Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
  • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• This invention relates to new dihydropyridine derivatives which possess antihypertensive properties.
• nifedipine is dimethyl 1,4-dihydro-2,6-dimethyl-4-o-nitrophenyl- pyridine-3,5-dicarboxylate.
• nilvadipine is characterized by having cyano group at the 2-position in 1,4-dihydropyridine in place of alkyl group.
• Patent No. 194,751 Japan Koukai No. 86-12662, Japan
• W represents a cyano or halo alkyl group in which the alkyl group has 1 to 6 carbon atoms
• R represents an alkyl group having 1 to 6 carbon atoms?
• R and R whxch may be the same or dxfferent, each represents an alkyl group having 1 to 6 carbon atoms
• X and Y which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a nitro group
• Ar represents an optionally substituted aryl group and A represents an alkylene group having 1 to 10 carbon atoms; or an acid addition salt thereof.
• the aryl group Ar is preferably an optionally substituted phenyl or naphthyl group.
• the substituents are in the ortho and/or para position to the oxy of the aryloxy group ArO-.
• Suitable substituents are for example alkoxy radicals having 1 to 6 preferably 1 to 4 carbon atoms, a halogen atom such as fluorine, chlorine or bromine and an alkyl group having 1 to 6 preferably 1 to 4 carbon atoms.
• Ar is a substituted phenyl group.
• Ar is substituted phenyl are 2-methoxyphenoxy, 4- methoxyphenoxy, 2-chloro-phenoxy, 4-chlorophenoxy 2- methylphenoxy, 2,4,6-trimethylphenoxy 4-bromophenoxy groups and 4-(N-methylsulphonyl)aminophenoxy.
• lower alkyl group means a saturated hydrocarbon grouping which is straight-chained or branched and which contains 1 to 6 preferably 1 to 4 carbon atoms.
• Suitable halogen atom associated with X and/or Y is, for example fluorine, chlorine or bromine and the preferred alkyl group associated with X and for Y is methyl.
• alkylene group of 1 to 10 carbon atoms means straight or branched bivalent paraffinic hydrocarbon residue of
• the acid-addition salt of the dihydropyridine derivatives of the invention may be for example, a salt derived from an inorganic acid, for example a hydrochloride or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, beta-naphthoate, adipate, methanesulphonate, benzenesulphonate or p- toluenesulphonate.
• an inorganic acid for example a hydrochloride or sulphate
• a salt derived from an organic acid for example an oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, beta-naphthoate, adipate, methanesulphonate, benzenesulphonate or p- tol
• the dihydropyridine derivatives of the invention may be proposed by any chemical process known to be useful for manufacture of chemically analogous compounds.
• One preferred process for preparing the dihydropyridine compounds of this invention comprises the reaction of an amine of the fo.rmula:
• reactive functional group for example, a methanesulphonyloxy, benzenesulphonyloxy, p- toluenesulphonyloxy, m-nitrobenzenesulphonyloxy, p- nitrobenzenesulphonyloxy, chloro, bromo or iodo group.
• a second preferred process for manufacturing the dihydropyridine compounds of this invention comprises the reaction of a dihydropyridine derivative of the formula:
• Z represents a suitable leaving group (reactive functional group) , for example, a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bromo or iodo group, with an a ine of the formula:
• dihydropyridine compounds of this invention may also be prepared, by reduction of an aminoketone of the formula:
• R denotes the remainder of the molecule of the compounds of this invention as hereinbefore defined, Ar being phenyl or naphthyl, with an appropriate reducing agent such as sodium borohydride in alcohol.
• W is a cyano group
• the dihydropyridines of this invention may be prepared by removal of acetic acid from an oxime acetate of the formula:
• R 1 represents the remainder of the molecule of the compounds of this invention as hereinbefore defined by means of heating, for example, in acetic anhydride.
• the dihydropyridine reaction product of this invention can be separated and isolated from the reaction mixture and purified by methods commonly used or such purposes for instance, extraction with a suitable solvent, chromatography precipitation, recrystallization etc.
• the dihydropyridines of this invention include at least two pairs of optical isomers due to the presence of an asymmetric carbon atom at the fourth position of the 1,4-dihydropyridine nucleus and an asymmetric carbon atom in the 3-aryloxy-2-hydroxypropylamino moiety and thus can exist as each optical isomer or a mixture thereof.
• a racemic mixture of the optical isomers may be resolved into each optical isomer by a conventional method for racemic resolution, such as a chemical resolution of the salts of the diastereomer with a conventional optically active acid (e.g. tartaric acid or camphor sulfonic acid, etc.).
• the compounds of this invention and their pharmaceutically acceptable salts possess strong and long lasting vasodilating and anti-hypertensive activities and are useful for therapeutical treatment in cardiovascular disorders and in hypertension such as coronary insufficiency, angina pectoris or myocardinal infarction, and hypertension.
• the radical W may be selected from the group consisting of cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, dichloromethyl, monochloromethyl,
• the preferred substitution pattern of the substituents on the phenyl ring at the fourth position on the dihydropyridine nucleus is selcted from 1,2,3,5-, 1,2,4,5-, 1,2,3-, 1,2,4-, 1,2,5-, 1,2,6-, 1,3,4-,
• the dihydropyridine compound of this invention may be administered in a daily dosage of from 0.1 to 500 g, preferably 1 to
• compositions of this invention comprise, as an active ingredient, the dihydropyridine compound or pharmaceutically acceptable salt thereof in an amount of about 0.01 mg. to about 500 g., preferably about 0.1 mg. to about 250 mg. per dosage unit for oral and parenteral use.
• the amount of the active ingredient in the dosage unit form may be determined by considering the activity of the ingredient as well as the size of the host human being.
• the active ingredient may usually be formulated in a solid form such as tablet, granule, powder, capsule, troche, lozenge or suppository, or a suspension or solution form such as syrup, injection, emulsion, lemonade, etc. and the like.
• a pharmaceutical carrier or diluent includes solid or liquid non-toxic pharmaceutically acceptable substances.
• solid or liquid carriers or diluents examples include lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil, or sesame oil, cacao butter, ethyleneglycol or the other conventional ones.
• the carrier or diluent may include a time delay material such as glyceryl monostearate, glyceryl distearate, a wax and the like.
• Three Wistar rats were used per group. Each animal was placed in a cage sized to the body after cannulation of catheters into the femoral artery and vein under ether anesthesia. Blood pressure was measured in the femoral artery by means of a pressure transducer and recorded as electrically integrated values of mean arterial pressure. Heart rate was counted from instant arterial pressure pulses by running the record paper at a faster speed periodically.
• test compound was administered intravenously through a catheter cannulated in the femoral vein more than 2 hours after the completion of the operation.
• Porcine thoracic aorta was obtained from a slaughterhouse. The fat and connective tissues were removed and the vascular tissue was frozen at -80°C. The frozen tissue was thawed in a buffer (0.25M sucrose, lOmM MOPS, pH7.4) and homogenized in the same buffer by polytoron (Kinematica) . After filtration of the homogenate through gauzes, the filtrated homogenate was homogenized using a teflon glass homogenizer. The homogenate was centrifuged (l,000g x 10 min). The supernatant was centrifuged (10,000g x 10 min.) twice.
• [ ⁇ i H]PN200-110 (O.lnM) was incubated with 50 ⁇ l of the membrane preparation at 37°C for 90 minutes in a final volume of 200 pi. At the end of the incubation period, reaction mixture was quickly filtrated over a
• SD strain rats were sacrificed by decapitation.
• the heart was removed and homogenized in buffer (0.25M sucrose, lOmM MOPS, pH7.4) by using Polytoron (Kinematica) .
• the homogenate was homogenized using a teflon glass homogenizer.
• the homogenate was centrifuged (l,000g x 10 min.) to remove tissue clumps and the supernatant was centrifuged (10,000g x 10 min) twice. The supernatant was again centrifuged
• Example 6 The procedure described in Example 6 was followed using 5-isopropyl 3-methyl 4-[2-(4-bromobutoxy)- 5-nitrophenyl]-2-trifluoromethyl-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (0.65g, 1.lOm ol) and 2-hydroxy-3-phenoxypropylamine (0.93g, 5.60mmol) as starting materials.
• Example 6 The procedure described in Example 6 was followed using dimethyl 4-[3,5-dichloro- 2-(4-bromobutoxy)phenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3 I 5- dicarboxyiate (0.74g) and 2-hydroxy-3-phenoxypropylami ⁇ e (1.08g) as starting materials.
• Example 6 The procedure described in Example 6 was followed using 3-ethyl 5-methyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-phenoxypropylami ⁇ e (0.45g) as starting materials. 3-Ethyl 5-methyl 4-[2- ⁇ 4-(2-hydroxy-3-phenoxypropylamino)butoxy ⁇ -5- nitrophenyl]-6-methyI-2-trifluoromethyl-1,4Hdihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.43g).
• Example 2 Under similar conditions to Example 1 starting from 5-ethyl 3-methyl 4- ⁇ 2-(2- bromoethoxy)-5-nitrophenyl ⁇ -2-cyano-6-methyl-1,4-dihydropyridine-3,5- dicarboxylate(405mg) and 2-hydroxy-3-phenoxypropylamine (548mg) was obtained 5- ethyl 3-methyl 2-cyano-4-[2- ⁇ 2-(2-hydroxy-3-phenoxypropylamino)ethoxy ⁇ -5- nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (86mg) as yellow crystals. mp 191-193 'C (from CH2CI2);
• Example 6 The procedure described in Example 6 was followed using 3-ethyl 5-isopropyl 4-[5- (4-bromobutoxy)-2-nitrophe ⁇ yI]-6-methyl-2-trifluoromethyI-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.40g) and 2-hydroxy-3-phenoxypropylamine (0.45g) as starting materials.
• Example 6 The procedure described in Example 6 was followed using diethyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-phe ⁇ oxypropylamine (0.43g) as starting materials. Diethyl 4-[2- ⁇ 4-(2-hydroxy-3-phenoxypropylamino)butoxy ⁇ -5- nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.45g).
• Example 6 The procedure described in Example 6 was followed using 3-ethyl 5-isopropyl 4-[2- (4-bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.30g) and 2-hydroxy-3-(2-methoxyphenoxy)propylamine (0.29g) as starting materials.
• Example 6 The procedure described in Example 6 was followed using 3-ethyl 5-isobutyl 4-[2-(4- bromobutoxy)-5- ⁇ itrophe ⁇ yl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.47g) and 2-hydroxy-3-phenoxypropylamine (0.42g) as starting materials.
• Example 6 The procedure described in Example 6 was followed using 3-ethyl 5-propyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.35g) and 2-hydroxy-3-ph ⁇ noxypropylamine (0.38g) as starting materials. 3-Ethyl 5-propyl 4-[2- ⁇ 4-(2-hydroxy-3-phe ⁇ oxypropylami ⁇ o)butoxy ⁇ -5- ⁇ itrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.30g ⁇ .
• Example 6 The procedure described in Example 6 was followed using diethyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifiuoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-(2-methoxyphe ⁇ oxy)propylami ⁇ e (0.51 g) as starting materials. Diethyl 4-[2- ⁇ 4-( 2-hydroxy-3-(2- metnoxyphenoxy)propylamino)butoxy ⁇ -5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4- dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.46g).
• Example 6 Under similar conditions to Example 6 starting from 3,5-diethyl 4- ⁇ 2-(4- bromobutoxyJ-S-nitrophenylJ-e-methyl ⁇ -trifluoromethyl-l ⁇ -dihydropyridine-S.S- dicarboxylate(750m g) and 2-hydroxy-3- ⁇ 4-(N-m et ylsulpho ⁇ yl-N- tetrahydropyran-2-yl ) aminophenox ⁇ propylamine ( 1340mg ) was obtained 3 , 5-diethyl 4- [ 2- [ 4- [ 2-hydroxy-3- ⁇ 4- ( N-methylsulphonyl-N- tetrahydropyranyl)aminophenoxy ⁇ propylamino]butoxy]-5-nitrophenyl]-6-methyl-2- trifluoromethyI-1 ,4-dihydropyridine-3,5-dicarboxylate (870mg) as a yellow stiff foam.
• Example 37 Under similar conditions to Example 37 starting from 5-isopropyl 3-methyl 4- ⁇ 2-(4-bromobutoxy)-5- ⁇ itrophenyl ⁇ -2-cyano-6-methyf-1,4-dihydropyridi ⁇ e-3,5- dicarboxylate(820mg) and 2-hydroxy-3- ⁇ 4-( ⁇ /-methylsulphonyl-/V- tetrahydropyran-2-yl)aminophenoxy ⁇ propylamine (1440mg) was obtained 5-isopropyl 3-methyl 4-[2-[4-[2-hydroxy-3- ⁇ 4-(N- methylsulphonyI)aminophenoxy ⁇ propylamino]butoxy]-5-nitrophenyl]-2-cyano-6-methyl-

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• 1991
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