Benzoyl guanidine derivatives, the preparation thereof and their

Details Benzoyl guanidine derivatives, the preparation thereof and their Benzoyl guanidine derivatives, the preparation thereof and their

1996-08-09

1998-07-21

Berch, Mark L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514243, 514248, 514249, 514252, 514253, 514256, 514259, 514267, 514272, 514273, 514274, 514307, 514309, 514310, 514311, 514312, 514313, 514314, 514316, 514317, 514318, 514326, 514329, 514331, 514332, 514401, 514403, 514426, 514429, 514618, 514619, 514620, 544182, 544183, 544224, 544235, 544237, 544250, 544284, 544287, 544293, 544295, 544296, 544291, 544292, 544309, 544310, 544311, 544312, 544315, 544316, 544317, 544319, 544321, 544322, 544323, 544324, 544325, 544328, 544329, 544331, 544332, 544333, 544335,

Patent

active

057835764

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new benzoyl guanidine derivatives, processes for the preparation thereof and their use in the manufacture of pharmaceutical compositions.
According to one aspect of the invention, we provide compounds of the formula (I) ##STR2## and acid-addition salts thereof, in which A represents one of the following groups bound to the benzoyl guanidine system via a nitrogen atom: ##STR3## R.sub.1 denotes F, Cl, CF.sub.3, R'--SO.sub.2 -- or R'--NH--SO.sub.2 -- (R' being C.sub.1-5 -alkyl, halogen- or phenyl-substituted C.sub.1-5 -alkyl; in which the phenyl groups may contain up to three substituents selected from the group halogen, C.sub.1-4 -alkyl or C.sub.1-4 -alkoxy), ##STR4## wherein R.sub.3, R.sub.4 and R.sub.4 ', which may be the same or different, denote hydrogen, C.sub.1-4 -alkyl, or R.sub.4 and R.sub.4 ' may also denote phenyl, benzyl and C.sub.3-7 -cycloalkyl; methyl, methoxy, hydroxy or halogen; C.sub.1-4 -alkyl, phenyl or halogen; substituted by phenyl or methyl-, methoxy- or halogen-substituted phenyl; methyl, methoxy, phenyl, benzyl, nitro, cyano, halogen, trifluoromethyl, amino, NR.sub.10 R.sub.13, 1-pyrrolidinyl, 1-pyrazolinyl, 1-imidazolidihyl, 1-piperidinyl, 1-piperazinyl or carbamoyl and R.sub.11 can also denote a benzene ring condensed to these systems which may carry up to three substituents selected from the group methyl, methoxy, halogen, CF.sub.3 and CN; substituted by phenyl, phenoxy or benzyloxy; and
The alkyl, alkenyl, alkynyl and alkylene groups mentioned in the above definitions may be straight-chained or branched. Lower groups have 1 to 4, particularly 1 to 3 and more especially 1 or 2 carbon atoms. Of the halogens, fluorine, chlorine and bromine and particularly fluorine and chlorine are preferred. The preferred unsaturated hydrocarbon groups are alkyl and propargyl. The letter m preferably denotes 2, 3 or 4 whilst p preferably denotes 2 or 3.
Where the new compounds may exist in different stereoisomeric or cis/trans-isomeric forms, the above formulae indicate the pure forms and mixtures thereof. The invention includes all stereoisomeric and cis/trans-isomeric forms, whether optically pure or in the form of mixtures thereof.
The groups R.sub.2 --A-- typically have structures of which those shown below are representative: ##STR5## and if A is bound via a nitrogen atom to the group R.sub.2, generally a group A is present in which the bond from R.sub.2 starts from a carbon atom as in (II'), (III') and IV').
The new compounds may be obtained by various methods, which comprise a further feature of the invention. Such methods include various processes known per se. Examples of processes according to the invention are ##STR6## with an amine of formula represents a group of formula II, III, or IV, the link may also be built up using another nitrogen of the radical R.sub.2. For example, compounds in which R2 denotes II can be prepared by reacting an amine of the general formula ##STR7## wherein A' is a group A which is bound via a nitrogen to R.sub.2 as in II', III' or IV', and R.sub.1 is as hereinbefore defined with a chinazolon derivative of general formula ##STR8## as described in (a) above c) reaction of a compound of formula ##STR9## wherein R is a lower alkyl group or benzyl group, and R.sub.1, R.sub.2 and A are as hereinbefore defined, which guanidine.
In reaction (a) above, the reaction is generally carried out at elevated temperature in a polar solvent or mixture of solvents, anhydrous if possible, particularly dimethylsulphoxide or dimethylformamide, and preferably in the presence of a base such as triethylamine, N-methylpiperidine or pyridine.
In reaction (c) above, the reaction is not restricted to the esters wherein R is as hereinbefore defined, the person skilled in the art will conveniently use an ester which is easy to prepare, such as the methyl- or ethylester, or an ester which produces an alcohol which will not affect the reaction or cause problems when it is formed.
It is preferable to use as a solvent for the reaction the alcohol which is also contained

REFERENCES:
patent: 3953476 (1976-04-01), Cragoe, Jr.

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