Abstract:
A compound of the formula: ##STR1## wherein X is hydrogen or fluorine and n is 2 or 3; or its pharmaceutically acceptable salt.

Description:
This is a continuation-in-part of U.S. patent application No. 654,473 filed 9/26/84 now U.S. Pat. No. 4,576,934 issued 3/18/86. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to a novel 1,4-dihydropyridine-5-phosphonic acid cyclic propylene ester, a process for the preparation thereof, and an antihypertensive agent or coronary or peripheral vasodilator composition containing the novel ester or its pharmaceutically acceptable salt. 
     2. Description of the Prior Art 
     1,4-Dihydropyridines are known to be useful for the medical treatment of coronary heart diseases, cerebral diseases, hypertension or arrhythmia, as they are capable of inhibiting the contraction of smooth muscle and cardiac muscle by calcium antagonistic effects (see A. Fleckenstein, Annu. Rev. Pharmacol. Toxicol., 17, 149-166 (1977)). However, the majority of 1,4-dihydropyridines known or being developed are substituted at the 3- and 5-positions by a carboxylic acid ester group. 
     Dihydropyridine-5-phosphonate derivatives are disclosed in prior art references. However, none of them suggests or indicates the specific compounds of the present invention. 
     RELEVANT REFERENCES ARE AS FOLLOWS 
     A. I. Razumov et al. synthesized a dihydropyridine-4-alkyl-5-phosphonate derivative (Zh. Obshch. Khim., 47, 1190-1191 (1977) and ibid., 51, 547-552 (1981)). Further, Von K. Issleib et al. synthesized 1,4-dihydropyridine-4-aryl-5-phosphonates (more specifically, diethyl 2,6-dimethyl-4-phenyl-3-ethoxy carbonyl-1,4-dihydropyridine-5-phosphonate and diethyl 2,6-dimethyl-4-(4-methoxyphenyl)-3-ethoxy carbonyl-1,4-dihydropyridine-5-phosphonate) (J. Prakt. Chem., Vol. 318, 207-220 (1976)). None of these references indicates the pharmacological activities. Furthermore, U.K. Patent Application GB 2105989A discloses a wide range of 1,4-dihydropyridine-5-phosphonate derivatives by a general formula, and teaches that the compounds represented by the general formula have cardiac activities. However, the specification of this Patent Application discloses no actual examples for the syntheses of 1,4-dihydropyridine-5-phosphonate derivatives and no pharmacological data relating to such derivatives. 
     SUMMARY OF THE INVENTION 
     The present invention provides a novel compound represented by the formula: ##STR2## wherein X is hydrogen or fluorine and n is 2 or 3, or its pharmaceutically acceptable salt. 
     Some of the compounds of the formula I have optical isomers of diastereomers. The present invention covers such optical isomers and diastereomers. 
     The present invention also provides an antihypertensive agent or coronary or peripheral vasodilator composition comprising an effective amount of the compound of the formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier. 
     DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The compounds of the present invention can be prepared in accordance with the flow chart of the following Scheme 1. ##STR3## 
     In Scheme 1, n and X have the same meanings as defined with respect to the formula I. 
     The acetonyl phosphonic acid cyclic propylene ester (a) can be prepared by means of a conventional technique (see D. W. White, J. Am. Chem. Soc., 92, 7125-7135 (1970)). Namely, as shown by Scheme 1, it is obtainable by the reaction of a 1-methoxy-4,4-dimethyl-1-phosha-2,6-dioxacyclohexane derivative (a-2) with iodoacetone. 
     The compounds of the present invention of the formula I can be obtained by reacting the compound of the formula II with the compound of the formula III in an inert solvent in accordance with the above Scheme 1. The starting compound of the formula II is obtainable by reacting the acetonyl phosphonic acid cyclic ester (a) with m-nitro-benzaldehyde by means of a conventional technique. Likewise, the starting compound of the formula III can readily be obtained by reacting the corresponding carbonyl compound with ammonia. The starting compound of the formula III may be formed in the reaction system simply by mixing the corresponding carbonyl compound with ammonia and is not necessarily required to be isolated. 
     The inert solvent includes an alcohol solvent such as methanol, ethanol, propanol or isopropanol, an ether solvent such as 1,2-dimethoxyethane or THF, an aromatic hydrocarbon solvent such as benzene, toluene or xylene, a nitrile solvent such as acetonitrile or benzonitrile, an amide solvent such as DAM, DMF or N-methylpyrrolidone, a sulfoxide solvent such as DMSO or sulfolane, an ester solvent such as ethyl acetate or butyrolactone, or pyridine. 
     The reaction is usually conducted at a temperature of from room temperature to 200° C., preferably from 60° to 140° C., for from 1 to 100 hours, preferably from 5 to 20 hours. 
     As mentioned above, the compounds of the present invention are not only capable of inhibiting the contraction of smooth muscle and cardiac muscle by the calcium antagonistic effects but also antihypertensively effective when administered orally. Thus, they are useful for the medical treatment of the coronary heart diseases, cerebral diseases or hypertension of mammals. 
     Thus, the present invention provides an anti-hypertensive agent or coronary or peripheral vasodilator composition comprising an effective amount of the compound of the formula I or its phamaceutically acceptable salt, and a pharmaceutically acceptable diluent or carrier. Such a composition may also be formulated into a veterinary composition by combining the compound of the present invention with a veterinarily acceptable diluent or carrier. 
     Such compositions may be used in the form suitable for oral administration, e.g. tablets or capsules, in the form suitable for transdermal administration, e.g. ointments or plasters, in the form suitable for inhalation, e.g. aerosols or solutions suitable for spraying, in the form suitable for injection administration, e.g. a sterilized aqueous solution, or in the form of a suppository suitable for use in anus, vagina or rectum. 
     The compositions of the present invention usually contain the compound of the formula I in an amount of from about 0.1 to about 99.5% by weight, preferably from about 0.5 to about 95% by weight, based on the total weight of the composition. 
     The compounds of the present invention or the compositions of the present invention may be used in combination with other pharmaceutically or veterinarily active compounds. Further, the composition of the present invention may contain a plurality of the compounds of the formula I. 
     The daily dose of the compounds of the formula I may be varied depending upon the type and the condition of the desease to be cured and the type of the patient (the age, sex, sensitivity, etc.). In the case of the intravenous administration, the daily dose is usually from 0.0001 to 10 mg, preferably from 0.0005 to 1 mg, of the active ingredient per 1 kg of the body weight. Likewise, in the case of the oral or transdermal administration, the daily dose is usually from 0.001 to 100 mg of the active ingredient per 1 kg of the body weight. Further, the daily dose in the case of the administration in the form of a suppository to e.g. a vagina or rectum, is usually from 0.001 to 200 mg, preferably from 0.005 to 100 mg, of the active ingredient per 1 kg of the body weight. The content of the active ingredient in an aerosol, is usually from 0.1 to 10% by weight, preferably from 0.1 to 2% by weight. Such a daily dose may be divided for administration twice or more times per day. 
     The above-mentioned compositions containing the compounds of the formula I may be prepared by a conventional method, and a conventional excipient may be incorporated therein. 
    
    
     The present invention will be now described in further detail with reference to Working Examples, Test Examples and various formulations. However, it should be understood that the present invention is by no means restricted by these specific Examples. 
     EXAMPLES 
     Test 1: Pharmacological activities of the compounds of the present invention. 
     (1) Calcium antagonistic effects 
     10 mm in situ length of taenia caecum of guinea pig was suspended at a tension of 1 g in a 20 ml organ bath filled with a physiological salt solution (NaCl: 135 mM, KCl: 5 mM etc.). 
     This solution was bubbled with a gas mixture of 95% O 2  -5% CO 2  and kept at 37° C. Then, the preparation was depolarized by a K +  rich solution (NaCl: 40 mM, KCl: 100 mM). After 10-20 minutes equilibration period, 10 mM of CaCl 2  was added to the bathing solution. The contraction was produced, and then the test compound applied cumulatively. The relaxation produced was expressed as percentage of the maximum relaxation produced by 10 -4  M papaverine, and the concentration of the compound producing 50% relaxation, i.e. ID 50  (M), was calculated. The values of pID 50  (pID 50  =-log [ID 50  ], are summarized in Table 3. 
     (2) Antihypertensive effects 
     After oral administration of the test compound dissolved in a H 2  O-PEG 400 solvent mixture (H 2  O:PEG 400 (w/w)=1:3) to the male spontaneously hypertensive rat (SHR), the systolic blood pressure was measured by a tail cuff method. Prior to the measurement, rats were warmed at 50° C. for five minutes. The results are summarized in Table 3. 
     
                       TABLE 3______________________________________Calcium antagonistic effects and antihyper-tensive effects of the compounds of thepresent invention.            Antihypertensive effects                  Dose     MaximumCompounds    pID.sub.50                  (mg/kg)  decrease(%)______________________________________Hydrochloride of        7.63      20       40Example 1Hydrochloride of        7.53      20       31Example 2Hydrochloride of        7.39      20       39Example 3Hydrochloride of        7.20      20       22Example 4______________________________________ 
    
     Test 2: Acute toxicity test. 
     ddY mice (♂, 4 weeks old) were divided into groups of five mice and the test compound dissolved in purified water was administered orally (5% solution) (p.o) or intraperitoneally (1% solution) (i.p) to the male ddY mice. 
     After seven days, LD 50  values were calculated from the dead rats recorded in the individual dosage groups by the method of Litchfield-Wilcoxon. The results are shown in Table 4. 
     
                       TABLE 4______________________________________               LD.sub.50 (mg/kg)Tested compound       i.p.    p.o.______________________________________Hydrochloride of the Compound                 163     194of Example 1______________________________________ 
    
     EXAMPLE 1 
     Synthesis of β-(4-diphenylmethyl-1-piperazinyl)-ethyl 5-(4,4-dimethyl-1-oxo-1-phospha-2,6-dioxacyclohexa-1-yl)-2,6-dimethyl-1,4-dihydro-4-(3-nitrophenyl)-pyridine-3-carboxylate 
     1.44 g of β-(4-diphenylmethyl-1-piperazinyl)-ethyl 3-aminocrotonate and 1.29 g of 1-(α-acetyl-3-nitrostyryl)-4,4-dimethyl-1-oxo-1-phospha-2,6-dioxacyclohexane were dissolved in 20 ml of toluene, and the solution was refluxed for 9 hours. Then, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography by using 10% ethanol-ethyl acetate as the developer. The fraction containing the desired substance was distilled under reduced pressure to remove the solvent, whereby the above-identified compound was obtained. 
     In a similar manner, compounds of Examples 2 to 4 were obtained. The characteristics of the compounds thus obtained are shown in Table 1, and their spectral data are shown in Table 2. 
     
                                           TABLE 1__________________________________________________________________________Compounds of Example 1 to 4 and their characteristics ##STR4##                              (I)Example No.     n    X    Yield (%)                        Characteristics__________________________________________________________________________1         2    H    56       Yellow oily Substance2         3    H    49       Yellow oily Substance3         2    F    62       Yellow oily Substance4         3    F    46       Yellow oily Substance__________________________________________________________________________ 
    
     
                       TABLE 2______________________________________Compounds of Example 1 to 4 and their spectral data                         Mass spectrumExample  NMR Spectrum           m/e (intensityNo.    δ-value (in CDCl.sub.3)                         ratio)______________________________________1      8.20-7.05(14H,m),4.85(1H,d,J=11Hz)                         167 (100)  4.50-3.20(7H,m),2.85-2.10(16H,m),                         246 (28)  0.97(6H,d,J=9Hz)       683 (10)2      8.20-7.00(14H,m),4.83(1H,d,J=11Hz)                         167 (100)  4.40-3.30(7H,m),2.75-1.50(18H,m),                         300 (23)  0.98(6H,d,J=9Hz)       697 (32)                         714 (2,M.sup.+)3      8.10-6.73(12H,m),4.85(1H,d,J=11Hz)                         203 (96)  4.40-3.30(7H,m),2.80-2.05(16H,m),                         300 (32)  0.98(6H,d,J=6Hz)       719 (100)                         736 (18,M.sup.+)4      8.10-6.65(12H,m),4.83(1H,d,J=11Hz)                         203 (100)  4.40-3.30(7H,m),2.65-1.50(18H,m),                         733 (49)  0.98(6H,d,J=8Hz)       750 (3,M.sup.+)______________________________________ 
    
     Now, examples will be given for various formulations containing the compound of the formula I. 
     Tablets 
     Composition (1,000 tablets) 
     
         ______________________________________Hydrochloride of the compound of the                  5.0       (g)Example 1Lactose                190.0Corn starch            75.0Crystal cellulose powder                  25.0Methyl cellulose       3.0Magnesium stearate     2.0                  300.0______________________________________ 
    
     The above ingredients in the respective amounts were introduced into a twin shell mixer and uniformly mixed. This powder mixture was tableted by a direct compression method to obtain tablets having a weight of 300 mg per tablet. 
     Capsules 
     Composition (1,000 capsules) 
     
         ______________________________________Hydrochloride of the Compound of                 5         (g)the Example 1Corn starch           145Crystal cellulose powder                 145Magnesium stearate    5                 300______________________________________ 
    
     The above ingredients in the respective amounts were introduced into a twin shell mixer and uniformly mixed. This powder mixture was packed in hard gelatin capsules in an amount of 300 mg per capsule. 
     Powder 
     Composition: 
     
         ______________________________________Hydrochloride of the compound of                 1.0       (g)the Example 1Lactose               88.0Crystal cellulose powder                 10.0Methyl cellulose      1.0                 100.0______________________________________ 
    
     The above ingredients in the respective amounts were introduced into a twin shell mixer and uniformly mixed to obtain a powder. 
     Syrup 
     Composition (2% syrup): 
     
         ______________________________________Hydrochloride of the compound of                 2.0       (g)the Example 1Sugar                 30.0Glycerin              5.0Flavoring agent       0.196% ethanol           10.0Methyl p-hydroxybenzoate                 0.03Purified water to make                 100.0     g______________________________________ 
    
     The sugar and the hydrochloride of the compound of Example 1 were dissolved in 60 g of warm water, and after cooling the solution, a solution of the flavoring agent in glycerin and ethanol was added. Then, water was added to this mixture to bring the total amount to 100.0 g.