Isoindoline derivatives for treating pain

Isoindoline derivatives are disclosed, as for instance of the formula: ##STR1## and methods of preparation of these compounds, such as the reaction of o-cyano-benzylbromide with a compound of formula ##STR2## and subsequent saponification. The compounds possess analgesic and anti-inflammatory activity.

BACKGROUND OF THE INVENTION 
In recent years the search for substances with analgesic and 
anti-inflammatory activity shifted from the fields of cortisone congeners 
(still endowed with hormonal actions) and morphine narcotics to other 
classes of chemical compounds. 
While products with undeniable pharmacological activity have been obtained, 
the problem is far from completely solved, because many of these products 
are quite toxic and poorly tolerated, causing as they do, among other 
things, ulcerations, gastrointestinal disturbances, nausea, etc.; 
furthermore, they cause harmful secondary effects. 
Certain isoindoline derivatives have now been found to be characterized by 
a negligible toxicity and to be tolerated very well, since they cause no 
secondary effects. 
DESCRIPTION OF THE INVENTION 
The present invention refers to certain compounds having analgesic and 
anti-inflammatory activity and to a process for their preparation. The 
compounds, object of this invention, have the following general formula: 
##STR3## 
wherein R is a member selected from the group consisting of hydrogen and 
lower alkyl of 1 to 4 carbon atoms, and R.sub.1 is a member selected from 
the group consisting of hydrogen, lower alkyl of 1 to 4 carbon atoms and a 
group of general formula 
##STR4## 
wherein n is 1 or 2 and R.sub.2 and R.sub.3 are independently selected 
from the group consisting of hydrogen and lower alkyl of 1 to 4 carbon 
atoms. 
The scope of the invention also comprises the salts of the compounds of 
general formula (I), wherein R.sub.1 is hydrogen, with physiologically 
acceptable organic or inorganic bases, in particular the salts with 
N,N-dimethylaminoethanol, as well as the salts of the compounds of general 
formula (I), wherein R.sub.1 is the group 
##STR5## 
with physiologically acceptable organic or inorganic acids. The compounds 
of general formula (I) may be prepared by the following methods: 
(a) reacting o-cyano-benzylbromide 
##STR6## 
as prepared by bromination of commercially available orthocyano-toluene 
with Br.sub.2 at a temperature of about 150.degree. C., with a compound of 
general formula 
##STR7## 
wherein X is a carbethoxy or a cyano group and R is as defined above, as 
prepared by reduction with Fe and NH.sub.4 Cl or by catalytic 
hydrogenation of the corresponding nitroderivative, obtained in its turn 
by nitration of the compound of formula 
##STR8## 
(Bull. Soc. Chim. France, page 866, 1960) with methods described in 
literature for analogous compounds, at a temperature of about 75.degree. 
to about 85.degree. C., in polar solvents, such as ethanol, methanol or 
the like, to form a compound of general formula 
##STR9## 
wherein R and X are as defined above, which is subsequently reacted by 
saponification with suitable bases, such as, for example, K.sub.2 
CO.sub.3, KOH, or the like, or with suitable acids, such as, for example, 
conc. H.sub.2 SO.sub.4, at a temperature of about 75.degree. to about 
180.degree. C., to give compounds of general formula (I), wherein R.sub.1 
is hydrogen, and subsequently, if desired, esterifying at a temperature of 
about 60.degree. to about 120.degree. C., the compounds of general formula 
(I), wherein R.sub.1 is hydrogen, thus obtained, with the proper alcohols 
or amino alcohols, according to the usual methods of organic chemistry; or 
(b) reacting commercially available phthalide 
##STR10## 
with a compound of general formula (II) at a temperature of about 
150.degree. to about 300.degree. C., so obtaining a compound of formula 
##STR11## 
wherein X and R are as defined above, which is subsequently reacted by 
saponification with suitable bases, such as, for example, K.sub.2 
CO.sub.3, KOH, or the like, or with suitable acids, such as, for example, 
conc. H.sub.2 SO.sub.4, at a temperature of about 75.degree. to about 
180.degree. C., to give compounds of general formula (I), wherein R.sub.1 
is hydrogen, and subsequently, if desired, esterifying at a temperature of 
about 60.degree. to about 120.degree. C., the compounds of general formula 
(I), wherein R.sub.1 is hydrogen, thus obtained, with the proper alcohols 
or amino alcohols according to the usual methods of organic chemistry; or 
reacting tiophthalide 
##STR12## 
as prepared according to the method of V. Prey and P. Kondler, Monat. fur 
Chemie, 89, 505 (1958), the disclosure of which is hereby incorporated by 
reference, with a compound of formula (II), at a temperature of about 
150.degree. to about 280.degree. C., preferably in sealed tube, so 
obtaining a compound of formula (IV) which is subsequently reacted by 
saponification to give compounds of general formula (I), wherein R.sub.1 
is hydrogen, which, if desired, are esterified as described in process 
(a); or 
(d) reacting commercially available phthalic aldehyde 
##STR13## 
with a compound of formula (II) at a temperature of about 50.degree. to 
about 150.degree. C. in polar solvents, such as, for example, 
dimethylformamide, dimethyl sulphoxide, and the like, so obtaining a 
compound of formula (IV), which is subsequently reacted by saponification 
to give compounds of general formula (I), wherein R.sub.1 is hydrogen, 
which, if desired, are esterified as described in process (a); or reacting 
commercially available phthalic anhydride 
##STR14## 
with a compound of formula (II), at a temperature of about 60.degree. to 
about 150.degree. C., so obtaining a compound of formula 
##STR15## 
wherein X and R are as defined above, which is subsequently reduced with a 
suitable reducing agent, such as, for example, Zn and CH.sub.3 COOH, and 
the like, at a temperature of about 60.degree. to about 150.degree. C., to 
give a compound of formula (IV), which is subsequently reacted by 
saponification to give compounds of general formula (I), wherein R.sub.1 
is hydrogen, which, if desired, are esterified as described in process 
(a); or reacting commercially available compounds of general formula 
##STR16## 
wherein the R.sub.4 groups are both hydrogen, both methyl groups, or both 
ethyl groups, with a compound of formula (II), at a temperature of about 
80.degree. to about 280.degree. C., in the presence or absence of a 
solvent, so obtaining a compound of formula (V), wherein X and R are as 
defined above, which is subsequently reduced to give a compound of formula 
(IV), which is then saponified to give compounds of general formula (I), 
wherein R.sub.1 is hydrogen, which, if desired, are esterified as 
described in process (a), 
From the above reaction sequences it appears evident that if compounds of 
general formula (I), wherein R.sub.1 is an ethyl group, are desired to be 
obtained, processes (b), (c), (d), (e), and (f) may be stopped, the case 
being, when the compounds of general formula (IV), wherein X is the 
carbethoxy group, are obtained. 
As hereabove described, esterification of the compounds of general formula 
(I), wherein R.sub.1 is hydrogen to give, if desired, compounds of general 
formula (I), wherein R.sub.1 is different from hydrogen, is performed 
according to the usual methods of organic chemistry, as is known to those 
skilled in the art. For example, the esters of the compound of general 
formula (I) wherein R.sub.1 is hydrogen, with N,N-dimethylaminoethanol may 
be prepared by treatment of said compounds with SOCl.sub.2 at a 
temperature of about 60.degree. to about 90.degree. C. in the presence or 
absence of solvents, and subsequently by reacting the acid chlorides, so 
obtained, with N,N-dimethylaminoethanol at room temperature in apolar 
solvents, such as, for example, dioxane, benzene, and the like. 
The compounds of general formula (I) wherein R.sub.1 is hydrogen, may also 
be converted, if desired, into their salts with physiologically acceptable 
inorganic bases, such as, for example, NaOH, Ca(OH).sub.2, and the like, 
or organic bases, such as, for example, N,N-dimethylaminoethanol, or the 
like, according to the usual methods of organic chemistry, as is known to 
those skilled in the art. For example, the salts of the compounds of 
general formula (I) wherein R.sub.1 is hydrogen, with 
N,N-dimethylaminoethanol may be obtained by reacting, at room temperature, 
these compounds with an aqueous solution containing the stoichiometric 
quantity of N,N-dimethylaminoethanol and by subsequent lyophilization. The 
compounds of general formula (I), wherein R.sub.1 is the group 
##STR17## 
may also be converted, if desired, into their salts with physiologically 
acceptable organic or inorganic acids, according to the usual methods of 
organic chemistry, as is known to those skilled in the art. 
The compounds, object of the present invention, possess a good analgesic 
and anti-inflammatory activity, as shown by the data reported in the table 
1 herebelow, where phenylbutazone is listed alongside as reference 
product. 
TABLE 1 
__________________________________________________________________________ 
Analgesic 
Anti-inflammatory 
Compound activity 
activity 
__________________________________________________________________________ 
##STR18## 100 20 
##STR19## 32 8 
##STR20## 40 13 
##STR21## 33 11 
##STR22## 54 42 
Phenylbutazone 1 1 
__________________________________________________________________________ 
Analgesic activity was assessed by means of phenylquinone test in mice 
according to Siegmund (Siegmund et al., Proc. Soc. Exper. Biol. Med., 95, 
729 (1957)). 
Anti-inflammatory activity was assessed by means of carrageenin induced 
edema test in rats according to Winter (Winter et al., Proc. Soc. Exper. 
Biol. Med., 111, 544 (1962) and J. Pharmac. Exp. Therap., 141, 369 
(1963)). 
Table 2 shows the anti-inflammatory activity of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (I) in 
comparison with 
.alpha.-[3-chloro-4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid (II), 
described in Belgian Pat. No. 753,600. 
Table 2 
______________________________________ 
Potency ratio 
Test I/II Limits for P = 0.05 
______________________________________ 
Carrageenin induced 
5.27 2.84 - 10.78 
edema in rat paw 
Granuloma pouch test 
12.66 6.60 - 58.58 
in the rat 
______________________________________ 
In table 2 anti-inflammatory activity was determined employing both the 
Winter's method, as previously indicated, and granuloma pouch technique 
(Boris A., Stevenson R. H., Arch. Int. Pharmacodyn., 153, 205 (1965). The 
potency ratios were estimated following the parallel line biological assay 
method (Finney D. I., Statistical Method in Biological Assay -- Griffin -- 
London (1952)). 
As shown by the data reported in Table 2, it was surprisingly found that 
the anti-inflammatory activity of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline is much 
higher than that of 
.alpha.-[3-chloro-4-(1-oxo-2-isoindolinyl)-phenyl]-propionic acid. The 
pharmacological data hereabove reported have been confirmed by clinical 
trials performed on man. 
The results of such clinical trials have shown that the dosage ranges for 
adult humans may vary from about 25 to about 150 mg. pro dose, and 
preferably from about 50 to about 100 mg. pro dose. 
The compounds of the present invention are preferably administered orally, 
but they can also be administered by parentheral or topical way. 
The pharmaceutical compositions containing the compounds of this invention 
can be therefore either capsules, tablets, pills, syrups, or vials, 
suppositories, ointments. 
Examples of the substances which can serve as pharmacological carriers or 
diluents for the pharmaceutical compositions of the compounds of the 
invention are talc, gelatin, lactose, starch, magnesium stearate, 
polyvinylpyrrolidone, as well as other non-toxic compatible substances 
used in pharmaceutical formulations.

The following examples illustrate, but do not limit, the scope of the 
present invention. 
EXAMPLE 1 
A mixture of ethyl p-amino-(.alpha.-methyl)-phenylacetate (24.15 g.; 0.125 
moles) and o-cyano-benzylbromide (24.5 g.; 0.125 moles) in EtOH 99.9 (400 
ml) is heated with a reflux condenser for 6 hours, added with char and 
filtered during heating. The filtrate is concentrated to about one third 
and then poured in ethyl ether (1500 ml). The precipitate is filtered and 
washed again with ethyl ether (100 ml) to obtain 
1-imino-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline. HBr 
(44.8 g., yield = 92%), m.p. 203.degree.-204.degree. C. 
In the same way, and by reacting o-cyano-benzylbromide with the proper 
amino esters, the following compounds are obtained: 
1-imino-2-[p-(carbethoxymethyl)-phenyl]-isoindoline. HBr, m.p. 
204.degree.-206.degree. C. 
1-imino-2-{p-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-isoindoline. HBr, 
m.p. 157.degree.-159.degree. C. 
1-imino-2-{p-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-isoindoline. HBr, 
m.p. 158.degree.-160.degree. C. 
1-imino-2-{p-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-isoindoline. HBr, 
m.p. 140.degree.-142.degree. C. 
EXAMPLE 2 
1-imino-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline. HBr, 
(9.73 g.; 0.025 moles) dissolved in EtOH 95% (65 ml) is added to K.sub.2 
CO.sub.3 (13.82 g.; 0.1 moles) dissolved in water (100 ml). The mixture of 
the reagents is heated with a reflux condenser under mixing for 18 hours 
thus obtaining a complete solution. Ethyl alcohol is evaporated under 
vacuum, the undissolved residue is filtered and the filtrate is acidified 
with HCl 8% (about 60 ml). 
The precipitate thus formed is filtered, washed with water (100 ml), with 
HCl 8% (30 ml), and again with water (50 ml) to obtain, after 
crystallization from EtOH 95%, 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (6 g., 
yield = 85%), m.p. 213.degree.-214.degree. C. 
In the same way, and by employing the compounds prepared according to 
Example 1, the following compounds are obtained: 
1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline, m.p. 
208.degree.-209.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
180.degree.-182.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
160.degree.-162.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
145.degree.-147.degree. C. 
EXAMPLE 3 
A mixture of o-cyano-benzylbromide (3.92 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenylacetic acid (3.3 g.; 0.02 moles) in EtOH 
99.9% (80 ml) is heated with a reflux condenser for 6 hours, evaporated to 
little volume (about 30 ml) under vacuum and then poured in ethyl ether 
(about 400 ml). The separated solid is crystallized from EtOH ethyl ether 
to obtain 
1-imino-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline. HBr 
(5.77, yield = 80%), m.p. 264.degree.-266.degree. C. (dec.). 
This produce dissolved in EtOH 95% (60 ml) is added to K.sub.2 CO.sub.3 
(6.91 g.; 0.05 moles) dissolved in water (50 ml). The mixture of the 
reagents is refluxed for 12 hours to obtain a complete solution. Ethyl 
alcohol is evaporated under vacuum, the undissolved residue is filtered 
and the filtrate is acidified with HCl 8% (about 30 ml). The precipitate 
thus formed is filtered, washed with water (80 ml), with HCl 8% (15 ml) 
and again with water (40 ml), to obtain, after crystallization from EtOH 
95%, 1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (4.7 
g., yield = 84%), m.p. 213.degree.-214.degree. C. 
In the same way, and by reacting o-cyano-benzylbromide with the proper 
amino acids, the following compounds are obtained: 
1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline, m.p. 
208.degree.-209.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
180.degree.-182.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
160.degree.-162.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
145.degree.-147.degree. C. 
EXAMPLE 4 
Phthalide (2.7 g.; 0.02 moles) and ethyl p-amino 
(.alpha.-methyl)-phenylacetate (11.6 g.; 0.06 moles) are heated to 
280.degree. for 4 hours in a sealed tube, then cooled, treated with water 
(100 ml), acidified with HCl 8% (40 ml), and extracted with ethyl acetate 
(200 ml). The organic layer is washed with water (80 ml), dried and 
evaporated to dryness in vacuum. The oily residue is crystallized from 
ligroin to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline (4.32 
g., yield = 70%), m.p. 99.degree.-101.degree. C. 
In the same way, and by reacting phthalide with the proper amino esters, 
the following compounds are obtained: 
1-oxo-2-[p-(carbethoxymethyl)-phenyl]-isoindoline, m.p. 
122.degree.-124.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
107.degree.-109.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
105.degree.-106.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
106.degree.-107.degree. C. 
EXAMPLE 5 
Tiophthalide (1.5 g.; 0.01 moles) and ethyl 
p-amino-(.alpha.-methyl)-phenylacetate (5.8 g.; 0.03 moles) are heated to 
190.degree.-200.degree. for 3 hours in a sealed tube, then cooled, treated 
with water (50 ml), acidified with HCl 8% (20 ml), and extracted with 
ethyl acetate (50 ml). The organic layer is washed with water (40 ml), 
dried and evaporated to dryness in vacuum. The residue is crystallized 
from ligroin to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}isoindoline (2.32 
g., yield = 75%), m.p. 99.degree.-101.degree. C. 
In the same way, and by reacting tiophthalide with the proper amino esters, 
the following compounds are obtained: 
1-oxo-2-[p-(carbethoxymethyl)-phenyl]-isoindoline, m.p. 
122.degree.-124.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
107.degree.-109.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
105.degree.-106.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
106.degree.-107.degree. C. 
EXAMPLE 6 
To a solution of phthalic aldehyde (2.94 g.; 0.022 moles) suspended in 
dimethylformamide (200 ml), heated to 60.degree., ethyl 
p-amino-(.alpha.-methyl)-phenylacetate (3.86 g.; 0.02 moles), dissolved in 
dimethylformamide (150 ml), is added in the course of an hour. The mixture 
is stirred again for 2 hours at 60.degree., the solvent is evaporated 
under vacuum. The oily residue is dissolved in ethyl acetate (80 ml), 
washed with HCl 8% (15 ml) and with water (30 ml). The organic layer is 
dried, evaporated to dryness under vacuum, and the residue is cristallized 
from ligroin to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline (5.25 
g., yield = 85%), m.p. 99.degree.-101.degree. C. 
In the same way, and by reacting phthalic aldehyde with the proper amino 
esters, the following compounds are obtained: 
1-oxo-2-[p-(carbethoxymethyl)-phenyl]-isoindoline, m.p. 
122.degree.-124.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
107.degree.-109.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
105.degree.-106.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
106.degree.-107.degree. C. 
EXAMPLE 7 
A mixture of phthalic anhydride (14.8 g.; 0.1 moles) and ethyl 
p-amino-(.alpha.-methyl)-phenylacetate (19.3 g.; 0.1 moles) in glacial 
acetic acid (70 ml) is heated with a reflux condenser for 4 hours, then 
cooled at about 40.degree., and diluted with water (50 ml). An oily 
precipitate, thus formed, solidifies after rubbing, is then cooled at 
0.degree., filtered and washed with water (40 ml), to obtain, after 
crystallization from EtOH 99,9%, 
N-{4-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-phthalimide (30 g., yield 
= 93%), m.p. 113.degree.-114.degree. C. 
In the same way, and by reacting phthalic anhydride with the proper amino 
esters, the following compounds are obtained: 
N-[4-(carbethoxymethyl)-phenyl]-phthalimide, m.p. 150.degree.-152.degree. 
C. 
N-{4-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
108.degree.-109.degree. C. 
N-{4-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
119.degree.-121.degree. C. 
N-{4-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
80.degree.-82.degree. C. 
EXAMPLE 8 
A mixture of phthalic acid (16.6 g.; 0.1 moles) and ethyl 
p-amino-(.alpha.-methyl)-phenyl-acetate (20 g.; 0.103 moles) is heated in 
an oil bath at 200.degree.-210.degree. for an hour and a quarter, then 
cooled, to obtain, after crystallization from EtOH 99%, 
N-{4-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-phthalimide (31 g., yield 
= 96%), m.p. 113.degree.-114.degree. C. 
In the same way, and by reacting phthalic acid with the proper amino 
esters, the following compounds are obtained: 
N-[4-(carbethoxymethyl)-phenyl]-phthalimide, m.p. 150.degree.-152.degree. 
C. 
N-{4-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
108.degree.-109.degree. C. 
N-{4-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
119.degree.-121.degree. C. 
N-{4-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
80.degree.-82.degree. C. 
EXAMPLE 9 
Ethyl ester of phthalic acid (4.44 g.; 0.02 moles) and ethyl 
p-amino-(.alpha.-methyl)-phenyl-acetate (3.86 g.; 0.02 moles) suspended in 
anhydrous dimethylformamide (100 ml) are heated with a reflux condenser 
for 4 hours. The mixture is evaporated to dryness under vacuum, the 
residue is redissolved in ethyl acetate (100 ml), then washed with HCl 8% 
(15 ml), with water (40 ml), dried and evaporated to dryness under vacuum, 
to obtain, after crystallization from EtOH 99%, 
N-{4-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-phthalimide (4.52 g.; 
yield = 70%), m.p. 113.degree.-114.degree. C. 
In the same way, and by reacting ethyl ester of phthalic acid with the 
proper amino esters, the following compounds are obtained: 
N-[4-(carbethoxymethyl)-phenyl]-phthalimide, m.p. 150.degree.-152.degree. 
C. 
N-{4-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
108.degree.-109.degree. C. 
N-{4-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
119.degree.-121.degree. C. 
N-{4-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-phthalimide, m.p. 
80.degree.-82.degree. C. 
EXAMPLE 10 
To a solution of 
N-{4-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-phthalimide (16.1 g.; 
0.05 moles) suspended in acetic acid (200 ml), Zn in powder (19.6 g.; 0.3 
moles) is added under stirring. The mixture is heated with a reflux 
condenser for 4 hours, filtered, and the residue is then washed with warm 
acetic acid (40 ml). The filtrate is evaporated to dryness under vacuum, 
the residue is redissolved in water (100 ml) and neutralized with sodium 
bicarbonate to give pH = 7. The solid, thus formed, is filtered to obtain, 
after crystallization from ligroin, 
1-oxo-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline (13.9 
g., yield = 90%), m.p. 99.degree.-101.degree. C. 
In the same way, and starting from phthalimides prepared according to 
Examples 7, 8 and 9, the following compounds are obtained: 
1-oxo-2-[p-(carbethoxymethyl)-phenyl]-isoindoline, m.p. 
122.degree.-124.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
107.degree.-109.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
105.degree.-106.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carbethoxymethyl]-phenyl}-isoindoline, m.p. 
106.degree.-107.degree. C. 
EXAMPLE 11 
A mixture of 
1-oxo-2-{p-[(.alpha.-methyl)-carbethoxymethyl]-phenyl}-isoindoline (12.36 
g.; 0.04 moles) and K.sub.2 CO.sub.3 (12.36 g.) in EtOH 95% (280 ml) and 
water (182 ml) is heated with a reflux condenser for 8 hours to obtain a 
complete solution. Ethyl ether is evaporated under vacuum, the aqueous 
solution is acidified with HCl 8% (55 ml), and the precipitate, thus 
formed, is filtered, washed with water (55 ml), to obtain, after 
crystallization from EtOH 95%, 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (9.1 g., 
yield = 81%), m.p. 213.degree.-214.degree. C. 
In the same way, and starting from the derivatives prepared according to 
Examples 4, 5, and 6, the following compounds are obtained: 
1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline, m.p. 
208.degree.-209.degree. C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
180.degree.-182.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
160.degree.-162.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
145.degree.-147.degree. C. 
EXAMPLE 12 
A mixture of o-cyano-benzylbromide (3.92 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (2.92 g.; 0.02 moles) in EtOH 
99,9% (80 ml) is heated with a reflux condenser for 6 hours and evaporated 
under vacuum (about 15 ml). The precipitate, thus formed, is filtered to 
obtain 
1-imino-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
HBr (5.47 g., yield = 80%), m.p. 253.degree.-255.degree. C. 
In the same way, and by reacting o-cyano-benzylbromide with the proper 
aminonitriles, the following compounds are obtained: 
1-imino-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline. HBr 
1-imino-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline. HBr 
2-imino-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
HBr 
1-imino-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline. HBr 
EXAMPLE 13 
To 1-imino-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
HBr (3.42 g.; 0.01 moles) dissolved in EtOH 99,9% (80 ml), K.sub.2 
CO.sub.3 (5.52 g.) dissolved in water (20 ml) is added. The mixture is 
heated with a reflux condenser for 10 hours and filtered. The residue is 
washed with water (50 ml) to obtain, after crystallization from EtOH 
99.9%, 1-oxo-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoli 
ne (2.22 g., yield = 85%), m.p. 192.degree.-194.degree. C. 
In the same way, and starting from the derivatives prepared according to 
Example 12, the following compounds are obtained: 
1-oxo-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline. 
1-oxo-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
1-oxo-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
1-oxo-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline. 
EXAMPLE 14 
A mixture of phthalide (2.7 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (8.8 g.; 0.06 moles) is 
heated to 280.degree. for 4 hours in a sealed tube, cooled, treated with 
water (100 ml), acidified with HCl 8% (40 ml) and extracted with ethyl 
acetate (200 ml). The organic layer is washed with water (80 ml), dried 
and evaporated to dryness under vacuum. The residue is crystallized from 
EtOH 99.9% to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline 
(3.57 g., yield = 68%), m.p. 192.degree.-194.degree. C. 
In the same way, and by reacting phthalide with the proper amino nitriles, 
the following compounds are obtained: 
1-oxo-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline 
1-oxo-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline 
EXAMPLE 15 
A mixture of tiophthalide (3 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (8.8 g.; 0.06 moles) is 
heated to 210.degree.-220.degree. C. for 4 hours in a sealed tube, cooled, 
redissolved in water (100 ml), acidified with HCl 8% (40 ml), and 
extracted with ethyl acetate (150 ml). The organic layer is washed with 
water (80 ml), dried and evaporated to dryness under vacuum. The residue 
is crystallized from EtOH 99.9% to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline 
(3.67 g., yield = 70%), m.p. 192.degree.-194.degree. C. 
In the same way, and by reacting tiophthalide with the proper amino 
nitriles, the following compounds are obtained: 
1-oxo-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline 
1-oxo-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline 
EXAMPLE 16 
To a solution of phthalic aldehyde (2.94 g.; 0.022 moles) suspended in 
dimethylformamide (200 ml), heated to 60.degree. C., 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (2.92 g.; 0.02 moles), 
dissolved in dimethylformamide (100 ml), is added in the course of an 
hour. The mixture is stirred again for 4 hours at 60.degree. C., the 
solvent is evaporated under vacuum. The oily residue is dissolved in ethyl 
acetate (100 ml), washed with HCl 8% (15 ml), then with water (30 ml). The 
organic layer is dried and evaporated to dryness under vacuum. The residue 
is crystallized from EtOH 99.9% to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline 
(3.94 g., yield = 75%), m.p. 192.degree.-194.degree. C. 
In the same way, and by reacting phthalic aldehyde with the proper amino 
nitriles, the following compounds are obtained: 
1-oxo-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline 
1-oxo-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline 
EXAMPLE 17 
a mixture of phthalic anhydride (17.8 g.; 0.12 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (14.61 g.; 0.1 moles) in 
glacial acetic acid (90 ml) is heated with a reflux condenser for 4 hours 
thus obtaining a complete solution. The mixture is then cooled, and the 
solid separated is filtered, washed with water and dried to obtain 
N-{4-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-phthalimide (22.1 g., 
yield = 80%), m.p. 213.degree.-215.degree. C. 
In the same way, and by reacting phthalic anhydride with the proper amino 
nitriles, the following compounds are obtained: 
N-[4-(carbonitrile-methyl)-phenyl]-phthalimide 
N-{4-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-phthalimide 
EXAMPLE 18 
A mixture of phthalic acid (3.32 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (2.96 g.; 0.02 moles) is 
heated in an oil bath to 220.degree.-230.degree. C. for an hour and a 
half, then cooled, redissolved with water and the solid, thus formed, is 
filtered to obtain 
N-{4-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-phthalimide (4.68 g.; 
yield = 85%), m.p. 213.degree.-215.degree. C. 
In the same way, and by reacting phthalic acid with the proper amino 
nitriles, the following compounds are obtained: 
N-[4-(carbonitrile-methyl)-phenyl]-phthalimide 
N-{4-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.butyl)-carbonitrile-methyl]-phenyl}-phthalimide 
EXAMPLE 19 
A mixture of ethyl ester of phthalic acid (4.44 g.; 0.02 moles) and 
p-amino-(.alpha.-methyl)-phenyl-acetonitrile (2.96 g.; 0.02 moles) 
suspended in anhydrous dimethylformamide (100 ml) is heated with a reflux 
condenser for 4 hours, evaporated to dryness under vacuum, the residue is 
then redissolved with ethyl acetate (100 ml), washed with HCl 8% (15 ml), 
then with water (40 ml), subsequently dried and evaporated to dryness 
under vacuum. The residue is crystallized from EtOH 99% to obtain 
N-{4-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-phthalimide (4.13 g., 
yield = 75%), m.p. 213.degree.-215.degree. C. 
In the same way, and by reacting ethyl ester of phthalic acid with the 
proper amino nitriles, the following compounds are obtained: 
N-[4-(carbonittrile-methyl)-phenyl]-phthalimide 
N-{4-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-phthalimide 
N-{4-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-phthalimide 
EXAMPLE 20 
To a suspension of 
N-{4-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-phthalimide (2.76 g.; 
0.01 moles) in glacial acetic acid (50 ml), heated to 70.degree. C., Zn in 
powder (4 g.) is added gradually. The mixture is then heated with a reflux 
condenser for 14 hours. The inorganic layer is filtered, the filtrate is 
cooled, and the solid product, thus formed, is filtered, treated with 
water, then with NaHCO.sub.3 8% (50 ml), and filtered again. The residue 
is crystallized from EtOH 99.9% to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carbonitrile-methyl]-phenyl}-isoindoline 
(1.83 g., yield = 70%), m.p. 192.degree.-194.degree. C. 
In the same way, and starting from the derivative prepared according to 
Example 17, 18 and 19, the following compounds are obtained: 
1-oxo-2-[p-(carbonitrile-methyl)-phenyl]-isoindoline 
1-oxo-2-{p-[(.alpha.-ethyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-propyl)-carbonitrile-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-butyl)-carbonitrile-methyl]-phenyl}-isoindoline 
EXAMPLE 21 
A suspension of 
1-oxo-2-{p-[(.alpha.-methyl-carbonitrile-methyl]-phenyl}-isoindoline (2.62 
g.; 0.01 moles) in conc. H.sub.2 SO.sub.4 (2.42 ml) and water (7.4 ml) is 
heated with a reflux condenser for 16 hours, then poured into cold water 
(100 ml). The solid separated is filtered, then treated with NaOH 8% (30 
ml). The insoluble residue is filtered, the filtrate is acidified with HCl 
8% (30 ml), the solid is filtered and crystallized from EtOH 95% to obtain 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (2.39 g., 
yield = 85%), m.p. 213.degree.-214.degree. C. 
In the same way, and starting from the derivative prepared according to 
Example 14, 15 and 20, the following compounds are obtained: 
1-oxo-2[p-(carboxymethyl)-phenyl]-isoindoline, m.p. 208.degree.-209.degree. 
C. 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
180.degree.-182.degree. C. 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
160.degree.-162.degree. C. 
1-oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline, m.p. 
145.degree.-147.degree. C. 
EXAMPLE 22 
A solution of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (15.4 g.; 
0.055 moles) and concentrated sulfuric acid (6 ml) in anhydrous methyl 
alcohol (180 ml) is heated with a reflux condenser for 6 hours, then 
cooled and filtered, and the precipitate is washed with NaHCO.sub.3 2% 
(100 ml) to obtain, after crystallization from methyl alcohol, 
1-oxo-2-{p-[(.alpha.-methyl)-carbomethoxy-methyl]-phenyl}-isoindoline 
(15.5 g., yield = 96%), m.p. 124.degree.-126.degree. C. 
In the same way, and by reacting methyl alcohol with the proper 
isoindolines, the following compounds are obtained: 
1-oxo-2-[p-(carbomethoxy-methyl)-phenyl]-isoindoline 
1-oxo-2-{p-[(.alpha.-ethyl)-carbomethoxy-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-propyl)-carbomethoxy-methyl]-phenyl}-isoindoline 
1-oxo-2-{p-[(.alpha.-butyl)-carbomethoxy-methyl]-phenyl}-isoindoline 
EXAMPLE 23 
A solution of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (20 g.; 
0.0714 moles) and SOCl.sub.2 (120 ml) is heated with a reflux condenser 
for 3 hours, the excess SOCl.sub.2 is then distilled away, then anhydrous 
benzene (150 ml) is added, and after evaporation to dryness, treatment 
with petroleum ether, a solid is filtered, which by crystallization from a 
mixture of benzene and petroleum ether gives the acid chloride of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (18.15 g., 
yield = 85%), m.p. 132.degree.-134.degree. C. 
This acid chloride (12 g.) is now dissolved in anhydrous dioxane (200 ml), 
and this solution is added dropwise, under effective agitation, to a 
solution of N,N-dimethylaminoethanol (12 ml) in anhydrous dioxane (200 ml) 
to produce a slightly exothermic reaction. The mixture is agitated for 3 
hours at room temperature, then let stand overnight. The precipitate thus 
formed is then filtered, and the filtrate is evaporated under vacuum to 
make an oily residue. This residue is dissolved in CHCl.sub.3 (150 ml), 
the chloroform solution is washed with NaHCO.sub.3 2% (100 ml), dried on 
anhydrous sodium sulfate and evaporated to dryness under vacuum. The 
residue is then extracted with hot hexane, and subsequently cooled to 
obtain N,N-dimethylaminoethanol ester of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (11.3 g., 
yield = 80%), m.p. 61.degree.-63.degree. C. 
In the same way, and by reacting N,N-dimethylaminoethanol with the acid 
chlorides of the proper isoindolines, the following compounds are 
obtained: 
N,n-dimethylaminoethanol ester of 
1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline 
N,n-dimethylaminoethanol ester of 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline 
N,n-dimethylaminoethanol ester of 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline 
N,n-dimethylaminoethanol ester of 
1-oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline. 
EXAMPLE 24 
N,N-dimethylaminoethanol (1 ml) is added to 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (2.8 g.; 
0.01 moles), suspended in water (100 ml). The solution is then lyophilized 
to obtain N,N-dimethylaminoethanol salt of 
1-oxo-2-{p-[(.alpha.-methyl)-carboxymethyl]-phenyl}-isoindoline (3.7 g., 
yield = 100%). 
In the same way, and by reacting N,N-dimethylaminoethanol with the proper 
isoindolines, the following compounds are obtained: 
N,n-dimethylaminoethanol salt of 
1-oxo-2-[p-(carboxymethyl)-phenyl]-isoindoline 
N,n-dimethylaminoethanol salt of 
1-oxo-2-{p-[(.alpha.-ethyl)-carboxymethyl]-phenyl}-isoindoline 
N,n-dimethylaminoethanol salt of 
1-oxo-2-{p-[(.alpha.-propyl)-carboxymethyl]-phenyl}-isoindoline 
N,n-dimethylaminoethanol salt of 
1oxo-2-{p-[(.alpha.-butyl)-carboxymethyl]-phenyl}-isoindoline.