Cyanoguanidine prodrugs

Details Cyanoguanidine prodrugs Cyanoguanidine prodrugs

2001-11-20

2003-02-25

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S306000

Reexamination Certificate

active

06525077

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel pyridyl cyanoguanidine prodrugs and their inclusion in pharmaceutical compositions, as well as their use in the manufacture of medicaments.
BACKGROUND OF THE INVENTION
Pyridyl cyanoguanidines such as pinacidil (N-1,2,2-trimethylpropyl-N′-cyano-N″-(4-pyridyl)guanidine) were originally discovered to be potassium channel openers and were consequently developed as antihypertensive agents. Replacement of the side chain of pinacidil by longer aryl-containing side chains caused a loss of the antihypertensive activity, but such compounds were, on the other hand, found to show antitumour activity on oral administration in a rat model carrying Yoshida ascites tumours.
Different classes of pyridyl cyanoguanidines with antiproliferative activity are disclosed in, for instance, EP 660 823, WO 98/54141, WO 98/54143, WO 98/54144, WO 98/54145, WO 00/61559 and WO 00/61561. The structure-activity relationships (SAR) of such compounds are discussed in C. Schou et al.,
Bioorganic and Medicinal Chemistry Letters
7(24), 1997, pp. 3095-3100, in which the antiproliferative effect of a number of pyridyl cyanoguanidines was tested in vitro on different human lung and breast cancer cell lines as well as on normal human fibroblasts. The compounds were also tested in vivo in nude mice carrying a human lung cancer tumour xenograft. Based on the SAR analysis, a specific compound (N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine) was selected for its high antiproliferative activity in vitro and potent antitumour activity in the nude mouse model.
P-J V Hjarnaa et al.,
Cancer Res.
59, 1999, pp. 5751-5757, report on the results of further testing of the compound N-(6-(4-chlorophenoxy)hexyl)-N′-cyano-N″-(4-pyridyl)guanidine in in vitro and in vivo tests. The compound exhibited a potency in vitro which was comparable to that of the reference cytostatic agents daunorubicin and paclitaxel, while showing considerably less antiproliferative activity on normal human endothelial cells. In in vivo tests using nude mice transplanted with human tumour cells, the compound showed substantial antitumour activity, also against tumour cells that were resistant to conventional anticancer drugs such as paclitaxel.
SUMMARY OF THE INVENTION
While, as indicated above, pyridyl cyanoguanidines are promising antitumour agents with an extremely interesting activity profile, they are highly lipophilic and consequently sparingly soluble compounds and are, as such, generally available for oral administration only. However, many cancer patients are in a severely debilitated condition as a result of their illness giving rise to problems with patient compliance with respect to oral administration of drugs.
It is therefore an object of the present invention to provide pyridyl cyanoguanidines in the form of prodrugs with an improved solubility profile which prodrugs may be included in pharmaceutical compositions suitable for parenteral administration, i.e. liquid compositions in which the prodrug is dissolved in sufficient amounts to be converted to therapeutically effective quantities of the active compound on administration of the composition.
Furthermore, it has been found that pyridyl cyanoguanidine prodrugs exhibit an improved gastrointestinal absorption on oral administration. Consequently, it is another object of the invention to provide oral formulations of pyridyl cyanoguanidines as prodrugs with improved bioavailability.
Accordingly, the present invention relates to a compound of the general formula I
wherein
X
1
and X
2
independently represent a bond; a straight, branched and/or cyclic hydrocarbon 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 hydrocarbon radical, hydroxyl, halogen, amino, nitro, cyano, aminosulfonyl, alkylsulfonylamino, alkylcarbonyl, formyl, aminocarbonyl or alkylcarbonylamino;
Y
1
and Y
2
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, SO
2
—N(R′), methylene or N(R′)—SO
2
wherein R′ and R″ independently represent straight or branched hydrocarbon diradicals containing up to 4 carbon atoms;
Y
3
represents O, O—C(O), C(O)—O, N(R
8
), R
8
being hydrogen or C
1-4
alkyl
R
1
represents hydrogen or straight, branched and/or cyclic alkyl, optionally substituted with phenyl; or an aromatic hydrocarbon radical;
R
2
represents aryl, heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which are optionally substituted; tetrahydropyranyloxy, di-(C
1-4
alkoxy)phosphinoyloxy or C
1-4
alkoxycarbonylamino;
R
3
represents hydrogen; a straight, branched and/or cyclic hydrocarbon radical, optionally substituted with one or more amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C
1-4
alkoxycarbonyl, C
1-4
alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl; heteroaryl or a non-aromatic heterocyclic hydrocarbon radical, all of which are optionally substituted with one or more straight, branched and/or cyclic hydrocarbon radical, amino, hydroxy, carboxy, halogen, nitro, cyano, alkoxy, aminocarbonyl, C
1-4
alkoxycarbonyl, C
1-4
alkoxycarbonylamino, sulfo, hydroxysulfonyloxy, dihydroxyphosphinoyloxy, phosphono, sulfamino, aminosulfonyl, aminoacylamino or dialkoxyphosphinoyl;
 wherein s is an integer from 1 to 200; R
6
is hydrogen or an optionally substituted non-aromatic hydrocarbon radical; R
7
is independently hydrogen or methyl;
R
4
and R
5
independently represent hydrogen; a straight, branched and/or cyclic hydrocarbon radical, optionally substituted with halogen, hydroxyl, halogen, amino, nitro or cyano;
A represents hydrogen, an optionally substituted, straight, branched and/or cyclic hydrocarbon radical, hydroxy, halogen, nitro, cyano, heteroaryl, heteroaralkyl or thiol;
m and r are independently integers from 0 to 4; and n is 0 or 1;
Z
−
is a pharmaceutically acceptable anion, such as chloride, bromide, iodide, sulfate, methanesulfonate, p-toluenesulfonate, nitrate or phosphate.
Furthermore, the invention also relates to a compound of formula II, which is the free base form of the compounds of formula I, provided R
4
is hydrogen
wherein A, R
1
, R
2
, R
3
, R
5
, X
1
, X
2
, Y
1
, Y
2
, Y
3
, m, n and r are as indicated above.
It is understood that the compounds of the present invention include any tautomeric forms, optical isomers or diastereoisomers thereof. It is further understood that the invention includes pharmaceutically acceptable salts of compounds of formula I or II comprising basic or acidic groups.
On administration of a compound of formula I or formula II to a patient, the ester group R
3
—(CH
2
)
r
—(Y
3
)
n
—(CH
2
)
m
—COOCHR
1
— is hydrolysed enzymatically to liberate the active compound of formula III
wherein A, R
2
, R
4
, R
5
, X
1
, X
2
, Y
1
, and Y
2
are as indicated above, together with the aldehyde R
1
CHO.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
In the present context, the term “prodrug” is intended to indicate a derivative of an active compound which does not, or does not necessarily, exhibit the physiological activity of the active compound, but which may be subjected to enzymatic cleavage such as hydrolysis in vivo so as to release the active compound on administration of the prodrug. In this particular instance, the prodrug comprises the active compound which in itself is highly lipophilic provided with a side chain with predominantly hydrophilic properties imparting improved solubility characteristics to the prodrug, thereby making it more suitable for parenteral administration in t

Affiliated with

Also associated with

Rating

Cyanoguanidine prodrugs does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyanoguanidine prodrugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyanoguanidine prodrugs will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3164681