Cyanoguanidine prodrugs

A cyano group and group technology, applied in the field of preparation of drugs, can solve the problem of loss of antihypertensive activity

Inactive Publication Date: 2005-03-02
LEO PHARMA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Replacing the side chain of pinacidil with a longer side chain containing an aryl group resulted in a loss of antihypertensive activity, but on the other hand, it was found that when administered orally, it was ineffective in the Yoshida ascites tumor-bearing rat model exhibit antitumor activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0245] 1-[2-[2-(2-(2-Methoxyethoxy)-ethoxy)-ethoxy-carbonyloxymethyl Base] -4-[N'-cyano-N"-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride thing

[0246] N-(6-(4-chlorophenoxy)-hexyl)-N'-cyano-N"-(4-pyridyl)-guanidine (1.13g) was mixed with chloromethyl carbonate 2-(2-( A mixture of 2-methoxyethoxy)-ethoxy)-ethyl ester (1.95 g) was placed in a preheated oil bath at 100° C. After 15 minutes, a clear orange melt formed and after 45 minutes , the mixture was cooled to room temperature and EtOAc (5ml) was added. The desired compound crystallized and was isolated by filtration. Recrystallization from isopropanol gave an analytically pure sample.

[0247] 13 C NMR (DMSO) δ = 157.4, 155.0, 153.0, 144.9, 129.1, 123.9, 116.1, 115.0, 112.8, 80.2, 71.1, 69.6, 69.5, 68.0, 67.7, 67.6, 57.9, 42.2, 28.3, 25.7, 25.0

Embodiment 2

[0249] 1-[2-(2-Methoxyethoxy)-ethoxy-carbonyloxymethyl]-4-[N'-cyano- N”-(6-(4-chlorophenoxy)-hexyl)-N-guanidino]-pyridinium chloride

[0250] Following the procedure described in Example 1, but substituting chloromethyl carbonate 2-(2-methoxyethoxy)-ethyl ester for chloromethyl carbonate 2-(2-(2-methoxyethoxy) (yl)-ethoxy)-ethyl ester, the title compound was isolated as a well crystalline compound.

[0251] 13 C NMR (DMSO) δ = 157.4, 155.0, 153.0, 144.9, 129.1, 123.9, 116.1, 115.0, 112.7, 80.2, 71.1, 69.4, 68.0, 67.7, 67.6, 58.0, 42.2, 28.3, 25.7, 25.0

Embodiment 3

[0253] 1-[2-Methoxyethoxy)-carbonyloxymethyl]-4-[N’-cyano-N”-(6-(4-chloro Phenoxy)-hexyl)-N-guanidino]-pyridinium chloride

[0254]Following the procedure described in Example 1, but substituting chloromethyl 2-methoxyethyl carbonate for chloromethyl 2-(2-(2-methoxyethoxy)-ethoxy)-ethyl carbonate base ester, the title compound was isolated as crystalline compound.

[0255] 13 C NMR (DMSO) δ = 157.4, 155.0, 153.0, 144.8, 129.1, 123.9, 116.1, 115.0, 112.8, 80.2, 69.2, 67.8, 67.6, 57.9, 42.1, 28.3, 28.2, 25.7, 25.0

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Abstract

The invention relates to compounds of formula (I), wherein X1 and X2 independently represent a bond; a straight, branched and/or cyclic hydrocarb on diradical, optionally substituted with one or more hydroxy, halogen, nitro, amino, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino; a heteroarylene or non-aromatic heterocyclic hydrocarbon diradical, all of which are optionally substituted with one or more straight, branched and/or cyclic non-aromatic hycrocarbon radical, hydroxyl, halogen, amino, nitro, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino; Y1 and Y2 independently represent a bond, an ether diradical (R'-O-R''), an amine diradical (R'-N-R''), O, S, S(O), S(O)2, C(O) , NH-CO, CO-NH, SO2-N(R'), methylene or N(R')-SO2 wherein R' et R'' independently represent straight or branched hydrocarbon diradicals containi ng up to 4 carbon atoms; Y3 represents O, O-C(O), C(O)-O, N(R8), R8 being hydrogen or C1-4alkyl; R1 represents hydrogen or straight, branched and/or cyclic alkyl, optionally substituted with phenyl; or an aromatic hydrocarbon radical; R2 represents aryl, heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which are optionally substituted; tetrahydropyranyloxy, di-(C1-4 alkoxy)phosphinoyloxy or C1-4 alkoxycarbonylamino; R3 represents hydrogen; a straight, branched and/or cyclic hydrocarbon radical, optionally substituted with one or more amino, hydroxy, carboxy, halogen, nitro, cyano, alcoxy, aminocarbonyl, C1- 4alkoxycarbonyl, C1-4alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; heteroaryl or a non-aromatic heterocyclic hydrocarbo n radical, all of which are optionally substituted by one or more group.

Description

field of invention [0001] The present invention relates to a new pyridyl cyanoguanidine prodrug, a pharmaceutical composition containing the prodrug, and an application of the prodrug in preparing medicine. Background of the invention [0002] Pyridylcyanoguanidine compounds such as pinacidil (N-1,2,2-trimethylpropyl-N'-cyano-N"-(4-pyridyl)guanidine) were originally developed as potassium channel openers discovered and subsequently developed as an antihypertensive drug. Replacing the side chain of pinacidil with a longer side chain containing an aryl group resulted in a loss of antihypertensive activity, but on the other hand, it was found that when administered orally , which exhibited antitumor activity in a Yoshida ascites tumor-bearing rat model. [0003] Different classes of pyridylcyanoguanidine compounds having antiproliferative activity are disclosed in eg EP660823, WO98 / 54141, WO98 / 54143, WO98 / 54144, WO98 / 54145, WO00 / 61559 and WO00 / 61561. The...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/196A61K31/198A61K31/282A61K31/337A61K31/4422A61K31/4425A61K31/475A61K31/513A61K31/675A61K31/704A61K31/7048A61K31/7068A61K45/00A61P35/00A61P35/02A61P43/00C07D211/84C07D213/50C07D213/74C07D213/75C07D217/22
CPCC07D213/50C07D211/84C07D213/75C07D217/22A61P35/00A61P35/02A61P43/00C07D213/74
Inventor E·T·宾德鲁普P-J·V·耶纳
Owner LEO PHARMA AS
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