2CH2, OCH2—C═C—CH2, CHCH2OCH3, CONH(CH2)1-2,
and
CH2CO, wherein n=1-6
R5═NHCONH2, NHCONHOH, ONHCONHOH, OCH2NHCONHCH2OH, NHCSNH2, NHCSNHOH, ONHCSNHOH, OCH2NHCSNHCH2OH, NHCNHNH2, NHCNHNHOH, ONHCNHNHOH, OCH2NHCNHNHCH2OH.

### Claim 9 (depends on 8)

The method according to claim 8, wherein in the compound of formula (I),
wherein n=1, and R5═NHCSNH2.

### Claim 10 (depends on 8)

The method according to claim 8, wherein the compound according to formula (I) is selected from the group consisting of:
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-[(aminocarbonothioyl)amino]-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-[(aminocarbonyl)amino]-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[amino(imino)methyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)carbonothioyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)carbonyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 4-{[(hydroxyamino)(imino)methyl]amino}-4-oxobutanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-[(aminocarbonothioyl)amino]-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-[(aminocarbonyl)amino]-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[amino(imino)methyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)carbonothioyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)carbonyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 5-{[(hydroxyamino)(imino)methyl]amino}-5-oxopentanoate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl {2-[(aminocarbonothioyl)amino]-2-oxoethoxy}acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl {2-[(aminocarbonyl)amino]-2-oxoethoxy}acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[amino(imino)methyl]amino}-2-oxoethoxy)acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)carbonothioyl]amino}-2-oxoethoxy)acetate;
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)carbonyl]amino}-2-oxoethoxy)acetate; and
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl (2-{[(hydroxyamino)(imino)methyl]amino}-2-oxoethoxy)acetate.

### Claim 11 (depends on 1)

The compound of claim 1 that inhibits a urease enzyme.