# US 2014/0194640 A1 · Quaternary n-(halomethyl) ammonium salts as therapeutic agents

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- Number: US 2014/0194640 A1
- Document ID: US20140194640A1
- Status: Published application
- Kind: A1
- Application number: 13/484,233
- Filed: 2012-05-30
- Published: 2014-07-10
- Earliest claimed: 2012-05-30
- Assignees: Universidad de Caldas; Universidad de Antioquia; The Board of Trustees of Illinois State University
- Inventors: Luz Amalia Rios Vasquez; Rogelio Ocampo Cardona; Sandra Milena Duque; Sara Maria Robledo Restrepo; Ivan Dario Velez Bernal; David Leonardo Cedeño Medina; Marjorie Ann Jones
- Web page: https://patentgrep.com/patent/US20140194640A1

## CPC

- C07C 211/63: having quaternised nitrogen atoms bound to acyclic carbon atoms
- A61K 31/14: Quaternary ammonium compounds, e.g. edrophonium, choline (betaines A61K31/205)
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/10: Anthelmintics
- C07F 7/10: containing nitrogen {having a Si-N linkage}
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The use of quaternary halogenated ammonium salts for treating leishmaniasis infections and other parasitic diseases is described. Although there have been previous reports in which quaternary ammonium salts are used as antimalarial, antifungal, and antileishmanial compounds, the use of such salts containing a halogenated N-methyl substituent as a therapeutic agent against leishmaniasis had not been reported. The compounds described here, in specific those with a terminal arylalkenyl or diarylalkenyl moiety, are shown to inhibit the growth of Leishmania panamensis parasites, a known causative agent of leishmaniasis disease. In addition, the series of compounds are also extensive against malaria, Chagas disease, toxoplasmosis, and other parasitic diseases.

## Claims

### Claim 1

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS characterized by a series of compounds with general structure consisting of the form [XCH2—N+(R)(R′)—W-G]A− a quaternary N-(halomethyl) ammonium cation head, a tail G, a chemical tether W, and a counter ion A−.

### Claim 2 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the counter ion A− is chloride (Cl−), bromide (Br−), iodide (I−), acetate (CH3COO−), tosylate (p-CH3C6H4SO3−), or any other pharmaceutically acceptable anion.

### Claim 3 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the substituents V and/or Y and/or Z correspond to hydrogen, phenyl group or any aromatic or heteroaromatic group, or any alkyl, alkenyl or alkynyl group.

### Claim 4 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the aromatic or heteroaromatic group bears hydrogen atoms or any kind and number of substituents in any place of the ring, with the aromatic substituents including hydroxyl, methoxy or any alkoxy group, O-acetyloxy or any O-acyloxy group, amino, N-acetylamino or any N-acylamino group, fluorine, chlorine, bromine, iodine, α,α,α-trifluoromethyl, any alkyl substituent, or any other pharmaceutically acceptable substituent and any substitution pattern, with a total number of substituents in the ring being zero, one, two, three, four, five or six.

### Claim 5 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because The chemical tether W is a carbon chain (CH2)n constituted by a number n of methylene units such that n=1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

### Claim 6 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because this chemical tether W is a branched hydrocarbon chain.

### Claim 7 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the series of compounds are effective against Leishmania tarentolae parasites, non-pathogenic species that are used for pre-screening processes in the promastigote stage, and axenic L. (V) panamensis and L. (L) amazonensis parasites, human pathogenic species that causes cutaneous and mucocutaneous leishmaniasis.

### Claim 8 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the kinetic studies using the choline kinase of L. (L) infantum reveal that the compound 14a is able to inhibit the enzyme, lowering its catalytic efficiency and reveal that compound 14a interferes with the in vitro uptake of choline by promastigotes of L. tarentolae and, also inhibits the in vitro production of phosphatidyl choline by these parasites.

### Claim 9 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the series of compounds for a topical treatment of cutaneous leishmaniasis on infected golden hamsters led to 100% healing of the lesion after three months of treatment.

### Claim 10 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the series of compounds that inhibit the growth of parasites with an application which is also extensive against malaria, Chagas disease, toxoplasmosis, and other parasitic diseases.

### Claim 11 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the series of compounds inhibit the growth of parasites with positive evolution of the skin lesion one month after treatment and that the tested animal is cured after three months of treatment, with a toxicity level which is tolerable by organisms and a low cost of production.

### Claim 12 (depends on 1)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 1 characterized because the series of compounds of the form [XCH2-N+(R)(R′)—W-G]A- that inhibit the growth of parasites, even though they work out with different capacities.

### Claim 13

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS characterized by a series of compounds with general structure consisting of the form [XCH2-N+(R)(R′)—W-G]A-, with the quaternary N-(halomethyl) ammonium cation head constituted by a nitrogen atom which is coordinated to four ligands with the following specific description: (i) a halomethyl group (CH2-X) where the halogen X is fluorine (F), chlorine (Cl), bromine (Br) or iodine (I); (ii) an alkyl group R, such as methyl, ethyl, n-propyl or n-butyl; (iii) another alkyl group R′, such as methyl, ethyl, n-propyl or n-butyl; (iv) a chemical tether W which joins the quaternary nitrogen head to the tail G.

### Claim 14 (depends on 13)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 13 characterized because the chemical tether W is a chain with structure —(CH2)p[-O—Si(CH3)2]q-O-(CH2)r- made of a number p of methylene units such that p=1, 2, 3, 4, and a number q of dimethylsiloxane units such that q=0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, and a number of r methylene units such that r=0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10.

### Claim 15 (depends on 13)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 13 characterized because the chemical tether W is an oxycarbonated chain with structure represented by —(CH2)s[(CH2)2-O-]t(CH2)u-, made of a number s of methylene units such that s=0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, and a number t of ethyleneoxy units such that t=0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10, and a number of u methylene units such that u=0, 1, 2, 3,4, 5, 6, 7, 8, 9, 10.

### Claim 16

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS characterized by a series of compounds with general structure consisting of the form [XCH2-N+(R)(R′)—W-G]A- where the tail G is a methyl group, a hydroxyl group, or an alkenyl system with groups V, Y and Z attached to the vinylic carbons; V, Y and Z are either the same group or different from each other when G is an alkenyl system.

### Claim 17 (depends on 16)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 16 characterized because these substituents may also be chemically connected with some others generating additional annular patterns.

### Claim 18

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS characterized by a series of compounds with general structure consisting of the form [XCH2-N+(R)(R′)—W-G]A- where the terminal arylalkenyl or diarylalkenyl (i.e. G=alkenyl system with V=H, Y=H, Z=C6H5 or V=H, Y=C6H5, Z=H or V=H, Y=C6H5, Z=C6H5) were more effective against the parasites than those without this moiety.

### Claim 19 (depends on 18)

QUATERNARY N-(HALOMETHYL) AMMONIUM SALTS AS THERAPEUTIC AGENTS according to claim 18 characterized because compounds with G being a terminal diarylalkenyl moiety (i.e. V=H, Y=C6H5, Z=C6H5) are the most effective.