Certain 1-indolylalkyl-4-(alkoxypyrimidinyl)piperazines of Formula I are useful antidepressant agents. The ##STR1## substituents R.sup.1, R.sup.2 and R.sup.5 are hydrogen or lower alkyl; R.sup.3 and R.sup.4 are hydrogen, alkyl, alkoxy, alkythio, carboxamido, halo, or trifluoromethyl; R.sup.6 is alkoxy; and n is the integer 2 or 3.

BACKGROUND OF THE INVENTION 
This invention generally pertains to heterocyclic carbon compounds having 
drug and bio-affecting properties and to their preparation and use. In 
particular the invention is concerned with 1,4-disubstituted piperazine 
derivatives wherein one substituent is indol-3-yl-alkyl and the other is a 
substituted pyrimidin-4-yl moiety. These compounds possess a unique 
serotonergic profile that should make them useful in treatment of 
depression. 
Archer disclosed a large series of CNS-depressant indolylalkylpiperazines 
in U.S. Pat. No. 3,188,313. Among a large number of possible substituents 
on the 4-nitrogen atom of the piperazine ring was pyrimidine 
(unsubstituted). In U.S. Pat. No. 3,562,278, Archer disclosed and claimed 
a series of 1-indolyl-ethyl-4-substituted-piperazines. Among the possible 
4-substituents listed is 2-pyrimidinyl, again unsubstituted. The 
pharmacologic action disclosed for these art compounds is general CNS and 
psychomotor depression--in direct opposition to the antidepressant effects 
of the novel compounds of the instant invention. 
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION 
In its broadest aspect, the present invention is concerned with piperazinyl 
derivatives having useful antidepressant properties characterized by a 
compound of Formula I. 
##STR2## 
In Formula I; R.sup.1 is selected from hydrogen, lower alkyl, and 
aryl-lower alkyl, e.g. benzyl. The descriptive term "lower" is used herein 
to denote an organic radical containing from 1 to 4 carbon atoms. Aryl 
means phenyl or R.sup.3 -substituted phenyl. R.sup.2 and R.sub.5 are 
independently selected from hydrogen and lower alkyl. R.sup.3 and R.sup.4 
are independently selected from among hydrogen, lower alkyl, lower alkoxy, 
lower alkylthio, carboxamide, halogen and trifluoromethyl. R.sup.6 is 
lower alkoxy and n is the integer 2 or 3. Preferred classes of compounds 
are those wherein R.sup.3 is 5-fluoro- and wherein R.sup.5 is 5-methoxy. 
Additionally compounds of Formula I also encompass all pharmaceutically 
acceptable acid addition salts and/or solvates thereof. The present 
invention is also considered to include stereoisomers as well as optical 
isomers, e.g. mixtures of enantiomers as well as individual enantiomers 
and diasteromers, which arise as a consequence of structural asymmetry in 
certain compounds of the instant series. Separation of the individual 
isomers is accomplished by application of various methods which are well 
known to practitioners in the art. 
It is to be understood that, as used herein, halogen denotes fluorine, 
chlorine, bromine and iodine; with the term "lower alkyl" referring to 
both straight and branched chain carbon radicals of from to 4 carbon atoms 
inclusive. Illustrative of these radicals are carbon chains which can be 
methyl, ethyl, propyl, isopropy, 1-butyl, 1-methylpropyl and 
2-methylpropyl. Carboxamide intends a 
##STR3## 
radical. 
The pharmaceutically acceptable acid addition salts of the invention are 
those in which the counter-ion does not contribute significantly to the 
toxicity or pharmacological activity of the salt and, as such, they are 
the pharmacological equivalents of the bases of Formula I. They are 
generally preferred for medical usage. In some instances, they have 
physical properties which makes them more desirable for pharmaceutical 
formulation such as solubility, lack of hygroscopicity, compressibility 
with respect to tablet formation and compatibility with other ingredients 
with which the substance may be used for pharmaceutical purposes. The 
salts are routinely made by admixture of a Formula I base with the 
selected acid preferably by contact in solution employing an excess of 
commonly used inert solvents such as water, ether, benzene, methanol, 
ethanol, ethyl acetate and acetonitrile. The may also be made by 
metathesis or treatment with an ion exchange resin under conditions in 
which the anion of one salt of the substance of the Formula I is replaced 
by another anion under conditions which allow for separation of the 
desired species such as by precipitation from solution or extraction into 
a solvent, or elution from or retention on an ion exchange resin. 
Pharmaceutically acceptable acids for the purposes of salt formation of 
the substances of Formula I include sulfuric, phosphoric, hydrochloric, 
hydrobromic, hydroiodic, citric, acetic, benzoic, cinnamic, mandelic, 
phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and others. 
The compounds of Formula I can be prepared by means of the processes shown 
in Scheme 1. 
Scheme 1 
##STR4## 
For the two processes of Schemes 1, R.sup.1 through R.sup.6 and n are as 
defined hereinabove. The reagent Y-X represents an organic leaving group 
reagent wherein X is the leaving group fragment such as tosyl, mesyl, 
halide, sulfate, phosphate and so forth; and Y is either a proton or a 
counter ion; e.g. Y-X can be HBr or tosyl chloride and the like. "Hydride 
reduction" concerns intended reductive amination of compound II by III, 
particularly the reduction of the initial complex of compound II and III 
to provide product I. Preferred reagents for this use in Process #1 are 
B.sub.2 H.sub.6 and LAH or an equivalent. The reagents of Scheme I and 
their acronyms are familiar to the practitioner skilled in organic 
synthesis and their structure and usage would be readily understood. 
Process #1 in Scheme I comprises the combination of an indole carboxylic 
acid or ester of formula II with a pyrimidinylpiperazine intermediate of 
formula III followed by treatment with diborane, lithium aluminum hydride 
or an equivalent to give the product of formula I. 
Process #2 comprises reduction of the indole intermediate of formula II to 
the corresponding alcohol of formula VI which is converted to an activated 
intermediate of formula V in which the alcoholic moiety is now an organic 
leaving group. Reaction of intermediate V with a pyrimidinylpiperazine of 
formula II then provides product I. 
Reagents, solvents, and reaction conditions for the above described steps 
of the two processes would be known to one skilled in organic synthesis as 
all the steps comprise standard organic reactions, the details of which 
are readily available in the chemical literature. These processes may be 
adapted to variation in order to produce other compounds embraced by this 
invention but not specifically disclosed. Variations of the methods to 
produce the same compounds in somewhat different fashion will also be 
evident to one skilled in the art. 
To provide greater descriptive detail, representative synthetic examples 
are provided hereinbelow in the "Description of Specific Embodiments" 
section. Similarly, preparations of reaction starting materials and 
intermediates, while readily available in the chemical literature, are 
also described using specific examples in that section of the paten 
specification. 
The compounds comprising the present invention inhibit the re-uptake of 
endogenous serotonin. Selective inhibitors of serotonin uptake are 
effective for the treatment of mental depression and have been reported to 
be useful for treating chronic pain (see: R. W. Fuller, "Pharmacologic 
Modification of Serotonergic Function: Drugs for the Study and Treatment 
of Psychiatric and Other Disorders", J. Clin. Psychiatry 47:4 (Suppl.) 
April 1986, pp. 4-8). Compounds of the present invention are also 
envisioned to be useful in the following disorders: obsessive-compulsive 
disorder, feeding disorders, anxiety disorders and panic disorders. 
Additionally, selected compounds of the invention potently inhibit 
norepinephrine re-uptake and blockade of endogenous norepinephrine 
re-uptake is also a mechanism through which it is believed that various 
antidepressant agents exert their therapeutic effect (see: 
"Antidepressants: Neurochemical, Behavioral, and Clinical Perspectives", 
edited by S. J. Enna, J. B. Malick and E. Richardson, (1981), Raven Press, 
New York, pp. 1-12). 
Determination of endogenous monoaminergic re-uptake inhibition values both 
for serotonin and norepinephrine was accomplished using test methods 
described by P. Skolnick, et al., Br. J. Pharmacology (1985), 86, pp. 
637-644; with only minor modifications. In vitro IC.sub.50 (nM) test 
values were determined for representative compounds of Formula I based on 
their inhibition of synaptosomal reuptake of tritiated serotonin. Test 
data IC.sub.50 values lower than 500 nM are considered to reflect activity 
as an inhibitor of serotonin reuptake. Compounds with Ic.sub.50 values 
lower than 100 nM comprise preferred compounds. 
Another aspect of the instant invention provides a method for treating a 
mammal afflicted with depression or chronic pain which comprises 
administering systemically to said mammal a therapeutically effective 
amount of a compound of Formula I or a pharmaceutically acceptable acid 
addition salt thereof. 
The administration and dosage regimen of compounds of Formula I is 
considered to be done in the same manner as for the reference compound 
fluoxetine, cf: Schatzberg, et al., J. Clin. Psychopharmacology 7/6 Suppl. 
(1987) pp. 44514 495, and references therein. Although the dosage and 
dosage regimen must in each case be carefully adjusted, utilizing sound 
professional judgment and considering the age, weight and condition of the 
recipient, the route of administration and the nature and gravity of the 
illness, generally the daily dose will be from about 0.05 to about 10 
mg/kg, preferably 0.1 to 2 mg/kg, when administered parenterally and from 
about 1 to about 50 mg/kg, preferably about 5 to 20 mg/kg, when 
administered orally. In some instances, a sufficient therapeutic effect 
can be obtained at lower doses while in others, larger doses will be 
required. Systemic administration refers to oral, rectal and parenteral 
(i.e. intramuscular, intravenous and subcutaneous). Generally, it will be 
found that when a compound of the present invention is administered 
orally, a larger quantity of the active agent is required to produce the 
same effect as a similar quantity given parenterally. In accordance with 
good clinical practice, it is preferred to administer the instant 
compounds at a concentration level that will produce effective 
antidepressant effects without causing any harmful or untoward side 
effects. 
The compounds of the present invention may be administered for 
antidepressant purposes either as individual therapeutic agents or as 
mixtures with other therapeutic agents. Therapeutically, they are 
generally given as pharmaceutical compositions comprised of an 
antidepressant amount of a compound of Formula I or a pharmaceutically 
acceptable salt thereof and a pharmaceutically acceptable carrier. 
Pharmaceutical compositions which provide from about 1 to 500 mg of the 
active ingredient per unit dose are preferred and are conventionally 
prepared as tablets, lozenges, capsules, powders, aqueous or oily 
suspensions, syrups, elixirs, and aqueous solutions. 
The nature of the pharmaceutical composition employed will, of course, 
depend on the desired route of administration. For example, oral 
compositions may be in the form of tablets o capsules and may contain 
conventional excipients such as binding agents (e.g. starch) and wetting 
agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula 
I compound with conventional pharmaceutical vehicles are employed for 
parenteral compositions such as an aqueous solution for intravenous 
injection or an oily suspension for intramuscular injection.