Cyanoguanidines as cell proliferation inhibitors

Details Cyanoguanidines as cell proliferation inhibitors Cyanoguanidines as cell proliferation inhibitors

1999-11-26

2001-03-06

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

06197797

ABSTRACT:

This application is the national phase of international application PCT/DK98/00197 filed May 15, 1998 which designated the United States.
This invention relates to a hitherto unknown class of compounds which shows strong activity in inhibiting undesirable cell proliferation in e.g. skin cells and cancer cells, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment and prophylaxis of diseases characterized by abnormal cell differentiation and/or cell proliferation such as e.g. psoriasis and cancer.
The compounds of the present invention are represented by the general formula I
or their tautomeric forms, the attachment to the pyridine being in the 3- or 4-position, in which formula R
1
stands for one or more substituents which can be the same or different and are selected from the group consisting of: hydrogen, halogen, trifluoromethyl, nitro, amino, cyano, carboxy, or alkyl, alkoxy, or alkoxycarbonyl, the C-content of which can be from 1 to 4; X stands for a straight or branched C
9
-C
20
carbon chain, saturated or unsaturated or Q—Ar—R; in which formula Ar stands for phenyl, Q stands for a C
5
-C
20
divalent hydrocarbon radical which can be straight, branched, saturated or unsaturated and R stands for hydrogen or for one or more substituents which can be the same or different and are selected from the group consisting of: hydroxy, amino, halogen, trifluoromethyl, cyano, nitro, carboxy, carbamoyl, or alkyl, alkoxy, alkylthio, alkylamino, or alkoxycarbonyl, the C-content of which can be from 1 to 4.
If the present compounds contain one or more asymmetric carbon atoms, these compounds may form optical isomers or diastereo-isomers. The present invention also comprises such isomers, and mixtures of same.
The compounds can be used in the form of their salts which are formed with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric, hydrobromic and hydroiodic acid, phosphoric acid, sulphuric acid, nitric acid, 4-toluenesulphonic acid, methanesulphonic acid, formic acid, acetic acid propionic acid, citric acid, tartaric acid, succinic acid, benzoic acid, and maleic acid.
Even if the present compounds are well absorbed after enteral administration, in some cases it can be advantageous to prepare suitable bioreversible derivatives of compounds of the invention, i.e. to prepare so-called prodrugs, preferably derivatives, the physicochemical properties of which leads to improved solubility at physiological pH and/or absorption and/or bioavailability of the compound in question.
Such derivatives are for instance pyridyl N-oxide derivatives of compounds of the invention, such compounds being prepared by oxidation of the pyridyl N by a suitable oxidising agent, e.g. with 3-chloroperbenzoic acid in an inert solvent, e.g. dichloromethane.
Other suitable methods to improve the physicochemical properties and/or solubility of the compounds concerned can be used as well.
N-Alkyl-N′-cyano-N″-pyridylguanidines, described in United Kingdom Patent No. 1,489,879, are potent potassium channel activators with a pronounced effect as pre-capillary vasodilators, reducing the total peripheral resistance in animals and in man, and are thus useful as antihypertensives. As stated in International Patent No. PCT/DK93/00291, filing date Sep. 13, 1993, Publication No. WO 94/06770 the introduction of aryloxy-containing radicals into the aliphatic groups from the above-cited U.K. Patent has led to structures showing more specific pharmacological effects on isolated tissues and cells and with no or a negligible effect on
86
Rb-efflux from potassium channels, as compared with the established effect of compounds covered by the above-mentioned U.K. Patent.
The compounds of the present invention inhibit the proliferation of various tumour cell lines in cultures at lower concentrations than the known compounds, confer table 1 below, and prolong the survival time of tumour-bearing rats, thus making them potentially useful in antineoplastic chemotherapy.
The inhibition of tumour cell proliferation was studied using different types of human cancer cell lines. The cell lines under investigation were small cell lung carcinoma (NYH), non small cell lung carcinoma (NCI-H460), and breast cancer (MCF-7) using the following general procedure.
The cells were cultured in vitro for 24 hours in the presence of the compound under investigation. DNA synthesis was measured by incorporation of [3H]thymidine, and the median inhibitory concentrations (IC
50
) of the compounds were calculated.
Results are shown in Table 1.
The results show that the compounds of the present invention are able to inhibit the proliferation of tumour cells in vitro at the same or lower concentrations then the compounds in the examples 14 and 18 in PCT/DK93/00291.
TABLE 1
Inhibition of tumour cell proliferation in vitro in human
small cell lung carcinoma (NYH), human non small
cell lung carcinoma (NCI-H460) and human breast
cancer (MCF-7) by compounds of the following
examples of the present invention
Compound
from
The median inhibition
Example
concentration (IC
50
, nM) of
No.
NYH
NCI-H460
MCF-7
1
not tested
not tested
40
5
5.3
5.8
29
10
7.3
135
54
12
5.5
49
138
14
6.1
78
74
18
5.0
61
19
prior art A
380
>1000
920
prior art B
45
67
250
A: N-Cyano-N′-(4-phenoxybutyl)-N″-4-pyridylguanidine, example 14 in PCT/DK93/00291′
B: N-Cyano-N′-(5-phenoxypentyl)-N″-4-pyridylguanidine, example 18 in PCT/DK93/00291′
The prolongation of survival time of tumour-bearing rats was studied in LEW/Mol inbred female rats inoculated with Yoshida sarcoma cells in a number of 2×10
7
cells. Tumour-bearing rats (6 animals per group) were dosed orally once daily from day 3 after the transfer of tumour cells and until death or for a maximum of 21 days or until the body weights had increased by 10% as a consequence of tumour proliferation. The mean survival day of treated versus non-treated rats is used to calculate ILS (Increased Life Span). ILS=((mean treated/mean control)−1)*100%. Results are shown in Table 2.
TABLE 2
Survival of Yoshida tumour-bearing rats treated
with compounds of the present invention
Dose
Increased
(mg/kg,
life span
Treatment
Compound
p.o.)
(ILS)
#
%
None
—
—
0.0¤
Compounds from
Example No. 1 
20
49
the present
Example No. 10
20
35
invention
prior art B
50
35
#
: ILS = ((mean treated/mean control)-1)*100%
¤: Untreated tumour carrying animals die between day 7 and 9
B: N-Cyano-N′-(5-phenoxypentyl)-N″-4-pyridylguanidine, example 18 in ‘patent PCT/DK93/00291’
These results show that the compounds of the present invention are better than the compound in example 18 in PCT/DK93/00291 to prolong the survival time of Yoshida sarcoma tumour-bearing rats.
The compounds of the invention are well tolerated and non-toxic and are exerting the described beneficial activities with no or minimal effect on the systemic blood pressure. In general, they may be administered by oral, intravenous, intraperitoneal, intranasal or transdermal routes.
The present invention also relates to methods for preparing the desired compounds of the general formula I. The compounds of the formula I may conveniently be prepared by standard procedures detailed in the art. The routes are outlined in the following reaction scheme.
Notes to scheme 1
a) Dicyclohexylcarbodiimide/cyanamide/triethylamine/acetonitrile/20° C./14 days (see general procedure 1)
b) Triethylamine/4-dimethylaminopyridine/pyridine/60° C./4 hours (see general procedure 2)
The present compounds are intended for use in pharmaceutical compositions which are useful in the treatment of the above mentioned diseases
The amount required of a compound of formula (I) (hereinafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular compound, the route of administration and the mammal under treatment. A suitable dose of a compound of formula (I) for systemic treatmen

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