Isoindole diuretic derivatives, compositions and use

The invention provides 3-oxoisoindole compounds useful as diuretics of the general formula ##STR1## wherein X is halogen or trifluoromethyl, A is alkylene (C.sub.2 -C.sub.4), R.sub.1 is alkyl, R.sub.2 is alkyl or phenylalkyl, or R.sub.1 and R.sub.2 taken together with nitrogen are piperidino, morpholino or pyridinyl.

FIELD OF THE INVENTION 
This invention relates to isoindole derivatives, pharmaceutically 
acceptable salts thereof and to processes for synthesis thereof. Other 
aspects of the invention concern pharmaceutical compositions containing an 
instant compound as active ingredient and method of treatment where there 
is an indicated need for a diuretic agent. 
DESCRIPTION OF THE PRIOR ART 
European Patent Application No. 26,749 discloses 
2-(benzylpiperidinyl)-phthalimidine derivatives useful as antipsychotic 
agents of the following general formula (1) 
##STR2## 
wherein R.sub.0, R.sub.1, and R.sub.2 are independently hydrogen, halogen, 
C.sub.1-3 alkyl, C.sub.1-3 alkoxy, or trifluoromethyl. The compounds of 
(1) are reportedly neuropharmacologically active and useful for treating 
psychotic disorders, especially schizophrenia and mania. 
Cornish, et al, J. Pharm. Pharmacol., 18, 65-80 (1966) disclose preparation 
of phthalimides and 1-oxoisoindolines related to the diuretic clorexolone 
(2). 
##STR3## 
Himori, et al, Jpn. J. Pharmacol. 1978, 28(6), 811-818; (Chem. Abs. 
90:97589t) studied the antihypertensive effect of a combination of 
clorexolone and the .beta.-adrenergic blocking agent, alprenolol in 
conscious renal hypertensive dogs and found a significant decrease in 
blood pressure after the second day of treatment. 
Suzuki, et al, Nippon Yakurigaku Zasshi, 1972, 68(3), 276-289 (Chem. Abs. 
81:58265d) reported that the hypotensive diuretics, hydroflumethiazide, 
triamterene, clorexolone, etc. have favorable effects in the spontaneously 
hypertensive rat. 
U.S. Pat. No. 3,579,524 to Van Dyke, Jr. discloses aminoalkyl derivatives 
of phthalimidine of general formula (3) 
##STR4## 
wherein n is 2 to 5, R.sup.2 is H and OH, and R.sup.1 amino nitrogen is 
part of a heterocyclic moiety such as piperidinyl, morpholinyl, 
piperazinyl, etc. The compounds are said to be antihypertensive agents 
producing a gradual decrease in blood pressure in dogs. 
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION 
In its broadest aspect, the present invention is concerned with 
3-oxoisoindole derivatives having diuretic properties characterized by a 
compound of Formula I 
##STR5## 
wherein X is halogen or trifluoromethyl; A is an alkylene radical of 2 to 
4 carbon atoms inclusive; R.sub.1 is lower alkyl; R.sub.2 is lower alkyl 
or phenylalkyl of 7 to 10 carbon atoms; or R.sub.1 and R.sub.2 taken 
together with the nitrogen to which they are attached may be piperidino, 
morpholino or pyridinyl; or a pharmaceutically acceptable acid addition 
salt thereof. 
It is to be understood that by the term "lower alkyl" and "lower alkoxy" 
used herein, it is meant both straight and branched carbon radicals 
containing from 1 to 6 carbon atoms, preferably not more than 4 carbon 
atoms. Exemplary of carbon chain radicals are methyl, ethyl, isopropyl, 
1-butyl, 1-methylpropyl, 2-methylpropyl, tert.-butyl, hexyl and the like. 
The term "alkylene" as used herein refers to a branched or preferably 
straight chain divalent radical of 2 to 4 carbon atoms. Further the term 
"halogen" used herein connotes all members of that group but preferably 
chlorine, bromine and fluorine. The term phenylalkyl comprehends such 
radicals as benzyl, phenethyl, phenylpropyl, phenylisopropyl and the like. 
The pharmaceutically acceptable acid addition salts of the invention are 
those in which the anion does not contribute significantly to toxicity or 
pharmacological activity of the salt, and therefore are considered 
pharmacological equivalents of Formula I bases. 
For purposes of salt formation of the substances of Formula I, there may be 
mentioned pharmaceutical acceptable acids such as hydrochloric and other 
hydrohalic acids, sulphuric, phosphoric, nitric, aliphatic, alicyclic, 
aromatic or heterocyclic carboxylic acids or sulphonic acids, such as 
formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, 
citric, ascorbic, maleic, hydroxymaleic or pyruvic, fumaric, benzoic, 
p-amino-benzoic, anthranilic, p-hydroxybenzoic, salicyclic, or 
p-aminosalicyclic, methanesulphonic, ethanesulphonic, 
hydroxyethanesulphonic, ethylenesulphonic; halogenobenzenesulphonic acid, 
toluenesulphonic acid, naphthalenesulphonic acid or sulphanilic acid. 
Conventional methods are used to prepare the salts. Thus, admixture of a 
Formula I base with the selected acid in an inert solvent such as water, 
ethyl acetate, methanol, dimethylformamide and the like with salt 
isolation by conventional concentration or crystallization techniques are 
employed. The Formula I salts are, in some instances, obtained in hydrated 
form, e.g., hemihydrates, monohydrates, sesquihydrates; and it is to be 
understood that such forms are within the ambit of the instant invention. 
According to the present invention, the compounds characterized by Formula 
I 
##STR6## 
wherein X is halogen or trifluoromethyl; A is a divalent straight or 
branched chain alkylene radical of 2 to 4 carbon atoms inclusive, R.sub.1 
is lower alkyl; R.sub.2 is lower alkyl or phenylalkyl of 7 to 10 carbon 
atoms; or R.sub.1 and R.sub.2 taken together with the nitrogen to which 
they are attached may be piperidino, morpholino or pyridinyl are obtained 
by a method comprising 
(a) reducing a 1,3-dioxoisoindole compound of Formula II or a 
1-hydroxy-3-oxoisoindole compound of Formula III 
##STR7## 
wherein X, A, R.sub.1 and R.sub.2 are as defined above; or 
(b) reacting a 4-aminopiperidine compound of Formula IV 
##STR8## 
wherein A, R.sub.1 and R.sub.2 are as defined above with a sulfamoyl 
compound of Formula V in an inert solvent 
##STR9## 
wherein X is as defined above, R.sub.3 is amino, halogen, lower alkoxy; 
and R.sub.4 is halogen or taken as the radical R.sub.4 CH.sub.2 -- is 
carbamoyl or formyl; and R.sub.3 and R.sub.4 taken together is oxygen. 
Reduction of the 1,3-dioxoisoindole compounds of Formula II or 
1-hydroxy-3-oxoisoindoles of Formula III is carried out with zinc and 
acetic acid or tin and concentrated hydrochloric acid at elevated 
temperatures generally ranging from 60.degree.-150.degree. for periods of 
about 6-48 hours in a reaction inert organic solvent. In the case of 
zinc-acetic acid, temperatures of 100.degree.-150.degree. are preferred 
and the reduction is conveniently carried out in acetic acid at reflux 
temperature. The compounds of Formula I obtained by reduction with 
zinc-acetic acid are purified by conventional techniques such as 
basification, extraction and trituration of the extract or precipitation 
of acid addition salts from crude extracts. In the case of the 
tin/concentrated hydrochloric acid reduction, preferably carried out at 
60.degree.-100.degree. in methanol, the Formula I products form relatively 
stable complexes with tin salts and purification is carried out by 
treating the tin complexed Formula I products with hydrogen sulfide under 
acidic conditions or tetramethylethylenediamine in an inert solvent such 
as methanol to precipitate the tin as the insoluble sulfide or 
tetramethylethylenediamine complex, respectively. Reduction of Formula II 
and Formula III compounds may be carried out by other conventional means 
such as use of light metal hydrides. 
The compounds of Formula III considered part of the present invention are 
obtained by reduction of the corresponding 1,3-dioxoisoindole with excess 
zinc in acetic acid below 100.degree., preferably at or near room 
temperature. 
The intermediates of Formula IV are generally known to the art or prepared 
by art-recognized methods. 
It is to be understood that the sulfamoyl intermediates of Formula V 
particularly comprehend such compounds as: 
##STR10## 
wherein X is halogen or trifluoromethyl, R.sub.3 is lower alkoxy, 
preferably methoxy and R.sub.4 is halogen. 
Known methods are employed in preparation of Formula V intermediates as 
illustrated by European Patent Application No. 26,749, supra. 
The compounds of Formula I have diuretic properties as can be demonstrated 
by standard pharmacological test models known to correlate with effects in 
man. By way of example, there can be mentioned the conscious rat diuretic 
screen of Lipschitz, et al (J. Pharmacol. Exp. Therap. 79, 97 (1943)). In 
this test, dose response assays of diuretic, naturiretic and kaliuretic 
activity are determined by oral administration of the test substance with 
the compounds of Formula I exhibiting significant diuretic properties at 
doses ranging from 0.3 to 30 mg/kg body weight. 
As stated above, Formula I compounds have diuretic properties. Thus, 
another embodiment of the instant invention is directed to a process 
comprising systemically administering to a mammal in need of diuresis a 
diuretic effective amount of a compound of Formula I or a pharmaceutically 
acceptable acid addition salt thereof. By systemic administration, it is 
intended to include both oral and parenteral routes with oral being 
preferred. Examples of parenteral administration are intramuscular, 
intravenous, intraperitoneal, rectal and subcutaneous administration. The 
dosage will vary with the form of administration and the particular 
compound chosen. However, from about 0.05 to 50 mg. per kg. of body weight 
of a mammal of a compound characterized by Formula I administered in 
effective single or multiple dosage units is generally satisfactory. In 
accordance with conventional clinical practice, a diuretic agent of 
Formula I is administered at a dosage substantially less than the dose of 
the compound which is thought to be effective. If the diuretic response is 
insufficient after a suitable trial, dosage is increased by small 
increments until the optimum diuretic effect is reached. In most cases, 
optimum doses fall within a range of 0.05 to 25 mg. per kg. or 0.05 to 10 
mg. per kg. of body weight and it is contemplated that the Formula I 
compounds can be used in the same manner as the clinically useful 
thiazides and related compounds described in AMA Drug Evaluations, 750-753 
(American Medical Association, Chicago, Ill., Fifth Edition). 
In carrying out the diuretic process, the active ingredient of Formula I 
and pharmaceutically acceptable acid addition salts thereof are preferably 
administered with a pharmaceutically acceptable carrier and such 
compositions constitute part of the instant invention. Suitable dosage 
forms for oral use are tablets, dispersible powders, granules, capsules, 
syrups and elixirs. Examples of parenteral forms are solutions, 
suspensions, dispersions, emulsions, and the like. The compositions for 
oral use may contain one or more conventional adjuvants, such as 
sweetening agents, flavoring agents, coloring agents and preserving 
agents, in order to provide a composition of suitable pharmaceutical 
elegance. Tablets may contain the active ingredient in admixture with 
conventional pharmaceutical acceptable excipients including inert diluents 
such as calcium carbonate, sodium carbonate, lactose and talc; granulating 
and disintegrating agents such as starch and alginic acid; binding agents 
such as starch, gelatin and acacia and lubricating agents such as 
magnesium stearate, stearic acid and talc. The tablets may be uncoated or 
coated by known techniques to delay disintegration and absorption in the 
gastrointestinal tract and thereby provide a sustained action over a 
longer period. Similarly, suspensions, syrups, and elixirs may contain the 
active ingredient in admixture with any of the conventional excipients 
utilized for the preparation of such compositions such as suspending 
agents (e.g., methylcellulose, tragacanth, and sodium alginate), wetting 
agents (e.g., lecithin, polyoxyethylene stearate) and preservatives such 
as ethyl-p-hydroxybenzoate. Capsules may contain the active ingredient 
alone or admixed with an inert solid diluent such as calcium carbonate, 
calcium phosphate and kaolin. The injectible compositions are formulated 
as known in the art and may contain appropriate dispersing or wetting 
agents and suspending agents identical or similar to those mentioned above 
.