Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
• • 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

Definitions

• This invention relates to new dihydropyridine derivatives which possess antihypertensive properties.
• Prcpranolol and atenolol which aire l-(naphth-l-yloxy)-3- isopropylaminopropan-2-ol and l-p-caxbamoylmethylphenox ⁇ -3- isopropylamino-propan-2-ol, respectively, -ire most widely used exajnoles.
• Prcpranolol and atenolol which aire l-(naphth-l-yloxy)-3- isopropylaminopropan-2-ol and l-p-caxbamoylmethylphenox ⁇ -3- isopropylamino-propan-2-ol, respectively, -ire most widely used exajnoles.
• Previously described attempts at combining these two types of chemical structure i.e.
• A represents a tetramethylene group
• Ar represents a 2-tolyl or 2-chlorophenyl group*, or
• W represents a trifluoromethyl group
• R 1 and R each represents a methyl group
• R ⁇ represents a methyl or ethyl group
• A represents a hexamethylene group, and Ar represents a phenyl group;
• R and R ⁇ each represents a methyl group, R represents an isopropyl group, A represents a tetramethylene group, and Ar represents a phenyl group )
• 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.
• alkylene group having 1 to 10 carbon atoms means straight or branched bivalent paraffinic hydrocarbon residue of 1 to 10 preferably 1 to 6 carbon atoms.
• Suitable halo alkyl groups associated with W are the above mentioned lower alkyl groups which further contain from 1 to 3 halogen atoms such as fluorine, chlorine or bromine.
• L stands for a suitable leaving group (reactive functional group) , for example, a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, m- nitrobenzenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bro o 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: wherein W, R , R , R , and A, have the meanings stated above, and wherein Z represents a suitable leaving group (reactive functional group) , for example, a methanesulpho ⁇ yloxy, benzenesulphonyloxy, p- toluenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bro o or iodo group, with an amine of the formula:
• dihydropyridine compounds of this invention may also be prepared, by reduction of an aminoketone of the formula:
• R' represents the remainder of the molecule of the compounds of this invention as hereinbefore defined by means of heating, for example, in acetic anhydride.
• optically active starting materials for example, se
• optical isomers of the 1 , 4 -dihyropyridine nucleus can be prepared, for instance, by the optical resolution of the race ic 1, 4-dihydropyridine nucleus as described above (see Schemes A, B and C) using chromatography (e.g. HPLC etc.) , chemical resolution of the salts of the enantiomers with the conventional optical active acid (e.g. tartaric acid or camphor sulphonic acid, etc.) or other conventional optical resolving method.
• the conventional optical active acid e.g. tartaric acid or camphor sulphonic acid, etc.
• the hydropy idine compound of the invention is useful for treating hypertension such as essential hypertension and renal hype tension.
• cardiopathy such as angina pectoris. arrhythmia and yocardial infarction and heart failure. - 1 D -
• the radical may be selected from the group consisting of cyano, trifluoromethyl, difluoromethyl , monofluoromethyl , 2, 2, 2-trifluoroethyl, tricholoromethyl, dichloromethyl, monochloromethyl, 2, 2, 2-trichloroethyl and preferably is selected from cyano and trifluoromethyl;
• R 1 may be selected from the group consisting of methyl, ethyl, propyl , isopropyl, butyl, isobutyl, amyl , isoamyl, hexyl, isohexyl and preferably is methyl;
• the radicals R 2 and R 3 may be independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, isohexyl and preferably R 2 is methyl, ethyl or isopropy
• the dihydropyridine compound of this invention may be administered in a daily dosage of from 0.1 to 500 g, preferably 1 to 250 mg.
• compositions of this invention may co orise, as an active ingredient, the dihydropyridine com ⁇ ound 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,
• a pharmaceutical carrier or diluent includes solid or liquid non-toxic pharmaceutically acceptable substances.
• solid or liquid carriers or diluents are 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 onostearate, glyceryl distearate, a wax and the like.
• Porcine thoracic aorta was obtained from a slaughterhouse. The fat and connective tissues were removed and the vascular tissue was frozen at -80 l, c.
• the frozen tissue was thawed in the buffer containing 0.25 M of sucrose and 10 mM of MOPS at a pH of 7.4 and homogenized in the same buffer by polytoron, named by Kinematica (tradename) .
• the filtrated homogenate was homogenized by a poly-fluo inated ethylene, Teflon (tradename) , glass homogenizer.
• the homogenate was centrifuged at 1.000 g for 10 minutes.
• the supernatant was centrifuged at 10,000 g for 10 minutes twice.
• the supernatant was centrifuged at 100,000g for 60 minutes to yield pellets.
• the pellets were resuspended in buffer containing 50 M of tris-HCl at a pH of 7.4, which were referred to as crude microsomal membrane fractions.
• the obtained suspensions were stored at -80°c until use.
• the dihydropyridine compound of the invention is useful to treat hypertension such as essential hypertension and renal hypertension, cardiopathy such as angina pectoris, arrhythmia and myocardial infarction, heart failure 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
• test compound was administered intravenously through a catheter cannulated in the femoral vein more than 2 hours after the completion of the operation.
• 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 (100,000g x 60 min.) to yield pellets.
• the pellets were resuspended in buffer (50mM Tris-HCl, pH7.4) , which were referred to as crude microsomal membrane fractions.
• the obtained suspensions were stored ar -80°C until use .
• KSr 3296, 2953, 2868, 1728, 1640, 1526, 1208, 1167, 1110, 740 cm '1 ;
• Example 3 The procedure described in Example 3 was followed using dimethyl ⁇ 4- ⁇ 2-(6- b romohex y ioxy)-5- • nitrophenyl ⁇ -1 ,4-dihydro-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (0.60 g) and 2-hydroxy-3- phenoxypropyiamine (0.52 g) as starting materials.
• Dimethyl 1 ,4- dihydro-4- ⁇ 2- ⁇ 6-(2-hydroxy-3-phenoxypropyiamino)hexyioxy ⁇ -5- ⁇ itropheny0-6-methyl-2-trifiuoromethyipyridine-3,5-dicarboxylate was
• Example 3 The procedure described in Example 3 was followed using 3-isopropyl 5-methyl 4- ⁇ 2-(4-bromobutoxy)-5-nitrophenyl ⁇ -1 ,4-dihydro-6-methyl-2- trifluoromethylpyridi ⁇ e-3,5-dicarboxylate (0.60 g) and 2-hydroxy-3- phenoxypropyiami ⁇ e (0.52 g) as starting materials.
• 3-isopropyl 5-methyl 1 ,4-dihydro-4-[2- ⁇ 4-(2-hydroxy-3-phenoxypropyiami ⁇ o)butoxy ⁇ -5- nitropheny -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxyiate was
• Example 3 The procedure described in Example 3 was followed using 5-ethyl 3- methyl 4- ⁇ 2-(6-bromohexyioxy)-5-nitrophe ⁇ yi ⁇ -1 ,4-dihydro-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate ⁇ (0.60 g) and 2-hydroxy-3- phe ⁇ oxypropylamine (0.51 g) as starting materials.
• Example 3 The procedure described in Example 3 was followed using dimethyl 4- ⁇ 2-(6-bromohexyioxy)-5-nitrophenyl ⁇ -l ,4-dihydro 6-methyi-2- trifiuoromethylpyridine-3,5-dicarboxyiate (1.00 g) and 3- ⁇ 1-(7,8-dihydro-5- oxo-6H-naphtoxy) ⁇ -2-hydroxypropylamine (1.20g) as starting materials.
• Example 13 The procedure described in Example 13 was followed using dimethyl 4-[2-(4-bromobutoxy)-5- nitrophenyl]-l,4-dibydro-6- methyl-2-trifluomethylpyridine-3,5-dicarboxylate (0.80g) and 3- (2-chlorophenoxy)-2-hydroxypropyla-nine (l.OOg) as starting materials.
• Dimethyl 4-[2-[4- ⁇ 3-(2-chlorophenoxy)-2- hydroxypropylamino ⁇ butoxy]-5-nitrophenyl] -1,4-dihydro -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride was obtained as a yellow powder (0.43 g) . mp107.5-110 * C;
• the compounds obtained as shown in Examples 1-15 include 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.
• dimethyl 1,4- dihydro-4 - [2- [4- ⁇ 2-hydroxy-3 - (2- methylphenoxy) propylamino ⁇ butoxy] -5-nitrophenyl] -6- methyl-2- trif luoromethylpyridine-3 , 5-dicarboxylate monohydrochloride as shown in Example 13 exists as a mixture of four optical isomers (isomers A,B,C and D) .
• Example 13 The procedure described in Example 13 was followed using (-)- dimethyl 1 ,4-dihydro-4- ⁇ 2-(4-bromobutoxy)-5-nitrophenyl ⁇ -6-methyl-2- trifiuoromethylpyridine-3,5-dicarboxylate (1.68 g) and (S)-(-)-2-hydroxy-3- (2-methylphenoxy) ⁇ ro ⁇ ylamine (1.68 g) as starting materials.
• Example 13 The procedure described in Example 13 was followed using (+)- dimethyl 1 ,4-dihydro-4- ⁇ 2-(4-bromobutoxy)-5- ⁇ itrophenyI ⁇ -6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (2.02 g) and (S)-(-)-2-hydroxy-3- (2-methylphe ⁇ oxy)propylamine (2.02 g) as starting materials.
• (+)- dimethyl 1 ,4-dihydro-4- ⁇ 2-(4-bromobutoxy)-5- ⁇ itrophenyI ⁇ -6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (2.02 g) and (S)-(-)-2-hydroxy-3- (2-methylphe ⁇ oxy)propylamine (2.02 g) as starting materials.
• optical isomer D of Example 19 has been found to be the most effective of isomers A to D, in terms of the pharmacological tests (1) and (2) described earlier in this specification.
• Optically active starting materials as shown in Example 16-19 were prepared by the method described below.
• ( S ) - (-) - 2 - hydroxy- 3 - ( 2 - methylphenoxy) propylamine was prepared by the addition of ammonia to (S) -1, 2 -epoxy-3- (2 -methylphenoxy) propane which was synthesized from (R) -epichlorohydrine and o -cresol.
• ( R) - ( + ) - 2 -hydroxy- 3 - ( 2 - methylphenoxy) ropylamine was prepared from (S) - eoichlorohydrine .

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• 1995
  • 1995-01-27 WO PCT/JP1995/000100 patent/WO1995020576A1/en not_active Application Discontinuation
  • 1995-01-27 AU AU14670/95A patent/AU1467095A/en not_active Abandoned
  • 1995-01-27 EP EP95906531A patent/EP0741705A1/de not_active Withdrawn
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