The present invention provides oxindole derivatives of the formula: ##STR1## wherein the various substituents are defined hereinbelow. The above compounds display nitrate-like as well as .beta.-blocking actions.

The present invention is concerned with new oxindole derivatives, processes 
for the preparation thereof and pharmaceutical compositions containing 
them, as well as intermediates for the preparation thereof. 
The new oxindole derivatives according to the present invention are 
compounds of the general formula: 
##STR2## 
wherein R.sub.1 is a C.sub.2 -C.sub.10 nitratoalkyl radical, X is a 
hydrogen atom or a C.sub.1 -C.sub.6 -alkyl radical and Y is a hydrogen 
atom, a C.sub.1 -C.sub.6 -alkyl radical or, together with X and the carbon 
atom to which they are attached, forms a C.sub.3 -C.sub.7 -cycloalkyl 
ring, or is a radical of the general formula: 
##STR3## 
wherein R.sub.2 is a hydrogen atom or, together with X, represents a 
valency bond, R.sub.3 is a hydrogen atom or a straight-chained or branched 
C.sub.1 -C.sub.6 -alkyl radical and R.sub.4 is a straight-chained or 
branched C.sub.1 -C.sub.6 -alkyl radical, a cycloalkyl radical or an 
optionally substituted aryl or a mono- or bicyclic-hetero radical as 
defined below or R.sub.3 and R.sub.4 together with the C-atom represent a 
C.sub.3 -C.sub.7 -cycloalkylene radical optionally interrupted by the 
group 
##STR4## 
in which R.sub.5 is a hydrogen atom or a C.sub.1 -C.sub.6 -alkyl radical: 
and the pharmacologically acceptable salts thereof. 
The aryl and hetaryl radicals can optionally be substituted one or more 
times by halogen, C.sub.1 -C.sub.6 -alkyl, hydroxyalkyl, hydroxyl, C.sub.1 
-C.sub.6 -alkoxy, C.sub.2 -C.sub.4 -alkenyl, C.sub.2 -C.sub.4 -alkenyloxy, 
C.sub.2 -C.sub.4 -alkynyl, amino, C.sub.1 -C.sub.4 -alkylamino, C.sub.2 
-C.sub.8 -dialkylamino, aminocarbonyl, C.sub.1 -C.sub.4 
-alkylaminocarbonyl, C.sub.2 -C.sub.8 -dialkylaminocarbonyl, cyano, 
C.sub.2 -C.sub.4 -alkanoyl, aminosulphonyl, C.sub.1 -C.sub.4 
-alkylaminosulphonyl, C.sub.2 -C.sub.8 -dialkylaminosulphonyl, carboxyl, 
C.sub.1 -C.sub.6 -alkoxycarbonyl, C.sub.1 -C.sub.6 -alkylthio, C.sub.1 
-C.sub.6 -alkylsulphinyl, C.sub.1 -C.sub.6 -alkylsulphonyl, C.sub.2 
-C.sub.4 -alkanoylamido, C.sub.1 -C.sub.4 -alkylsulphonylamido or nitro 
groups or by a C.sub.1 -C.sub.2 -alkylenedioxy radical. However, as 
mentioned above, R.sub.3 and R.sub.4 can together with the C-atom also 
represent a C.sub.3 -C.sub.7 -cyclo-alkylene radical optionally 
interrupted by the group 
##STR5## 
wherein R.sub.5 is a hydrogen atom or a C.sub.1 -C.sub.6 -alkyl radical. 
Since the compounds of general formula (I) possess either one asymmetric 
carbon atom or, when Y is a radical of the general formula 
##STR6## 
and X and R.sub.2 each represent hydrogen atoms, possess two asymmetric 
carbon atoms, the present invention also provides the optically-active 
forms and racemic mixtures of these compounds. 
When X and R.sub.2 together represent a valency bond in compounds of 
general formula (I), the E- and Z-isomers are also provided by the present 
invention. 
The compounds according to the present invention, as well as their 
pharmacologically acceptable salts, display, in the same dosage range, 
nitrate-like as well as .beta.-blocking actions and can, therefore, be 
used for the treatment and prophylaxis of circulatory and heart diseases, 
for example high blood pressure and angina pectoris. 
The C.sub.2 -C.sub.10 -nitratoalkyl radicals of the substituents R.sub.1 
are straight-chained or branched radicals, for example nitratoethyl, 
nitratopropyl, nitratobutyl, nitratopentyl, nitratohexyl, 
1-methyl-2-nitratoethyl, 1-methyl-3-nitratopropyl, 
1,1-dimethyl-3-nitratopropyl, 1,3-dimethyl-3-nitratopropyl or 
2,2-dimethyl-3-nitratopropyl radicals. However, the 
1-methyl-3-nitratopropyl, 1,1-dimethyl-3-nitratopropyl and 
1,3-dimethylnitratopropyl radicals are especially preferred. 
By C.sub.1 -C.sub.6 -alkyl radicals in the substituents R.sub.3, R.sub.4, 
R.sub.5, X and Y are to be understood straight-chained and branched 
radicals, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, tert.-butyl and n-hexyl radicals. However, methyl, ethyl, 
isopropyl and tert.-butyl radicals are preferred. 
By C.sub.3 -C.sub.7 -cycloalkyl rings which are formed by X and Y and the 
carbon atom to which they are attached, there are preferably to be 
understood cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl radicals. 
Cycloalkyl radicals in the case of substituent R.sub.4 are especially the 
cyclopentyl and cyclohexyl radicals. 
Aryl radicals in the case of the substituents R.sub.4 are preferably phenyl 
radicals. 
The alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, 
alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 
alkylaminosulphonyl, dialkylaminosulphonyl, alkanoyl, alkylsulphonylamido, 
dialkylamino and alkanoylamido radicals which can be substituents of the 
aryl and hetaryl radicals contain 1-8 and preferably 1-6 carbon atoms. The 
methyl and ethyl radicals, as well as the various isomeric propyl, butyl 
and pentyl radicals, are especially preferred. 
In the case of the alkenyl and alkynyl radicals, the allyl and propargyl 
radicals are especially preferred. 
By halogen, within the meaning of the present invention, there are to be 
understood fluorine, chlorine, bromine and iodine, fluorine, chlorine and 
bromine being preferred. 
By mono- or bicyclic-hetero radicals R.sub.4, according to the present 
invention, there are to be understood mono- and bicyclic radicals with one 
or more heteratoms. Preferred radicals include the furan, thiophene, 
pyrrole, pyrazole, imidazole, triazole, tetrazole, imidazolinone, 
pyridine, pyrimidine, uracil, indole, indazole and dihydropyran radicals. 
Preferred cycloalkyl rings, which can be formed together with the C-atom, 
are cyclopropyl, cyclopentyl and cyclohexyl. Preferred rings interrupted 
by the group 
##STR7## 
are pyrrolidine and piperidine. Methyl and Ethyl are preferred R.sub.5 
substituents. 
The preparation of the compounds of general formula (I) can be carried out 
in known manner by 
(a) reacting a compound of the general formula: 
##STR8## 
wherein X and Y have the same meanings as above, with a compound of the 
general formula: 
EQU H.sub.2 --N--R.sub.1 (III), 
in which R.sub.1 has the same meaning as above; or 
(b) condensing a compound of general formula (II), in which X and Y are 
hydrogen atoms, with a compound of the general formula: 
##STR9## 
in which R.sub.3 and R.sub.4 have the same meanings as above, and 
subsequently reacting with a compound of general formula (III); or 
(c) reducing a compound of the general formula: 
##STR10## 
in which R.sub.6 is a group which can be split off, and reacting with a 
compound of general formula (III); and cyclising the compound thereby 
obtained of the general formula: 
##STR11## 
in which R.sub.1 and R.sub.6 have the same meanings as above; or 
(d) reacting a compound of the general formula: 
##STR12## 
in which R.sub.1 has the same meaning as above, with a compound of general 
formula (IV); or 
(e) reacting a compound of the general formula: 
##STR13## 
in which X and Y have the same meanings as above and R.sub.7 is a C.sub.2 
--C.sub.10 -hydroxyalkyl radical, with nitric acid or a reactive 
derivative thereof; 
whereafter, if desired, the compound obtained is converted into a 
compatible salt. 
The preparation of compounds of general formula (II), as well as of some 
representatives thereof, especially those which are 4-substituted, is 
described in Federal Republic of Germany Patent Specification No. P 33 10 
891.1. New compounds can be prepared in an analogous manner. 
Compounds of general formulae (III) and (IV) can be prepared by processes 
known from the literature or are commonly available. 
Some of the compounds of general formula (V) are described in European 
Patent Specification No. 00 149 28 and new compounds can be prepared 
analogously. 
The compounds of general formula (VI) are new. Thus, the present invention 
also provides the new intermediates of general formula (VI) for the 
preparation of compounds of general formula (I). 
Groups in compounds of general formulae (V) and (VI) which can be split off 
include amino, imidazolyl, hydroxyl and C.sub.1 -C.sub.6 -alkoxy radicals, 
hydroxyl, methoxy, ethoxy and propoxy radicals being preferred. 
The reaction of compounds of general formula (VII) with compounds of 
general formula (IV) can be carried out without the use of a solvent or in 
an inert solvent, for example methanol, ethanol n-butanol, diethyl ether, 
methylene chloride, toluene, ethyl acetate, tetrahydrofuran, dioxan, 
dimethylformamide or dimethyl sulphoxide, with the addition of an 
appropriate catalyst, for example, ammonia, triethylamine, 
N-ethyldiisopropylamine, tributylamine, piperidine, morpholine, 
1-methylpiperidine, 4-methylmorpholine or sodium methylate. However, 
especially preferred are methanol, ethanol and dimethyl sulphoxide, as 
well as triethylamine, piperidine and 1-methylpiperidine. 
Compounds of general formula (VII) are themselves pharmacologically 
effective but can also be used as intermediates for the preparation of 
other active compounds of general formula (I). 
The compounds of general formula (I) according to the present invention can 
be obtained in the form of racemic mixtures. The separation of the 
racemate into the optically-active forms take place by known methods via 
the diastereomeric salts of optically-active acids, for example tartaric 
acid, malic acid or camphorsulphonic acid. 
Compounds of general formula (VIII) are also new and form part of the 
subject matter of the present invention. The preparation of these 
compounds is preferably carried out by reacting epoxides of general 
formula (II) or (V) with a compound of the general formula: 
EQU H.sub.2 N--R.sub.7 (IX), 
in which R.sub.7 has the same meaning as above. 
The reaction with nitric acid or with a reactive derivative thereof, for 
example nitronium tetrafluoroborate, is preferably carried out with 
acetonitrile. 
For converting the compounds of general formula (I) into their 
pharmacologically acceptable salts, these are reacted, preferably in an 
organic solvent, with the equivalent amount of an inorganic or organic 
acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, 
sulphuric acid, acetic acid, citric acid, tartaric acid, maleic acid, 
fumaric acid, benzoic acid or cyclohexylsulphamic acid. 
For the preparation of pharmaceuticals, the compounds of general formula 
(I) are mixed in known manner with appropriate pharmaceutical carrier 
substances, aroma, flavouring and colouring materials and formed, for 
example, into tablets or dragees or, with the addition of appropriate 
adjuvants, suspended or dissolved in water or in an oil, for example olive 
oil. 
The new compounds of general formula (I) according to the present invention 
and the salts thereof can be administered enterally or parenterally in 
liquid or solid form. As injection medium, it is preferred to use water 
which contains the additives usual in the case of injection solutions, 
such as stabilising agents, solubilising agent or buffers. 
Such additives include, for example, tartrate and citrate buffers, ethanol, 
complex forming agents (such as ethylenediamine-tetraacetic acid and the 
nontoxic salts thereof) and high molecular weight polymers (such as liquid 
polyethylene oxide) for viscosity regulation. Solid carrier materials 
include, for example, starch, lactose, mannitol, methyl cellulose, talc, 
highly dispersed silicic acids, high molecular weight fatty acids (such as 
stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, 
animal and vegetable fats and solid high molecular weight polymers (such 
as polyethylene glycols). Compositions suitable for oral administration 
can, if desired, contain flavouring and sweetening materials. 
The compounds are administered in amounts of 20-500 mg per day, based on 75 
kg body weight. It is preferable to administer this dosage gradually, 
either by administering 1-2 tablets with an active substance content of 
10-200 mg, 2 or 3 times a day, or to use slow release formulations so that 
only once a day 1-2 tablets with 20-500 mg active substance can be 
administered. The active substance can also be administered by injection 
1-8 times per day or by continuous infusion, amounts of 5-200 mg/day 
normally sufficing in that case. 
TEST PROTOCOL 
The compounds claimed have beta-blocking as well as nitrate-like properties 
and can therefore be used as antianginal therapy (heart disorder 
characterized by attacks of pain where there is an insufficiency of 
oxygen). 
At present pharmaceuticals are available either for their nitrate-like 
properties, e.g. nitroglycerin, isosorbide dinitrate, 
isosorbide-5-mononitrate, or for their beta-blocker properties, e.g. 
propanolol, pindolol. Combinations of these drugs are also used, but so 
far no compound is available which by its working principle incorporates 
both qualities. The invention provides compounds which, surprisingly, have 
nitrate-like as well as beta-blocking qualities in overlapping dosage 
ranges. Thus, a single compound can be used to treat two separate (but 
usually related in occurrence) ailments. 
Since such substances have so far not been developed specifically, a method 
for screening the nitrate-like action is not known. It is for this reason 
that the following method was developed: 
(a) to show denitration properties (which constitutes the working principle 
of all nitrates; see U. Abshagen in Handbook of Experimental Pharmacology, 
Vol. 76, 1985, Chapter 10.) the denitration rate was evaluated in relation 
to that of the known isosorbide dinitrate metabolite 
isosorbide-5-mononitrate (V.sub.rel). To that end, rats were killed under 
narcosis and their livers re-perfused 4 min with a corresponding 
concentrated equimolar (5.times.10.sup.-5 M/l) solution of 
isosorbide-5-mononitrate and the substances to be tested respectively (a 
blood sediment solution was pumped through the liver vessels) and the 
freed amount in NO.sub.2 determined in the perfusate (outflowing fluid). 
To have comparable conditions, the perfusion with isosorbide-5-mononitrate 
(standard substance) was administered as control at the second time as if 
it were an unknown substance (in this way a liver performance change under 
the test conditions can be recognized and accordingly allowed for). 
High V.sub.rel -values show a fast denitration, low values a slow 
denitration. 
(b) The .beta.-blocking effectiveness was shown by administering rabbits 
isoprenaline in an amount of 1 mcg/kg i.v. and determining the dose, which 
causes an inhibition of 50% of the increase of the frequency through 
isoprenaline (ID 50.sub.fcor =inhibition dose 50%). 
TABLE 
______________________________________ 
ID 50 fcor ID 50 fcor 
Example mcg/kg i.v. 
Vrel Example 
mcg/kg i.v. 
Vrel 
______________________________________ 
Isosorbide- 
-- 0.86 1 (c) 5083 1.77 
5-mononitrate 
Isosorbide- 
-- 17.5 2 (c) 1968 0.59 
dinitrate 
Propranolol 
331 -- 4 (a) 9.6 0.65 
Pindolol 104 -- 1 (f) -- 3.01 
2 11 1.12 1 (i) 3358 0.81 
1 6.6 1.60 BV 40 690 3.51 
1 (b) 3.8 2.02 4 (b) 27.6 0.54 
4 (h) 39 1.39 1 (g) 5308 0.70 
1 (a) 15 1.23 4 (j) -- 0.49 
1 (e) -- 1.79 BV 43 9.6 0.83 
2 (a) -- 2.40 BV 2 -- 2.99 
4 (d) 9.6 1.00 4 (k) -- 1.88 
1 (d) -- 1.81 BV 4 1095 1.22 
4 (g) 13 1.59 BV 6 &gt;4000 0.74 
2 (b) 172 0.86 BV 9 765 0.60 
4 (f) -- 1.80 BV 20 113 0.71 
______________________________________ 
EXAMPLES 
Apart from the compounds described in the Examples, preferred compounds 
according to the present invention include the following: 
1. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-methylindolinone 
2. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3,3-dimethylindoli 
none fumarate (m.p. 140.degree.-142.degree. C., recrystallised from 
ethanol; yield 40% of theory) 
3. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-spiro-tetramethy 
leneindolinone 
4. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(3-chlorobenzyli 
dene)-indolinone fumarate (m.p. 97.degree.-100.degree. C. recrystallised 
from propan-2-ol; yield 30% of theory) 
5. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-fluorobenzyli 
dene)-indolinone 
6. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-methylbenzyli 
dene)-indolinon fumarate (m.p. 80.degree.-85.degree. C. recrystallised from 
propan-2-ol, yield 20% of theory) 
7. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-hydroxymethyl 
benzylidene)-indolinone 
8. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-hydroxybenzyl 
idene)-indolinone 
9. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(3-methoxybenzyl 
idene)-indolinone acetate (m.p. 80.degree.-83.degree. C. recrystallised 
from ethyl acetate, yield 25% of theory) 
10. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-allyloxybenzy 
lidene)-indolinone 
11. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-aminobenzylid 
ene)-indolinone 
12. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-dimethylamino 
benzylidene)-indolinone 
13. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-acetamidobenz 
ylidene)-indolinone 
14. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-methanesulpho 
nylamidobenzylidene)-indolinone 
15. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-acetylbenzyli 
dene)-indolinone 
16. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-aminocarbonyl 
benzylidene)-indolinone 
17. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-dimethylamino 
carbonylbenzylidene)-indolinone 
18. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-carboxybenzyl 
idene)-indolinone 
19. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-methoxycarbon 
ylbenzylidene)-indolinone 
20. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-nitrobenzylid 
ene)-indolinone (m.p. 135.degree.-137+ C. recrystallised from methanol, 
yield 30% of theory) 
21. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-dimethylamino 
sulphonylbenzylidene)-indolinone 
22. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(3-methoxy-4-hyd 
roxybenzylidene)-indolinone 
23. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-hydroxy-4-met 
hylthiobenzylidene)-indolinone 
24. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(3,4-methylenedi 
oxybenzylidene)-indolinone 
25. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-methylaminosu 
lphonylfuran-5-yl)-methyleneindolinone 
26. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(4-methylimidazo 
lin-2-on-5-yl)-methyleneindolinone 
27. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(pyridin-4-yl)-m 
ethyleneindolinone 
28. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(5,6-dihydro-2H- 
pyran-3-yl)-methyleneindolinone 
29. 
4-[2-hydroxy-3-(1-methyl-3-nitropropylamino)-propoxy]-3-(indol-3-yl)-methy 
leneindolinone 
30. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-ethylideneindoli 
none 
31. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-ethylindolinone 
32. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-methylpropyli 
dene)-indolinone 
33. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(2-methylpropyl) 
-indolinone 
34. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-cyclohexylmethyl 
eneindolinone 
35.5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-cyclohexylmeth 
ylindolinone 
36. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-cyclohexylidenei 
ndolinone 
37. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-cyclohexylindoli 
none 
38. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(1-methylpiperid 
in-4-ylidene)-indolinone 
39. 
5-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(1-methylpiperid 
yl-4)-indolinone 
40. 4-[2-hydroxy-3-(2,2-dimethyl-3-nitratopropylamino)-propoxy]-indolinone 
hemifumarate (m.p. 154.degree.-158.degree. C., recrystallised from 
methanol; yield 35% of theory) 
41. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-benzylindolinone 
42.4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(pyrazol-5-yl) 
-methylindolinone (m.p. 127.degree.-129.degree. C., recrystallised from 
ethyl acetate; yield 25% of theory) 
43. 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(3-methylpyrazol 
-5-yl)-methyleneindolinone. 
Preferred intermediates of general formula (VI) include the following: 
2-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-6-aminophenyl 
acetic acid 
2-[2-hydroxy-3-(1,1-dimethyl-3-nitratopropylamino)-propoxy]-6-aminophenyl 
acetic acid 
2-[2-hydroxy-3-(1,3-dimethyl-3-nitratopropylamino)-propoxy]-6-aminophenyl 
acetic acid 
2-[2-hydroxy-3-(2,2-dimethyl-3-nitratopropylamino)-propoxy]-6-aminophenyl 
acetic acid as well as the imidazolides, methyl and ethyl esters and other 
reactive derivatives thereof. 
Apart from the compounds mentioned in the Examples, preferred intermediates 
of general formula (VIII) include the following: 
5-[2-hydroxy-3-(1-methyl-3-hydroxypropylamino)-propoxy]-indolinone 
4-[2-hydroxy-3-(1,1-dimethyl-3-hydroxypropylamino)-propoxy]-indolinone 
4-[2-hydroxy-3-(1,3-dimethyl-3-hydroxypropylamino)-propoxy]-indolinone 
4-[2-hydroxy-3-(2,2-dimethyl-3-hydroxypropylamino)-propoxy]-indolinone 
4-[2-hydroxy-3-(1-methyl-3-hydroxypropylamino)-propoxy]-3-methylindolinone 
4-[2-hydroxy-3-(1,1-dimethyl-3-hydroxypropylamino)-propoxy]-3-methylindolin 
one 
5-[2-hydroxy-3-(1,1-dimethyl-3-hydroxypropylamino)-propoxy]-3-methylindolin 
one 
4-[2-hydroxy-3-(1,3-dimethyl-3-hydroxypropylamino)-propoxy]-3-methylindolin 
one 
4-[2-hydroxy-3-(2,2-dimethyl-3-hydroxypropylamino)-propoxy]-3-methylindolin 
one 
4-[2-hydroxy-3-(1-methyl-3-hydroxypropylamino)-propoxy]-3,3-dimethylindolin 
one 
4-[2-hydroxy-3-(1,1-dimethyl-3-hydroxypropylamino)-propoxy]-3,3-dimethylind 
olinone 
4-[2-hydroxy-3-(1,3-dimethyl-3-hydroxypropylamino)-propoxy]-3,3-dimethylind 
olinone 
5-[2-hydroxy-3-(1,3-dimethyl-3-hydroxypropylamino)-propoxy]-3,3-dimethylind 
olinone 
4-[2-hydroxy-3-(2,2-dimethyl-3-hydroxypropylamino)-propoxy]-3,3-dimethylind 
olinone 
4-[2-hydroxy-3-(1-methyl-3-hydroxypropylamino)-propoxy]-3-(pyrazol-5-yl)-me 
thyleneindolinone 
4-[2-hydroxy-3-(1,1-dimethyl-3-hydroxypropylamino)-propoxy]-3-(pyrazol-5-yl 
)-methyleneindolinone 
4-[2-hydroxy-3-(1,3-dimethyl-3-hydroxypropylamino)-propoxy]-3-(pyrazol-5-yl 
)-methyleneindolinone 
4-[2-hydroxy-3-(2,2-dimethyl-3-hydroxypropylamino)-propoxy]-3-(pyrazol-5-yl 
)-methyleneindolinone 
5-[2-hydroxy-3-(2,2-dimethyl-3-hydroxypropylamino)-propoxy]-3-(pyrazol-5-yl 
)-methyleneindolinone.

The following Examples are given for the purpose of illustrating the 
present invention: 
EXAMPLE 1 
4-[2-hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-indolinone benzoate 
4.1 g. 4-(2,3-Epoxypropoxy)-indolinone (see Federal Republic of Germany 
Patent Specification No. 33 10 891.9) are suspended in 100 ml. methanol 
and mixed with 14.6 g. 1-methyl-3-nitratopropylamine. The reaction mixture 
is stirred for 3 days at ambient temperature, evaporated in a vacuum and 
the residue taken up in ethyl acetate and extracted several times with 
water. After drying with anhydrous sodium sulphate, the solution is 
filtered with suction and the filtrate mixed with the calculated amount of 
benzoic acid, evaporated in a vacuum and purified over a column of silica 
gel using methylene chloride/methanol (95/5 v/v). The eluate is evaporated 
in a vacuum, taken up with a little ethyl acetate and filtered with 
suction. There are obtained 3.9 g. of the title compound (42% of theory); 
m.p. 133.degree.-134.degree. C. 
The following compounds are obtained in a manner analogous to that 
described in Example 1: 
______________________________________ 
yield m.p. (.degree.C.) 
designation (%) solvent 
______________________________________ 
(a) 4-[2-hydroxy-3-(1,1-dimethyl- 
10 134-136 
3-nitratopropylamino)-propoxy]- 
isoprop- 
indolinone hemifumarate anol/water 
from 
4-(2,3-epoxypropoxy)-indolinone 
and 1,1-dimethyl-3-nitrato- 
propylamine 
(b) 4-[2-hydroxy-3-(1,3-dimethyl- 
15 149-150 
3-nitratopropylamino)-propoxy]- 
isopropanol 
indolinone fumarate 
from 
4-(2,3-epoxypropoxy)-indolinone 
and 1,3-dimethyl-3-nitrato- 
propylamine 
(c) 5-[2-hydroxy-3-(1-methyl-3- 
15 100 
nitratopropylamino)-propoxy]- 
(decomp.) 
indolinone fumarate ethanol 
from 
5-(2,3-epoxypropoxy)-indolinone 
and 1-methyl-3-nitratopropylamine 
(d) 6-[2-hydroxy-3-(1-methyl-3- 
20 127-128 
nitratopropylamino)-propoxy]- 
ethanol 
indolinone fumarate 
from 
6-(2,3-epoxypropoxy)-indolinone 
and 1-methyl-3-nitratopropylamine 
(e) 7-[2-hydroxy-3-(1-methyl-3- 
18 141-142 
nitratopropylamino)-propoxy]- 
ethanol 
indolinone fumarate 
from 
7-(2,3-epoxypropoxy)-indolinone 
and 1-methyl-3-nitratopropylamine 
(f) 5-[2-hydroxy-3-(1-methyl-3- 
25 95-97 
nitratopropylamino)-propoxy]- 
ethanol 
3-isopropylindolinone 
from 
5-(2,3-epoxypropoxy)-3-iso- 
propylindolinone and 1-methyl- 
3-nitratopropylamine 
(g) 5-[2-hydroxy-3-(1-methyl-3- 
25 133-135 
nitratopropylamino)-propoxy]- 
ethyl 
3-(.alpha.-methylbenzyl)-indolinone 
acetate 
hemifumarate 
from 
5-(2,3-epoxypropoxy)-3-(.alpha.- 
methylbenzyl)-indolinone and 
1-methyl-3-nitratopropylamine 
(h) 5-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
3-isopropylideneindolinone 
from 
5-(2,3-epoxypropoxy)-3-iso- 
propylideneindolinone and 1- 
methyl-3-nitratopropylamine 
(i) 5-[2-hydroxy-3-(1-methyl-3- 
20 155-157 
nitratopropylamino)-propoxy]- 
ethanol 
3-(.alpha.-methylbenzylidene)- 
indolinone hemifumarate 
from 
5-(2,3-epoxypropoxy)-3-(.alpha.- 
methylbenzylidene)- 
indolinone and 1-methyl-3- 
nitratopropylamine 
______________________________________ 
The intermediates required for the preparation of the compounds of Examples 
(1c), (1d) and (1e) are prepared according to the methods described in 
European Patent Specification No. 0014928 and in Federal Republic of 
Germany Patent Specification No. 33 10 891.9. 
______________________________________ 
yield m.p. (.degree.C.) 
designation (%) solvent 
______________________________________ 
5-(2,3-epoxypropoxy)-indolinone 
50 129-130 
diethyl ether 
6-(2,3-epoxypropoxy)-indolinone 
40 130-131 
ethyl acetate 
7-(2,3-epoxypropoxy)-indolinone 
45 183 
ethyl acetate 
______________________________________ 
Intermediates used for the preparation of the compounds of Examples (1f), 
(1g), (1h) and (1i) are prepared in the following manner: 
5-Hydroxy-3-isopropylideneindoline 
A mixture of 20 g. 5-hydroxyindolinone, 80 ml. acetone and 80 ml. ethanol 
is saturated with gaseous ammonia and heated under reflux for 3 hours. 
After evaporation, the reaction mixture is filtered off with suction. 
There are obtained 27.7 g. of the title compound (94% of theory); m.p. 
235.degree. C. 
5-Hydroxy-3-(.alpha.-methylbenzylidene)-indolinine is obtained analogously; 
yield 60% of theory; m.p. 175.degree.-178.degree. C., after 
recrystallisation from diethyl ether. 
5-Hydroxy-3-isopropylindolinone 
23 g. 5-Hydroxy-3-isopropylideneindolinone are dissolved in 100 ml. ethanol 
and 150 ml. tetrahydrofuran and hydrogenated in the presence of 1 g. 10% 
palladium-charcoal at ambient temperature and 1 bar hydrogen pressure. 
After filtering off the catalyst with suction, the filtrate is distilled 
off in a vacuum and the residue is triturated with diethyl ether and 
filtered off with suction. There are obtained 19 g. of the title compound; 
yield 81% of theory; m.p. 175.degree. C. 
5-Hydroxy-3-(.alpha.-methylbenzyl)-indolinone is obtained analogously; 
yield 73% of theory; m.p. 215.degree.-216.degree. C., after 
recrystallisation from diethyl ether. 
5-(2,3-Epoxypropoxy)-3-isopropylindolinone 
18 g. 5-Hydroxy-3-isopropylindolinone are dissolved in 150 ml. ethanol, 22 
ml. epichlorohydrin are added thereto, the mixture is mixed with 5.3 g. 
potassium hydroxide in 5 ml. water and the reaction mixture is stirred for 
2 days at ambient temperature. After the addition of 200 ml. water, the 
reaction mixture is extracted with ethyl acetate and the extract purified 
over a column of silica gel with methylene chloride/methanol (95:5 v/v). 
There are obtained 11 g. of the title compound; yield 50% of theory; m.p. 
122.degree.-125.degree. C., after recrystallisation from diethyl ether. 
The following compounds are obtained in analogous manner: 
5-(2,3-epoxypropoxy)-3-isopropylideneindolinone; 
m.p. 167.degree. C.; yield 45% of theory 
5-(2,3-epoxypropoxy)-3-(.alpha.-methylbenzyl)-indolinone; viscous oil; 
yield 50% of theory 
5-(2,3-epoxypropoxy)-3-(.alpha.-methylbenzylidene)-indolinone; m.p. 
153.degree.-155.degree. C., after recrystallisation from diethyl ether; 
yield 64% of theory. 
EXAMPLE 2 
4-[2-Hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-3-(pyrazol-5-yl)-me 
thyleneindolinone benzoate 
3.7 g. 4-(2,3-Epoxypropoxy)-3-(pyrazol-5-yl)-methyleneindolinone (see 
Federal Republic of Germany Patent Specification No. P 33 10 891.9) are 
stirred for 3 days at ambient temperature with 100 ml. methanol and 10 g. 
1-methyl-3-nitratopropylamine. After removal of the solvent, the residue 
is dissolved in ethyl acetate and shaken out several times with water. 
After drying the organic phase over anhydrous sodium sulphate, it is 
filtered with suction and the filtrate is mixed with the calculated amount 
of benzoic acid. After suction filtration, there are obtained 2.5 g. of 
the title compound; yield 35% of theory; m.p. 148.degree.-150.degree. C. 
The following compounds are obtained in a manner analogous to that 
described in Example 2: 
______________________________________ 
yield m.p. (.degree.C.) 
designation (%) solvent 
______________________________________ 
(a) 4-[2-hydroxy-3-(1-methyl-3- 
10 161-163 
nitratopropylamino)-propoxy]- 
ethanol 
3-(pyrrol-2-yl)-methylene- 
indolinone hemifumarate 
from 
4-(2,3-epoxypropoxy)-3- 
(pyrrol-2-yl)-methylene- 
indolinone and 1-methyl-3- 
nitratopropylamine 
(b) 4-[2-hydroxy-3-(1-methyl-3- 
15 153-155 
nitratopropylamino)-propoxy]- 
ethanol 
3-(pyridin-2-yl)-methylene- 
indolinone fumarate 
from 
4-(2,3-epoxypropoxy)-3- 
(pyridin-2-yl)-methylene- 
indolinone and 1-methyl-3- 
nitratopropylamine 
(c) 4-[2-hydroxy-3-(1-methyl-3- 
20 155-158 
nitratopropylamino)-propoxy]- 
ethanol 
3-benzylideneindolinone fumarate 
from 
4-(2,3-epoxypropoxy)-3- 
benzylideneindolinone and 
1-methyl-3-nitratopropylamine 
______________________________________ 
EXAMPLE 3 
4-[24-Hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-indolinone 
fumarate 
38.2 g. Ethyl 2-(2,3-epoxypropoxy)-6-nitrophenyl acetate (see European 
Patent Specification No. 00 14 928) are dissolved in a mixture of 140 ml. 
ethyl acetate, 140 ml. ethanol and 30 ml. water, mixed with 3 ml. Raney 
nickel and hydrogenated at 1 bar hydrogen pressure. After filtering off 
the catalyst with suction, the filtrate is evaporated, the residue is 
dissolved in 200 ml. ethanol, 20 g. 1-methyl-3-nitratopropylmine are added 
thereto and the reaction mixture is stirred for 1 day at ambient 
temperature. After the addition of 30 ml. acetic acid, the reaction 
mixture is further stirred for 1 day. The solution is then evaporated and 
the residue is dissolved in 750 ml. water and 750 ml. ethyl 
acetate/diethyl ether (1:1 v/v). The aqueous phase is neutralised with 
sodium bicarbonate and the base is extracted with ethyl acetate. After 
drying and evaporating the extract, there is obtained 11 g. of base. This 
is taken up in isopropanol and the calculated amount of fumaric acid is 
added thereto to give the salt. After suction filtration, there are 
obtained 10 g. of the title compound; yield 20% of theory; m.p. 
123.degree.-125.degree. C. 
By catalytic hydrogenation and subsequent reaction with amines and 
cyclisation, the following compounds can be obtained in an analogous 
manner: 
______________________________________ 
yield m.p. (.degree.C.) 
designation (%) solvent 
______________________________________ 
(a) 4-[2-hydroxy-3-(1,1-dimethyl- 
15 134-136 
3-nitratopropylamino)-propoxy]- 
isopropanol 
indolinone hemifumarate 
from 
2-(2,3-epoxypropoxy)-6-nitro- 
phenyl acetic acid ethyl ester 
and 1,1-dimethyl-3-nitratopropylamine 
(b) 4-[2-hydroxy-3-(1,3-dimethyl- 
25 150 
3-nitratopropylamino)-propoxy]- 
isopropanol 
indolinone fumarate 
from 
2-(2,3-epoxypropoxy)-6-nitro- 
phenyl acetic acid ethyl ester 
and 1,3-dimethyl-3-nitratopropylamine 
(c) 5-[2-hydroxy-3-(1-methyl-3- 
20 100-103 
nitratopropylamino)-propoxy]- ethanol 
indolinone fumarate 
from 
3-(2,3-epoxypropoxy)-6-nitro- 
phenyl acetic acid ethyl ester 
and 1-methyl-3-nitratopropylamine 
(d) 6-[2-hydroxy-3-(1-methyl-3- 
20 128-129 
nitratopropylamino)-propoxy]- ethanol 
indolinone fumarate 
from 
4-(2,3-epoxypropoxy)-6-nitro- 
phenyl acetic acid ethyl ester 
and 1-methyl-3-nitratopropylamine 
(e) 7-[2-hydroxy-3-(1-methyl-3- 
25 141-142 
nitratopropylamino)-propoxy]- ethanol 
indolinone fumarate 
from 
5-(2,3-epoxypropoxy)-6-nitro- 
phenyl acetic acid ethyl ester 
and 1-methyl-3-nitratopropylamine 
______________________________________ 
EXAMPLE 4 
4-[2-Hydroxy-3-(1-methyl-3-nitraopropylamino)-propoxy]-3-(pyrrol-2-yl)-meth 
yleneindolinone hemifumarate 
5.5 g. 4-[2-Hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-indolinone 
(see Example 1) are stirred in 100 ml. ethanol with 3.4 g. 
pyrrol-2-aldehyde and 5 ml. triethylamine for 2 days at ambient 
temperature. After removing the solvent in a vacuum, the residue is 
dissolved in ethyl acetate and dilute lactic acid. The aqueous phase is 
rendered alkaline with potassium carbonate and extracted with ethyl 
acetate. After purification over a column of silica gel with methylene 
chloride-methanol (97:3 v/v), the hemifumarate is prepared in ethanol. 
After suction filtration, there is obtained 1.6 g. of the title compound 
(20% of theory); m.p. 161.degree.-163.degree. C. 
The following compounds are prepared in an analogous manner: 
______________________________________ 
yield m.p. (.degree.C.) 
designation (%) solvent 
______________________________________ 
(a) 4-[2-hydroxy-3-(1-methyl-3- 
35 155-158 
nitratopropylamino)-propoxy]- 
ethanol 
3-(furan-2-yl)-methylene- 
indolinone fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
furan-2-aldehyde 
(b) 4-[2-hydroxy-3-(1-methyl-3- 
30 152-153 
nitratopropylamino)-propoxy]- 
methanol 
3-(thiophen-2-yl)-methylene- 
indolinone fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
thiophene-2-aldehyde 
(c) 4-[2-hydroxy-3-(1-methyl-3- 
25 168-170 
nitratopropylamino)-propoxy]- 
methanol 
3-(pyrazol-5-yl)-methylene- 
indolinone fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
pyrazole-5-aldehyde 
(d) 4-[2-hydroxy-3-(1-methyl-3- 
40 174 
nitratopropylamino)-propoxy]- 
methanol 
3-(1,2,4-triazol-3-yl)- 
methyleneindolinone fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
1,2,4-triazol-3-aldehyde 
(e) 4-[2-hydroxy-3-(1-methyl-3- 
15 153-155 
nitratopropylamino)-propoxy]- 
ethanol 
3-(pyridin-2-yl)-methylene- 
indoline fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
pyridine-2-aldehyde 
(f) 4-[2-hydroxy-3-(1-methyl-3- 
15 190 
nitratopropylamino)-propoxy]- 
methanol 
3-(uracil-4-yl)-methylene- 
indolinone acetate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
uracil-4-aldehyde 
(g) 4-[2-hydroxy-3-(1,1-dimethyl- 
25 143-145 
3-nitratopropylamino)-propoxy]- 
methanol 
3-(pyrazol-5-yl)-methylene- 
indolinone hemifumarate 
from 
4-[2-hydroxy-3-(1,1-dimethyl- 
3-nitratopropylamino)-propoxy]- 
indolinone (see Example 1a) and 
pyrazole-5-aldehyde 
(h) 4-[2-hydroxy-3-(1,3-dimethyl- 
30 70 
3-nitratopropylamino)-propoxy]- 
(decomp.) 
3-pyrazol-5-yl)-methylene- isopropanol 
indolinone fumarate 
from 
4-[2-hydroxy-3-(1,3-dimethyl- 
3-nitratopropylamino)-propoxy]- 
indolinone (see Example 1b) and 
pyrazole-5-aldehyde 
(i) 4-[2-hydroxy-3-(1-methyl-3- 
25 155-158 
nitratopropylamino)-propoxy]- 
ethanol 
3-benzylideneindolinone fumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
benzaldehyde 
(j) 4-[2-hydroxy-3-(1-methyl-3- 
20 155-157 
nitratopropylamino)-propoxy]- 
methanol 
3-(4-cyanobenzylidene)- 
indolinone hemifumarate 
from 
4-[2-hydroxy-3-(1-methyl-3- 
nitratopropylamino)-propoxy]- 
indolinone (see Example 1) and 
4-cyanobenzaldehyde 
(k) 4-[2-hydroxy-3-(2,2-dimethyl-3- 
80 150-151 
nitratopropylamino)-propoxy]- 
methanol 
3-(3-methylpyrazol-5-yl)- 
methyleneindolinone 
from 
4-[2-hydroxy-3-(2,2-dimethyl- 
3-nitratopropylamino)-propoxy]- 
indolinone and 3-methylpyrazol- 
5-aldehyde 
______________________________________ 
EXAMPLE 5 
4-[2-Hydroxy-3-(1-methyl-3-nitratopropylamino)-propoxy]-indolinone fumarate 
2.94 g. 4-[2-Hydroxy-3-(1-methyl-3-hydroxypropylamino)-propoxy]-indolinone 
in 100 ml. acetonitrile are mixed at 30.degree. C., while stirring, with a 
mixture of 1.16 ml. acetic anhydride, 0.52 ml. fuming nitric acid and 20 
ml. acetonitrile. After stirring for 3 hours at -30.degree. C., the 
reaction mixture is stirred into 300 g. ice water, the pH is adjusted to 8 
with 1N aqueous sodium hydroxide solution and then stirred for 2 hours 
with ethyl acetate at 5.degree. C. The pH is then adjusted to 10 and after 
30 minutes the organic phase is separated off. After drying and adding the 
calculated amount of fumaric acid, there is obtained 0.9 g. of the title 
compound; yield 20% of theory; 
m.p. 122.degree.-124.degree. C. 
The above-mentioned hydroxy compound is obtained from ethyl 
2-(2,3-epoxypropoxy)-6-nitrophenyl acetate and 
1-methyl-3-hydroxypropylamine; yield 50% of theory; m.p. 
112.degree.-115.degree. C., after recrystallisation from ethyl acetate. 
It will be understood that the specification and examples are illustrative 
but not limitative of the present invention and that other embodiments 
within the spirit and scope of the invention will suggest themselves to 
those skilled in the art.