Certain aminoalkyl derivatives of naphthyl-piperidines and tetrahydro-pyridines of Formula (I) are useful antidepressant agents. ##STR1## The symbol (Aryl) denotes phenyl, naphthyl, pyridinyl, pyrimidinyl and pyrazinyl ring systems with n being an integer of 2-4.

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 4-(1-naphthyl)-piperidines and 
tetrahydropyridines with substituted aryl or hetarylaminoalkyl moieties 
attached at the N-1 position of the monazine. These compounds inhibit the 
reuptake of serotonin and potently bind at 5-HT.sub.1A, 5-HT.sub.1D and 
5-HT.sub.2 receptor sites. This pharmacology renders the compounds useful 
in treating depression. In addition, these compounds have reduced 
dopaminergic and .alpha.-adrenergic binding activities compared to diazine 
analogs such as piperazines. 
Simple naphthylalkylamines and naphthylpiperazines have been reported to 
bind at 5-HT.sub.1D receptor sites. (See: Glennon, et al., Drug 
Development Research, 22:25-36 (1991).) 
Chenard, et al., WO 94 121619 disclosed a series of 1,7-disubstituted 
naphthalene derivatives (1) claimed to have, inter alia, antidepressant 
action. The central heterocyclic ring in (1) was 
##STR2## 
piperazine, dihydropyridine or piperidine while R.sup.3 was hydrogen, 
alkyl, alkoxyalkyl, aryl or arylalkyl. 
The most relevant art appears to be a series of U.S. patents to Lavielle, 
et al., that disclose and claim an extensive series of 5-HT.sub.1A 
agonists (2) that are disclosed as being useful in treating a variety of 
disorders including depression. 
##STR3## 
Lavielle, et al., discloses naphthylpiperidine (U.S. Pat. No. 5,250,544); 
naphthyl tetrahydropyridine (U.S. Pat. No. 5,292,711); and naphthyl 
piperazine (U.S. Pat. No. 5,166,156) analogs of (2), wherein B is an 
amido, sulfonamido, imido or phthalimido moiety. Also disclosed as 
synthetic intermediates are compounds wherein B is --CN and --NH.sub.2. 
Of less interest are the series of compounds of Tran, et al., WO 94 02473, 
wherein piperazine amides (3) were disclosed as having, inter alia, 
antidepressant properties. 
##STR4## 
In (3), A is either --NHCO-- or --CONH--. 
Similarly, Perrone, et al., WO 94 00441 disclose piperazine derivatives (4) 
having antidepressant action among other biological activities. 
##STR5## 
A in (4) is either --NH(CH.sub.2)n-- or --(CH.sub.2)n--. 
The foregoing references do not teach nor suggest the specific combination 
of structural variations leading to the novel secondary and tertiary 
aminoalkyl derivatives of 4-(1-naphthyl)-tetrahydropyridines and 
piperidines which not only possess specific 5-HT binding properties but 
also inhibit 5-HT reuptake. The added advantage of reduced dopaminergic 
and .alpha.-adrenergic activities make the instant compounds superior 
antidepressant agents. 
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION 
The present invention relates to novel secondary and tertiary aminoalkyl 
derivatives of 4-(1-naphthyl)-tetrahydropyridines and piperidines; their 
therapeutic use as specific serotonin receptor binders and serotonin 
reuptake inhibitors, particularly for treatment of depression with reduced 
side-effect potential; and their pharmaceutical compositions. 
In a broad aspect, the present invention concerns compounds of Formula (I) 
having potent inhibition of serotonin reuptake and specific binding 
properties at certain 5-HT receptors. In addition, these compounds possess 
reduced dopaminergic and .alpha.-adrenergic activities, thereby imbuing 
them with a reduced potential for unwanted side-effects. 
In Formula (I), 
##STR6## 
R.sup.1 is hydrogen, lower alkyl, lower alkoxy, and halogen. The symbol n 
is an integer from 2 to 4. The solid and dotted lines denote either a 
single or a double covalent bond. 
R.sup.2 is hydrogen and lower alkyl and R.sup.3 is hydrogen, lower alkyl, 
lower alkoxy, halogen and trifluoromethyl. 
(Aryl) is selected from phenyl, naphthyl, pyridine, pyrimidine, and 
pyrazine. 
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 including optical 
isomers, e.g. mixtures of enantiomers as well as individual enantiomers 
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. 
The term "lower" refers to both straight and branched chain carbon radicals 
of from 1 to 4 carbon atoms inclusive. Illustrative of these radicals are 
carbon chains which can be methyl, ethyl, propyl, isopropyl, 1-butyl, 
1-methylpropyl, 2-methylpropyl. "Halogen" is fluorine, chlorine, bromine, 
or iodine. 
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. They 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, fumaric, 
mandelic, phosphoric, nitric, mucic, isethionic, palmitic, heptanoic, and 
others. 
The compounds of Formula (I) and intermediate compounds can be prepared by 
adaptation of the synthetic processes shown in Schemes 1 and 2. In Scheme 
1, two general reactions are depicted. The symbols "R.sup.1, R.sup.2, 
R.sup.3, aryl, and n" are as defined supra. The monazine ring can be 
either a pipiradine or a tetrahydropyridine moiety. The symbol "X" denotes 
an organic synthetic leaving group such as a bromide, iodide, mesylate, 
tosylate and the like. Leaving groups (or nucleofuges) are well known to 
those skilled in synthetic organic chemistry. In reaction A, an amino 
intermediate of Formula (II) reacts with an electrophilic center in an 
aryl or hetaryl intermediate of Formula (III) to provide Formula (I) 
product. Reaction B shows the monazine intermediate of Formula (IV) 
undergoing nucleophilic displacement of X by compound (V) to also give a 
Formula (I) product. 
Scheme 2 depicts the synthesis of several intermediate compounds, e.g. 
(II), (IV), (VI) and (X). In addition to the symbols previously described, 
other symbols in Scheme 2 are: "PG" meaning a protective group that 
insulates a nucleophilic moiety, e.g. an amino or hydroxy group; from 
reaction. Again, protective groups and their use are well known to 
synthetic organic chemists. The reagent "XY" denotes a leaving group X and 
its counter ion such as a proton or a halogen ion, e.g. XY could be 
Br.sub.2, HBr, or tosyl bromide. Reaction A of Scheme 2 illustrates 
synthesis of the naphthylmonazine intermediates, either a 
tetrahydropyridine (XA) or piperidine (XB). 
Reduction of the tetrahydropyridine ring to a piperidine can also be done 
further downstream in the synthesis of Formula (I) product such as at the 
compound (VI) or (II) stage. 
Reaction sequence B shows the conversion of intermediate (X) to either the 
intermediate alcohol compound (VI) or the primary amine intermediate (IIA) 
via a Gabriel synthesis-type process. 
Reaction sequence C illustrates the preparation of intermediates (IV) and 
(IIB) (R.sup.2 is lower alkyl) from the alcohol compound (VI). These 
reactions and their application to ultimately arrive at the novel Formula 
(I) compound of this invention would be familiar to a practitioner skilled 
in organic chemical synthesis. Modifications of conditions and reagents to 
adapt these processes for preparation of specific Formula (I) compounds, 
including compounds embraced by this invention but not specifically 
disclosed, would be known to the skilled organic chemist. 
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 detail in description, representative synthetic examples 
are provided infra in the "Specific Embodiments" section. 
The compounds of Formula (I) show potent inhibition of 5-HT re-uptake and 
can be envisioned as potential agents for disorders associated with 
dysfunction in serotonergic neurotransmission. Such disorders may include 
depression, anxiety, eating disorders, obesity, and drug abuse. In 
particular, the active compounds of the instant series are envisioned as 
specific agents for treating depression. 
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. 
As a further indication of clinical antidepressant utility, the present 
series of compounds also demonstrate good 5-HT.sub.1A, 5-HT.sub.1D, and 
5HT-.sub.2, binding activity. Side-effect potential in putative 
antidepressant agents can be ascertained by examination of the affinity of 
the agents for dopaminergic and adrenergic receptors. In the case of the 
instant compounds, these binding affinities are diminished. 
Determination of endogenous monoaminergic re-uptake inhibition values for 
serotonin 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 re-uptake of tritiated serotonin. Test data IC.sub.50 values 
lower than 500 nM are considered to reflect activity as an inhibitor of 
serotonin re-uptake. Compounds with IC.sub.50 values lower than 100 nM 
comprise preferred compounds and those with IC.sub.50 value less than 10 
nM are most preferred. 
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. 4451-4495, and references therein. Although the dosage and 
dosage regimen must in each case be carefully adjusted, utilizing sound 
professional judgement 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 1 mg/kg, when administered parenterally and from 
about 0.5 to about 10 mg/kg, preferably about 1 to 5 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, transdermal 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 or 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. 
DESCRIPTION OF SPECIFIC EMBODIMENTS 
The compounds which constitute this invention, their methods of preparation 
and their biologic actions will appear more fully from consideration of 
the following examples, which are given for the purpose of illustration 
only and are not to be construed as limiting the invention in sphere or 
scope. In the following examples, used to illustrate the foregoing 
synthetic processes, temperatures are expressed in degrees Celsius and 
melting points are uncorrected. The nuclear magnetic resonance (NMR) 
spectral characteristics refer to chemical shifts (.delta.) expressed as 
parts per million (ppm) versus tetramethylsilane (TMS) as reference 
standard. The relative area reported for the various shifts in the .sup.1 
H NMR spectral data corresponds to the number of hydrogen atoms of a 
particular functional type in the molecule. The nature of the shifts as to 
multiplicity is reported as broad singlet (bs), singlet (s), muitiplet 
(m), heptet (hept), quartet (q), triplet (t) or doublet (d). Abbreviations 
employed are DMSO-d.sub.6 (deuterodimethylsulfoxide), CDCl.sub.3 
(deuterochloroform) and are otherwise conventional. The infrared (IR) 
spectral descriptions include only absorption wave numbers (cm.sup.-1). 
Analytical thin-layer chromatography (TLC) was performed on 0.25 mm EM 
silica gel 60 F-254 coated glass plates and preparative flash 
chromatography was performed on EM silica gel (36-62 .mu.m). The solvent 
systems used are reported where appropriate. All reaction, extraction and 
chromatography solvents were reagent grade and used without further 
purification except tetrahydrofuran (THF) which was distilled from 
sodium/benzophenone ketyl. All non-aqueous reactions were carried out in 
flame-dried glassware under a nitrogen atmosphere. 
A. SYNTHESIS OF INTERMEDIATES 
Compounds of Formula (X)