CA1337421C - 1-indolylalkyl-4-(substituted-pyridinyl)piperazines - Google Patents

Abstract

A series of 1,4-disubstituted piperazine derivatives comprised of indol-3-ylalkyl and substituted pyridin-2-yl substituent groups. These compounds are useful as anti-depressant agents. The compounds more particularly are of the formula wherein R1 and R2 are independently selected from hydrogen and lower alkyl, wherein lower means C1-4;
R3, R4, R8 and R9 are independently selected from hydrogen, lower alkyl, lower alkoxy, carboxamide, halogen, trifluoromethyl and thio-lower alkyl, with the proviso that R8 and R9 cannot both be hydrogen at the same time;
A is a C5-7 cycloalkanyl or cycloalkenyl ring, or A is

Description

t 33 74 2 ~ CT-1916 A

l-Indolylalkyl-4-(Substituted-Pyridinyl)Piperazines Back~round 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 l,4-disubstituted piperazine derivatives wherein one substituent is indol-3-yl-alkyl and the other is a substituted pyridin-2-yl moiety. These compounds possess a unique serotonergic profile that should make them usefu~ in treatment of depression.
Archer disclosed a large series of CNS-depressant indolylalkylpiperazines in U.S. 3,188,313 which issued June 8, 1965. Among the large number of moieties listed for possible substituent selection on the 4-nitrogen atom of the ~piperazine ring was pyridyl (unsubstituted). ~n U.S.
3,562,278, issued February 9, 1971, Archer claimed a series of l-(indol-3-ylethyl)-4-substituted-piperazines having psychomotor depressant activity. Among the possible 4-sub~tituents listed was pyridyl, again unsubstituted.
~'~ Of less relevance is U.S. 3,472,855, issued October 1969 to Archer, which discloses extension of the series to benz[glindolyl moieties as replacements for indolyl.
Similarly less relevant is U.S. 4,302,589, issued November 1981 to Fanshawe, et al., which discloses a series ~S Of related compounds wherein indoline has replaced the indole moiety. These compounds were disclosed as having antipsychotic properties.
None of the aforementioned references disclose or suggest the l-indolylalkyl-4-(substituted-pyridinyl)--,~ piperazine derivatives and their antidepressant utility of the present invention.

- 1- ~

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. R6 j~R

In Formula I; R1 and R2 are independently selected from hydrogen or lower alkyl. The descriptive term "lower" is used herein to denote an organic radical containing from 1 to 4 carbon atoms. The symbol6 R3, R4, R8 and R9 refer to moieties which are independently selected from among hydrogen, lower alkyl, lower alkoxy, carboxamide, halogen, trifluoromethyl, and thio-lower alkyl; with the proviso that both R8 and R9 cannot be hydrogen at the same time.
The symbol A represents a cycloalkanyl or cycloalkenyl ring comprised of from 5 to 7 carbon atoms. These bridging rings may be 1,2-; 1,3-; or 1,4-disubstituted bridging cycloalkanes or cycloalkenes. In the cycloalkenyl ring the double bond i6 adjacent to the point of attachment of the 3-indolyl ring. The symbol A can also be the ~tructural fragment: -(CH2)n-CH-. In this fragment linking the indole and piperazine rings, n is an integer from 1 to 3 and R can be either hydrogen or lower alkyl. The carbon atom to which R5 i~ attached is adjacent to the piperazine ring.

1 ~37421 CT-1916A

Lastly, R6 and R7 are independently selected from hydrogen or methyl, or R6 and R7 can be taken together as a methylene bridge. Subclasses of compounds envisioned would be: A is cyclic or linear in structure; the piperazine ring is bridged or unbridged. Preferred classes of compounds are those wherein the indolyl and piperazinyl rings are connected by a 2 or 3 carbon linking chain and wherein R9 is other than hydroqen and is attached to the 6-position of the 2-pyridinyl ring.
Additionally compounds of Formula I also encompass all pharmaceutically acceptable acid addition salts and/or 601vates thereof. The present invention is also considered to include stereoisomers as well as optical isomer6, e.g.
mixtures of enantiomer6 as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers i8 accomplished by application of various methods which are well known to practitioner6 in the art.
It i6 to be under6tood that, as used herein, halogen denotes fluorine, chlorine, bromine and iodine; with the term "lower alkyl" referring to both straight and branched chain carbon radical6 of from 1 to 4 carbon atoms inclusive.
Illustrative of these radicals are carbon chains which can be methyl, ethyl, propyl, isopropyl, l-butyl, l-methylpropyl and 2-methylpropyl. Carboxamide intends a -CNH2 radical.
The pharmaceutically acceptable acid addition salts of the invention are tho6e in which the counter-ion does not contribute significantly to the toxicity or pharmacological activity of the salt snd, as such, they are the pharmaco-logical equivalents of the bases of Formula I. They are generally preferred for medical usage. In some instance6, ~ 33742 l CT-1916 A

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 treat-ment 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, hydro-chloric, 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 Prc>cesS ~1 R~
R3 (C~2 ~n~C2u R3 (CH2~n~~HOH

7~ 1) R5~ R~

(II) ~VI) ~Y-x H~--\~ RS

(V~

Prc?cess ~2 R~ ~ IV

l~?

1 3~ 742 1 CT-1916 A

Scheme 1 ( ccntinued ~rocess ~3 A. R6 III)1) 'ri(O-iPr)y ~ ,CH2.~ R~
(~2C)~-/~cH2~2) h'aBH~ tClH ~0 ~CHz~ \~ N~Rq Il , ~
~X) ~X~ /
, 3 o+

R3 R6 ~ 2 ) ~;aOH

R~
(VII) 1tohOI (VI I I
catalyst ~C~2)r r \ ~ ~q R3 ~(CH2) R~2 ~ Ib) ~t "t ~6 ~q 3 ,~

R~ ~ (Ic) Scheme 1 ( continued ) Proce ~ ~; #3 B.

V 1 I I ~ X ~ I c oho 1 R
X J ~

1 ) 10~ Pdf C, H2 . a I c oho I
2) .~2-T~OU
ac Qton~ fH20 R3 /--7~C
Ic l l l ~J

1) ;i~O-iPr~, R~l \Rl Xl Z ) E tOH~c ~anoboroh~dr i de For the three processes depicted in Scheme l; Rl through R , and n are as defined hereinabove. Additional symbols appearing in Scheme 1 are f, g, M, X and Y. The 8ymbols f and g are integers from 0 to 5 with the proviso that f~g must be equal to 3, 4 or 5. M represents a metalloid species such as magnesium, lithioaluminum, and the like; which, taken with R5 are either hydride-type reducing agents such as lithium aluminum hyride~, diborane complexes, etc.; or organometallic alkylating agents such as Grignard reagents, etc. 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 ~o forth; and Y is either a proton or a counter ion: e.g. XY can be HBr or tosyl chloride and the like. These reagents, symbolized by R5-M and Y-X, as well as other reagent acronyms, are familiar to the practitioner skilled in organic synthesis and their structure and usage would be readily understood.

Process #1 in Scheme 1 comprises the following steps:
1) Treatment of an indole carboxylic acid II with R5-M, which is either a hyride reducing agent or alkylating agent depending on the selection of R5 (hydrogen or lower alkyl~. Thi6 results in generation of the indolylalkanol VI which is a secondary alcohol when R5 is lower alkyl and a primary alcohol when R5 is hydrogen.
2) Conversion of the alcohol VI to an organic leaving group (also referred to as a nucleofuge in ~ynthetic organic reaction terminology) by use of an appropriate Y-X reagent such as HBr or to~yl chloride to give intermediatc V.
- 3) Displacement of the leaving group anion by the nucleophilic pyridinylpiperazine III to provide the desired product of formula Ia.

~ 337q2 ~ CT-1916A

Process #2 in Scheme 1 comprises a two-step reaction fiequence:
1) Condensation of the indolylcarboxylic acid II with the pyridinylpiperazine III, using standard condensation agents such as acid chlorides, acid anhydrides, dicyclohexylcarbodiimide, and the like, to afford the amide intermediate IV.
2) Treatment of the amide IV with R5-M to reductively alkylate or reduce to the desired formula Ia product.

Process #3 in Scheme 1 comprises the following sequence of steps:
A.
1) The pyridinylpiperazine III is reductively alkylated with a cycloalkanedione mono-ethylene ketal X to give the ketal intermediate IX.
2) Deprotecting the ketal IX to produce the cycloalkanone intermediate VIII.
3) Condensing the cycloalkanone VIII with indole VII to yield the cycloalkenyl product Ib which can be catalytically reduced to the cycloalkanyl product Ic if desired.
B.
1) The indole VII, cycloalkanedione mono-ethylene ketal X, and an acid or base catalyst (e.g. pyrrolidine) are refluxed in alcohol to give the condensation product XII.
2) Intermediate XII i~ catalytically reduced to the saturated cycloalkane ketal which is deketalized to the cycloalkanone intermediate XI.
3) Cycloalkanone XI i~ condensed with the pyridinyl-piperazine III using condition~ as shown to yield product Ic.

t 33742 1 Reagents, solvents, and reaction conditions for the above described steps of the three processes would be known to one skilled in organic synthesi6 as all the 6teps 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 6killed in the art. As example of this, VI intermediate compounds wherein n is 1 are conveniently prepared by treating various substituted 3-indoleglyoxylic acid esters with LiAlH4.
To provide greater descriptive detail, representative synthetic examples are provided hereinbelow in the "Description of Specific Embodiments" 6ection. Similarly, preparations of starting intermediate compounds such as II and III, while readily available in the chemical literature, are also described using specific examples in that section of the patent specification.
The compounds comprising the present invention inhibit the re-uptake of endogenous 6erotonin. 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, "Pharmocologic 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 envi6ioned to be useful in the following disorders: obsessive-compulsive disorder, feeding disorderE, anxiety disorder6 and panic disorder6.
Additionally, selected compounds of the invention potently inhibit norepinephrine re-uptake and blockade of endogenou~ norepinephrine re-uptake i8 al60 a mechani6m ~ 337~ i through which it is believed that various antidepressant agents exert their therapeutic effect (see: "Antidepressants:
Neurochemical, Behavioral, and Clinical Perspectivesn, 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. Pharmacoloqy (1985), 86, pp. 637-644; with only minor modifications. In vitro IC50 ~nM) test values were determined for representative compounds of Formula I based on their inhibition of synaptosomal reuptake of tritiated serotonin. Test data IC50 values lower than 500nM are considered to reflect activity as an inhibitor of serotonin reuptake. Compounds with Ic50 values lower than lOOnM
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 6alt 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. 445-495, 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, generalIy the daily dose will be from about 0.05 to about 10 mg/Xg, preferably 0.1 to 2 mg/kg, when administered parenterally and from about 1 to about 50 mg/kg, preferably about 5 to 20 1 33 742 i mg/kg, when administered orally. In some instances, a ~ufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be reguired. 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 guantity given parenterally. In accordance with good clinical practice, it i8 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 6alt 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 a~ tablets, lozenges, capsules, powders, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions.
The nature of the pharmaceutical compo~ition 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). Solution~ or suspensions of a Formula I compound with conventlonal pharmaceutical vehicles are employed for parenteral ~ ~3~4~ ~

composition~ such a6 an aqueou~ solution for $ntravenous inje~tion or an oily su~pension for intramu6cular injection.

Description of Specific Embodiment~
The compounds which constitute this invention, their methods of preparation and their biologic actions will appear more fully from considerati~n of the following examples, which are given for the purpose of illustration only and are not 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 Celsiu6 and melting points are uncorr~cted. The nuclear magnetic resonances (NMR) 6pectral characteristics refer to chemical shift6 (~) expressed as parts per million (ppm) versus tetramethyl6ilane (TMS) as reference standard. The relative area reported for the various 6hift6 in the H NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the Ehifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m) or doublet (d). Abbreviation6 employed are DMS0-d6 (deuterodimethyl6ulfoxide), CDC13 (deuterochloroform) and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm 1) having functional group identification value. The IR
determinations were employed using pota6sium bromide (KBr) as diluent. The elemental analyse6 are reported as percent by weight and are given in Table 3.
The following example6 describe in detail the preparation of compounds of Formula I, as well as synthetic ~ntermediate~ in each process. It will be apparent to tho~e skilled in the art that modifications, both of materials and methods, will allow preparation of other compounds disclosed herein. From the oregoing description and the following 1 337~2 i CT-l9l6A

examples it is believed that one skilled in the art is able to use the invention to the fullest extent.

A. Preparation of Intermediate Compounds Some representative procedures for preparation of synthetic intermediate compounds utilized in the three processes of Scheme 1 are given hereinbelow. Most starting materials and certain intermediates (e.g. Formula II and VII
compounds), are either commercially available or procedures for their synthesis are readily available in the chemical literature allowing their full utilization by one skilled in the art of organic synthetic chemistry.

Compounds of Formula III

Example 1 1-(3-Methoxy-2-pyridinyl)piperazine To a stirred mixture of 2-bromo-3-pyridinol (71.0 g) and pulverized KOH (77.8 g) in DMSO (500 mL) at 55-60C and under N2 atmosphere was added dropwise a solution of CH3I
(72.4 g) in DMSO (100 mL). After the addition was complete, the reaction was maintained at 55-60C for ~ h. The mixture was then poured into ice water (800 g) and the precipitate filtered. The precipitate was triturated with Et20 (3 x 500 mL) and the combined extracts treated in turn with 1 N NaOH
(500 mL), water (500 mL), 1 N HCl (3 x 250 mL), and sat.
NaCl solution (500 mL). The organic phase was dried with anhydrous MgS04, filtered, and concentrated under reduced pressure to afford 2-bromo-3-methoxypyridine (52.3 g; 68%).

1 337~2 i CT l9l6A

Anhydrous piperazine (45.6 g) and 2-bromo-3-methoxy-pyridine ~10.0 g) were heated neat in an autoclave at 100C
for 20 h. Upon cooling, the mixture was treated with 5%
NaC03 (20 mL) and extracted with CH2C12 (3 x 50 mL). The extracts were dried using anhydrous K2C03, filtered, and concentrated under reduced pres~ure to yield l-(3-methoxy-2-pyridinyl)piperazine (III; 8.43 g; 82%) after silica gel chromatography (CH2C12/MeOH/NH40H; 93:7:0.7).

Example 2 1-(3-Trifluoromethyl-2-pyridinyl)piperazine A mixture of 2-chloro-3-trifluoromethyl pyridine (5.0 g), anhydrous piperazine (7.22 g), and micropulverized anhydrous K2C03 (7.73 g) in acetonitrile (50 mLj was heated at reflux with ~tirring while under N2 atmosphere for 20 h.
The excess acetonitrile was removed under reduced pres~ure and water (15 mL) added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 50 mL). The com~ined CH2C12 extracts were washed with ~at. NaCl ~olution, dried with anhydrous MgS04, and concentrated under reduced pressure. Silica gel chromatography (CH2C12/MeOH/NH40H;
94:6:0.6) of the residue yielded 1-(3-trifluoromethyl-2-pyridinyl)piperazine (III; 5.50 g; 85X).

Example 3 1-(6-Methoxy-2-pyridinyl)piperazine A mixture of 1-(6-chloro-2-pyridinyl)piperazlne (6.0 g) and NaOMe (16.42 g) in DMF (25 mL) was heated at 100C
under nitrogen atmosphere for 20 h. The exces~ DMF wa~
then removed under reduced pressure. Water (5 mL) was added 3 ` 4, 1 CT 1 9 1 6 A

to the residue and the mixture extracted with CH2C12. The combined organic layers were washed with sat. NaCl solution, dried with anhydrous MgS04, filtered and concentrated under reduced pressure. Silica gel chromatography (CH2C12/MeOH;
98:2) of the concentrate yielded the 4-(6-methoxy-2-pyridinyl)-l-piperazinecarboxaldehyde (5.13 g; 81%).
A mixture of the formamide intermediate, prepared above, (3.55 g) in 6 N HCl (30 mL) was heated at reflux for h. The reaction was cooled to 0C, made basic with 10 N
NaOH, and extracted with CH2C12 (3 x 50 mL). The combined organic layers were washed with sat. NaCl solution, dried with anhydrous K2C03, filtered, and concentrated under reduced pressure to afford 1-(6-methoxy-2-pyridinyl)piperazine (2.72 g; 83%).

Example 4 1-(6-Chloro-2-pyridinyl)piperazine A mixture of 2,6-dichloropyridine (4.0 g), anhydrous piperazine (6.97 g), and micropulverized anhydrous K2C03 (7.45 g) in acetonitrile (50 ml) was heated at reflux with stirring while under N2 atmosphere for 20 h. The excess acetonitrile was removed under reduced pressure and water (15 mL) added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with sat. NaCl solution, dried with anhydrous MgS04, and concentrated under reduced pressure.
Silica gel chromatography (CH2C12/MeOH/NH40H; 94:6:0.6) of the residue yielded 1-(6-chloro-2-pyridinyl)piperazine (4.80 g; 90%).

1 ~ 3 7 4 ~ ~ CT-1916A

Example 5 2-(3-Methoxy-2-pyridinyl)-(15~45)-2~5-diazabicYclo[2.2~l]
heptane A. Preparation of (15,45)-N-Benzyl-2~5-diazabicyclo-12.2.11heptane (cf: J. Org. Chem. (1966), 31, 1059-1062) 1) N-Tosylhydroxy-L-proline To a solution of hydroxy-L-proline (80 g) in 2N NaOH (800 mL) was added tosyl chloride (136.1 g) in Et2O (700 mL). The reaction mixture was stirred at 0C
for 1~ h and continued for an additional 3~ h at 23C.
The aqueous layer was separated, acidified with concen-trated HCl to pH 1 and allowed to stand at -10C for 12 h. The precipitate was filtered, washed with cold water, and concentrated in vacuo to a volume of 300 mL.
The precipitate obtained was combined with the previous precipitate. The combined solids were recrystallized from ethyl acetate. Drying in vacuo at 50C for 24 h afforded trans-4-hydroxy-1-(4-toluenesulfonyl)-L-proline (107.38 g, 62%).

2) Potassium salt of trans-4-hydroxy-1-(4-toluene-sulfonyl)-L-proline To a solution of trans-4-hydroxy-1-(4-toluene-sulfonyl)-L-proline (107.38 g) in acetone (450 mL) was added potassium 2-ethyl hexanoate in BuOH (1.91 N; 189.5 mL). After standing at 23C for 20 min, the insoluble material was filtered and the re~ulting solution was concentrated to 320 mL. Et2O (1000 mL) was added to the concentrate and the solvents removed under reduced pressure yielding a solid (122.90 g). The hygro~copic product was used in the next ~tep without further purification.

t 337421 3) N-Tosylhydroxy-L-proline methyl e~ter To a solution of potas~ium trans-4-hydroxy-1-(4-toluenesulfonyl)-L-proline (122.90 g) in 250 mL of N,N-dimethylacetamide was added methyl iodide (24.5 mL) while under nitrogen atmosphere. The light protected mixture was stirred 16 h. The mixture was poured onto ice water and extracted with CH2C12 (3 x 400 mL). The combined organic extracts were washed with 2% NaHC03 (400 mL), H20 (4 x 1.5 L), dried over MgS04, filtered, and concentrated under reduced pressure to leave a viscous oil. The crude oil was triturated within petroleum ether to give N-tosylhydroxy-L-proline methyl ester as a pale yellow solid (63.20 g, 56.2%) which was used in the next step without further purification.

4) (2S,4R)-1-(4-toluenesulfonyl)-2-hydroxymethyl-4-hydroxy pyrrolidine To a solution of N-tosylhydroxy-L-proline methyl ester (62.20 g, 0.21 mol) in THF (600 mL) at O C
was added LiSHy (15.8g, 0.73 mol) in small portions.
The reaction mixture was stirred at O C for lh and allowed to stand at 23 C for 18h. The reaction mixture was cooled to -20 C, made neutral with 6N HC1, and concentrated under reduced pressure. The residue was treated with water (550 mL) and extracted with EtOAc (4 x 300 mL). The combined organic extracts were washed with H20, dried over MgS04, filtered, and concentrated under reduced pressure to give N-tosylhydroxy-L-prolinol as a white solid (50.56 g, 88.8%) which was used in the next step without further purification.

5) (25,4R)-1-(4-toluenesulfonyl)-2-(4-toluene-fonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine To a 601ution of D-toluenesulfonyl chloride (155 g) in pyridine (330 mL) at 0C was added N-tosylhydroxy-L-Prlinl (104.40 g). The reaction mixture was kept at 6C for 72 h and then poured into cold 2N HCl (2.5 L). The aqueous layer was extracted with CH2C12 (3 x 1000 mL). The combined organic extracts were dried over MgS04, filtered, and concentrated under reduced pressure to give an oil. The oil was triturated with EtOH and the solid that formed was collected by filtration. The crude produc~ was recrystallized from EtOH (3.5 L) to give tritosylhydroxy-L-prolinol (99.87 g, 44.2%, m.p. 130-132C, I~]D24=-57.1, c=1.2, acetone).

6) (lS,4S)-2-(4-toluenesulfonyl)-5-phenylmethyl-2,5-diazabicyclol2.2.1]heptane To a suspension of tritosylhydroxy-L-prolinol (98.87 g) in toluene (350 mL) was added benzylamine (54.83 g).
The resulting mixture was heated at reflux for 18 h and allowed to cool to 23C. The reaction mixture was filtered and the 601vent removed under reduced pressure.
The residue was triturated with ethanol and the solid that formed was collected by filtration to give (lS,4S)-2-(4-toluenesulfonyl)-5-phenylmethyl-2,5-diazabicyclo-heptane (54.18 g, 93.2%) which was used in the next step without further purification.

7) (lS, 4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide A mixture of (lS,4S)-2-(4-toluenesulfonyl)-5-phenyl-methyl-2,5-diazabicyclo[2.2.1]heptane (54.0 g) in acetic acid (830 mL) containing hydrobromic acid (30% wt) was heated at 70C for 18 h. The reaction mixture was allowed to cool and concentrated under reduced pressure to a final volumen of ca. 300 mL. The precipitate that formed was filtered and washed with acetone to give (lS,4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane (50.30 g 91.3%, m.p. 272-275C).

1 ~3742 1 By adjusting the starting materials and using the foregoing synthetic scheme the other isomer, (lR,4R)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane can be obtained (cf: J. Org. Chem. (1981), 46 2954-2960).

B. 2-(3-methoxy-2-pyridinyl)-(lS,4S)-2,5-diazabicYclo-[2.2.1]heptane 1) 2-(3-methoxy-2-pyridinyl)-5-phenylmethyl-(lS,4S)-2,5-diazabicyclo[2.2.1]heptane A mixture of 2-bromo-3-methoxy pyridine (9.9 g) and (lS,4S)-N-benzyl-2,5-diazabicyclo[2.2.1]heptane (10.9 g) was heated at 100C in a Parr 7 bomb for 67 h. The reaction mixture was cooled to 23C, dissolved in CH2C12, extracted with 5% NaHC03, and finally with H20. The organic layer was dried over K2C03, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (CH2C12:MeOH; 96:4) to give the desired product (7.93 g, 51%).

2) 2-(3-methoxy-2-pyridinyl)-5-phenylmethyl-(lS,4S)-2,5-diazabicyclo[2.2.1]heptane (7.88 g) in EtOH (250 mL) was acidified to a pH of 1 with ethanolic HCl. The reaction mixture was treated with 5% palladium-on-carbon (2.05 g) and hydrogenated at 50 psi at 60C for 6 h. After this time, the heating was discontinued and the reaction mixture was allowed to cool to room temperature and the hydrogenation continued for 16 h. The reaction mixture was filtered through celite. The filtrate was concen-trated under reduced pressure and the residue was made alkaline by the addition of 5N NaOH. The solution was extracted with CH2C12 (4 x 250 mL) and combined CH2C12 extracts were dried over K2C03, filtered, and concen-trated under reduced pressure to give 2-(3-methoxy-2-I 7)37421 pyridinyl)-(lS,4S)-2,5-diazabicyclo[2.2.1]heptane (4.67 g; 85.2%).

Compounds of Formula IV

Example 6 1-[4-(lH-indol-3-yl)-1-oxobutyl]-4-(3-methoxy-2-pyridinyl)-piperazine To a mixture of 1-(3-methoxy-2-pyridinyl)piperazine (III; 1.28 g), 3-indolebutyric acid (1.08 g), and triethyl-amine (1.02 g) in CH2C12 (50 mL) was added 1-methyl-2-chloro-pyridinium iodide (1.62 g). The reaction was heated at reflux with stirring and under N2 atmosphere for 4 h. After cooling to ambient temperature, the solution was extracted with aqueous 5% HCl followed by aqueous 5% NaHC03. The organic phase was dried with anhydrous K2C03, filtered, and concentrated under reduced pressure. Silica gel chroma-tography (CH2C12/MeOH; 98:2) of the concentrate afforded the amide product (IV; 1.00 g; 50%).

Compounds of Formula V

Example 7 3-(3-bromopropyl)-lH-indole Phosphorus tribromide (17.4 g) in Et20 (30 mL) was added dropwise to a Et20 ~olution (100 mL) containing 3-(3-hydroxypropyl)indole (VI; 7.5 g) at 0C with stirring and under N2 atmosphere. After the addition was complete, the reaction was allowed to warm to 23C and continuously stirred for 16 h. At the end of this time, the reaction was cooled to 0C and ice (ca. 25 mL) added portionwi~e and stirred an additional 2 h. The organic phase was separated from the aqueous phase and the aqueous layer extracted with Et20. The combined organic phases were washed with sat.
NaCl ~olution, dried with MgS04, filtered, and concentrated under reduced pressure to afford 3-(3-bromopropyl)indole (V;
1.51 g; 15%).

Example 8 5-Fluoro-3-(2-bromoethyl)indole To a ~olution of 5-fluoro-3-(2-hydroxyethyl)indole (10.3 g, 0.056 mol) and CBr4 (24.8 g, 0.073 mol) in 100 mL
of dry acetonitrile at 0C under Ar was added a ~olution of triphenylphosphine (19.6 g, 0.073 mol) in 200 mL of dry acetonitrile. The mixture was stirred at 0C for 1 h and then at room temperature for 2 h. The resulting mixture was evaporated and the residue was chromatographed (SiO2/ethyl acetate-hexane = 1:4) to give the product (8.50 g, 61%) as a brown solid;

IR (neat) 3440 cm 1;

Hnmr (80 MHz, CDC13) ~ : 7.75 (br ~, lH), 7.15-6.57 (m, 4H), 3.53-3.32 (m, 2H), 3.17-2.94 (m,2H).

Compounds of Formula VI

Example 9 3-(3-hydroxypropyl~-lH-indole 3-(3-hydroxyprop~l)-1H-indole Into a suspension of LAH
(4.02 g, 0.106mmol) in anhydrous THF (150 mL) at 0 C was added dropwise indole-3-propanoic acid in THF (100 mL).
After the addition was complete, the reaction mixture was refluxed for 2 h. The cooled reaction mixture was quenched with H20 (4 mL), 15% NaOH (4 mL), followed by H20 (12 mL). The reaction was then allowed to warm to 23 C and stirred at this temperature for 18 h. The precipitate was filtered through a~celite pad and the filter cake was washed with THF. Combined washings were dried over MgS04, filtered and concentrated under reduced pressure to give the title compound. The product was used in the next step without further purification.

Example 10 3-(2-hydroxyethY~ H-indole To a stirred suspension of LiAlH4 (3.24 g) in THF (200 mL) at 0C and under N2 atmosphere was added dropwise a THF
solution (50 mL) containing indole-3-acetic acid (10.0 g).
After the addition was complete, the reaction was heated at reflux for 3 h, after which time the mixture was cooled to 0C and water (3.3 mL) added, followed by 15% NaOH (3.3 mL), and finally additional water (9.9 mL). The reaction was filtered and the filter cake washed with Et2O. The organic layers were combined, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure to yield 3-(2-hydroxyethyl)indole (VI; 7.4 g; 80X).

1 3374~ 1 Example 11 5-Floro-3-(2-hydroxyethyl)indole To a suspension of LiAlH4 (8.60 g, 0.23 mol) in 400 mL
of dry THF was added 5-fluoro-3-indoleglyoxylic acid ethyl ester (13.50 g, 0.057 mol) portionwi6e at room temperature.
Preparation of this ester intermediate is given hereinbelow.
The mixture was heated to reflux under Ar for 1 h and was then cooled at 0C and ~uenched according to the method of Fieser (Fieser and Fieser, "Reagent6 for Organic Synthesis", Vol. 1, pg. 584). The resulting slurry was filtered and the filter cake was washed with THF. The filtrate was dried (Na2SO4) and evaporated to give the product (10.00 g, 100%) as a yellow oil. It was used as such without further purification;

IR (neat) 3420 cm 1 Hnmr (80 MHz, CDC13) ~ : 7.73 (br 6, lH), 7.1-6.4 (m, 4H), 3.57 (t, J=8 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 1.20 (br 8, lH).

5-Fluoro-3-indoleqlyoxylic acid ethyl ester To a solution of 5-fluoroindole (7.35 g, 0.054 mol) in 75 mL of anhydrous ether was added oxalyl chloride (5.60 mL, 0.064 mol) dropwise at 0C under Ar.
The yellow suspension was stirred at 0C for 1~ h and then the solid was collected by filtration and dried in vacuo to give 5-fluoro-3-indoleglyoxylyl chloride (12.0 g, 100~) as a yellow solid; IR (neat) 1765, 1627 cm 1.

This solid was taken up in 160 mL of absolute ethanol and was then treated with triethylamine (8.1 mL, 0.058 mol) dropwise at 0C under Ar. The mixture was refluxed for 4~2 h and was then allowed to cool to room temperature. The resulting precipitate was iltered and then dried in vacuo to give the product (10.8 g, 87%) as a yellow solid which was used without further purification.

Compounds of Formula VIII

Example 12 ~4-(6-Chloro-2-pyridinyl)-l-Piperazinyl]-cyclohexan-l-one A solution of 4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-cyclohexan-l-one ethylene ketal (IX, Example 11: 7.56 g, 22 mmole) in 10% aqueous HCl (200 mL) was refluxed for 16 h.
The solution was cooled and then neutralized with 30%
aqueous NaOH solution. The mixture was then extracted with ethyl acetate (3 x 75 mL) and the extracts were dried over Na2C03. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate as the eluent to give the desired ketone product (VIII) as an oil (5.70 g, 92X).

Compounds of Formula IX

Example 13 4-[4-(6-Chloro-2-pyridinyl)-1-piperazinyl]-cyclohexan-1-one ethylene ketal A solution of 1-(6-chloro-2-pyridinyl)-piperazine (8.00 g, 40 mmole), 1,4-cyclohexanedione mono-ethylene ketal (6.25 g, 40 mmole), and titanium(IV) isopropoxide (15 mL, 14.21 g, 50 mmole) was heated to 80C for 30 min. The mixture was cooled and diluted with absolute ethanol (40 mL). Sodium borohydride (ten 0.4 g tablets, 0.1 mole) was added and the mixture was stirred for 4 h. Water (10 mL) was added to the solution with stirring and the solid titanium dioxide was filtered off. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (75 mL). The solution was again filtered and the filtrate concentrated in vacuo.
The residue was chromatographed on silica gel using ethyl acetate as the eluent to give the desired ketal product (IX) as an oil (7.56 g, 56%).

B. Preparation of Formula I Products By Process 1 (Ia Products) Example 14 4-~6-Chloro-2-pyridinyl]-1-l2-(lH-indol-3-yl)-ethyl]-piperazine hydrochloride A mixture of 3-(2-bromoethyl)indole (2.05 gj, 1-(6-chloro-2-pyridinyl)piperazine (3.61 g), micropulverized K2CO3 (2.52 g) and tetrabutylammonium hydrogen sulfate (0.16 g) in acetonitrile (25 mL) was heated at reflux under 1 3374~1 N2 atmosphere for 2~ h. The excess acetonitrile was removed under reduced pressure and water (15 mL) added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with sat. NaCl solution, dried with anhydrous K2C03, and concen-trated under reduced pressure. Silica gel chromatography (EtOAc/Hexanes; 70:30) of the residue yielded the free base (3.10 g; 99%) which was treated with ethanolic HCl to provide the desired Ia product (2.63 g; 77%).

Anal. Calcd. for ClgH21N4Cl-HCl:
C, 60.49; H, 5.88; H, 14.85 found: C, 60.27; H, 5.88; N, 14.66 NMR (DMSO-d6): 3.24 (8H, m); 3.72 (2H, m); 4.40 (2H, m); 6.81 (1, d, 7.4 Hz); 7.02 (3H, m); 7.25 (lH, d, 1.0 Hz);
7.39 (lH, m); 7.64 (2H, m); 10.85 (lH, bs); 10.98 (lH, bs).

IR (KBr): 750, 770, 960, 1140, 1270, 1420, 1460, 1550, 1600, 2440 and 3240 cm 1.

Example 15 ~[2-(lH-indol-3-yl)-ethYll-4-[6-trifluoromethyl-2 pyridinyl]piperazine hYdrochloride A mixture of 3-(1-bromoethyl)indole (1.12 g), 1-(6-tri-fluoromethyl-2-pyridinyl)piperazine (2.31 g), micropulverized K2C03 (1.38 g) and tetrabutylammonium hydrogen sulfate (0.08 g) in acetonitrile (50 mL) was heated at reflux under N2 atmosphere for 2~ h. The excess acetonitrile was removed under reduced pressure and water (10 mL) added to the concentrate. The aqueous phase wa~ extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with sat.

1 3 3 7 4 2 1 CT_1gl6A

NaCl 601ution, dried with anhydrous K2C03, and concentrated under reduced pre6~ure. Silica gel chromatography (CH2C12/MeOH; 98:2) of the residue yielded the free ba6e (1.56 g; 83%) which was treated with ethanolic ~Cl to yield the hydrochloride 6alt of the de~ired Ia product (1.17 g;
68%).

Anal. Calcd. for C20H21N4~3 H
C, 58.47; H, 5.40; N, 13.64 Found: C, 58.37; H, 5.38; N, 13.56.

NMR (DMS0-d6): 3.25 (8H, m); 3.72 (2H, d, 13.4 Hz);
4.48 (2H, d, 13.4 Hz); 7.10 (5H, m); 7.34 (lH, d, 7.0 Hz);
7.61 (lH, d, 7.0 Hz); 7.83 (lH, m); 10.60 (lH, bs); 10.95 (lH, b6).

IR (K~3r): 740, 800, 960, 1120, 1130, 1340, 1490, 1610, 2600, 2925 and 3250 cm 1.

Example 16 1-[2-(lH-indol-3-yl)-ethyl]-4-16-methoxy-2-pyridinyl]-PiperaZine hYdrate A mixture of 3-(2-bromoethyl)indole (1.66 g), 1-(6-methoxy-2-pyridinyl)piperazine (2.86 g), micropulverized K2C03 (2.04 g) and tetrabutylammonium hydrogen ~ulfate (0.13 g) in acetonitrile (50 mL) was heated at reflux under N2 atmosphere for 2 h. The excess acetonitrile was remo~ed under reduced pre66ure and water (10 mL) added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with sat. NaCl solution, dried with anhydrous K2C03, and concen-trated under reduced pre~sure. Silica gel chromatography ~ 3 3 7 4 2 1 CT_1916A

(CH2C12/MeOH; 96:4) of the residue yielded the free base of the desired Ia product (2.20 g; 89%).

Anal. Calcd- for C20H24N4 5 C2 6 2 C, 68.46; H, 7.66; N, 15.21; H20, 2.45 Found: C, 68.24; H, 7.59; N, lS.35; H20, 2.30.

NMR (CDC13): 2.70 (6H, m); 3.08 (2H, m); 3.61 (4H, m);
3.90 (3H, s); 6.11 (lH, d, 9.5 Hz); 6.20 (lH, d, 9.0 Hz);
7.12 (3H, m); 7.40 (2R, m); 7.68 (lH, m); 8.00 (lH, bs).

IR (KBr): 745, 790, 985, 1250, 1450, 1460, lS90, 2840, 3180 and 3550 cm 1 Example 17 1-[2-(lH-indol-3-yl)-ethyl]-4-[3-trifluoromethyl-2-pyridinyl]piperazine hydrochloride A mixture of 3-(2-bromoethyl)indole (1.79 g), 1-(3-trifluoromethyl-2-pyridinyl)piperazine (1.85 g), micro-pulverized K2C03 (2.21 g) and tetrabutylammonium hydrogen culfate (.014 g) in acetonitrile (50 mL) was heated at reflux under N2 atmosphere for 3 h. The excess acetonitrile was removed under reduced pressure and water (10 mL) added to the concentrate. The aqueou~ pha~e was extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with sat. NaCl solution, dried with anhydrous K2C03, and concentrated under reduced pressure. Silica gel chromatography (CH2C12/MeOH; 97:3) of the re~idue yielded the free base (1.66 g; 56%) which was treated with ethanolic HCl to yield the hydrochloride salt of the desired Ia product (1.45 g; 80X)-Anal. Calcd. for C20H21N4F3 H
C, 58.47; H, 5.40; N, 13.64 Found: C, 58.60; H, 5.43; N, 13.66.

NMR (DMSO-d6): 3.30 (lOH, m); 3.72 (2H, m); 7.08 (2H, m); 7.22 (lH, d, 4.9 Hz); 7.35 (2H, m); 7.66 (lH, m); 8.12 (lH, m); 8.60 (lH, m).

IR (KBr): 750, 1040, 1130, 1320, 1450, 1580, 1595, 2460, 2580 and 3230 cm 1.

Example 18 1-~2-(lH-indol-3-yl)-ethyl]-4-[3-methoxy-2-pyridinyl]-piperazine A mixture of 3-(2-bromoethyl)indole (2.00 g), 1-(3-methoxy-2-pyridinyl)piperazine (1.72 g), micropulverized K2C03 (2.46 g) and tetrabutylammonium hydrogen ~ulfate (0.15 g), in acetonitrile (50 mL) was heated at reflux under N2 atmosphere for 5 h. The exces~ acetonitrile was removed under reduced pressure and water (10 mL) was added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 50 mL). The combined CH2C12 extracts were washed with ~at. NaCl ~olution, dried with anhydrous K2C03, and concen-trated under reduced pressure. Silica gel chromatography (CH2C12/MeOH; 96:4) of the residue yielded the free base of the desired Ia product (1.32 g; 44X)-Anal. Calcd- for C20H24N40:
C, 71.41; H, 7.20; N, 16.66 Found: C, 71.34; H, 7.23; N, 16.55.

CT-l9l6A

NMR (CDC13): 2.80 (6H, m); 3.04 (2H, m); 3.55 (4H, m);
3.90 (3H, s); 6.86 (lH, dd, 4.8, 7.6 Hz); 7.14 (4H, m); 7.36 (lH, m); 7.66 (lH, m); 7.92 (lH, dd, 1.4, 4.8 Hz); 8.14 (lH, bs).

IR (film): 740, 1210, 1240, 1440, 1450, 1470, 1590, 2840, 2940, 3200 and 3450 cm 1.

Example 19 1-(6-Chloro-2-pyridinyl)-4-[3-(lH-indol-3-yl)propyl]-piperazine hydrochloride An acetonitrile solution (25 mL) containing 3-(3-bromo-propyl)indole (V; 1.51 g), 1-(6-chloro-2-pyridinyl)piperazine (III; 2.50 g), micropulverized K2C03 (1.75 g), and tetrabutyl-ammonium hydrogen sulfate was heated at reflux with stirring and under N2 atmosphere for 1 h. Excess acetonitrile was removed under reduced pressure and the remaining mixture was extracted with CH2C12. The solid residue was dissolved in water (10 mL) and extracted with CH2C12. The combined organic extracts were dried with anhydrous K2C03, filtered, and concentrated under reduced pressure to afford a vi~cous material. Silica gel chromatography (EtOAc/CH2C12; 4:1) yielded the free base (1.67 g; 74%) which was treated with ethanolic HCl to provide the hydrochloride salt of the desired Ia product (1.6 g; 87%).

Anal. Calcd. for C20H23ClN4-HCl:
C, 61.39; H, 6.19; N, 14.32 Found: C, 61.49, H, 6.24; N, 14.35.

NMR (DMSO-d6): 2.14 (2H, m); 2.80 (2H, t, 6.9 Hz);
3.18 (4H, m); 3.55 (4H, m); 4.36 (2H, d, 13.6 Hz); 6.82 (lH, ` 1 ~37421 d, 8.1 Hz); 6.91 (lH, d, 8.1 Hz); 7.05 (3H, m); 7.40 (lH, d, 9.2 Hz); 7.62 (2H, m); 11.00 (lH, bs); 11.55 (lH, bs).
.

IR (KBr): 740, 785, 950, 1130, 1260, 1440, 1590, 2600, 2920 and 3150 cm 1.

Example 20 1-~3-(lH-indol-3-yl)-propyl]-4-[3-methoxy-2-pYridinyl~-piperazine dihydrochloride hydrate A mixture of 3-(3-bromopropyl)indole (1.55 g), 1-(3-methoxy-2-pyridinyl)piperazine (2.51 g), micropulverized K2C03 (1.79 g) and tetrabutylammonium hydrogen ~ulfate (0.11 g) in acetonitrile (100 mL) wa~ heated at reflux under N2 atmosphere for 3 h. The exce~ acetonitrile was removed under reduced pressure and water (15 mL) added to the concentrate. The aqueous phase was extracted with CH2C12 (3 x 60 mL). The combined CH2C12 extracts were washed with sat. NaCl solution, dried with anhydrous K2C03, filtered, and concen-trated under reduced pressure. Silica gel chromatography (CH2C12/MeOH; 95:5) of the residue yielded the free base which was treated with ethanolic HCl to yield the dihydrochloride salt of the desired Ia product (1.30 g; 45%).

Anal. Calcd. for C21H26N40 2 HCl 0.95 H20:
C, 57.27; H, 6.85; N, 12.72; H20, 3.89 Found: C, 57.67; H, 6.82; N, 12.67; H20, 4.18.

NMR (DMS0-d6): 2.16 (2H, m); 2.7B (2H, t, 6.7 Hz);
3.20 (6H, m) 3.57 (2H, d, 12.5 Hz); 3.85 (3H, S); 4.08 (2H, d, 12.5 Hz); 4.80 (3H, bs); 7.02 (4H, m); 7.39 (2H, m); 7.56 (lH, d, 7.8 Hz); 7.81 (lH, dd, 5.8, 0.8 Hz); 10.85 (2H, bs).

CT-l91 IR (KBr): 760, 770, 1010, 125~, 1430, 1470, lS55, 1610, 2450, 2910 and 3210 cm 8y Process 2. (Ia Product~) Example 21 1-[4-(lH-indol-3-yl)butyl]-4-(3-methoxy-2-pyridinyl)-piperazine dihydrochloride Borane-methyl ~ulfide complex (3.3 mL; 2.0 M THF ~oln.) was added dropwise to a THF (9 m~) ~olution containing 1-[4-(indol-3-yl)-1-oxobutyl]-4-(3-methoxy-2-pyridinyl)-piperazine (IV; 1.0 g) at 0C while under N2 atmosphere.
After the addition wa~ complete, the reaction wa~ heated at reflux for 3 h. Upon cooling to 0C, MeOH (5 m~) was added and the react~on allowed to ~tand 20 h at 22C. The reaction was cooled to 0C and HCl gas introduced until a pH<2 was attained, after which the colution wa~ gently refluxed for 1 h. The reaction was cooled, MeOH (10 mL) added, and concentrated under reduced pressure. The residue wa~ heated at reflux in 4 N acetic acid for 5 h. After cooling, the reaction was made basic with 10 N NaOH (pH>10) and extracted with Et20. The combined Et20 extracts were dried with anhydrous K2C03, filtered, and concentrated under reduced pressure. Silica gel chromatography (EtOAc/MeOH; 97:3) afforded the free base which was treated with ethanolic HC1 to provide the dihydrochloride of the desired Ia product (83 mg; 8%).
Anal. Calcd. for C22H28N40 2 HCl:
C, 60.42; H, 6.92; N, 12.81 Found: C, 60.15; H, 6.78; N, 12.67.

1 3 3 7 4 2 l CT-1916A

NMR (DMSO-d6): 1.73 (4H, m); 2.74 (2H, t, 6.6 Hz);
3.18 (4H, m); 3.33 (2H, m); 3.53 (2H, d, 12.0 Hz); 4.00 (v, m, bs: CH2, H , H2O); 3.85 (3H, s); 7.04 (3H, m); 7-16 (lH, d, 2.2 Hz); 7.34 (lH, d, 7.6 Hz); 7.42 (lH, dd, 8.0, 1.2 Hz);
7.52 (lH, d, 7.2 Hz), 7.83 (lH, dd, 5.2, 1.2 Hz).

IR (KBr): 740, 805, 1000, 127.0, 1460, 1550, 1560, 1600, 2570, 2930 and 3250 cm 1.

Example 22 4-[6-Chloro-2-pyridinyl]-1-[2-(lH-indol-3-yl)-propYl]-piperazine To a mixture of 1-(6-chloro-2-pyridyl)piperazine (1.418 g, 7.2 mmol), triethylamine hydrochloride (994 mg, 7.2 mmol) and NaCNBH3 (1.512 g, 24 mmol) in 12 mL of dry tetrahydrofuran was added a solution of 3-(2-oxopropyl)indole (416 mg, 2.4 mmol) in 5 mL of tetrahydrofuran. The reaction mixture was vigorously stirred at room temperature under Ar for 17 h and then it was poured into saturated aqueous NaHC03 and extracted with ethyl acetate (x3). The organic phase was washed with H20 (x2) and O.lN HCl (25 mL) and then it was dried (Na2504) and evaporated to give a gum. Chromatography (SiO2/CH2Cl2-acetonitrile = 1:1) of this gum gave the product (714 mg, 84%) as a white foam.

NMR (CDCl3) ~ : 7.98 (br s, lH), 7.64-7.59 (m, lH), 7.43-7.343 (m, 2H), 7.24-7.08 (m, 2H), 7.06 (d, J=2.3 Hz, lH), 6.59 (d, J=7.3 Hz, lH), 6.50 (d, J-8.4 Hz, lH), 3.62-3.57 (m, 4H), 3.18-3.09 (m, lH), 3.06-2.93 (m, lH), 2.79-2.74 (m, 4H), 2.65 (dd, J=13.5, 9.1 Hz, 1.03 (d, J=6.5 Hz, 3H).

The hydrochloride was prepared by treating an ethereal solution of the product with anhydrous HCl. The resulting white fluffy solid was crystallized from ethanol-ether to give the hydrochloride salt (660 mg, 85%) as a white, micro-crystalline solid: m.p. 242-244C (dec).

By Process 3 (Ib and Ic Products) Example 23 3-[4-[4-(6-Chloro-2-pyridinyl)-1-piperazinyl]-1-cyclohexen-l-Yl]-5-methoxY-lH-indole A solution of S-methoxyindole (0.26 g, 1.8 mmole), 4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-cyclohexan-1-one (VIII; 0.50 g, 1.7 mmole), and pyrrolidine (0.5 mL) in ethanol (10 mL) was refluxed for 18 h. The solution was concentrated in vacuo and the residue chromatographed on silica gel using ethyl acetate as the eluent to give the desired product of formula Ib (0.59 g, 82~, m.p. 210-213C).

Anal. Calcd. for C27H27ClN40:
C, 68.16; H, 6.44; N, 13.25 Found: C, 68.00; H, 6.57; N, 12.97 NMR(DMS0-d6): 1.52 (lH, m); 2.04 (lH, m), 2.22 (lH, m);
2.40 (2H, m); 2.64 (6H, m); 3.48 (4H, m); 3.75 (3H, s); 8.07 (lH, m); 6.63 (lH, d, 7.4 Hz); 6.75 (2H, m); 7.26 (3H, m);
7.53 (lH, dd, 7.9, 8.1 Hz); 10.91 (lH, bs).

IR (KBr): 780,B00, 980, 1140, 1260, 1450, 1480, 1550, 1600, 2840 and 2920 cm 1.

Example 24 3-[4-[4-(Substituted-2-pyridinyl)-1-Piperazinyl]-l-cyclohexan-l-yl]-lH-indole 4-(lH-indol-3-yl)cyclohex-3-enone, ethylene ketal, XII

Indole (1.17 g, 10 mmol), 1.4-cyclohexanedione mono-ethylene ketal (1.95 g, 12.5 mmol), and pyrrolidine (1.77 g, 25 mmol, 2.1 mL) were refluxed in ethanol (50 mL) for 3 days.
The solution was concentrated in vacuo. The residue was washed with ethyl acetate (30 mL) and the solid product was collected and dried (yield: 2.05 g, 80%). The product was recrystallized from methanol (20 mL) to give compound XII as a white powder (1.75 g).

4-(lH-indol-3-yl)cyclohexanone, XI

Compound XII (1.75 g, 6.9 mmol) was hydrogenated for 18 h at 60 psi using 10% Pd/C (0.15 g). The mixture was filtered and the filtrate concentrated in vacuo. The residue was refluxed for 18 h in acetone (150 mL) with water (10 mL) and p-toluene sulfonic acid (0.10 g). Sodium carbonate (5.0 g) was added and the mixture refluxed for 30 min. The mixture was cooled and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel u~ing ethyl acetate as the eluent to give the XI de~ired product (1.29 g, 88%).

3-[4-(4-(Substituted-2-pyridinyl)-1-piperazinyl)-1-cyclohexyl]-lH-indole, Ic A mixture of compound II (10 mmol), the desired substituted-pyridinyl piperazine (III; 10 mmol), and titanium(IV) i~opropoxide (3.72 mL, 12.5 mmol) would be stirred until IR spectrum of the mixture showed no ~1 remaining ketone band (gentle heating may be required). The viscous solution would then be diluted with ethanol (10-20 mL) and sodium cyanoborohydride (0.42 g, 6.7 mmol) added. After ~tirring for 20 hr, water (2 mL) would be added and the resulting inorganic precipitate filtered and washed with ethanol. The filtrate could then be concentrated in vacuo and the crude product purified by chro~atography on ~ilica gel.
Alternately, cyclohexenyl products of Formula Ib may be hydrogenated to yield products of Formula Ic in cases where other substituents on the precursor molecule are stable to the hydrogenation process.
Compound preparation data for these and other Formula I
compounds, prepared in a manner similar to the above procedures, i8 shown in Table 1. Selection of appropriate starting materials and intermediates as well as adjustments of the procedures would be well within the ~kill of one ~killed in the art.

Table 1 Formula I Compounds Ex. No. Structure %Yield MP(C) Cryst. Sol.

14 ~ ~Cl Cl 77 250-252 EtOH

~ Cl CF3 68 206-208 EtOH

16 ~ OMe 60-85 EtOH
H SOlvate 17 ~ ~ ~ 80 242-243 EtOH

H HCl 0~
18 U ~ ~ 44 138-140 EtOH

19 ~ ~ 87 221-222 EtOH
H NCI Cl OMe ~ N~_~JN ~ 45 216-219 EtOH
2HcI~H2o OMe N~ N~ 23 228-230 EtOH

22 ~ N
H H
~ ,, Table 1 (continued) Formula I Compounds Ex. No. Structure SYield MP(C) Cryst. Sol.

MeO ~ 3 ~ 82 210-213 EtOAc Me OMe 25~ ~_J ~ 11 155-194 EtOH

OMe ~ N ~ N ~
26( lr, 4r) 4 55-60 EtOH

hydrate OMe 27~ N ~ N ~ 43 234-236 PrOH/EtOH/

(ls, 4s) 28~ ~ ~ 67 239-241 iPrOH/EtOH

(ls, 4s) 29~ ~ ~ 53 239-242 iPrOH/EtOH

H HCl (lr, 4r) 30~ ~ ~ 14 212-214 Hex/CH2Cl2 H HCl CF3 31 ~ ~ N\__~N ~ ~ 1 99-101 EtOH
H hydrate Cl ~ 32 ~ ~ 50 83-86 Hex/CH2Cl2 t H CF3 ~ 337421 Table 1 (continued) Formula I Compounds Ex. No. StruCture~Yield MP(C) crYst. Sol.
_ ~F3 33 ~ ~ ~ ~ ~ 28 90-93 EtOH

OMe 34 ~ ~ ~ ~ 22 103-125 MeOH

oxalate (ls, 4s) OMe ~ ~ - N $N ~ 64155-186 EtOH
2HCl H (lr, 4r) 36 ~ ~ ~ 85242-244 Et2O/CH3CN/

37 ~N~ ~ 21150-225 EtOH

H ~Ie MeO ~N~ ~ 35 182-185 MeOH/EtOAc H '2HCl OMe F ~ ~ N~ - ~ 36140-142 EtOAc MeO~ ~ 19195-196 MeOH/Et2O

4l ~ HCl Cl 23 205-~08 MeOH/EtOAc H

Table 1 (continued) Formula I Compounds Ex. No. Structure %Yield MP(C) Cryst. Sol.

42 ~ ~ ~ 42 213-216 EtOH

43 ~ N V N ~ F3 hexane ~eO ~ 3 ~CF 31 140-142 Ethyl acetate H 3 hexane C 1 66 226-230 MeOH
H fumarate ~N ~ 1 63 225-230 10%MeOH/EtOAc 47 ~ V ~ 46 125-127 Ethyl acetate Me Me~ ~ 137-139 Ethyl acetate 49 Me~ 3~ 42 160-163 Ethyl acetate MeO N MeO

2 H C 1 EtOH

ke OMe Table 1 (continued) Formula I Compounds Ex. No. Structure 1 ~Yield MP(C) Cryst. Sol.

51 ~ ~ ~ 83 200-203 EtOH
\ HC1 Me F, ~ ~N ~ HC 1 52 ~ \ N Cl 81 210-212 EtOH

53 ~N ~ 72 127 CH2cl2/Et2o/
N\ OMe hexane 1~ ~ ~c 1 54 N 38 253-255 EtOH
H HCl ~ c1 72 115-116 Ethyl acetate Me C 1~N~N ~ H C 1 56 H O~e 41 205-207 Ethyl acetate C 1 ~N~N ~ H C 1 57 N C1 4 238-242 MeOH/Et2O

.~
.

. CT-1916A

Table 2 Biological Activities of Formula I Compounds:
Inhibition of Serotonin Uptake (in vitro) Ex. No. IC50(nM) Ex. No. 50(nM) 17 37 39 0.2 19 98 41 2.8 1.1 42 520 8.6 45 100 27 12.5 47 24 29 106 50 3.7 34 5.6 Additional Detailed Description of the Invention Some additional compounds of Formula I have been made, tested and found to have useful CNS properties, particularly antidepressant properties. The additional compounds were prepared by employing the synthetic processes described hereinabove, using alterations which would be apparent to a skilled chemist in order to produce the desired product compound. Some additional examples are given here for further guidance.

Additional Intermediate Compounds.
Compounds of Formula III
Example 58 1-(6-Chloro-2-pyridinyl)-2-methylpiperazine A mixture of 2-methylpiperazine (21.31 g), 2,6-dichloropyridine (10.0 g) and micropulverized K2C03 (27.99 g) in CH3CN (200 mL) was heated at reflux under nitrogen atmosphere for 24 h. The reaction was filtered and the filtrate concentrated under reduced pressure. The concentrate was dissolved in CH2C12 and extracted with 5%
NaHC03 and water. The organic phase was dried with K2CO3, filtered and concentrated under reduced pressure. Silica gel chromatography (CH2C12/MeOH/NH40H; 96:4:0.4) of the residue yielded product, (13.34 g, 93%).

Example S9 1-(3-Methoxy-2-pyridinyl)-2-methylpiperazine A mixture of 2-methylpiperazine (6.66 g) and 2-bromo-3-methoxypyridine (2.5 g) was heated in an autoclave at 100 C for 24 h. The reaction mixture was dissolved in CH2C12 and extracted with 5% NaHC03 and water. The organic phase was dried with K2CO3, filtered, and concentrated under reduced pressure. Silica gel chromatography (CH2C12/MeOH/NH40H; 92:8:0.8) of the residue yielded the product (2.28 g, 83%).

Example 60 1-(5-Chloro-3-methoxy-2-pyridinyl)piperazine a) 2-bromo-5-chloro-3-pyridinol A solution of bromine (12.35 g) in 10% NaOH (70 mL) was added dropwise with stirring to a solution of 5-chloro-3-pyridinol (10.00 g) in 10% NaOH (70 mL). After the addition was complete, the reaction was stirred at 22 C for 20 h. The reaction was cooled to OC and acidified to p~ 5.3 with concentrated HCl (aq). The precipitate was filtered and dried under vacuum for 60 h to afford a) (15.66 g, 97%).

b) 2-bromo-5-chloro-3-methoxypyridine To a stirred mixture of 2-bromo-5-chloro-3-pyridinol (15.66 g) and pulverized KOH (16.79 g) in DMSO (100 mL) at 55-60 C was added dropwise a solution of CH3I (13.27 g) in DMSO (35 mL) while under nitrogen atmosphere. After the addition was complete, the reaction was maintained at 55-60 C
for 1 h. The reaction was extr~cted with Et20 (3 x 150 mL) and the combined Et20 extracts were treated in turn with lN
NaOH (150 mL), water (150 mL), lN HC1 (150mL), water (150 mL), and a ~aturated NaC1 ~olution (150 m~). The o~ganic phase was dried with MgSO4, filtered, and concentrated under reduced pressure to yield a ~olid material. Recrystallization of the solid from hexane afforded b) (3.52 g, 21%).

. ..
A

1 ~3742 1 c) l-(5-chloro-3-methoxy-2-pyridinyl)piperazine Anhydrous piperazine (13.41 g) and 2-bromo-5-chloro-3-methoxypridine (3.50 g) were heated in an autoclave at 100 C for 20 h. The mixture was dissolved in water (10 mL) and extracted with CH2Cl2 (3 X 100 mL). The combined organic extracts were washed with a saturated NaCl solution, dried with K2C03, filtered, and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2/MeOH;
90:10) of the residue yielded product (1.17 g, 33%).

Compounds of Formula V

Example 61 3-(2-Bromoethyl)-1-methylindole a) Methyl 1-methylindole-3-acetate A dispersion of 35% KH in oil (21.0 g, 0.18 mol) was washed free of oil with dry pentane under an Ar atmosphere.
To a suspension of the resulting solid in 100 ml of dry dimethylformamide was added a solution of indole-3-acetic acid (10.5 g, 0.060 mol) in 60 ml of dimethylformamide, dropwise at -20C under Ar. The mixture was stirred at the same temperature for 2 h and then CH3I (12.0 ml, 0.19 mol) was added dropwise. Stirring was continued at -20 to 10C for 2 1/2 h and then the mixture was stored at 5C for 16 h.
Ether was then added and the mixture was washed (H20, brine), dried (Na2S04) and evaporated to give an orange oil. Flash chromatography (SiO2/10-20% ethyl acetate-hexane x 2) of this oil afforded the product (5.25 g, 43%) as an oil: IR (neat) 1745 cm 1; lHnmr (80 MHz, CDCl3) ~ 7.75-7.55 (m, lH), 7.40-7.07 (m, 4H), 3.83 (s, 2H), 3.80 (s, 3H), 3.75 (s, 3H).

~ ~3742 1 b) 3-(2-Hydroxyethyl)-l-methylindole To a suspension of LiAlH4 (2.0 g, 0.052 mol) in 50 mL of dry tetrahydrofuran was added dropwise a solution of methyl 1-methylindole-3-acetate (5.25 g, 0.026 mol) in 70 mL of dry tetrahydrofuran at -10C under Ar. The mixture was refluxed for 1 h and then it was cooled at 0C and quenched by the sequential addition of 2 mL of H2O, 2 mL of 15% aqueous NaOH
and finally 6 mL of H2O. The resulting slurry was filtered and the filter cake was washed with additional tetrahydrofuran. Evaporation of the filtrate gave the product (4.0 g, 89%) as an oil which was used without further purification.

c) 3-(2-Bromoethyl)-1-methylindole To a solution of 1-methyl-3-(2-hydroxyethyl)indole (4.00 g, 0.023 mol) in 50 mL of acetonitrile at -20C under Ar was added a solution of CBr4 (10.16 g, 0.031 mol) in 25 mL of acetonitrile, followed by a solution of triphenylphosphine (8.00 g, 0.031 mol) in 125 mL of acetonitrile. The mixture was stirred and allowed to warm to 0C over 2 h. The resulting mixture was evaporated and the residue was chromatographed (SiO2/hexane, then ethyl acetate-hexane=1:4) to give the product (4.00 g, 74%) as a brown oil: IR (neat) 2940, 1617, 1552 cm 1; 1Hnmr (200 MHz, CDC13) ~ 7.58 (d, J=7.6 Hz, lH), 7.33-7.09 (m, 3H), 6.95 (s, lH), 3.77 (s, 3H), 3.62 (t, J=7.9 Hz, 2H), 3.32 (t, J=7.7 Hz, 2H).

Example 62 3-[1-Methyl-3-(p-toluenesulfonyloxy)propyl]indole To a suspension of LiAlH4 (1.50 g, 39 mmol) in 100 mL of ~ 33742 ~
dry THF at -10C under Ar was added a solution of ethyl 3-(3-indolyl)-3-methylpropionate1 (7.00 g, 30 mmol) in 50 mL
of THF. The mixture was stirred at room temperature for 3 h and then it was quenched at 0C with 2 mL of H20. The resulting slurry was filtered and the filter cake was washed with THF. The filtrate was then dried (Na2SO4) and evaporated to give the intermediate VI product, 3-(1-methyl-3-hydroxy-propyl)indole (5.05 g, 88%) as an oil: IR (neat) 3420, 3300 cm To an ice cold solution of 3-(1-methyl-3-hydroxy-propyl)indole (5.00 g, 0.026 mol) in 100 mL of CH2C12 was added triethylamine (4.1 mL, 0.03 mol), p-toluenesulfonyl chloride (5.50 g, 0.029 mol) and 4-N,N-dimethylaminopyridine (DMAP) (0.6 g). The mixture was stirred at room temperature under Ar for 18 h and then it was evaporated and the residue was chromatographed (SiO2/ethyl acetate-hexane = 1:9, then ethyl acetate) to give the product (7.75 g, 86%) as a light brown gum: IR (neat) 3420, 1357, 1175 cm 1. Oikawa, et. al , Tetrahedron Lett., 1759 (1978).

Additional Formula I Compounds.

Example 36 - Alternate Preparation 3-L2-[4-(6-Chloro-2-pyridyl)-1-piperazinyl]propyl]-indole To a mixture of 1-(6-chloro-2-pyridyl)piperazine (1.418 g, 7.2 mmol), triethylamine hydrochloride (994 mg, 7.2 mmol) and NaCNCH3 (1.512 g, 24 mmol) in 12 mL of dry tetrahydrofuran was added a solution of 3-(2-oxopropyl)indole (416 mg, 2.4 mmol) in 5 mL of tetrahydrofuran. The reaction mixture was vigorously stirred at room temperature under Ar for 17 h and then it was poured into saturated aqueous NaHC03 and extracted with ethyl acetate (x3). The organic phase was washed with H20 (x2) and 0.1 N HCL (25 mL) and then it was dried (Na2S04) and evaporated to give a gum. Chromatography (SiO2/CH2C12-acetonitrile=l:l) of this gum gave the product (714 mg, 84%) as a white foam: Hnmr (200 MHz, CDC13) ~ 7.98 (br s, lH), 7.64-7.59 (m, lH), 7.43-7.343 (m, 2H), 7.24-7.08 (m, 2H), 7.06 (d, J=2.3 Hz, lH), 6.59 (d, J=7.3 Hz, lH), 6.50 (d, J=8.4 Hz, lH), 3.62-3.57 (m, 4H), 3.18-3.09 (m, lH), 3.06-2.93 (m, lH), 2.79-2.74 (m, 4H), 2.65 (dd, J=13.5, 9.1 Hz, lH), 1.03 (d, J=6.5 Hz, 3H). The hydrochloride salt was prepared by treating an ethereal solution of the product with anhydrous HCl. The resulting white fluffy solid was crystallized from ethanol-ether to give the hydrochloride salt (660 mg, 85%) as a white, micro-crystalline solid: m.p. 242-244C (dec); IR
(KBr) 3430, 3190, 1590 cm 1.

Additional Formula I compounds which have been prepared by appropriate modifications of the reaction schemes and procedures given hereinabove, are displayed in Table lA.

Table lA
Additional Formula I Compounds Ex. No. ~tructure %Yield MP(C) Cryst. Sol.
Cl ~ ~ ~ 49 158-62 Me2CO-Et2O

64~ N ~ ~ 53 174-85 EtOH-Et20 OMe H .2HC1-hydrate 65~ ~ 69 103-05 EtOAc MeO
e ~ N~__JN ~ 41 218 MeOH-Et2O

M N 2HC1 OMe 67 ~ \--/ ~ 44 110-115 MeOH-THF

H Oxalate 68 ~ ~ ~N N ~ 30 55 Et2O

H Oxalate Me Me0 ~ N ~ ~ 43 122-25 EtOAc 70 ~ .N~ ~ N N ~ 15 168-170 EtOAc hydrate Cl 1 ~37~1 Table lA (continued) Additional Formula I Compounds Ex. No. Structure Cl %Yield MP(C) Cryst. Sol.

71 ~ ~ ~ 65 194-98 EtOH
OMe H C 1 h y d r a t e 72 ~ )~ _~ 65 13Z-35 EtOH

~- --5 l--Ji,~' 1 337~21 Table 2A
Biological Activities of Some Additional Formula I Compounds Inhibition of Serotonin Uptake (in vitro) Ex. No. lC,O(nM)Ex. No. lCrO(nM) 56 <1 67 142 57 166 68 36.7 64 cl 70 141 134 71 4.9 66 35.9 72 18.7

Claims (57)

1. A compound of Formula I or a pharmaceutically acceptable acid addition salt thereof wherein R1 and R2 are independently selected from hydrogen and lower alkyl, wherein lower means C1-4;
R3, R4, R8 and R9 are independently selected from hydrogen, lower alkyl, lower alkoxy, carboxamide, halogen, trifluoromethyl and thio-lower alkyl, with the proviso that R8 and R9 cannot both be hydrogen at the same time;
A is a C5-7 cycloalkanyl or cycloalkenyl ring, or A is wherein n is an integer from 1 to 3 and R5 is the same as R1; and R6 and R7 are independently selected from hydrogen, methyl or R6 and R7 can be taken together as a methylene bridge.

2. The compound of claim 1 wherein A is a C5-7 cycloalkanyl or cycloalkenyl ring.

3. The compound of claim 1 wherein A is

4. The compound of claim 1 wherein R6 and R7 are selected from hydrogen or methyl.

5. The compound of claim 1 wherein R6 and R7 are taken together as a methylene bridge.

6. The compound of claim 1; 1-12-(1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

7. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(3-trifluoromethyl-2-pyridinyl)piperazine.

8. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine.

9. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-5-(3-methoxy-2-pyridinyl)-(1R,4R)-2,5-diazabicyclo[2.2.1]
heptane.

10. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(6-chloro-2-pyridinyl)piperazine.

11. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(6-methoxy-2-pyridinyl)piperazine.

12. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-5-(3-methoxy-2-pyridinyl)-(lS,4S)-2,5-diazabicyclo[2.2.1]
heptane.

13. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)piperazine.

14. The compound of claim 1; 1-13-(1H-indol-3-yl)propyl]-4-(6-chloro-2-pyridinyl)piperazine.

15. The compound of claim 1; 1-[4-(1H-indol-3-yl)butyl]-4-(3-methoxy-2-pyridinyl)piperazine.

16. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

17. The compound of claim 1; 2-[2-(1H-indol-3-yl)ethyl]-5-(6-chloro-2-pyridinyl)-(1S,4S)-2,5-diazabicyclo[2.2.1]
heptane.

18. The compound of claim 1; 2-[2-(1H-indol-3-yl)ethyl]-5-(6-chloro-2-pyridinyl)-(1R,4R)-2,5-diazabicyclo[2.2.1]
heptane.

19. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

20. The compound of claim 1; 1-14-(1H-indol-3-yl)butyl]-4-(6-chloro-2-pyridinyl)piperazine.

21. The compound of claim 1; 1-[4-(1H-indol-3-yl)butyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

22. The compound of claim 1; 1-[3-(1H-indol-3-yl)propyl]-4-(4-trifluoromethyl-2-pyridinyl)piperazine.

23. The compound of claim 1; 2-[3-(1H-indol-3-yl)propyl]-5-(3-methoxy-2-pyridinyl)-(1S,4S)-2,5-diazabicyclo[2.2.1]
heptane.

24. The compound of claim 1; 2-13-(1H-indol-3-yl)propyl]-5-(3-methoxy-2-pyridinyl)-(1R,4R)-2,5-diazabicyclo[2.2.1]
heptane.

25. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(6-chloro-2-pyridinyl)-2-methylpiperazine.

26. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(4-trifluoromethyl-2-pyridinyl)piperazine.

27. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

28. The compound of claim 1; 1-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

29. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-4-(6-chloro-2-pyridinyl)piperazine.

30. The compound of claim 1; 1-[2-(5-fluoro-1H-indol-3-yl)-ethyl3-4-(6-chloro-2-pyridinyl)piperazine.

31. The compound of claim 1; 1-12-(1H-indol-3-yl)-ethyl]-4-(3-chloro-2-pyridinyl)piperazine.

32. The compound of claim 1; 1-12-(5-fluoro-1H-indol-3-yl)-ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

33. The compound of claim 1; 1-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

34. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-1-cyclohexen-1-yl]-5-methoxyindole.

35. The compound of claim 1; 3-14-l4-(6-chloro-2-pyridinyl)-1-piperazinyl3-1-cyclohexen-1-yl]-1H-indole

36. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-1-cyclohexen-1-yl]-1H-indole-5-carboxamide.

37. The compound of claim 1; 1-[2-(N-methyl-1H-indol-3-yl)-ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

38. The compound of claim 1; 1-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

39. The compound of claim 1; 1-[3-(N-methyl-1H-indol-3-yl)-propyl]-4-(3-methoxy-2-pyridinyl)piperazine.

40. The compound of claim 1; 1-[3-(N-methyl-1H-indol-3-yl)-propyl]-4-(6-chloro-2-pyridinyl)piperazine.

41. The compound of claim 1; 1-[3-(5-fluoro-1H-indol-3-yl)-propyl]-4-(6-chloro-2-pyridinyl)piperazine.

42. The compound of claim 1; 1-13-(5-fluoro-1H-indol-3-yl)-propyl]-4-(3-methoxy-2-pyridinyl)piperazine.

43. The compound of claim 1; 1-[2-(1H-indol-3-yl)ethyl]-4-(5-chloro-2-pyridinyl)piperazine.

44. The compound of claim 1; 1-[2-[N-methyl-1H-indol-3-yl)-ethyl]-4-(6-chloro-2-pyridinyl)piperazine.

45. The compound of claim 1; 1-[2-(5-chloro-1H-indol-3-yl)-ethyl]-4-(3-methoxy-2-pyridinyl)piperazine.

46. The compound of claim 1; 1-12-(5-chloro-1H-indol-3-yl)-ethyl]-4-(6-chloro-2-pyridinyl)piperazine.

47. The compound of claim 1; 1-[2-(5-chloro-1H-indol-3-yl) ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

48. The compound of claim 1; 4-(6-chloro-2-pyridinyl)-1-[2-(6-methoxy-1H-indol-3-yl)ethyl]-piperazine.

49. The compound of claim 1; 1-[2-(6-methoxy-1H-indol-3-yl) ethyl]-4-(3-methoxy-2-pyridinyl)-piperazine.

50. The compound of claim 1; 1-[3-(1H-indol-3-yl)-3-methyl-propyl]-4-(6-chloro-2-pyridinyl)-piperazine.

51. The compound of claim 1; 1-[3-(1H-indol-3-yl)-3-methyl-propyl]-4-(3-methoxy-2-pyridinyl)-piperazine.

52. The compound of claim 1; 1-[2-(5,6-dimethoxy-1H-indol-3-yl)ethyl]-4-(6-trifluoromethyl-2-pyridinyl)piperazine.

53. The compound of claim 1; 3-[4-[4-(6-chloro-2-pyridinyl)-1-piperazinyl]-1-cyclohexen-1-yl]-5-fluoro-1H-indole.

54. The compound of claim 1; 4-(5-chloro-3-methoxy-2-pyridinyl) -1-[3-(1H-indol-3-yl)propyl]-piperazine hydrochloride.

55. The compound of claim 1; 4-(6-chloro-2-pyridinyl)-1-[3-(1H-indol-3-yl)propyl]-2-methyl-piperazine.

56. A pharmaceutical composition in dosage unit form suitable for systemic administration to a mammalian host comprising a pharmaceutical carrier and from about 1 to 500 mg of an active compound selected from the compounds claimed in any one of claims 1 to 55.

57. The use of an effective amount of a compound claimed in any one of claims 1 to 55 as an antidepressant.