IP Library › Granted Patent US 7,169,784

Granted Patent B2

US 7,169,784 · App. 10/951,316 · Granted Jan 30, 2007

Medical devices employing triazine compounds and compositions thereof

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Quick Facts

Patent No.: US 7,169,784
App. No.: 10/951,316
Granted: Jan 30, 2007
Kind: B2

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Abstract

The present invention relates to methods and compositions comprising compounds that treat pathophysiological conditions arising from inflammatory responses. In particular, the present invention is directed to compounds that inhibit or block glycated protein produced induction of the signaling-associated inflammatory response in endothelial cells. The present invention relates to compounds that inhibit smooth muscle proliferation. In particular, the present invention is directed to compounds that inhibit smooth muscle cell proliferation by modulating HSPGs such as Perlecan. The present invention further relates to the use of compounds to treat vascular occlusive conditions characterized by smooth muscle proliferation such as restenosis and atherosclerosis.

Claims (149)

1. A stent comprising:

a compound disposed on or within the stent, the compound having the formula Id:

or a sterioisomer thereof or a salt thereof, wherein

G is selected from NH or O;

Z is selected from H or

wherein X 1 is selected from F or Cl, and X 2 is selected from OCH 3 , NH 2 , OC(O)CH 3 , or OH;

A is selected from NR 1 or O;

Y 1 is selected from R 1 ,

B is selected from NR 1 or O; and

Y 2 is selected from

wherein q is 0 or 1, E is selected from O or NR 2 wherein R 2 is selected from R 1 , OR 1 , C(O)R 1 , C(O)OR 1 , C(O)NH 2 , or CH 2 NH 2 ;

wherein R 3 is selected from R 1 , C(O)R 1 , C(O)OR 1 , or C(O)NH 2 ; and

wherein R 1 is in each occurrence independently selected from H, or a linear or branched alkyl with up to 10 carbon atoms.

2. The stent as claimed in claim 1 , wherein the compound is 6-(3-Chloro-4-methoxy-phenoxy)-N-cycloheptyl-N′-methyl-N′-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4-diamine,

N-Cycloheptyl-6-(3-fluoro-4-methoxy-phenoxy)-N′-methyI-N′-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4-diamine,

N-(3-Chloro-4-methoxy-phenyl)-6-cycloheptyloxy-N′-methyl-N′-(1-methylpiperidin-4-yl)-[1,3,5]triazine-2,4-diamine,

6-Cycloheptyloxy-N-(3-fluoro-4-methoxy-phenyl)-N′-methyl-N′-(1-methylpiperidin-4-yl)-[1,3,5]triazine-2,4-diamine,

N-Cycloheptyl-N′-(3-fluoro-4-methoxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-[1,3,5]triazine-2,4-diamine,

N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-6-(1-methyl-piperidin-4-yloxy)-[1,3,5]triazine-2,4-diamine,

N-Cycloheptyl-N′-(3-fluoro-4-methoxy-phenyl)-6-(piperidin-4-yloxy)-[1,3,5]triazine-2,4-diamine,

N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-6-(piperidin-4-yloxy)-[1,3,5]triazine-2,4-diamine,

(3-Chloro-4-methoxy-phenyl)-[4-cycloheptyloxy-6-(1-methyl-piperidin-4yloxy)-[1,3,5]triazin-2-yl]-amine,

[4-Cycloheptyloxy-6-(1-methyl-piperidin-4-yloxy)-[1,3,5]triazin-2-yl]-(3-fluoro-4-methoxy-phenyl)-amine,

N-Cycloheptyl-N′-(1-ethyl-pyrrolidin-2-ylmethyl)-6-(3-fluoro-4-methoxy-phenoxy)-[1,3,5]triazine-2,4-diamine,

6-(3-Chloro-4-methoxy-phenoxy)-N-cycloheptyl-N′-(1-ethyl-pyrrolidin-2ylmethyl)-[1,3,5]triazine-2,4-diamine,

6-Cycloheptyloxy-N-(1-ethyl-pyrrolidin-2-ylmethyl)-N′-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine,

N-(3-Chloro-4-methoxy-phenyl)-6-cycloheptyloxy-N′-(1-ethyl-pyrrolidin-2-ylmethyl)-[1,3,5]triazine-2,4-diamine,

N-Cycloheptyl-6-(1-ethyl-pyrrolidin-2-ylmethoxy)-N′-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4-diamine,

N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-6-(1-ethyl-pyrrolidin-2-ylmethoxy)-[1,3,5]triazine-2,4-diamine,

[4-Cycloheptyloxy-6-(3-fluoro-4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]methyl-(1-methyl-piperidin-4-yl)-diamine,

[4-Cycloheptyloxy-6-(piperidin-4-yloxy)-[1,3,5]triazin-2-yl]-(3-fluoro-4-methoxy-phenyl)-amine,

Cycloheptyl-[4-(3-fluoro-4-methoxyphenoxy)-6-(1-methyl-piperidin-4-yloxy)-[1,3,5]triazin-yl]-amine,

2-Cycloheptyloxy-4-(3-fluoro-4-methoxy-phenoxy)-6-(1-methyl-piperidin4-yloxy)-[1,3,5]triazine,

2-(3-Chloro-4-methoxy-phenoxy)-4-cycloheptyloxy-6-(1-methyl-piperidin4-yloxy)-[1,3,5]triazine,

[4-Cycloheptyloxy-6-(3-fluoro-4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-(1-ethyl-pyrrolidin-2-ylmethyl)-amine,

[4-Cycloheptyloxy-6-(1-ethyl-pyrrolidin-2-ylmethoxy)-[1,3,5]triazin-2yl]-(3-fluoro-4-methoxy-phenyl)-amine,

Cycloheptyl-[4-(1-ethyl-pyrrolidin-2-ylmethoxy)-6-(3-fluoro-4-methoxy-phenoxy)-[1,3,5]triazin-2-yl]-amine,

2-Cycloheptyloxy-4-(1-ethyl-pyrrolidin-2-ylmethoxy)-6-(3-fluoro-4-methoxy-phenoxy)-[1,3,5]triazine,

N-(4-Amino-3-chloro-phenyl)-N′-cycloheptyl-N″-methyl-N″-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine,

1-{4-[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-piperidin-1-yl}-ethanone,

4-[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid,

4-[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-piperidine-1-carboxylic acid amide,

4-[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-piperidin-1-ol,

2{[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid,

2-{[4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-methyl}-pyrrolidine-1-carboxylic acid amide,

Acetic acid 2-chloro-4{4-cycloheptylamino-6-[methyl-(1-methyl-piperidin-4-yl)-amino]-[1,3,5]triazin-2-ylamino)-phenyl ester,

N-Cycloheptyl-N′-(3-fluoro-4-methoxy-phenyl)-N″-(tetrahydro-pyran-4-yl)-[1,3,5]triazine-2,4,6-triamine,

N-Cycloheptyl-N′-(3-fluoro-4-methoxy-phenyl)-N″-methyl-N″-(tetrahydro-pyran-4-yl)-[1,3,5]triazine-2,4,6-triamine,

4-[4-Cycloheptylamino-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-2-fluoro-phenol,

2-Chloro-4-[4-cycloheptylamino-6-(piperidin-4-ylamino)-[1,3,5]triazin-2-ylamino]-phenol,

N-(4-Aminomethyl-cyclohexyl)-N′-cycloheptyl-N″-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4,6-triamine,

N-(4-Aminomethyl-cyclohexyl)-N′-(3-chloro-4-methoxy-phenyl)-N″-cycloheptyl-[1,3,5]triazine-2,4,6-triamine,

4-[4-(4-Aminomethyl-cyclohexylamino-6-cycloheptylamino-[1,3,5]triazin-2-ylamino]-2-fluoro-phenol,

N-Cycloheptyl-N′-(3-fluoro-4-methoxy-phenyl)-N″-piperidin-4-ylmethyl[1,3,5]triazine-2,4,6-triamine,

N-(3-Chloro-4-methoxy-phenyl)-N′-cycloheptyl-N″-piperidin-4-ylmethyl[1,3,5]triazine-2,4,6-triamine,

4-{4-Cycloheptylamino-6-[(piperidin-4-ylmethyl)-amino]-[1,3,5]triazin-2-ylamino}-2-fluoro-phenol,

N-Cycloheptyl-N′-methyl-N′-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine,

N-Cycloheptyl-N′-piperidin-4-yl-[1,3,5]triazine-2,4,6-triamine,

N-(3-Fluoro-4-methoxy-phenyl)-N′-methyl-N′-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4,6-triamine,

4-(3-Fluoro-4-methoxy-phenylamino)-6-(methyl-(1-methyl-piperidin-4-yl)-amino]-[1,3,5]triazin-2-ol,

4-(3-Chloro-4-methoxy-phenylamino)-6-[methyl-(1-methyl-piperidin-4-yl)-amino]-[1,3,5]triazin-2-ol,

4-(3-Chloro-4-methoxy-phenylamino)-6-cycloheptylamino-[1,3,5]triazin-2-ol,

4-Cycloheptylamino-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ol,

4-Cycloheptylamino-6-(methyl-(1-methyl-piperidin-4-yl)-amino]-[1,3,5]triazin-2-ol,

N-(4-Amino-cyclohexylmethyl)-N′-(3-chloro-4-methoxy-phenyl)-N″-cycloheptyl-[1,3,5]triazine-2,4,6-triamine,

N-(4-Amino-cyclohexylmethyl)-N′-cycloheptyl-N″-(3-fluoro-4-methoxy-phenyl)-[1,3,5]triazine-2,4,6-triamine,

4-Cycloheptylamino-6-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-[1,3,5]triazin-2-ol,

4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ol;

4-(3-Chloro-4-methoxy-phenylamino)-6-[(1-ethyl-pyrrolidin-2-ylmethyl)amino]-(1,3,5]triazin-2-ol,

4-(Cyclohexylmethyl-amino)-6-(3-fluoro-4-methoxy-phenylamino)-[1,3,5]triazin-2-ol, or

4-(Cyclohexylmethyl-amino)-6-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-[1,3,5]triazin-2-ol, or any combination thereof.

3. A stent comprising:

a composition disposed on or within the stent, the composition comprising a pharmaceutically acceptable carrier and a compound of the formula Id:

or a stereoisomer thereof or a salt thereof, wherein

G is selected from NH or O:

Z is selected from H or

wherein X 1 is selected from F or Cl, and X 2 is selected from OCH 3 , NH 2 , OC(O)CH 3 , or OH;

A is selected from NR 1 or O:

Y 1 is selected from R 1 ,

B is selected from NR 1 or O, and

Y 2 is selected from

wherein q is 0 or 1, E is selected from O or NR 2 wherein R 2 is selected from R 1 , OR 1 , C(O)R 1 , C(O)OR 1 , C(O)NH 2 , or CH 2 NH 2 ;

wherein R 3 is selected from R 1 , C(O)R 1 , C(O)OR 1 , or C(O)NH 2 ; and

wherein R 1 is in each occurrence independently selected from H, or a linear or branched alkyl with up to 10 carbon atoms.

4. The stent as claimed in claim 3 , wherein the compound is selected from:

6-(3-Chloro-4-methoxy-phenoxy)-N-cycloheptyl-N′-methyl-N′-(1-methyl-piperidin-4-yl)-[1,3,5]triazine-2,4-diamine,