# US 8,772,502 B2 · Alkylsulfinyl-substituted thiazolide compounds

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- Number: US 8,772,502 B2
- Document ID: US8772502B2
- Status: Granted
- Kind: B2
- Application number: 13/284,242
- Filed: 2011-10-28
- Published: 2012-05-03
- Granted: 2014-07-08
- Earliest claimed: 2010-11-01
- Assignees: Romark Laboratories L.C.
- Applicants: J. Edward Semple; Jean-Francois Rossignol
- Inventors: J. Edward Semple; Jean-Francois Rossignol
- Web page: https://patentgrep.com/patent/US8772502B2

## CPC

- C07D 277/54: Nitrogen and either oxygen or sulfur atoms
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A new class of alkylsulfinyl thiazolides is described. These compounds show strong activity against hepatitis viruses.

## Claims

### Claim 1

A compound of structural Formula (1):
and pharmaceutically acceptable salts thereof,
wherein R1 is selected from the group consisting of hydrogen and Q-C(═O)—, any of which may be optionally substituted;
R2 to R5 are independently selected from the group consisting of hydrogen, D, hydroxy, F, Cl, Br, CN, NO2, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl, amino, (C1-C6)-acylamino, amido, (C1-C6)-alkylamido, (C1-C6)-dialkylamido, (C1-C6)-alkylsulfonylamino, (C1-C6)-haloalkyl, (C1-C6)-perhaloalkyl, (C1 -C6)-perhaloalkoxy, (C1-C6)-alkyithio, (C1-C6)-alkylthioalkyl, (C1-C6)-alkylsulfonyl, (C3-C8)-cycloalkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, (C1-C6)-alkylsulfonamido, N,N′-(C1-C6)-dialkylsulfonamido, aryl, aryloxy, arylthio, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylalkylthio, heterocycloalkyl, heterocycloalkoxy, and Q-C(═O)— , any of which may be optionally substituted; or any two contiguous R1, R2 or R3 moieties may be combined together with the atoms to which they are attached and joined to form an optionally substituted 5-to 8-membered heterocycloalkyl ring;
wherein when one of R6 or R7 is hydrogen, the other is independently selected from the group consisting of (C1-C6)-alkylsulfinyl, (C1-C6)alkylsulfinyalkyl, (C2-C6)-alkenylsulfinyl, (C2-C6)-alkynylsulfinyl, (C3-C8)-cycloalkylsulfinyl, (C5-C8)-cycloalkenylsulfinyl, arylsulfinyl, arylalkylsulfinyl, arylalkenylsulfinyl, heteroarylsulfinyl, heteroarylalkylsulfinyl, heteroarylalkenylsulfinyl, and heterocycloalkylsulfinyl, any of which may be optionally substituted; or the R6 and R7 moieties may be combined together with the atoms to which they are attached and joined to form an optionally substituted 5-to 8-membered ring that incorporates a sulfinyl (—S[O]—) moiety; and
wherein Q is R8, OR8, NHR8, or NR8R9; R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C2-C12)-alkynyl, (C3-C8)-cycloalkyl, aryl, arylalkyl, arylalkenyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, any of which may be optionally substituted; or R8 and R9, together with the atoms to which they are attached, may be joined to form an optionally substituted 5-to 8-membered heterocycloalkyl ring; any of which may be optionally substituted.

### Claim 2 (depends on 1)

The compound according to claim 1,
R2 to R5 are independently selected from the group consisting of hydrogen, D, hydroxy, F, Cl, Br, CN, NO2, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1 -C6)-alkoxycarbonyl, (C1-C6)dialkylamido, (C1-C3)-haloalkyl, (C1-C4)-perhaloalkyl, (C1-C4)-perhaloalkoxy, (C1-C6)-alkylthio, (C1-C6)-alkylsulfonyl, (C3-C6)-cycloalkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heterocycloalkyl, and heterocycloalkoxy, any of which may be optionally substituted;
wherein when one of R6 or R7 is hydrogen, the other is independently selected from the group consisting of (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfinylalkyl, (C3-C8)-cycloalkylsulfinyl, (C5-C8)-cycloalkenylsulfinyl, arylsulfinyl, arylalkylsulfinyl, heteroarylsulfinyl, heteroarylalkylsulfinyl, and heterocycloalkylsulfinyl, any of which may be optionally substituted; or the R6 and R7 moieties may be combined together with the atoms to which they are attached and joined to form an optionally substituted 5- to 7-membered ring that incorporates a sulfinyl (—S[O]—) moiety; and
wherein Q is R8, OR8, NHR8, or NR8R9; R8 and R9 are independently selected from the group consisting of hydrogen, (C1-C12)-alkyl, (C2-C12)-alkenyl, (C3-C8)-cycloalkyl, aryl, arylalkyl, arylalkenyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, and heteroarylalkenyl, any of which may be optionally substituted; or R8 and R9, together with the atoms to which they are attached, may be joined to form an optionally substituted 5-to 7-membered heterocycloalkyl ring; any of which may be optionally substituted.

### Claim 3 (depends on 2)

The compound according to claim 2,
wherein R2 to R5 are independently selected from the group consisting of hydrogen, D, F, Cl, Br, CN, (C1-C6)-alkyl (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkyl, (C1-C4)-perhaloalkyl, (C1-C4)-perhaloalkoxy, (C1-C6)-alkyithio, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycloalkyl, and heterocycloalkoxy, any of which may be optionally substituted: and
wherein R7 is hydrogen and R6 is independently selected from the group consisting of (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfinylalkyl, (C3-C6)-cycloalkylsulfinyl, arylsulfinyl, arylalkylsulfinyl, heteroarylsulfinyl, heteroarylalkylsulfinyl, and heterocycloalkylsulfinyl, any of which may be optionally substituted; or the R6 and R7 moieties may be combined together with the atoms to which they are attached and joined to form an optionally substituted 5- to 7-membered ring that incorporates a sulfinyl (—S[O]—) moiety.

### Claim 4 (depends on 3)

The compound according to claim 3,
wherein R2 to R5 are independently selected from the group consisting of hydrogen, D, F. Cl, Br, CN, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkyl, (C1-C4)-perhaloalkyl, (C1-C4)-perhaloalkoxy, and (C1-C6)-alkylthio, any of which may be optionally substituted.

### Claim 5 (depends on 4)

The compound according to claim 4,
wherein R1 is selected from the group consisting of hydrogen, and Q is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-1-propyl, sec-butyl, tert-butyl, 2,3-dimethylbutan-2-yl, cyclohexyl, 2,6-dimethylcyclohexyl, 1-methylcyclohexyl, phenyl, 4-pyridyl, benzyl, 4-pyridylmethyl, phenylethyl, (S)-1-hydroxy-(phenylethyl), 2-pyrazinyl, phenyethenyl, (E)-2-(4-pyridazinyl)-1-ethenyl, (E)-4-(2-)-1H-imidazolyl-1-ethenyl, 3-acetoxyl-1-propyl, ethoxycarbonylethyl, methoxylcarbonylpropyl, N-methylaminocarbonylethyl, N-ethylaminocarbonylpropyl, 3-(N-ethylaminocarbonyl)-2,2-dimethyl-1-propyl, N-(morpholinoethyl)aminocarbonylethyl, 3-pyridylmethylaminocarbonylethyl, 4-pyridylmethylaminocarbonylethyl, 4-pyridylmethylaminocarbonylpropyl, carboxyethyl, carboxypropyl, 2-piperidinyl,3-piperidinyl, 4-piperidinyl, 2-piperazinyl, (S)-1-aminoethyl, (R)-1-aminoethyl, (S)-1-aminoisobutyl, 1-aminocyclopropyl, methoxy, ethoxy, isopropoxy, isobutoxy, neopentyloxy, cyclohexyloxy, 4-piperdinyloxy,3-acetoxy-2methyl-1-propoxy, tert-pentyloxy, 4-acetoxybenzyloxy, 3-(4-acetoxyphenyl)-2-propenyloxy, (E)-2-methyl-4-(2-oxo-2,3-dihydrobenzofuran-5-yl)but-3-en-2-yloxy, pivaloyloxymethoxy, pivaloyloxy-1-ethoxy, isopropoxycarbonyloxymethoxy, isopropoxycarbonyloxy-1-ethoxy, amino, N-methylamino, N-ethylamino N,N-dimethylamino, N-propylamino, N-isopropylamino, N-butylamino, N-piperidinyl, N-piperazinyl, N-4methylpiperazinyl, N-cyclohexylamino, N-benzylamino, N-(2,4-dimethoxy)benzylamino, 2-(N-methylcarboxamido)phenylamino, N-methyl-2-hydroxyethylamino, N1,N2-dimethyl-1,2-ethanediamin-1yl, N1, N2-diethyl-1,2-ethanediamin-1-yl, N1,N2-dimethyl-1,3-propanediamin-1-yl, and N1-methyl-N2-(2-morpholinoethyl)-1,2-ethanediamin-1-yl.

### Claim 6 (depends on 5)

The compound according to claim 5,
wherein R2 to R5 are independently selected from the group consisting of hydrogen, D, F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, n-hexyl, cyclopropyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, tetrafluroethoxy, methylthio, and t-butylthio, any of which may be optionally substituted; and
wherein R6 is selected from the group consisting of methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfinylmethyl, 2-(ethylsulfinyl)ethyl, t-butylsulfinylmethyl, cyclopropylsulfinyl, cyclopentylsulfinyl, phenylsulfinyl, benzylsulfinyl, phenethylsulfinyl, 2-pyridylsulfinyl, 2-pyrazinylsulfinyl, 4-thiazolylsulfinyl, 4-pyridylmethylsulfinyl, 3-thienylmethylsulfinyl, 4-piperidinylsulfinyl, tetrahydro-2H -pyranylsulfinyl, any of which may be optionally substituted.

### Claim 7 (depends on 6)

The compound according to claim 6,
wherein R1 is selected from the group consisting of hydrogen and R8 and R9in Q-C(═O)— is selected from the group consisting of methyl, ethyl, ethoxy, isopropoxy, isobutoxy, phenyl, phenylethenyl, 4-piperidinyl, N-piperazinyl, N-(2,4-dimethoxy)benzylamino, 2-(N-methylcarboxamido)-phenylamino, N1, N2-dimethyl-1,2-ethanediamin-1-yl, N1,N2-dimethyl-1,2-ethanediamin-1-yl, N1,N2-dimethyl-1,3-propanediamin-1-yl, and N1-methyl-N2-(2-morpholinoethyl)-1,2-ethanediamin-1-yl;
wherein R2 to R5 are independently selected from the group consisting of hydrogen, F, Cl, methyl, ethyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl and methylthio, any of which may be optionally substituted; and
wherein R6 is selected from the group consisting of methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfinylmethyl, t-butylsulfinylmethyl, cyclopropylsulfinyl, and benzylsulfinyl.

### Claim 8 (depends on 7)

The compound according to claim 7,
wherein R1 is selected from the group consisting of hydrogen and Q-C(═O)— , where R8 is methyl;
wherein R2 through R5 are hydrogen; and
wherein R6 is methylsulfinyl.

### Claim 9 (depends on 2)

The compound according to claim 2,
wherein to R2 to R5 are independently selected from the group consisting of hydrogen, D, F, Cl, Br, CN, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkyl, (C1-C4)-perhaloalkyl, (C1-C4)-perhaloalkoxy, (C1-C6)-alkylthio, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycloalkyl, and heterocycloalkoxy, any of which may be optionally substituted; and
wherein R6 is hydrogen and is independently selected from the group consisting of (C1-C6)alkysulfinyl, (C1-C6)-alkysulfinylalkyl, (C3-6)-cycloalkylsulfinyl, arylsulfinyl, arylalkylsulfinyl, heteroarylsulfinyl, heteroarylalkylsulfinyl, and heterocycloalkylsulfinyl, any of which may be optionally substituted; or the R6 and R7 moieties may be combined together with the atoms to which they are attached and joined to firm an optionally substituted 5- to 7-membered ring that incorporates a sultinyl (—S[O]—) moiety.

### Claim 10 (depends on 9)

The compound according to claim 9,
wherein R2 to R5 are independently selected from the group consisting of hydrogen,D, F, Cl, Br, CN, (C1-C6)-alkyl, (C3-C6)cycloalkyl, (C1-C6)-alkoxy, (C1-C3)-haloalkyl, (Cl-C4)-perhaloalkyl, (C1-C4)-perhaloalkoxy, and (C1-C6)-alkylthio, any of which may be optionally substituted.

### Claim 11 (depends on 10)

The compound according to claim 10,
wherein R1 is selected from the group consisting of hydrogen, and Q is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methyl-1 -propyl, sec-butyl, tert-butyl, 2,3-dimethylbutan-2-yl, cyclohexyl, 2,6-dimethylcyclohexyl, 1-methylcyclohexyl, phenyl, 4-pyridyl, benzyl, 4-pyridylmethyl, phenylethyl, (S)-1 -hydroxy-(phenylethyl), 2-pyrazinyl, phenylethenyl, (E)-2-(4-pyridazinyl)-1-ethenyl, (E)-4-(2-)-1 H imidazolyl-1-ethenyl, 3-acetoxyl-1-propyl, ethoxycarbonylethyl, methoxylcarbonylpropyl, N-methylaminocarbonylethyl, N-ethylaminocarbonylpropyl, 3-(N-ethylaminocarbonyl)-2,2-dimethyl-1-propyl, N-(morpholinoethyl)aminocarbonylethyl, 3-pyridylmethylaminocarbonylethyl, 4-pyridylmethylaminocarbonylethyl, 4-pyridylmethylarninocarbonylpropyl, carboxyethyl, carboxypropyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperazinyl, (S)-1-aminoethyl, (R)-1-aminoethyl, (S)-1 -aminoisobutyl, 1-aminocyclopropyl, methoxy, ethoxy, isopropoxy, isobutoxy, neopentyloxy, cyclohexyloxy, 4-piperidinyloxy, 3-acetoxy-2-methyl-1-propoxy, tert-pentyloxy, 4-acetoxybenzyloxy, 3-(4-acetoxyphenyl)-2-propenyloxy, (E)-2-methyl-4-(2-oxo-2,3-dihydrobenzofuran-5-yl)but-3-en-2-yloxy, pivaloyloxymethoxy, pivaloyloxy-1-ethoxy, isopropoxycarbonyloxymethoxy, isopropoxycarbonyloxy-1-ethoxy, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N-propylamino, N-isopropylamino, N-butylamino, N-piperidinyl, N-piperazinyl, N-4-methylpiperazinyl, N-cyclohexylamino, N-benzylamino, N-(2,4-dimethoxy)benzylamino, 2-(N-methylcarboxamido)phenylamino, N-methyl-2-hydroxyethylamino, N1,N2-dimethyl-1,2-ethanediamin-1-yl, N1,N2diethyl-1 ,2-ethanediamin-1-yl, N1,N2-dimethyl-1,3-propanediamin-1-yl, and N1-methyl-N2-(2-morpholinoethyl)-1,2-ethanediamin-1-yl.

### Claim 12 (depends on 11)

The compound according to claim 11,
wherein R2 to R5 are independently selected from the group consisting of hydrogen, D, F, Cl, CN, methyl, ethyl, n-propyl, isopropyl, n-hexyl, cyclopropyl, merhoxy, ethoxy, isopropoxy, trifluoromethyl, tetrafluoroethoxy, methylthio, and t-butylthio, any of which may be optionally substituted; and
wherein R7 is selected from the group consisting of methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfinylmethyl, 2-(ethylsulfinyl)ethyl, t-butylsulfinylmethyl, cyclopropylsulfinyl, cyclopentylsulfinyl, phenylsulfinyl, benzylsulfinyl, phenethylsulfinyl, 2-pyridylsulfinyl, 2-pyrazinylsulfinyl, 4-thiazolylsulfinyl, 4-pyridylmethylsulfinyl, 3-thienylmethylsulfinyl, 4-piperidinylsulfinyl, and tetrahydro-2H -pyranylsulfinyl, any of which may be optionally substituted.

### Claim 13 (depends on 12)

The compound according claim 12,
wherein R1 is selected from the group consisting of hydrogen and R8 and R9 in Q-C(═O )— is selected from the group consisting of methyl, ethyl, ethoxy, isopropoxy, isobutoxy, phenyl, phenylethenyl, 4-piperidinyl, N-piperazinyl, N-(2,4-dimethoxy)benzylamino, 2-(N-methylcarboxamido)-phenylamino, N1,N2-dimethyl-1,2-ethanediamin-1-yl, N1,N2-diethyl- ,1,2-ethanediamin-1-yl, N1,N2-dimethyl-1,3-propanediamin-1-yl, and N1-methyl-N2-(2-morpholinoethyl)-1,2-ethanediamin-1-yl ;
wherein R2 to R5 are independently selected from the group consisting of hydrogen, F, Cl, methyl, ethyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl and methylthio, any of which may be optionally substituted; and
wherein R7 is selected from the group consisting of methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, methylsulfinylmethyl, t-butylsulfinylmethyl, cyclopropylsulfinyl, and benzylsulfinyl.

### Claim 14 (depends on 13)

The compound according to claim 13,
wherein R1 is selected from the group consisting of hydrogen and Q-C(═O)— , where R8 is methyl;
wherein R2 through R5 are hydrogen; and
wherein R7 is methylsulfinyl.

### Claim 15

A compound selected from the group consisting of:

### Claim 16

A compound selected from the group consisting of:

### Claim 17 (depends on 1)

The compound according to claim 1,
wherein the salt is selected from the group consisting of acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate, undecanoate, lithium, sodium, calcium, potassium, aluminum, ammonium, tetraethylammonium, methylammonium, dimethylammonium, N-methylmorpholinium and ethanolammonium.