Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
  • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • 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
  • A61P9/06—Antiarrhythmics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• • 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
  • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/14—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• • 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
  • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

• the present invention is concerned with antiarrhythmic drugs in particular class III
• antiarrhythmic agents which are potassium channel blockers.
• antiarrhythmic compounds are based on studies by Vaughan Williams 1 .
• drugs that increase the action potential duration (APD) and refractory period of cardiac muscle without any other significant effects are designated class III antiarrhythmics.
• Sotalol is a drug developed as a ⁇ -blocker
• class III activity is much less than class II activity.
• Gupta et al 7 have investigated a number of 3 methanesulphonamido phenoxy-2-hydroxy 1- aminoproopanes as CNS depressants and hypotensive agents.
• the present inventors have now prepared a series of phenoxypropanolamine derivatives of sotalol which exhibit a potassium channel blocking action and are consequently class III antiarryhthmics but which possess substantially no ⁇ blocking action.
• A is an acidic group, preferably a methanesulphonamyl or carboxyl group.
• R 1 is a C 6 -C 12 aralkyl or aralkenyl group which may carry 1 to 3 C 1 -C 4 alkyl, alkenyl, alkoxy, haloalkyl or halogen substituents.
• R 2 is C 1 -C 6 alkyl, alkenyl, haloalkyl, C 6 - C 1 2 aralkyl or aralkenyl group which may carry 1 to 3 C 1 - 4 alkyl, alkenyl, alkoxy, haloalkyl or halogen substitutents or
• R 1 and R 2 may together with the N atom form a hetrocyclic ring selected from
• R 3 is not alkoxy or halogen.
• the acidic group is preferably an alkylsulphonyl amide group most preferably methyl sulphonamide group which should be unsubstituted at the N atom.
• a further preferred acidic group is a carboxyl group.
• the acidic group is most preferably located in the 4- position, i.e. para position, but may be located in other positions, the 3- position for example.
• the side chain amino group is a
• R 1 is preferably a hydrophobic phenyl alkyl group optionally substituted with one or more
• substituents include halogen, haloalkyl or C 1 -C 4 alkoxy
• R 2 is also preferably a hydrophobic group and preferred groups are as for R 1 in addition,other preferred groups are methyl, isopropyl or aralkyl.
• R 1 and R 2 may also together form a hetrocyclic ring. Preferred rings are
• Preferred substituents are C 1 -C 4 alkoxy, haloalkyl or halogen, particularly preferred are dihalo substituted compounds.
• Figure 1 also shows the reaction scheme for the synthesis of secondary amine compounds included for comparative purposes.
• methanesulphonyl chloride was then added and the mixture was left under a drying tube for 1 hour at 0°C. After this time the solution was left to slowly warm to room temperature over 2 hours after which 200mL of ether was added. An oil precipitated and after decanting the ether the oil was dissolved in 15mL of 2N NaOH. 50mL of ethylacetate was added and the aqueous layer was then extracted. The organic layer was further extracted with 2 x 10mL of 2N NaOH. The combined aqueous fractions were then neutralized with concentrated HCL to pH 7 causing an oil to precipitate. This aqueous solution was then extracted with 3 x 50mL ethylacetate and dried over magnesium sulphate. Removal of the solvent under reduced
• oxazolidine was dissolved in 30mL of ethanol along with 1mL of 2N NaOH and 100 mg 10% Pd/C. On shaking in 1 atm. of H 2 (g) there was a quantitative uptake of hydrogen within 40 minutes. The reaction mixture was then centrifuged and the solvent was decanted and evaporated under reduced pressure leaving a colourless opaque oil. This was then extracted with ether, washed with 2 x 50mL of water, dried over magnesium sulphate and the solvent removed leaving a colourless oil 0.90g (2.4 mmol, 97%). The amine was pure enough to use directly in the mesylation.
• oxazolidine was dissolved in 10mL of sodium dried ether and cooled to 5-10°C. The atmosphere above the solution was kept dry using a CaCl 2 (s) drying tube. A solution of 0.20mL (2.6 mmol) of methanesulphonyl chloride in 10mL of sodium dried ether was then added slowly and gradually a white precipitate formed. The solution was left for 12 hours warming to room
• Pharmacological activity was assessed by the ability to prolong the action potential in isolated guinea-pig ventricular rayocytes stimulated with 2 ms rectangular current pulses at a frequency of 1 Hz (Terrar & Mitchell, 8 ). Response was measured as the prolongation of the action potential at the 90% repolarization level (APD 90 ).
• the delayed rectified potassium current, I k was recorded by applying step depolarizations under voltage-clamp conditions, e.g. to +40 m V from a holding potential of -50 m V for 300 ms, and was measured as the size of the outward tail current on repolarization to the holding potential (see Matsuura et al, 9 for a similar procedure).
• the effect of the present compounds on I k was assessed from the extend of reduction of the outward tail current.
• a single- electrode voltage-clamp electrodes containing
• ni ⁇ oldipine (3 ⁇ M) was present in the external solution to block currents carried by calcium, and in others cells were injected with the calcium, and in others cells were injected with the calcium chelator BAPTA (1,2-bis(2- Aminophenoxy) ethane N,N,N',N'-Tetraacetic Acid) to suppress currents activated by increases in cytosolic calcium.
• BAPTA 1,2-bis(2- Aminophenoxy) ethane N,N,N',N'-Tetraacetic Acid
• Table 3 shows results obtained for the prolongation at the 90% repolarization level produced in isolated guinea pig ventricular cells by examples of compounds of the present invention.
• Table 4 shows results obtained with comparative compounds including sotalol and secondary amine derivatives and a
• substitution of the ring may produce very potent compounds.
• Comparison of compounds H, W and Y shows increasing potassium channel blocking activity with increasing hydrophobicity of the tertiary amino group. There is in particular a surprising increas in
• substituted compound retains activity although with reduced activity although the 4- position is preferred.
• FIG. 1 shows typical results obtained for compounds A and C, secondary amines, and compounds H, S and Q of the present invention.
• Compound C has a phenylethyl nitrogen substituent but still retains antiadrenergic activity. However on making the amine of the propanlamine side chain a tertiary amine as in compounds H, S and Q there is no blockage of ⁇ receptors.

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• Engineering & Computer Science (AREA)
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• 1990
  • 1990-03-09 GB GB909005318A patent/GB9005318D0/en active Pending
• 1991
  • 1991-03-11 EP EP91905586A patent/EP0518939A1/en not_active Ceased
  • 1991-03-11 JP JP91505414A patent/JPH05505797A/ja active Pending
  • 1991-03-11 WO PCT/GB1991/000379 patent/WO1991013865A1/en not_active Application Discontinuation

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