Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-09-03
1994-08-02
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514326, 514422, 514428, 514445, 514448, 514652, 514821, 546213, 548527, 548571, 549 64, 560 27, 564349, A61K 31165, A61K 31138, C07C22510, C07D33332
Patent
active
053346025
DESCRIPTION:
BRIEF SUMMARY
The invention concerns new, therapeutically valuable aryloxy-alkylamine derivatives, their preparation and compositions which contain these derivatives as active material.
In EP 53 603 are described derivatives of 1-[3-(2-hydroxy-3-alkylaminopropoxy)-2-thienyl]-3-phenyl-1-propanone as well as their acid addition salts which are useful as anti-arrhythmic medicaments and, in part, even display properties superior to propafenone.
Similar compounds are also known from DE-OS 33 16 155. They also have the hydroxypropoxy group.
Furthermore, from DE-OS 20 01 431 are known 2-hydroxyalkylaminopropoxyphenylpropiophenone derivatives which are also said to display anti-arrhythmic properties.
In general, these known compounds display satisfactory effectiveness in the case of administration by injection but, in the case of oral administration, they leave something to be desired and require considerably higher dosages for the achievement of satisfactory effectiveness. However, since, as a rule, anti-arrhythmic agents are to be orally administered in order the patient encounter no problems in self-administration, there is a need for active materials with better effectiveness in the case of oral administration.
Surprisingly, it has now been found, that this task can be solved by conversion of the free OH group in the 2-hydroxy-3-aminopropoxy group into an ether or ester group.
Therefore, the subject of the invention are aryloxy-alkylamine derivatives of the general formula I ##STR2## in which A signifies a benzene or thiophene ring, R and R.sub.1, independently of one another, are each hydrogen, alkyl, halogen, CF.sub.3 or alkoxy, R.sub.2 is alkyl, cycloalkyl, alkenyl, alkynyl, alkaryl or saturated or unsaturated aliphatic or aromatic acyl, R.sub.3 and R.sub.4 are each hydrogen, alkyl, alkenyl, alkynyl or cycloalkyl with, in each case, up to 8 C-atoms, whereby R.sub.3 and R.sub.4 can be the same or different but are not simultaneously hydrogen or R.sub.3 and R.sub.4, together with the nitrogen atom connecting them, form a 5- to 7-membered saturated ring or a saturated heterocyclic ring which may contain an oxygen or nitrogen atom as a further heteroatom in the ring, whereby an additional nitrogen atom can be substituted by an alkyl radical with up to 3 C-atoms, as well as their acid-addition salts.
In the substituents R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4, the alkyl groups and their unsaturated derivatives and the alkyl radicals in the acyl group contain 1 to 8 C-atoms. The alkyl, alkenyl, alkynyl, alkoxy and acyl groups preferably have 1 to 4 C-atoms. Especially preferred are those compounds of the general formula I in which R and R.sub.1 are H or CH.sub.3.
By the compounds of the formula I in which A signifies the thiophene ring, especially preferred are those wherein R is hydrogen and R.sub.1 is methyl. In the case of the corresponding compounds in which A signifies the benzene ring, especially preferred are those where R and R.sub.1 are hydrogen.
Independently of the meaning of A, the isobutyl group is especially preferred for R.sub.3.
The compounds according to the invention contain an asymmetric carbon atom and, therefore, when a stereospecific synthesis is not employed, are normally present in the form of a racemate. The racemate can be separated into its isomers according to usual methods. The optically-active isomers are also a subject of the invention.
A further subject of the invention is a process for the preparation of compounds of the general formula I, which is characterised in that one reacts a compound of the general formula II or IIa ##STR3## in which A, R, R.sub.1, R.sub.3 and R.sub.4 have the meaning given for formula I, with an alkylation agent, such as an alkyl halide, alkyl sulphuric acid ester or alkyl sulphonic acid ester, or with an acyl halide, in the presence of at least one equivalent of a base in an inert organic solvent, if desired converts the compounds obtained of the general formula III ##STR4## by treatment with acid into the corresponding compounds of the formula I, in which R.sub.4 si
REFERENCES:
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patent: 4425362 (1984-01-01), Berthold et al.
patent: 4816604 (1989-03-01), Louis et al.
H. G. Hege, et al., Arzneim-Forsch; "Studies on the Meta bolisim of Propagenone," 34(II), (8), pp. 843-849 (1984).
T. Green, "Protective Groups in Organic Synthesis," pp. 222-235, John Wiley & Sons, New York (1981).
R. Neidlein et al., Arzneim-Forsch, "Synthesis of Glucuronides of Propafenone . . . ", 38 (II) (9), pp. 1275-1262 (1988).
T. C. Wascher, et al., Arzneim-Forsch, " Antiarihythmic Effects of Two New Propafenone Related Drugs," 41 CI) (2), pp. 119-124 (1991).
R. Morrison et al., "Organic Chemistry" 3rd ed., pp. 555 and 673, Allyn cd Bacon, Boston (1973).
Greier Gerhard
Lotz Bernhard
Laevosan-Gesellschaft GmbH
Raymond Richard L.
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