Certain derivatives of 1,4-dihydro-5-isopropoxy-1,6-naphthyridine-3-carboxylic acid, pharmaceutical compositions containing them, and methods of using them

The present invention concerns the fumaric acid salts of 1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl) 1,6-naphthyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)ethyl]ester, processes for preparing them, and pharmaceutical compositions containing them. Methods of using the compounds for treating high blood pressure and diseases of heart and blood vessels.

BACKGROUND OF THE INVENTION 
Germany Patent Application 34 31 303, 1,6-naphthyridine derivatives with 
calcium antagonistic properties are described. 
(.+-.)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-n 
aphthyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)-ethyl] 
ester in the form of the hydrochloride is included. The corresponding U.S. 
Pat. Nos. are 4,711,901, 4,751,228, and 4,760,081, which are incorporated 
herein by reference. 
SUMMARY OF THE INVENTION 
The present invention is concerned with new derivatives of 
1,6-naphthyridine-3-carboxylic acid, a process for the preparation 
thereof, pharmaceutical compositions containing the, and methods of using 
them. The present invention covers 
(.+-.)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-n 
aphthyridine-3-carboxylic acid [2-(N-methyl-N-phenyl-methylamino)-ethyl] 
ester fumarate and 
(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naph 
thyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)-ethyl] ester 
fumarate. The crystalline form of the (+) isomer is also included. 
A pharmaceutical composition comprising a blood pressure lowering amount of 
(.+-.)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-n 
aphthyridine-3-carboxylic acid [2-N-methyl-N-phenylmethylamino)-ethyl] 
ester fumarate, 
(.+-.)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-n 
aphthyridine-3-carboxylic acid [2-(N-methyl-N-phenyl-methylamino)-ethyl] 
ester fumarate, 
(-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naph 
thyridine-3-carboxylic acid [2-(N-methyl-N-phenyl-methylamino)-ethyl] ester 
fumarate, or the crystalline form of 
(+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)1,6-napht 
hyridine-3-carboxylic acid [2-(N-methyl-N-phenyl-methylamino)-ethyl] ester 
fumarate together with a pharmaceutically acceptable carrier is also 
included. 
A method for treating high blood pressure using the above compositions is 
included. 
A pharmaceutical composition comprising an effective amount of 
(.+-.),(+),(-) or the crystalline form of (+) for treating diseases of the 
heart and blood vessels is also included. 
A method for treating diseases of the heart and blood vessels using the 
above composition is also included. 
DETAILED DESCRIPTION 
Surprisingly, it has now been found that, in comparison with the other 
derivatives, the (.+-.) possesses especially marked blood pressure 
lowering activity. The pharmacological results are even more marked in the 
case of the optical results which were obtained according to the usual 
methods of racemate separation. Especially active is 
(+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoro-methylphenyl)-1,6-nap 
hthyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)-ethyl] 
ester. 
This ester is an oily base and the hydrochloride displays an instability 
wit regard to temperature and light, undesirable properties for galenical 
development and for clinical use. The hydrochloride is unstable even at 
ambient temperature and a stress test gave, after heating for 2 weeks at 
45.degree. C. in the dark, 10% of decomposition products and at ambient 
temperature in the light 30% of the compound had decomposed after 2 weeks. 
Furthermore, in animal experiments, an undesirable, very rapid 
commencement of activity was found which was attributable to the good 
solubility of the compound in water. 
The present invention provides 
(+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naph 
thyridine-3-carboxylic acid [2-N-methyl-N-phenymethylamino)-ethyl] ester in 
a crystalline, light- and temperature-stable form for clinical use which, 
in addition, displays a slower commencement of activity. 
Surprisingly, it has been found that the fumarate can be obtained as a 
crystalline salt with a melting point of 180.degree.-182.degree. C. In 
addition, it is also stable under the above-mentioned stress conditions (2 
weeks at 45.degree. C. in the dark and 2 weeks at ambient temperature in 
the light). Furthermore, the fumarate also displays a considerable lower 
water solubility, as can be seen from the following Table 1: 
TABLE 1 
______________________________________ 
Solubility in 
Artificial 
Compound Water Gastric Juice 
______________________________________ 
Hydrochloride 20% 20% 
Fumarate 0.1% 1.5% 
______________________________________ 
Pharmacological experiments on rats showed that the commencement of 
activity after oral administration takes place somewhat later in the case 
of the fumarate than in the case of the hydrochloride, and, in addition, 
the blood pressure lowering action is, surprisingly, also substantially 
stronger in the case of the fumarate, as is shown in the following Table 
2: 
TABLE 2 
______________________________________ 
Spontaneously Hypertensive Rats 
1 mg/kg PO; n = 6 
______________________________________ 
Hydrochloride 17% .+-. 4.4 
Fumarate 26% .+-. 1.7 
______________________________________ 
The present invention is also concerned with the use of the compounds 
according to the present invention for the treatment of high blood 
pressure and of heart and blood vessel diseases, as well as with 
pharmaceutical compositions containing these compounds, optionally 
together with conventional adjuvant and additive materials. 
The compounds according to the present invention can be administered orally 
or parenterally in liquid or solid form. As injection solution, it is 
preferable to use water which contains the additives usual in the case of 
injection solutions, such as stabilizing agents, solubilizing agents, 
and/or buffers. Such additives include, for example, tartrate and citrate 
buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic 
acid and the nontoxic salts thereof), as well as high molecular weight 
polymers (such as liquid polyethylene oxide) for viscosity regulation. 
Solid carrier materials include, for example, starch, lactose, mannitol, 
methylcellulose, talc, highly dispersed silicic acids, high molecular 
weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium 
phosphate, magnesium stearate, animal and vegetable fats, and solid high 
molecular weight polymers (such as polyethylene glycol). Compositions 
suitable for oral administration can, if desired, also contain sweetening 
and/or flavoring materials. 
1-4-Dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyri 
dine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)-ethyl] ester 
fumarate can be prepared, for example, by mixing together solutions of the 
base and of fumaric acid in appropriate solvents or by heating a mixture 
of equimolar amounts of base and fumaric acid in an appropriate solvent 
and subsequent crystallization by cooling. As solvents, there can be used, 
for example, ethyl acetate, lower aliphatic alcohols and lower aliphatic 
ketones, possibly in admixture with water.

The following Example is given for the purpose of illustrating the present 
invention: 
EXAMPLE 1 
400 g 
(+)-1,4-Dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naph 
thyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)ethyl] ester, 
together with 8.6 g fumaric acid, are dissolved in 1000 mL ethyl acetate 
while boiling under reflux. The solution is filtered and the filtrate 
concentrated to a volume of about 180 mL, a crystalline product thereby 
precipitating out. This is filtered off with suction and washed with 180 
mL ethyl acetate. After drying, the product is dissolved in 300 mL ethanol 
with gentle warming and thereafter mixed with 1500 mL of water, while 
stirring. The solution is then allowed to cool to ambient temperature, 
while stirring. The product which crystallizes out is filtered off with 
suction and subsequently washed with 100 mL of water. The product is dried 
in a vacuum to constant weight. Yield: 43.1 g (88.7% of theory); m.p. 
180.degree.-182.degree. C.; [.alpha.].sub.D =3.8.degree. (c=1/methanol); 
enantiomeric purity 99% (PMR). 
EXAMPLE 2 
2.9 g 
(-)-1,4-Dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naph 
thyridine-3-carboxylic acid [2-(N-methyl-N-phenylmethylamino)ethyl] ester, 
together with 0.58 g fumaric acid, are dissolved in 75 mL ethyl acetate 
while boiling under reflux. The solution is filtered and the filtrate 
concentrated to a volume of about 20 mL, a crystalline product thereby 
precipitating out. This is filtered off with suction and washed with 10 mL 
ethyl acetate. After drying, the product is dissolved in 19.5 mL ethanol 
with gentle warming and thereafter mixed with 110 mL of water, while 
stirring. The solution is then allowed to cool to ambient temperature 
while stirring. The product which crystallizes out is filtered off with 
suction and subsequently washed with 20 mL of water. The product is dried 
in a vacuum to constant weight. Yield: 2.1 g (64.2% of theory); m.p. 
181.degree.-183.degree. C.; [.alpha.].sub.D =-3.6.degree. (c=1/methanol); 
enantiomeric purity 99% (PMR).