US 6,943,191 B1Granted

Disubstituted lavendustin A analogs and pharmaceutical composition comprising the analogs

AssigneeThe United States of America as represented by the Department of Health and Human Services

InventorsVenkatachala L. Narayanan, Edward A. Sausville, Gurmeet Kaur, Ravi K. Varma

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Abstract

Disubstituted lavendustin A analogs that are PTK inhibitors having antiproliferative activity are described. Preferred compounds of the disclosure, without limitation, satisfy either Formula 1 or Formula 2. The present disclosure also provides pharmaceutical compositions comprising effective amounts of disubstituted lavendustin A analogs and potentially comprising other active ingredients, other materials conventionally used in the formulation of pharmaceutical compositions, and mixtures thereof. The compounds and compositions of the disclosure can be used for treating subjects to, for example, inhibit the proliferation of living cells in the treatment of proliferative diseases.

Claims22

Dependent claims

A compound having an in vivo biological activity of 4 or greater as measured by an IP+SC score, the compound satisfying Formula 1

where both A and B are hydrogen, X is either hydrogen or halogen, Y is a single bond and R1 is hydrogen, R2 is selected from the group consisting of aliphatic groups having from about 3 to about 16 carbon atoms, aliphatic alcohols having from about 3 to about 16 carbon atoms, aliphatic amides having from about 3 to about 16 carbon atoms, aliphatic esters having from about 3 to about 16 carbon atoms, aliphatic ketones having from about 3 to about 16 carbon atoms, and aliphatic phosphonic acid esters, and R3 is either ortho, meta or para with respect to R, and is selected from the group consisting of hydrogen, hydroxyl and halogen when at least one of A, B or X is other than hydrogen, and from the group consisting of hydrogen and halogen when A, B and X are hydrogen,
or Formula 2
where A and B independently are selected from the group consisting of hydrogen and halogen, or both are carbon atoms in an aromatic ring, X is either hydrogen or halogen, Y is either a single bond or a double bond, R is either carbon or nitrogen, R1, is hydrogen or an aliphatic group having from about 1 to about 30 carbon atoms, R2 is meta or para to R and is selected from the group consisting of amino, aliphatic amine, aliphatic alcohols, aliphatic amides, aliphatic esters, aliphatic ketones and phosphonic acid esters with the aliphatic groups comprising from about 1-30 carbon atoms, and R3 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen.

A compound according to Formula 1

where A and B independently are selected from the group consisting of hydrogen and halogen, or are carbon atoms in an aromatic ring, X is either hydrogen or halogen, Y is a single bond or a double bond, R is carbon or nitrogen, R1 is hydrogen or an aliphatic group, R2 is either meta or para to R, is sufficiently bulky to maintain in vivo biological activity, and is selected from the group consisting of amino, aliphatic amines, aliphatic alcohols, aliphatic amides, aliphatic phosphonic acid esters, the aliphatic groups comprising from 1 to about 30 carbon atoms, aliphatic esters having from 3 to about 30 carbon atoms and aliphatic ketones having from 3 to about 30 carbon atoms, and R3 is either ortho, meta or para with respect to R, and is selected from the group consisting of hydrogen, hydroxyl and halogen when at least one of A, B or X is other than hydrogen, from the group consisting of hydroxyl and halogen when R2 is an amino group para to R and A, B and X are hydrogen, and from the group consisting of hydrogen and halogen when A, B and X are hydrogen, or Formula 2
where A and B independently are selected from the group consisting of hydrogen and halogen, or both are carbon atoms in an aromatic ring, X is either hydrogen or halogen, Y is either a single bond or a double bond, R is either carbon or nitrogen, R1 is hydrogen or an aliphatic group having from about 1 to about 30 carbon atoms, R2 is meta or para to R and is selected from the group consisting of amino, aliphatic amine, aliphatic alcohols, aliphatic amides, aliphatic esters, aliphatic ketones and phosphonic acid esters with the aliphatic groups consisting of from about 1-30 carbon atoms, and R3 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen;
where, with respect to Formula 1, R2 includes a carbonyl.

A pharmaceutical composition, comprising:

an amount of a compound effective to inhibit the proliferation of cells in a subject, the compound having an in vivo biological activity of 4 or greater as measured by an IP+SC score, the compound satisfying Formula 1
where A and B independently are selected from the group consisting of hydrogen and halogen, or are carbon atoms in an aromatic ring, X is either hydrogen or halogen, Y is either a single bond or a double bond, R is carbon or nitrogen, R1 is hydrogen or an aliphatic group, R2, is either meta or para to R and is selected from the group consisting of amino, aliphatic amine, aliphatic alcohols, aliphatic amides, aliphatic phosphonic acid esters, the aliphatic groups comprising from 1 to about 30 carbon atoms, aliphatic esters having from 3 to about 30 carbon atoms and aliphatic ketones having from 3 to about 30 carbon atoms, and R3 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen, or Formula 2
where A and B independently are selected from the group consisting of hydrogen and halogen, or both are carbon atoms in an aromatic ring, X is a halogen atom, Y is either a single bond or a double bond, R is either carbon or nitrogen, R1 is hydrogen or an aliphatic group having from about 1 to about 30 carbon atoms, R2 is meta or para to R and is selected from the group consisting of amino, aliphatic amine, aliphatic alcohols, aliphatic amides, aliphatic esters, aliphatic ketones and phosphonic acid esters with the aliphatic groups comprising from about 1-30 carbon atoms, and R3 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen;
wherein the compound is selected from the group consisting of 4′-adamantylbenzoate-1′-2,5-dihydroxybenzylamine, 4′-adamantylmethylbenzoate-1′-N-2,5-dihydroxybenzylamine, 5′-chloro-4′isopropylbenzoate-1′-N-2,5-dihydroxybenzylamine, 4′-(trifluoromethylethanol)-1′-N-2,5-dihydroxybenzylamine, 4′-phenylphosphonate-1-′N-2,5-dihydroxylbenzylamine, 4′isopropylbenzoate-1′-N-5-bromo-2,5-dihydroxybenzylamine, 4′-chloro-5′-methylbenzoate-1′-N-3-bromo-2,5-dihydroxybenzylamine, 5′-hydroxy-4′-methylbenzoate-1′-N-5-bromo-2,5-dihydroxybenzylamine, 3′-hydroxy-4′-methylbenzoate-1′-N-p-quinone-2-methyl amine, 4′-isopropylbenzoate-1′-N-p-quinone-2-methyl amine, 4′-adamantylbenzoate-1′-N-p-quinone-2-methyl amine, 4′-adamantylbenzoate-1′-N-2-bromo-p-quinone-3-methyl amine, 4′-t-butylbenzoate-1′-N-2-bromo-p-quinone-3-methyl amine, 3′-chloro-4′-methylbenzoate-1′-N-2-bromo-p-quinone-3-methyl amine, 3′-chloro-4′-isopropylbenzoate-1′-N-p-quinone-2-methyl amine and mixtures thereof;
and
a material selected from the group consisting of inert carriers, excipients, diagnostics, direct compression binders, buffers, solvents, stabilizers, fillers, disintegrants, flavors, colors, lubricants, other active ingredients, other materials conventionally used in the formulation of pharmaceutical compositions, and mixtures thereof.

3 more elements

A method for inhibiting the proliferation of living cells in a subject, comprising:

providing a compound, or a composition comprising the compound, having an in vivo biological activity of 4 or greater as measured by an IP+SC score, the compound satisfying Formula 1
where A and B independently are selected from the group consisting of hydrogen and halogen, or are carbon atoms in an aromatic ring, X is either hydrogen or halogen, Y is a single bond or a double bond, R is carbon or nitrogen, R1 is hydrogen or an aliphatic group, R2 is either meta or para to R and is selected from the group consisting of amino, aliphatic amines, aliphatic alcohols, aliphatic amides, aliphatic ketones aliphatic phosphonic acid esters, the aliphatic groups comprising from 1 to about 30 carbon atoms, and aliphatic esters having from 3 to about 30 carbon atoms, and R3 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen, or Formula 2
where A and B independently are selected from the group consisting of hydrogen and halogen, or both are carbon atoms in an aromatic ring, X is a halogen atom, Y is either a single bond or a double bond, R is either carbon or nitrogen, R1 is hydrogen or an aliphatic group having from about 1 to about 30 carbon atoms, R2 is meta or para to R and is selected from the group consisting of amino, aliphatic amine, aliphatic alcohols, aliphatic amides, aliphatic esters, aliphatic ketones and phosphonic acid esters, with the aliphatic groups comprising from about 1-30 carbon atoms, and R1 is either ortho, meta or para to R and is selected from the group consisting of hydrogen, hydroxyl and halogen;
and
administering an effective amount of the compound, or composition comprising the compound, to the subject to inhibit the proliferation of living cells in the subject.

2 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/623,000Filed 24 Feb 1999 · us provisional application
Priority: 27 Feb 1998
Granted: 13 Sep 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07C 229/60
With amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring: with amino and carboxyl groups bound in…
A61P 35/00
Antineoplastic agents
C07C 69/94
Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring: of polycyclic hydroxy carboxylic acids,…
C07C 69/95
Esters of carboxylic acids; Esters of carbonic or haloformic acids: esters of quinone carboxylic acids