1-R.sub.1 -4- or 5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q derivatives, useful as cardiotonics, bronchodilators, anti-asthmatics, anti-allergics and anti-cholinergics, are prepared by cyclization of N-{3- or 4-[4-pyridinyl-(CH.sub.2).sub.n ]phenyl}glyoxalamide oxime with acid; reaction of the product thus obtained with a carbonyl reactive reagent to prepare a compound where Q is other than O; and reaction of a compound where Q is either O or other than O with a lower-alkyl, hydroxy-lower-alkyl or di-lower-alkylamino-lower-alkyl ester of a strong mineral acid or with a carbo-lower-alkoxy-lower-alkyl halide to prepare compounds where R.sub.1 is other than hydrogen.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
This invention relates to 4- and 5-[4-pyridinyl-(CH.sub.2).sub.n 
]-1H-indole-2,3-dione derivatives useful as cardiotonics, bronchodilators 
and anti-asthmatics. 
(b) The Prior Art 
Kost et al., Khim. Geterostsikl. Soedin., 5, 722-728 (1966); Chem. Abs. 66, 
115538m (1967) disclose 1-lower-alkyl-5-(4-pyridinyl)-1,2-dihydroindoles 
for which no utility is disclosed. 
Hartman et al., Helv. Chim. Acta, 19, 1327-1332 (1936) disclose 
1H-indole-2,3-dione derivatives substituted in the 5-position by an amino, 
acetylamino or dimethylamino group. No utility for the compounds is 
disclosed. 
Bauer et al., Brit. J. Pharmacol., 15, 101-110 (1960) disclose 
1-lower-alkyl-1H-indole-2,3-dione 3-thiosemicarbazones useful as 
anti-viral agents. 
5-Methyl-1H-indole-2,3-dione is a known, commercially available compound 
which finds use as an intermediate for organic synthesis. 
SUMMARY OF THE INVENTION 
In a composition of matter aspect, this invention relates to certain 
1-R.sub.1 -4- or 5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q 
derivatives and their acid-addition salts, useful as cardiotonics, 
bronchodilators, anti-asthmatics, anti-allergics and anti-cholinergics. 
In a process aspect, this invention relates to a process for preparing the 
1-R.sub.1 -4- or 5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q 
derivatives of the invention which comprises cyclizing an N-{3- or 
4-[4-pyridinyl-(CH.sub.2).sub.n ]phenyl}-glyoxalamide oxime in the 
presence of a strong mineral acid in order to prepare a 4- or 
5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione; if desired, 
reacting the latter with a carbonyl reactive reagent in order to prepare a 
4- or 5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q 
derivative; and, if desired, reacting the 4- or 
5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione where Q is either O 
or the moiety resulting from the carbonyl reactive reagent with a 
lower-alkyl, hydroxy-lower-alkyl or di-lower-alkylamino-lower-alkyl ester 
of a strong mineral acid or with a carbo-lower-alkoxy-lower-alkyl halide 
in the presence of an acid-acceptor to prepare a 1-lower-alkyl-4- or 
5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q derivative, 
where Q is either O or other than O as defined below, and R.sub.1 is other 
than hydrogen as defined below. 
DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS 
More specifically, this invention provides valuable compounds having the 
formula: 
##STR1## 
where Py represents the 4-pyridinyl group; R.sub.1 represents hydrogen, 
lower-alkyl, hydroxy-lower-alkyl (having from two to seven carbon atoms, 
at least two of which are linear), di-lower-alkylamino-lower-alkyl or 
carbo-lower-alkoxy-lower-alkyl; R.sub.2 represents hydrogen or 
lower-alkyl; Q represents O, H(OH), NOH, NNH.sub.2, NNH(lower-alkyl), 
NN(lower-alkyl).sub.2, NNHC.sub.6 H.sub.5, NNH(hydroxy-lower-alkyl) 
(having from two to seven carbon atoms, at least two of which are linear), 
NNHC(.dbd.S)NH.sub.2, NNHC(.dbd.NH)NH.sub.2 (only when R.sub.1 is 
lower-alkyl), NNHCOCH.sub.2 N (lower-alkyl).sub.3.sup.+ X.sup.- or 
NNHCOCH.sub.2 -Pyr.sup.+ X.sup.-, where Pyr.sup.+ is the pyridinium cation 
and X.sup.- in the latter two instances is the anion of a strong mineral 
acid; n is 0 (zero) or the integer 1; the 4-pyridinyl-(CH.sub.2).sub.n 
group occupies either the 4- or 5-position of the 1H-indole-2,3-dione 
nucleus; and the N-(Py)-oxides thereof, which are useful as cardiotonics, 
bronchodilators, anti-asthmatics, anti-allergics and anti-cholinergics. 
The compounds of formula I above are thus either 1H-indole-2,3-diones (Q is 
O); the reduced 2-oxo-1H-indol-3-ol derivatives thereof [Q is H(OH)]; or 
the 3-oximes (Q is NOH), 3-hydrazones (Q is NNH.sub.2), 
3-lower-alkylhydrazones [Q is NNH(lower-alkyl)], 
3-di-lower-alkylhydrazones [Q is NN (lower-alkyl).sub.2 ], 
3-phenylhydrazones [Q is NNHC.sub.6 H.sub.5 ], 
3-(hydroxy-lower-alkyl)hydrazones [Q is NNH(hydroxy-lower-alkyl)], 
3-thiosemicarbazones [Q is NNHC(.dbd.S)NH.sub.2 ], 3-imidosemicarbazones 
[Q is NNHC(.dbd.NH)NH.sub.2 ], 3-[(tris-lower-alkyl quarternary 
ammonium)-acetyl]hydrazones [Q is NNHCOCH.sub.2 
--N(lower-alkyl).sub.3.sup.+ X.sup.- ] or 3-(pyridinium acetyl)hydrazones 
[Q is NNHCOCH.sub.2 --Pyr.sup.+ X.sup.- ]thereof. 
The above-indicated limitation in the definition of the group Q as 
NNHC(.dbd.NH)NH.sub.2 is made in order to exclude from the ambit of the 
invention species which have been found to be inactive as cardiotonics, 
bronchodilators, anti-asthmatics, anti-allergics or anti-cholinergics. 
However the species where Q is NNHC(.dbd.NH)NH.sub.2 and R.sub.1 is 
hydrogen are useful as intermediates for preparing the corresponding 
species where R.sub.1 is lower-alkyl, which latter species are useful for 
the purposes of the present invention. The compounds where Q is 
NNHC(.dbd.NH)NH.sub.2 and R.sub.1 is hydrogen are thus considered to be 
within the purview of the present invention. 
The compounds within the ambit of formula I which have been found useful as 
cardiotonics are those where each of R.sub.1, Q and n has each of the 
meanings given above, except for the species where Q is 
NN(lower-alkyl).sub.2 or NNHC.sub.6 H.sub.5, the species where R.sub.1 is 
di-lower-alkylamino-lower-alkyl or carbo-lower-alkoxy-lower-alkyl and the 
N-(Py)-oxides of the subject compounds. 
The compounds within the ambit of formula I which have been found useful as 
bronchodilators, anti-asthmatics, anti-allergics and anti-cholinergics are 
those where each of R.sub.1, Q and n has each of the meanings given above, 
except for the species where Q is NOH, NNHC(.dbd.NH)NH.sub.2, 
NNHCOCH.sub.2 N(lower-alkyl).sub.3.sup.+ X.sup.- or NNHCOCH.sub.2 
--Pyr.sup.+ X.sup.- and the species where R.sub.1 is hydroxy-lower-alkyl. 
Except as defined above in connection with the NNH(hydroxy-lower-alkyl) 
moiety as one of the definitions of the group Q and the 
hydroxy-lower-alkyl moiety as one of the definitions of the group R.sub.1, 
the term lower-alkyl as used herein otherwise means a saturated, acyclic 
group which may be straight or branched and containing from one to about 
seven carbon atoms as exemplified by methyl, ethyl, propyl, isopropyl, 
n-butyl, t-butyl, pentyl, hexyl or heptyl. 
The anion represented by X.sup.- in the compounds of formula I where Q is 
NNHCOCH.sub.2 N(lower-alkyl).sub.3.sup.+ X.sup.- or NNHCOCH.sub.2 
--Pyr.sup.+ X.sup.- is the anion of a strong mineral acid such as a 
hydrohalic acid (i.e. hydrofluoric acid, hydrochloric acid, hydrobromic 
acid or hydriodic acid), sulfuric acid or the like. 
The compounds of formula I are prepared using a modification of the 
Sandmeyer isonitrosoacetanilide isatin synthesis, described in detail in 
Organic Syntheses, Coll. Vol. I, 327 (1941), which involves reaction of an 
appropriate 3- or 4-[4-pyridinyl-(CH.sub.2).sub.n ]aniline of formula II 
with chloral hydrate and hyroxylamine in an acid medium and cyclization of 
the resulting N-{3- or 4-[4-pyridinyl-(CH.sub.2).sub.n 
]phenyl}glyoxalamide oxime of formula III with concentrated sulfuric acid 
to produce the compounds of formula I where R.sub.1 is hydrogen and Q is 
O. The initial reaction to prepare the glyoxalamide oximes of formula III 
is carried out by adding an aqueous solution of chloral hydrate and sodium 
sulfate to an aqueous solution of the 3- or 
4-[4-pyridinyl-(CH.sub.2).sub.n ]aniline of formula II containing a molar 
excess of a mineral acid at ambient temperature and, after formation of 
the glyoxalamide, treating the aqueous solution with an aqueous solution 
of hydroxylamine in the form of an acid-addition salt thereof and, if 
desired, warming the mixture to effect complete solution of all reactants 
and the product. Cyclization of the glyoxalamide oximes of formula III to 
the compounds of formula I is carried out by heating a solution of the 
former in concentrated sulfuric acid at a temperature in the range from 
around 30.degree. to 100.degree. C. 
The compounds of formula I where R.sub.1 is hydrogen and Q is O thus 
prepared can then be subsequently reacted with an appropriate carbonyl 
reactive reagent, for example hydroxylamine, hydrazine, a 
lower-alkylhydrazine, a di-lower-alkylhydrazine, phenylhydrazine, a 
hydroxy-lower-alkylhydrazine, thiosemicarbazide, imidosemicarbazide, a 
tris-lower-alkyl quaternary ammonium acethydrazide salt or a 
pyridinium-acethydrazide salt to give the compounds of formula I where Q 
is, respectively, NOH, NNH.sub.2, NNH(lower-alkyl), NN(lower-alkyl).sub.2, 
NNHC.sub.6 H.sub.5, NNH(hydroxy-lower-alkyl), NNHC(.dbd.S)NH.sub.2, 
NNHC(.dbd.NH)NH.sub.2, NNHCOCH.sub.2 N(lower-alkyl).sub.3.sup.+ X.sup.- or 
NNHCOCH.sub.2 --Pyr.sup.+ X.sup.- ; and R.sub.1 is hydrogen. 
The reaction of the compounds of formula I where R.sub.1 is hydrogen and Q 
is 0 with a carbonyl reactive reagent is carried out by heating a mixture 
of the starting material of formula I with the appropriate carbonyl 
reactive compound in an inert organic solvent. Suitable solvents are 
lower-alkanols (for example methanol, ethanol, isopropanol or the like) or 
a lower-alkanoic acid (for example acetic acid). The use of an acid 
catalyst, for example acetic acid or hydrochloric acid, is advantageous. 
The reaction takes place at a temperature in the range from 20.degree. to 
90.degree. C. 
The compounds of formula I thus prepared are then reacted with a 
lower-alkyl, hydroxy-lower-alkyl or di-lower-alkylamino-lower-alkyl ester 
of a strong mineral acid, for example a hydrohalic acid or sulfuric acid, 
or with a carbo-lower-alkoxy-lower-alkyl halide, in the presence of an 
acid-acceptor, to produce the compounds of formula I where R.sub.1 is, 
respectively, lower-alkyl, hydroxy-lower-alkyl, 
di-lower-alkylamino-lower-alkyl or carbo-lower-alkoxy-lower-alkyl, and Q 
is other than O. Alternatively the compounds of formula I where Q is O and 
R.sub.1 is hydrogen can be alkylated to produce the compounds where 
R.sub.1 is lower-alkyl, hydroxy-lower-alkyl, 
di-lower-alkylamino-lower-alkyl or carbo-lower-alkoxy-lower-alkyl and Q is 
O. 
Alkylation of the compounds of formula I where R.sub.1 is hydrogen is 
carried out by reaction of the latter with an appropriate lower-alkyl, 
hydroxy-lower-alkyl or di-lower-alkylamino-lower-alkyl ester of a strong 
mineral acid, for example a halide or sulfate, or with a 
carbo-lower-alkoxy-lower-alkyl halide, in an inert organic solvent, for 
example a lower-alkanol, acetone or dimethylformamide (DMF), in the 
presence of a molar equivalent amount of an acid-acceptor, for example an 
alkali metal hydride or alkali metal carbonate. The reaction is carried 
out at a temperature in the range from 20.degree. to about 90.degree. C. 
The overall synthetic method is illustrated by the reaction sequence: 
##STR2## 
where R.sub.1, R.sub.2, Q, Py and n have the meanings given above. 
The compounds where Q is H(OH) are prepared by reduction of the 
corresponding compounds where Q is O with sodium hydrosulfite. The 
reaction is carried out by heating the reactants in an aqueous medium at 
the reflux temperature thereof. 
The N-(Py)-oxides of the compounds of formula I are prepared by oxidizing 
the latter with an organic peracid, for example performic, peracetic, 
perbenzoic or 3-chloroperbenzoic acids. The reaction is preferably carried 
out in an inert organic solvent, for example a lower-alkanoic acid, and at 
a temperature in the range from 15.degree.-60.degree. C. 
The compounds of formula II where n is 0 are generally known, having been 
described by Heilbron et al., J. Chem. Soc., 1279(1940); Forsyth et al., 
J. Chem. Soc., 2921(1926); and British Pat. No. 518,886. The compounds 
where n is 1 are prepared from the commercially available 
Py(CH.sub.2).sub.n -substituted nitrobenzenes by reduction of the latter 
with hydrogen over a platinum oxide catalyst in acetic acid at a hydrogen 
pressure around 55 p.s.i.g. 
Due to the presence of a basic amino grouping in the 4-pyridinyl (Py) 
moiety, the free base form represented by formula I above reacts with 
organic and inorganic acids to form acid-addition salts. The acid-addition 
salt forms are prepared from any organic or inorganic acid. They are 
obtained in conventional fashion, for instance either by direct mixing of 
the base with acid or, when this is not appropriate, by dissolving either 
or both the base and the acid separately in water or an organic solvent 
and mixing the two solutions, or by dissolving both the base and the acid 
together in a solvent. The resulting acid-addition salt is isolated by 
filtration, if it is insoluble in the reaction medium, or by evaporation 
of the reaction medium to leave the acid-addition salt as a residue. The 
acid moieties or anions in these salt forms are in themselves neither 
novel nor critical and therefore can be any acid anion or acid-like 
substance capable of salt formation with the base. 
Representative acids for the formation of the acid-addition salts include 
formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, 
trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic 
acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic 
acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic 
acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicylic 
acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 
2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric 
acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, 
sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, 
benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, 
methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric 
acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, 
sulfuric acid, phosphoric acid, arsenic acid and the like. 
All of the acid-addition salts are useful as sources of the free base forms 
which are generated by reaction of the salts with an inorganic base. It 
will thus be appreciated that if one or more of the characteristics, such 
as solubility, molecular weight, physical appearance, toxicity, or the 
like of a given base or acid-addition salt thereof render that form 
unsuitable for the purpose at hand, it can be readily converted to 
another, more suitable form. For pharmaceutical purposes, acid-addition 
salts of relatively non-toxic pharmaceutically-acceptable acids, for 
example hydrochloric acid, lactic acid, tartaric acid, methanesulfonic 
acid and the like are of course employed. 
With the exceptions previously noted in the definitions of Q and R.sub.1, 
the compounds of formula I, and their acid-addition salts, have been found 
to be useful as cardiotonics. Their utility as cardiotonics was 
established by their effectiveness in standard pharmacological test 
procedures, for example in causing a significant increase in the 
contractile force of the isolated cat atria and papillary muscle, that is 
greater than 25% increase in papillary muscle force and right atrial 
force, while causing only a lower percentage increase (about one-third or 
less than the percentage increase in right atrial or papillary muscle 
force) in right atrial rate and also in causing a significant increase in 
the cardiac contractile force in the anesthetized dog with low or minimal 
changes in heart rate and blood pressure, that is, an increase of greater 
than 25% in cardiac contractile force (or cardiac contractility) and less 
than 25% change in heart rate and blood pressure. The isolated cat atria 
and papillary muscle procedure and the anesthetized dog procedure are 
described in detail by Alousi et al., Circ. Research, 45 666-667 (1979). 
With the other exceptions previously noted in the definitions of Q and 
R.sub.1, the compounds of formula I, and their acid-addition salts, have 
been found to be useful as bronchodilators, anti-asthmatics, 
anti-allergics and anti-cholinergics. 
Their utility as bronchodilators, anti-asthmatics, anti-allergics and 
anti-cholinergics was established by their effectiveness in standard 
pharmacological test procedures, for example the passive cutaneous 
anaphylaxis test in rats described by Mielens et al., Int. Arch. Allergy, 
47, 633-649 (1974); a modified procedure of the bronchoconstriction 
activity test in dogs described by Minatoya, J. Pharm. Exp. Therap., 206, 
515-527 (1978); the anaphylactic bronchoconstriction activity test in 
guinea pigs, a modified procedure of Miller et al., Brit. J. Pharmacol., 
58, 442P-443P (1976); and a modification of the human basophils test 
described by Margo Immunochem., 12, 389 (1975) and by Conroy et al. 
Monogr. Allergy, 14, 307-309 (1979). 
Bronchoconstrictor activity was also determined using a test procedure 
based on bronchoconstriction induced by histamine, acetylcholine and 
immune complex in guinea pigs which procedure is described as follows: 
guinea pigs of either sex, weighing 250-350 g. each, was fasted overnight, 
then anesthetized with 1.5 g. of urethane/kg. (i.p.), and the jugular vein 
and trachea were cannulated. The guinea pigs thus prepared were 
artificially respired with a rodent pump, and the intratracheal pressure 
was recorded continuously using a Statham transducer on a Grass polygraph. 
At five minute intervals, 5 .mu.g./kg. of histamine phosphate (determined 
as base) was injected intravenously in order to ascertain that the maximum 
achievable bronchoconstrictor responsiveness (i.e. the increase in 
intratracheal pressure in mm.Hg) had been obtained, and the average of the 
last two increases in the intratracheal pressure was recorded. 
Acetylcholine was then injected intravenously at 15 .mu.g./kg. five 
minutes after the last injection of histamine, and the increase in 
intratracheal pressure was again recorded. Two minutes following the 
injection of acetylcholine, 0.1 mg./kg. of propranolol was injected 
intravenously, and immune complexes [pure antibovine serum albumin (BSA) 
antibody/BSA complexes dissolved in excess BSA] were injected 
intravenously at 1.0 mg./kg. (in terms of their antibody content) three 
minutes following the injection of propranolol, and the increase in 
intratracheal pressure was again recorded. 
Inhibition of bronchoconstriction was scored for each of the 
bronchoconstriction-inducers (i.e. histamine, acetylcholine and immune 
complex) with respect to the average bronchoconstriction in negative 
control guinea pigs (minimum of four guinea pigs in four days) according 
to the following criteria: 
______________________________________ 
% Inhibition Score 
______________________________________ 
81-100 4 
61-80 3 
41-60 2 
21-40 1 
0-20 0 
______________________________________ 
Test compounds scoring 3 or 4 against the three 
broncho-constriction-inducers were considered active; those scoring 2 were 
considered marginally active; and those scoring 0 or 1 were considered 
inactive. Aminophylline, which was used as a reference drug, gave scores 
from 3-3-2 to 4-4-3 for bronchoconstriction induced by histamine, 
acetylcholine and immune complex, respectively. 
Generally speaking, the various bronchoconstrictor activity tests described 
above, i.e. the histamine induced bronchoconstriction activity test in 
dogs (Minatoya) and the histamine/acetylcholine/immune complex-induced 
bronchoconstriction test in guinea pigs, are used to define bronchodilator 
activity, while the passive cutaneous anaphylaxis test and the human 
basophils test can be used to define anti-allergic activity. Moreover, 
activity by test species against one of the types of bronchoconstriction 
in guinea pigs (induced by histamine, acetylcholine or immune complex) can 
indicate utility, respectively, as anti-histamines, anti-cholinergics or 
prostaglandin synthetase inhibitors. Species useful as anti-asthmatics 
ideally show both bronchodilator and anti-allergic parameters of activity, 
but species useful for such purpose can have either parameter alone 
without the other. 
The actual determination of the numerical pharmacological data for a 
particular compound of the invention is readily obtained according to the 
above-described standard test procedures by technicians versed in 
pharmacological test procedures without the need for any extensive 
experimentation. 
In clinical practice, the compounds of formula I are normally administered 
orally or parenterally in a wide variety of dosage forms. 
Solid compositions for oral administration include compressed tablets, 
pills, powders and granules. In such solid compositions, at least one of 
the active compounds is admixed with at least one inert diluent such as 
starch, calcium carbonate, sucrose or lactose. These compositions can also 
contain additional substances other than inert diluents, for example 
lubricating agents such as magnesium stearate, talc and the like. 
Liquid compositions for oral administration include 
pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and 
elixirs containing inert diluents commonly used in the art, such as water 
and liquid paraffin. Besides inert diluents, such compositions can also 
contain adjuvants, such as wetting and suspending agents, sweetening, 
flavoring, perfuming and preserving agents. According to this invention, 
the compounds for oral administration also include capsules of adsorbable 
material such as gelatin containing the active component either with or 
without the addition of diluents or excipients. 
Preparations according to the invention for parenteral administration 
include sterile aqueous, aqueous-organic and organic solutions, 
suspensions and emulsions. Examples of organic solvents or suspending 
media are propylene glycol, polyethylene glycol, vegetable oils such as 
olive oil and injectable organic esters such as ethyl oleate. The 
compositions can also contain adjuvants such as stabilizing, preserving, 
wetting, emulsifying and dispersing agents. 
They can be sterilized, for example by filtration through a 
bacteria-retaining filter, by incorporation of sterilizing agents in the 
compositions, by irradiation or by heating. They can also be manufactured 
in the form of sterile solid compositions, which can be dissolved in 
sterile water or some other sterile injectable medium immediately before 
use. 
The percentages of active component in such compositions may be varied so 
that a suitable dosage is obtained. The dosage administered to a 
particular patient is variable, depending upon the clinician's judgment 
using as criteria: the route of administration, the duration of treatment, 
the size and physical condition of the patient, the potency of the active 
component and the patient's response thereto. An effective dosage amount 
of the active component can thus only be determined by the clinician after 
a consideration of all criteria and utilizing his best judgment on the 
patient's behalf. 
The structures of the compounds of the invention were established by the 
mode of synthesis, by elementary analyses and by ultraviolet, infrared and 
nuclear magnetic resonance spectra. The course of reactions were followed, 
and the homogeneity of the products were ascertained, by thin layer 
chromatography. 
The manner and process of making and using the invention, and the best mode 
contemplated by the inventors of carrying out the invention, will now be 
described so as to enable any person skilled in the art to which it 
pertains to make and use the same. The melting points are uncorrected.

EXAMPLE 1A 
To a solution of 9.0 g. (0.054 mole) of chloral hydrate, 57 g. of sodium 
sulfate and 8.5 g. (0.05 mole) of 3-(4-pyridinyl)benzenamine in 225 ml. of 
water containing 4.3 ml. of concentrated hydrochloric acid was added a 
solution of 11.0 g. (0.16 mole) of hydroxylamine hydrochloride, and the 
mixture was stirred with warming for thirty minutes and then heated to 
boiling for five minutes. The mixture was then allowed to cool to ambient 
temperature, and the solid which separated was collected to give 12.8 g. 
of crude product which was recrystallized from water to give 9.7 g. of 
N-[3-(4-pyridinyl)phenyl]glyoxalamide oxime hydrochloride, m.p. 
207.degree.-208.degree. C. 
The latter (100 g., of 0.36 mole) was added with stirring to 350 ml. of 
sulfuric acid at 60.degree. C. over a thirteen minute period while 
maintaining the temperature around 85.degree.-90.degree. C. by cooling, as 
necessary, with an ice bath. The dark solution was then poured onto about 
3 kg. of crushed ice, and when the ice had melted the mixture was 
neutralized by the careful addition of solid sodium carbonate until the 
mixture was alkaline (pH 9-10), water being added as necessary to 
facilitate stirring. The mixture was filtered, and the solid material was 
washed repeatedly with boiling water and recrystallized from DMF to give 
26.4 g. of 4-(4-pyridinyl)-1H-indole-2,3-dione, m.p. &gt;300.degree. C. 
A small amount of the free base was suspended in water, the suspension was 
treated with concentrated hydrochloric acid until the solid dissolved, and 
the solvent was removed in vacuo to give 
4-(4-pyridinyl)-1H-indole-2,3-dione hydrochloride, m.p. &gt;300.degree. C. 
Following a procedure similar to that described in Example 1A above, the 
following compounds of formula I where R.sub.1 is hydrogen and Q is O were 
prepared. 
EXAMPLE 1B 
5-(4-Pyridinyl)-1H-indole-2,3-dione, m.p. 305.degree.-308.degree. C. (14.3 
g. from DMF), prepared by reaction of 85.1 g. (0.05 mole) of 
4-(4-pyridinyl)benzenamine with 110 g. (0.66 mole) of chloral hydrate and 
110 g. (1.58 moles) of hydroxylamine hydrochloride in a total of 2850 ml. 
of water in the presence of 570 g. (4.0 moles) of sodium sulfate and 46 
ml. of concentrated hydrochloric acid and cyclization of 37.6 g. (0.14 
mole) of the resulting N-[4-(4-pyridinyl)phenyl]glyoxalamide oxime 
hydrochloride (108.6 g., m.p. 215.degree.-220.degree. C. from isopropanol) 
in 200 ml. of concentrated sulfuric acid. A sample recrystallized from 
water gave material having m.p. 231.degree.-232.degree. C. 
A sample of the free base was converted to the methanesulfonate salt to 
give 5-(4-pyridinyl)-1H-indole-2,3-dione methanesulfonate, m.p. 
235.degree.-237.degree. C. (from DMF/diethyl ether). 
EXAMPLE 1C 
5-(4-Pyridinylmethyl)-1H-indole-2,3-dione, m.p. 247.degree.-250.degree. C. 
(16.1 g. from DMF), prepared by reaction of 17.79 g. (0.097 mole) of 
4-(4-pyridinylmethyl)benzenamine with 17.57 g. (0.11 mole) of chloral 
hydrate and 21.3 g. (0.31 mole) of hydroxylamine hydrochloride in a total 
of 528 ml. of water in the presence of 110.7 g. (0.78 mole) of sodium 
sulfate and 8.9 ml. of concentrated hydrochloric acid, and cyclization of 
the resulting (27.4 g., 0.09 mole) 
N-[4-(4-pyridinylmethyl)phenyl]glyoxalamide oxime hydrochloride with 100 
ml. of concentrated sulfuric acid. 
EXAMPLE 1D 
4-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione, m.p. &gt;315.degree. C. (26.5 
g., from DMF), prepared by reaction of 66 g. (0.36 mole) of 
3-methyl-4-(4-pyridinyl)-benzenamine with 64.8 g. (0.39 mole) of chloral 
hydrate and 79.2 g. (1.19 mole) of hydroxylamine hydrochloride in a total 
of 1260 ml. of water in the presence of 410 g. (2.9 moles) of sodium 
sulfate and 34 ml. of concentrated hydrochloric acid, and cyclization of 
64 g. (0.24 mole) of the resulting (82.5 g.) 
N-[3-methyl-4-(4-pyridinyl)phenyl]glyoxalamide oxime hydrochloride with 
180 ml. of concentrated sulfuric acid. 
EXAMPLE 1E 
6-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione, m.p. 292.degree.-294.degree. 
C. (6.7 g., from methanol), isolated as a second product from the mother 
liquors resulting from recrystallization of the 
4-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione described above in Example 
1D. 
EXAMPLE 2A 
To a stirred suspension of 12.2 g. (0.05 mole) of 
4-(4-pyridinyl)-1H-indole-2,3-dione in a solution of 300 ml. of ethanol 
and 13.5 ml. of acetic acid was added 8.1 g. (0.16 mole) of hydrazine 
hydrate, and the mixture was stirred and refluxed for twenty hours, then 
cooled and the solid collected by filtration. Recrystallization of the 
solid from DMF afforded 8.5 g. of 4-(4-pyridinyl)-1H-indole-2,3-dione 
3-hydrazone, m.p. 253.degree.-254.degree. C. 
Following a procedure similar to that described in Example 2A above, the 
following compounds of formula I, where R.sub.1 is hydrogen and Q is other 
than O, were prepared: 
EXAMPLE 2B 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-hydrazone, m.p. 
185.degree.-187.degree. C. (10.05 g., from DMF), prepared by refluxing a 
suspension of 13.45 g. (0.06 mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione 
with 10.3 ml. of an 85% aqueous solution of hydrazine in 300 ml. of 
ethanol and 15 ml. of acetic acid. 
A sample of the free base was reacted with concentrated hydrochloric acid 
in DMF/water to give 5-(4-pyridinyl)-1H-indole-2,3-dione 3-hydrazone 
hydrochloride, m.p. 285.degree. C. 
EXAMPLE 2C 
5-(4-Pyridinylmethyl)-1H-indole-2,3-dione 3-hydrazone, m.p. 
200.degree.-202.degree. C. (4.0 g., from aqueous DMF), prepared by 
refluxing a mixture of 5.48 g. (0.023 mole) of 
5-(4-pyridinylmethyl)-1H-indole-2,3-dione with 3.95 ml. of 85% aqueous 
hydrazine in a solution of 115 ml. of ethanol and 25 ml. of acetic acid. 
EXAMPLE 2D 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-oxime hydrochloride hemihydrate, m.p. 
275.degree.-278.degree. C. (6.84 g., from methanol/diethyl ether), 
prepared by refluxing a mixture of 11.21 g. (0.05 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione with 17.37 g. (0.25 mole) of 
hydroxylamine hydrochloride in 300 ml. of pyridine. 
EXAMPLE 2E 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-methylhydrazone, m.p. 
244.degree.-245.degree. C. (7.2 g., from DMF containing 10% by volume of 
triethylamine), prepared by refluxing a mixture of 11.2 g. (0.05 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione with 3.5 g. (0.075 mole) of 
methylhydrazine in a solution of 300 ml. of ethanol and 10 ml. of acetic 
acid. 
EXAMPLE 2F 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-(t-butyl)hydrazone, m.p. 
198.degree.-199.degree. C. (8.0 g., from ethanol), prepared by refluxing a 
mixture of 11.2 g. (0.05 mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione with 
9.4 g. (0.075 mole) of t-butylhydrazine hydrochloride in 300 ml. of 
ethanol. 
EXAMPLE 2G 
4-(4-Pyridinyl)-1H-indole-2,3-dione 3-(N,N-dimethyl)hydrazone, m.p. 
213.degree.-214.degree. C. (4.5 g., from ethanol), prepared by refluxing a 
mixture of 6.6 g. (0.03 mole) of 4-(4-pyridinyl)-1H-indole-2,3-dione with 
30 ml. of N,N-dimethylhydrazine in a solution of 150 ml. of ethanol 
containing fifteen drops of acetic acid. 
EXAMPLE 2H 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-dimethylhydrazone, m.p. 
211.degree.-212.degree. C. (5.8 g., from isopropanol), prepared by 
refluxing a mixture of 11.2 g. (0.05 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione with 38.0 ml. (0.5 mole) of 
N,N-dimethylhydrazine in a solution of 300 ml. of ethanol and 10 ml. of 
acetic acid. 
EXAMPLE 2J 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-(2-hydroxyethyl)hydrazone, m.p. 
244.degree.-245.degree. C. (11.0 g., from DMF containing about 5% by 
volume of triethylamine), prepared by reacting 11.2 g. (0.05 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione with 5.7 g. (0.075 mole) of 
(2-hydroxyethyl)hydrazine in a solution of 300 ml. of ethanol and 10 ml. 
of acetic acid. 
EXAMPLE 2K 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-thiosemicarbazone, m.p. &gt;300.degree. 
C. (9.9 g., from DMF), prepared by refluxing a mixture of 11.2 g. (0.05 
mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione with 6.8 g. (0.075 mole) of 
thiosemicarbazide and 1.5 g. of sodium acetate in 300 ml. of ethanol. 
EXAMPLE 2L 
5-(4-Pyridinyl)-1H-indole-2,3-dione imidosemicarbazone, m.p. &gt;310.degree. 
C. (23.8 g.), prepared by refluxing a mixture of 
5-(4-pyridinyl)-1H-indole-2,3-dione and 20.4 g. (0.15 mole) of 
aminoguanidine bicarbonate in a solution of 600 ml. of absolute ethanol 
containing twenty drops of acetic acid. 
EXAMPLE 2M 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-[(trimethylammonium)acetyl]hydrazone 
chloride hemihydrate, m.p. &gt;305.degree. C. (6.64 g., from 
methanol/acetone), prepared by refluxing a mixture of 12.33 g. (0.055 
mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione and 9.7 g. (0.056 mole) of 
trimethylammonium acethydrazide chloride (Girard's reagent T) in 100 ml. 
of acetic acid. 
EXAMPLE 2N 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-phenylhydrazone, m.p. 
280.degree.-281.degree. C. (9.5 g., from DMF), prepared by refluxing a 
mixture of 11.2 g. (0.05 mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione and 
8.1 g. (0.075 mole) of phenylhydrazine in a solution of 300 ml. of ethanol 
and 10 ml. of glacial acetic acid. 
EXAMPLE 2P 
4-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-hydrazone, m.p. 
238.degree.-240.degree. C. (11.7 g., from DMF), prepared by refluxing a 
mixture of 14 g. (0.06 mole) of 
4-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione and 8.8 g. (0.18 mole) of 
hydrazine hydrate in a solution of 15 ml. of ethanol and 15 ml. of acetic 
acid. 
EXAMPLE 2Q 
4-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 
3-[(trimethylammonium)acetyl]hydrazone chloride hemihydrate, m.p. 
266.degree.-268.degree. C. (4.9 g., from ethanol), prepared by refluxing a 
mixture of 10 g. (0.042 mole) of 
4-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione and 8 g. (0.053 mole) of 
trimethylammonium acethydrazide chloride (Girard's Reagent T) in 200 ml. 
of ethanol and 10 ml. of glacial acetic acid. 
EXAMPLE 2R 
5-(4-Pyridinyl)-1H-indole-2,3-dione 3-(pyridiniumacetyl)hydrazone chloride 
dihydrochloride hydrate (4:3), m.p. &gt;315.degree. C. (16.34 g., from 
methanol), prepared by refluxing a mixture of 28.83 g. (0.09 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione and 17.22 g. (0.092 mole) of 
pyridinium acethydrazide chloride (Girard's Reagent P) in 200 ml. of 
glacial acetic acid in the presence of 7.38 g. (0.090 mole) of anhydrous 
sodium acetate. 
EXAMPLE 3A 
To a stirred suspension of 11.2 g. (0.05 mole) of 
4-(4-pyridinyl)-1H-indole-2,3-dione and 7.6 g. (0.055 mole) of potassium 
carbonate in 75 ml. of DMF was added 7.8 g. (0.05 mole) of methyl iodide, 
and the mixture was stirred and heated gently on a steam bath for 
forty-five minutes. The mixture was then taken to dryness, the solid 
residue was partitioned between water and methylene dichloride, the 
organic layer was separated, and the aqueous layer was extracted with 
additional portions of methylene dichloride. The combined organic 
extracts, on evaporation to dryness, afforded 3.6 g. of an orange solid 
which was recrystallized from DMF to give 3.0 g. of 
1-methyl-4-(4-pyridinyl)-1H-indole-2,3-dione, m.p. 231.degree.-232.degree. 
C. 
Following a procedure similar to that described in Example 3A above, the 
following compounds of formula I, where R.sub.1 is methyl, were prepared: 
EXAMPLE 3B 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione, m.p. 198.degree.-204.degree. 
C. (2.12 g. from isopropanol), prepared by reaction of 0.48 g. (0.01 mole) 
of sodium hydride (as a 50% dispersion in mineral oil) with 2.24 g. (0.01 
mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione in 150 ml. of DMF and 
reaction of the resulting sodium salt with 0.69 ml. (0.01 mole) of methyl 
iodide. 
EXAMPLE 3C 
Ethyl .alpha.-[5-(4-pyridinyl)-1H-indole-2,3-dion-1-yl]-acetate 
methanesulfonate, m.p. 205.degree.-207.degree. C. (10.3 g., from ethanol), 
prepared by reaction of 2.7 g. (0.059 mole) of a 50% dispersion of sodium 
hydride in mineral oil with 11.2 g. (0.05 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione in 75 ml. of DMF, reaction of the 
resulting sodium salt with 5.6 ml. (0.05 mole) of ethyl bromoacetate and 
conversion of the final product to the methanesulfonate salt. 
EXAMPLE 3D 
1-[2-(Diethylamino)ethyl]-5-(4-pyridinyl)-1H-indole-2,3-dione 
trihydrochloride, m.p. 261.degree.-265.degree. C. (13.2 g., from ethanol), 
prepared by reaction of 7.2 g. (0.15 mole) of a 50% dispersion of sodium 
hydride in mineral oil with 33.6 g. (0.15 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione in 400 ml. of DMF, reaction of the 
resulting sodium salt with 20.2 g. (0.15 mole) of diethylaminoethyl 
chloride and conversion of the final product to the trihydrochloride salt. 
EXAMPLE 3E 
t-Butyl .alpha.-[5-(4-pyridinyl)-1H-indole-2,3-dion-1-yl]acetate, m.p. 
158.degree.-160.degree. C. (23.4 g., chromatographed on 800 g. of silica 
gel with 10% methanol in diethyl ether as eluent), prepared by reaction of 
12 g. of (0.26 mole) of a 50% dispersion of sodium hydride in mineral oil 
with 57 g. (0.25 mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione in 400 ml. 
of DMF and reaction of the resulting sodium salt with 50 g. (0.25 mole) of 
t-butyl bromoacetate. 
EXAMPLE 3F 
1-(2-Hydroxyethyl)-5-(4-pyridinyl)-1H-indole-2,3-dione, m.p. 
214.degree.-215.degree. C. (4.7 g., from ethanol), prepared by reaction of 
5.6 g. (0.12 mole) of a 50% dispersion of sodium hydride in mineral oil 
with 22.4 g. (0.1 mole) of 5-(4-pyridinyl)-1H-indole-2,3-dione in 200 ml. 
of DMF and reaction of the resulting sodium salt with 10 g. (0.12 mole) of 
ethylene carbonate. 
EXAMPLES 4A-4D 
Following a procedure similar to that described in Example 2A above, the 
following compounds of formula I, where R.sub.1 is methyl and Q is other 
than O, were prepared: 
EXAMPLE 4A 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-oxime hydrochloride, m.p. 
&gt;315.degree. C. (soft. 295.degree. C.) (11.85 g., from methanol/diethyl 
ether), prepared by refluxing a mixture of 
1-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione with 17.37 g. (0.25 mole) of 
hydroxylamine hydrochloride in 300 ml. of pyridine. 
EXAMPLE 4B 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-hydrazone, m.p. 
178.degree.-180.degree. C. (9.0 g., from aqueous DMF), prepared by 
refluxing a mixture of 31 g. (0.13 mole) of 
1-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione with 19 ml. (0.39 mole) of 
85% hydrazine hydrate in 200 ml. of glacial acetic acid. 
EXAMPLE 4C 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-(2-hydroxyethyl)hydrazone, 
m.p. 210.degree.-211.degree. C. (6.75 g., from isopropanol), prepared by 
refluxing a mixture of 11.91 g. (0.05 mole) of 
1-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione with 10.2 ml. (0.15 mole) of 
(2-hydroxyethyl)hydrazine in 400 ml. of ethanol. 
EXAMPLE 4D 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-imidosemicarbazone, m.p. 
304.degree.-306.degree. C. (12.1 g.), prepared by refluxing a mixture of 
11.91 g. (0.05 mole) of 1-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione, 7.49 
g (0.06 mole) of aminoguanidine bicarbonate and 9.12 g. (0.07 mole) of 
sodium acetate trihydrate in a solution of 400 ml. of ethanol and 50 ml. 
of water. 
EXAMPLE 4E 
1-Methyl-5-(4-pyridinyl)-1H-indole-2,3-dione 3-methylhydrazone, m.p. 
204.degree.-205.degree. C. (10.5 g., from methanol), prepared by refluxing 
a mixture of 11.91 g. (0.05 mole) of 
1-methyl-5-(4-pyridinyl)-1H-indole-2,3-dione and 8.1 ml. (0.15 mole) of a 
98% solution of N-methylhydrazine in 400 ml. of ethanol. 
EXAMPLE 5 
To a stirred, boiling suspension of 20.0 g. (0.09 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione in one liter of water was added, in 
portions over a six minute period, 26.4 g. (0.15 mole) of sodium 
hydrosulfite. The mixture was stirred at reflux for two hours, then 
chilled and filtered, and the resulting solid (18.8 g.) was recrystallized 
from methanol to give 7.8 g. of 2-oxo-5-(4-pyridinyl)-1H-indol-3-ol, m.p. 
305.degree.-350.degree. C. 
EXAMPLE 6 
A stirred suspension of 27.3 g. (0.122 mole) of 
5-(4-pyridinyl)-1H-indole-2,3-dione in 70 ml. of glacial acetic acid at 
20.degree. C. was treated dropwise with a solution of 38.0 g. (0.187 mole) 
of 3-chloroperbenzoic acid in 265 ml. of glacial acetic acid over a period 
of eighty-five minutes. When addition was complete, the temperature of the 
mixture was raised to 60.degree. C., stirred for one hour and then allowed 
to cool to room temperature. The orange solid which had separated was 
collected by filtration, dried and recrystallized from 875 ml. of DMF to 
give 13.0 g. of 5-(4-pyridinyl)-1H-indole-2,3-dione-N-(Py)-oxide, m.p. 
294.degree.-295.degree. C.