There are disclosed compounds of the formula ##STR1## where m, n, p, R, R.sub.1, R.sub.2 and R.sub.3 are as defined in the specification which compounds are useful for enhancing memory and also as analgesic and antidepressant agents.

The present invention relates to novel compounds of the formula 
##STR2## 
where m is 1 or 2; n is 1 or 2; P is 0 or 1; each R is independently 
hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro, amino, 
loweralkylamino, loweralkylcarbonylamino, cyano, formyl, 
loweralkoxycarbonyl, loweralkylthio or loweralkoxycarbonylloweralkylthio; 
each R.sub.1 is independently hydrogen, loweralkyl, loweralkenyl, formyl, 
loweralkylcarbonyl, arylloweralkylcarbonyl, arylcarbonyl, halogen, 
arylloweralkenyl, arylloweralkyl, heteroarylloweralkenyl, 
heteroarylloweralkyl, cyanoloweralkenyl, cyanoloweralkyl, 
methoxyloweralkenyl, methoxyloweralkyl, loweralkoxycarbonylloweralkenyl, 
loweralkoxycarbonylloweralkyl, cycloalkylloweralkenyl or 
cycloalkylloweralkyl, the term heteroaryl signifying a group of the 
formula 
##STR3## 
where W is O, S, NH or CH.dbd.N; cyano, --CH(OH)R.sub.4, --C(OH)R.sub.4 
R.sub.5 or --CH.sub.2 OR.sub.5, R.sub.4 being hydrogen, loweralkyl, 
arylloweralkyl or aryl and R.sub.5 being loweralkyl, arylloweralkyl or 
aryl; each R.sub.2 is independently hydrogen, loweralkyl, loweralkenyl, 
loweralkynyl, loweralkoxycarbonylloweralkyl, 
loweralkylaminocarbonylloweralkyl, aminocarbonylloweralkyl, 
arylloweralkyl, phenyl, nitrophenyl, cyanophenyl, triflouromethylphenyl, 
aminophenyl, loweralkanoylaminophenyl, loweralkoxycarbonyl, 
arylloweralkoxycarbonyl, aryloxycarbonyl, loweralkylaminocarbonyl, 
arylloweralkylaminocarbonyl, arylaminocarbonyl, alkanoyl, 
arylloweralkanoyl, aroyl, alkenoyl, alkynoyl or --R.sub.6 --NR'R" where 
R.sub.6 is loweralkylene, loweralkenylene or loweralkynylene and R' and R" 
are each independently loweralkyl or alternatively the group --NR'R" as a 
whole is 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 
4-loweralkyl-1-piperazinyl or 4-aryl-1-piperazinyl; and R.sub.3 is 
hydrogen, nitro, amino, halogen, loweralkanoylamino, 
arylloweralkanoylamino, aroylamino, alkylamino, arylloweralkylamino or 
loweralkyl; which compounds are useful for enhancing memory and also as 
analgesic and antidepresant agents; pharmaceutical compositions comprising 
an effective amount of such a compound and a method of treating a patient 
in need of memory enhancement, relief from pain or relief from depression 
which comprises administering such a compound to the patient. 
Throughout the specification and the appended claims, a given chemical 
formula or name shall encompass all stereo, optical, and geometrical 
isomers thereof where such isomers exist, as well as pharmaceutically 
acceptable acid addition salts thereof and solvates thereof such as for 
instance hydrates. 
The following general rules of terminology shall apply throughout the 
specification and the appended claims. 
Unless otherwise stated or indicated, the term loweralkyl denotes a 
straight or branched alkyl group having from 1 to 6 carbon atoms. Examples 
of said loweralkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, 
iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and 
hexyl. 
Unless otherwise stated or indicated, the term loweralkoxy denotes a 
straight or branched alkoxy group having from 1 to 6 carbon atoms. 
Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy, 
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and 
branched-chain pentoxy and hexoxy. 
Unless otherwise stated or indicated, the term halogen shall mean fluorine, 
chlorine, bromine or iodine. 
Unless otherwise stated or indicated, the term aryl shall mean a phenyl 
group having 0, 1, 2 or 3 substituents each of which being independently 
loweralkyl, loweralkoxy, halogen, CF.sub.3, NO.sub.2 or CN. 
Unless otherwise stated or indicated, the term alkyl shall mean a saturated 
hydrocarbon group of 1 to 20 carbon atoms, the term alkenyl shall mean a 
hydrocarbon group of 1-20 carbon atoms having one or more carbon-carbon 
double bonds, and the term alkynyl shall mean a hydrocarbon group of 1-20 
carbon atoms having one or more carbon-carbon triple bonds. 
The term loweralkanoic acid shall mean a carboxylic acid in which the 
carboxyl group is attached to hydrogen or an alkyl group of from 1 to 5 
carbon atoms. 
The term loweralkanoyl shall mean a group obtained by removing a hydroxy 
group from the carboxyl group of a loweralkanoic acid, and thus it 
includes for instance formyl, acetyl and the like. 
The term arylloweralkanoyl shall mean a loweralkanoyl group having an aryl 
substituent thereon, the term loweralkanoyl and aryl having the respective 
meanings defined above. 
The term aroyl shall mean arylcarbonyl, an example being benzoyl. 
The term arylloweralkyl shall mean a loweralkyl group having an aryl 
substituted thereon, the terms loweralkyl and aryl having the respective 
meanings defined above. 
The terms alkanoyl, alkenoyl and alkynoyl shall mean groups obtained by 
removing a hydroxy group from the carboxyl group of alkanoic acid, 
alkenoic acid and alkynoic acid, respectively. Thus, for instance, 
linoleyl group derived from linoleic acid is an example of the term 
alkenoyl as defined above. 
The term acyl shall mean loweralkanoyl or arylloweralkanoyl as defined 
above. 
The term cycloalkyl in each occurrence shall mean an alicyclic group of 3 
to 7 ring carbons. 
The term heteroaryl in each occurrence shall mean a group of the formula 
##STR4## 
where W is O, S, NH or CH.dbd.N. 
The compounds of formula (I) of this invention can be synthesized by 
following or combining one or more of the steps described below, not 
necessarily in the order presented. For the sake of simplification, the 
description of synthetic schemes is presented below for compounds in which 
m=n=1, but it will be apparent that other compounds in which m and/or n is 
2 can be prepared by utilizing the synthetic schemes and making necessary 
modifications. Throughout the description of the synthetic steps, the 
definitions of R, R.sub.1 through R.sub.6, R', R", m, n and p are as given 
above unless otherwise stated or indicated, and other nomenclatures 
appearing below shall have the same meanings defined in their respective 
first appearances unless otherwise stated or indicated. 
STEP A 
A compound of formula (II) where R.sub.7 is H, halogen, loweralkyl, 
loweralkoxy, nitro, cyano, formyl, loweralkylthio or 
loweralkoxycarbonylloweralkylthio and R.sub.8 is H, loweralkyl, halogen or 
cyano and R.sub.9 is H or loweralkyl is reacted with a compound of formula 
(III) where X is chlorine or fluorine and R.sub.10 is H, NO.sub.2, halogen 
or loweralkyl to afford a compound of formula (IV). 
##STR5## 
Said reaction is typically conducted in an ethereal solvent such as 
bis(2-methoxyethyl) ether, diethyl ether, dimethoxy ether, dioxane or 
tetrahydrofuran or polar aprotic solvent such as dimethylformamide, 
dimethylacetamide, hexamethylphosphoramide or dimethylsulfoxide or protic 
solvent such as ethanol or isopropanol at a temperature of between about 
20.degree. C. and 150.degree. C. 
STEP B 
A compound of formula IVa obtained from STEP A is treated with a strong 
base such as sodium hydride or potassium hydride in a suitable solvent 
such as polar aprotic solvent including dimethylformamide, 
dimethylsulfoxide and ethereal solvents or aromatic hydrocarbon at a 
temperature of between about -10.degree. and 50.degree., preferably 
0.degree.-25.degree. to form the anion of IVa, which is reacted with a 
chloride compound of the formula R.sub.11 --Cl, where R.sub.11 is 
loweralkyl, loweralkoxycarbonylloweralkyl, loweralkenyl, loweralkynyl, 
arylloweralkyl, loweralkoxycarbonyl, arylloweralkoxycarbonyl or 
aryloxycarbonyl at a temperature of between about -10.degree. and 
80.degree., preferably between 0.degree. and 25.degree. to obtain a 
compound of formula V. 
##STR6## 
STEP C 
The anion of compound IVa prepared as in STEP B is reacted with 
fluoro-nitrobenzene, cyano-fluorobenzene or fluoro-trifluoromethylbenzene 
of the formula 
##STR7## 
where Y is nitro, cyano or trifluoromethyl to afford a compound of formula 
VI below. Said reaction is conducted in substantially the same manner as 
in STEP B. 
##STR8## 
STEP D 
Compound IVa is reacted with a loweralkyl isocyanate, arylloweralkyl 
isocyanate or aryl isocyanate of the formula R.sub.12 NCO where R.sub.12 
is loweralkyl, arylloweralkyl or aryl to afford a compound of formula VII. 
##STR9## 
Said reaction is typically conducted in a suitable solvent such as 
aromatic hydrocarbon including benzene, toluene and the like, halogenated 
hydrocarbon or ethereal solvent at a temperature of about 
0.degree.-80.degree., preferably 30.degree.-60.degree. C. 
STEP E 
Compound IVa is reacted with an alkanoyl chloride, arylloweralkanoyl 
chloride, aroyl chloride, alkenoyl chloride or alkynoyl chloride of 
formula (VIII) where R.sub.13 is alkyl, arylloweralkyl, aryl, alkenyl or 
alkynyl to afford a compound of formula (IX). Said reaction is typically 
conducted in substantially the same manner as in STEP D. 
##STR10## 
Where the compound R.sub.13 COCl is not commercially available, it is 
prepared from the corresponding carboxylic acid R.sub.13 COOH and thionyl 
chloride in a suitable solvent, for instance, in benzene at the reflux 
temperature. 
STEP F 
As an alternative to STEP A or B, a compound of formula (IVb) where 
R.sub.14 is loweralkyl can be prepared by reacting compound IVa with a 
strong base such as sodium hydride or potassium hydride and then reacting 
the product with a diloweralkyl sulfate of the formula (R.sub.14).sub.2 
SO.sub.4. Said two steps are conducted under substantially the same 
conditions as used in STEP B. 
##STR11## 
STEP G 
A compound of formula Va obtained in STEP B is subjected to Mannich 
reaction with formaldehyde and a secondary amine of the formula HNR'R", 
where R' and R" are independently loweralkyl or --NR'R" taken together is 
1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 4-loweralkyl-1-piperazinyl 
or 4-aryl-1-piperazinyl to afford a compound of formula X. 
##STR12## 
The above reaction can be conducted under conditions usually used in the 
art for carrying out Mannich reactions. Typically, it is conducted by 
preparing a mixture of compound Va, paraformaldehyde, HNR'R", cuprous 
chloride (used as a catalyst) and a suitable medium including ethereal 
solvents such as dioxane, and heating the mixture at 
25.degree.-100.degree.. 
STEP H 
Compound X is catalytically hydrogenated to afford a compound of formula XI 
or XII by making a suitable selection of reaction conditions in a manner 
known to the art. 
##STR13## 
STEP I 
As an alternative to the foregoing steps, a compound of formula XIV where 
R.sub.15 is loweralkyl, loweralkoxycarbonylloweralkyl, arylloweralkyl, 
aryl, loweralkoxycarbonyl, arylloweralkoxycarbonyl, aryloxycarbonyl, 
alkanoyl, arylloweralkanoyl or aroyl can be prepared by reacting a 
compound of formula XIII with a suitable chlorinating agent such as 
sulfuryl choride (SO.sub.2 Cl.sub.2) in a manner known in the art. 
##STR14## 
STEP J 
A compound of formula (XV) where R.sub.16 is loweralkyl, 
loweralkoxycarbonyl, alkanoyl, alkenoyl, alkynoyl, arylloweralkanoyl or 
aroyl, and R.sub.17 is H, NO.sub.2, halogen or loweralkyl which is 
prepared by use of one or more of the reaction steps described in this 
specification is reacted with phosphorus oxychoride and dimethylformamide 
to afford a compound of formula (XVI). 
##STR15## 
Said reaction can be conducted under conditions usually used for carrying 
out Vilsmeier reactions. Typically, it is conducted in a suitable solvent 
such as halogenated hydrocarbon at a temperature of about 
20.degree.-100.degree.. 
Where the positional isomer of compound XVI in which the formyl group is at 
the 2-position of the indole ring is desired, compound XV is reacted with 
secondary butyllithium and the resultant lithio compound reacted with 
N-formyl-N-methyl-aniline in a manner known in the art. 
STEP K 
Compound XV is reacted with a loweralkanoyl chloride, arylloweralkanoyl 
chloride or aroyl chloride of formula R.sub.12 COCl in the presence of 
zinc chloride to afford a compound of formula (XVII). Said reaction is 
typically conducted in a suitable solvent such as halogenated hydrocarbon 
at a temperature of about 20.degree.-100.degree. C. 
##STR16## 
Where the positional isomer of compound XVII in which the group 
--C(O)R.sub.12 is at the 2-position of the indole ring is desired, 
compound XV is reacted with secondary butyllithium and the resultant 
lithio compound reacted with R.sub.12 COCl in a manner known to the art. 
STEP L 
A compound of formula XVIII below where R.sub.18 is H, halogen or 
loweralkyl is reduced to a compound of formula XIX below with NaBH.sub.4, 
LiAlH.sub.4 or borane complexes. 
##STR17## 
When NaBH.sub.4 is used, said reduction is conducted typically in a lower 
aliphatic alcohol such as isopropanol or ethanol or loweralkanoic acid at 
a temperature of about 0.degree.-80.degree.. After the reaction, water is 
added to the reaction mixture. When LiAlH.sub.4 is used, said reduction is 
conducted typically in an ethereal solvent such as tetrahydrofuran or 
ether at a temperature of about 0.degree.-80.degree.. When borane 
complexes are used, the reaction temperature is typically 
0.degree.-80.degree. C. 
STEP M 
Compound XVIII is reacted with a Grignard reagent of the formula R.sub.5 
MgBr and the product is thereafter hydrolyzed to afford a compound of 
formula XX below. 
##STR18## 
STEP N 
A compound of formula XXI which is prepared by use of one or more of the 
reaction steps described in this specification is catalytically 
hydrogenated with hydrogen gas and a suitable catalyst such as palladium 
on carbon to afford a compound of formula (XXII). 
##STR19## 
Said catalytic hydrogenation is typically conducted in a suitable solvent 
such as loweralkanol or loweralkyl ester of loweralkanoic acid at a 
temperature of 20.degree.-50.degree. C. 
STEP O 
As an alternative to the foregoing steps, compound IVa can be prepared by 
hydrolyzing a carbamate compound of formula Vb. (Needless to say, the 
purpose of this STEP is not to reverse aforementioned STEP B in order to 
regain the starting compound of STEP B. This STEP can be useful, for 
instance, for the purpose of converting R.sub.8 in formula IVa from 
hydrogen to 3-chloro. Thus, for this purpose, one can first convert the 
amino hydrogen in formula IVa to ethoxycarbonyl by use of STEP B or 
similar to STEP E and then introduce a chlorine atom into the 3-position 
of the indole ring by use of STEP I and thereafter hydrolyze the resultant 
product by use of this STEP, instead of conducting the chlorination 
reaction directly with compound IVa. Similarly, this STEP can also be 
useful for introducing the group --COR.sub.12 into the indole ring 
according to STEP K above or the group --CHO according to STEP J when 
R.sub.2 is hydrogen. 
##STR20## 
Said hydrolysis is conducted typically by stirring a mixture comprising 
compound Vb, an alkali such as NaOH and a suitable medium such as ethanol 
plus water at a temperature of about 70.degree.-100.degree. C. 
STEP P 
Compound XXII is reacted with phenyl formate to afford a compound of 
formula (XXIII) 
##STR21## 
Typically said reaction is conducted by stirring a solution of compound 
XXII in excess phenyl formate at a temperature of about 
20.degree.-50.degree. C. The same reaction can also be conducted with 
loweralkyl formate under substantially the same conditions. 
STEP Q 
Compound XXII is reacted with an acyl chloride of the formula R.sub.12 COCl 
or acid anhydride of the formula R.sub.12 CO--O--COR.sub.12 to afford a 
compound of formula XXIV. 
##STR22## 
Said reaction is conducted under substantially the same conditions as used 
in STEP E. 
STEP R 
As an alternative to the foregoing steps, a compound of formula XXV where 
R.sub.1 is H or loweralkyl, and R.sub.2 is loweralkyl, arylloweralkyl, 
phenyl, nitrophenyl, or trifluoromethylphenyl, can be prepared by reacting 
a compound of formula (IVc) with a loweralkyl lithium of the formula 
R.sub.19 Li where R.sub.19 is loweralkyl. 
##STR23## 
Said reaction is usually conducted in a suitable solvent such as ethereal 
solvent, preferably tetrahydrofuran at a temperature of between about 
-10.degree. and 50.degree. C. 
STEP S 
A compound of formula XIXa below is reacted with a strong base such as 
sodium hydride or potassium hydride and the resultant alkoxide anion is 
reacted with a halide of the formula R.sub.5 X to afford an ether of 
formula XXVI below. Said two-step procedure is conducted in substantially 
the same manner as in STEP B above. 
##STR24## 
STEP T 
Compound XVI is subjected to Witting reaction with an ylide of the formula 
(C.sub.6 H.sub.5).sub.3 P.dbd.CR.sub.20 R.sub.21 to afford a compound of 
formula XXVII where R.sub.20 and R.sub.21 are each independently hydrogen, 
loweralkyl, aryl, arylloweralkyl, heteroaryl, heteroarylloweralkyl, cyano, 
methoxy, loweralkoxycarbonyl or together form a cycloalkylidene. 
##STR25## 
The above reaction can be conducted under conditions usually used for 
carrying out Wittig reactions. Thus, the ylide is prepared in a routine 
manner by first preparing a phosphonium salt from a bromide of the formula 
BrCHR.sub.20 R.sub.21 and triphenylphosphine and thereafter reacting the 
phosphonium salt with a suitable base such as sodium hydride, potassium 
tert-butoxide or n-butyllithium in a suitable solvent such as anhydrous 
ethereal solvent. Thereafter a solution of compound XVI in a suitable 
solvent such as anhydrous ether is added to the freshly prepared ylide 
solution and the mixture is stirred at a temperature of between about 
-10.degree. C. and 80.degree. C. 
It will be apparent that by making a suitable selection of the groups 
R.sub.20 and R.sub.21 and/or conducting Wittig reaction more than once if 
necessary, one can obtain compounds of formula XXVIII where the group 
R.sub.22 is loweralkenyl, arylloweralkenyl, heteroarylloweralkenyl, 
cyanoloweralkenyl, methoxyloweralkenyl, loweralkoxycarbonylloweralkenyl, 
or cycloalkylloweralkenyl. 
##STR26## 
STEP U 
Compound XXVIII is catalytically hydrogenated in a suitable manner known to 
the art to afford a compound of formula XXIX where R.sub.23 is loweralkyl, 
arylloweralkyl, heteroarylloweralkyl, cyanoloweralkyl, methoxyloweralkyl, 
loweralkoxycarbonylloweralkyl or cycloalkylloweralkyl. 
##STR27## 
STEP V 
Substantially the same hydrogenation technique as described in STEP N or U 
can be used to hydrogenate a compound of formula XXX below to afford a 
compound of formula XXXI below. 
##STR28## 
STEP W 
Substantially the same reaction technique as described in STEP P can be 
used to convert compound XXXI to a compound of formula XXXII below. 
##STR29## 
STEP X 
Substantially the same reaction technique as described in STEP Q can be 
used to convert compound XXXI to a compound of formula XXXIII below. 
##STR30## 
STEP Y 
As an alternative to the foregoing steps, introduction of a cyano group 
into the 2- or 3-position of the indole ring can be accomplished by using, 
as a starting compound, the formyl compound of formula XXXIV and 
converting the formyl group into a cyano group. For this purpose, compound 
XXXIV is first reacted with hydroxylamine in a routine manner to obtain 
the corresponding oxime and thereafter the oxime is reacted with 
benzenesulfonyl chloride to obtain a nitrile compound of formula XXXV. The 
second step is typically conducted in a suitable solvent such as ethereal 
solvent by warming the reaction mixture at 60.degree.-100.degree. C. 
##STR31## 
STEP Z 
For the purpose of preparing a compound of formula I where R.sub.2 is 
aminocarbonylloweralkyl, a compound of formula I where R.sub.2 is 
loweralkoxycarbonylloweralkyl (preferably ethoxycarbonylloweralkyl) is 
reacted with ammonia in a manner known to the art. 
The compounds of formula I of the invention are useful in the treatment of 
various memory dysfunctions characterized by decreased cholinergic 
function, such as Alzheimer's disease. 
This utility is demonstrated by the ability of these compounds to restore 
cholinergically deficient memory in the Dark Avoidance Assay, where they 
are generally active over a broader dose range than heretofore known 
compounds, a distinct therapeutic advantage. 
Dark Avoidance Assay 
In this assay mice are tested for their ability to remember an unpleasant 
stimulus for a period of 24 hours. A mouse is placed in a chamber that 
contains a dark compartment; a strong incandescent light drives it to the 
dark compartment, where an electric shock is administered through metal 
plates on the floor. The animal is removed form the testing apparatus and 
tested again, 24 hours later, for the ability to remember the electric 
shock. 
If scopolamine, an anticholinergic that is known to cause memory 
impairment, is administered before an animal's initial exposure to the 
test chamber, the animal re-enters the dark compartment shortly after 
being placed in the test chamber 24 hours later. This effect of 
scopolamine is countered by an active test compound, resulting in a 
greater interval before re-entry into the dark compartment. 
The results for active compound are expressed as the percent of a group of 
animals in which the effect of scopolamine is countered, as manifested by 
an increased interval between being placed in the test chamber and 
re-entering the dark compartment. 
The results of some of the compounds of this invention are presented in 
Table 1 along with the result of physostigmine. 
TABLE 1 
______________________________________ 
% of Animals 
Dose With Scopolamine 
mg/kg Body Induced Memory 
Compound Weight s.c. 
Deficit Reversed 
______________________________________ 
Physostigmine (namely, 
0.31 20% 
(3aS--cis)-1,2,3,3a,8,8a- 
hexahydro-1,3a,8-trimethyl- 
pyrrolo[2,3-b]indol-5-ol, 
methyl carbamate) 
N--Methyl-N--(4-pyridinyl)- 
0.04 53% 
1H--indol-1-amine maleate 
N--(4-Pyridinyl)-1H--indol- 
0.31 33% 
1-amine maleate 
N--Propyl-N--(4-pyridinyl)- 
0.08 27% 
1H--indol-1-amine maleate 
N--Ethyl-N--(4-pyridinyl)- 
0.63 33% 
1H--indol-1-amine maleate 
N--(3-Fluoro-4-pyridinyl)- 
0.31 33% 
N--propyl-3-methyl-1H-- 
indol-1-amine 
hydrochloride 
3-Methyl-N--propyl-N-- 
0.31 27% 
(4-pyridinyl)-1H--indol- 
1-amine maleate 
______________________________________ 
Additionally, some of the compounds of this invention exhibit 
antidepressant activities, which activities being particularly helpful for 
patients suffering from Alzheimer's disease. The antidepressant activities 
were evaluated in this invention on the basis of prevention of 
Tetrabenazine-induced ptosis in mice. The test method and results are 
described below. 
Prevention Of Tetrabenazine-Induced Ptosis In Mice 
Tetrabenazine (TBZ) induces behavioral depression with concomitant ptosis 
in mice similar to reserpine. Antidepressant compounds, both 
monoamineoxidase inhibitors and tricyclics, are known to prevent or 
antagonize these effects and the degree of antagonism correlates with 
clinical efficacy. The prevention of TBZ-induced ptosis in mice is used as 
a preliminary screen for possible antidepressant activity. The method used 
in this invention is as follows: 
Male mice weighing 20 to 30 grams are used in test groups of five subjects. 
All compounds are dissolved or suspended with a suitable surfactant in 
distilled water and administered in volumes of 10 ml/kg of body weight. 
TBZ solution is made from the methanesulfonate salt and the concentration 
is adjusted to enable administration of 60 mg/kg of base by 
intraperitoneal (i.p.) injection. 
The pretreatment time is measured from the time of dosing to observation. 
Therefore, when a 30-minute pretreat is utilized, drug and TBZ are given 
simultaneously. A control group received solvent and TBZ at intervals 
indentical to drug group. For a primary screen, the drug is administered 
i.p. and a group size of five is utilized. Eight animals/group are used 
for a dose range. 
Thirty minutes after TBZ, the subjects are placed in individual plastic 
containers (10.5.times.8.times.6 inches) in the presence of white noise 
and one minute after the transfer, they are scored for ptosis on the 
following scale: Eyes closed=4, eyes 3/4 closed=3, eyes 1/2 closed=2, eyes 
1/4 closed=1, eyes open=0. The total score for each group of five in a 
primary screen will, therefore, be from 0 to 20 and these scores are used 
as indications of drug activity. 
The vehicle control group score is used as a determinant of the validity of 
each test. If the control score is less than 17, the results are discarded 
and the test repeated. The calculation of percent inhibition of ptosis is: 
##EQU1## 
For ED.sub.50 estimation, four or five doses are administered in order to 
bracket the estimated value and only vehicle control scores of 27 to 32 
are accepted to assure the accuracy of the ED.sub.50 estimation. 
Linear regression analysis is used to estimate ED.sub.50 values and 95% 
confidence intervals. 
The results of some of the compounds of this invention are shown in Table 2 
along with a result for desipramine (prior art compound). 
TABLE 2 
______________________________________ 
Compound ED.sub.50 (mg/kg) 
______________________________________ 
N--methyl-N--(4-pyridinyl)-1H-- 
3.3 (p.o.) 
indol-1-amine maleate 
N--(4-pyridinyl)-1H--indol-1- 
3.3 (p.o.) 
amine maleate 
N--propyl-N--(4-pyridinyl-1H-- 
5.1 (p.o.) 
indol-1-amine maleate 
N--ethyl-N--(4-pyridinyl)-1H-- 
5.6 (p.o.) 
indol-1-amine maleate 
N--methyl-N--(4-pyridinyl)-1H-- 
9.7 (p.o.) 
indol-1-amine-3-carboxaldehyde 
maleate 
N--ethyl-N--(4-pyridinyl)-1H--indol- 
11.9 (p.o.) 
1-amine-3-carboxaldehyde maleate 
5-methoxy-N--propyl-N--(4-pyridinyl)- 
29.8 (p.o.) 
1H--indol-1-amine maleate 
3-Methyl-N--(4-pyridinyl)-1H-- 
1.0 (i.p.) 
indol-1-amine oxalate 
3-Methyl-N--propyl-N--(4-pyridinyl)- 
1.8 (i.p.) 
1H--indol-1-amine maleate 
N--(2-Propen-1-yl)-N--(4-pyridinyl)- 
4.2 (i.p.) 
1H--indol-1-amine maleate 
(Prior Art Compound) 
Desipramine 2.3 (p.o.) 
______________________________________ 
Compounds I of the present invention are also useful as analgesic agents 
due to their ability to alleviate pain in mammals. The activity of the 
compounds is demonstrated in the 2-phenyl-1,4-benzoquinone-induced 
writhing (PQW) test in mice, a standard assay for analgesia [Proc. Soc. 
Exptl. Biol. Med., 95, 729 (1957)] and in modified Haffner's analgesia. 
The latter assay is used to evaluate analgesic activity by measuring 
drug-induced changes in the sensitivity of mice to pressure stress by 
placing an artery clip (21/2 inches long) on their tail. The procedure 
used is a modification of the test developed by Haffner, Dtsch. Med. 
Wschr. 55, 731 (1929), and it is described below. 
METHOD: 
Male mice (Charles River, CD-1) from 18-30 grams are used for the test. An 
artery clip is applied to the root of the tail of a mouse (approximately 
1/2 inch from the body) to induce pain. The animals quickly responds to 
this noxious stimuli by biting the clip or the location of the clip. This 
reaction time, the interval between stimulus onset and response, is 
recorded in 1/10 second increments by a stop watch. 
For a time response, the screening dose (25 mg/kg) is administered 
subcutaneously (10 ml/kg) to the animal receiving food and water ad 
libitum before testing. Animals receiving the compound orally are fasted 
18-24 hours before drug administration. Drug to be tested is prepared with 
distilled water and if insoluble, one drop of a surfactant is added. 
Twenty-eight animals (seven/group) are administered the drug 15, 30, 45 and 
60 minutes prior to testing. 
The cut-off time (CO) is determined by taking the (x) average+3 standard 
(SD) deviation of the combined response latencies of the control mice in 
all time periods. 
EQU CO=x+3 SD (seconds) 
Any reaction time, in subsequent drug tests, which is greater than the CO 
(for the same time period) therefore exceeds 99% of a noraml Gaussian 
distribution and is called "positive response" indicative of analgesic 
activity. A time response indicates the period of greatest analgesic 
effect after dosing. The ED.sub.50 is determined at the peak time of drug 
activity. A minimum of three dose groups are used. ED.sub.50 's are 
calculated using computer analysis. 
The results of some of the compounds of this invention are shown in Table 3 
along with those of a prior art compound. 
TABLE 3 
______________________________________ 
ANALGESIC ACTIVITY (ED.sub.50, mg/kg, s.c.) 
Modified 
Compound PQW Haffner's Analgesia 
______________________________________ 
N--methyl-N--(4-pyridinyl)- 
3.2 16.3 
1H--indol-1-amine maleate 
N--(4-pyridinyl)-1H--indol- 
0.86 5.7 
1-amine maleate 
N--propyl-N--(4-pyridinyl)- 
5.1 31.0 
1H--indol-1-amine maleate 
3-ethyl-N--methyl-N--(4- 
0.9 1.0 
pyridinyl)-1H--indol-1- 
amine hydrochloride 
3-ethenyl-N--methyl-N--(4- 
1.0 1.0 
pyridinyl)-1H--indol-1- 
amine maleate 
N--Methyl-5-nitro-N--(4- 
1.0 
pyridinyl)-1H--indol-1- 
amine maleate 
3-Methyl-N--(4-pyridinyl)- 
0.4 0.7 
1H--indol-1-amine oxalate 
3-Methyl-N--propyl-N--(4- 
4.1 1.4 
pyridinyl)-1H-indol-1- 
amine maleate 
N--(2-Propen-1-yl)-N-- 
1.3 3.8 
(4-pyridinyl)-1H--indol- 
1-amine maleate 
(Prior Art Compound) 
1.3 3.9 
Pentazocin 
______________________________________ 
Effective quantities of the compounds of the invention may be administered 
to a patient by any of the various methods, for example, orally as in 
capsules or tablets, parenterally in the form of sterile solutions or 
suspensions, and in some cases intravenously in the form of sterile 
solutions. The free base final products, while effective themselves, may 
be formulated and administered in the form of their pharmaceutically 
acceptable acid addition salts for purposes of stability, convenience of 
crystallization, increased solubility and the like. 
Acids useful for preparing the pharmaceutically acceptable acid addition 
salts of the invention include inorganic acids such as hydrochloric, 
hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as 
organic acids such as tartaric, citric, acetic, succinic, salicylic, 
maleic, fumaric and oxalic acids. 
The active compounds of the present invention may be orally administered, 
for example, with an inert diluent or with an edible carrier, or they may 
be enclosed in gelatin capsules, or they may be compressed into tablets. 
For the purpose of oral therapeutic administration, the active compounds 
of the invention may be incorporated with excipients and used in the form 
of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, 
chewing gum and the like. These preparations should contain at least 0.5% 
of active compound, but may be varied depending upon the particular form 
and may conveniently be between 4% to about 70% of the weight of the unit. 
The amount of active compound in such compositions is such that a suitable 
dosage will be obtained. Preferred compositions and preparations according 
to the present invention are prepared so that an oral dosage unit form 
contains between 1.0-300 milligrams of active compound. 
The tablets, pills, capsules, troches and the like may also contain the 
following ingredients: a binder such as micro-crystalline cellulose, gum 
tragacanth or gelatin; an excipient such as starch or lactose, a 
disintegrating agent such as alginic acid, Primogel, cornstarch and the 
like; a lubricant such as magnesium stearate or Sterotex; a glidant such 
as colloidal silicon dioxide; and a sweetening agent such as sucrose or 
saccharin may be added or a flavoring agent such as peppermint, methyl 
salicylate, or orange flavoring. When the dosage unit form is a capsule, 
it may contain, in addition to materials of the above type, a liquid 
carrier such as a fatty oil. Other dosage unit forms may contain other 
various materials which modify the physical form of the dosage unit, for 
example, as coatings. Thus tablets or pills may be coated with sugar, 
shellac, or other enteric coating agents. A syrup may contain, in addition 
to the active compounds, sucrose as a sweetening agent and certain 
preservatives, dyes, coloring and flavors. Materials used in preparing 
these various compositions should be pharmaceutically pure and non-toxic 
in the amounts used. 
For the purpose of parenteral therapeutic administration, the active 
compounds of the invention may be incorporated into a solution or 
suspension. These preparations should contain at least 0.1% of active 
compound, but may be varied between 0.5 and about 30% of the weight 
thereof. The amount of active compound in such compositions is such that a 
suitable dosage will be obtained. Preferred compositions and preparations 
according to the present invention are prepared so that a parenteral 
dosage unit contains between 0.5 to 100 milligrams of active compound. 
The solutions or suspensions may also include the following components: a 
sterile diluent such as water for injection, saline solution, fixed oils, 
polyethylene glycols, glycerine, propylene glycol or other synthetic 
solvents; antibacterial agents such as benzyl alcohol or methyl parabens; 
antioxidants such as ascorbic acid or sodium bisulfite; chelating agents 
such as ethylenediaminetetraacetic acid; buffers such as acetates, 
citrates or phosphates and agents for the adjustment of tonicity such as 
sodium chloride or dextrose. The parenteral preparations can be enclosed 
in disposable syringes or multiple dose vials made of glass or plastic. 
Examples of the compounds of this invention include: 
N-(4-pyridinyl)-1H-indol-1-amine; 
N-methyl-N-(4-pyridinyl)-1H-indol-1-amine; 
N-ethyl-N-(4-pyridinyl)-1H-indol-1-amine; 
N-propyl-N-(4-pyridinyl)-1H-indol-1-amine; 
5-methoxy-N-propyl-N-(4-pyridinyl)-1H-indol-1-amine; 
N-methyl-N-(4-pyridinyl)-1H-indol-1-amine-3-carboxaldehyde; 
N-ethyl-N-(4-pyridinyl)-1H-indol-1-amine-3-carboxaldehyde; 
N-(4-nitro-3-pyridinyl)-1H-indol-1-amine-N.sup.1 -oxide; 
N-(4-amino-3-pyridinyl)-1H-indol-1-amine-N.sup.1 -oxide; 
3-ethenyl-N-methyl-N-(4-pyridinyl)-1H-indol-1-amine; 
3-ethyl-N-methyl-N-(4-pyridinyl)-1H-indol-1-amine; 
5-chloro-N-(4-pyridinyl)-1H-indol-1-amine; 
5-chloro-N-propyl-N-(4-pyridinyl)-1H-indol-1-amine; 
5-bromo-N-(4-pyridinyl)-1H-indol-1-amine; 
5-bromo-N-methyl-N-(4-pyridinyl)-1H-indol-1-amine; 
5-bromo-N-propyl-N-(4-pyridinyl)-1H-indol-1-amine. 
5-Nitro-N-(4-pyridinyl)-1H-indol-1-amine; 
N-Methyl-5-nitro-N-(4-pyridinyl)-1H-indol-1-amine; 
3-Methyl-N-(4-pyridinyl)-1H-indol-1-amine; 
3-Methyl-N-propyl-N-(4-pyridinyl)-1H-indol-1-amine; 
N-(3-Fluoro-4-pyridinyl)-3-methyl-1H-indol-1-amine; 
N-(3-Fluoro-4-pyridinyl)-N-propyl-3-methyl-1H-indol-1-amine; 
N-(2-Propen-1-yl)-N-(4-pyridinyl)-1H-indol-1-amine; and 
N-(3-Fluoro-4-pyridinyl)-N-propyl-1H-indol-1-amine.