IP Library › Granted Patent US 8,981,114

Granted Patent B2

US 8,981,114 · App. 14/307,272 · Granted Mar 17, 2015

Derivatives of 1-(substituted sulfonyl)-2-aminoimidazoline as antitumor and antiproliferative agents

Inventors: Stanislaw Wieslaw Pikul (Jaslo, PL); Wieslaw Marek Cholody (Frederick, MD)

C07D403/12 C07D405/14 A61K31/4178 A61K45/06 C07C247/06 C07D401/14 A61K31/454 C07D409/14 C07D403/14 A61K31/506 A61K31/4439 A61K31/4709

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Quick Facts

Patent No.: US 8,981,114
App. No.: 14/307,272
Granted: Mar 17, 2015
Kind: B2

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Abstract

The invention provides novel, water-soluble 2-aminoimidazoline derivatives having general Formula (I) as well as some precursors of Formula (I), which are very potent inducers of G2/M cell cycle arrest. In treated tumor cells, compounds of Formula (I) give gene expression profile distinct from known antimitotic agents. The invention also provides methods for preparing the compounds, and methods of using the compounds for the treatment of cancer or other mammalian diseases characterized by undesirably high levels of cell proliferation. The compounds of the invention are also expected to have utility as research tools.

Claims (125)

1. A compound having a structure according to Formula (I),

wherein:

R 1 is

a substituted or unsubstituted alkyl; or

a substituted or unsubstituted aryl or heteroaryl;

in either S or R configuration;

R 2 is

(a) a substituted or unsubstituted alkyl;

(b) a substituted or unsubstituted phenyl;

(c) a 5- or 6-membered, optionally substituted, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

(d) a saturated or unsaturated fused ring carbocyclic group, optionally substituted, having from 8 to 10 ring atoms;

(e) a saturated or unsaturated fused ring heterocyclic group, optionally substituted, having from 8 to 10 ring atoms including one to three heteroatoms selected from nitrogen, oxygen and sulfur;

X is a hydrogen atom, carbonyl, thiocarbonyl or imine,

If X is a hydrogen atom then R 3 is null,

If X is not hydrogen then R 3 is:

(a) a substituted or unsubstituted linear, branched or cyclic alkyl which additionally can be connected to an aromatic or heterocyclic moiety,

(b) a substituted or unsubstituted phenyl,

(c) a 5- or 6-membered, saturated or unsaturated heterocyclic group, optionally substituted, having from one to three heteroatoms selected from nitrogen, oxygen and sulfur;

(d) NR'(CH 2 ) n R″ where

R′ is hydrogen or alkyl,

n is 0-3,

R″ is unsubstituted or substituted alkyl, cycloalkyl, phenyl, benzyl, a 5- or 6-membered, optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and

R′ and R″ can be connected or not,

(e) O(CH 2 ) n R″ or S(CH 2 ) n R″ where R″ and n are as defined above,

or a tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof.

2. A compound according to claim 1 , wherein R 1 is unsubstituted or substituted alkyl, cycloalkyl, aryl, benzyl, 5- or 6-membered heterocycle, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, with all of them optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups.

3. A compound according to claim 1 , wherein R 1 is attached to the 4,5-dihydro-1H-imidazole ring with S stereochemistry.

4. A compound according to claim 3 , wherein R 1 is phenyl optionally substituted with lower alkyl, halide or alkoxy groups.

5. A compound according to claim 1 , wherein R 2 is a heterocyclic moiety having more than 6 carbon atoms and one or more nitrogen, sulfur and/or oxygen atoms; the moieties may contain the atoms in a single ring or in fused rings and may be saturated or unsaturated and additionally substituted with amino or carboxy groups.

6. A compound according to claim 5 , wherein R 2 is indolyl, quinolyl, chromanyl, benzimidazolyl, benzoxazolyl, benzothienyl, benzofuranyl, or quinolinyl.

7. A compound according to claim 5 , wherein R 2 is indolinyl and X represents carbonyl moiety attached at position 1.

8. A compound according to claim 1 , wherein R 3 is unsubstituted or substituted alkyl, heteroalkyl, aryl, benzyl, 5- or 6-membered heterocycle, saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, with all of them optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups.

9. A compound according to claim 1 , wherein R 3 is:

a. alkoxy, alkylthio, aryloxy or arylthio group optionally having 1-3 substituents selected from halo, alkyl, alkenyl, alkynyl, hydroxy, amino and alkoxy groups.

b. NR'(CH 2 ) n R″ wherein R′ is hydrogen or alkyl; n is 0-3; R″ is hydroxy or amino group, unsubstituted or substituted alkyl, phenyl, benzyl, a 5- or 6-membered, optionally substituted saturated or unsaturated heterocyclic group having from one to three heteroatoms selected from nitrogen, oxygen and sulfur, and R′ and R″ can be connected or not.

10. A compound according to claim 1 , wherein R 3 is NH(CH 2 ) n R′″; n is 0-3;

R′″ is lower alkyl, branched lower alkyl or cycloalkyl ring containing 3-7 carbon atoms.

11. A compound according to claim 1 , selected from the group consisting of:

(S)-4-phenyl-1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-N-methylamino-phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-N-acetyl-N-methylamino)-phenylsulfonyl-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[4-(2-furanoylamino)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[4-(1-pyrrolidin-2-onyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine, and

(S)-4-phenyl-1-[4-(1-pyrrolidine-2,5-dionyl)-phenylsulfonyl]-4,5-dihydro-1H-imidazol-2-amine, or a tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof.

12. A compound according to claim 1 , selected from the group consisting of:

(S)-4-phenyl- 1-((N-1-methyl- 1H-pyrrol-2-yloyl)indoline-5-sulfonyl)-4,5-dihydro- 1H-imidazol-2-amine,

(S)-4-phenyl-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-(5-(2-amino-4-isopropyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-yl) methanone,

(S)-(5-(2-amino-4-cyclohexyl-4,5-dihydro-1H-imidazol-1-ylsulfonyl)indolin-1-yl)(furan-2-y) methanone,

(S)-4-phenyl-1-(thiophene-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(acetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(propionylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(butyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(isobutyrylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(thiophen-2-ylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(benzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-nitrobenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(4-dimethylaminobenzoyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(4-ethoxybenzoylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(phenylacetylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(methoxycarbonylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-acetyl-piperidin-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-(cyclohexanyloyl-indoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(naphthalen-4-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(pyridin-3-yloyl)-indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl- 1-[(4-aminobenzoyl)-2-methylindoline-5-sulfonyl] -4,5-dihydro- 1H-imidazol-2-amine,

(S)-4-phenyl- 1-[(isopropylaminothiocarbonyl)-indoline-5-sulfonyl] -4,5-dihydro- 1H-imidazol-2-amine,

(S)-4-phenyl- 1-[1-butanoyl-3 ,4-dihydroquinoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(R)-4-phenyl- 1-[1-butanoylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-(furan-2-yloylindoline-5-sulfonyl)-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(2,4-difluorophenyl)-1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(4-chlorophenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(4-methoxyphenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(3-chlorophenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(2-chlorophenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(3-methylphenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(2-methylphenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-methyl- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H-imidazol-2-amine,

(S)-4-(3 ,5-dichlorophenyl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H -imidazol-2-amine,

(S)-4-(pyrimidin-2-yl)- 1-((1-methyl- 1H-pyrrol-2-yl)indoline-5-sulfonyl)-4,5-dihydro- 1H-imidazol -2-amine,

(S)-1-(indolin-5-ylsulfonyl)-4-phenyl-4,5-dihydro-1H-imidazol-2-amine

(S)-4-phenyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol -2-amine,

(S)-4-phenyl-1-[(3-dimethylaminopropyl-methylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol -2-amine,

(S)-4-phenyl-1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-benzylpiperidin-4-ylamino)carbonylindoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-isopropyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5--dihydro -1H-imidazol-2-amine,

(S)-4-cyclohexyl-1-[(3-dimethylaminopropylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro -1H-imidazol-2-amine,

(S)-4-phenyl-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-[(1-propylaminocarbony)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(4-methoxyphenyl)-1-[(1-propylaminocarbony)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(3-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(3-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-chlorophenyl)-1-[(1-propylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-phenyl-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(4-fluorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol -2-amine,

(S)-4-(4-methoxyphenyl)-1-[(1-butylaminocarbony)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(3-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(3-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(4-chlorophenyl)-1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-phenyl-1-[(isopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[((cyclopropylmetyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-phenyl-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-phenyl-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(tert-butylaminocarbony)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-phenyl-1-[(neopentylaminocarbony)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(cyclopropylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[((cyclopropylmetyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[((cyclopropylethyl)aminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(neopentylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

(S)-4-(2-methylphenyl)-1-[(tert-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine, and

(S)-4-(2-methylphenyl)-1-[(isobutylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H -imidazol-2-amine,

or a tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof.

13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a tautomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound of claim 1 , its salt, hydrate, or solvate thereof, together with a pharmaceutically acceptable carrier and an anti-cancer agent.

15. A compound selected from the following:

1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-amine;

1-[(2-methoxyethanamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine;

1-[(2-aminoethylamino)-carbonylindoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine; and

1-[(1-butylaminocarbonyl)indoline-5-sulfonyl]-4,5-dihydro-1H-imidazol-2-amine.

Assignments (2)

CHANGE OF NAME Recorded May 5, 2017

From: ONCOARENDI THERAPEUTICS SP. Z.O.O.

To: ONCOARENDI THERAPEUTICS SPOLKA AKCYJNA

Reel/Frame 042421/0094 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 25, 2015

From: PIKUL, STANISLAW WIESLAW; CHOLODY, WIESLAW MAREK

To: ONCOARENDI THERAPEUTICS SP. Z.O.O.

Reel/Frame 036661/0583 →

Priority Claims (1)

PL 403491 · Apr 10, 2013 · national

Continuity (4)

Continuation 14249226 · Apr 9, 2014

Continuation PCTIB2014060200 · Mar 27, 2014

Provisional Application 61810276 · Apr 10, 2013

Related Publication 20140309259A1 · Oct 16, 2014