Ortho-aminomethylphenol compounds

Details Ortho-aminomethylphenol compounds Ortho-aminomethylphenol compounds

1986-03-25

1987-11-24

Reamer, James H.

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

564256, 564257, 564265, 514456, 514640, A61K 3115, C07C13100

Patent

active

047090952

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel and pharmaceutically useful ortho-aminomethylphenol compounds or pharmaceutically acceptable salts thereof, a method of preparing said compounds and a pharmaceutical composition containing said compounds.


BACKGROUND OF THE INVENTION

2-Aminomethyl-4-tertiary-butyl-6-iodophenol hydrochloride (MK-447) possessing saluretic, diuretic, hypotensive and antiinflammatory activities is disclosed in Journal of Medicinal Chemistry, vol. 23, p. 1414 (1980), and 2-aminomethyl-4-tertiary-butyl-6-methylsulfonylphenol (Hoe-365) possessing diuretic, saluretic and antihypertensive activities is disclosed in European Patent Application No. 88346.


DISCLOSURE OF THE INVENTION

The present inventors paid attention to the above prior arts and intensively investigated to prepare pharmaceutical compounds with more preferable properties such as higher safety and more potent activities.
As a result of such investigations, the present inventors have found that ortho-aminomethylphenol compounds having an oxime group in the 4 position to the hydroxyl group exhibit significantly pharmacological activities, and have completed the present invention.
The present invention relates to ortho-aminomethylphenol compounds of the formula: ##STR2## wherein X is hydrogen or halogen (chlorine, bromine, iodine or fluorine), R is hydrogen or alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary-butyl), A is alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tertiary-butyl), phenyl, benzyl or a bivalent radical selected from --(CH.sub.2).sub.3 --and --O(CH.sub.2).sub.2 --and joined together with the 3 or 5 position of the benzene nucleus to form a bicycle, or pharmaceutically acceptable salts thereof, a method of preparing said compounds and a pharmaceutical composition containing said compounds.
Preferable compounds of the present invention are the compounds of formula (I) wherein X is chlorine, bromine or iodine, R is hydrogen or alkyl having 1 to 4 carbon atoms and A is alkyl having 1 to 4 carbon atoms.
The compounds of formula (I) can be, for example, prepared by reacting a compound of the formula: ##STR3## with a compound of the formula: ##STR4##
The reaction is usually carried out by using an acid addition salt (e.g. hydrochloride) of the compound of formula (III) in an inert solvent in the presence of an alkali hydroxide or an organic base. The obtained compounds can be, if necessary, purified by a conventional manner such as reprecipitation, recrystallization or a column chromatography.
While the compounds of formula (I) may occur geometrical isomers of syn and anti isomers (E and Z isomers) with respect to the oxime group (--C.dbd.N--OR), whichever of these isomers and the mixtures thereof can be included in the present invention.
The compounds of formula (I) can be, if desired, converted into salts with sodium, potassium, magnesium, calcium, aluminum or an amine with respect to phenol or oxime, or salts with an inorganic acid (e.g. hydrochloric acid, hydrobromic acid or sulfuric acid) or an organic acid (e.g. oxalic acid, maleic acid, succinic acid, fumaric acid or tartaric acid) with respect to the amino group.
The starting compounds of formula (II) wherein X is hydrogen can be, for example, prepared by subjected a compound of the formula: ##STR5## to an amidomethylation reaction and then hydrolysis. The compounds of formula (II) wherein X is halogen can be prepared by reacting the obtained compound with halogen or a halogenating agent to introduce halogen atom into the 6 position of the benzene nucleus.
The starting compounds can also be prepared by halogenating the compound of formula (IV) and then aminomethylating the obtained compound. The product is identical with the compound prepared by the above method or position isomer with respect to the substituent of X and the aminomethyl group. These compounds can be distinguished one from the other based on their properties on spectrum.
The

REFERENCES:
patent: 3692835 (1972-09-01), Van Dijk et al.
patent: 3864401 (1975-02-01), Schultz et al.
patent: 4071686 (1978-01-01), Van Dijk et al.
Conant, James Bryant et al., The Chemistry of Organic Compounds, 4th Ed., (1954), The MacMillan Company, Publ. at p. 113.

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