Fluorophenyl-substituted alkenylcarboxylic acid guanidides,...

Details Fluorophenyl-substituted alkenylcarboxylic acid guanidides,... Fluorophenyl-substituted alkenylcarboxylic acid guanidides,...

2001-12-20

2003-01-07

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C514S617000, C514S821000, C514S921000, C564S161000, C564S142000, C564S138000

Reexamination Certificate

active

06504057

ABSTRACT:

This invention relates to fluorophenyl-substituted alkenylcarboxylic acid guanidides, process for their preparation, their use as a medicament or diagnostic, and medicament containing them.
The invention further relates to alkenylcarboxylic acid guanidides carrying fluorophenyl groups, of the formula I:
in which:
R(6) is hydrogen, (C
1
-C
9
)-alkyl, (C
3
-C
8
)-cycloalkyl or phenyl,
the phenyl group being unsubstituted or substituted by 1-3 substituents selected from the group consisting of F, Cl, CF
3
, methyl, methoxy and NR(9)-R(10);
R(9) and R(10) are hydrogen, (C
1
-C
4
)-alkyl or (C
1
-C
4
)-perfluoroalkyl;
R(7) is independently defined in the same way as R(6); and
R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F,
it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
and their pharmaceutically tolerated salts.
Preferred compounds of the formula I are those in which:
R(6) is hydrogen, (C
1
-C
4
)-alkyl or (C
3
-C
6
)-cycloalkyl;
R(7) is independently defined in the same way as R(6); and
R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F,
it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
and their pharmaceutically tolerated salts.
Particularly preferred compounds of the formula I are those in which:
R(6) is hydrogen or CH
3
;
R(7) is hydrogen; and
R(1), R(2), R(3), R(4) and R(5) independently of one another are hydrogen or F,
it being necessary, however, for at least one of the radicals R(1), R(2), R(3), R(4) and R(5) to be fluorine;
and their pharmaceutically tolerated salts.
If the compounds of the formula I contain one or more centers of asymmetry, these can have either the S or the R configuration. The compounds can exist as optical isomers, as diastereoisomers, as racemates or as mixtures thereof.
The double bond geometry of the compounds of the formula I can be either E or Z. The compounds can exist as a mixture of the double bond isomers.
The indicated alkyl radicals can be either linear or branched.
The invention further relates to a process for the preparation of the compound I, which comprises reacting a compound of the formula II:
with guanidine, R(1) to R(7) being defined as indicated and L being a leaving group readily susceptible to nucleophilic substitution.
The activated acid derivatives of the formula II, in which L is an alkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio, methylthio or 2-pyridyl-thio group or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained in a manner known per se from the corresponding carboxylic acid chlorides (formula II, L=Cl), which can in turn be prepared in a manner known per se from the corresponding carboxylic acids (formula II, L=OH), for example with thionyl chloride.
Apart from the carboxylic acid chlorides of the formula II (L=Cl), other activated acid derivatives of the formula II can also be prepared, in a manner known per se, directly from the corresponding benzoic acid derivatives (formula II, L=OH), examples being the methyl esters of the formula II, where L=OCH
3
, by treatment with gaseous HCl in methanol, the imidazolides of the formula II by treatment with carbonyldiimidazole [L=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], the mixed anhydrides II with Cl—COOC
2
H
5
or tosyl chloride in the presence of triethylamine in an inert solvent, and the benzoic acids activated with dicyclohexylcarbodiimide (DCC) or with O-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetra-methyluronium tetrafluoroborate (“TOTU”) [Proceedings of the 21. European Peptide Symposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom, Leiden, 1991]. A number of suitable methods for the preparation of activated carboxylic acid derivatives of the formula II are given in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350, in which source literature is cited.
The reaction of an activated carboxylic acid derivative of the formula II with guanidine is carried out in a manner known per se in a protic or aprotic, polar but inert organic solvent. Solvents which have proved satisfactory in the reaction of the benzoic acid methyl esters (II, L=OMF) with guanidine are methanol, isopropanol or THF at 20° C. up to their boiling point. The majority of reactions of compounds II with salt-free guanidine have advantageously been carried out in aprotic inert solvents such as THF, dimethoxyethane or dioxane, although water can also be used as a solvent in the reaction of II with guanidine, in combination with a base such as e.g. NaOH.
If L=Cl, the reaction is advantageously carried out with the addition of an acid acceptor, e.g. in the form of excess guanidine, in order to bind the hydrohalic acid.
Some of the corresponding benzoic acid derivatives of the formula II are known and are described in the literature. The unknown compounds of the formula II can be prepared by methods known in the literature. The alkenylcarboxylic acids obtained are converted to compounds I according to the invention by one of the process variants described above.
The introduction of some substituents is effected by methods known in the literature, involving the palladium mediated cross-coupling of aryl halides or aryl triflates with e.g. organostannanes, organoboric acids, organoboranes or organocopper or organozinc compounds.
Carboxylic acid guanidides I are generally weak bases and can bind acid to form salts. Suitable acid addition salts are salts of any pharmacologically tolerated acids, for example halides, especially hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates and p-toluenesulfonates.
The compounds I are substituted acylguanidines. The most prominent representative of the acylguanidines is the pyrazine derivative amiloride, which is used in therapy as a potassium-sparing diuretic. Numerous other compounds of the amiloride type are described in the literature, examples being dimethylamiloride or ethylisopropylamiloride.
amiloride: R′,R″=H
dimethylamiloride: R′,R″=CH
3
ethylisopropylamiloride: R′=C
2
H
5
, R″=CH(CH
3
)
2
Furthermore, studies have been disclosed which indicate that amiloride has antiarrhythmic properties (Circulation 79, 1257-63 (1989)). However, an obstacle to broad application as an antiarrhythmic is the fact that this effect is not strongly pronounced and is accompanied by a hypotensive and saluretic action, these side effects being undesirable in the treatment of cardiac dysrhythmia.
Indications of the antiarrhythmic properties of amiloride have also been obtained from experiments on isolated animal hearts (Eur. Heart J. 9 (suppl. 1): 167 (1988) (book of abstracts)). Thus, for example, it has been found on the rat heart that an artificially produced ventricular fibrillation can be completely suppressed by amiloride. The abovementioned amiloride derivative ethylisopropylamiloride was even more potent than amiloride in this model.
WO 84/00875 has disclosed cinnamic acid guanidides (R
a
and R
c
or R
b
and R
d
=double bond; R(1)=substituted phenyl); in all cases, however, these are additionally substituted on the guanidine by alkyl groups, which is why they should not exhibit NHE inhibition. Moreover, halogen is only mentioned in general terms as a substituent on the phenyl ring and, although it is defined as “all four halogens”, no individual example with fluorine substitution is given.
U.S. Pat. No. 2,734,904 (granted 1956) has disclosed cinnamic acid guanidides (R=substituted phenyl, alkyl=alkenylene), but only chlorine, bromine and iodine, and not fluorine, are described as halogen substituents on the phenyl ring; fluorine is excluded in the claim (halogens with an atomic number of >9 and <53).
German Offenlegungsschrift 44 21 536.3 proposes

Affiliated with

Also associated with

Rating

Fluorophenyl-substituted alkenylcarboxylic acid guanidides,... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fluorophenyl-substituted alkenylcarboxylic acid guanidides,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fluorophenyl-substituted alkenylcarboxylic acid guanidides,... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3009226