1,4-DIHYDROPYRIDINES

Abstract: Compounds useful for treating coronary insufficiency, hypertension, angina pectoris, cardiac arrythmia, heart attack or coronary vasospasm and represented by general formula (I), in which R1 and R2 are each independently selected from the group consisting of lower alkyl, N-alkylphthalimido and and derivatives of N-alkylphthalimido wherein said N-alkyl group comprises at least 2 carbon atoms; A is a straight or branched chain hydrocarbon moiety containing from 1 to 12 carbon atoms and from 0 to 2 double bonds; R3 is selected from the group of radicals consisting of hydrogen, -NH2 and -NCS; R4 is an aryl or heteroaryl radical; and R5 is a lower alkyl radical or A-R3; provided that when R3 is a hydrogen radical at least one of R1 and R2 is not lower alkyl, including both pure enantiomers as well as mixtures thereof; and pharmaceutically-acceptable salts thereof.

Description: 1.4-DIHYDROPYRIDINES packαround of the Tnvention This invention is concerned with certain 1,4- dihydropyridines, their preparation, pharmaceutical * compositions containing them and their use as therapeutic agents, particularly as anti-ischaemic and anti- hypertensive agents. The compounds of the invention delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under iεchaemic conditions. Calcium overload, during ischae ia, can have a number of additional adverse effects which would further compromise the ischae ic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis. Thus, the compounds are useful in the treatment or prevention of cardiac conditions, such as angina pectoris, cardiac arrythmias, heart attacks and cardiac hypertrophy. The compounds also process vasodilator activity and are thus useful as antihypertensives and for the treatment of coronary vasospasm. The structure and presumed mode of action of the 1,4- dihydropyridine calcium antagonists have been reviewed recently in the literature, see Meyer et al.. Annual Reports in Medicinal Chemistry, 1983, Chapter 9 and Janis et al., J. Med. Chem 26, 775 (1983). One of the earliest compounds discovered, and still a standard against which new compounds are measured, is nifedipine (U.S. Patent 3,485,847 to Bossert), in which the 2 and 6 positions are substituted by methyl groups, the 4 position by 2- nitrophenyl and the 3 and 5 positions by carboxylic acid π.athyl ester groups. Similar compounds are disclosed in U.S. Patents 3,455,945; 3,325,505; and 3,441,468 to oew and 3,470,297 and 3,511,837 to Bossert, which introduced variations in the 4-substituent. U.S. Patents 3,905,970 to Bossert et al., ' and 3,985,758 to Maraka i et al., introduced certain mono- or dialkylamino-alkylene and nitrogen-containing heterocyclic alkylene groups into one or both of the 3,5 ester groups. U.S. Patent Nos. 4,307,103 and 4,393,070 to Sato disclose 1,4- dihydropyridines in which the 2 position is not subtituted by alkyl, but instead is substituted with cyano, formyl or certain other substituents and the ester group in the 3 position may contain various substituted alkyl groups including substituted alkylaminoalkyl, heterocyclic aminoalkyl and aroyla inoalkyl, including phthaiimidoethy1. U.S. Patent No. 4,448,964 to Muto et al, discloses compounds in which the 3-position ester group contains certain substituted piperidinyl alkylene groups. It is recognized that useful 1,4-dihydropyridines have a wide variety of structures; however, the need for superior activity and specificity remains, and the effect of any particular structural modification on the properties of the compound is generally unpredictable. This is particularly true of modifications in the esters at the 3 and 5 positions, and of modifications at the 2 and 6 positions. -3- Summary of the Invention According to the invention, there are provided novel compounds of the formula: wherein R j and R 2 are independently selected f rom the group consisting of lower alkyl, N-alkylphthalimido and derivatives of N-alkylphthal imido, wherein said N-alkyl group comprises at least 2 carbon atoms; A is a straight or branched chain hydrocarbon moiety containing f rom 1 to 12 car bon atom s and f r om 0 to 2 double bonds ; R3 is selected f rom the group of radicals consisting of hydrogen, - H2 and -NCS; R4 is an aryl or heteroaryl radical ; and R 5 is a lower alkyl radical or A-R3; provided that when R3 is a hydrogen radical ; at least one of R^ and R 2 is not lower alkyl; and pharmaceutically-acceptable salts thereof. Preferably, A is a radical represented by the general formula - < CH 2> m- wherein is an integer of 1 to 12. R4 is preferably a 3-nitrophenyl, 3-methylphenyl or a 3-trifluoromethylphenyl, radical. In one preferred embodiment of the instant invention at least one of the radicals represented by R j and R 2 are represented by the general formula -(CH 2 ) n - R 6 wherein Rg is selected from the group consisting of: wherein 7 is hydrogen, nitro, cyano, azido, amino, trifluoromethyl, alkylamino, dialkylamino, halo, carboxyl, carbalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyla ino, carboxamido, sulfona ido, and S0 o -(lower alkyl) ; wherein n is an integer of from 2 to 12, and o is an integer from 0 to 2. More preferably, n is 2 and Rg is phthalimido. In another preferred embodiment of the instant invention, R 3 is selected f rom the group consisting of radicals represented by the formulae -NH 2 and -NCS. In this embodiment, R-^, R 2 and R5 are preferably methyl radicals and is preferably 2 , 3 , 6 or 8. In particular, the present invention provides the following novel compounds: 1 , 4-Dihydro-2 , 6-dimethy 1-4- ( 3-ni tropheny 1) -3 , 5- pyridine dicarboxylic acid, 3-(6-aminohexyl) -5-methyl ester. -5- l,4-Dihydro-2, 6-dimeth 1-4- (3-nitrophenyl) -3, 5- pyridine dicarboxylic acid, 3-(3-aminopropyl)-5-methyl ester. 1, 4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5- pyridine dicarboxylic acid, 3-(2-aminoethyl)-5-methyl ester. 1, 4-Dih dro-2, 6-dimethy 1-4- (3-nitrophenyl) -3, 5- pyridine dicarboxylic acid, 3-(6-isothiocyanatohexyl)-5- methyl ester. 1 , 4-Dihydro-2, 6-dimeth 1-4- ( 3-nitropheny 1) -3,5- pyridine dicarboxylic acid, 3-(3-isothiocyanatopropyl)-5- ethyl ester. 1, 4-Dihydro-2, 6-dimethy 1-4- ( 3-nitrophenyl) -3,5- pyridine dicarboxylic acid, 3-(2-isothiocyanatoethyl)-5- methyl ester. 1 , 4-Dihydro-6-methy 1-4- ( 3-nitropheny 1) -2- ( 2- phthalimidoethyl)-3,5-pyridine dicarboxylic acid, 3-ethyl- 5-methyl ester. • 1 , 4-Dihy r 0-4- ( 3-nitr opheny 1) -2, 6- ( 2- phthalimidoethyl)-3,5-pyridine dicarboxylic acid, diethyl ester. 1, 4-Dihydro-2 , 6-dimethy 1-4- ( 3-me hy lpheny 1) -3 , 5- pyridine dicarboxylic acid, 5-methyl-3-(6-phthalimido hex-4-enyl) ester. 1, 4-Dihydro-2, 6-dimethy l-4-(3-methy lpheny 1) -3,5- pyridine dicarboxylic acid, 3-(6-aminohex-4-enyl)-5-methyl ester. 1, 4-Dihy dr o-2, 6-dimethy 1-4 (3-methy lpheny 1) -3,5- pyridine dicarboxylic acid, 3-(6-amino[4,5- 3 H 2 ]hexyl)-5- methyl ester. 1, 4-Dihy dr o-2, 6-dimethy 1-4- (3-me hy lpheny 1) -3,5- pyridine dicarboxylic acid, 3-(2-aminoethyl)-5-methyl ester. l, 4-Dihydro-2, 6-dimethyl-4- (3-methylphenyl) -3 , 5- pyridine dicarboxylic acid, 3-(6-aminohexyl) -5-methyl ester. 1 , 4-Dihydr o-2, 6-dimethy 1-4- (3-meth lpheny 1) -3,5- pyridine dicarboxylic acid, 3-(2-isothiocyanatoe thyl) -5- ethyl ester. 1 , 4-Dih dro-2, 6-dimeth 1-4- (3-meth lpheny 1) -3,5- pyridine dicarboxylic acid, 3-(6-i sothiocyanatohexyl) -5- methyl ester. These compounds are usef ul in the treatment of coronary insufficiency, angina pectoris and hypertension. The invention also provides pharmaceutical compositions containing the above novel compounds and a pharmaceutically acceptable carrier. Preferably these composi tions are in dosage form comprising a cl inically effective amount of the active compound. The invention further provides a method of antagoniz ing the util ization of calcium in the body of a human being or animal and of treating the above disorders. In another embodiment of the invention there is provided a method for preparing the novel compounds. It will be appreciated that certain compounds of the invention are chiral due to their different ester functions. Accordingly, the invention embraces the pure enantiomers as well as mixtures thereof. Pharmaceutically acceptable sal ts of the compounds of the formula are prepared in the conventional manner. Acid addition salts are derived f rom a therapeutically acceptable acid such as hydrochl oric acid, hydrobromic acid, acetic acid, propionic acid and, more preferably, from a di- or poly-basic acid such as phosphoric acid, succinic acid, fumaric acid, citric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, maleic acid or ascorbic acid. A preferred embodiment of this invention is a method of treatment which comprises administering a therapeutically effective amount of a compound of the above formula. In general the daily dose can be from 0.01 mg/kg to 10 mg/kg per day and preferably from 0.2 mg/kg to 4 mg/kg per day, bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must- be given to the patient's weight, general health, metabolism, age and other factors which influence response to the drug. The parenteral dosage will be approximately an order of magnitude lower than the oral dosage. Because the activities of the compounds vary somewhat, the effective dosages will also vary. In another embodiment of this invention there are provided pharmaceutical compositions in dosage unit form which comprise from about 1 g to about 150 mg of a compound of the above formula, and preferably from about 5 mg to about 100 mg. The pharmaceutical composition may be in any form suitable for oral use, such as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents elected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate; granulating and disintegrating agents, such as corn starch, gelatine or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaoline, or as soft gelative capsules wherein the active ingredient is mixed with an oil medium, for example, arachis oil, liquid paraffin or olive oil. The present invention also embraces aqueous suspensions containing the active compound in admixture with suitable pharmacologically-accepted excipients. Such excipients include suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example lecithin, or a condensation product of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyoxyethylene sorbitol monooleate, or condensation product of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin, aspartame, mannitol, sorbitol, or sodium or calcium cyclamate. Dispersable powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents, may also be present. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may also be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension. This suspension may be formulated in a conventional manner using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a sol ution in 1 , 3-butanediol. The pharmaceutical compositions may be tableted or ' otherwise f ormulated so that f or every 100 parts by weight of the composition there are present between 5 and 95 parts by weight of the active ingredient and preferably betw een 25 and 85 pa r ts by wei ght of the active ingredient. The dosage unit form f or humans w ill generally contai n be tw een about 1 mg and 100 mg of the active ingredient of the formula set f orth above. From the foregoing formulation discussion it should be apparent that the compositions of this invention can be administered orally or parenterally. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscul ar, or intrasternal inj ection or inf usion techniques. The compounds of the present invention may also be administered transdermally with the use of an appropriate tranεdermal vehicl e. The preferred vehicle is 1-n- dodecyl azacycl oheptan-2-one, as disclosed in U. S. Patent 4, 405, 616. This invention also includes a method f or treating coronary insufficiency (poor circulation, due to cardiac hypertrophy or to other causes) , hypertension, angina pectoris, cardiac arrythmia, heart attack, or coronary vasospasm by administering an effective amount of a compound of the present invention. The invention also compounds a method for effecting calcium channel antagonist activity in a mammal, such as a human, by administering an effective amount of a compound represented by the above f ormula. The compounds represented by the formula above, may be prepared by the methods used in the Examples, below: The invention is further illustrated by the following examples which are illustrative of various aspects of the invention, and are not intended as limiting the scope of the invention as defined by the appended claims. Example 1 (a) Preparation of 1-Phthalimidomethvl acetoacetate A solution of 10. Og (0.056mol) of N- (hydroxymethyl)phthalimide and 8.02g (0.056mol) of 2,2,6- trimethyl-l,3-dioxen-4-one in 100ml of toluene was refluxed for 24 hours under nitrogen. Recrystallization in ethyl acetate gives 14.3g (97%) of an off-white solid: mp 106-109°C; NMR (CDC1 3 ) 7.6 (4H,m), 5.6 (2H,s), 3.4 (2H,s), 2.18 (3H,s); lb) Preparation of 1.4-Dihydro-2.6-dimethvl-4-(3- - nitrophenyl-3.5-pyridine dicarboxylic acid. 5-methγl-3- phthalimidomethyl ester A solution of 4.0g (0.015mol) of 1- phthalimidomethylacetoacetate, 1.76g (0.015mol) of methyl 3-aminocrotonate, and 2.31g (0.015mol) of m- nitrobenzaldehyde in 50 ml of isopropanol was refluxed overnight under N 2 . The yellow solid formed was filtered, washed with ethyl acetate, and dried in vacuo. Recrystalliza in ethyl acetate gives 4.38g (59%) of a yellow powder: mp 24 252°C; NMR (CDCI3) 7.6 (9H,m), 5.5 (2H,m), 4.84 (lH,s), 3.48 (3H,s), 2.3 (6H,s). 1— Preparation ___a l,4-Pihy3ro-2,6-<aijDethyl~4-(3- nitrophenvl)-3.5-pyridine dicarboxylic acid. 3- aminomethγl-5-methγl ester To a solution of (3.15mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 5-methyl-3-phthalimidomethyl ester in chlorof or /methanol (1:2 V/V) is added 0.9ml (12.6mmol) of 40% aqueous methylamine and the mixture is stirred at ambient temperature for 24 hours. The solvent is removed in vacuo and the residue is subjected to flash chromatography (silica gel/ethyl acetate) to yield a pale yellow hygroscopic solid. Example 2 Preparation of 1.4-Dihydro-2.6-dimethγl-4-(3- methylphenyl)-3.5-pyridine dicarboxylic acid. 3-(2- aminoethyl)-5-methyl ester To a solution of l,4-dihydro-2, 6-dimethy l-4-(3-methyl phenyl)-3,5-pyridine dicarboxylic acid, 5-methyl-3-(2- phthalimidoethyl) ester in chlorof orm/methanol (1:2 V/V) was added 0.9ml (12.6mmol) of 40% aqueous methylamine and the mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was subjected to flash chromatography (silica gel/ethyl acetate) to yield 400mg (38%) of a pale yellow hygroscopic solid: NMR (CDC1 3 ) 6.9 (4H,m), 6.0 (lH,bs), 4.7 (lH,s), 3.9 (2H,q), 3.5 (3H,s), 2.6 (2H,t), 2.3 (3H,ε), 2.2 (6H,s), 1.5 (2H,ε). Anal. Calcd. C 19 H 2 N 2 0 4 : C,66.26; H, 7.02; N, 8.13. Found: C,66.10; H,7.23; N,7.89. Example 3 Preparation of 1.4-Dihydro-2.6-dimethyl-4-(3-nitrophenγl)- 3.5-py rifling dicarb xyl c acid. 3- ( 2-aminoethyl ) -5-methγl ester To a solution of 0.5g (0.99mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 5-methyl-3-(2-phthalimidoethyl) ester in chlorof orm/methanol (1:1 V/V) was added 0.34ml (3.96mmol) of 40% aqueous methylamine and the mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was purified by thin layer chromatography on silica gel using 1:1 V/V ethyl acetate/methanol to give 150mg (31%) of a pale yellow hygroscopic solid: mp 152-154°C; NMR (CDC1 3 ) 7.9- 7.1 (4H,m), 6.5 (lH,s), 5.0 (lH,s), 4.0 (2H,t), 3.6 (3H,ε), 2.9 (2H,t) " , 2.35 (6H,s) 1.3 (2H,s). Example 4 J_xe£_aj_a on of l,4-Dihydro-2.6-diJDethyl-4-(3-nitrophenyl)- 3.5-pyridine dicarboxylic acid. 3-(3-aminopropyl)-5- roethyl ester To a solution of l.Og (1.92mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 5-methyl-3-(3-phthalimidopropyl) ester was added 0.663ml (7.7mmol) of 40% aqueous methylamine in chlorof orm/methanol (1:1 V/V) and the mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo and the residue was subjected to flash chromatography on silica gel using a 1:1 V/V ethyl acetate/methanol to give 0.46g (62%) of a yellow oil: NMR (CDCI3) 7.45 (5H,m), 4.95 (lH,s), 4.0 (2H,t), 3.51 (3H,s), 2.55 (2H,m), 2.29 (6H,s), 1.6 (4H,m). Example 5 Preparation of 1.4-Dihydro-2.6-dimethyl-4-(3- jpethylphenyl)-3,5-pyridine dicarboxylic acid, 3-(6- aminQhexyl)-5-methyl ester To a solution of 350mg (0.66mmol) of l,4-dihydro-2,6- dimethyl-4-(3-methylphenyl)-3,5-pyridine dicarboxylic acid-5-methyl-3-(6-phthalimidohexyl) ester was added 0.68ml (7.9mmol) of 40% aqueous methylamine and the -14- mixture was stirred at ambient temperature for 5 days. The solvent was removed in vacuo and upon acid/base extraction of the residue a yield of 140mg (55%) of a pale yellow solid was obtained: mp 133-139°C; NMR (CDC1 3 ) 6.9 (4H,m), 6.4 (lH,s), 4.8 (lH,s), 3.9 (2H,t), 3.6 (3H,s), 2.6 (2H,m), 2.2 (9H,s), 1.4 (10H,m). Example 6 ■ EJ..eg.aJ..atiQn of 1.4-Dihγdro-2.6-dimethyl-4-(3-nitrophenyl)- 3.5-pyridine dicarboxylic acid. 3-(6-aminohexyl)-5- methyl ester To a solution of 1.43g (2.55mmol) of 1,4-dihydro- 2, 6-dimethy 1-4- (3-nitrophenyl) -3, 5-pyridine dicarboxylic acid, 5-methyl-3-(6-phthalimidohexyl) ester was added 0.88ml (7.1mmol) of 40% aqueous methylamine in chlorof orm/methanol (1:1 V/V) and the mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo, and the residue was subjected to flash chromatography on silica gel using ethyl acetate/methanol (1:1 V/V) to give a yellow oil. Recrystallization from diethyl ether and chloroform gave 0.72g (66%) of the product: p 141-143°C; NMR (CDCI3) 7.5 (5H,m), 4.98 (lH,s), 3.94 (2H,t), 5.7 (3H,s), 2.63 (2H,m), 2.32 (6H,ε), 1.4 (10H,m). The "deblocking" of the phthalimido derivativeε (to yield the corresponding amine) by reaction with a primary alkyl amine, preferably an alkylamine having up to 5 carbon atomε, e.g. methylamine or ethylamine, waε effected without reaction of the eεter group in the 5-position of the 1,4-dihydropyridine ring. Thiε is in contrast to "deblocking" of similar phthalimido derivatives with reactants such as hydrazine. -15- Example 7 Preparation of 1.4-Dihγdro-2.6-dimethvl-4-(3- nitrophenyl)-3ι5-pyridine dicarboxylic acid, 3-(2- isothiocyanatoethyl) -5-methyl ester A solution of 183.2mg (0.488mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 3-(2-aminoethyl) -5-methyl ester in chloroform, 239 mg (2.84 mmol) of sodium bicarbonate in water, and 65 microliter (0.855mmol) of thiophosgene waε vigorouεly εtirred for 1 hour at room temperature. The chloroform phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by thin layer chromatography on silica gel using 8:2 V/V chloroform/ethyl acetate to yield a yellow hydroscopic solid: mp 162-164°C; Anal. Calcd. for C 19 H lg N 3 0 6 S: C, 54.67; H, 4.59; N, 10.07. Found: C,54.46; H, 4.80; N,9.96. Example 8 Preparation of 1.4-Dihydro-2.6-dimethyl-4-(3-nitrophenyl)- 3.5-pyridine dicarboxylic acid. 3-(3- isothjocyanatopropyl) -5-methyl ester A solution of 227mg (0.583mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 3-(3-aminopropyl) -5-methyl ester in chloroform, 0.263 mg (3.13mmol) of sodium bicarbonate in water, and 78 microliters (1.02mmol) of thiophoεgene was vigorously stirred for 1 hour at room temmperature. The chloroform phaεe waε waεhed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by thin layer chromatography on silica gel using 8:2 V/V chloro orm/ethyl acetate to yield a yellow, hygroscopic solid: mp 154-155°C; Anal. Calcd. for C 20 H 21 N 3°6 S: C,55.68; H,4.91; N,9.74. Found: C,55.81; H,5.13; N, 9.46. Example 9 Preparation of 1.4-Dihydro-2.6-dimethγl-4-(3-nitrophenvl)- 3.5-pyridine dicarboxylic acid. 3-(6-isothiocyanatohexγl)- 5-methyl ester A solution of 182.6mg (0.423mmol) of l,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid, 3-(6-aminohexyl) -5-methyl ester in chloroform, 207 mg (2.45mmol) of sodium bicarbonate in water, and 57 icroliters (0.741mmol) of thiophosgene was vigorously stirred for 1 hour at room temperature. The chloroform phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by thin layer chromatography on silica gel using 8:2 V/V chloroform/ethyl acetate to yield a yellow, hygroscopic solid: mp 67-68°C; Anal. Calcd. for C 23 H 27 N 3°6 S; C,58.34; H, 5.75; N,8.87. Found: C, 58.13; H,6.00; N,8.71. Example 10 1—. Preparation of 4-Tetrahydropγranγloxy-l-butanol A solution of 11.72g (0.13 mol) of 1,4-butanediol, 10. Og (0.12mol) of dihydropyran and lOmg of p-toluene sulfonic acid in tetrahydropyran waε stirred under nitrogen for 24 hours. Pyridine was added, and the solvent was removed in vacuo. The residue was subjected to flash chromatography (silica gel; petroleum ether/ethyl acetate 3:2 V/V) to give 9.64g (43%) of a clear oil: NMR (CDC1 3 ) 4.45(lH,s), 3.52(6H,m), 2.68(lH,m), 1.6(10H,m). Ibl Preparation of 4-Tetrahvdropvranvloxv-l-butanal A solution of 10.7g (62mmol) of 4-tetrahydropyranyloxy- 1-butanal in dichl or ome thane was added to 34.7g (92mmol) of pyridinium dichromate in dichloromethane and stirred for 24 hours at ambient temperature. Petroleum ether/diethyl ether (1:1 V/V) was added, and the mixture was filtered. The filtrate was concentrated in vacuo and the residue distilled to give 3.23g of a clear oil: bp 58- 60°C/0.5mm Hg; NMR (CDCI3) 9.5(lH,s), 4.4(lH,ε), 3.45(4H,m),2.41 (2H,m), 1.53(8H,m). —ύ Preparation of 2-(Phthalimidoethyl)-triphenyl phoεphonium bromide according to a method of Olsen et al.. JOC 45 4049 (1980) A solution of ll.llg (44mmol) of 2-bromoethyl phthalimide and 11.47g (44mmol) of triphenylphosphine in xylene was refluxed for 36 hours. The mixture was cooled, filtered, washed with diethyl ether, and dried to yield 12.5g of a white solid: mp 246-247°C; NMR (CDCI3) 7.5 (19H,m), 4.34 (4H,m). Iβl Preparation of l-Phthaliιτιido-6-tetrahydropyranyloxy- 2-hexene To a solution of 1.5g (2.9mmol) of 2-(phthalimidoethyl) triphenylphosphonium bromide and 325 mg (2.9mmol) of potaεεium tert-butoxide in tetrahydropyran waε added 0.5g (2.9mol) of 4-tetrahydropyranyloxy-l-butanal. The mixture was refluxed for 17 hours, filtered, and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, the organic phase dried, concentrated in vacuo, and the residue subjected to flash chromatography (silica gel; petroleum ether/ethyl acetate 9:1 V/V) to give O.llg of a yellow oil: NMR (CDCI3) 7.53 (4H,m), 5.38 (2H,m), 4.48 (lH,s), 4.2 (2H,d), 3.5 (4H,m), 2.24 (2H,m), 1.54 (8H,m). (e) Preparation of 1.4-Dihydro-2.6-dimethvl-4-(3-methvl phenyl)-3,5-pyridine dicarboxylic acid, 5-methγl-3-(6- phthalimidohex-4-enyl) ester A solution of 1.8g (5.7mmol) of l-phthalimido-6- tetrahydropyranyloxy-2-hexene, 2.67g (δ.lmmol) of 1,4- dihy dr 0-2, 6-dimethy 1-4- ( 3-methy lpheny 1) -3,5-pyridine dicarboxylic acid, dimethyl ester and 10 mg of p-toluene sulfonic acid in toluene was refluxed under nitrogen for 72 hours. The solvent was removed in vacuo, and the residue was subjected to flash chromatography (silica gel; petroleum ether/diethyl ether 3:2 V/V) to give 0.69g of a yellow, hygroscopic solid: NMR (CDCI3) 7.57(4H,m), 6.9(4H,m), 6.12(lH,s), 5.35(2H,m), 4.85(lH,ε), 4.05(4H,m), 3.56(3H,ε), 1.6-2.4 (13H, m) . 1£1 Preparation __ 1.4-Dihydro-2.6-dimethvl-4-(3- methγlphenyl)-3.5-pyridine dicarboxylic acid. 3-(6- aminohex-4-enγl) -5-methyl ester A solution of 0.69g (1.3mmol) of l,4-Dihydro-2,6- di e hy 1-4- (3-methy lpheny 1) -3, 5-pyri dine dicarboxylic acid, 5-methyl-3-(6-phthalimidohex-4-enyl) ester and 1.2 ml (14 mmol) of 40% aqueous methylamine in chlorof orm/methanol (1:1) V/V was stirred at ambient temperature for 48 hours. The solvent was removed in vacuo and upon acid/base extraction of the residue, 0.23g of product was obtained as a yellow oil: NMR (CDCI3) 6.85(4H,m), 6.4(lH,s), 4.85(lH,ε), 3.9(2H,t), 3.52(3H,ε), 3.1(2H,m), 2.2-1.3(15H,m). Anal. Calcd. for C 23 H3 0 N 2 O : C, 69.32; H, 7.59; N, 7.03. Found: C, 69.43; H, 7.60; N, 7.13. Example 11 Preparation of 1, 4-Dihydro-2r6-dijnethy 1-4(3- methylphenyl)-3.5-pyridine dicarboxylic acid. 3-(6- amino f 4.5-^H l hexyl) -5-methyl ester Tritiation of the 4-hexenyl double bond was performed by the National Tritiation Facility, Berkeley, CA. To a solution of 85mg (0.21mmol) of l,4-dihydro-2, 6-dimethy 1- 4-(3-methylphenyl)-3,5-pyridine dicarboxylic acid, 3-(6- aminohex-4-enyl) -5-methyl ester in tetrahydrof uran was added 30 mg of 10% Pd/C and 2 drops of [ 3 H] acetic acid. This mixture was subjected to hydrogenation using tritium gas. After removal of the excess tritium, catalyst, and solvent, the residue was treated with thiophosgene as described in the preparation of l,4-dihydro-2,6-dimethyl- 4(3-methylphenyl)-3,5-pyridine dicarboxylic acid, 3-(6- isothiocyanatohexyl)-5-methyl ester, above. The tritiated NCS derivative was identified by comparison with the untritiated material, which has virtually the same physical and spectral characteristics. Example 12 la} preparation of N-Phtha ylalanine A mixture of 89.09g (l.Omol) of ^-alanine and 148.12g (l.Omol) of phthallic anhydride was stirred at 180°-190°C for 30 minutes. Upon adding water, a solid formed which was filtered, washed with water, and recrystallized in ethanol/water to give 178.0g of a white powder: mp 152- 153°C; NMR (CDC1 3 ) 7.8 (4H,s), 4.0 (2H,t), 2.7 (2H,t). lb) Preparation of (3-Phthalimido) ropionvl chloride 87.6g (0.4mol) of N-phthalylalanine was added to a stirring suspenεion of 83.2g (0.4mol) of phosphorus pentachloride in toluene at 60°C under nitrogen. After the mixture was stirred for 2 hours, the solvent and excess phosphoruε pentachloride were removed to give a white solid. Recryεtallization in benzene/petroleum ether yielded 76.0g of a hygroscopic white powder: mp 94-99°C; NMR (CDCI3) 7.7 (4H,m), 3.9 (2H,t), 3.2 (2H,t). lsl Preparation of 2-(l-Oxo-3-phthalij_idopropyl) diethylmalonate A solution of 18.9g (llδmmol) of diethyl alonate in ethanol was added slowly to a mixture of 2.8g (llδmmol) of magnesium turnings in ethanol under nitrogen. Upon complete addition, diethyl ether was added and the reaction mixture was refluxed for 3 hours. The solvent was removed in vacuo, the residue dissolved in diethyl ether, and a solution of 28g (llδmmol) of (3-phthalimido) propionyl chloride in diethyl ether/tetrahydrof uran (3:1) V/V was added to the disεolved residue. After refluxing for 2 hours, 150 ml of 10% H 2 S0 4 (by wt.) was added to the mixture. The organic layer was separated, washed with 10% sodium bicarbonate and water, dried, and the solvent removed to give a viscouε oil which cryεtallized. Recryεtallization in dichloromethane/diethyl ether/petroleum ether yielded 32.0g of a white powder: mp 66-69°C; NMR (CDCI3) 7.6 (4H,bε), 4.0 (6H,m), 2.8 (3H,m), 1.2 (6H,m). 1_2_ Preparation of 3-Oxo-5-Phthalimidopentanoic acid. Ethyl Ester 2-(l-Oxo-3-phthalimidopropyl)diethyl malonate (6.4g, 180mmol) waε εteam diεtilled for 3 hours. The pot flask was cooled, extracted into dichloromethane, dried, and the solvent removed in vacuo to give a pale yellow solid. Recrystallization in ethanol yielded 40.Og of a white solid: mp 90-92°C; NMR (CDC1 3 ) 7.6 (4H,m), 3.9 (4H,m), 3.4 (2H,s), 2.9 (2H,t), 1.3 (3H,t). I—. Preparation of 1.4-Dihydro-6-methγl-4(3-nitrophenyl)- 2-(2-phthalijπidoethyl)-3 t 5-pyridine dicarboxylic acid-3-ethyl-5-methyl ester A solution of 6.0g (20mmol) of 3-Oxo-5- p thalimidopentanoic acid, ethyl eεter, 3.1g (20mmol) of 3-nitrobenzaldehyde, 2.3g (20mmol) of methyl 3- aminocrotonate and 2-propanol waε refluxed under nitrogen for 20 hours. The solvent was removed in vacuo, and the residue subjected to flash chromatography (silica, 8:1 V/V diethyl ether/pe roleum ether) to give a yellow soli3. Recrystallization in dichloromethane/diethyl ether/petroleum ether yielded 4.0g of a yellow solid: mp 136-138°C; NMR (CDCI3) 7.5 (δH,m), 6.6 (lH,s), 5.0 (lH,ε), 4.0 (2H,q), 3. δ (2H,m), 3.5 (3H,ε), 3.0 (2H,q), 2.2 (3H,ε), 1.2 (3H,t). Example 13 Preparation of 1.4-Dihydro-4(3-nitrophenyl)-2.6-(2- phthalimidoethyl)-3.5-pyridine dicarboxylic acid, ethyl ester A εolution of 5.0g (17mmol) of 3-oxo-5- phthalimidopentanoic acid, ethyl eεter, 1.28g (9mmol) of 3-nitrobenzaldehyde, 0.62ml (9.4mmol) of concentrated ammonium hydroxide, and ethanol waε refluxed for 72 hours under nitrogen. The εolvent waε removed in vacuo and the residue waε εubjected to flash chromatography (silica, 8:2 V/V petroleum ether/diethyl ether) to give 2.0g of a yellow solid: mp 115-117°C; NMR (CDCI3) 7.5 (12H,m), 4.9 (lH,s), 3.9 (8H,m), 3.4 (4H,q), 1.2 (6H,t). Example 14 The activity of the compounds of this invention may be demonstrated by the following binding aεεay. The assay was carried out as described by Fairhurεt et al., Life Scienceε, 32, 1331 (1983). Washed rabbit skeletal muscle membranes (fraction 2-8X) were incubated for 30 minutes at 25°C in 2 ml final volume of medium containing 12.5 mM HEPES buffer pH 7.4 and 0.5 x 10 "9 M/ 3 H- nitrendipine having a specific activity of approximately • 17 Ci/mmol. Parallel experiments contained, additionally, unlabelled nifedipine at a final concentration of 10~ 6 M, to give the non-specific binding values. The incubation tubes were rapidly chilled in ice and the contents filtered through Whatman GF/B filters on a Millipore manifold, and the filters washed with 2 x 10 ml ice-cold HEPES buffer. The filters were placed in scintillation counting vials with δ ml of Cytoscint cocktail, disrupted mechanically by shaking for 30 minutes and counted. Specific binding was determined by subtracting the radioactivity in the presence of nifedipine from that in the absence. Drugs which interact at the dihydropyridine (DHP) site will reduce this specific binding in a dose- dependent manner. The assays for the compounds of this invention were made with logarithmically spaced concentrations, the data were plotted on a probit- concentration plot, and the IC50 read off. The K χ of the compound was calculated by εtandard techniques. The results of the asεay were εhown in Table I below. -23- Table I Ex. No. *1 JB 2 AcBj B A H Bindinα Assa KI (moles) 2 CH CHr C 2 H 4 NH 2 3-methy 1- CH 3 1.25 x 10 "6 phenyl 3 CH CH. C 2 H 4 NH 2 3-nitro- CH 3 >10 "7 phen l " 7 CH CH- C 2 H 4 NCS 3-nitro- CH 3 1.3 x 10~ 9 phenyl CH- CH- C 3 HgNCS 3-nitro- CH 3 1.6 x 10 "9 phenyl CH-. CH-. CgH 12 NCS 3-nitro- CH 3 1.9 x 10 "9 phenyl 12(e) CH 3 2-phthali- C 2 H 5 3-nitro- CH 3 1.05 x 10 "7 midoethyl phenyl 13 2- 2-ph hali- 2 H 5 3-nitro- C 2 H 5 1.12 x 10 "6 phthal- midoethyl phenyl imido- ethyl 14 nifedipine CH 3 7.6 x 10 -9 -24- While particular embodiments of the invention have been described it w ill be understood of course that the . invention is not limited thereto since many obv ious modifications can be made and it is intended to include within this invention any such modif ications as will fall within the scope of the appended claims.

Claims: What is claimed is: 1. Compounds represented by the general formula: ^ and R are each independently selected from the group consiεting of lower alkyl, N-alkylphthalimido and derivatives of N-alkylphthalimido, wherein said N-alkyl group comprises at least 2 carbon atoms; A is a straight or branched chain hydrocarbon moiety containing from 1 to 12 carbon atoms and from 0 to 2 double bonds; R3 is selected from the group of radicals consisting of hydrogen, -NH 2 and -NCS; R 4 is an aryl or heteroaryl radical; and R5 is a lower alkyl radical or A-R 3 ; provided that when R3 is a hydrogen radical at least one of R^ and R 2 is not lower alkyl, including both pure enantiomers as well as mixtures thereof; and pharmaceutically-acceptable salts thereof. 2. A compound according to Claim 1 wherein A is a radical represented by the general formula -< CH 2>πT and is an integer of from 1 to 12. 3. A compound according to Claim 2 wherein R 4 is a radical selected from the group consisting of 3- nitrophenyl, 3-methyl phenyl and 3-trifluoromethylphenyl. 4. A compound according to Claim 3 wherein at least one of the radicals represented by R- and R 2 are represented by the general formula -(CH 2 ) n -Rg wherein Rg is selected from the group consiεting of: wherein R7 iε hydrogen, nitro, cyano, azido, amino, trifluoromethyl, alkylamino, dialkylamino, halo, carboxyl, carbalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, acylamino, carboxamido, εulfona ido, and SO Q -(lower alkyl); wherein n iε an integer of from 2 to 12 and o iε an integer from 0 to 2. 5. A compound according to Claim 4 wherein n is 2 and Rg is phthalimido. 6. A compound according to Claim 5 wherein R^ is methyl. 7. A compound according to Claim 5 wherein both R^ and R 2 are N-ethylphthalimido radicals. 8. A compound according to Claim 6 wherein R 5 is a methyl radical, and A-R 3 together represent an ethyl radical. 9. A compound according to Claim 7 wherein R 5 is an ethyl radical and A-R 3 together represent an ethyl radical. 10. A compound according to Claim 3 wherein R 3 is selected from the group consisting of -NH 2 and -NCS. 11. A compound according to Claim 10 wherein R 5 is a methyl radical and m is an integer of from 2 to 12. 12. A compound according to Claim 11 wherein R j and R 2 are methyl radicals. 13. A compound according to Claim 12 wherein m iε 2, 3, 6 or 8 and R 3 is -NH . 14. A compound according to Claim 12 wherein m is 2, 3, or' 6 and R 3 is -NCS. 15. A compound according to Claim 13 wherein R 4 iε 3-nitrophenyl and m is 2. 16. A compound according to Claim 14 wherein R is 3-nitrophenyl and m is 2. 17. A compound according to claim 13 wherein m is 3 and R 4 is 3-nitrophenyl. 18. A compound according to claim 14 wherein m is 3 and R 4 is 3-nitrophenyl. 19. A compound according to Claim 13 wherein R 4 is 3-nitrophenyl and m iε 6. 20. A compound according to Claim 14 wherein R 4 is 3-nitrophenyl and m is 6. 21. A compound according to claim 13 wherein m is 6, and R is 3-methyl phenyl. 22. A compound according to claim 14 wherein m is 6 (with a double bond at carbons 4-5) and R is 3- me thy 1 phenyl. 23. A compound according to claim 13 wherein R 4 is 3-methylphenyl and m is 2. 24. A compound according to claim 14 wherein R 4 is 3 -methyl phenyl and m is 2. 25. A compound according to claim 13 wherein R 4 is 3-methyl phenyl and m is 6. 26. A compound according to claim 14 wherein R is 3-methyl phenyl and n is 6. 27. A method for treating coronary insufficiency, hypertension, angina pectoris, cardiac arrythmia, heart attack, or coronary vasospasm, comprising the step of administering an effective amount of a compound of Claim 1. 28. The method of Claim 27, wherein the compound is a compound of Claim 3. 29. The method of Claim 27, wherein the compound is a compound of claim 4. 30. The method of Claim 27, wherein the compound is a compound of claim 7. 31. The method of Claim 27, wherein the compound is a compound of Claim 8. 32. The method of Claim 27, wherein the compound is a compound of Claim 12. 33. The method of Claim 27, wherein the compound is a compound of Claim 13. 34. The method of Claim 27, wherein the compound is a compound of Claim 14. 35. A process for the preparation of l,4-Dihydro-4- aryl-(or 4-heteroaryl-)3,5-pyridine dicarboxylic acid, 3- aminoalkyl-5-alkylester which compriεeε reacting the correεponding l,4-Dihydro-4-aryl (-or 4-heteroaryl-)3,5- pyridine dicarboxylic acid, 3-phthalimidoalkyl-5-alkyl eεter with a primary alkylamine. 36. The process of claim 35 wherein said primary alkylamine is selected from the group consiεting of alkylamineε having from 1 to about 5 carbon atomε. 37. The proceεε of claim 36 wherein εaid primary alkylamine iε selected from the group consiεting of methylamine and ethylamine. 3δ. The proceεε of claim 37 wherein εaid primary alkylamine is methylamine. 39. As a compound, l,4-dihydro-2,6-dimethyl-4-(3- methylphenyl)-3,5-pyridine dicarboxylic acid, 3-(6- aminohex-4-enyl) -5-methyl eεter. 40. As a compound, l,4-dihydro-2,6-dimethyl-4-(3- methylphenyl)-3,5-pyridine dicarboxylic acid, 3-(6- amino [4, 5- 3 H 2 ]hexyl) -5-methyl ester. 41. The method of claim 27, wherein the compound is the compound of claim 39. 42. The method of claim 27, wherein the compound is the compound of claim 40.

Inventors: MINASKANIAN GEVORK, MINASKANIAN, GEVORK
Applicants: NELSON RES & DEV, NELSON RESEARCH AND DEVELOPMENT COMPANY
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, C07D211, C07D401