AU629535B2 - N-substituted-arylalkyl and arylalkylene aminoheterocyclics as cardiovascular antihistaminic and antisecretory agents - Google Patents

Description

7' w 1

AUSTRALIA

PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Application Number: Lodged:

U-

4 U

U

Complete Specification Lodged: Accepted: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: SAddress of Applicant Actual Inventor: Address for Service: A.H. ROBINS COMPANY, INCORPORATED, C0C&L aJAt) 1407 Cummings Drive, Richmond, Virginia, U.S.A.

ARTHUR S. CAVE CO.

Patent Trade Mark Attorneys Level Barrack Street SYDNEY N.S.W. 2000

AUSTRALIA

Complete. Specification for the inventiornN-SUBSTITUTED-ARYLALKYL

AND

ARYLALKYLENE AMINOHETEROCYCLICS AS CARDIOVASCULAR ANTIHISTAMINIC AND ANTISECRETORY

AGENTS

The following statement is a full description of tnis invention including the best method of performing it known to me:- 1 ASC 49 L i-r -la- AHR-438A-CIP #1 44 ft 4 4r 4 44 4 4 4 44D 4 9 40 4440o 4s 9 4. 4 6* C 4 #4 4. 4 .4 BACKGROUND OF THE INVENTION 1. Field of Invention.

This invention relates to certain N-substituted arylalkyl and arylalkylenepyrrolidines, piperidines and homopiperidines useful in methods of treating cardiovascular disfunctions, countering effects of histamine in allergies and countering gastric secretion excesses. Certain of the compounds are novel and certain intermediates useful in their preparation are novel and all the methods of treatment novelly use the compounds.

2. Information Disclosure Statement.

U.S. Patent 3,956,296 and a divisional patent thereof, U.S.

4,032,642, disclose pertinent compounds, among which some would fall within a generic structure as follows: wherein Ar is phenyl, p-fluorophenyl or m-trifluorophenyl; R is phenyl, pfluorophenyl or cyclohexyl; A is hydrogen or hydroxy; X is hydrogen or acetyl; and Y is hydrogen or loweralkoxy, the compounds having utility as anti-inflammatory agents, sedatives and tranquilizers and pharmaceutical compositions therefor. The compounds of this structure are within the scope AHR-438A-CIP of novel treatment methods of the present invention but are excluded from Sformulas representing novel compounds.

U.S. Patent 3,922,276 discloses compounds, among which would fall within a generic structure as follows:

Y

Ar-C N-(CH,)n-O x 1 0 wherein Ar is phenyl or p-fluorophenyl and R is phenyl, p-fluorophenyl, m- So" trifluorophenyl or cyclohexyl; X is hydrogen or acetyl; and Y is hydrogen or S' loweralkoxy, the compounds having utility as anti-inflammatory agents and S' tranquilizers and pharmaceutical compositions therefor. The compounds of this structure are within the scope of novel treatment methods of the present invention but are excluded form formulas representing novel compounds.

U.S. Patent 4,163,790 discloses compounds which fall within a generic structure as follows: a

A

N-Z

a R 0 0 wherein Ar and R are phenyl and p-fluorophenyl and Z is hydrogen, acetyl, pfluorobenzoylpropyl, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, phenylcarbamoyl, or N-(co-morpholinoethyl)carbamoyl; A is hydrogen, hydroxy or forms a double bond as indicated by the dotted line. The compounds were active in increasing coronary blood flow; however, the compounds while substituted in the 4-piperidine position and also disclosed in the above-mentioned patents, differ substantially in structure from the compounds of the present invention in the substitution in the 1-position of the piperidine radical and are not within the scope of generic formulas hereof of compounds for novel treatment methods or novel compounds.

AHR-438A-CIP U.S. Patent No. 4,632,925 discloses compounds which fall within the generic structure RKQi

-N-R

2 -Het R4 wherein R 3 and R 4 are hydrogen, halogen or loweralkoxy; R 1 is CHI, C =CHI 999 or CH-CH 2

R

2 is alkylene or -C(O)-(CH 2 )n where n is 0-11; and Het is pyridinyl, pyrimidinyl or imidazoyl. The compounds are disclosed to have insulin lowering activity and to be useful as antiobesity agents. Certain of the compounds disclosed in U.S. 4,632,925, wherein R 1 is C CHI or CH- CH2 are encompassed by Formulas I and Ia.

1-Benzyl-(,-diphenyl)-4-benzylidinepiperidines of the formula is o(phenyl) 2 -C C N-CH 2 -phenyl are disclosed in Ger. Offen. 2,800,919 as having anticonvulsant and vasodilating properties. Similar 1-benzyl-(,a-diphenyl)-4-benzylidinepiperidines of the formula {j (phenyl) 2 -CHC N-OH 2 Q R'R are disclosed in U.S. Patent No. 4,035,372 as having vasodilating properties.

The compounds are excluded from the present invention by proviso.

1-Benzyl-(a,c-diphenyl)-4-benzylpiperi dines of the general formula X 0R (phenYl) 2 C 0T S-4- AHR-438A-CIP are disclosed in U.S. 3,965,257 as having antihistaminic activity. The compounds are ketones and, as contrasted to the ethers, useful in the present methods.

4-(Diphenylmethylene)-l-benzylpiperidines of the general formula

RI

R C= -CH2having hemodynamic, antiarrhythmic and antihistaminic activities are disclosed in U.S. Patent 3,759,928 and are excluded from the present invention by proviso.

The compound 4-diphenylmethylene-l-benzyl piperidine maleate is disclosed in Japanese kokai 62,145,018 to be an antiallergy agent not liberating histamine. The compound is not encompassed by Formulas I or Ia.

U.S. Patent 3,984,557 discloses compounds which fall within a generic structure as follows:

NO

ya 'a o a.

wherein R represents loweralkyl, lowercycloalkyl or phenylloweralkyl and Y is carbamoyl, cyano or hydrogen, the compounds having utility as antiarrhythmic agents. In the compounds of the present invention, the radical on the 1-position of the cycloalkylamino moiety has an aryloxy, arylamino or an aryl group other than phenyl on the alkyl chain.

Australian specification No. 580444 is directed to the use of certain compounds of Formula I as anti-allergy agents wherein (B)z is confined to oxygen

-LJ

I

AHR-438A-CIP and A is hydrogen, hydroxy, cyano or forms a double bond This :specification is hereby incorporated by reference.

SUMMARY OF THE INVENTION The present invention is concerned with methods of correcting cardiovascular disturbances, and antihistiminic and antisecretory agents in animals and humans utilizing heterocyclic amines of the general formula I, and certain novel compounds thereof as composition of matter. The compounds useful in the methods of the invention have the formula: (A)d N-(CH,)m-(B)z-D (CH2)e

P)

R/ Fprmula I wherein; P is zero, one or two; O 0 0 If ,R 1 II II A is hydrogen, -O-RI, -C N, -C-N R 2

,-C-R

I

-C-O-R

1

O

II R 1

R

I

-CHOR, -CH 2

-NR

2 -N R2 or-NHC(O)CH,; m is zero to six inclusive;

OH

Q is -CH 2 or

H

*e d, e and n are selected from zero or one and the dotted lines represent S'.I double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of a a a 4 a a a r AHR-438A-CIEP 9. 00 9 0 0 9 9 99 9 0 9 90 9 99 0 9 0 0 90 9909 0 0 0 09 9 00 0 9 9 9 90 5990 4 00 99 9 9 59 99 0 97.

9 04 *409 7. 0 0.a~ *04000 0 9 x or and in addition, R may have the values of cycloalkyl or loweralkyl; and D may have additionally the values: 0 0 N X H 2 0 2 0 0 0 0o 0 or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen,

-NO

2 -0-Rl,-C-Rl, -N ,-OH-loweralkyl, -CH 2

C(O)-

0 R2 R2 -I0/R OR', S(O) 2 R4, -SR4, S (Q)R4, -N-O-R4, -CH 2 O(O)OM, -S(O) 2 N -NS(O) 2 0H 3

-INC-IN

R1O R2 R, R1 R2 0 lowerhydroxyalkanyl, -N-O(O)C(O)-O-loweralkyl, or -NC-0R2; B is selected from 0, S, H R 0 0 0 11 11 1 11 or -N-C-O-R1; itI 0 R AHR-438A-CIP z is one or zero with the proviso that z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is aminocarbonyl, or a double bond forms between the a carbon and a carbon of the central heterocyclic amine ring.

R R 2 and R 3 same or different, are selected from hydrogen, loweralkyl, phenyl or phenylloweralkyl; R 4 is selected from loweralkyl, phenyl or phenylloweralkyl; M is a pharmaceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof.

In the further definition of symbols in the formulas hereof and where they appear elsewhere throughout this specification and in the claims, the terms have the following significance.

The term "loweralkyl" as used herein, unless otherwise specified, includes straight and branched chain radicals of up to eight carbons inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, and octyl radicals and the like. The term "loweralkoxy" has the fomula -O-loweralkyl. The terzi "lowerhydroxyalkyl" refers to loweralkyl radicals carrying a hydroxy radical.

The term "cycloalkyl" as used herein includes primarily cyclic alkyl radicals containing 3-7 carbon atoms inclusive and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and methyleyclohexyl and the like.

I The term "halo" or "halogen" when referred to herein includes fluorine, S chlorine, bromide and iodine unless otherwise stated.

i The term "central heterocyclic amine ring" refers to that portion of Formula I represented by 0 4 wherein the dotted line may represent a double bond. The term "saturated central heterocyclic amine ring" refers to the foregoing radical having no double bond.

The term "phenylloweralkyl" as used herein includes phenyl connected Itt by hydrocarbon chains exemplified by loweralkyl above and wherein phenyl may be I- i AHR-438A-CIP substituted by non-reactive or non-interfering radicals such as halo, loweralkyl, loweralkoxy and the like.

"Pharmaceutically acceptable salts" include acid addition salts, hydrates, alcoholates and quaternary salts of the compounds of Formula I which are physiologically compatible in warm-blooded animals. The acid addition salts may be formed by either strong or weak acids. Representative of strong acids are hydrochloric, hydrobromic, sulfuric and phosphoric acids.

Representative of weak acids are fumaric, maleic, mandelic, tartaric, citric, oxalic, succinic, hexamic and the like. Suitable quaternary salts include the loweralkyl halides and loweralkyl sulfates.

The compounds of Formula I have been found to be calcium antagonists with potential use as coronary vasodilators, antihypertensives, antiarrhythmic, antiallergy, antihistaminic and antisecretory agents. As stated above, .an application directed to use of certain compounds of Formula I as .ntiallergy agents where (B)z is confined to oxygen and A is hydrogen, hydroxy, cyano or forms a double bond has been filed on December 20, 1985 is hereby incorporated by reference and serves to demonstrate utility of those com- S. pounds as antiallergy agents.

Pharmacological testing methods used for screening in support of methods of treatment of this invention excluding antiallergy method of treatment as described herein below.

Certain compounds encompassed by Formula I are novel as represented by Formula Ia.

6 a (A)d Q N-(CH 2 )m-(B)z-D (CH2)e p R Ia wherein p, m, e, d, Q, n, A, Ar, D, R, m, B and z are as defined under Formula I with the following additional proviso: (B)z cannot represent oxygen at the same time D is phenyl or substituted phenyl when n is zero and (A)d is hydrogen or hydroxyl; or when d is zero and a double bond forms between the a-carbon of a saturated central heterocyclic amine ring.

I, I M AHR-438A-CIP Certain intermediate compounds useful in the preparation of compounds of Formula I wherein (A)d is amino and are represented by formula

R

2

R

1

N

NH

(CH2)e p)

R

Formula *e 1 aO *4 *4

I

4' 44 4,44 1 44 44 44 4 4 4 4, 1 I *0 44 4 4 44 4 44 1*44 4 4e, 499444g 4 4 wherein Ar, e, R 1

R

2 n and p are as defined under Formula I and the dotted lines represent double bonds which may form consistent with the valence of carbon; and wherein R is defined as under Formula I except loweralkyl.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula I may be prepared by methods described in U.S. Patents 3,922,276 and 4,032,642 and as set forth in Charts I, II, m, IV and V, VI, VII and VIII, which give a description of the preparation of Intermediates, Preparations and Examples contained herein. One of the general methods used is outlined by equations in Chart I. This reaction can be carried out in alcoholic solvents, preferably refluxing butanol, or in dimethylformamide or dimethoxyethane in the presence of an acid receptor, as for example, an alkali-metal carbonate and preferably using potassium iodide catalyst. The reaction time may vary from a few hours to 24 hr, depending on reactivity of the aryloxyalkyl halide and temperature.

Temperature can vary from about 80 0 C to 125°C. Products are isolated, usually by partitioning in a solvent such as methylene chloride, chloroform or benzene and the like and a weak basic aqueous solution and washing, drying and concentrating the organic layer to give the free base which may then be converted, if desired, to an acid addition salt in a conventional manner.

Alternate Method B is shown by equation in Chart II. This reaction may be carried out in a suitable solvent such as tetrahydrofuran at room temperature for several hours. Preparation and isolation of the free base and a salt is typically described in Example 4.

I

AHR-438A-CIP Alternate Method C is shown by equation in Chart I. This reaction is suitable only when there is no other hydroxy radical present.

Mesylation or tosylation with such as mesyl or tosyl chloride is conducted in the presence of an acid receptor such as a tertiary amine; e.g., triethylamine, while cooling. The final reaction of the mesylate or tosylate with the DOeM9 is conducted in a suitable organic solvent and the product free base is isolated by conventional means such as washing, extracting with an acid solution and an organic solvent and evaporating the solvent. Salts ,4 may be prepared as described hereinabove.

SAlternate Method D is shown by equation in Chart IV. When the halo compound is reacted with the DOeMe compound, a suitable solvent is S"R R may be used as solvent and a temperature of about 100 0 C or above is suitable.

-Alternate Method E is shown by euqation in Chart V. The method is limited to preparation of certain derivatives such as wherein D is 2-pyridinyl or 2-quinolinyl. Dimethyl sulfoxide is a suitable solvent and 600C is at suitable temperature for the reaction.

Method F is shown by equation in Chart VI, the method is limited to preparation of derivatives wherein (A)d is and R 1 is other than hydro- Sgen, from Formula I compounds wherein (A)d is hydroxy. N,N-dimethylformamide is a suitable solvent and 800C is a suitable temperature for the 4R R reaction. The reactant RaX is advantageously used at about 10-100% excess to enhance desired product yield.

Method G is shown by equation in Chart VII, the method is limited to preparation of Formula I compounds wherein (A)d is aminomethyl from Formula I compounds wherein (A)d is cyano, tetrahydrofuran is a suitable solvent and 25-60°C is a suitable temperature for the reaction.

Method H is also shown by equation in Chart VI, the method is limited to the preparation of Formula I compounds wherein (A)d is -C(O)-OH from compounds of Formula I wherein (A)d is cyano, ethanol is a suitable solvent, and 780C is a suitable temperature for the reaction.

Method I is shown by equation in Chart VIII, the method is limited to o R1 0 00 A is hydrogen, -C-R 1 0C -C-N /2 *1 AHR-43 8A-CIP 0 11 the preparation of compounds of Formula I wh.erein (A)d is loweralkyl-C-0from compounds wherein (A)d is hydroxyl, by reaction of the desired hydroxyl compound with an appropriate acid anhydride. Methylene chloride is a suitable reaction mixture solvent and room temperature is a suitable temperature to carry out the reaction.

ii 0 00 I 0* 00 0 0 00 ''It I I I II 0 II I $0 0I 111.1 0 40 0 0I 0 0 00 00 0 0I 00 0*00 I 0 000t 00 0~ 00 or-ArkUt:12h.4-; A, i, ana z, are selecTea irom mne group coIibibL.ig ui IyL.uLzU6I, loweralkyl, halogen, 0

R

-CH

2 ,-C(O)0R 1 2

R

4 /3 AHR-438A-CIEP CHART I Preparation of Compounds of Formula I: Method A.

05 0 0 ~0 S 50 0 05

S

00 5 0 50 0000 0 00 00 0 00 0 O SO 5040 01 19 9 0 54 0 0 0 05 (A)d Ar~ H (CH 2 )m-(B)z-D

(CH

2 )e Solvent, e.g., butanol, DMF, Acid Receptor, e.g., Na 2

CO

3 NaHCO 3

KOO

KI Catalyst (optional) 05 0 ,0 00 0~5~ 0 0 0 00 0 0 (Ad Ar~ )d -(CH)m-O-D

(CH

0 )e )p Optionally when A =OH and n=zero Ar

(CH

2 )M-(B)z-D k(CH 2 )e Rp halide' L -bvuL~iuea xy x, y and Z where X is -CH(QH)-lower alkyl or -NH-C(Ck) C(O)-O-lower alkyl.

i) 7;

'I

I,

AHR-438A-CI:P CHART II Alternate Preparation of Compounds of Formula I: Method B.

(R Ar, n Of (Q)n is zero) 44 44 4 4 4 4 0 4 44 44 4 44 14 4 9 44 6990 44 44 6 ii 4 14 44 4949 1. ii 49 4 4, 46 4 4 44 94 4 44 44 4~4 4 4 0 4444 4 4.~44, 4 o 4 Ar 11 Ar~ (CH2)m-(B)z-D Ar I HP \c

(CH

2 )m-(B)z-D Ar

X

CN- (CH 2 )M-(B)z-D EtOX C halo 2ArMgX*

HI

1 ASC 49 -14- AHR-438A-CIP CHART III Alternate Preparation of Compounds of Formula L Method C.

0 Ar (A)d Ar ~(CH,)m-OH when no other

(CH

2 )e hydroxyl is p present (A~d acid receptor Ar 0,I

(CH

2 (CHk 2 )e )I *4444 (A)dMeOD Ar I 444 -(CH 2 )m-0-D 4 (0H' 2 )e 0 Footnotes: a 4 4 halo.

0 Ib#4 1 mesyl, tosyl, etc.

alkali-metal ion.

compositions therefor. The compounds of this structure are within the scope AHR-438A-CIP CHART IV Alternate Preparation of Compounds of Formula I: Method D.

00 00 0 0 0 00 0 0 0-0 0 00 0 00 00 0 4~ *0 *000 0 00 00 0 00 0 4 00 00 0000 O 00 00 0- 0 0~ 0-0 0 0 00 00 0 0 00 0 &0 0,0 0- 0 0- 00-0,0 0 00)00-i 0 0 (A)d Ar -(GH,)mOD (CH1 2 )e R )p DOeMO (A)d Ar I -(CH 2

)M-X*

(CH

2 )e

I-

N-D

Ar(A)d R C N- -Q (CH 2 )m-N-D

R

halo alkali-metal ion.

L_ poLuncs ul wne presenT, invention in Tne SUDS~tit1of in tfle 1-position ot thle piperidine radical and are not within the scope of generic formulas hereof of compounds for novel treatment methods or novel compounds.

-16- AHR-438A-CIEP CHART V Alternate Preparation of Certain Compounds of Formula I: Method E.

Ar(A)d Ar Cgnye.

(0H 2 )e (CO) _eq *0 *~0 00 0 00 0 C 00 0 00 o o* O 0 0 o oo 000 0 *0 00 0 Co o 0 00 0 0000 0 00 00 0 0 0.0 00 0 0 00 0* 0 0 00 0 0.0 o~ JO 0 0 0.J 0.0 0 *0.00 ~0 0 or N N Ar(A)d I N-(0H 2 )m-4D** (CH.)e I

R

*MD= alkali-metal cation pyridin-2-yl or quinolin-2-yl.

halo (Br, Cl).

x 0 R (pheny) 2 -C N.(CH)n-C 4

V

N

-17- AHR-438A-CIEP 00 44 00 0 0 *0 4 00 0 ~'4 4 04 00 9 00 0004 0 4 0 00 0 94 0 40 0 44 4*04 4 40 *4 0 4 04 00 0 0 00 &4 4 4 00 4 4,* 0. 4 *4 4 01~04 0 0 CHART VI Method F.

Certain compounds of Formula I wherein (A)d is hydroxyl may be converted to compounds of Formula I wherein (A)d is -0-R 1 when desired (when no other hydroxyl is present), as is illustrated by the following equation:

OH

Ar~ I_ 11-1 (Q)n (CH,)m-(B)z-D

(CH

2 )e NaH R'X* halogen)

DMF

01 Ar

(Q)V

N-(CH,)m-(B)z-D (CH2)e)

R

1 is not hydrogen, and R'X is reacted in about 10-100% molar excess.

When RI is phenyl or phenyl loweralkyl, phenyl substitution is restricted to electron withdrawing groups, nitro radicals.

-D)z is contined to Oxygen

~NT

-18- AHR-438A-CIIP CHART VII Method G.

Certain compounds of Formula I wherein (A)d is aminomethyl. may be prepared via compounds of Formula I wherein (A)d is cyano, and is illustrated by the following equation;

N

C

a~ n a C1) (CH 2 )m-(B)z-D R

P

aa ~NH 2

~LAH

Li*la

CH

2 n

N-(CH

2 )m-(B)z-D ~(UkH 2 )e a a :Method H.

Certain compounds of Formula I wherein (A)d is cyano, may be 0 11 a a hydrolized to compounds wherein (A)d is -C-OH, as illustrated by the following equation:

N

C

I~ (CH.)m-(B)z-D (CH1 2 )e O0I 1. KOH, 2 M, A C-H2. H+ Ar

(CH

2 )e(CH 2 )M(B)z-D

R

o s iNOON WM -19- AHR-438A-CIP CHART VIII Method I.

0 Certain compounds of Formula I wherein (A)d is R may be prepared from compounds of Formula I wherein (A)d is hydroxyl when desired, as is illustrated by the following equation: t

OH*

Ar (Q)n 0" I- (CH,)m-(B)z-D (CH,)e 04 O 4R R c=o 4CO 0 Ar

I

C (Q)n I(H e- (CH)m-(B)z-D (CH2)e I )p 4424

R

*No other hydroxyl present S* R' is loweralkyl To prepare acid addition salt, the free base is reacted with the calculated amount of organic or inorganic acid in aqueous miscible solvent such as ethanol or isopropanol, with isolation by concentrating and/or cooling, or the base is reacted with an excess of the acid in aqueous immiscible solvent such as diethyl ether or isopropyl ether, with the desired salt separating directly.

Exemplary of such organic salts are those formed with oxalic, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, 00 0 II II 1 it or 0 Ri AHR-438A-CIP glutamic and stearic acid and the like. Exemplary of such inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

To prepare quaternary salts the free base of a formula I compound may be reacted with a loweralkyl halide, preferably methyl iodide or methylbromide, or may be reacted with a loweralkyl sulfate, preferably methyl sulfate.

If desired, the free base may be regenerated by proportioning the acid addition salt between an organic solvent such as methylene chloride and a ,t weakly basic aqueous solution of, for example, sodium bicarbonate and separating the methylene chloride layer and evaporating it.

SPrecursors (Chemical Intermediates) used in the synthesis of compounds of Formula I are prepared in a number of ways as illustrated by 'the following 1 to 13 sets of equations which are also applicable to pyrrolidinyl and homopiperidinyl derivatives. (See also U.S. Patents 3,922,276 and 3,956,296).

tn II' 1 t 4 L( 44 4£ 4 vwtLdr9~yIas used herein includos pnenyl connected by hydrocarbon chains exemplified by loweralkyl above and wherein phenyl may be AHR.-438A-CIEP 0

OH

S ArMgX Ir NO -j~ -ArMgX A 94 04 #0 0 0 40 0 0 0 00 00 9 4 0 40 4009 4 4 04 4 94 0 4 #4 4 00 .49, 0 4I 94 0 t 04 4 4 4 04 00 0 4 49 00 4440 4 0 #040 *~000o 0 0 HiI, HOAC, A

H

2 Pd/C or NAO Hr ,iodiuimli Al J90 0

C

Pd/C HOAC, A HI, P, HOAC 0H C-r

OH

HNa7-Ar 2 (2) HND-COEt PhCH-NajCHAr 2

H

2 Pd/C HNZCHAr 2 Ph phenyl.

HND ~c /Ar HN1Z Ar PhCH 2

X

(X C1, Br)

HI

P, HOAC

A

H

2 Pd/C HOAC, A PhCH 2 N- O 2 Et IArMgX PhCHN -Ar 2 H 2 Pd/C

H

2 Pd/C; HOAC; A or HI, P, HOAC; A Pd/C; HCI 'HOAC; A substituted phenyl when n is zero and (A)d is hydrogen or hydroxyl; or when d is zero and. a double bond forms between the a-carbon of a saturated central heterocyclic amine ring.

p

A>

AHR-438A-CTEP HNaDCOEt PhSOCI PhSO 2 NZD-COEt -Ar T) J ii MgXArz O H Li HBr PhSO 2 -N -Ar 2 Phenol A1H,

OH

HNa C-Ar 2 HI, P, HOAC, 04 44 4 4 94 4 6 4 .9 4 46 4 6 64 4.4.

4 44 44 4 44 0 66 4044 49 4 40 4 4 4 4 44 49 4 4 44 4 04 4 4 4 0~4 0 4 H IP, HOA C, HNajCHAr 2 HND7-CO 2 Et H D=CAr

CH

2 0O* CH 2 (N7a.COEt), HCl, H 2 0

A

IArMgX

OH

CH

2 (Na C-Ar 2 2 HI, P, HOAC HNQ2GHAr 2 0 Q -H Ar-H Hr N. _CH He H2,PdIC .H1J>CHAr 2 HOAC or HE, alcohol HNZ-c 2 Et D-O-(CH 2 )M-X -p-D-O-(CH 2 )M-N _CO.Et X Cl, Br I(1) ArMgBr

HE)

-Ar

OH

HSO, ~~C2mN I -C-Ar 2 H2, Pd/C D-04CHOm-NO -C-Ar2

HOAC

Ph phenyl.

AtTernate ivietnoa ts is snown Dy equation in '..nartui. inis reaction may be carried out in a suitable solvent such as tetrahydrofuran at room temperature for several hours. Preparation and isolation of the free base and a salt is typically described in Example 4.

AHR-438A-CIEP 0= C-H e RArCHM*

N

e

C

RArOHC(O)H E +0

M

1 RArC-0H, (2)H 6

D

4* 49 4* 4 4* 0 4 4 4 *4 *4 4 9 0 4.

44.4 4 '4 44 4 4f 4 *4 *04 4 00 44 4 4 44 4 4 '4 *4 04 4 *4

CH,

0

N

Strong base, BuLi 2) tence O)Ar R OH Ar

C

OH

2 1) and IH 2 Pt.

R zAr

CH

CHOH

H

SH +,A R Ar

C

N

H

SH,, Pd pressure, high temp.) R OH Ar

C

*4,4 O 444.

44 4

OH

2 H ,Pt

-H

NN

OH

OH

2 0

N

H

2 Pt R Ar

OH

N

H

M9 =Lie9or MgBr9 4Miulu vi -v uriuia i compouncts wherein (A)d is -U(U)-OH from compounds of Formula I wherein (A)d is cyano, ethanol is a suitable solvent, and 7800 is a suitable temperature for the reaction.

Method I is shown by equation in Chart VIII, the method is limited to

V.

-24- AHR-438A-CIP A CHCH

N

Ar~ Ph 0 ArN Ph-O-C-C1 30 NaODH-W Ar~ 'I=C r4 A9 4 4 9 9 4* 9 A 9 9 4 99 4 49 4 9 9 44 gAlA 4 4 4 49 4 99 4 g 4 4 9 99 P(Ph), P(Ph), Base PPh, N N Ph Ph Cl

N

Ph eHCI 4149 9 99 II 4 4 99 9 1 4 99 44 4 9 94 I 4* 9444 4 9 14,44 44 49 0 Ar 11

OCH-C-H

Ar1 HCR

'NH

Ar/ fH 2 Pt tCr0 3 A CHCHCNIH Ar/ 1 'N aOH Ar,

CCH

I/CH

2 0 11

I,

Ar NCCHC PPh, Base Ar *Commercially available Ph phenyl Ph NO 'H-C PPh 3 Ar

H

Ar Ph AHR-438A-CIP A)d Ar-C /Q H X-(CH,)m-OH

(CH

2 )e

R

R A)d Ar-C

-(CH)M-QH

X =halo.

(C;H

2 )e to N p

CN

C~N (10) (C 2 v 4 4 R a( CH lO-S-

C=

nI 0,1 R= 20 0aO OH r H9c--

CC=N

t~ I I "It~(H)nC F) 2 4 C 2

N~

N X0= phenyl

H

halid6 AHR-438A-CIP

H

Ar-C- A)d*

IC

2 RUl lithium dipropylarnine Li" e Ar-C- (A)d kCH 2 )e ii a.

a. j S S a~i a 1 *5 4 *5 5 4 #4 0 ii ii I it I S S 5 *6 45*4

S

IS I 4 *5 a 'Ad Ar- C

D

(CH

2 )e (12)

R

Ts-O (A)d -HAr-C

-CH

2 -Ph

H

2 /Pd I(CH2)e O

R

11 11 is -C-O-R 1 or Ph phenyl Ts tosyl 0 Ar-C S0 2 -Ph

R-CH

2 -MgBr

*CH

2 -Ph *4*5 5 0*1* 4004

HI

HOAc, Ar-OH

-H

CH

2

R

OH

kr-C N-S0 2 -Ph

OH

2 \iAIH, Ar-C

H

OH

2 AHR-438A-CIP

N

C

Ar-CH Ph Butyllithium sq 4~ I q t 9 Ia a 4 a a *4 S a a 4 ag I a I al I a. a I I a I aa

N

III

C

Ar-C

CH

2 )Ph

I

R-CH

2 Br 0 11 C]-C-O-Ph-

N

III

C

Ar-C NH

CH

2 NaOH

H

2 0 s ~a t I 14 41 4 r Ga S I 4 I 1* The method of preparation of certain starting materials wherein D is phenyl substituted by hydroxy is illustrated by the following equation: II 4 1 04 4 *0 a. a I 144 a 104404

OH

HO- C--CH,+ 0

CH,

The preparation of other hydroxyphenyl intermediates and compounds is illustrated by the following equation: -28- AHR-438A-CIEP 00 00 0 0 0 00 0 00 I 00 0 @0 4 0 0 0 00 0040 *4 04 4 00 0 0 *0 0 00 Q9 Cl- (CH 2 )M-CI

(H)C

Na as in *Chart I 0= phenyl.

The preparation of certain substituted phenol starting materials is illustrated by the following equations: 00*0 0 00 *0 0 0 00 00 0 0 04 40 0 0 0 0 0 04 0040 0 0 4000 0*4000

-CH

2 Q -NH 2

CISOCH,

CHN =C 0 0 11 CICOEt

OICH

2 Q NHSO 2

CH,

O 0 11 0-CH 2 9 NHC-NH OH 3 0 11 .2-CH 2 9 NHC-QM Pd/C

H

2 HO- NHSO 2

CH,

0 11 HO- yj NHC-NHCH, 0

II

HO- NHC-OEt 0 phenyl.

i -29- AHR-438A-CIP v The preparation of chemical intermediates is further illustrated in the following Preparations 1 to 192. Examples 1 to 232 illustrate the synthesis methods for preparing compounds of Formula I. The scope of the invention is not limited by the descriptive methods and procedures of the preparations and examples, however.

00 00 0 4 rI o 0 O0 0 06 00 00 4 00 0* 0 0 0 *0 OtkOG Sa a 00 9 0* 00 0 o 00 0 *r 0 0 0*40O 0 0 t ~n rrr '-II- AHR-438A-CIP Preparation 1 4-Diphenylmethylenepiperidine.

A solution of 7.0 g of 1-acetyl-4-diphenylhydroxymethylpiperidine in ml of absolute alcohol and 76 ml of concentrated hydrochloric acid was heated at reflux for seven hours, cooled and made basic with 50% sodium hydroxide. The oil which separated was extracted with benzene and the combined extracts washed with water. After drying over magnesium sulfate the solvent was evaporated at reduced pressure. The residual oil which crystallized on cooling was recrystallized twice from petroleum ether to give g of white crystals, m.p. 85-860C.

S" Analysis: Calculated for C 18

H

19 N: C, 86.70; H, 7.68; N, 5.62 Found C, 86.70; H, 7.83; N, 5.73 Preparation 2 [a,a-Bis(p-fluororL?-onyl)]-4-pipeidinemethanol hydrochloride hydrate [1:1:0.51.

0 This compound was prepared by the method described in Preparation 1 of U.S. Patent 4,032,642, m.p. 243-243.5oC from the Grignard reagent formed with p-fluorobromobenzene and 1-acetyl-4-(p-fluorobenzoyl)piperidine followed by hydrolysis and conversion to the salt.

"Preparation 3 l1-(Phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride A mixture of 100 g (0.637 mole) of ethyl isonipecotate, 80.64 g (0.64 mole) of benzyl chloride and 67.84 g (0.64 mole) of sodium carbonate in 1 liter of absolute ethanol was refluxed for 8 hours and then was stirred at room temperature for 10 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.

The methylene chloride phase was dried over magnesium sulfate, and the solvent was removed in vacuo to give the free base of the title compound as a liquid. The free base was converted to the hydrochloric acid salt, and the salt was recrystallized from ethanol-ether to give 89.33 g of white crystalline solid, m.p. 154-1550C.

-31- AHR-438A-CIP Analysis: Calculated for C 1 5

H

2 2

NO

2 C1: C, 63.48; H, 7.81; N, 4.94 Found C, 63.07; H, 7.82; N, 4.91 Preparation 4 a,a-Bis-(4-fluorophenyl)-l-(phenylmethyl)-4-piperidinemethanol.

To a 6.08 g (0.25 mole) of magnesium turnings and an iodine crystal in 600 ml of dry tetrahydrofuran and under an atmosphere of nitrogen was added, dropwise, a solution of p-bromofluorobenzene in 125 ml of tetrahydrofuran. The temperature of the reaction was kept below 10°C by cooling in an S' ice-methanol bath. The mixture was stirred at room temperature for a* hours. A solution of 24.7 g (0.10 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 17 hours. The reaction was S I poured into an icy, aqueous solution of ammonium chloride, and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over S omagnesium sulfate. The solvent was removed in vacuo to give an oil. This So was crystallized from ether-hexane to give 19.87 g of the title a, compound, m.p. 113-1150C.

r Analysis: Calculated for C 25

H

25

NOF

2 C, 76.31; H, 6.40; N, 3.56 SFound C, 76.24; H, 6.38; N, 3.50 o, •Preparation [a.a-Bis(p-fluorophenyl)]-4-piperidinemethanol.

A solution of 31.2 g (0.079 mole) of a,a-bis-(4-fluorophenyl)-l- (phenylmethyl)-4-piperidinemethanol in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70°C over 5% palladium on carbon over the weekend. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue, and the gum crystallized. The mixture was diluted with petroleum ether, and the solid was collected by filtration, washed with petroleum ether, and dried to yield 22 g of white solid which was recrystallized from 2-propyl ether/2-propanol, m.p. 159.5-160.50C.

Analysis: Calculated for C 18

H

19

F

2 NO: C, 71.27; H, 6.31; N, 4.62 Found C, 70.93; H, 6.71; N, 4.38

C-OH

Ar H S I (CH 2 )m-(B)z-D (CH)e

R

-32- AHR-438A-CIP Preparation 6 1-(Phenylsulfonyl)-4-piperidinecarboxylic acid, ethyl ester.

To a solution of 10.1 g (0.0642 mole) of ethyl isonipecotate in 300 ml of pyridine and cooled in an ice bath was added 13.2 g (0.075 mole) of benzene sulfonyl chloride. The mixture was stirred for 2 hours at room temperature, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in 0 vacuo to give a solid. This was recrystallized from ethanol-ether to give 4.59 g of crystalline solid; m.p. 85-86.5 0

C.

0 0 Analysis: Calculated for C 14

H

19 NO4S: C, 56.55; H, 6.44; N, 4.71 Found C, 56.53; H, 6.55; N, 4.67 In another preparation, 100 g (0.634 mole) of ethyl nipecotate and 130.4 g (0.74 mole) of benzene sulfonyl chloride were reacted by the above procedure for 4.5 hrs to give the title product in 78.1% yield.

00 0 0° Preparation 7 0 o04e a,a-Bis(4-fluorophenyl)-l-(phenylsulfonyl)-4-piperiainemethanol.

o To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of tetrahydrofuran (dried over molecular sieves 5A) under an atmosphere of nitrogen and cooled in an ice bath was added dropwise a solution of 243.25 g (1.39 mole) of p-bromofluorobenzene in 150 ml of tetrahydrofuran.

*The mixture was stirred for 2 hr after the addition was completed. To this 0 0 mixture was added 103 g (0.346 mole0 of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The phases were separated, and the solvent was removed in vacuo from the organic phase. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and was reduced in vacuo to 1 liter volume. The title compound was obtained by adding hexane and cooling, recrystallizing the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 1300C for 45 min at which time the product had partially melted, m.p. 142.5-144 0

C.

oase is reacrea witn an excess or te aca in aqueous immiscible solvent such as diethyl ether or isopropyl ether, with the desired salt separating directly.

Exemplary of such organic salts are those formed with oxalic, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, citraconic, itaconic, hexamic, p-aminobenzoic, -33- AHR-438A-CIP Analysis: Calculated for C 24

H

23 N0 3

SF

2 C, 65.00; H, 5.23; N, 3.16 Found C, 65.21; H, 5.30; N, 3.10 Preparation 8 4-[Bis(4-fluorophenyl)methylene]-l-(phenylsulfonyl)piperidine.

A solution of 5.23 g (0.0118 mole) ofa,a-bis(4-fluorophenyl)-l- (phenylsulfonyl)-4-piperidinemethanol in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was refluxed for 2-1/2 hours and then poured over ice. The mixture was made basic with 50% sodium hydroxide, and the basic mixture was extracted with methylene chloride. The methylene chloride solution was S: i, dried (anhydrous sodium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g of white crystalline solid, m.p. 90-92.5 0

C.

Analysis: Calculated for C 24

H

2 1 N0 2

SF

2 C, 67.75; H, 4.98; N, 3.29 Found C, 67.73; H, 5.00; N, 3.21 Preparation 9 4-[Bis(4-fluorophenyl)methylene]piperidine hydrobromide A mixture of 164 g (0.342 mole) of a,a-bis(4-fluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol and 80 g (0.85 mole) of phenol in 700 ml of 48% hydrobromic acid was refluxed for 7 hr and then was stirred at room temperature for 9 hr. The hydrobromic acid solution was decanted from a, a gum in the bottom of the reaction flask. The gum was triturated with -1 I liter of ether, and a tan solid formed. The solid was washed with several portions of ether and was dried under high vacuum to give 9.13 g of slightly impure title product, m.p. 211-215 0 C. A small sample of this solid was recrystallized from methanol to give an analytically pure sample as a crystalline solid; m.p. 216-218°C.

Analysis: Calculated for C 18

H

18 NBrF 2 C, 59.03; H, 4.95; N, 3.82 Found 58.96; H, 4.98; N, 3.76 Preparation 4-[Bis(4-fluorophenyl)methyl]piperidine fumarate hydrate [1:0.5:0.51.

A mixture of 30.6 g (0.99 mole) of phosphorous and 15.1 g (0.059 mole) of iodine in 90 ml of glacial acetic acid was stirred for 20 min at room tempera-

I-

-34- AHR-438A-CIP ture. A mixture of 6 ml of water, 70 ml of methanesulfonic acid, 56.19 g (0.197 mole) of 4-[bis(4-fluorophenyl)methylene]piperidine and 110 ml of glacial acetic acid was added, and the mixture was refluxed for 7 hr. The solvent was removed in vacuo, and the resulting viscous liquid was poured over ice. The icy mixture was made basic with 50% sodium hydroxide, and the basic suspension was extracted with methylene chloride. The methylene chloride solution was extracted with an aqueous solution of sodium thiosulfate and was dried over anhydrous sodium sulfate, and the solution was filtered through Celite®. The solvent was removed in vacuo to give a gum.

The gum was dissolved in 400 ml of hot methanol, and 4.25 g of an unknown S"o tan solid was collected from the warm solution. Funaric acid (22 g, 0.190 S* mole) was added to the methanolic solution followed by the addition of ether.

A white precipitate was collected to give 22.55 g of crystalline solid; m.p. 208-209C.

Analysis: Calculated for C 20

H

22 N0 2 .5F2: C, 67.78; H, 6.26; N, 3.95 Found C, 67.86; H, 6.12; N, 3.81 Preparation 11 S 4-[a-(p-Fluorophenyl)-a-phenyl]methylpiperidine hydrochloride This compound was prepared as described in U.S. Patent 4,032,642 by hydrogenation of a-(p-fluorophenyl)benzylidinepiperidine over palladium charcoal catalyst, m.p. 81-82 0

C.

Analysis: Calculated for C 18

H

2 1 C1FN: C, 70.69; H, 6.92; N, 4.58 Found C, 70.69; H, 6.93; N, 4.52 Preparation 12 1-[4-(3-Chloropropoxy)-3-methoxyphenyllethanone.

To a mixture of 15.15 kg (96.26 mole) of 1-bromo-3-chloropropane and liter of water heated to 86°C was added a solution of 8 kg (48.13 mole) of acetovanillone in 3.93 kg (48.6 mole) of 50% aqueous sodium hydroxide and 89 liter of water over a 2.5 hr period. The mixture was heated at 80-85°C for hr after addition was complete. The mixture was cooled and extracted twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal, and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate ~i i Pd/C; HCI Ph phenyl. HOAC; A AHR-438A-CIP and concentrated under reduced pressure. The residue was heated to reflux Sin 15 gal of diisopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by filtration together with additional compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 kg Acetovanillone recovered was 3.4 kg. The product was recrystallized twice from cyclohexane and twice from ligroin, m.p. 57.8- 58.50C.

Analysis: Calculated for C 12

H

15 C10 3 C, 59.39; H, 6.23 Found C, 59.07; H, 6.22 9 Preparation 13 S1-(3-Phenoxypropyl)-4-piperidinecarboxylic acid ethyl ester oxalate SttA mixture of ethyl isonipecotate (35.5 g, 0.226 mole) 3-phenoxy-1bromopropane (51.6 g, 0.24 mole) and sodium carbonate (25.4 g, 0.24 mole) in 500 ml of absolute ethanol was refluxed for 16 hr. The solvent was removed S in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give a liquid. The liquid was dissolved in absolute ethanol, and a solution of oxalic acid (-0.23 mole) in absolute ethanol was added. The product 73.43 g precipitated as a white, crystalline solid, m.p. 180-181.50 T it Analysis: Calculated for C 19

H

27 NO7: C, 59.83; H, 7.14; N, 3.67 Found C, 59.76; H, 7.17; N, 3.64 SPreparation 14 4-[Bis(4-fluorophenyl)methylene]-l-(phenvlmethyl)piperidine maleate [1:1.

A mixture of a-a-bis(4-fluorophenyl)- -(phenylmethyl)-4-piperidinemethanol (5.09 g, 0.013 mole) in 200 ml of acetic acid and 10 ml of 2M sulfuric acid was refluxed for 2 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.

The-methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give the free base of the title compound as a solid. The free base was dissolved in methanol-diethylether and maleic acid solid. The free base was dissolved in methanol-diethylether and maleic acid§ i i i 'Ar

S-H

2 ,PdIC D-O-(CH)m-N -C-Ar 2

HOAC

Ph phenyl.

-36- AHR-438A-CIP (excess) was added. The product (5.24 g, 82.1%) precipitated as a white, crystalline solid, m.p. 180-181.5 0

C.

-Analysis: Calculated for C 29

H

27

NF

2 0 4 C, 70.86; H, 5.54; N, 2.85 Found C, 70.80; H, 5.45; N, 2.79 Preparation a-a-Bis(4-fluorophenyl)-4-pyridinemethanol.

The Grignard reagent was prepared from 4-bromofluorobenzene (66.6 g, 0.381 mole) and magnesium (9.13 g, 0.381 mole) in tetrahydrofuran (ice V o bath). The Grignard reagent was stirred at room temperature for 1.5 hr and *o transferred (under nitrogen) to an addition funnel. This solution was added 0.o, dropwise to a tetrahydrofuran solution of ethyl isonicotinate (25.0 g, 0.165 mole) (ice bath cooling). The reaction mixture was stirred 3 hr at room temperature and poured onto ice containing ammonium chloride (28 g, mole). The mixture was allowed to stand overnight. The reaction mixture was diluted to 3 liter with water and extracted with chloroform. The 0*o chloroform layer was back extracted with dilute sodium hydroxide. Removal 0' of chloroform gave a gummy brown solid. The brown solid was triturated with methanol-diethyl ether (10-120 v/v) and placed in the refrigerator o freezer. Solid was filtered off and dried overnight in vacuo at 8 0 'C to give 11.86 g of white crystalline product, m.p. 185-189°C Analysis: Calculated for C 1 8

H

13

NOF

2 C, 72.72; H, 4.41; N, 4.71 0 Found C, 72.76; H, 4.39; N, 4.67 0 Preparation 16 4-[Bis(4-fluorophenyl)methyl]-l-(phenylmethyl)piperidine, fumarate S[1:1].

A mixture of 4.3 g (0.139 mole) of phosphorous, 44 g (0.196 mole) of a aqueous solution of hydrogen iodide and 4.15 g (0.0106 mole) of 4-[bis(4fluorophenyl)methylene]-l-(phenylmethyl)piperidine in 60 ml of glacial acetic acid was refluxed for 1 hr. The mixture was poured over ice and was made basic with 50% sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with an aqueous solution of sodium sulfite and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3.89 g of the free L j

NK

*M =Li orMgBr® H 9 |t -37- AHR-438A-CIP base of the title compound. The free base was converted to the fumarate salt, and the salt was recrystallized from methanol-ether to give 3.62 g (69.3%) white solid; m.p. 201-202°C.

Analysis: Calculated for C 29

H

29 N0 4

F

2 C, 70.57; H, 5.92; N, 2.84 Found C, 70.69; H, 5.95; N, 2.81 Preparation 17 4-(2-Chloroethoxy)benzoic acid ethyl ester.

A mixture of 71.7 g (0.5 mole) of 1-bromo-2-chloroethane, 83.1 g So mole) of ethyl p-hydroxybenzoate and 69.1 g (0.5 mole) of potassium 0 eo carbonate in 200 ml of acetone was heated at reflux for 40 hr. The solids were o o removed by filtration and the filtrate was evaporated under reduced pressure to leave a semi-solid residue. The residue was triturated with 200 ml of o sodium hydroxide solution and filtered.1 The filter cake was washed with water (100 ml) and dried to give 42.4 g (80%)2 of a solid. A sample was recrystallized from benzene-petroleum ether (30-60°C) to give white solid, m.p.74-76°C.

Analysis: Calculated for CllHi 3 C10 3 C, 57.78; H, 5.73 Found C, 57.87; H, 5.82 1The filtrate pH was adjusted to 2 with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water (100 ml) and dried to give 44.4 g of ethyl p-hydroxybnzoate.

2The yield is based on unrecovered starting material.

Preparation 18 1-[4-(2-Chloroethoxy)-3-methoxyphenyl]ethanone.

To a solution of 12.7 g (0.55 mole) of sodium metal in 750 ml of absolute ethanol was added 83.1 g (0.5 mole) of acetovanillone to give a slurry. This slurry was then added over a 3-hr period to a solution of 107.6 g (0.75 mole) of 1-bromo-2-chloroethane in 500 ml of absolute ethanol at reflux. An additional 250 ml of ethanol was used to wash the slurry into the reaction mixture. The mixture was heated at reflux overnight and then concentrated under reduced pressure to give a solid as residue. The solid was partitioned, between 1 liter of benzene and 1 liter of water. The aqueous layer was Ar *Commercially available .CHCH N Ph phenyl Ar Ph -38- AHR-438A-CIP extracted with 500 ml of benene and the combined organic layers were washed successively with three 200 ml portions of a 5% sodium hydroxide solution, once with water and once with brine. The benzene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil which gradually crystallized. The solid was triturated with petroleum ether, collected by filtration and recrystallized from 2propanol to yield 48.5 g of off-white solid. An analytical sample was prepared from isopropyl ether, m.p. 69-710C.

Analysis: Calculated for CllH 13 C10 3 C, 57.78; H, 5.73 Fournd C, 57.55; H, 5.74 a Preparation 19 1-[4-(4-Bromobutoxy)-3-methoxyphenvilethanone.

.extracted with 500 ml ofbenene and the combined organic layers were SwsTo a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated.

The mixture was stirred at ambient temperature for 1 hr and then added over .3 ita 3-hr period to a solution at refdux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was S heated at reflux overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated, and the organic layor was washed with four 300 m portions of a 5% sodium hydroxide solution, once Swith water, and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 138 g of gummy solid as residue.

This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethyl acetate in benzene to yield 69.6 g of title compound as an off-white solid. Te solid was recrystallized from isopropyl ether, m.p. 52-54C.

Analysis: Calculated for C 13

H

1 7BrO 3 C, 51.84; H, 5.69 Found C, 52.03; H, 5.76

N

SPreparation 4-(DiphenIlm thl)pyridine.

A mixture of 99 g (0.379 mole) of diphenyl-4-pyridylmethanol, 50 ml of cone. hydrochloric acid, 200 ml of 57% hydroiodic acid and 200 ml of glacial acetic acid was refluxed for 4-1/2 hr and then was stirred at room temperature for 12 hr. The reaction mixture was poured over ice and was made basic with 50% sodium hydroxide. An aqueous solution of sodium thiosulfate was 4 i of methylene chloride-ether-hexane to give two crops of crystalline solids: Crop I, 40.87 g m.p. 124-126'C; Crop II, 25.38 g m.p. 123- 125°C. Analysis of the mixture of the Crops I and II was as follows: 04 Analysis: Calculated for Cs 1

H

15 N: C, 88.13; H, 6.16; N, 5.71 Found C, 87.67; H, 6.01; N, 5.56 Preparation 21 S1-(3-Chloropropoxy)-4-methoxybenzene.

A solution of sodium hydroxide 20.0 g (0.5 mole) in 300 ml of water and p-methoxyphenol, 62.1 g (0.5 mole) in 300 ml ofdioxane was stirred for 1 hour at room temperature. 1-Chloro-3-bromopropane (472.35 g, 3.0 mole) in 100 ml of dioxane was added, and the reaction mixture was stirred overnight at 0 C. The lower layer was separated, and the aqueous layer extracted with 4 hexane. The lower layer and hexane layer were combined, dried, and solvent was removed in vacuo. The residue was dissolved in chloroform and extracted v:ith 5% sodium hydroxide; removal of chloroform by evaporation gave a yellow oil. A 10-g sample of the oil was subjected to column chromatography on silica gel with an elution series composed of hexane-methylene chyride-methanol. This furnished 9.64 g (79.3% based on the aliquot taken) of pure clear oil.

Analysis: Calculated for C 1 0

H

1 3 0 2 C1: C, 59.86; H, 6.53 Found C, 59.39; H, 6.56 SPeri2 Ar-CH

-H

R

Ar-C

H

CH

2

R

:i :I ~i~ AHR-438A-CIP a a oi a a a a a a'a *d C Q 4:0 Sao *6 44 ,a a 4 O) 4441L a a 00 4 a 0 a.

o 0'4 04 4) o -o a 0.4 alr a C V~a a 4k a Preparation 22 1-[4-(3-Chloropropoxy)phenyl]ethanone.

The sodium salt of p-hydroxyacetophenone was prepared in 200 ml of dioxane-400 ml of water from p-hydroxyacetophenone (68.08 g, 0.5 mole) and sodium hydroxide (20.0 g, 0.5 mole). The reaction mixture was stirred 3/4 hr at room temperature. Next, chlorobromopropane, (472.35 g, 3.0 mole) was added along with 200 ml of dioxane, and the mixture was heated at 80-90 C overnight with stirring. The mixture was diluted to 4 liters with water; the aqueous phase was extracted with hexane and chloroform. These were combined and back extracted with 5% sodium hydroxide. The solvent was removed in vacuo with heating. A 10-g sample of the oil was subject to column chromatography on silica gel using hexane-methylene chloridemethanol. Fractions with similar TLCs were combined, and solvent removed. The oil from the column did not analyze, therefore a short-path bulbbulb distillation was carried out. This produced 4.38 g of clear oil.

Analysis: Calculated for CllH 13 0 2 C1: C, 62.12; H, 6.16 Found C, 61.70; H, 6.17 1 H NMR (CDC13) Analysis: 8 8.1 doublet 8 6.8-7.0 doublet 84.1-4.3 triplet 83.6-3.8 triplet 8 2.5 singlet aromatic portons aromatic portons

CH

2 -CH2-

-C-CH

3 or COCH 3

O

8 2-2.4 triplet Preparation 23 4-(Diphenylmethyl)piperidine hydrochloride A mixture of 62.69 g (0.256 mole) of diphenyl-4-pyridylmethane and 6.4 g of 10% palladium on carbon (0.0060 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 850 for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene i -Y I r -41- AHR-438A-CIP chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanol-acetonitrile, and excess ethereal hydrogen chloride was added. A precipitate was collected to give 59.13 g of slightly impure title compound as a white crystalline solid, m.p. 273-274C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, m.p.

275.5-2770C.

Analysis: Calculated for C 1 8

H

22 NC1: C, 75.11; H, 7.70; N, 4.87 Found C, 75.03; H, 7.73; N, 4.93 o0 T Preparation 24 o o S" a-(4-Fluorophenyl)-a-phenyl-4-pyridinemethanol.

To a suspension of 18.5 g (0.761 mole) of magnesium turnings and several crystals of iodine in 800 ml of anhydrous ether, cooled in an ice bath and under an atmosphere of argon, was slowly added a solution of pbromofluorobenzene in 200 ml of ether. The solution was stirred for 2 hr at and 97.02 g (0.530 mole) of 4-benzoylpyridine was added as a solid. An additional 1 liter of anhydrous ether was added, and the solution was stirred at 25°C for 3 hr. The reaction mixture was poured into an icy, aqueous solution of ammonium chloride. The mixture stood in the hood overnight and a white solid was collected. The solid was dissolved in a mixture of methanolmethylene chloride. The solution was filtered and the solvent was removed in vacuo. The residue was crystallized from chloroform-hexane to give 66.68 4 g of title compound as a white, crystalline solid, m.p. 189-1920C. Part of this was recrystallized from methylene chloride-acetonitrile-hexane, m.p.

190-1920C.

Analysis: Calculated for C18H 14 NOF: C, 77.40; H, 5.05; N, 5.02 Found C, 77.24; H, 5.03; N. 4.90 Preparation t,a-Bis(4-chlGrophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.

Following the procedure of Preparation 7, but substituting pbromochlorobenzene for p-bromofluorobenzene, the title compound was prepared.

Ii 1 0 0 phenyl. HO NHC-OEt i .i\ -42- AHR-438A-CIP Preparation 26 4-[Bis(4-chlorophenyl)methylene]piperidine hydrobromide hydrate A mixture of 69.33 g (0.146 mole) of a,a-bis(4-chlorophenyl)-l-(phenylsulfonyl)-4-piperidinemethanol and 26 g (0.277 mole) of phenol in 400 ml of 48% hydrobromic acid was refluxed for 6 hr and then was stirred at room temperature for 10 hr. The reaction solution was decanted from a gum which had formed in the bottom of the reaction flask. The gum was washed with several portions of water and then was crystallized from ether to give a solid.

S" o The solid was recrystallized from a mixture of methanol-diethyl ether to give 26.52 g of white crystalline solid, m.p. 106-109°C.

Analysis: Calculated for Ci 8

H

2 0NBrC120: C, 51.83; H, 4.83; N, 3.36 Found C, 52.13; H, 4.62; N, 3.38 0 ~Preparation 27 1-Chloro-4-(3-chloropropoxy)benzene.

0 A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 189 g (1.2 mole) of 1bromo-3-chloropropane, 249 g (1.8 mole) of anhydrous potassium carbonate, and 600 ml of acetone was stirred vigorously and heated to reflux for 16 hr 0: under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration, and the acetone and excess bromochloropropane were removed by heating under reduced pressure. The residue was dissolved in 0o petroleum ether, and the resulting solution was cooled in an ice-isopropyl alcohol bath to produce a white solid. The solid was collected by filtration and washed with cold petroleum ether. The filtrate was concentrated and cooled to yield two more crops of white crystals. The combined solids were dried under vacuum at ambient temperature to yield 107 g of white, flaky solid, m.p. 35-36°C.

Analysis: Calculated for C 9 HioOC12: C, 52.71; H, 4.92 Found C, 52.99; H, 4.87 Preparation 28 4-(3-Chloropropoxy)benzoic acid methyl ester.

Ethyl 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 1bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were -43- AHR-438A-CIP mechanically stirred in 600 ml of refluxing acetone under nitrogen overnight. The potassium carbonate was removed by filtration, and the filtrate was evaporated under reduced pressure to give 122 g of a liquid. This liquid was dissolved in 250 ml of petroleum ether and with stirring and cooling in an ice/2-propanol bath. A white precipitate formed and was collected by filtration and washed with cold petroleum ether to yield 108 g of a solid. An additional 6 g of the product was obtained from the mother liquor. A small sample of the solid was dissolved in petroleum ether at room temperature.

The solution was stirred and cooled in an ice bath. White crystals were collected by filtration, washed with cold petroleum ether and dried under ,H vacuum at room temperature, m.p. 24-25oC.

*Analysis: Calculated for C 12

H

1 5 03C1: C, 59.39; H, 6.23 SFound C, 59.69; H, 6.30 0 0 I "Preparation 29 1-(3-Chloropropoxy)-4-nitrobenzene.

S, aA mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of 1- S' bromo-3-chloropropane and 20.7 g (0.15 mole) of anhydrous potassium carbonate in 350 ml of acetone was heated at reflux for 17 hr. The mixture .o was cooled, filtered, and the filtrate was concentrated to give an oil which o crystallized. The solid was collected by filtration, washed with petroleum ether, and dried to yield 10.1 g of the title compound. An analytical sample was prepared from ethyl ether-petroleum ether, m.p. 37-39°C.

Analysis: Calculated for Cg 9 10 oC1NO 3 C, 50.13; H, 4.67; N, 6.50 Found C, 49.95; H, 4.71; N, 6.51 Preparation 4-[Bis(4-fluorophenyl)methyl]1-1piperidinepropanol oxalate hydrate[l:l:l].

A mixture of 10.67 g (0.0372 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 5.42 g (0.039 mole) of 3-bromo-l-propanol and 8 g (0.095 mole) of sodium bicarbonate in 400 ml of 1-butanol was refluxed for 21 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in i solvent was removed in vacuo to give the free base of the title compound as a liquid. The free base was converted to the hydrochloric acid salt, and the salt was recrystallized from ethanol-ether to give 89.33 g of white crystalline solid, m.p. 154-155 0

C.

-44- AHR-438A-CIP vacuo to give 8.88 g of oil, the free base of the title compound. A small sample of this oil was converted to the oxalate salt, and the salt wa's recrystallized from methanol-ether to give a white solid, m.p. 89-94 0

C.

Overall yield was calculated to be 75.1%.

Analysis: Calculated for C 23

H

29

NO

6

F

2 C, 60.92; H, 6.45; N, 3.09 Found C, 61.49; H, 6.15; N, 3.03 Preparation 31 4-(3-Chloropropoxy)-3-methoxybenzoic acid methyl ester.

wa A mixture of 100 g (0.549 mole) of methyl vanillate, 172.8 g (1.1 mole) of S"o l-bromo-3-chloropropane and 228 g (1.65 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a white solid as residue. The solid was triturated with petroleum ether, collected by So" filtration, and dried to yield 137.8 g of white powder which was recrystallized from isopropyl alcohol, m.p. 104-105 0

C.

,n Analysis: Calculated for C 12

H

1 5 C104: C, 55.71; H, 5.84 Found C, 55.87; H, 5.94 Preparation 32 0 0 0 4-[Bis(4-methoxyphenyl)methyl]pyridine.

Anisole, 108.13 g (1.0 mole) was cooled in an ice bath. Concentrated sulfuric acid, 115.3 ml (2.0 mole) was added while stirring the mixture in an Sice bath. The temperature rose to 55°C. The reaction was then cooled in the Sice bath. To this solution was added 4-pyridine carboxaldehyde, 53.5 g mole). The temperature rose to 95 0 C and further cooling and stirring brought the temperature down to 20°C. The reaction mixture was heated at 70°C for 3-1/2 hr. The red gel was made alkaline with 50% sodium hydroxide-ice mix.

The alkaline phase was extracted with toluene and the toluene extracted with a saturated sodium chloride solution. The product crystallized from the toluene solution while standing at room temperature. The white solid can be recrystallized from hot hexane-isopropyl alcohol.

A small 2.2 g sample of the product was recrystallized from methylene chloride-hexanes (1:9 v/v) and dried overnight at 80°C in vacuo. This petroleum etner, ana ariea to yiem h. g uI wL, oun;L A .a recrystallized from 2-propyl ether/2-propanol, m.p. 159.5-160.5 0

C.

Analysis: Calculated for C 18

H

19

F

2 NO: C, 71.27; H, 6.31; N, 4.62 Found C, 70.93; H, 6.71; N, 4.38 AHR-438A-CIP furnished 1.08 g (48.6% yield based on the aliquot taken) of white crystalline product, m.p. 111.5-113.5 0

C.

Analysis: Calculated for C 20 oH9NOz: C, 78.66; H, 6.27; N, 4.59 Found C, 78.14; H, 6.24; N, 4.54 Preparation 33 4-[Bis(4-methoxyphenyl)methyl]piperidine hydrochloride hydrate The precursor pyridine derivative 4-[bis-4-methoxyphenyl)methyl]pyridine was prepared from the reaction of anisole and 4-pyridine carboxaldehyde in the presence of sulfuric acid.

To prepare the title compound, a solution of 4-[bis(4-methoxyphenyl)methyl]pyridine (70.8 g, 0.232 mole) in 350 ml of acetic acid was hydrogenated with 5% palladium on carbon (7.08 g) for five hours with heat. The hydrogenation was continued overnight at room temperature. The reaction mixture was filtered and rinsed with methanol. The filtrate was stripped of solvent via a rotary evaporator, and the residue was partitioned between t° sodium hydroxide and toluene. The aqueous layer was back extracted with toluene. The organic layer was dried over anhydrous sodium sulfate and filtered. Removal of solvent by means of a rotary evaporator gave 64 g of white solid, the free base. The free base was then converted to the hydrochloride salt by dissolving it in methanol and treating with ethereal hydrogen chloride. The white solid was filtered off and dried overnight at 0 80°C in vacuo in the amount of 2.08 g, m.p. 132-135 0

C.

Analysis: Calculated for C 20

H

2 8

NO

3 C1: C, 65.65; H, 7.71; N, 3.83 Found C, 65.63; H, 7.53; N, 3.90 Preparation 34 4-[Bis(4-methylphenyl)methyl]piperidine hydrochloride The free base of the title compound was prepared by hydrogenation of 4- [(bis-4-methylpenyl)methyl]pyridine in acetic acid using palladium on carbon as catalyst and converted to the hydrochloride salt in methanoldiethyl ether. The salt was recrystallized from methanol-diethyl ether and isopropanol-diethyl ether and dried overnight in vacuo at 80 0 C. White solid amounting to 46% yield, m.p. 232°C was obtained.

O .L liler volume. Lic LL L. cUIIJpULLILU. wa .U VU LACIuL U J 6 C .Ar, rs a cooling, recrystallizing the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130°C for 45 min at which time the product had partially melted, m.p. 142.5-144 0

C.

-46- AHR-438A-CIP Analysis: Calculated for C 20

H

26 NC1: C, 76.05; H, 8.30; N, 4.43 Found C, 75.51; H, 8.33; N, 4.33 Preparation N-[4-(3-Chloropropoxy)phenyl]acetamide.

A mixture of 4-acetamidophenol, (182.2 g, 1.2 mole), 1-bromo-3-chloropropane, 157.4 g (1.0 mole), and potassium carbonate 145.0 g (1.05 mole) was refluxed overnight in 700 ml of acetone. The acetone solution was refrig- Serated overnight and white crystals formed. This white solid wEs filtered and washed with acetone. The filtrate was stripped to dryness, and the residue ,4 was dissolved in chloroform and extracted with 5% sodium hydroxide.

4, Removal of chloroform gave an oil. The white solid was also dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave a white solid. The white solid and oil were combined and placed in acetone in the refrigerator; white crystals were obtained. The white crystals 4, were recrystallized twice from acetone. A 5-g sample of the white crystals 4 owas recrystallized from acetone. This furnished 1.76 g after drying in vacuo overnight at 80°C of white crystalline product; m.p. 125-127°C.

Analysis: Calculated for CjlH 14 N0 2 C1: C, 58.03; H, 6.20; N, 6.15 Found C, 58.21; H, 6.28; N, 6.15 Preparation 36 e 1-(3-Chloropropoxy)-3,5-dimethoxybenzene.

A mixture of 3,5-dimethoxyphenol (100.0 g, 0.6486 mole) chlorobromopropane 148.0 g (0.96 mole) and potassium carbonate (89.6 g, 0.96 mole) was heated overnight at gentle reflux in 600 ml of acetone. The reaction mixture was cooled at room temperature, filtered, and stripped to dryness via a rotary evaporator. The resulting oil was dissolved in chloroform, and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave 122.62 g of a dark brown oil. A 5-g sample of the oil was pumped in vacuo overnight at 80°C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil.

H

1 NMR(CDC13): 6 2-2.4 (quintuplet, center methylene protons, 2H), 3.6-4.2 aliphatic protons, 4H), 3.8 OCH 3 6H), 6.1 aromatic protons, 3H).

L rreparaLuon Iu 4-[Bis(4-fluorophenyl)methyl]piperidine fumarate hydrate [1:0.5:0.51.

A mixture of 30.6 g (0.99 mole) of phosphorous and 15.1 g (0.059 mole) of iodine in 90 ml of glacial acetic acid was stirred for 20 min at room tempera- -47- AHR-438A-CIP Analysis: Calculated for CllH 15 0 3 C1: C, 57.27; H, 6.56 Found C, 56.96; H, 6.49 Preparation 37 4-(3-Chloropropoxy)benzonitrile.

A mixture of 4-cyanophenol (125.0 g, 1.05 mole) bromochloropropane (189.0 g, 1.2 mole) and potassium carbonate (145.0 g, 1.05 mole)-was heated overnight at reflux in 750 ml of acetone. The reaction mixture was filtered and stripped to dryness. The resulting residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave Se 205.1 g (100%) of an oil which crystallized to a white solid. A 5-g sample was recrystallized from isopropyl ether. This furnished 1.22 g of white solid, m.p. 40-440C which contained a dimer impurity.

4 Analysis: Calculated for C 10

H

20 NOCI: C, 61.39; H, 5.15; N, 7.16 Found C, 61.57; H, 5.14; N, 7.20 Preparation 38 1-[4-(3-Chloropropoxy)-3-methylphenyl]ethanone.

A mixture of 25 g (0.166 mole) of 4-hydroxy-3-methylacetophenone, 45.8 g (0.33 mole) of 1-bromo-3-chloropropane and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil as residue. The oil was crystallized in petroleum ether. The solid was collected by filtration, washed with petroleum ether and dried to yield 35.8 g of an off-white powder. An analytical sample, m.p. 41.5-42.5°C was prepared from petroleum ether.

Analysis: Calculated for C 12

H

15 C102: C, 63.58; H, 6.67 Found C, 63.40; H, 6.64 Preparation 39 4-(3-Chloropropoxy)benzamide.

A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure, and the residue was L _j r z.o nr alter adaition was complete. ine nmlxure ws; cuuiLu u cAi, iu%-uCU twice with 49 kg portions of toluene. The combined extracts were washed once with 1.9 kg of 50% sodium hydroxide diluted to 5 gal, and once with 5 gal of water. The toluene layer was dried over 3 lb of anhydrous sodium sulfate -48- AHR-438A-CIP stirred with 1.2 liter of water to remove inorganic solids. The mixture was filtered and the filter cake was washed with water and petroleum ether ahd dried to yield 75.5 g of white solid. The solid was recrystallized from ethyl acetate, m.p. 142-145°C.

Analysis: Calculated for C 10

H

12 C1N0 2 C, 56.22; H, 5.66; N, 6.56 Found C, 55.92; H, 5.61; N, 5.56 Preparation 1-[4-(5-Chloropentoxy)-3-methoxyphenyl]ethanone.

A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0.539 mole) of and 138 g (1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which crystallized in petroleum ether (30-60 0 The solid was collected by filtration, washed with petroleum ether and dried to yield 81.4 g of fluffy, white solid. The solid was recrystallized from isopropyl ether, m.p. 57- 58 0

C.

Analysis: Calculated for C 14

H

19 C10 3 C, 62.11; H, 7.07 SFound C, 62.14; H, 7.10 Preparation 41 4-(3-Chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester.

A mixture of 50 g (0.238 mole) of ethyl homovanillate, 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystallized from ethyl ether-petroleum ether (30-60°C) to yield 44.4 g of white solid, m.p. 36-38 0

C.

Analysis: Calculated for C 1 4H 19 C10 4 C, 58.64; H, 6.68 Found C, 58.74; H, 6.74 Prepartion 4 l-[4(5-hlorpenoxy-3-mthoyphnyl~thaone Aam ,itr of (03 moe of. l,10 g(.53 mole).of w ab aiLiuLUlleu ueLweeUIIullt wIi. iciUli u l LuL dAIL U J LL The.methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give the free base of the title compound as a solid. The free base was dissolved in methanol-diethylether and maleic acid -49- AHR-438A-CIP SPreparation 42 1-(3-Chloropropoxy)-4-(methylsulfonyl)benzene.

To a solution of 21.7 g (0.1 mole) of 1-(3-chloropropoxy)-4-(methylthio)benzene in 100 ml of chloroform was cautiously added a slurry of 51.8 g (0.3 mole) of m-chloroperbenzoic acid in 450 ml of chloroform. The mixture was stirred at ambient temperature for 2 days and then filtered. The filtrate was washed with four portions of a solution comprised of 110 ml of saturated sodium bicarbonate, 110 ml of water, and 30 ml of 20% sodium hydroxide, once with brine, dried (sodium sulfate) and concentrated under reduced Spressure to give a solid as residue. The solid was triturated with petroleum e° ether, collected by filtration and air dried to yield 24.3 g of white solid.

An analytical sample, m.p. 84-86 0 C was recrystallized from 2-propanol.

Analysis: Calculated for C 10

H

1 3C103S: C, 48.29; H, 5.27 S Found C, 48.38; H, 5.30 Preparation 43 O 5-Oxo-l-(phenylmethyl)-3-pyrrolidinecarboxylic acid, methyl ester.

0: 4 A solution of 158.2 g (1.0 mole) of dimethylitaconate and 107.2 g mole) of benzylamine in 750 ml of methanol was let stand at ambient temo o, perature over the weekend. The solution was filtered, and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30-60 0 The solid was collected by filtration and dried to yield 225.5 g of white powder.

An analytical sample, m.p. 63-65°C was prepared from diisopropyl ether.

Analysis: Calculated for C 13

H

1 5 N0 3 C, 66.94; H, 6.48; N, 6.01 Found C, 66.82; H, 6.48; N, 6.01 Preparation 44 1-Benzyl-3-(hydroxymethyl)-pyrrolidine oxalate A solution of (60.0 g, 0.2553 mole) 5-oxo-l-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in dry dimethoxyethane was added to a mixture of dimethoxyethane and 47.0 g (1.23 mole) of lithium aluminum hydride. The reaction mixture was stirred 2 hrs at room temperature and then heated at reflux 2 hrs. The mixturewas then stirred overnight at room temperature, then quenched by the slow addition of ethyl acetate. More ethyl I_ maue Dasic witn ou/o souium nyaroxiue. ne aqueous mixure was exuracea with methylene chloride. The methylene chloride solution was extracted with an aqueous solution of sodium sulfite and was dried over magnesium sulfate. The solvent was removed in vacuo to give 3.89 g of the free AHR-438A-CIP acetate was added and the use of Celite® allowed the solid material to be Sseparated from filtrate by filtration. The filtrate was stripped to dryness, and dissolved in chloroform. The chloroform layer was extracted with sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. A portion of the oil was converted to the oxalate salt.

The salt was recrystallized from methanol-diethyl ether and dried at 80 0 C in vacuo overnight to give 2.27 g, 39.4% yield of white crystalline solid, m.p. 98- 102 0

C.

Analysis: Calculated for C 14

H

19 NO5: C, 59.78; H, 6.81; N, 4.98 Found C, 59.43; H, 6.79; N, 4.95 Preparation 1-[4-(6-Chlorohexyloxy)-3-methoxyphenyl]ethanone.

A mixture of 41.6 g (0.25 mole) of acetylvanillone, 76 g (0.375 mole) of 1bromo-6-chlorohexane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux 20 hr. The mixture was cooled, filtered, and the filter cake washed with acetone. The combined S° filtrates were concentrated under vacuum pump pressure at 90 0 C to give an 0°0 oil which gradually crystallized. The residue was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 59.6 g of offwhite solid. An analytical sample, m.p. 35-38°C, was prepared from isopropyl ether.

"Analysis: Calculated for C 1 5

H

21 C10 3 C, 63.26; H, 7.43 0"0 Found C, 63.50; H, 7.60 ooc*oo Preparation 46 4-(3-Chloropropoxy)benzenesulfonamide.

A mixture of 25 g (0.144 mole) of p-hydroxybenzenesulfonamide, 45.5 g (0.289 mole) of 1-bromo-3-chloropropane and 59.7 g (0.432 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90°C to give 32.2 g of tan gum as residue. The gum was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were w 1 v A uI, =uLLi1u was ubea w wasn tne slurry into me reaction mixture. The mixture was heated at reflux overnight and then concentrated under reduced pressure to give a solid as residue. The solid was partitioned, between 1 liter of benzene and 1 liter of water. The aqueous layer was Analysis: Calculated for C 9

H

12

NO

3 S: C, 43.29; H, 4.84; N, 5.61 Found C, 43.48; H, 4.92; N, 5.62 Preparation 47 7-(3-Chloropropoxy)-2H-l-benzopyran-2-one.

A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was filtered with difficulty to give a milky filtrate. The filtrate was treated with charcoal and filtered through Celite® to give a clear filtrate. The filtrate was concentrated under reduced pressure to give a solid residue. The solid C was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 19.1 g of fluffy, white solid. An analytical sample, m.p.

100-102°C, was obtained on recrystallization from 2-propanol.

Analysis: Calculated for C 1 2HuC103: C, 60.39; H, 4.65 Found C, 60.35; H, 4.68 Preparation 48 7-(3-Chloropropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester.

SA mixture of 23.4 g (0.1 mole) of 7-hydroxy-4-oxo-4H-l-benzopyran-2carboxylic acid ethyl ester, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and recrystallized from 2-propanol to yield 22.5 g of white solid, m.p. 107-108 0

C.

Analysis: Calculated for C 1 5 H15C10 5 C, 57.98; H, 4.87 Found C, 58.21; H, 4.88 r UJIIU -52- AHR-438A-CIP Preparation 49 1-[4-(3-Chloproproxy)-2-methoxypheny ]ethanone.

A mixture of 10.6 g (0.637 mole) of 1-(4-hydroxy-2-methoxyphenyl)ethanone, 20 g (0.127 mole) of 1-bromo-3-chloropropane and 26.4 g (0.19 mole) of anhydrous potassium carbonate in 250 ml of acetone was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated under vacuum pump pressure at 90 0 C to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 14.6 g of white solid, m.p. 47- "49°C on recrystallizing from isopropyl ether.

Analysis: Calculated for C12H15C103: C, 59.39; H, 6.23 SFound C, 59.32; H, 6.26 Preparation 1-(3-Chloropropoxy)-4-methylsulfinylbenzene.

The title compound is prepared by treating 1-(3-chloropropoxy)-4methylthiobenzene with sodium perborate in glacial acetic acid.

Preparation 51 2-(3-Chloropropoxy)benzonitrile.

A mixture of 2-cyanophenol (50.0 g, 0.42 mole), 1-bromo-3-chloropropane (67.7 g, 0.43 mole), and potassium carbonate (58.0 g, 0.42 mole) was heated overnight at gentle reflux in 500 ml of acetone. The reaction mixture o 0* 4was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was removed, to give a brown oil (80.09 g, A ten gram portion of this oil was subjected to flash chromatography on silica gel with 10% ethyl acetate-hexanes and 20% ethyl acetate-hexanes used for elution. Fractions were combined, and solvent removed in vacuo. The clear oil obtained was dried 18 hrs in vacuo at room temperature and 8 hrs at 80°C in vacuo. This furnished 5.24 g (50.0% yield based on aliquot taken) of clear oil. H 1

NMR

(CDC13); 6 2.1-2.5 2, -CH2), 3.8 2, -C1CH 2 4.2 2, -OCH 2 6.9 2, aromatic protons ortho and para to ether), 7.5 2, aromatic protons ortho and para to CN group).

Analysis: Calculated for C 10

H

13 0 2 C1: C, 59.86; H, 6.53 Found C, 59.39; H, 6.56 -53- AHR-438A-CIP Analysis: Calculated for C 10 Ho 1 NOC1: C, 61.39; H, 5.15; N, 7.16 Found C, 61.27; H, 5.15; N, 7.14 Preparation 52 1-Phenylmethyl-3-pyrrolidinemethanol methanesulfonate (ester) oxalate A solution of 113.80 g (0.596 mole) of 1-benzyl-3-(hydroxymethyl)pyrrolidine and triethylamine, (66.6 g, 0.66 mole) in 600 ml of acetonitrile was prepared. This solution was cooled in an ice bath. A solution of tosyl chloride (125.9 g, 0.66 mole) in 300 ml of acetonitrile was added dropwise with o stirring. The solution was allowed to stir overnight at room temperature. A solid precipitated, and the solution was filtered. The solvent was removed by orotary evaporator, and the residue was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 232.9 g of a dark brown oil. This oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether. After drying at in vacuo overnight, 181.63 g of white crystalline solid was Sobtained. A five gram sample was recrystallized again from methanoldiethyl ether and dried at 80°C in vacuo overnight. A yield of 1.41 g (19.7% overall adjusted for the aliquot taken) of white crystalline solid, m.p. 147- 149 0 C was obtained.

Analysis: Calculated for C 21

H

25 N0 7 S: C, 57.92; H, 5.79; N, 3.22 Found C, 57.62; H, 5.82; N, 3.22 t 4 Preparation 53 a,a-Diphenyl-3-pyrrolidineacetamide maleate A 1.13 g sample of 1-benzyl-a,a-diphenyl-3-pyrrolidineacetamide dissolved in 50 ml of methanol was hydrogenated with 0.5 g of palladium-on-charcoal catalyst at 75°C overnight in a Parr hydrogenation apparatus. After removal of the catalyst by filtration the filtrate was concentrated to give 0.783 g of light tan gum. The mass spectra and infrared spectra were consistent with its structure. A sample of this free base in methanol was treated with one molar equivalent of a solution of maleic acid in methanol. After evaporation of the methanol, the residue crystallized i y' g of 10% palladium on carbon (0.0060 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 850 for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene -54- AHR-438A-CIP and was recrystallized twice from isopropanol-ether. The material was dried at 100°C/0.1 mm for 3 hr, m.p. 110-145°C (softens and turns liquid). Thematerial appears to be an amorphous solid.

Analysis: Calculated for C 22

H

24

N

2 0 5 C, 60.,@7 H, 6 0; N, 7.07 Found C, 1, 6.05; N, 7.04 Preparation 54 a,a-DiTrhenyl-3-pyrrolidineacetamide N-cyclohexylsulfamate hydrate A 1.15 g sample of free base of the above compound (obtained by proportioning a,a-diphenyl-3-pyrrolidineacetamide maleate in chloroform and So0', aqueous besic solution and evaporating the chloroform layer) and 0.735 g of hexamic acid were dissolved in 10 ml of ethanol. The solvent was evaporated, the residue crystallized, and then was recrystallized from ethanol, m.p. 103o 1060C.

Analysis: Calculated for C 24

H

33

N

3 S0 4 .1.5 H 2 0: C, 59.24; H, 7.46; N, 8.64 Found C, 58.97; H, 6.98; N, 8.51 S09 Preparation l-(Phenylmethyl)-4-piperidinol ester with 4-methylbenzenesulfonic acid maleate A solution of 100 g (0.524 mole) of N-benzyl-4-hydroxypiperidine and 13 ,g (0.684 mole) of tosylchloride in 600 ml of pyridine was stirred at room temperature overnight. One liter of methylene chloride and 500 ml of 0.5 M aqueous sodium hydroxide were added to the reaction mixture. The reaction mixture was stirred for 10 min, and the phases were separated. The methylene chloride layer was extracted with several portions of the dilute sodium hydroxide, dried over magnesium sulfate and evaporated in vacuo to give an oil, the free base of the title compound. The free base was converted to the maleate salt, which was recrystallized from methylene chloride-diethyl ether to give white crystalline solid, m.p. 159-160oC.

Analysis: Calculated for C 23

H

27 N0 7 S: C, 59.86; H, 5.90; N, 3.04 Found C, 59.79; H, 5.86; N, 2.95 i a,a-.ist 4-cncropnenyl)- -(phenylsultonvl)-4-piperidinemethanol.

Following the procedure of Preparation 7, but substituting pbromochlorobenzene for p-bromofluorobenzene, the title compound was prepared.

AHR-438A-CIP Preparation 56 1-[2-(Phenylthio)ethyl]-4-piperidinecarboxylic acid ethyl ester hydrochloride A mixture of 69.3 g (0.40 mole) of 2-chloroethylphenylsulfide, 61.65 g (0.393 mole) of ethyl isonipecotate and 53 g (0.50 mole) of sodium carbonate in 1 liter of absolute ethanol was refluxed for 30 hr in the presence of molecular 3A sieves. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide, and the methylene chloride solution was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the free base of the title compound as an oil. The free base was converted to the hydrochloride salt, and the salt was recrystallized from absolute ethanol-ether to give 38.62 g of white crystalline solid, m.p.

44 125-1260C.

Analysis: Calculated for C 16

H

24 N0 2 SCl: C, 58.26; H, 7.33; N, 4.25 Found C, 58.11; H, 7.32; N, 4.20 0 a Preparation 57 1-[(4-Methylphenyl)sulfonyl]-4-piperidinol ester with 4methylbenzenesulfonic acid.

A solution of 1.63 g (0.016 mole) of 4-hydroxypiperidine and 13.9 g (0.0732 mole) of tosyl chloride in 80 ml of pyridine was stirred overnight at 25 0 C. The mixture was quenched in 200 ml of water, and the aqueous mixture was extracted with several portions of methylene chloride. The combined methylene chloride layer was extracted with several portions of 1M sulfuric acid followed by 1M sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. This was recrystallized from methylene chloride-diethyl ether to give 4.82 g of the product, m.p. 140.5-141 0

C.

Analysis: Calculated for C 19

H

23 N05S2: C, 55.73; H, 5.66; N, 3.42 Found C, 55.60; H, 5.64; N, 3.39

L

Preparation 28 4-(3-Chloropropoxy)benzoic acid methyl ester.

Ethyl 4-hydroxybenzoate 83.1 g (0.50 mole), 107 ml (1.0 mole) of 1bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were -56- AHR-438A-CIP Preparation 58 1-[(4-Methylphenny)sulfnyl-aa-diphenyl-4-piperidine-acetonitrile.

The sodium salt of diphenylacetonitrile was formed in toluene from diphenylacetonitrile, (94.5 g, 0.488 mole) and sodium hydride, (19.6 g, 0.488 mole). The reaction mixture was heated at reflux for approximately two hours. A color change from green to brown was detected during the reaction.

1-[(4-Methylphenyl)sulfonyl]-4-piperidinol ester with methylbenzenesulfonic acid (200.0 g, 0.488 mole) was added in small portions as a solid while stirring the reaction mixture under nitrogen at room temperature. The solution 4 became green. The solution/mixture was stirred overnight at 100oC. The 4 omixture was filtered and the toluene was removed by rotary evaporation.

S* The filter cake and the residue from removal of toluene were combined Sand dissolved in chloroform. The chloroform was extracted several times with 5% sodium hydroxide followed by extraction with IN sulfuric acid and Ssodium hydroxide. The -hloroform was removed in vacuo to give a reddishbrown oil (193, 98 g, 92.4%).

A sample of the oil was crystallized from toluene. The solid obtained O was then recrystallized from methylene chloride-hexanes and dried at 8000 in vacuo overnight to give white solid title compound in 26.7% yield based on aliquot taken, m.p. 183-1840C.

4 Analysis: Calculated for C 26

H

26

N

2 0 2 S: C, 72.53; H, 6.09; N, 6.51 Found C, 72.11; H, 6.07; N, 6.45 Preparation 59 Sa,a-Diphenyl-4-piperidineacetonitrile oxalate [2:11.

A solution of 1-[(4-methylphenyl)sulfonyl-Qa,a-diphenyl-4-piperidineacetonitrile (183.83 g, 0.428 mole) and phenol (150.0 g, 1.60 mole) in 750 ml of 48% hydrobromic acid was stirred vigorously and heated at reflux for 3-1/2 hrs. The reaction mixture was cooled and made alkaline with ice/50% sodium hydroxide. The reaction mixture was extracted with chloroform, and the chloroform layer was back extracted with 5% sodium hydroxide. The chloroform layer was dried, filtered over anhydous sodium sulfate and solvent removed to furnish a red oil (150.55 g, quantitative). This oil, the free base of the title compound, was converted to the oxalate salt using a methanoli i pipenaine, o.4Z g tU.ua mole) ot a-oromo-i-propanoi ana o g tu.uuo mole) oi sodium bicarbonate in 400 ml of 1-butanol was refluxed for 21 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in Found C, 74.51; H, 6.52; N, 8.60 Preparation a,a-Diphenyl-4-piperidineacetamide fumarate a,a-Diphenyl-4-piperidineacetonitrile oxalate (60.34 g, 0.165 mole) was converted to the free base by partitioning in 5% sodium hydroxide and 1 I chloroform. Removal of chloroform from the chloroform layer gave an oil which was then dissolved in a mixture of 280 ml concentrated sulfuric acid and 30 ml of water. The solution was 6iL red overnight at 90'C. The reaction mixture was poured into ice and carefully made alkaline with 50% sodium A" *hydroxide. The aqueous layer was extracted several times with chloroform.

The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give an oil (32.36 g, 66.7%) which crystallized. A two gram sample of the oil was converted to the fumarate salt and the salt was v recrystallized from methanol-diethyl ether. A white solid was obtained (47.9% yield based on aliquot taken) which was dried overnight in vacuo at S. 80 0 C, m.p. 234-235 0

C.

Analysis: Calculated for C 2 5

H

28

N

2 0 7 C, 64.09; H, 6.02; N, 5.98 Found C, 63.82; H, 6.14; N, 5.82 Preparation 61 S1-[(4-Methvlphenvl)sulfonvl]-a-a-diphenyl-3-piperidinepropanenitrile.

The sodium salt of diphenylacetonitrile was formed in 400 ml of dimethylsulfoxide from sodium hydride 39.0 g, 0.975 mole) and diphenylacetonitrile (188.90 g, 0.975 mole). The resulting solution was stirred under nitrogen for 1 hr at room temperature. A 90-10 mixture of 3- (chloromethyl)-l-[(4-methylphenyl)sulfonyl]piperidine and 4-methylbenzenesulfonic acid 1-[(4-methylphenyl)sulfonyl]piperidin-3-yl methyl ester (221.42 g, 0.975 mole) dissolved in 400 ml of dimethylsulfoxide was added.

The reaction mixture was heated to 85C and stirred overnight at 73 0 C. The dimethylsulfoxide was removed in vacuo, and the residue obtained was dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric toluene solution while standing at room temperature. The white solid can be recrystallized from hot hexane-isopropyl alcohol.

A small 2.2 g sample of the product was recrystallized from methylene chloride-hexanes (1:9 v/v) and dried overnight at 800C in vacuo. This

I

-58- AHR-438A-CIP acid. The chloroform layer was dried, filtered, and the chloroform was removed by rotary evaporator. A brown residue was obtained which was triturated with isopropyl ether to give a brown solid. A 5-g sample was recrystallized from ethyl acetate-isopropyl ether. This gave 4 g (56.8% based on aliquot taken) of white solid, m.p. 136.5-137°C.

Analysis: Calculated for C 27

H

2 8

N

2 0 2 S: C, 72.94; H, 6.35; N, 6.30 Found C, 72.82; H, 6.36; N, 6.29 Preparation 62 a,a-Diphenyl-3-piperidinepropanenitrile fumarate P, A mixture of 1-[(4-methylphenyl)sulfonyl]-a,a-diphenyl-3-piperidine- S« propanenitrile (302.41 g, 0.68 mole), hydrogen bromide 750 ml), and phenol (260 g, 2.76 mole) was stirred vigorously while heating a; reflux for 3- S' 1/2 hr. The reaction mixture was cooled to room temperature and made Salkaline with 50% hydroxide-ice. The aqueous phase was extracted several times with chloroform, and the chloroform layer was back extracted with sodium hydroxide. The chloroform layer was dried, filtered, and solvent 4 &0 removed. NMR showed about 80% product was obtained. The same sequence S° was repeated. The chloroform layer gave a brown oil which was converted to o the oxalate salt (148.8 g, A portion of this oxalate salt was converted to the free base by partitioning in chloroform and dilute aqueous sodium hydroxide and separating and evaporating the chloroform layer. The free 4 base was converted to the fumarate salt. This salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight to give 6.53 g white crystals, m.p. 181-182°C.

Analysis: Calculated for C 2 4

H

26

N

2 0 4 C, 70.92; H, 6.45; N, 6.89 Found C, 70.46; H, 6.41; N, 6.86 Preparation 63 a.a-Diphenyl-3-piperidinepropanamide maleate A solution of 52.01 g (0.179 mole) ofa,a-diphenyl-3-piperidinepropanenitrile was stirred overnight at 85°C in 280 ml of 90% sulfuric acid. The reaction mixture was allowed to cool to room temperature and then poured into 50% sodium hydroxide/ice mix. The basic layer was extracted with the solvent removed to give 52.1 g of a fluffy solid, the free base of the i L L(bis-4-methylpenyl)methyiJpyriaine in acetic acia using panaaum on carbon as catalyst and converted to the hydrochloride salt in methanoldiethyl ether. The salt was recrystallized from methanol-diethyl ether and isopropanol-diethyl ether and dried overnight in vacuo at 800C. White solid amounting to 46% yield, m.p. 2320C was obtained.

-59- AHR-438A-CIP title compound. A 3 g portion of the free base was converted to the maleate salt and recrystallized from methanol-diethyl ether. The salt obtained was dried in vacuo overnight at 80°C. This furnished 2.15 g of white crystalline product, m.p. 177-179 0

C.

Analysis: Calculated for C 24

H

28

N

2 0 5 C, 67.91; H, 6.65; N, 6.60 Found C, 67.85; H, 6.85; N, 6.55 Preparation 64 1-[(2-Chloroethyl)sulfonyl]-4-fluorobenzene.

4* A solution of 30% hydrogen peroxide (153 g, 1.34 mole) in 400 ml of glacial acetic acid was prepared. To this ice cooled solution was added a r solution of 2-chloroethyl p-fluorophenylsulfide (70.11 g, 0.369 mole) in 200 ml of glacial acetic acid. The resulting solution was stirred 72 hours at room temperature. The volume of acetic acid was concentrated on a rotary f evaporator. The residual material was dissolved in chloroform and extracted with a solution of sodium bicarbonate and sodium sulfite. The chloroform ,,layer was then dried, filtered, and solvent removed to give a white solid. A g portion of this white solid was recrystallized from methylene chlorideisopropyl ether. The white solid was dried in vacuo at 80 C overnight. This furnished 1.84 g (32.6% yield base on aliquot taken) of white crystalline solid, m.p. 72.5-74 0

C.

Analysis: Calculated for C 8

H

s

SO

2 FC1: C, 43.15; H, 3.62 Found C, 43.52; H, 3.66 Preparation 4-Fluoro-a-(4-fluorophenyl)benzeneacetonitrile.

4-Fluorophenylacetonitrile (70.0 g, 62.2 ml, d= 1.126,0.518 mole) was heated to 120°C, Bromine (83.0 g, 26.6 ml, d=3.119, 0.525 mole) was added dropwise over 1 hr while maintaining a temperature of 1200C. The solution was stirred for 1/2 hr at 120°C and then flushed vigorously with nitrogen for 3/4 hr (solution A).

In a separate 2-liter flask was placed aluminum chloride (85.0 g, 0.644 mole). Fluorobenzene (200 g, 2.08 mole, d= 1.024, 195.3 ml) was added dropwise with stirring over 1/2 hr while flushing with nitrogen (Mixture B).

L i i 122.62 g of a dark brown oil. A 5-g sample of the oil was pumped i vacuo overnight at 80°C. This produced 3.23 g (53.2% yield based on the aliquot taken) of dark brown oil.

H

1 NMR(CDC1 3 8 2-2.4 (quintuplet, center methylene protons, 2H), 3.6-4.2 aliphatic protons, 4H), 3.8 OCH3, 6H), 6.1 aromatic protons, 3H).

AHR-438A-CIP Solution A was added dropwise to mixture B starting at room temperature. The temperature rose to 50 0 C. The reaction mixture was stirred at'this temperature for 1/3 hr. The temperature was raised to 70°C and maintained there for 1/3 hr. At this point the reaction became uncontrollable and part of the mixture was lost. The remainder was added to ice/75 ml of concentrated hydrochloric acid. The aqueous phase was extracted several times with chloroform. The solvent layer was dried, filtered, and solvent removed to give a green solid. The solid was recrystallized from isopropanol; the solid was washed with cold isopropanol twice and dried in vacuo at 55°C overnight.

This produced 29.72 g of light yellow solid, m.p. 62-63.5°C.

a \0 Analysis: Calculated for C 14

H

9

NF

2 C, 73.36; H, 3.96; N, 6.11 Found 73.55; H, 3.88; N, 6.10 Preparation 66 a,a-Bis(4-fluorophenyl)--[(4-methylphe )sulfonyl]-4-piperidineacetonitrile..

The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was O o prepared in dimethyl sulfoxide from its free base, 28.0 g (0.1223 mole) and 4.90 g of 60% sodium hydride (0.1227 mole). The salt was stirred for 1 hr at room temperature. To the mixture was added 50.0 g (0.1223 mole) of methylphenyl)sulfonyl]-4-piperidinol ester with 4-methylbenzenesulfonic acid over five minutes in solid form while stirring under nitrogen. The resulting solution was stirred 15 hours at 65°C and then allowed to stand at room temperature for 72 hours. The solution was stripped to dryness, the residue was dissolved in chloroform, and the solution was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 11,.36 g of solid. The solid was triturated with isopropyl ether and placed in the freezer. After washing the solid several times with isopropyl ether, 55.41 g of white solid was obtained. A 3 g sample was then triturated with 50-50 hot isopropyl alcohol-methanol and placed in the freezer. The white solid collected was washed with isopropyl ether and dried in vacuo at overnight. This produced 2.28 g of white crystalline product, m.p. 190-191°C.

Analysis: Calculated for C 26

H

24

N

2 0 2

SF

2 C, 66.94; H, 5.18; N, 6.00 Found C, 66.92; H, 5.17; N, 5.99 A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure, and the residue was "ii -61- AHR-438A-CIP Preparation 67 a,a-Bis(4-fluorophenyl)-4-piperidineacetonitrile oxalate, diethyl ether A solution of 52.41 g (0.1125 mole) of a,a-bis-(4-fluorophenyl)-l-[(4methylphenyl)sulfonyl]-4-piperidine acetonitrile was heated at reflux for 3- 1/2 hr in 200 ml of 48% hydrobromic acid with phenol (50.0 g, 0.53 mole). The reaction mixture was cooled to room temperature and then made alkaline with ice/50% sodium hydroxide mixture. The alkaline phase was extracted several times with chloroform. The chloroform layer was back extracted with sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 34.24 g of dark brown oil. The entire oil was converted to the oxalate salt and recrystallized from methanolo diethyl ether. The salt obtained was dried in vacuo overnight at 80°C to give \34.24 g of white crystalline solid, m.p. 124-127C.

Analysis: Calculated for C 23

H

2 5

N

2

F

2 0 4 5 C, 62.86; H, 5.73; N, 6.37 Found C, 62.30; H, 5.78; N, 6.17 69 0 SO Preparation 68 N-[3-(3-Chloropropoxy)phenyl]urea.

A mixture of 45.6 g (0.3 mole) of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 mole) of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium carbonate and 1 liter of acetone was heated at reflux with mechanical stirring for 20 hr. The mixture was concentrated and the residue was slurried with 1.5 liters of water. The mixture was filtered and the filter cake was recrystallized from isopropanol to yield 57.0 g of off-white solid, m.p.

141-143 0

C.

Analysis: Calculated for C 10

H

1 3 C1N 2 0 2 C, 52.52; H, 5.73; N, 12.25 Found C, 52.37; H, 5.79; N, 12.17 Preparation 69 N-[4-(3-Chloropropoxy)phenyl]carbamic acid ethyl ester.

A mixture of 6.6 g (0.036 mole) of (4-hydroxyphenyl)carbamic acid ethyl ester, 11.5 g (0.072 mole) of 1-bromo-3-chloropropane, 13.8 g (0.10 mole) of i r una U, 0. 11 Z, W. :1 -62- AHR-438A-CIP anhydrous potassium carbonate and 150 m of acetone was heated at reflux for 21 hr. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30-600C) collected by filtration and recrystallized from isopropanol to yield 7.7 g of white solid, m.p. 91-93°C.

Analysis: Calculated for C 12

H

16 C1NO3: C, 55.93; H, 6.26; N, 5.43 Found C, 55.93; H, 6.28; N, 5.46 Preparation a-(4-Fluorophenyl)-2-pyridineacetonitrile.

S. d A sample of sodium hydride 1.60 g, 0.04 mole) was washed with S" dry hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide was added. To this mixture was added a solution of 4-fluorophenylacetonitrile (5.41 g, 0.04 mole). The mixture was stirred 3 hrs at room tempera- S !i ture under nitrogen. 2-Bromopyridine (6.32 g, 0.04 mole) was added to the mixture, the reaction mixture was then stirred overnight at 65 0 C. The reaction mixture was poured into 1200 ml of water, and the aqueous phase was extracted several times with chloroform (the chloroform layer was Sfiltered using Celite®). The combined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium Ssulfate, filtered, and solvent removed to give a red oil. The oil was subjected to flash chromatography on silica gel using 10% ethylacetate-90% hexanes and 20% ethylacetate-80% hexanes for elution. Fractions of similar purity was combined and solvent removed in vacuo. The oil obtained was dried in vacuo overnight at 80 0 C to give 2.43 g of clear oil.

1H (CDCl 3 5 8.5 1, proton adjacent to N in pyridine nucleus), 6.8-7.8 (m, 7, aromatics), 5.3 1, methine).

4 Analysis: Calculated for C 13

H

9

N

2 F: C, 73.57; H, 4.27; N, 13.20 Found C, 73.23; H, 4.23; N, 13.12 Preparation 71 a-(4-Fluorophenyl)-a-[1-[(4-methylphenyl)sulfonyl]-4-piperidinyl]-2pyridineacetonitrile hydrate [1:0.51.

ti dinecarboxylic acid methyl ester in dry dimethoxyethane was added to a mixture of dimethoxyethane and 47.0 g (1.23 mole) of lithium aluminum hydride. The reaction mixture was stirred 2 hrs at room temperature and then heated at reflux 2 hrs. The mixture was then stirred overnight at room temperature, then quenched by the slow addition of ethyl acetate. More ethyl -63- AHR-438A-CIP The sodium salt of the free base of a-(4-fluorophenyl)-2-pyridineacetonitrile was formed in dimethylsulfoxide from sodium hydride 5.16 g, 0.129 mole) and the free base of a-(4-fluorophenyl)-2-pyrirlineacetonitrile (27.36 g, 0.129 mole). The salt was stirred in dimethylsulfoxide for 4-1/2 hr at room temperature. Next, 4-methylphenylsulfonic acid ester with 1-[(4-methylbenzene)sulfonyl]-4-piperidinol (52.8 g, 0.129 mole) was added and the reaction mixture was stirred 2 hr at room temperature. The reaction mixture was stirred overnight at 80°C. The solvent was removed i vacuo and the residue obtained was dissolved in chloroform. The chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. Solvent was removed to give a o dark brown residue. This material was triturated with acetone to give 36.2 g S' of white solid. A one gram portion was triturated with acetone and then 4 00 recrystallized from methylene chloride-acetone. The solids were dried in ,o vacuo overnight at 80 0 C to give 0.74 g (62.4% based on aliquot taken) of white crystals, m.p. 228-229 0

C.

Analysis: Calculated for C 25

H

25

N

3 0 2 .5SF: C, 65.90; H, 5.49; N, 9.16 04 Found C, 65.86; H, 5.27; N, 9.16 0 Preparation 72 S* a-(4-Fluorophenyl)-a-(4-piperidinyl)-2-pyridineacetonitrile oxalate [2:31.

A solution of a-(4-fluorophenyl)-a-[1-[(4-methylphenyl)sulfonyl]-4- 0, piperidinyll-2-pyridineacetonitrile (30.86 g, 0.0687 mole) and phenol (75 g, 0.8 mole) in 200 ml of 48% hydrobromic acid was heated at reflux for 3 hrs.

The resultant was cooled in ice and made alkaline with ice-50% sodium hydroxide. The aqueous layer was extracted with chloroform and the chloroform layer was extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil (26.35 g, The entire oil was converted to the oxalate salt in methanol-diethyl ether. A one gram portion was taken and recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight. This furnished 0.90 g (80.2% based on aliquot taken) of white crystalline product, m.p. 98°C (soften, Analysis: Calculateed for C 21

H

21

N

3 06F: C, 58.60; H, 4.92; N, 9.76 L i pump pressure at 90°C to give 32.2 g of tan gum as residue. The gum was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were i -64- AHR-438A-CIP Found C, 58.77; H, 5.01; N, 10.04 Preparation 73 at room temperature. 3-Chloro-1-propanol (24.0 g, 0.25 mole) was added and the solution was heated overnight at 70 0 C. The solution was poured into 500 ml of water. A brown solid/mass was obtained. The solid was washed with several portions of water and then triturated with acetone. The solid was filtered and dried in vacuo at 80C00 overnight to give 35.67 g of light brown solid, m.p. 126-1270C.

4' Analysis: Calculated for C 12

H

13

NO

2 C, 70.92; H, 6.45; N, 6.89 SFound C, 70.94; H, 6.49; N, 6.87 4 4 Preparation 74 8-(3-Chloropropoxy)quinoline.

A solution of 3-(8-quinolinyloxy)-l-propanol (32.0 g, 0.158 mole) and Sr thionyl chloride (24.0 g, 0.203 mole) was heated at reflux for 5 hours in 300 ml of dry benzene (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml of water). The gummy residue was dissolved in chloroform and extracted with the potasslum carbonate solution. The chloroform layer was dried over anhydrous I: sodium sulfate, filtered, and solvent removed to give a dark mass which crystallized. The mass was treated with 500 ml of boiling hexane. The hexane layer was decanted off from insoluble oil. A white solid crystallized on cooling, the hexane layer was filtered off. The solid was dried in vacuo at room temperature overnight to give 26.69 g of white crystalline solid, m.p. 69-71C.

Analysis: Calculated for C 12

H

12 NOC1: C, 65.02; H, 5.45; N, 6.32 Found C, 65.19; H, 5.51; N, 6.27 2 AHR-438A-CIP Ie r t I I I 'I I Preparation a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonyl]-3-piperidineacetonitrile..

The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was formed in 500 ml of dimethylsulfoxide from (39.42 g, 0.172 mole) of its free base and sodium hydride (6.88 g, 0.172 mole). The reaction mixture was stirred for one hour at room temperature. 1-[(4-Methylphenyl)sulfonyl]- 3-piperidinol-4-methylphenylsulfonate ester (70.4 g, 0.172 mole) was added, and the solution was stirred overnight at 65°C. The solution was stripped to dryness on a rotary evaporator. The residue obtained was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and also water. Removal of chloroform gave a dark brown oil. An eight gram portion of this oil was subjected to flash chromatography on silica gel using 15% ethyl acetate-85% hexane for elution. Fractions of similar purity were combined and solvent was removed in vacuo. The residue was dried in vacuo overnight at 80°C to give 4.75 g (45.9% based on aliquot taken) of white amorphous material.

1H NMR (CDC13): 6.9-7.6 5 12, aromatic), 3.7-4.0 2, protons adjacent to sulfonamide nitrogen), 2.4 3, methyl), 1.3-2.9 7, aliphatics).

Analysis: Calculated for C 26

H

24

N

2 0 2 SF2: C, 66.93; H, 5.18; N, 6.00 Found C, 66.62; H, 5.20; N, 5.89 Preparation 76 a.a-Bis(4-fluoroDhenvl)-3-piperidineacetonitrile maleate A solution of a,a-bis(4-fluorophenyl)- -[(4-methylphenyl)suil nyl]-3piperidineacetonitrile (25.00 g, 0.0536 mole) in 125 ml of 48% hydrobromic acid containing phenol (25.00 g, 0.2657 mole) was heated at reflux for 3-1/2 hours. The solution was cooled to room temperature and diluted to 1 liter with ice while being made alkaline with 50% sodium hydroxide. The purple aqueous phase was extracted with three 300 ml portions of chloroform. The chloroform layer was back extracted with two 150 ml portions of IN sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a light brown oil. The oil was converted to the maleate salt which was recrystallized from methanol-diethyl ether.

'j i

!I

:i i ,r 1 tli -66- AHR-438A-CIP SThe precipitate was dried in vacuo overnight at 80°C to give 13.05 g (56.8%) of white crystals, m.p. 115-118°C.

Analysis: Calculated for C 23

H

2 2

N

2 0 4

F

2 C, 64.48; H, 5.18; N, 6.54 Found C, 64.04; H, 5.15; N, 6.50 Preparation 77 4-[Bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine.

A solution of 4-[bis(4-fluorophenyl)methyl]-l-piperidinepropanol (40.27 g, 0.117 mole free base) and thionyl chloride (17.90 g, 0.150 mole) in I 350 ml of chloroform was stirred at room temperature for 1/2 hour. The SO. solution was heated at reflux for 6 hours, cooled to room temperature, and then stripped to dryness. The gum obtained was dissolved in chloroform and extracted with saturated sodium bicarbonate. The chloroform layer was 0* dried (anhydrous sodium sulfate), filtered, and solvent removed to give a °o reddish-brown oil (42.11 An eight gram sample was subjected to flash chromatography on silica gel using 50-50 v/v of ethyl acetate-hexane for elution. After combining fractions, removing solvent and drying the oil in vacuo, 6.84 g (84.6% yield-based on aliquot) of brown oil was obtained.

Analysis: Calculated for C 21

H

24

NOF

2 C1 2 C, 69.32; H, 6.65; N, 3.85 Found C, 69.09; H, 6.60; N, 3.84 o Preparation 78 7-Hvdroxv-4-oxo-4H-1-benzoyran-2-carboxvlic acid ethyl ester.

To a warm, stirred solution of (18.4 g, 0.8 mole) sodium metal in 250 ml 0lr° of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 2,4dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in 50 ml of absolute ethanol and 50 ml of absolute ethyl ether over a 30-min period. The mixture was heated at reflux for 4 hr and then poured into a solution of S* ml of concentrated hydrochloric acid and 1.8 liter of water. The mixture was i; extracted with two 500-ml portions of ethyl ether and the combined extracts Swere concentrated under reduced pressure to give a solid residue.

The solid was dissolved in a mixture of 250 ml of ethanol and 3 ml of concentrated hydrochloric acid and heated at reflux for 2 hr. The mixture was concentrated under reduced pressure and the solid residue was

I

AHR-438A-CIEP

B

I

I

r x tr r t t I I LIc triturated with ethyl ether, collected by filtration, and recrystallized from ethanol to yield 28.1 g of tan powder, m.p. 217-221°C.

Analysis: Calculated for C 12

HI

0 0 5 C, 61;54; H, 4.30 Found C, 61.68; H, 4.34 Preparation 79 a,a-Diphenyl- -(phenylmethyl)-4-piperidineacetonitrile hydrochloride To a prewashed slurry of 8.00 g (0.19 mole), 57% sodium hydride in 300 ml of dimethylsulfoxide was added 32.80 g (0.17 mole) diphenylacetonitrile. The solution was heated at 65°C for 1 hr during which time the solution became deep red. 1-(Phenylmethyl)-4-piperidinol ester with benzenesulfonic acid (0.17 mole) was then added in 50 ml of dimethylsulfoxide and the solution stirred overnight at 60°C. The solution was cooled and poured into 1 liter of water. The aqueous solution was extracted with toluene (3 x 150 ml). The toluene extracts were treated with 500 ml of sulfuric acid which caused a gummy residue to precipitate. The residue was taken up in a mixture of methylene chloride and 10% sodium hydroxide. The layers were separated, the aqueous layer extracted with methylene chloride and the combined extracts dried over magnesium sulfate. Concentration gave 35.0 g of a tan solid, m.p. 138-142°C.

A small portion was converted to the hydrochloride salt which was recrystallized from methanol/diethyl ether to give white powder, m.p.

2500C.

Analysis: Calculated for C 26

H

27 C1N 2 C, 77.50; H, 6.75; N, 6.95 Found C, 77.09; H, 6.76; N, 7.04 Preparation a,a-Diphenyl-l-(phenylmethyl)-3-piperidinepropanenitrile hydrochloride A mixture of (7.25 g, 0.025 mole) a,a-diphenyl-3-piperidinepropanenitrile, 4.28 g, (0.025 mole) of benzyl bromide and potassium carbonate (5.53 g, 0.04 mole) was stirred overnight at room temperature in 300 ml of acetonitrile containing potassium iodide (0.3 The reaction mixture was stripped to dryness, and the resulting residue was dissolved in chloroform.

-68- AHR-438A-CIP Pt I tit i r rr j r ti ft I 1 r r i I r t r r i d i i r cl

I

i i Irrrt i r ~r The chloroform layer was extracted several times with water, dried, filtered, and solvent removed to give an oil. The oil was converted to the hydrochloride salt via ethereal hydrogen chloride. The white solid was recrystallized from methanol-diethyl ether and dried in vacuo at overnight. A yield of 7.04 of white solid, m.p. 243-246°C with decomposition was obtained.

Analysis: Calculated for C 27

H

29

N

2 C1: C, 77.77; H, 7.01; N, 6.72 Found C, 77.36; H, 6.97; N, 6.67 Preparation 81 a.a-Diphenyl-l-(phenylmethyl)-4-piperidineacetamide fumarate A solution of (5.88 g, 0.02 mole) a,a-diphenyl-4-piperidineacetamide in acetonitrile was prepared by warming with a heat gun. To this solution was added (3.42 g, 0.02 mole) of benzyl bromide and potassium carbonate (6.91 g, 0.05 mole). This mixture was stirred ovrnight at room temperature and then heated at reflux for 5 hours. The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloroform-water and sodium hydroxide. Removal of chloroform gave an oil which was subjected to column chromatography on silica gel using mixtures of ethyl acetate-dimethoxyethane for elution. Suitable fractions were combined and converted to the fumarate salt. The salt was recrystallized from methanoldiethyl ether and dried overnight at 80°C in vacuo. A yield of 1.65 g of white crystalline material, m.p. 218-220°C was obtained.

Analysis: Calculated for C 30

H

32

N

2 0 5 C, 71.98; H, 6.44; N, 5.60 Found C, 71.60; H, 6.47; N, 5.51 Preparation 82 a,a-Diphenyl- -(phenylmethyl)-3-piperidinepropanamide hydrate [1:0.51.

A mixture of (7.70 g, 0.025 mole) a,a-diphenyl-3-piperidinepropanamide, 4.28 g (0.025 mole) of benzyl bromide and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 300 ml of acetonitrile containing potassium iodide (0.3 The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform 5% sodium hydroxide. Removal of chloroform gave an oil. This oil was -69- AHR-438A-CIP subjected to column chromatography on silica gel using dimethoxyethane and ethyl acetate for elution. A yield of 3.34 g of yellow amorphous solid, after combining column fractions and drying at 80C in vacuo overnight was obtained.

1H NMR (CDC13) 5 7.1-7.6 15, aromatic), 5.5-6.0 (br, s, 2, NH 2 3.4 2, CH2), 3.1 1, 1/2 H 2 0) 1.0-2.7 11, alphatic).

Analysis: Calculated for C 27

H

31

N

2 01.

5 C, 79.57; H, 7.67; N, 6.87 Found C, 79.65; H, 7.46; N, 6.88 i Preparation 83 S, a,a-Bis(4-fluorophenyl)-1-(phenylmethyl)-4-piperidineacetonitrile S, hydrochloride hydrate S*A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (6.05 g, 0.019 mole), benzyl bromide (3.32 g, 0.019 mole), and potassium carbonate 1 "(5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of acetoi nitrile containing potassium iodide. The reaction mixture was stripped to dryness and partitioned between chloroform and water. The chloroform layer S' was dried over anhydrous sodium sulfate, filtered, and solvent removed to give 7.55 g of light yellow oil. The oil was converted to the hydrochloride salt using ethereal hydrogen chloride, and the salt was recrystallized from methanol-diethyl ether. The white solid obtained by filtration was washed Swith diethyl ether and dried in vacuo overnight at 80 0 C. A yield of 3.85 g of white crystals, m,p. 283°C with decomposition was obtained.

Analysis: Calculated for C 26

H

2 6

N

2 0 0 .5F 2 Cl: C, 69.71; H, 5.85; N, 6.25 Found C, 70.07; H, 5.68; N, 6.25 Preparation 84 a,a-Bis(4-fluorophenyl)- -(phenylmethyl)-3-pyrrolidinepropanenitrile hydrate The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in dimethyl sulfoxide from 41.9 g (0.183 mole) of the free base and 7.32 g (0.183 mole) of 60% sodium hydride. After stirring at room temperature for 3 hrs, a solution of (63.18 g, 0.183 mole) 1-phenylmethyl-3-pyrrolidinemethanol methanesulfonate ester in dimethylsulfoxide was added.

The resulting solution was stirred overnight at 60 0 C. The solvent was AHR-438A-CIP removed in vacuo via a rotary evaporator. The oil obtained was dissolved in chloroform and the solution was extracted several times with 1N sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide, dried over anhydrous sodium sulfate, filtered, and solvent removed to give 59.6 g of dark brown oil. A 10 g fraction was subjected to flash chromatography on silica gel using 50-50 v/v ethyl acetate-hexane and 100% ethyl acetate for elution. Fractions of similar purity were combined, and sovlent was removed in vacuo. A dark brown oil was obtained and dried at 80°C in vacuo overnight. A yield of 4.13 g (33.5% based on aliquot used) of dark brown oil was obtained.

1H NMR (CDC13): 8 6.8-7.4 13 aromatic), 3.5 2, N-CH2 1.1-2.8 9, aliphatic).

*t #4 Wr 4 .4 I4 f N 4( 4 Analysis: Calculated for C 2 6

H

25

N

2 0 0 5

F

2 Found C, 75.89; H, 6.12; N, 6.81 C, 75.93; H, 6.00; N, 6.55 ii :.14 tg Preparation a-(4-Fluorophenyl)-a-[l-(phenylsulfonl)-4-piperidinyl]-2-pyridinemethanol.

A solution of 2-bromopyridine (9.26 g, 0.059 mole) in 250 ml of tetrahydrofuran was prepared and cooled to -65°C in an acetone/dry ice bath. To this solution was added n-butyl lithium (10.5 M in hexane, 5.60 ml, 0.05 mole) while maintaining a temperature of-45 C to -65°C. The solution was stirred for 2 hr at -65°C. A tetrahydrofuran solution of(4-fluorophenyl)[1- (phenylsulfonyl)-4-piperidinyl]methanone (18.2 g, 0.0525 mole) was added dropwise while maintaining a temperature of-65°C. The solution was stirred 72 hr while reaching room temperature. The solution was stripped to dryness. The residue was dissolved in chloroform and extracted with several portions of water. The chloroform layer was dried over sodium sulfate and solvent was removed in vacuo to give a brown oil. This oil was subjected to flash chromatography on silica gel using 30% ethyl acetate/hexanes and ethyl acetate/hexanes for elution. Fractions of similar purity were combined and solvent removed to give a white crystalline solid. This solid was triturated with diethyl ether and chilled in the freezer for 12 hr. The solid was isolated and dried at 80°C in vacuo overnight. This process provided 12.12 g (54.1% yield) of white crystalline solid, mp 160-163°C.

AHR-438A-CIP ft *r fr 9 9 f 99 1 t If~ I f Analysis: Calculated for C 23

H

23

N

2 0 3 SF: C, 64.78; H, 5.44; N, 6.57 Found C, 64.74; H, 5.43; N, 6.49 Preparation 86 2-[(4-Fluorophenyl)(4-piperidinyl)methyl]pyridine hydrochloride hydrate A mixture of a-(4-fluorophenyl)-a-[l-(phenylsulfonyl)-4-piperidinyl]- 2 pyridinemethanol (62.0 g, 2.0 mole) and 500 ml of 57% hydriodic acid was heated at reflux for 6 hours. The reaction mixture was concentrated and then filtered with Celite®. The filtrate obtained was stripped to dryness. Ice/ water was added, and the mixture was made alkaline with 50% sodium hydroxide. The aqueous phase was extracted several times with chloroform.

The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to obtain an oil which crystallized on standing at room temperature.

The oil was converted to the hydrochloride salt and the salt was recrystallized from methanol-diethyl ether. A white solid was obtained which was dried at 80°C in vacuo overnight. This furnished 15.45 g (71.9% yield) of yellow solid, mp 182-185°C.

Analysis: Calculated for C 17

H

21

N

2 0 0 .5FCl: C, 57.96; H, 6.30; N, 7.95 Found C, 57.46; H, 6.26; N, 7.88 Preparation 87 a,a-Diphenyl-l-(phenylmethyl)-4-piperidinemethanol.

A Grignard solution was prepared by the addition of 94.2 g (0.6 mole) of bromobenzene in 250 ml of dry (freshly distilled from lithium aluminum hydride) tetrahydrofuran to a mixture of (12.5 g, 0.5 mole) magnesium chips in 500 ml of dry tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To this Grignard reagent at ambient temperature, was added a solution (44.2 g, 0.179 mole) of the base of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of tetrahydrofuran in a stream. The solution was stirred overnight at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 ml of methylene chloride and -72- AHR-438A-CIP twice with 250 ml of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide j solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give a gum as residue. The gum was Sdissolved in 500 ml of ethyl ether, and the solution was treated with activated charcoal, filtered through Celite®, and then concentrated to give a gum as residue. The gum crystallized when triturated with petroleum ether 0 The solid was collected by filtration and dried to yield 49.0 g of title compound as a white solid. An analytical sample, mp 89.5-90.5°C, was S, prepared by recrystallization from isopropanol.

l Analysis: Calculated for C 25

H

27 NO: C, 83.99; H, 7.61; N, 3.92 Found C, 84.09; H, 7.63; N, 3.97 IPreparation 88 S ,a-Dipheyl-4-piperidinemethanol.

A mixture of 35.8 g (0.1 mole) of a,a-Diphenyl-l-(phenylmethyl)-4piperidinemethanol and 5% palladium on carbon catalyst in 500 ml of absolute ethanol was hydrogenated at 60°C in a Parr apparatus for 3 days.

S The mixture was filtered through Celite® and the filtrate was concentrated to i give a solid residue. The solid was triturated with petroleum ether (30-60 0

C),

collected by filtration and dried to give 26.7 g of title compound as a white i solid. An analytical sample was obtained by recrystallization from 2propanol-isopropyl ether, mp 160-161C.

Analysis: Calculated for C 18

H

21 NO: C, 80.86; H, 7.92; N, 5.24 Found C, 80.98; H, 7.96; N, 5.30 Preparation 89 a-(4-Fluorophenyl)-a-methyl-4-piperidinemethanol.

To a solution of 49.9 g (0.2 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 500 ml of tetrahydrofuran was added dropwise 110 ml (0.35 mole) of a 3.2 molar solution of methylmagnesium bromide in ethyl ether* at ambient temperature. After addition was complete, the mixture was heated at reflux for 1 hr and then at ambient temperature overnight. The mixture was poured into 1.5 liters of a saturated ammonium chloride solution with vigorous stirring. The layers were separated and the aqueous layer was -73- AHR-438A-CIP Ir I I Ir II f c I rIf I I I I IIr

I

(I

extracted twice with 300 ml portions of methylene chloride. The combined organic layers were washed successively with 250 ml of water, 250 ml of a sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 37.3 g (70% yield) of crude alcohol as a gum.

The gum was dissolved in 400 ml of 95% ethanol and the solution was heated with a solution of 22.4 g (0.4 mole) potassium hydroxide in 100 ml of water and then heated at reflux overnight. The solution was concentrated under reduced pressure, and the residue was triturated with water. The resulting solid was collected by filtration and recrystallized from 2-propanol to yield 19.8 g of title compound as an off-white powder, mp 184-186°C.

Analysis: Calculated for C 13

H

18 FNO: C, 69.93; H, 8.13; N, 6.27 Found C, 70.00; H, 8.21; N, 6.27 *Available commercially, Aldrich Chemical Co., Inc., 940 West Saint Paul Avenue, Milwaukee, Wisconsin 53233 USA.

Preparation a,a-Bis(4-methylphenyl)-l-(phenylmethyl)-4-piperidinemethanol.

A Grignard solution was prepared by the addition of 102.6 g (0.6 mole) of 4-bromotoluene in 500 ml of dry tetrahydrofuran to a mixture of 12.5 g mole) of magnesium chips in 250 ml of tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 1 hr to complete formation. To this Grignard reagent at ambient temperature was added in a stream 42.9 g (0.173 mole) of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of dry tetrahydrofuran. The solution was stirred at ambient temperature and then poured into 2.5 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted twice with 375 ml portions of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine.

The organic layer was dried over sodium sulfate and concentrated under pressure to give a gum as residue. The gum gradually crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration and dried to yield 63.6 g of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 115-117 0

C.

I

j -74- AHR-438A-CIP o. Analysis: Calculated for C2 7

H

3 1 NO: C, 84.11; H, 8.10; N, 3.63 Found 84.23; H, 8.13; N, 3.66 Preparation 91 a,a-Bis(4-methylphenyl)-4-piperidinemethanol.

A solution of 38.5 g (0.1 mole) of a,a-bis(4-methylphenyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated at 50 psi and over one 5% palladium on carbon catalyst in a Parr apparatus for 3 days. The cooled mixture was filtered through Celite® and the filtrate was concentrated Sunder reduced pressure to give a glass as residue. The glass was crystallized from 2-propanol to yield 17.7 g of title compound as a white solid, mp 150-153°C.

t t Analysis: Calculated for C2 0

H

2 5 NO: C, 81.31; H, 8.53; N, 4.74 Found C, 81.18; H, 8.62; N, 4.72 i Preparation 92 a,a-Bis(4-methoxyphenyl)-1-(phenylmethyl)- 4 -piperidinemethanol I 'oxlate hydrate compound with ethanol A Grignard reagent was prepared by the addition of a solution of 112.2 g i (0.6 mole) of 4-bromoanisole in 500 ml of dry tetrahydrofuran to a mixture of i 12.5 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the additon was complete, the mixture was heated at reflux for 0.5 hr to complete formation. To this Grignard reagent at ambient temperature was added a solution of 42.8 g (0.173 mole) of the base of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester in 250 ml of tetrahydrofuran in a stream. The mixture was stirred at ambient temperature overnight and then poured into liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was exracted twice with 375 ml portions of methylene chloride. The combined organic layers were washed successively with 500 ml of water, 750 ml of a 3% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum was dissolved in 2-propanol and converted to the oxalic acid salt. The solid was collected by filtration, washed with 2-propanol and ethyl ether and dried AHR-438A-CIP 00 00 00 0 0 00 0 0 *P 0 00 0? *0 0 *I 9* 0040P 00 00 0 It 0 0 0 0( ii

I

I

;I

i 11 to yield 84.8 g of title compound as a white powder. An analytical sample was recrystallized from absolute ethanol, mp 128-131 0 C (with decomposition) (slow heating; rapid heating gives mp -110°C).

Analysis: Calc'd for C 29

H

33

NO

7 5 -0.5C2H 5 0H: C, 66.74; H, 6.91; N, 2.60 Found C, 67.08; H, 6.77; N, 2.67 Preparation 93 4-(3-Chloropropoxy)benzoic acid methyl ester.

A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate*, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was cooled and filtered, and the filtrate concentrated to give an oil as residue. The oil crystallized when triturated with cold petroleum ether 60°C). The solid was collected by filtration and recrystallized from petroleum ether (60-110°C) to yield 42.9 g of title compound as a white solid, mp 56.5-59 0

C.

Analysis: Calculated for C 1 1

H

13 C10 3 C, 57.78; H, 5.73 Found C, 57.91; H, 5.80 *Available commercially, Aldrich Chemical Co., Inc., 940 West Saint Paul Avenue, Milwaukee, Wisconsin 53233 USA.

Preparation 94 a.a-Bis (4-methoxvphenvl)-4-piperidinemethanol.

A solution of 36.7 g (0.088 mole) of a,a-bis(4-methoxyphenyl)-1- (phenylmethyl)-4-piperidinemethanol in 500 ml of absolute ethanol was hydrogenated over 5% palladium on carbon catalyst at 60°C in a Parr apparatus for 3 days. The mixture was cooled, filtered through Celite®, fresh catalyst added to the filtrate and the mixture hydrogenated. This process was repeated until no starting material was present by mass spectral analysis. The filtrate was concentrated, and the residue was partitioned between methylene chloride and a 5% sodium hydroxide solution. The organic layer was dried over sodium sulfate and concentrated to give a solid residue. The solid was recrystallized from 2-propanol to yield 8.6 g of title compound as a white solid, mp 153-155°C.

-76- AHR-438A-CIP Analysis: Calculated for C 20

H

25 N03: Found C, 73.37; H, 7.70; N, 4.28 C, 73.42; H, 7.72; N, 4.30 I #1 e, rr Si t .e.

I,

1k".

Preparation 4-(3-Chloropropoxy)-1,1'-biphenyl.

A mixture of 34 g (0.2 mole) of 4-phenylphenol, 63 g (0.4 mole) of 1bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled and filtered, and the filtrate concentrated under reduced pressure.

The residue was triturated with petroleum ether (30-60°C), and a solid crystallized. The solid was collected by filtration and was subjected to flash chromatography on 400 g of silica gel on a 10-cm diameter column to remove starting phenol. The column was eluted with a 1:2 mixture of benzene and cyclohexane, and fractions containing title compound were combined and concentrated to give a solid residue. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 35.1 g of title compound as a white solid. An analytical sample was recrystallized from petroleum ether (60-110°C), mp 65-66 0

C.

Analysis: Calculated for C 15

H

15 C10: C, 73.02; H, 6.13 Found C, 73.08; H, 6.12 Preparation 96 1-[4-(3-Chloropropoxy)phenyl]-1-Droanone.

A mixture of 37.6 g (0.25 mole) of 4'-hydroxypropiophenone 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.5 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The oily residue was dissolved in 500 ml of benzene, and the solution stirred with potassium hydroxide pellets for 1.5 hr to remove unreacted phenol. The mixture was filtered, and the filtrate was concentrated to give 56.1 g (99% yield) of title compound as an oil. The oil gradually crystallized and a portion of the solid was recrystallized from petroleum ether (60-110°C) to yield title compound as a fluffy, white solid, mp 41-43 0

C.

ia :si -77- AHR-438A-CIP Analysis: Calculated for C 12

H

15 C10 2 C, 63.58; H, 6.67 Found C, 63.46; H, 6.82 *Available commercially, Aldrich Chemical Co., Inc., 940 West Saint Paul Avenue, Milwaukee, Wisconsin 53233 USA.

Preparation 97 4-[Bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-1-piperidinecarboxamide.

A Grignard solution was prepared by the treatment of a slurry of 8.5 g '8 (0.35 mole) of magnesium chips in 200 ml of dry tetrahydrofuran with a solution of 72.8 g (0.38 mole) of 1-bromo-4-chlorobenzene in 400 ml of tetrahydrofuran. After the addition was complete, the mixture was heated at reflux for 15 min to complete formation. To the Grignard solution at ambient temperature was added a solution of 38.4 g (0.15 mole) of 1-[(diethylamino)carbonyl]-4-piperidine carboxylic acid ethyl ester in 200 ml of tetrahydrofuran in a stream. The solution was stirred at ambient temperature overnight and poured into 2.5 liters of a saturated ammonium chloride solution.

t The layers were separated, and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride.

The combined organic layers were filtered through Celite® and the filtrate was washed successively with 500 ml of water, 750 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The solution was dried over sodium sulfate and concentrated under reduced pressure to give a gum which gradually crystallized. The solid was triturated with petroleum 4 ether (30-60°C), collected by filtration, and dried to yield 56.7 g of title compound as a white solid. An analytical sample was recrystallized from isopropanol, mp 172-175 0

C.

Analysis: Calculated for C 23

H

28 C1 2

N

2 0 2 C, 63.54; H, 6.48; N, 6.43 Found C, 63.60; H, 6.64; N, 6.25 SPreparation 98 3-Methoxy-4-(phenylmethyloxy)benzaldehyde.

A mixture of 4-hydroxy-3-methoxybenzaldehyde (100.0 g, 0.657 mole), benzyl bromide (112.4 g, 0.657 mole), and potassium carbonate (90.8 g, 0.657 mole) was heated overnight at reflux in 600 ml of dry acetonitrile (dried over -78- AHR-438A-CIEP I I ~t 4 1 11 41 ft I f+ I 1 14 1 4 If f: 14i 4A molecular sieves). The reaction mixture was stripped to dryness on a rotary evaporator. A white solid was obtained which was recrystallized form ethanol and dried in vacuo overnight at 80°C, to give 147.45 g (92.6% yield) of white crystalline product, mp 58-63°C.

Analysis: Calculated for C 15

H

14 0 3 C, 74.36; H, 5.83 Found C, 74.36; H, 5.78 Preparation 99 5-Methoxy-2-nitro-4-(phenylmethoxy)benzaldehyde.

Reference: J. Med. Chem. 1977, Vol. 20, No. 1, p. 147 3-Methoxy-4-(phenylmethyloxy)benzaldehyde (48.0 g, 0.198 mole) was added in small portions over 0.5 hour to 200 ml of concentrated nitric acid cooled to 0 C in an acetone-dry :ce bath. The temperture was maintained at 0-1°C for ten minutes. The temperature was allowed next to reach 15 0 C and suddenly but briefly allowed to rise to 45 0 C. The temperature was cooled to and then the reaction mixture was povred in ice/water. A yellow solid was obtained and filtered and washed with diethyl ether. A two gram sample was recrystallized from isopropanol. The light yellow solid isolated was dried in vacuo overnight at 80 0 C to give 0.92 g (32.5% yield) of light yellow solid, mp 122-124 0

C.

Analysis: Calculated for C 15

H

13

NO

5 C, 62.72; H, 4.56; N, 4.88 Found C, 62.42; H, 4.57; N, 5.17 Preparation 100 5-Methoxy-2-nitro-4-(phenylmethyloxy)benzoic acid.

A solution of 5-methoxy-2-nitro-4-(phenylmethyloxy)benzaldehyde (45.11 g, 0.157 mole) in 600 ml of acetone was prepared. To this solution was added 400 ml of 10% potassium permanganate solution over 1 hr. The resultant mixture was stirred for 1 hr at room temperature. The reaction mixture was cooled to room temperature and filtered with Celite®, acetone was removed. The resulting material was made acidic with concentrated hydrochloric acid. A yellow solid formed and was separated from aqueous solution, and air dried. The yellow solid was dissolved in ethyl acetate, and filtered through sodium sulfate to remove traces of manganese dioxide, after which 25.84 g of yellow solid was obtained. A 2 g sample was recrystallized it ii AHR-438A-CTEP t v #4 4 o o 4 4 4, t 4f) #454':" *r 4 4f 44

~O

from isopropyl alcohol. The yellow solid isolated was dried in vacuo overnight at 80°C, to give 1.85 g (50% yield) of yellow solid, mp 188 0 C (with decomposition).

Analysis: Calculated for C 15

H

13 N0 6 C, 59.41; H, 4.32; N, 4.62 Found C, 59.27; H, 4.40; N, 4.46 Preparation 101 4-(4-Chlorobutoxy)benzoic acid methyl ester.

A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate, 68.6 g (0.4 mole) of 1-bromo-4-chlorobutane and 82.9 g (0.6 niole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled and filtered, and the filtrate concentrated under reduced pressure to give an oil which crystallized. The solid was triturated with cold petroleum ether (30-60 0 collected by filtration, and dried to yield 44.3 g of title compound as a white solid. An analytical sample, mp 28.5-29 0

C,

was prepared from petroleum ether (30-60°C).

Analysis: Calculated for C 12

H

15 C10 3 C, 59.39; H, 6.23 Found C, 59.30; H, 6.34 Preparation 102 1-[4-(4-Chlorobutoxy)-3-methoxyphenyl]ethanone.

A mixture of 16.6 g (0.1 mole) of acetovanillone, 34.3 g (0.2 mole) of 1bromo-4-chlorobutane and 41.4 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 18 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil which readily crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration, and dried to yield 24.4 g of title compound as an off-white solid. An analytical sample, mp 68.5-70.5 0 C, was prepared from isopropyl ether.

Analysis! Calculated for C 13 H1 7 C103: C, 60.82; H, 6.67 Found C, 60.83; H, 6.91 41~ 4 44 I I I 1:

I-

4~ i 4 AHR-438A-CIP r t I Il rf T

SI

I I Preparation 103 1-Acetyl-a-(4-fluorophenyl)-a-phenyl-4-piperidinemethanol.

A solution (667 ml, 2 mole) phenylmagnesium bromide* (3 molar in ethyl ether) was diluted with 2 liters of anhydrous ethyl ether, cooled to 0and treated with a solution of 148 g (0.6 mole) of 1-acetyl-4-(p-fluorobeazoyl)piperidine in 1.5 liters of anhydrous tetrahydrofuran dropwise over a hr period. The mixture was stirred at ambient temperature overnight arid then poured into a solution of 107 g (2 mole) of ammonium chloride in 2 liters of cold water. The mixture was extracted thrice wit'.i 1 liter portions of benzene. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated to give a semi-solid as residue. The semi-solid was triturated with isopropyl ether, and the mass crystallized. The solid was collected by filtration and dried to yield 87.8 g of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 173-175 0

C.

Analysis: Calculated for C 20

H

22 FN0 2 C, 73.37; H, 6.77; N, 4.28 Found C, 73.20; H, 6.93; N, 4.22 *Available commercially, Morton Thiokol, Inc., Alpha Products, 152 Andover Street, Danvers, Mass. 01923 USA.

Preparation 104 a.a-Bis(4-chlorophenyl)-4-piperidinemethanol.

To a slurry of 8.5 g (0.225 mole) of lithium aluminum hydride in 400 ml of anhydrous tetrahydrofuran was added a solution of 39.2 g (0.09 mole) of 4- [bis(4-chlorophenyl)hydroxymethyl]-N,N-diethyl-l-piperidinecarboxamide in 400 ml of tetrahydrofuran in a stream over a 15 min period. The mixture was heated at reflux for 24 hr, cooled, and treated successively with 8.5 ml of water, 25 ml of a 3 N sodium hydroxide solution and 8.5 ml of water. The mixture was stirred for 0.5 hr and then filtered. The filtrate was concentrated under reduced pressure to give E gum which crystallized. The solid was triturated with petroleum ether (30-60°C), collected by filtration and recrystallized from benzene to yield 10.5 g of title compound as a white solid. An analytical sample was recrystallized from 2-propanol, mp 184- 188 0

C.

i-: 1' c i

I

-81- AHR-438A-CrP *O 0 0* 0 C 00 IL t 0t I Analysis: Calculated for C18H19C12NO: C, 64.30; H, 5.70; N, 4.17 Found C, 64.59; H, 5.79; N, 4.16 Preparation 105 a,a-Bis(4-fluorophenyl)-4-pyridineethanol.

A solution of 27.8 g (0.30 mole) of 4-picoline in 400 ml of tetrahydrofuran and under an atmosphere of nitrogen was cooled to -30°C in a dry-ice acetone bath. A solution of 2.5 moles n-butyllithium in hexane (119 ml, 0.30 mole) was added over 1 hr and the mixture was stirred for an additoinal min at -30°C. The reaction mixture was allowed to warm to room temperature over 1.5 hr, and 66.7 g (0.30 mole) of4,4'-difluorobenzophenone in 100 ml of tetrahydrofuran was added. The mixture was stirred for 2 hr and then was poured into an icy solution of ammonium chloride. A white solid was collected. The aqueous mixture was extracted with several portions of methylene chloride and the methylene chloride then removed in vacuo to give additional solid. The solid fractions were combined and recrystallized from a mixture of ether-hexane to give 63.14 g (67.9% yield) of title compound as a white crystalline solid: mp 158-159.5 0

C.

Analysis: Calculated for C1 9 H1 5 NOF2: C, 73.30; H, 4.86; N, 4.50 Found C, 73.27; H, 4.79; N, 4.51 Preparation 106 a.a-Bis(4-fluorophenvl)-4-piperidineethanol.

A mixture of 12.25 g (0.0394 mole) of a,a-bis(4-fluorophenyl)-4pyridineethanol and 1.3 g of 5% platinum on carbon catalyst in 250 ml of acetic acid was shaken under an atmosphere of hydrogen (53 psi) for 9 hr.

The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give a solid.

Recrystallization from acetonitrile gave 10.62 g (85.0% yield) of title compound as a white crystalline solid: mp 169-171°C.

Analysis: Calculated for C1 9 H21NF20: C, 71.90; H, 6.67; N, 4.41 Found C, 71.98; H, 6.75; N, 4.54 r rr r: 1 3 i

T:

8i: 1 1 -82- AHR-438A-CIP Preparation 107 a-(4-Fluorophenyl)-a-phenyl-4-piperidinemethanol.

A mixture of 16.3 g (0.05 mole) of 1-acetyl-a-(4-fluorophenyl)-a-phenyl- 4-piperidinemethanol and 5.6 g (0.1 mole) of potassium hydroxide in 150 ml of 95% ethanol and 20 ml of water was heated at reflux for 18 hr. The mixture was poured into 1.5 liters of ice-water and a solid precipitated. The gummy solid was collected by filtration and dried. The solid was dissolved in ethyl ether, filtered, and the filtrate slowly evaporated to 50 ml. The resulting solid was collected by filtration and recrystallized from isopropanol-isopropyl ether to yield 3.5 g of title compound as a white solid, m.p.

144.5-146 0

C.

So.' Analysis: Calculated for C 18

H

20 FNO: C, 75.76; H, 7.06; N, 4.91 Found C, 75.91; H, 7.20; N, 4.93 Preparation 108 I r 4-[2-2,Bis(4-fluorophenyl)ethyllpyridine hydrochloride A mixture of 15.05 g (0.0484 mole) of a, a-bis(4-fluorophenyl)ethyl]-4pyridineethanol, 3.2 g (0.10 mole) of phosphorus and 50 ml of 56.9% hydrogen iodide in 150 ml of glacial acetic acid was refluxed for 11 hr. The solvent was S( removed in vacuo, and the residue was partitioned between methylene chlor- S" ide and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil.

This was dissolved in a mixture of methanol and ether, and an excess of ethereal hydrogen chloride was added. The solvent was removed in vacuo, and the residue was recrystallized from a mixture of acetonitrile and ether to give 13.89 g (86.7% yield) of title compound as a white crystalline solid, m.p.

197-199 0

C.

Analysis: Calculated for C 19

H

16

NF

2 C1: C, 68.78; H, 4.86; N, 4.22 Found C, 68.58; H, 5.17; N, 4.23 Preparation 109 4-[2,2-Bis(4-fluorophenyl)ethyl]piperidine hydrochloride hydrate A mixture of 10.0 g (0.30 mole) a,a-bis(4-fluoropheny)-4-pyridineethanol and 1.2 g of 5% platinum on carbon catalyst in 200 ml of acetic acid was L1: AHR-438A-CIP i 1I ;i 4# 44 4r 4 4i 44 t SI I 4C 4 14 4 shaken under an atomsphere of hydrogen (49 psi) for 16 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide.

The solvent was removed in vacuo to give an oil. This was dissolved in methanol, an excess of ethereal hydrogen chloride was added and ether was added. A precipitate was collected to give 7.58 g as a white crystalline solid, m.p. 171-173oC.

Analysis: Calculated for C 19

H

23

NF

2 C1Oo.5: C, 65.80; H, 6.68; N, 4.04 Found C, 65.79; H, 6.80; N, 4.05 Preparation 110 4-[2,2-Bis(4-fluorophenyl)ethylene]piperidine oxalate A mixture of 8.44 g (0.0266 mole) of a,a-bis(4-fluorophenyl)-4-piperidineethanol and 25 ml of concentrated sulfuric acid in 200 ml of glacial acetic acid was refluxed for 4 hr. The solvent was removed in vacuo, and the residue was made basic with 50% sodium hydroxide. The basic mixture was extracted with methylene chloride, and the methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo to give an oil. The oil was dissolved in a mixture of methanol ether, and a slight excess of oxalic acid was added. Ether as added, and a precipitate was collected to give 8.79 g (85.0% yield) of title compound as a white crylstalline solid, m.p.

225-225.5 0 C with decomposition.

Analysis: Calculated for C 2 1

H

21

NF

2 0 4 C, 64.78; H, 5.44; N, 3.60 Found C, 64.95; H, 5.56; N, 3.61 Preparation 111 4-[Bis(4-chlorophenyl)methyl)piperidine oxalate hydrate A mixture of 4-[bis(4-chlorophenyl)methylene]piperidine (13.05 g, 0.041 mole), phosphorus (45.0 g, 1.45 mole), glacial acetic acid (300 ml) and 57% hydriodic acid (230 ml) was heated at reflux for 72 hr. The mixture was cooled to room temperature, stirred 5 min with Celite®, and filtered. The filtrate was made basic with ice/50% sodium hydroxide. The alkaline layer was extracted with chloroform. The chloroform layer was dried over sodium sulfate and filtered, and solvent removed to give a brown oil. A 0.65 g portion of the oil was converted to the oxalate salt and the salt was recrystallized

L

AHR-438A-CP at *a a 4 o a oa o a rr oo *o a 0 o e« 9000 I t t I *4 it

'€II

r I) a tt a* a I t t t t I t 4 a p 4 a t aa*t It from ethanol-diethyl ether. A white solid was isolated and dried in vacuo overnight at 80°C. This provided 0.46 g (59.1% yield) of white crystalline solid, m.p. 219-220 0

C.

Analysis: Calculated for C 20

H

22 NO4.5C1 2 C, 57.29; H, 5.29; N, 3.34 Found C, 57.26; H, 4.99; N, 3.36 Preparation 112 Cyclohexyl[1-(phenylsulfonyl)-4-piperidinyl]methanone.

To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid, ethyl ester in 500 ml of dry, cooled to 0°C and under an atmosphere of nitrogen, was added 95 ml of a 2 molar solution (0.19 mole) of cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at ambient temperature and then was quenched on an icy solution of ammonium chloride. The mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a semisolid material. This was recrystallized from ethanol to give 8.50 g (29.8% yield) of title compound as a white crystalline solid, m.p. 141-1430C.

Analysis: Calculated for C 18

H

2 5

NO

3 S: C, 64.45; H, 7.51; N, 4.18 Found C, 64.39; H, 7.82; N, 4.20 Preparation 113 4-[2.2-Bis(4-fluorophenyl)ethvlene]pyridine.

A mixture of 1.57 g (0.0050 mole) of a,a-bis(4-fluorophenyl)-4-pyridineethanol, 10 ml of concentrated sulfuric acid and 80 ml of glacial acetic acid was heated at reflux for 2 hr. The solvent was removed in vacuo, and the residue was made basic with an icy solution of dilute sodium hydroxide. The aqueous mixture was extracted with methylene chloride, and the methylene chloride extract was dried over magnesium sulfate. The solvent was removed in vacuo to give a colorless oil. This was crystallized from ether-hexane to give 0.74 g (50% yield) of title compound as a white crystalline solid, m.p.

111-112.50C.

Analysis: Calculated for C 19

H

13

NF

2 C, 77.80; H, 4.47; N, 4.78 Found C, 77.78; H, 4.42; N, 4.74 r i 1 i iN' AHR-438A-CFP Preparation 114 a-Cyclohexyl-a-(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.

A solution of (4-fluorophenyl)[l-(phenylsulfonyl)-4-piperidinyl]methanone (20.8 g, 0.06 mole) in 250 ml of tetrahydrofuran (dried over 4A sieves) was prepared. This solution was stirred 0.5 hr under nitrogen atmosphere in an ice bath. Next, cyclohexylmagnesium chloride (35 ml of 2 molar in diethyl ether, 0.070 mole) was added dropwise with a syringe (under nitrogen atmosphere). The resulting solution was stirred for 48 hr allowing the reaction solution to cool to room temperature. The reaction mixture was stripped to dryness and treated with aqueous ammonium chloride. The aqueous solution was extracted with chloroform, and the chloroform layer was back extracted I with water. The chloroform layer was dried over sodium sulfate and filtered, t and solvent removed to give a fluffy white residue. This material was subjected to flash chromatography on silica gel using 20% ethyl hexanes, and 30% ethyl acetate-70% hexanes for elution. Fractions containing a single spot were combined, and solvent was removed in vacuo. A fluffy white residue was obtained and dried in vacuo overnight at 80°C in the t, presence of phosphorus pentoxide. This procedure produced 16.72 g (64.7% yield) of the title compound as a white crystalline solid, m.p. 106-109oC.

Analysis: Calculated for C 24

H

3 0NO 3 SF C, 66.79; H, 7.01; N, 3.24 Found C, 66.78; H, 7.09; N, 3.21 PreDaration 115 a.a-Bis(3-fluorophenyl)- -(phenylsulfonyl)-4-Diperidinemethanol.

To a suspension of 7.78 g (0.33 mole) of magnesium turnings and a crystal of iodine in 800 ml of anhydrous ether under an atmosphere of nitrogen was slowly added a solution of 3-bromofluorobenzene in 200 ml of ether.

The mixture was stirred for 1.5 hr and 30.6 g (0.103 mole) of ethyl 1-benzene- 0i sulfonylisonipecotate was added as a solid. Tetrahydrofuran (300 ml) was added, and the mixture was stirred at room temperature for 12 hr. The mixture was poured into an icy solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, and the resulting residue was recrystallized from ether to give 24.14 g of the title compound as a white crystalline solid, m.p. 183-185°C.

*i -7 -86- AHR-438A-CIP uo 9 9* 9 9 9 4r 9999 9 0 9 99 9 *0 9 9.

ol 9 S St 0* 9 0S~ 9 4C Analysis: Calculated for C 24

H

23 N0 3

SF

2 C, 65.00; H, 5.23; N, 3.16 Found C, 64.95; H, 5.38; N, 3.15 Preparation 116 4-[Bis(3-fluorophenyl)methyl]piperidine hydrochloride A mixture of 15.25 g (0.0344 mole) of a,a-bis(3-fluorophenyl)-l-phenylsulfonyl-4-piperidinemethanol, 50 ml of 57% hydrogen iodide and 3.4 g (0.11 mole) of phosphorous in 300 ml of glacial acetic acid was heated at reflux for hr. The reaction mixture was filtered, and the solvent was removed from the filtrate in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was dissolved in methanol, excess ethereal hydrogen chloride was added and anhydrous ether was added. A white precipitate was collected to give 7.04 g (63.2% yield) of title compound as a white crystalline solid, m.p. 260-262°C.

Analysis: Calculated for C 1 iH 20

NF

2 C1 C, 66.77; H, 6.23; N, 4.33 Found C, 66.45; H, 6.26; N, 4.28 P F Iparation 117 5-Methoxy-2-nitro-4-(phenylmethoxy)benzamide.

A solution of 5-methoxy-2-nitro-4-(phe:ylmethoxy)benzoic acid (25.84 g, 0.085 mole) and thionyl chloride (200 ml) was heated overnight at gentle reflux in 100 ml of methylene chloride. The reaction mixture was stripped to dryness and dried in vacuo. To this residue was added 200 ml of dioxane (dried over molecular sieves). Ammonia was slowly added to the soution with constant agitation. A brown solid was formed and the mixture was filtered.

The brown solid was washed with dioxane, water, and isopropanol. The grey solid thus obtained was dried in vacuo at room temperature (23.2 A 2 g portion was triturated in refluxing ethanol and then cooled to room temperature. A white solid was filtered and dried in vacuo at 80°C overnight. This furnished 1.72 g (77.5% yield) of white crystalline solid, m.p. 222-223.5°C with decomposition.

Analysis: Calculated for C 15

H

14

N

2 0 5 C, 59.60; H, 4.67; N, 9.27 Found C, 59.48; H, 4.68; N, 9.19

I

'A

-4-

I

AHR-438A-CIP 4 *4 4 *0 *440 4 44 04 4 44 Preparation 118 4-[(Cyclohexyl)(4-fluorophenyl)methyl]pyridine.

A mixture of the free base of a-cyclohexyl-a-(4-fluorophenyl)-4-piperidinemethanol (16.54 g, 0.058 mole), 57% hydrogen iodide (250 ml), glacial acetic acid (250 ml), and phosphorus (50.0 g) was heated overnight at reflux.

The reaction mixture was cooled and filtered with Celite®. The volume of the filtrate was concentrated to 100 ml. Ice/50% sodium hydroxide was added, and the aqueous phase was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and water. The organic layer was dried over sodium sulfate and filtered, and solvent removed to give a green oil. A 4 g portion of this oil was subjected to flask. chromatography on silica gel using 20% ethyl acetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil. This oil was dried in vacuo overnight at 80°C. The oil crystallized to give 2.95 g (18.9% yield) of white crystalline solid, m.p. 78-81 0

C.

Analysis: Calculated for C 18

H

20 NF C, 80.26; H, 7.48; N, 5.20 Found C, 79.96; H, 7.45; N, 5.23 Preparation 119 4-[(Cyclohexyl)(4-fluorophenvl)methyl]piperidine.

A mixture of 4-[(cyclohexyl)(4-fluorophenyl)methyl]piperidine (10.42 g, 0.039 mole), platinum oxide (1.5 and 10 drops of concentrated hydrochloric acid in 200 ml of glacial acetic was subjected to hydrogenation at 80°C and 300 p.s.i. overnight, after which NMR analysis showed 50% desired product and 50% starting material. The reaction was repeated using 5% platinum on carbon at 85°C and 1400 p.s.i. overnight. The reaction mixture was then cooled to room temperature and filtered. Solvent was removed by rotary evaporator. The oil obtained was dissolved in chloroform and the solution was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate and filtered, and the solvent removed to give 9.94 g of brown oil. NMR analysis showed a 75%-25% mixture of product and starting material. The 9.94 g of oil obtained was dissolved in methanol and subjected to flash chromatography on silica gel using methanol and ammonium hydroxide methanol for elution. Fractions of similar purity were *4 4 0 4 44 0S 0

IY

i! si: AHR-438A- CP i

I

i ii i 1 i x t if It Itr 14 t t I I r t I: I

I

I combined and solvent removed. The clear oil obtained was dried in vacuo overnight at 80°C, to give 5.86 g (59.6% yield) of title compound as a clear oil.

H

1 NMR (CDC13): 8 6.9 7.2 7, aromatic), 8 0.8 3.3 22, alaphatics) Analysis: Calculated for C 18

H

26 NF C, 78.50; H, 9.52; N, 5.09 Found C, 78.26; H, 9.41; N, 5.06 Preparation 120 1-Acetyl-4-(p-fluorobenzoyl)piperidine.

A mixture of 93 g (0.7 mole) of aluminum chloride in 150 ml of fluorobenzene was stirred while 70 g (0.37 mole) of 1-acetylisonipecotic acid chloride was added in small portions. After the addition was complete, the mixture was refluxed for 1 hr. The mixture was poured onto ice and the 2 resulting layers were separated. The aqueous layer was extracted twice with chloroform, and the chloroform extracts were added to the fluorobenzene which was separated previously. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and 73.7 g yield) of 1-acetyl-4-(p-fluorobenzoyl)-piperidine was obtained as a crystalline residue. Recrystallization from ligroin-isopropyl ether gave a white crystalline product melting at 75-78°C.

Analysis: Calculated for C 14

H

16 FN0 2 C, 67.45; H, 6.47; N, 5.62 Found C, 67.26; H, 6.50; N, 5.54 Preparation 121 (4-Fluorophenvl)[1-(phenylsulfonyl)-4-piperidinvl]methanone.

A mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (53.30, 0.219 mole) and benzenesulfonyl chloride (44 g, 0.25 mole) in 500 ml of pyridine was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was extracted with dilute sulfuric acid and then dried over magnesium sulfate. The volume was reduced to 400 ml, hexane was added and 39.20 g of title compound was collected as a white, crystalline solid, m.p. 156.5-158.

III

4 4 I-r -89- AHR-438A-CIP Analysis: Calculated for C 1 sH 18 N03, F: C, 62.23; H, 5.22; N, 4.03 Found C, 62.13; H, 5.20; N, 4.13 Preparation 122 4-[Bis(4-fluorophenyl)methyl]-1-(3-chloropropyl)piperidine.

A solution of 4-[bis(4-fluorophenyl)methyl]-l-piperidinepropanol (40.27 g, 0.117 mole) and thionyl chloride (17.90 g, 0.150 mole) in 350 mL of chloroform was stirred at room temperature for 0.5 hr. The solution was heated at reflux for 6 hr, cooled to room temperature, and then stripped to dryness. The gum obtained was dissolved in chloroform and extracted with t' saturated sodium bicarbonate. The chloroform layer was dried (anhydrous sodium sulfate) and filtered, and solvent removed to give a reddish-brown oil (42.11 g, An 8 gram sample was subjected to flash chromatography on ,I silica gel using 50-50 v/v of ethyl acetate-hexanes for elution. After combining fractions, removing solvent, and drying the oil obtained in vacuo, 6.84 g (84.6% yield) of brown oil was obtained, the title compound.

H1 NMR (CDC13) 6: 6.7-7.3 8, aromatics), 3.4-3.7 3, methine adjacent to aromatics and methylenes adjacent to Cl), 1.0-3.0 13, remaining j alaphatics).

Analysis: Calculated for C 12

H

24

NF

2 C1 C, 69.32; H, 6.65; N, 3.85 Found C, 69.09; H, 6.60; N, 3.84 Preparation 123 (4-Fluorophenyl) (4-pyridinyl)methanone.

A solution of 4-cyanopyridine (20.8 g, 0.2 mole) in 300 ml of tetrahydrofuran was cooled in an ice bath. Next, a 100 ml soution of p-fluorophenyl magnesium bromide (2 moles in diethyl ether) was added with a syringe under nitrogen atmosphere with stirring. The resulting solution was stirred at room temperature for 1 hr and then heated at reflux for 6 hr. The solution was stripped to dryness and then transferred (via chloroform) to a mixture of ice and concentrated hydrochloric acid (100 ml). The aqueous phase was made alkaline (using 5% sodium hydroxide solution) and the chloroform layer separated with the aid of Celite®. The chloroform layer was dried over AHR-438A-CIP sodium sulfate and filtered, and solvent removed to give a dark brown oil (33.1 g, The oil was subjected to flash chromatography on silica gel using 40% ethyl acetate-hexanes and 50% ethyl acetate-hexanes for elution.

Fractions of similar purity were combined and solvent removed to give a yellow solid (25.81 A 2 g portion was recrystallized from 100 ml of hexanes. A light yellow solid was isolated and dried in vacuo overnight at room temperature, to give 1.88 g (77.3% yield) of light yellow solid, m.p. 88 0

C.

Analysis: Calculated for C 12

H

8 NOF C, 71.64; H, 4.01; N, 6.96 Found C, 71.83; H, 3.95; N, 6.99 Preparation 124 a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)-1-(phenylsulfonyl)-4- Str piperidinemethanol.

v A three-necked round bottom flask, equipped with a mechanical stirrer, flushed with nitrogen, and containing 3.74 g (0.154 mole) of magnesium turnings, was dried with a bunsen burner. After the flask had cooled, 600 ml of tetrahydrofuran was added. To this mechanically stirred mixture was slowly added a solution of 29.4 g (0.152 mole) of 4-bromo-1,2-difluorobenzene in 50 ml of tetrahydrofuran. The mixture was stirred for 1 hour, and 45.11 g (0.13 mole) of (4-fluorophenyl)[l-(phenylsulfonyl)-4-piperidinyl]methanone was added as a solid. The solution was stirred at ambient temperatures for 3 hours and was poured into an icy aqueous solution of ammonium chloride.

The aqueous mixture was extracted with methylene chloride, the methylene chloride solution was dried (magnesium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from methylene chloridehexane to give 58.89 g of title compound. A small sample was recrystallized from a mixture of methylene chloride-ether-hexane to give an analytically pure sample of the title compound: mp 97-99 0

C.

Analysis: Calculated for C 2 4H 2 2 N0 3

SF

3 C, 62.46; H, 4.81; N, 3.04 Found C, 62.63; H, 4.86; N, 3.02 -91- AHR-438A-CIP Preparation 125 4-[(3,4-Difluorophenyl)(4-floophenyl)methylene]piperidine oxalate [1:11.

A mixture of 30.19 g (0.065 mole) of a-(3,4-difluorophenyl)-a-(4-fluorophenyl)-l-phenylsulfonyl-4-piperidine methanol, 4.0 g (0.125 mole) of phosphorus and 160 ml of 47% hydriodic acid in 400 ml of glacial acetic acid s refluxed for 52.5 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.

The methylene chloride solution was dried over sodium sulfate and was filtered through a sentered glass funnel (fine porosity), and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel, elution with methanol and then with a 99/1 mixture of methanol/ammonium hydrox- S. ide) to give two separate products: the non-salt forms of the title compound Sand 4-[(3,4-difluorophenyl)(4-fluorophenyl)methyl]piperidine. Both of these t were converted to the oxalate salts. The title compound was recrystallized i from methanol ether to give 0.47 g of product as a white crystalline solid, mp 195-198 0

C.

Analysis: Calculated for C 20

H

18

NF

3 0 4 C, 61.07; H, 4.61; N, 3.56 Found C, 60.88; H, 4.57; N, 3.57 Preparation 126 4-[(3,4-Difluorophenyl)(4-fluorophenyl)methyl]piperidine oxalate hydrate I A mixture of 30.19 g (0.065 mole) of a-(3,4-difluoropheny)-a-(4-fluorophenyl)-l-phenylsulfonyl-4-piperidinemethanol, 14.0 g (0.125 mole) of phosphorus and 160 ml of 47% hydriodic acid in 400 ml of glacial acetic acid was refluxed for 52.5 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide.

The methylene chloride solution was dried over sodium sulfate and was filtered through a sentered glass funnel (fine porosity), and the solvent was removed in vacuo. The residue was flash chromatographed (silica gel, elution Swith methanol and then with a 99/1 mixture of methanol/ammonium hydroxide) to give the non-salt forms of 4-[(3,4-difluorophenyl)(4-fluorophenyl)methylene]piperidine and the title compound. The title compound -92- AHR-438A-CIP was recrystallized from acetonitrile to give 5.64 g of a white solid, Sm.p. 78-83 0

C.

Analysis: Calculated for C 2 0

H

2 1

NF

3 0 4 .5 C, 59.40; H, 5.23; N, 3.46 Found C, 59.58; H, 5.05; N, 3..8 Preparation 127 1-[(4-Methylphenyl)sulfonyl]-3-pyrrolidinol (4-methylphenyl)sulfonate ester.

A solution of N-benzyl-3-pyrrolidinol (50.0 g, 0.282 mole) and triethylamine (100 ml) in 300 ml of acetonitrile (dried over 4A molecular sieves) was prepared and chilled in an ice bath. A solution of tosyl chloride (88.6 g, 0.465 mole) in 00 ml of acetonitrile was prepared and added dropwise with stirring S° to the pr or solution. The solution obtained was stirred overnight and o gallowed to reach room temperature. The reaction mixture was filtered, and Sthe solvent was removed by rotary evaporator. The residue obtained was o o dissolved in chloroform, and the organic layer extracted successively with sodium hydroxide and water. The chloroform layer was dried (sodium sulfate) and filtered, and solvent was removed to give a dark brown oil. This oil was stirred overnight at room temperature in isopropanol. A brown oil B crystallized, and the solid was separated by filtra tion and washed with ou isopropanol. The brown solid was dried in vacuo (27.67 g, A one 0 gram sample of this material was recrystallized from ethyl acetate; a light brown solid was isolated and dried at 80°C overnight in vacuo. This procedure furnished 0.13 g yield based on aliquot) of light brown solid, mp 121-122 0

C.

Analysis: Calculated for C 18

H

21 N0 5

S

2 C, 54.67; H, 5.35; N, 3.54 Found C, 54.71;H, 5.41;N,3.52 Preparation 128 a,a-Bis(4-fluorophenyl)-l-[(4-methylphenyl)sulfonyl]-3-pyrrolidineacetonitrile.

The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in dimethylsulfoxide from 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile (11.60 g, 0.0506 mole) and sodium hydride 2.02 g, 0.0506 mole).

Next, 1-[(4-methylphenyl)sulfonyl]-3-pyrrolidinol (4-methylphenyl)sulfonate -93- AHR-438A-CIP ester (20.0 g, 0.0506 mole) in 200 ml of dimethyl sulfoxide was added. The solution was stirred overnight at 55°C. The solvent was then removed. A dark brown oil was obtained and dissolved in chloroform. The organic layer was extracted with 1N sulfuric acid and 5% sodium hydroxide. The chloroform layer was dried (over sodium sulfate) and filtered; solvent was removed to give a dark brown oil. The oil was triturated with isopropanol and placed in th, fr tzer over the weekend. A brown solid was separated by filtration (18.33 g, A one gram sample of the solid was recrystallized from isopropanol. A light brown solid was separated and dried in vacuo overnight at 80 0 C in the presence of phosphorus pentoxide. This process furnished 0.57 g (45.7% based on aliquot taken) of light brown solid, m.p. 181-183°C based upon the aliquot taken.

Analysis: Calculated for C 25

H

22

N

2 0 2

SF

2 C, 66.36; H, 4.90; N, 6.19 Found C, 65.80; H, 4.91; N, 6.03 i i Preparation 129 a.Q-Bis(4-fluorophenyl)-3-pyrrolidineacetonitrile oxalate hydrate A mixture of a,a-bis(4-fluorophenyl)-l-[(4-methylphenyl)sulfonyl]-3- Spyrrolidineacetonitrile (16.6 g, 0.0367 mole), phenol (50 g, 0.53 mole) and 300 ml of 48% hydrobromic acid was heated at reflux for two hours. The reaction mixture was cooled to room temperature and made alkaline with sodium hydroxide. The aqueous layer was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide, dried over sodium sulfate, filtered, and solvent removed to produce a dark brown oil.

"The dark brown oil was dissolved in chloroform and extracted with 1N sulfuric acid. This acidic layer was discarded. The chloroform layer was extracted with base and solvent was removed to give a dark brown oil. This oil was converted to the oxalate salt, and the salt was recrystallized from methanol-diethylether. A white solid was isolated and dried in vacuo overnight at 80°C, to give 7.17 g of the title compound as an off-white solid, mp 88.5-90 0

C.

Analysis: Calculated for C 2 0

H

19

N

2 0 4 5

F

2 C, 60.45; H, 4.82; N, 7.05 Found C, 60.52, H, 4.56; N, 7.01 hbh -94- AHR-438A-CIP Preparation 130 1-[(4-Methylphenyl)sulfonyl]-3-piperidinemethanol (4-methylphenyl)sulfonate ester.

A solution of 3-piperidinemethanol (50.0 g, 0.434 mole) in 300 ml of acetonitrile (dried over 4A molecular sieves) was prepared. This solution was cooled in an ice bath, and a solution of triethylamine (150 ml in 200 ml of acetonitrile) was added while simultaneously adding a solution of p-toluenesulfonyl chloride (191 g, 1.0 mole) in 300 ml of acetonitrile. After the additions were complete, the resulting solution was stirred 3.5 hours at room temperature. The mixture was filtered and solvents were removed by a rotary evaporator to give a dark brown oil. The oil was dissolved in chloroform and 1 extracted with 5% sodium hydroxide and also 1N sulfuric acid. The chloroo form layer was dried over sodium sulfate and filtered, and solvent was removed to give a dark brown oil. This oil was triturated with isopropyl ether to give a brownish-white solid. This light brown solid was separated and s .then triturated with hot isopropanol. The mixture was chilled in the freezer and filtered. A light brown solid was isolated and dried in vacuo overnight at (142.29 g, A give gram sample of this material was recrystallized from isopropyl alcohol, and the brown solid isolated was dried overnight ft t9 Sin vacuo at 80°C. This provided 3.55 g (55% yield based on aliquot taken) of light brown solid, m.p. 108-109 0

C.

Analysis: Calculated for C 20

H

25

NO

5

S

2 C, 56.72; H, 5.95; N, 3.31 "Found C, 56.43; H, 6.00; N, 3.32 Preparation 131 1a,a-Bis(4-fluorophenyl)-1-[(4-methylphenyl)sulfonvl]-3-piperidine- Spropanenitrile.

The sodium salt of 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile was prepared in 350 ml of dimethyl sulfoxide (dried over 4A molecular sieves) from sodium hydride (60% 4.37 g, 0.109 mole) and 4-fluoro-a-(4-fluorophenyl)benzeneacetonitrile (25.0 g, 0.109 mole). The resulting dark brown solution was stirred at room temperature for 1 hour. 1-[(4-Methylphenyl)sulfonyl]piperidinemethanol (4-methylphenyl)sulfonate ester (46.18 g, 0.109 mole) was added and the resulting solution was stirred for 2 hours at room temperature. The solution was then stirred overnight at 60 0 C. The dimethyl AHR-438A-CIP sulfoxide was removed by rotary evaporator. A dark brown residue was obtained which was dissolved in chloroform. The chloroform layer was extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a thick brown oil. The oil was triturated with isopropyl ether to give a white solid (46.54 g, 82.7%).

A 5 g portion of this solid was recrystallized from isopropanol to give a white solid and was isolated and dried in vacuo overnight at 80 0 C. This furnished 3.96 g (70.4% yield) of the title compound as a white crytalline product, m.p.

142-143 °C.

Analysis: Calculated for C 27

H

2 6

N

2 0 2

SF

2 C, 67.48; H, 5.45; N, 5.83 Found C, 67.17; H, 5.46; N, 5.75 I' o, Preparation 132 Sa, ,a-Bis(4-fluorophenyl)-3-piperidinepropanenitrile.

SA mixture of a,a-bis(4-fluorophenyl)-l-[(4-methylphenyl)sulfonyl]-3- S, piperidinepropanenitrile (41.21 g, 0.0858 mole) and phenol (100 g, 1.06 mole) 't in 200 ml of 48% HBr was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature and made alkaline with ice and 50% sodium hydroxide. The aqueous layer was extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide. The organic layer Swas then dried over sodium sulfate and filtered, and solvent was removed to give a dark brown oil. This oil was subjected to flash chromatography on silica gel using methanol for elution. Fractions of similar purity were combined and solvent removed. The oil obtained was dried in vacuo overnight at to give 18.83 g (67.2% yield) of brown oil.

H

1 NMR (CDC13): 8 6.9-7.6 8, aromatics), 1.1-3.1 12, aliphatics) Analysis: Calculated for C 20

H

20

N

2 F2 C, 73.60; H, 6.18; N, 8.58 Found C, 73.19; H, 6.11; N, 8.56 Preparation 133 gk a,a-Bis(4-flurophenyl)-4-piperidineacetamide hydrochloride SA solution of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (free base of Preparatio- 67) (9.31 g, 0.0298 mole) in 100 ml of 90% sulfuric acid soluj tion was heated overnight at 85°C. The solution was cooled to room temperai' -96- AHR-438A-CIP ture and made basic with 50% sodium hydroxide solution/ice. The aqueous layer was extracted with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo. A white solid was obtained upon removal of solvent (9.19 g, A portion (2.25 g) of the white solid was converted to the hydrochloride salt and recrystallized from isopropyl alcohol/diethyl ether to give a white solid which was dried in vacuo overnight at 80°C. This provided 0.54 g (20.3% yield) of title compound as a white crystalline solid; mp 328 0 C with decomposition.

Analysis: Calculated for C 19

H

2 1

N

2 0F 2 C1: C, 62.21; H, 5.77, N, 7.64 Found C, 61.81; H, 5.89; N, 7.45 Preparation 134 o 0 4-[Bis(3,4-diflurophenyl)methyl]piperidine hydrochloride SA mixture of 4-a,a-bis(3,4-difluorophenyl)methyl]pyridine (20.05 g, S* 0.063 mole) in glacial acetic acid (200 ml), concentrated hydrochloric acid (8 Sml) and 5% platinum on carbon catalyst (3.0 g) was subjected to hydrogenation for 3 days at 60°C. The reduction mixture was filtered through Celite®, and the solvent removed in vacuo. The residue obtained was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was dried over magnesium sulfate, filtered, and solvent removed to give an oil.

The oil was pumped in vacuo to a weight of 19.18 g (clear oil). The oil was first dissolved in methanol and a white solid crystallized. Methanol was removed by a rotary evaporation, and the white solid was dissolved in a small amount of methylene chloride and placed on a flash-chromatography column.

The column was eluted with methanol and 1/99 ammonium hydroxide/ methanol. Fractions of similar purity were combined, and solvent removed to S. give a clear oil (15.30 g, 67.5% yield). A 2-g portion of the oil was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride. A white solid was isolated and dried in vacuo overnight at 80°C to give 1.35 g (41% yield) of d white crystalline solid, m.p. 263-268 0

C.

Analysis: Calculated for C 1 8

H

18

NF

4 C1: C, 60.09; H, 5.04; N, 3.89 Found C, 59.71; H, 5.01; N, 3.87 L

A

-97- AHR-438A-CIEP Preparation 135 When in the procedure of Preparation I and substituting the following for I- acetyl-4-diphenylhydroxymethylpi peri dine: a,a-bis(3,4-difluorophenyl)-4-piperidinemethanol, Qi,-bi s(2,5-di fl uorophenyl)-4- pi peri di nene than ol, Q,-biS(2,4-diiluorophenyl)-4-piperidinemethanol, ,-bis(3-trifluorornethylphenyl).A.-piperidinemethanol, and Qi,-bis(4-trifluoromethylphenyl)-4-piperidinemethanol.

there are obtained: 4 [Q,o.-bi s(3 4 -di flu oropheny1)me th,.-lenel pi peri dine, b 4 L a b s 2 5 dt.4o h e y e h l n l i e i i e 4 [a,-bi s(2,4-di flu oroph enyl)rnethylenelIpiperi dine, 4 [QL,a-bis(3,-ifluoromtphenyl)ethylenelpiperidine, an v f 4 [a,Q-bis(-trifluoromethylphenyl)methylenelpiperidine n Litt Preparation 136 When in the procedure of Preparation 15 and substituting the following for 4-bromoflurobenzene: 1-bromo- 3,4- di flu orobe nzene, 1-bromo-2,5-difluorobenzene, 1-bromo-2,4-difluorobenzene, 3-bromobenzotrifluoride, and 4-bromobenzotrifluoride.

There are obtained the following: Q,Q-bis(3 4 -difluorophenyl)-4-pyridinemethanol, ,-bis(2,5-difluorophenyl)-4-pyridinemethanol, ,-bis(2,4-difluorophenyl)-4-pyridinemethanol, a,a-bis(3-trifluoroznethylphenyl)-4-pyridinemethanol, and a,Q-bis(4-trifluoromethylphenyl)-4-pyridinemethanol.

-98- AHR-438A-CIP Preparation 137 When in the procedure of Preparation 106 and substituting the following for QL,-bis(4-fiuorophenyl)-4-pyridineethanol: a,Q-bis(3,4-difluorophenyl)-4-pyridinemethanol, Qi,o-bis(2,5-difluorophenyl)-4-pyridinemethanol, ,Qi-bis(2,4-difluorophenyl)-4-pyridinemethanol, ,c-bis(3-trifluoromethylphenyl)-4-pyridinemethanol, QL,-bis(4-trifluoromethylphenyl)-4-pyridinemethanol, and ,-bis(4-fluorophenyl)-4-pyridinemethanol.

there are obtained the following: Q,QL-biS(3 ,4-difluorophenyl)-4-piperidinemethanol, ,-bis(2,5-dfluorophenyl)-4-piperidinemethanol, QL,a-bis(2,4-difluorophenyl)-4-piperidinemethanol, ,-bis(3-tri fluoromethylphenyl)-4-pi peri din emethanol, ca,a.-bis(4-trifluoroinethylphenyl)-4- pi peridinemethanol, and QL,-bis(4-fluorophenyl)-4-piperidinernethanol.

Preparation 138 When in the procedure of Preparation 16 and substituting the -following for 4-[bis(4-fluorophenyl)naethylenr 1-(phenylmethyl)piperidine: a,a-bis(3,4-difluorophenyl)-4-methylenepi peri dine, (b Lab (,-iloohny)4mtyeeipr ie o,c-bis(2,-difluorophenyl)-4-rethylenepiperidine,an c,a-bis(4-trifluoromethylphenyl)-4-rnethylenepi peri dine.

there are obtained the following free bases before optional conversion to their fumaric salts: 4- CQ,c-bis(3 di fl uropheny I)methyll piperi dine, 4-[c,a-bis(2,5-difluorophenyl)methyllpiperidine, 4-{a,a-bis(3-trifluoromethylphenyl)methyllpiperidine, and 4- [Q,c-bis(4- trifl uoromethylphenyl1)methyllpi peri dine.

-99- AHR-438A-CIP Preparation 139 a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)-4-piperidinemethanol.

A solution of a-(3,4-difluorophenyl)-a-(4-fluorophenyl)-l- (phenylsulfonyl)-4-piperidinemethanol (obtained in Preparation 124) and lithium aluminum hydride in tetrahydrofuran is refluxed for approximately 8 to 18 hr. The reaction mixture is filtered, filtrate dried over sodium sulfate, and the filtrate concentrated to a residue. The residue is partitioned between an alkaline aqueous solution of sodium hydroxide and water, and chloroform.

The chloroform layer is dried, filtered and solvent evaporated to give the title compound as an oil which may or may not crystallize upon standing.

a a 4 <Preparation 140 S4-Ethyl-2-methoxyphenol.

Q A mixture of zinc powder, 150 ml of water and 49.9 g (0.3 mole) of ,c o acetovanillone was stirred and treated dropwise with 150 ml of concentrated St hydrochloric acid. The solution was heated at reflux for 3.5 hr, during which time, after each hour 10 ml of addtional concentrated hydrochloric acid was added. After 3.5 hr the solution was diluted with ethyl alcohol and treated l with aqueous ferric chloride solution. The mixture was cooled and filtered r*t and the filter cake washed with water, and the combined filtrates saturated with sodium chloride and extracted with diethyl ether (3 x 150 ml). The combined extracts were dried over sodium sulfate and concentrated to yield 1.4 g of a pink oil. The filter cake was washed with 250 ml of diethyl ether.

The mixture was filtered and the filtrate dried over sodium sulfate and concentrated to a gum residue. The above obtained pink oil and gum residue were combined and chromatographed on a 750 g column of silica gel using 1:1 benzene:ligroin as the eluting solvent. Appropriate fractions were combined and concentrated to give 13.2 g (29% yield) of the title compound as an oil.

Preparation 141 4-[a,a-Bis(4-fluorophenyl)methyll-1-(3-chloropropyl)piperidine.

A solution of 4-[a,a-bis(4-fluorophenyl)methyl]piperidine, 3-bromopropanol and potassium carbonate in acetonitrile is refluxed for 12 hr to give 4-[a,a-bis(4-fluorophenyl)methyl]-l-piperidinepropanol, which is then i

J

-100- AHR-438A-CIP *e 0 09 4 o c o r e I ftC ft t1 t tt reacted neat for approximately 2 hr with thionyl chloride to give the hydrochloride salt of the title compound; which is reacted with sodium bicarbonate in chloroform to give the title compound.

Preparation 142 3-(3-Chloropropoxy)benzoic acid ethyl ester.

A mixture of 25 g (0.149 mole) of ethyl-3-hydroxybenzoate, 46.9 g (0.3 mole) of l-bromo-3-chloropropane and 62 g (0.45 mole) of anhydrous potassium carbonate is one liter of acetone was heated at reflux for 23 hr. The mixture was cooled, filtered, and the filtrate concentrated to give an oil as residue. The oil was dissolved in 200 ml of benzene, treated with potassium hydroxide pellets and stirred for 1 hr. The mixture was filtered through Celite@ and the filtrate was concentrated to give 36.5 g of oil as residue.

NMR analysis showed it was the desired product.

Preparation 143 l-[(Diethylamino)carbonyl]-4-piperidine carboxylic acid ethyl ester.

To a solution of 72.4 g (0.46 mole) of ethylisonipecotate and 46.5 g (0.46 mole) of triethylaiine in 400 ml of methylene chloride was added dropwise with stirring a solution of diethylcarbamyl chloride 62.4 g (0.46 mole) in 100 ml of methylene chloride. The reaction was exothermic, and the reaction mixture began to reflux during addition of the diethylcarbamyl chloride solution. The mixture was allowed to stir at ambient temperature for 24 hr and then treated with 50 ml of water. The layers were separated, and the organic layer washed with 25 ml of a 2N hydrochloric acid (twice), 50 ml of a saturated sodium bicarbonate solution, 100 ml of a saturated sodium chloride solution and dried over sodium sulfate and finally concentrated to give a tan oil. The oil was subjected to vacuum distillation and appropriate fractions (0.2-0.5 mmHg, bp 112-118 0 C) collected to give 100.6 g (85% yield) of the desired product.

Preparation 144 3-(4-Ethyl-2-methoxyphenoxy)propyl chloride.

A mixture of 13.2 g (0.87 mole of 4-ethyl-2-methoxyphenol, 27.3 g (0.173 mole) of 1-bromo-3-chloropropane, 35.9 g (0.26 mole) of anhydrous potassium if

.IIII

i i

L

7 -101- AHR-438A-CIIP 9 ra a a Sl 0 4r a.

a a a A; 9 a.a *t 4 a, a a. a carbonate and 500 ml of acetone was heated at reflux for 20 hr. The reaction mixture was cooled, filtered and the filtrate concentrated to give 18.7 g (94% yield) of oil as a residue. The oil was chromatographed on a 400 g silica gel column using 2:1 benzene:ligroin as the eluting solvent and appropriate solvents collected. NMR indicated approximately 10-15% of the starting phenol compound remained. The oil was dissolved in 250 ml of benzene and stirred with potassium hydroxide pellets for approximately 4 hr. The mixture was filtered through Celite® and filtrate concentrated to give 10.3 g (52% yield) of the desired product.

Preparation 145 1-Chloro-3-(4-isopropylphenoxy)propane.

A mixture of 27.4 g (0.2 mole) of p-isopropylphenol, 63 g (0.4 mole of 1bromc-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and filtrate concentrated. The residue was dissolved in 200 ml of benzene and treated with potassium hydroxide pellets to remove excess starting phenol. The mixture was stirred at ambient temperature for hr, filtered through Celite® and the filtrate concentrated to give 36.4 g (87% yield) of the title compound as an oil residue.

Preparation 146 1-Chloro-3-(4-methvlphenoxy)propane.

A mixture of 27 g (0.25 mole) of p-cresol, 78.7 g (0.5 mole) of 1-bromo-3chloropropane and 103.7 g (0.75 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and concentrated in vacuo at 90°C to give 47.1 g of an oil residue. The oil was subjected to vacuum distillation to give 39.3 g of clear oil, bp 85-90°C at 0.1 mmHg.

Preparation 147 3-(2-Benzyloxyphenoxy)propyl chloride.

A mixture of 50 g (0.25 mole) of o-benzyloxyphenol, 78.7 g (0.5 mole) of 1-bromo-3-chloropropane and 103.7 g of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was

U

.4 1 i

S

i 1: 1 -j -102- AHR-438A-CIP *o 00 0 O0 0 0 0000 0 00 *0 0 00 0 0 00 0I I 06 0* 0 0 0 0 O' £000 o t cooled, filtered and concentrated in vacuo to give 67.2 g of a tan oil as residue.

The oil was dissolved in 300 ml of diethyl ether and washed with 100 ml of a sodium hydroxide solution. A solid precipitated, about 200 ml of water was added and the precipitated sold redissolved. Solvent layers were separated and the diethyl ether layer washed twice with a 5% sodium hydroxide solution. The organic layer was next washed with water, brine, and dried over sodium sulfate and concentrated to give 58.4 g of oil as product.

Preparation 148 1-[4-(3-Chloropropoxy)-2-methoxyphenyl]ethanone.

A solution of 4-hydroxy-2-methoxyacetophenone, 1-bromo-3-chloropropane and potassium carbonate in acetone is heated at reflux for about 12 hr to give the title compound.

Preparation 149 1-[4-(3-Chloropropoxy)-3-methoxyphenyl]ethanone.

A solution of acelovanillone, 1-bromo-3-chloropropane and potassium carbonate in acetone is refluxed for about 12 hr to give the title compound.

Preparation 150 4-[Bis(2,4-difluorophenyl)methyllpyridine hydrochloride Sulfuric acid (40 ml) was cooled in an acetone-dry ice bath. 1,3-difluorobenzene (45.6 g, 0.4 mole) was added with stirring while maintaining a temperature of 0OC. The resulting soluton was stirred until room temperature was obtained. 4-Pyridinecarboxaldehyde (21.4 g, 0.2 mole) was added dropwise while maintaining a temperature of 0 C. The reaction mixture was stirred until room temperature was obtained, and the reaction mixture was then stirred overnight at 70°C. The mixture was cooled to room temperature and made alkaline with ice/50% sodium hydroxide. The aqueous layer was extracted several times with chloroform, and the organic layer was back extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. The organic solvent was removed in vacuo to give a clear oil (28.30 g, A 1 g portion of the clear oil was dissolved in isopropanol and, treated with ethereal hydrogen chloride. A white crystalline i!:

:II

ii -103- AHR-438A-CIP solid formed and was separated. The solid was dried in vacuo overnight at This furnished 0.97 g of white crystalline solid mp 218-222 0

C.

Analysis: Calculated for C 8

H

12

NF

4 C1: C, 61.12; H, 3.42; N, 3.96 Found 61.00; H, 3.32; N, 3.94 Preparation 151 4-[Bis(2,4-difluorophenyl)methyl]piperidine hydrochloride A mixture of 4-[bis(2,4-difluorophenyl)methyl]pyridine (23.84 g, 0.0752 mole) and 5% platinum on carbon (2.0 g) was subjected to hydrogenation for three days at 60°C in 400 ml of glacial acetic acid containing 3 ml of concentrated hyrochloric acid. Following hydrogenation the reaction mixture was cooled to room temperature and dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium S, sulfate and filtered. The chloroform layer was removed by rotary evaporator to give a dark residue (24.40 A one gram sample of this material was converted to the hydrochoride salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C. This provided 1.06 g of white crystalline solid, mp 215-217 0

C.

S. Analysis: Calculated for Ci 8 H8NF 4 CI: C, 60.09; H, 5.04; N, 3.89 j Found C, 59.77; H, 5.02; N, 3.87 Preparation 152 Utilizing the procedure of Preparation 65 and substituting the following reactants for the reactants 4-fluorophenylacetonitrile and fluorobenzene: S(a) 3,4-difluorophenylacetonitrile and 1,2-difluorobenzene, 2,5-difluorophenylacetonitrile and 1,4-difluorobenzene, 2,4-difluorophenylacetonitrile and 1,3-difluorobenzene, 3-trifluoromethylphenylacetonitrile and trifluoromethylbenzene, and 4-trifluoromethylphenylacetonitrile and trifluoromethylbenzene, there are obtained: 3,4-difluorophenyl-a-(3,4-difluorophenyl)benzeneacetonitrile, S(b) 2,5-difluorophenyl-a-(2,5-difluorophenyl)benzeneacetonitrile, -104- AHR-438A-CIP 2,4-difluorophenyl-a- (2,4-difluorophenyl)benzeneacetoni tri le, 3-trifluoromethylphenyl-a-(3-trifluoroinethylphenyl)benzeneacetonitrile, and 4-trifluoromethylphenyl-a-(4-trifluoromethylphenyl)benzeneacetonitrile.

Preparation 153 Utilizing the procedure of Preparation 66 and substituting the following for 4-fluoro-Q-(4-fluorophenyl)benzeneacetonitrile: 3 ,4-di fluorophe nyl ,4-di flu orophenyl) benze n eace toni trilIe, 2,-iloohnla-25dfurpeyQbneectnti 2,5-di fluorophenyl-a- (2,5-di fl uorophenyl) benzene ace toni tri le, ()3-trifluoromethylphenyl-a-(3-trifluoromethylphenyl)benzeneacetonitrile, and 4-trifluoromethylphenyl-Q-(4-trifluoromethylphenyl)benzenethere are obtained: aQc-bis(3,4-di flu orophenyl)- 1-[(4-methylphenyl)sulfonyl]-4piperidineacetonitrile, Q,a-biS(2,5-difluorophenyl)-l1-[(4-inethylphenyl)sulfonyll-4piperidineacetonitrile, ,-bis(2,4-difluorophenyl)-1-t(4-methylphenyl)sulfonyl]-4piperidineacetonitrile, a, a-bi s(3 -tri flu oror-nethylphenyl) 1- [(4-xnethylphenyl) sulIfonyl] -4piperidineacetonitrile, and a,a-bis(4-trifluoromethylphenyl)-1-I(4-methylphenyl)sulfonyll-4piperidineacetonitrile.

Preparation 154 Utilizing the procedure of Preparation 67 and substituting the V following for a,a-bis(4-fluorophenyl)- 1-I(4-methylphenyl)sulfonyl]-4piperidineacetonitrile: a,a- bis(3 ,4-difluorophenyl)- 1-[(4-methylphenyl)sulfonyl]-4piperidineacetonitrile, -105- -05-AHR-438A-CIP Q,-bis(2,5-difluorophenyl)- 1-[(4-methylphenyl)sulfonyl]-4piperidineacetonitrile,I Q,c-bis(2,4-difluorophenyl)- 1- [(4-methylphenyl)sulfonyil-4piperidineacetonitrile, ,-bis(3-trifluoromethylphenyl)- 1-[(4-methylphenyl)sulfonyl]-4piperidineacetonitrile, and ,-bis(4-trifluoromethylphenyl)-1-Ii(4-methylphenyl)sulfonyll-4piperidineacetonitrile, there are obtained: Q,Q-bis(3 ,4-difluorophenyl)-4-piperidineacetonitrile oxalate, Q,a-bis(2,5-difluorophenyl)-4-piperidineacetonitrile oxalate, 9 0 Qi,a-bis(2,4-difluorophenyl)-4-piperidineacetonitrile oxalate, S S ,-bis(3-trifluoromethylphenyl)-4-piperidineacetonitrile oxalate, and Q,a-bi s(4- tri fl uoromethyl ph enyl) -4-pipe ri dine acetoni tri le oxalate.

Preparation 155 The following compounds: 3,4-difluoro-ci-(3,4-difluorophenyl)benzeneacetic acid ethyl ester, b 4 1- i l o o a i l o o h n l b n e e c e i c d e h l e t r 2,5-difluoro-a-(2,5-difluorophenyl)benzeneacetic acid ethyl ester, 3-trifluoromethyl-Q-(3-trifluoromethylphenyl)benzeneacetic acid 11 ethyl ester, 4-trifluoromethyl-c.-(4-trifluorornethylphenyl)benzeneacetic acid ethyl ester, 1 -bi s[ 3 diflu orophenyll -2-butan one, (gt,1iis ,-if urpeyl-2btnoe 1,1-bisII2,-difluorophenyl]-2-butanone, 1, 1-bisL2,-ifluoromelphenyl-2-butanone, an 1 ,1-bis[3-(trifluoromethyl)phenyl]-2-butanone,an are reacted stepwise with lithium dipropylamine 4-[(4-phenylinethy1)sulfonyloxy1-3,-(phenylmethyi, )piperidine -106- AHR-438A-CIEP 4* .9 4, 4 9. 0 .9 4 9, 4 4 9 99 9994 9 99 ft 9 14 9 f 4 9 r *4 Cr C CC 9 9 C CC 'C C C C

CC

C(C~

CC'

and hydrogenated over palladium catalyst to give the following compounds: a,Q-bi s(3 ,4-difl uoroph en yl) -4 -pipe ridi n eacetic acid ethyl ester, Q,a-biS(2 ,5-difl uorophe.nyl)-4-pipexidineacetic acid ethyl ester, a,ci-bis(2 ,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, QL,a-bisfL(3-trifluoromethy1)phenyl]-4-pi peridineacetic acid ethyl ester, ,a-bis[(4-trifluoromethyl)phenyll-4-piperidineacetic acid ethyl ester, Mf 1,1-bis(3,4-difluorophenyl)-1-(4-piperidinyl)-2-butanone, 1,1-bis(2,5-difluorophenyl)-1-(4.-piperidinyl)-2-butanone, (h 1,1-bis(2,4-difluorophenyl)-l-(4-piperidinyl)-2-butanone, 1,1-bis[(3-trifluoromethyl)phenyl]-l-(4-piperidinyl)-2-butanone, and 0j) 1,1-bisl(4-trifluoromethyl)phenyll-1-(4-piperidinyl)-2-butanone.

Preparation 156 1-14-(3-Chloropropoxy)-3-methoxyphenyl]ethanone.

A solution of acelovanillone, 1-bromo-3-cliloropropane and potassium carbonate in acetone is refluxed for about 12 hr to give the title compound.

Preiuaration 157 1-(Phenvlmethvl)-4-piperidinol 4-methvlberizenesulfon ate (ester2 hydrochloride A solution of 1-benzyl-4-hydroxypiperidine (95.6 g, 0.5 mole) in 500 mL of pyridine was cooled in an ice bath. To this 73olution was added dropwise a.

solution of tosyl chloride (133.5 g, 0.7 mole) in 400 mL of acetonitrile (dried over 4A molecular sieves). Upon the addition to the second solution, a color change from yellow to dark-red was observed. The resulting solution was stirred at room temperature for 4.5 hours. The reaction mixture was stripped to dryness, and a dark-brown mass was obtained. This material was dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and filtered. The chloroform 4 4 hh. -107- AHR-438A-CIP layer was removed in vacuo to give a dark brown mass. This material was converted to the hydrochloride salt, and the salt was recrystallized from methanol-diethyl ether. A light brown solid was isolated and dried in vacuo overnight at 80°C. This procedure provided 68.17 g of light brown solid, mp 169-171.5°C.

Analysis: Calculated for C 19

H

24

NO

3 SC1: C, 59.75; H, 6.33; N, 3.67 Found C, 59.74; H, 6.38; N, 3.69 Preparation 158 a,a-Bis(3,4-Difluorophenyl)-4-pyridinemethanol.

To a magnetically stirred solution of ethyl isonicotinate in dry tetrahydrofuran at 0°C and under an atmosphere of nitrogen is slowly added a o solution 2.2 equivalents of 3,4-difluorophenyl magnesium bromide in tetrahydrofuran. The solution is stirred at ambient temperature for 4 h and is poured into an icy solution of ammonium chloride. The mixture is extracted with methylene chloride, and the organic phase was dried over sodium sulfate. The solvent was removed in vacuo to give a solid. This was recrystallized from ethylene chloride/hexane to give the title compound as a white crystalline solid, mp 147-149 0

C.

Analysis: Calculated for C 18

H

11

NOF

4 C, 64.84; H, 3.33; N, 4.20 Found C, 64.54; H, 3.22; N, 4.20 Preparation 159 4-[Bis-(4-fluorophenvl)methvl]- -(phenylsulfonvl)piperidine.

A solution of 15.18 g (0.0529 mole) of 4-[bis(4-fluorophenyl)methylene]piperidine and 10.89 g (0.0617 mole) ofbenzenesulfonyl chloride in 350 mL of pyridine was stirred at room temperature for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sulfuric acid. The methylene chloride solution was extracted with dilute sodium, and the methylene chloride solution was dried over sodium sulfate. The solvent was removed in vacuo, and the residue was dissolved in S' y i 200 mL of methanol. A precipitate was collected. This was recrystallized from methylene chloride methanol to give 11.14 g of the title compound as a white solid, mp 180-184°C.

-108- AHR-438A-CIP Analysis: Calculated for C 24

H

23 N0 2

SF

2 Found C, 67.43; H, 5.42; N, 3.28 C, 67.17; H, 5.42; N, 3.27 *r 4 t 4 44 44 4 Preparation 160 a,a-Bis(3,4-difluorophenyl)-4-piperidinemethanol oxalate hydrate [1:0.5:0.51.

A solution of 4.02 g (0.012 mole) of a,a-bis(3,4-difluorophenyl)-4-pyridinemethanol in 150 mL of glacial acetic acid was subjected to catalytic hydrogenation with 0.70 g of 5% platinum on carbon (Parr hydrogenation apparatus; 63 psi of hydrogen) at room temperature for 70 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo.

The residue was partitioned between methylene chloride and dilute sodium hydroxide, and the methylene chloride solution was dried sodium sulfate. The solvent was removed in vacuo to give a white solid. This was dissolved in methanol, 1.0 g (0.011 mole) of oxalic acid was added, and anhydrous ether was added. After being cooled in the freezer, the solution produced 0.51 g of the title compound as a white crystalline solid.

Anhydrous either was added to the filtrate, and the solution was placed in the freezer. An additional 2.70 g of the title compound was collected as a white solid, mp 278-279 C with decomposition.

Analysis: Calculated for C 19

H

19 N03.

5 F C, 58.02; H, 4.87; N, 3.56 Found C, 58.42; H, 4.66; N, 3.61 Preparation 161 a-(4-Fluorophenyl)--(4-piperidinyl)-2-pyridinemethanol.

To a stirred solution of 36.3 g (0.23 mole) of 2-bromopyridine in 500 mL of anhydrous tetrahydrofuran (THF) at -65 0 C was added 88 mL (0.22 mole) of a commercial solution of 2.5 molar n-butyllithium in hexane at such a rate that the temperature did not exceed -60 0 C. The dark solution was stirred at 0 C for 1 hr and then treated dropwise with a solution of 24.9 g (0.1 mole) of 1-acetyl-4-(p-fluorobenzoyl)piperidine in 250 mL of THF at such a rate that the temperature did not exceed -60 0 C. The mixture was stirred for 1 hr at and overnight at ambient temperature. The dark mixture was poured into 2 liters of a saturated ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with a 500-ml portion of t44r a -109- AHR-438A-CIP 9 00 9 *0 0009 o 00 0 0 .0a 0* 000* to 4 0 0 4r 0000 094 methylene chloride. The combined organic layers were washed successively with 500 ml of water, 500 ml of a 4% sodium hydroxide solution, 250 ml of water, and 250 ml of brine.

All of the aqueous layers were combined and allowed to stand in a filter flask for several weeks. As the soluble organic solvents in the aqueous solution evaporated, a solid precipitated. The aqueous solution was decanted, and the solid was slurried with water, collected by filtration, and dried. The solid was recrystallized from absolute ethanol-pyridine to yield 4.5 g of the title compound as an off-white solid, mp 228-230°C (dec.) Analysis: Calculated for C 17

H

19

FN

2 0 C, 71.31; H, 6.69; N, 9.78 Found C, 71.43; H, 6.54; N, 9.52 Preparation 162 Q,Q-Bis(4-fluorophenyl)- -(phenylmethyl)-3-piperdinemethanol.

The title compound was synthesized by the procedure described in Preparation 4 except that 1-phenylmethyl-3-piperidine carboxylic acid ethyl ester was used in place of 1-(phenylmethyl)-4-piperidinecarboxylic acid ethyl ester hydrochloride. The melting range of the white solid thus obtained was 104-111.5 0

C.

Analysis: Calculated for C 25

H

25

NOF

2 C, 76.31; H, 6.40; N, 3.55 Found C, 76.75; H, 6.46; N, 3.55 Preparation 163 [a.a-Bis(4-fluorovhenvl)]-3-ovridineethanol.

A Grignard solution was prepared from 19.4 g (0.8 mole) of magnesium chips and 148.8 g (0.85 mole) of 1-bromo-4-fluorobenzene in 1.25 liters of dry tetrahydrofuran (THF). To this solution was added in a stream a solution of 41.3 g (0.25 mole) of ethyl-3-pyridylacetate (Aldrich) on 250 ml of THF. The mixture was stirred at ambient temperature overnight and then poured into liters of a saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted once with 500 mL of methylene chloride and twice with 250 ml of methylene chloride. The combined organic layers were washed successively with 250 ml water, 250 ml of a 4% sodium hydroxide solution, 250 ml of water and 250 ml of brine. The organic layer was dried over sodium sulfate and concentrated to give a gum which crystalij.

j j ,i r.

-110- AHR-438A-CIP t *r V t V I lized when triturated with a mixture of 100 ml of petroleum ether (30-60 0

C)

and 100 ml of isopropyl ether. The solid was collected by filtration, dried and slurried with 500 ml of water.

The solid was collected by filtration, washed with petroleum ether and dried to yield 32.5 g of tan solid. Mass spec shows m/e 312. The solid was slurried with 500 ml of water, collected by filtration and dried.

The solid was next heated to reflux in -300 ml of 2-propanol and filtered to remove insolubles. The filtrate was concentrated to give a solid residue.

The solid was recrystallized from cyclohexane-benzene to yield 24.3 g (31%) of off-white solid, mp 137-141 0

C.

Analysis: Calculated for C 19

H

15

F

2 NO C, 73.30; H, 4.86; N, 4.50 Found C, 73.42; H, 4.77; N, 4.51 Preparation 164 [a.a-Bis(4-fluorophenyl)]-3-piperidinethanol hydrochloride A mixture of 23.8 g (0.076 mole) of [a,a-bis(4-fluorophenyl)]-3-pyridineethanol hydrochloride in 500 ml of glacial acetic acid was hydrogenated over 2.4 g of 5% platinum on carbon in a Parr apparatus for 24 hr.

The mixture was filtered through Celite®, and the filtrate was concentrated to give a gummy residue. The residue was partitioned between 300 ml of methylene chloride and 300 ml of a 5% sodium hydroxide solution and a solid precipitated. The solid was collected by filtration and partitioned between 200 ml of methylene chloride and 100 ml of a 5% sodium hydroxide solution.

The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was dissolved in ethyl ether and converted to the hydrochloride salt. The solid was collected by filtration and dried to yield 19.2 g of the title compound as a white solid, mp 248 0 C (dec) (absolute ethanol).

Analysis: Calculated for C 19

H

22 C1F 2 NO C, 64.50; H, 6.27; N, 3.96 Found C, 64.30; H, 6.28; N, 3.98 Ii; v;:i -111- AHR-438A-CIP *0 'It, Itr r I I I I It Ii Preparation 165 1-(Phenylmethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide To a stirred mixture of 35.4 g (0.225 mole) of ethylnipecotate (Aldrich) and 31.8 g (0.3 mole) of anhydrous sodium carbonate in 300 ml of absolute ethanol was added dropwise 41 g (0.24 mole) ofbenzylbromide and the mixture was stirred at ambient temperature for 24 hr. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between 250 ml of methylene chloride and 250 ml of a 5% sodium hydroxide solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give a gummy residue. The residue was triturated with ethyl ether, filtered, and the filtrate treated with hydrogenbromide gas. The solid which precipitated was collected by filtration and recrystallized from 2propanol to yield 35.0 g of the title compound as a white solid, mp 148- 152 0

C.

Analysis: Calculated for C 15

H

22 BrNO 2 C, 54.89; H, 6.76; N, 4.27 Found C, 54.83; H, 6.83; N, 4.30 Preparation 166 [a.a-Bis(4-fluorophenyl)]-3-piperidinemethanol.

A solution of 26.6 g (0.0676 mole) of a,a-bis(4-fluorophenyl)-l-(phenylmethyl)-3-piperidinemethanol in 750 ml of absolute ethanol was hydrogenated at 60 0 C and 50 psi over 5% palladium on carbon in a Parr apparatus for 18 hr. The mixture was filtered through Celite®, and the filtrate was concentrated to give a gum which crystallized when triturated with petroleum ether (30-60°C). The solid was collected by filtration and recrystallized from cyclohexane to yield 14.8 g of the title compound as a white solid, mp 114.5-115.5 0

C.

Analysis: Calculated C 18

H

19

F

2 NO C, 71.27; H, 6.31; N, 4.62 Found C, 71.43; H, 6.33; N, 4.64 Preparation 167 1-Chloro-3-[(2-phenylmethoxy)phenoloy]propane.

A mixture of 50 g (0.25 mole) of o-benzyloxyphenol (Aldrich), 78.7 g mole) of 1-bromo-3-chloropropane and 103.7 g (0.75 mole) of anhydrous 4

I

-112- AHR-438A-CIP O a oq 0 0 On 0 0) *0 O 0I 0 *0a 0 n 00 00 0 C 01 0 potassium carbonate in one liter of acetone was heated at reflux for -24 hr.

The mixture was worked up to give 67.2 g of tan oil as residue. The oil was dissolved in -300 ml ofdiethyl ether and washed with 100 ml of 5% sodium hydroxide solution and a solid precipitated. Approximately 200 ml of water was added and the solid dissolved. The layers were then separated. This process was repeated twice with 100 ml of 5% sodium hydroxide solution.

The organic layer was washed with water and brine, dried over sodium carbonate, and concentrated to give 58.4 g of oil as residue. NMR was consistent for the title compound.

Preparation 168 1-Chloro-3-[2,6-(dimethoxy)phenoxy]propane.

A reaction mixture consisting of the following was heated for about 18 hr at gentle reflux in 750 ml of acetone: 1. 2,6-dimethoxyphenol (154.17 g, 1 mole), 2. 1-bromo-3-chloropropane (314.8 g, 2 mole), and 3. potassium carbonate (290.0 g, 2.1 mole).

The reaction mixture was filtered and stripped to dryness to give a dark brown oil which was dissolved in chloroform and extracted with dilute sodium hydroxide solution. An emulsion resulted, which was broken by the addition of saturated sodium chloride. The aqueous layer was extracted several times with chloroform. The chloroform layer was back extracted with sodium hydroxide. Removal of chloroform gave a dark brown oil (83.55 g, 36.3% yield). NMR analysis was consistent with the desired product.

Preparation 169 1-Chloro-3-[(2-methoxy-4-methyl)phenoxy]propane.

A mixture of 50 g (.362 mole) of 2-methoxy-4-methylphenol (Lancaster), 113.9 g (.72 mole) of 1-bromo-3-chloropropane and 150 g (1.1 mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux with stirring for -20 hr. The mixture was cooled, filtered, and the filtrate concentrated to yield 66.3 g of oil as residue. NMR showed 75% product, and phenol present.

The oil was dissolved in 500 ml of acetone and treated with 28 g of 1bromo-3-chloropropane and 35 g of anhydrous potassium carbonate, and the Al i$

A

*11 113- AHR-438A-CIP 4$ If 4 O 4 i It 4 i* Si.

4$ I 4 *O 4 *4 44e 4 4 4 4r 4,44 4 mixture was heated at reflux for -16 hr. The mixture was worked up as above to yield 67 g of an oil. NMR indicated it was mostly product, but that some replaceable proton was still present.

The oil was dissolved in 300 ml of benzene and stirred with potassium hydroxide pellets for 21 hr. The mixture was filtered through Celite® and the filtrate was concentrated to yield 54.7 g of clear oil. NMR was consistent with the title compound.

Preparation 170 1-[2-(3-Chloropropoxy)phenyl]ethanone.

A mixture of 40.8 g mole) of o-hydroxyacetophenone Aldrich), 94.4 g mole) of 1-bromo-3-chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of of acetone was heated at reflux for -18 hr. The mixture was cooled to room temperature, filtered and the filtrate concentrated under vacuum pump pressure to give -45 g of oil as residue. The oil was dissolved in 200 ml of benzene and stirred with potassium hydroxide pellets for -2 hr. The mixture was filtered through Celite® and the filtrate was concentrated to yield 29.6 g of light yellow oil. NMR was consistent for desired product. Mass Spectra Analysis shows m/e 213.

Preparation 171 1-[3-(3-Chloropropoxv)phenyl]ethanone.

A mixture of 40.8 g mole) of m-hydroxyacetophenone Aldrich), 94.4 g mole) of 1-bromo-3-chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for hr. The mixture was worked up to yield 61.4 g of dark oil as residue.

NMR analysis was consistent for the desired product. Mass Spectra Analysis showed m/e 213.

Preparation 172 1-Chloro-3-[(3-methoxy)phenoxy]propane.

A mixture of 37.2 g mole) of m-methoxyphenol (Pfaltz Bauer), 94.4 g mole) of 1-bromo-3-chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for 20 hr (the reaction mixture turned a dark color when the potassium carbonate was

I"

ii

I

i;

II

r, -114- AHR-438A-CIP added). The mixture was worked-up to give 57.7 g of yellow oil as residue. NMR analysis was perfect for desired compound. Mass Spectra Analysis showed m/e 201.

Preparation 173 1-Chloro-3-(4-ethylphenoxy)propane.

SA mixture of 36.6 g mole) of 4-ethylphenol Aldrich), 94.4 g (.6 mole) of 1-bromo-3-chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for -24 hr. The mixture was worked-up to yield 48 g of pale yellow oil. NMR was perfect for desired product. Mass Spectra Analysis showed m/e 199.

SPreparation 174 4-(3-Chloropropoxy)benzeneacetic acid methyl ester.

A mixture of 24.3 g (.146 mole) of methyl-4-hydroxyphenylacetate (99%, S Aldrich), 47.2 g mole) of 1-bromo-3-chloropropane and 62.1 g (.45 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for -24 hr. The mixture was cooled, filtered and the filtrate concentrated to give 34.8 g of oil as residue. Mass Spectra Analysis showed m/e 243.

NMR was consistent for the desired product.

Preparation 175 1-Chloro-3-(2-methylphenoxy)prouane.

A mixture of 32.4 g mole) of o-cresol, 94.4 g mole) of 1-bromo-3chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for 24 hr. The mixture was worked-up to yield 34.5 g of pale yellow oil. NMR looked perfect for the desired product. Mass Spectra Analysis showed m/e 185.

Preparation 176 1-Chloro-3-(2-ethoxyphenoxy)propane.

A mixture of 41.5 g mole) of o-ethoxyphenol (Eastman), 94.4 g (.6 mole) of 1-bromo-3-chlorophenol and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for -20 hr.

i -115- AHR-438A-CIP 00 00 0 0 00O 0 0 00a 0) 04 0 00 E 04 '0 '0 00 404 0) 00 00 0 00, 0 0P '00 06 0 0000 0 00 00 0 0 009 0a 00*4 Qo0 6 Ii 04 The mixture was worked-up to give 34.3 g of clear oil as residue. NMR was perfect for the desired product. Mass Spectra showed m/e 215.

Preparation 177 L-Chloro-3-(3-methylphenoxy)propane.

A mixture of 32.4 g (3 mole) ofm-cresol (Fisher), 94.4 g mole) of 1bromo-3-chloropropane and 124.4 g mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for -20 hr. The mixture was worked-up to yield 45 g of pale yellow oil as residue. NMR was consistent for desired product. Mass Spectra Analysis showed m/e 185.

Preparation 178 1-Chloro-3-[2-(1-methylethoxy)phenoxy]propane.

A mixture of 25 g (.164 mole) of 2-isopropoxyphenol Aldrich), 51.7 g (.33 mole) of 1-bromo-3-chloropropane, and 67.9 g (.49 mole) of anhydrous potassium carbonate in 500 ml acetone was heated at reflux for -20 hr. The mixture was cooled and filtered, and the filtrate concentrated. The residue was dissolved in 200 ml of benzene, treated with potassium hydroxide pellets and stirred overnight. The mixture was filtered through Celite® and the filtrate concentrated to yield 23.2 g of oil as residue. NMR was perfect for desired product. Mass Spectra Analysis showed m/e 229.

Prepartion 179 [4-(3-ChloroproDoxy)phenvl]henvlmethanone.

A mixture of 49.7 g (.20 mole) of 4-hydroxybenzophenone, 78.7 g mole) of 1-bromo-3-chloropropane and 103.5 g (.75 mole) of anhydrous potassium carbonate in one liter of acetone was heated at reflux for 20 hr. The mixture was cooled to room temperature, filtered and the filtrate concentrated to give a dark oil as residue. Mass Spectra Analysis showed m/e 275. The oil was dissolved in 300 ml of benzene and stirred with potassium hydroxide pellets over the weekend. The mixture was filtered through Celite® and the filtrate was concentrated to give 67.4 g of reddishbrown oil as residue. NMR was perfect for the desired compound.

d

'I

ii: ri :I

I

i'-U ;9 m:r -116- AHR-438A-CTIP Pi 0 0a 0 0 C'0 00 0 O 00 0900 9 00 90 0 00 0 00 O 00 04.91 9 0 9 *a 4.

r I 99.

Preparation 180 5-Oxo-l-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester.

A solution of 158.2 g (1.0 mole) ofdimethylitaconate and 107.2 g mole) of benzylamine in 750 ml of methanol was let stand at ambient temperature over the weekend. The solution was filtered, and the filtrate was concentrated under reduced pressure to give an oil as residue. The oil crystallized when it was triturated with petroleum ether (30 0 The solid was collected by filtration and dried to yield 225.5 g of the title compound as a white powder. An analytical sample, m.p. 63-65°C, was prepared from 2-propyl ether.

Analysis: Calculated for C 13

H

15

NO

3 C, 66.94; H, 6.48; N, 6.01 Found C, 66.82; H, 6.48; N, 6.01 Preparation 181 4-[Bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)-2-pyrrolidinone.

A Grignard solution was prepared by the addition of 96.3 g (0.55 mole) of 4-bromofluorobenzene in 150 ml of dry tetrahydrofuran to a mixture of 12.2 g (0.5 mole) of magnesium chips in 250 ml of tetrahydrofuran. After the reaction had subsided, the mixture was diluted with 350 ml of tetrahydrofuran and heated at reflux for 15 min to complete formation.

The Grignard solution was added to a solution of 46.7 g (0.2 mole) of oxo-l-(phenylmethyl)-3-pyrrolidinecarboxylic acid methyl ester in 250 ml of tetrahydrofuran, and the mixture was stirred at ambient temperature overnight. The solution was poured into 2.5 liters of a cold ammonium chloride solution. The layers were separated, and the aqueous layer was extracted once with 500 ml of methylene chloride and once with 250 ml of methylene chloride. The combined organic layers were washed once with 250 ml of water, once with 250 ml of a 4% sodium hydroxide solution, once with 250 ml of water and once with 250 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum crystallized when saturated with peteroleum ether. The solid was collected by filtration, washed with petroleum ether and recrystallized from 2-propanol to yield 39.4 g of the title compound as an off-white solid, m.p. 158-160 0

C.

I :4

,'I

-117- AHR-438A-CrP I t o I to 4 It 11 4 Itr It Analysis: Calculated for C 24

H

2 1

F

2 N0 2 C, 73.27; H, 5.38; N, 3.56 Found C, 73.09; H, 5.38; N, 3.53 Preparation 182 a,a-Bis(4-fluorophenyl)-l-(phenylmethyl)-3-pyrrolidinemethanol.

To a stirred slurry of 7.6 g (0.02 mole) of lithium aluminum hydride in 150 ml of freshly distilled tetrahydrofuran was added dropwise, over a 45 min period, a solution of 38.5 g (0.098 mole) of 4-[bis(4-fluorophenyl)hydroxymethyl-l-(phenylmethyl)-2-pyrrolidinone in 150 ml of tetrahydrofuran.

After the addition was complete, the mixture was heated at reflux for 2 hr and then let stir at ambient temperature overnight. The excess lithium aluminum hydride was decomposed by the successive addition of 8 ml of water, 8 ml of a 15% sodium hydroxide solution, and 24 ml of water. The mixture was stirred for 30 min and filtered. The filtrate was concentrated under reduced pressure and the residue crystallized when triturated with petroleum ether (30 0 The solid was collected by filtration and recrystallized from 2-propanol to yield 30.3 g of the title compound as a white solid, mp 99-100oC.

Analysis: Calculated for C 24

H

23

F

2 NO C, 75.97; H, 6.11; N, 3.69 Found C, 76.07; H, 6.06; N, 3.70 Preparation 183 a.a-Bis(4-fluorophenyl)-3-pyrrolidinemethanol.

A solution of 26.6 g (0.07 mole) of a,a-bis(4-fluorophenyl)-l-(phenylmethyl)-3-pyrrolidinemethanol in 500 ml of ethanol was hydrogenated at psi and and 70°C over 5% palladium on carbon catalyst for 2 days. The mixture was cooled and filtered through Celite®. The filtrate was concentrated under reduced pressure to give a solid as residue. The solid was triturated with petroleum ether (30 0 -60 0 collected by filtration and dried to yield 18.5 g of the title compund as a white solid, m.p. 152-153°C with 2-propanol given off.

Analysis: Calculated for C 17

H

17

F

2 NO C, 70.57; H, 5.92; N, 4.84 Found C, 70.90; H, 6.02; N, 4.83

II

ft ii i4' Preparation 184 -118- AHR-438A-CIP 1-[4-(3-Chloropropoxy)-2-methoxyphenyl]ethanone.

SA solution of 4-hydroxy-2-methoxyacetophenone, 1-bromo-3-chloropropane and potassium carbonate in acetone is heated at reflux for about 12 hr to give the title compound.

Preparation 185 a-Cyclohexyl-a-(4-fluorophenyl)-4-piperidinemethanol.

A solution of (4-fluorophenyl)(4-pyridinyl)methanone (23.44 g, 0.117 mole) was prepared in 400 ml of tetrahydrofuran. The solution was chilled in an ice bath and stirred under nitrogen atmosphere for 0.5 hr. A solution of a, cyclohexylmagnesium chloride (70 ml of 2 molar solution) was added via Ssyringe and a dark brown solution resulted immediately. This soution was stirred 0.5 hr at room temperature and then heated at reflux for 4 hr. The solution was cooled to room temperature and solvents were removed. The residue was treated with aqueous ammonium chloride and extracted with So chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown residue. This residue was triturated with diethyl ether and then chilled at about 0 C and solvent removed to give 4 an oil. This oil was dried in vacuo overnight at 80°C. The oil crystallized to oo give 2.95 g (33.8% yield) of white crystalline solid, m.p. 78-81 0

C.

Analysis: Calculated for C 1 8

H

20 NF C, 80.26; H, 7.48; N, 5.20 Found C, 79.96; H, 7.45; N, 5.23 Preparation 186 a.a-Bis(3,4-difluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol.

To a mechanically stirred mixture of 2.70 g (0.11 mole) of magnesium turnings and a crystal of iodine in 100 ml of dry tetrahydrofuran was slowly added a solution of 19.6 g (0.102 mole) of 1,2-difluro-4-bromobenzene in 50 ml of tetrahydrofuran. The three-necked reaction flash was fitted with a reflux condenser, and the reaction mixture was stirred under an atmosphere of nitrogen. The mixture was stirred for 1 hour, and 11.88 g (0.040 mole) of ethyl N-benzenesulfonylnipecotate was added as a solid. The solution was stirred at 23°C for 12 hours and was poured into an icy solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, and -119- AHR-438A-CIP 4.4 O 04 9 9 9 4d 9 QI1 4 9 r 99d 9 99O 94 9 99 9 9 41 94g the methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from methylene chloride-hexane to give 17.43 g of the title compound as a white solid, m.p. 152-154 0

C.

Analysis: Calculated for C 24

H

2 1 N03SF 4 C, 60.12; H, 4.41; N, 2.92 Found C, 60.18; H, 4.40; N, 2.95 Preparation 187 4-[Bis(3,4-difluorophenyl)methylene]piperidine oxalate A mixture of 15.0 g (0.0313 mole) of a,a-bis(3,4-difluorophenyl)-1- (phenylsulfonyl)-4-piperidinemethanol, 21 g (0.22 mole) of phenol, and 200 ml of 48% hydrobromic acid was refluxed for 5 hours and stirred at ambient temperature for 6 hours. The reaction mixture was poured over ice, and the mixture as made basic with 50% sodium hydroxide soution. The basic mixture was extracted with methylene chloride, and the methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in 300 ml of methanol, 2.90 g (0.032 mole) of oxalic acid was added, and the voume of the solution was reduced to 200 ml.

Ether was added until the soution became cloudy, and the solution was placed in the freezer. A white solid was collected to give 8.91 g of the title compound as a crystalline solid. m.p. 202-203 0

C.

Analysis: Calculated for C 20

H

17 NF40 4 C, 58.40; H, 4.17; N, 3.41 Found C, 58.28; H, 4.11; N, 3.38 Preparation 188 4-[a,a-Bis(3-fluorophenyl)hydroxvmethyl]-1-phenvlmethvlpiperidine fumarate A Grignard solution was prepared from 100 g (0.57 mole) of 1-bromo-3fluorobenzene and 12.2 g (0.5 mole) of magnesium chips in 750 ml of dry tetrahydrofuran. This solution was treated with a solution of 45.8 g (0.185 mole) of ethyl-N-bernzylisonipecotate in 250 ml of dry tetrahydrofuran and the mixture was stirred at ambient temperature overnight. The solution was poured into 2.5 liters of a saturated ainmonium chloride solution and the layers were separated. The aqueous layer was extracted once with 500 ml of methylene chloride and twice with 250 ml of water, 250 ml of a 4% sodium 9Q d 944 4DB 44f* li -120- AHR-438A-CIP it t :1 r rI I t I it r hydroxide solution, 250 ml of water and 250 ml of brine, dried over sodium sulfate and concentrated to give a glass as residue. The glass was dissolved in 2-propanol and converted to the fumaric acid salt. The solid was collected by filtration and dried to yield 85 g of the title compound as a white solid. An analytical sample was recrystallized from acetonitrile water, m.p.

212-214°C with decomposition.

Analysis: Calculated for C 29

H

29

F

2 N0 5 C, 68.36; H, 5.74; N, 2.75 Found C, 68.46; H, 5.74; N, 2.83 Preparation 189 4-[a,a-Bis(3-fluorophenyl)hydroxymethyl]piperidine.

A solution of 39.3 g (0.1 mole) of the free base of 4-[a,a-bis(3-fluorophenyl)hydroxymethyll-1-phenylmethylpiperidine (free base obtained in Preparation 188) in 750 ml of absolute ethanol was hydrogenated over palladium on carbon in a Parr apparatus at 50 psi and 60°C for 3.5 days. The mixture was cooled and filtered through Celite®. The filtrate was concentrated, and the residue was dissolved in diethyl ether and filtered through cotton to remove some insoluble material. The filtrate was concentrated to give a gum which crystallized when triturated with petroleum ether The solid was collected by filtration and dried to yield 27.9 g of the title compound as a white solid. An analytical sample, m.p. 117-118 0

C,

was recrystallized from 2-propyl ether- 2-propanol.

Analysis: Calculated for C 1 8

H

19

F

2 NO C, 71.27; H, 6.31; N, 4.62 Found C, 71.24; H, 6.27; N, 4.66 Preparation 190 1-Phenylsulfonyl-4-piperidin ecarboxvlic acid.

In the preparation of a,-Bis(3,4-difluorophenyl)-l-(phenylsulfonyl)-4piperidinemethanol, the title compound was obtained as a side product. To a mixture of 6.56 g (0.27 mole) of magnesium trimmings and a few crystals of iodine in 500 ml of anhydrous ether under an atmosphere of nitrogen was slowly added a solution of 49.0 g (0.25 mole) of 4-bromo-l,2-difluorobenzene in 100 ml of diethyl ether. The mixture was then stirred for 45 min. Ethyl Nbenzenesulfonylisonipecotate (32.77 g, 0.11 mole) was added as a solid, and a gum formed in the bottom of the reaction flask after 20 min. Dry tetrahydro- .11 -121- AHR-438A-CIP furan (200 ml) was added, and the reaction mixture was stirred for an additional hour. The reaction mixture was poured into an icy aqueous solution of ammonium chloride. The organic and aqueous phases were separated and the aqueous phase was extracted with several portions of ether. The organic phases were combined and dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. A NMR of this oil showed it to be a mixture of 4-(phenylthio)butanamide and ethyl N-benzenesulfonylisonipecotate. A solution of the reaction mixture oil in 800 ml of 95% ethanol and 200 ml of 10% was heated at refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride solution was concentrated on to give 32.89 g of a,a-bis(3,4-difluorophenyl)-l-(phenylsulfonyl)-4.piperidinemethanol. The aqueous solution was made acidic with dilute sulfuric acid solution, and the acidic solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from methylene chloride-hexane to give 5.36 g of the title compound as a crystalline solid, m.p. 156-157.5°C.

Analysis: Calculated for C 12

H

15 N0 4 S C, 53.52; H, 5.61; N, 5.20 Found C, 53.19; H, 5.54; N, 5.16 Preparation 191 4-[a.a-Bis(3.4-difluorophenyl)methvl]pvridine.

A mechanically stirred mixture of 49.0 g (0.43 mole) of 1,2-difluorobenzene, 20.6 g (0.19 mole) of 4-pyridylcarboxaldehyde and 80 ml of concentrated sulfuric acid was heated at 70°C for 21 hr. The reaction mixture was poured over ice, and the icy mixture was made basic with 50% sodium hydroxide solution. The resulting mixture was extracted with methylene chloride and the methylene chloride solution was dried over sodium sulfate.

The solvent was removed in vacuo to give 54.95 g of a solid. This was recrystallized from a mixture of methylene chloride and hexane to give 44.82 g of the title compound as a crystalline solid, m.p. 79-82°C. Proton NMR showed that this sample contained of the 2,3-difluoro isomer.

i"I.

1 -122- AHR-438A-CIP *4 04 0r 0 0* 0 Ir 4P I *000 I 4 0 r Analysis: Calculated for C 1 8 HllNF4 C, 68.14; H, 3.50; N, 4.14 Found C, 68.14; H, 3.36; N. 4.46 Preparation 192 4-(3,4-Difluorobenzoyl)pyridine hydrochloride To a mechanically stirred mixture of 3.36 g (0.14 mole) of magnesium turnings and a few crystals of iodine in 300 ml of tetrahydrofuran under a nitrogen atmosphere was added dropwise a solution 25.48 g (0.13 mole) of 1,2difluoro-4-bromobenzene in 50 ml of tetrahydrofuran. The mixture was stirred at ambient temperature for 1 hr, and 14.0 g (0.14 mole) of 4-cyanopyridine was added as a solid. The mixture was stirred for 7 hr at room temperature and then was poured over ice. The icy mixture was made acidic with dilute sulfuric acid solution, and the aqueous acidic solution was allowed to stand for 40 hr. The aqueous solution was made basic with arfnonium hydroxide, and was extracted with methylene chloride. The methylene chloride layer was dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was subjected to flash column chromatography (silica gel, gradiently elution with methylene chloride/methanol) to give 1.80 g of the nonsalt form of the title compound which was converted to the hydrochloride salt, and recrystallized from methanol-ether to give 1.40 g of the title compound as a white, crystalline solid, m.p. 146-148'C with decomposition.

Analysis: Calculated for C1 2 HsNOF2Cl C, 56.38; H, 3.15; N, 5.48 Found C, 56.41; H, 3.07; N, 5.49 Example 1 4-(Diphenylmethylene)-l-(3-phenoxvpropvl)piperidine oxalate SA mixture of 3.3 g (0.013 mole) of 4-diphenylmethylenepiperidine, 3.3 g (0.015 mole) of (3-bromopropoxy)benzene and 5.3 g (0.05 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated -123- AHR-438A-CIP 9t 9r 9a 4 9 9 o 9 9 9* 9 *.9 9a 9 o es 9999~ 9 9 9* o 99 4.

9 4.9 999,( 9 99 9 o1 99 99 9 9 9 9 4.9 99*4o 9 9 *9*9 9 9 under reduced pressure to give an oil as residue, the free base of the title compound. The free base was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 4.3 g(70%) of the title product as a white powder, m.p. 175-178°C.

Analysis: Calculated for C 29

H

3 1 NO5: C, 73.55; H, 6.60; N, 2.96 Found C, 73.59; H, 6.64; N, 2.83 Example 2 a,a-Bis-(4-fluorophenyl)-l-(3-phenoxypropyl)-4-piperidinemethanol oxalate hydrate A mixture of 3.37 g (0.011 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 2.52 g (0.011 mole) of (3-bromopropoxy)benzene and sodium bicarbonate (0.92 g, 0.011 mole) in 200 ml of 1-butanol was heated overnight to reflux. The butanol was removed by the rotary evaporator, and the residue partitioned between chloroform and water. Removal of the chloroform i vacuo gave a dark brown oil, the free base of the title compound. The base was converted to the oxalate salt and recrystallized from methanol-diethyl ether to give 1.41 g of white solid, m.p. 163 0

C.

Analysis: Calculated for C 29

H

32 N06.

5

F

2 C, 64.92; H, 6.01; N, 2.61 Found C, 65.27; H, 5.87; N, 2.61 Example 3 4-[Bis(4-fluorophenyl)methylene]-1-(3-phenoxypropl)piperidine oxalate A solution of 7.37 g (0.0168 mole) a,a-bis(4-fluorophenyl)-l-(3-phenoxypropyl)-4-piperidinemethanol in 100 ml of methanol containing 100 ml of 6N hydrochloric acid was gently refluxed for 4 hr. The reaction mixture was cooled, made alkaline with ice/50% sodium hydroxide, and diluted to 1 liter with water. The aqueous phase was extracted with chloroform, and removal of chloroform gave an oil. The oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether to give 3.45 g of white solid, m.p. 190-192°C.

Analysis: Calculated for C 29

H

29 N0 5

F

2 C, 68.36; H, 5.74; N, 2.75 Found C, 68.43; H, 5.75; N, 2.69 Ii -124- AHR-438A-CTP ri:: tt 4 0 440 4141 4 4 1 P4 4 4i 4 f 4 4 44I 4 C 4 1 Example 4 aa-Bis(4-fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanol oxalate To a mixture of 5.10 g (0.21 mole) of magnesium turnings and a crystal of iodine in 800 ml of dry tetrahydrofuran (distilled from lithium aluminum hydride) was added a solution of 36.75 g (0.21 mole) of p-bromofluorobenzene in 100 ml of tetrahydrofuran. The reaction flask was cooled in an ice bath during this addition, and the reaction mixture was under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hr. A solution of 20.17 g (0.0693 mole) of ethyl N-(3-phenoxypropyl)isonipecotate in 100 ml of tetrahydrofuran was added and the solution was stirred at room temperature for 16 hr. The mixture was poured into an icy solution of ammonium chloride, and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and was dried over magnesium sulfate. The solvent was removed in vacuo to give a gummy residue. The residue was treated with a solution of oxalic acid in methanol, and the salt was recrystallized from methanol-ether to give 24.17 g of white crystalline solid, m.p. 153-155 0

C.

Analysis: Calculated for C 29

H

3 1 N0 6

F

2 C, 66.02; H, 5.92; N, 2.66 Found C, 65.78; H, 5.93; N, 2.63 Example 4-(Diphenvlmethvl)-l-(4-nhenoxvbutyl)Diperidine fumarate A solution of 6.99 g (0.0278 mole) of4-diphenylmethylpiperidine, 6.64 g (0.029 mole) of (4-bromobutoxy)bentene and 5 g (0.060 mole) of sodium bicarbonate in 400 ml of 1-butanol was refluxed for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil, the free base of the title compound. The base was dissolved in 500 ml of ether, and a small amount of solid was filtered from the solution. To the filtrate was added a solution of 3.2 g (0.0276 mole) of fumaric acid in 60 ml of methanol. A white precipitate was collected to give 7.97 g of white crystalline solid, m.p. 146-147 0

C.

01, 1,1, 1, o 0 1, 0 0~ 4 1, 0~ 1,1,1,4 1, 1,4 0 00 4 1, 00 1,40* (1 1, 0 44 1, 1,1, 0 4 4 4 41, 44 4 4 01, -125- AHR-438A-CIEP Analysis: Calculated for C 3 2

H

37 N0 5 C, 74.54; H, 7.23; N, 2.72 Found 74.68; H. 7.24; N, 2.68 Example 6 4-(Diphenylrnethvyl)-1-(3-phenoxypropyl)piperidine fumnarate [1:11.

Following the procedure of Example 5, 4-(di phenylmethyl)piperi dine and (3-bromopropoxy)benzene were reacted to give the free base of the title compound which was reacted with fumaric acid in methanol to give the white fumnarate salt in 71% yield, m.p. 171-172'C.

Analysis: Calculated for C 3 jH 35 N0 5 C, 74.23; H, 7.03; N, 2.79 Found 7 4.6 2; H, 7.0 3; N, 2.7 3 Example 7 4-[Bis(4-fluorophenyl)methyll-l-(3-phenoxypropyl)piperidine oxalate Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl]piperidine and (3-bromopropoxy)benzene were reacted to give the free base of the title compound which was reacted with oxalic acid, and recrystallizing frorh' methanol-di ethyl ether to give the white oxalate salt in 60% yield, rn.p.

178-181 0

C.

Analysis: Calculated for C 29

H

3 jN0 5

F

2 68.09; *F 6.11; N, 2.74 Found 68.37; H, 8 .13; N, 2.76 Example 8 4-(Diphen ylmethyl)- 1- phenoxyethyl)piperi dine fumarate Following the procedure of Example 5, 4-(di phenylmethyl)piperi dine and (2-bromoethoxy)benzene were reacted to give the free base of the title compund which was reacted with fumaric acid in ether-methanol mixture to give the white fumnarate salt in 85% yield, m.p. 189-190TC.

Analysis:. Calculated for C 30

H

3 3 N0 5 C, 73.90; H, 6.82; N, 2.87 Found C, 74.07; H, 6.91; N, 2.85 0040 1, 4 4004 1,441040

I

.:i -126- AHR-438A-CIP aa a.

a~ i V a ti a a a at a ar Example 9 4 -[Bis(4-fluorophenyl)methyl]-1-(2-phenoxyethyl)piperidine oxalate A mixture, 5.83 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.02 g (0.02 mole) of (2-bromoethoxy)benzene and sodium carbonate (3.18 g, 0.03 mole) as heated overnight at gentle reflux in 300 ml of 1-butanol.

The reaction was filtered and solvent removed in vacuo. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide.

Removal of chloroform gave an oil which was converted to the oxalate salt.

The salt was recrystallized from ethanol-diethyl ether to give 6.0 g of white crystalline product, m.p. 180-182 0

C.

Analysis: Calculated for C 28

H

29 N0 5

F

2 C, 67.60; H, 5.88; N, 2.82 Found C, 67.68; H, 5.87; N, 2.81 Example 4 -[Bis(4-fluorophenyl)methyl]-l-(4-phenoxybutyl)piperidine oxalate [1:11.

Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methyl]piperidine and (4-bromopropoxy)benzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from ethanol-diethyl ether), in 48% yield, m.p.

206 0

C.

Analysis: Calculated for C 3 0

H

3 3

NO

5

F

2 C, 68.56; H, 6.33; N, 2.67 Found C, 68.79; H, 6.35; N, 2.67 Example 11 4 -Fluorophenyl)-phenylmethyl]-1-(3-phenoxypropyl)piperidine fumarate A mixture of 5.4 g (0.02 mole) of 4 -[a-(p-fluorophenyl)-a-phenylmethyl]piperidine, 4.5 g(0.021 mole) of (3-bromopropoxy)benzene and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 150 ml of acetonitrile was refluxed for about 20 hr and concentrated under reduced pressure to give a gummy residue. The residue was purified by column chromatography on 160 g of Florisil®, and the product was eluted with 2% acetone in benzene to give an oil, the free base of the title compound. The free base was reacted with fumi i

I~

ii j: i d t;i -127- AHR-438A-CIP .4.4 46 p* a ft .4 *4 itt ric aric acid, and the salt was recrystallized from isopropyl alcohol to give 4.0 g of white solid, m.p. 169-171°C (with decomposition).

Analysis: Calculated for C 3 1

H

34 FN0 5 C, 71.66; H, 6.60; N, 2.70 Found C, 71.37; H, 6.55; N, 2.66 Example 12 4-[Bis(4-fluorophenyl)methyl]-1-[2-(2-6-dichlorophenoxy)ethyl]piperidine.

A mixture of 6.13 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 5.38 g (0.03 mole) of 2-(2-bromoethoxy)-1,3-dichlorobenz3ne was heated overnight at gentle reflux in 200 ml of 1-butanol. The reaction mixture was filtered and stripped to dryness. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide solution. The oil which was obtained was chromatographed on 300 g of silica gel using hexane-ethyl acetate (50/50 v/v) as eluant. The fractions containing product were combined and solvent removed to furnish an oil. The oil was dried overnight in vacuo at 80°C. This furnished 5.99 g of product oil.

Analysis: Calculated for C 26

H

2 5

NOF

2 C1 2 C, 65.55; H, 5.29; N, 2.94 Found C, 65.43; H, 5.34; N, 2.77 The 'H NMR spectrum of the subject compound was obtained in CDC1 3 containing tetramethylsilane and is consistent with the structure indicated by the title, 2.2-2.3 8 aliphatic protons (cyclic) 7H 2.8 8 or triplet CH 2 next to N 2H 2.8-3.1 8 Hydrogen next to N 2H 6 doublet methine proton 1H 4.1 8 triplet CH 2 next to oxygen 2H 6.8-7.4 8 aromatic protons 11H Example 13 1-[3-(4-Chlorophenoxy)propyl]-a,a-bis(4-fluorophenyl)-4-piperidnemethanol.

A mixture of 3.0 g (0.01 mole) ofa,a-bis(p-fluorophenyl)4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-4-(3-chloropropoxy)benzene, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in -128- AHR-438A-CIP 100 ml of 1-butanol was refluxed for 20 hr to give, after working up as in Example 1 (recrystallizing the free base from isopropyl alcohol), 1.7 g (36%) of white solid, m.p. 92-93°C.

Anaysis: Calculated for C 27

H

28 C1F 2 N0 2 C, 68.71; H, 5.98; N, 2.97 Found C, 68.66; H, 5.99; N, 2.92 i Example 14 4-[Bis(4-fluorophenyl)methyl-1-[3-(2-fluorophenoxy)propyl]piperidine oxalate A mixture of 5.85 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 3.76 g (0.02 mole) of 2-(3-chloropropoxy)-l-fluorobenzene, and S: sodium carbonate (4.80 g, 0.045 mole) in 300 ml of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and the resulting oil partitioned between S, chloroform-5% sodium hydroxide and then between chloroform-water.

S: Removal of chloroform gave an oil which was converted to the oxalate salt.

The salt was recrystallized from ethanol-diethyl ether. The salt was subsequently triturated with isopropanol, and was dried overnight at 80°C to give t 5.82 g of product, m.p. 182-183°C.

I Analysis: Calculated for C 29

H

30 N0 5

F

3 C, 65.78; H, 5.71; N, 2.65 Found C, 66.05; H, 5.79; N, 2.59 Example 4-[Bis(4-fluorophenvl)methvll--[3-(3-fluorophenoxv)Dropvl1piperidine mandelate Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]piperidine and 3-(3-chloropropoxy)-l-fluorobenzene were reacted to give the free base of the title compound which was reacted with mandelic acid to give the white mandelate salt (recrystallizing from isopropyl alcohol) in 62% yield, m.p. 145-147.5 0

C.

Analysis: Calculated for C 35

H

36

NO

4

F

3 C, 71.05; H, 6.13; N, 2.37 Found C, 71.10; H, 6.20; N. 2.36 AHR-438A-CIP -129- *4 *4 4

S

4* 4 1 *4 14 4 4 Example 16 4-[Bis(4-fluorophenyl)methyl]-l-[3-(4-chlorophenoxy)propy1]piperidine fumnarate (1:11.

Following the procedure of Example 14, 4-[bis(4-fluorophenyl)rnethyl]piperidine and 1-14-(3-chloropropoxy)lchlorobenzene were reacted to give the free base of the title compound. The free base was chromatographed on silica gel eluting with hexane-ethyl acetate and reacted with fumnaric acid (recrystallizing from methanol-di ethyl ether) in 9% yield, m.p. 169-170'C.

Analysis: Calculated for C 3 lH 3 2 N0 5

F

2 CI C, 65.10; H, 5.64; N, 2.45 Found C, 64.85; H, 5.63; N, 2.46 Example 17 4-f Bis(4- fluorop henyl)methyll- 1- fluorop henoxy)propflipiperi din Following the combined procedures of Examples 14 and 16, 4-Ilbis(4fluorophenyl)methyllpiperidine and 4-(3-chloropropoxy)-l1-fluorobenzene were reacted and worked up by chromatography as in Example 16, to give the free base in 53% yield as a yellow oil after drying in vacuo at 80'C overnight.

Analysis: Calculated for C 2 7

H

2 8 N0F 3 73.78; H, 6.42; N, 3.19 Found 73.64; H, 6.39; N, 3.14 Example 18 4-f Bis(4-fluorophenyl)methyl]-l-f 3-(4-methoxyphenoxy)propyllpiperidine fumarate Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]piperidine and 1- (3 -chl oro pro poxy)- 4-methoxybenze ne were reacted to give the free base of the title compound which was reacted with fumnaric acid to give the white fumnarate salt (recrystallizing from methanol- di ethyl ether) in 64% yield, m.p. 172-173'C.

Analysis: Calculated for C 32

H

3 5 N0 6

F

2 67.71; H, 6.22; N, 2.47 Found 67.89; H, 6.25; N, 2.39 Example 19 4-[Bis(4-fluorophenyl)methvli- 1-12-methoxyphenoxy)propvllpiperi dine.

A mixture of 5.99 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyllpiperidine, 4.35 g (0.022 mole) of 2-(3-chloropropoxy)-1-methoxybenzene, and 1+ 7 -130- AHR-438A-CIEP 4P 9 9t 9 sodium carbonate (3.18 g, 0.03 mole) in 1-butanol was heated overnight at gentle reflux. The reaction mixture was filtered and stripped to dryness.. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide. Removal of chloroform gave a dark brown oil. The oil was chromatographed on silica gel using acetone-ethyl acetate for elution. After combining fractions and removing solvent, an oil was obtained. The oil was dried in vacuo at 80°C overnight. This gave 3.18 g of title product.

Analysis: Calculated for C 28

H

3 1 N0 2 F2 C, 74.48; H, 6.92; N, 3.12 Found C, 74.42; H, 6.95; N, 3.00 The 'H NMR spectrum of the subject compound was obtained in CDC1 3 containing tetramethylsilane and is consistent with the structure indicated by the title, 6.8 8 singlet; or protons on ring 4H 6.8-7.3 8 4.08 3.88 3.48 0.8-3.18 containing methoxy group.

aromatic protons on fluorophenyl rings.

triplet CH 2

-O.

singlet O-CH 3 doublet; methine proton.

multiplet.

8H 2H 3H 1H 13H

,I

I ,t I it ii '1 Example .a-Bis(4-fluorophenvl)-1-[3-(2-methoxvphenoxv)propDl]-4-iperidinemethanol.

Following the procedure of Example 1 a,a-bis(p-fluorophenyl)-4-piperidinemethanol and 1-chloro-3-(2-methoxyphenoxy)propane were reacted using in addition potassium iodide catalyst to give the title compound in 66% yield, (recrystallizing from isopropyl alcohol), m.p. 127-218 0

C.

Analysis: Calculated for C 2 8

N

3 1

F

2

NO

3 C, 71.93; H, 6.68; N, 3.00 Found C, 71.88; H, 6.67; N, 2.98 -131- AHR-438A-CIP B I Oo 0 0 40 t*4# 0 0 0..

*0 4r 4 0 4440 4 44

S

4e**1 Example 21 4-Bis(4-fluorophenyl)methylene]-1-[3-(2-methoxyphenoxy)propyl3 piperidine oxalate Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methylene]piperidine and 2-(3-chloropropoxy)- l-methoxybenzene were reacted using in addition potassium iodide catalyst to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 73% yield, m.p. 184-186°C.

Analysis: Calculated for C 3 oHasNOeF 2 C, 66.78; H, 5.79; N, 2.60 Found C, 66.74; H, 5.79; N, 2.61 Example 22 4-[Bis(4-fluorophenyl)methyl]- 1-[3-(3,4-dimethoxyphenoxy)propyl]piperidine oxalate A mixture of 6.02 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate (5.52 g, 0.04 mole) was refluxed overnight in 300 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was stripped to dryness and partitioned between chloroform and water several times. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. The chloroform was removed by rotary evaporator. The oil obtained was converted to the oxalate salt and then recrystallized from methanol-diethyl ether and methanol isopropanol ether. This furnished 7.77 g of white solid, m.p. 188°C.

Analysis: Calculated for C 3 1

H

35

N

7

F

2 C, 65.14; H, 6.17; N, 2.43 Found C, 64.78; H, 6.14; N, 2.44 Example 23 4-[Bis(4-methylphenyl)methyl]-1-[3-(2,6-dimethoxyphenoxy)propyl]piperidine fumarate Following the procedure of Example 22, 4-[bis(4-methylphenyl)methyl]piperidine and 2-(3-chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with fumaric acid to give the white fumarate salt (recrystallizing from methanol-diethyl ether) in 66% yield, m.p. 206-207 0

C.

4i ,i -132- AHR-43 8A-CTIP 99 94 99 9 9 49 9 4 .74 .7 99 4 4* 44 4 9 94 4*4 4 9 *9 44 9 44 9 44 4 4W It,, 4 4 WI 4 44 9 4 4 94 '4 I 4 44 Analysis: Calculated for C 3 5

H

4 3 N0 7 C, 71.29; H, 7.35; N, 2.38 Found C, 71.24; H, 7.38; N, 2.36 Example 24 4-IIBis(4-fluorophenyl)methylenel-1-[3-(3 ,4-dimethoxyphenoxy)propyl] piperidine oxalate [1:11.

Following the procedure of Example 22, 4-[bis(4-fluorophenyl)methylenelpiperidine and 4-(3-chloropropoxy)-1,2-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the cream colored oxalate salt (recrystallizing from methanol- di ethyl ether) in 51% yield, m.p. 173-176'C.

Analysis: Calculated for C 3 jH 3 3 N0 7

F

2 65.37; H, 5.84; N, 2.46 Found 65.02; H, 5.83; N, 2.50 Example 4-[Bis(4-fluorophenyl)methyl]-1. [3-(2,6-dimethoxyphenoxy)propvl] piperidine oxalate hydrate Following the procedure of Example 22, but substituting dimethoxy ethane for butanol, 4- [bis(4-fluorophenyl)methyllpiperi dine and 2-(3chloropropoxy)-1,3-dimethoxybenzene were reacted to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-di ethyl ether) in 9%o yield, m.p.

132-1340C.

Analysis: Calculated for C 31

H

37 N0 8

F

2 63.15; H, 6.32; N, 2.38 Found 62,89; H, 5.98; N, 2.41 Example 26 4-[Bis(4-fluorophenyl )methyl--13-(3 ,5-dimeth oxyphenoxy)propyl] piperidine.

A mixture of 5.51 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyllpiperidine, 4.42 g (0.019 mole) of 1-(3-chloropropoxy)-3,5-dimethoxybenzene and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was stripped to dryness and the residue partitioned between sodium hydroxide and chloro form- water. Removal of chloroform gave a -133- AHR-438A-CIP brown oil. The oil was subjected to chromatography on a silica gel column using a gradient elution series of hexane-ethyl acetate and ethyl acetate-.

dimethoxyethane. After combining proper fractions eluted from the column and removing solvent, the residue oil was dried in vacuo overnight at This produced 2.61 g of brown oil.

Analysis: Calculated for C 29

H

33 N0 3

F

2 C, 72.33; H, 6.91; N, 2.91 Found C, 71.62; H, 6.80; N, 2.98 The 'H NMR spectrum of the subject compound was obtained in CDC13 containing tetramethylsilane and is consistent with the structure indicated by the title: 7.0 8 (multiplet, aromatic protons on fluorophenyl ring), S o o(singlet, aromatic protons on methoxyphenyl ring, 3H), 2.8 (triplet, methylene next to ether oxygen, 2H), 3.75 (singiet, OCH 3 6H), 3.4 (doublet, methine o 0 attached to two aromatic rings, 1H), 0.75 2.6 (multiplet, remaining aliphatics, 13H).

Example 27 S, 4-[Bis(4-methoxyphen yl)methyl]- -[3-(3,4-dimethoxyphenoxy)propyl]piperidine.

A mixture of 5.58 g (0.02 mole) of 4-[bis(4-nethoxyphenyl)methyl]- •44 piperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-1,2-dimethoxybenzene, and potassium carbonate, 5.52 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was stripped to dryness, and the residue partitioned between chlorosodium hydroxide and chlorof~~i-water. Removal of chloroform gave a dark brown oil. The oil was sub ted to column chromatography on a *t4 t silica gel column with elution via ethyl acetate-dimethoxy ethane. This produced 4.72 g of dark brown oil.

Analysis: Calculated for C 3 1

H

39

NO

5 C, 73.64; H, 7.77; N, 2.77 Found C, 72.38; H, 7.70; N, 2.72 The 1H NMR spectrum of the subject compound v: as obtained in CDC13 Scontaining tetramethylsilane and is consistent with the structure indicated by the title: 8 7.1 (multiplet, aromatic protons ortho to methine of

H

-C-(4-OCH 3

CH

4 2 4H), 6.75 (multiplet, aromatic protons adjacent to methoxy groups, 5H), 6.4 (multiplet, aromatic protons adjacent to ether linkage, 2H), 3.9 (triplet, methylene protons next to ether linkage, 2H), 3.7 -134- AHR-438A-CIP 00 00 0 0 0 0 00 0 0 00 0 00 0 00 00 0 00 ~0 00 0 00 00 0 00 0 0 0 0 *0

(OCH

3 6H), 3.6 (OCR 3 6H), 3.3 (doublet, methine attached to aromatic rings, 1H), 0.75-3.0 (multiplet, aliphatic protons, 13H).

Example 28 4-fBis(4-methoxyphenyl)methyll- 1-[3-(4-methoxy Phenoxy)Propy-jj piperidine fumarate hydrate Following the procedure of Example 22, 4-[Ibis(4-methoxyp henyl)meth ylpiperi dine and 4-(3-chloropropoxy)- 1-methoxybenzene were reacted to give the free base of the title compound which was separated by extracting with sodium hydroxi de-chloro form and reacted with fumaric acid to give the title salt (recrystallizing from meth anol- di ethyl ether several times as well as isopropyl alcohol) in 15% yield, m.p. 163-165'C.

Analysis: Calculated for C 34 11 4 2 N0 8 5 67.98; HI, 7.05; N, 2.33 Found 68.16; H, 6.97; N, 2.34 Example 29 1-44 3-14-Bis(4-fluorophenyl)methylene-l-piperidinyl]propoxylphenyllethanone oxalate [1l:1]1.

Following the procedure of Example 2, 4-[bis(4-fluorophenyl)methylenelipiperidine and 1-t4-(3-chloropropoxy)phenylilethanone, substituting sodium carbonate for sodium bicarbonate, were reacted to give the free base of the title compound which was reacted with oxalic *acid to give the oxalate salt (recrystallizing from ethanol-diethyl ether) in 59% yield, m.p. 196-198'C.

Analysis: Calculated for C 3 lH 3 lF 2 -N0 6 67.50; H, 5.66; N. 2.54 Found 67.18; H, 5.68; N, 2.43 Example 1-14-E34-4-Bis(4-fluorophenyl)methyl]- 1-piperidinyllpropoxylphenyllethanone oxalate 1:1].

Following the procedure of Example 2, 4-Ilbis(4-fluorophenyl)methyllpiperidine and 1-14-(3-chloropropoxy)phenyllethanone and substituting sodium carbonate for sodium bicarbonate were reacted to give the free base of the title compound which was reacted with oxalic acid to give the oxalate salt (recrystallizing from methanol-di ethyl ether) in 75% yield, m.p. 141-143TC.

00*0 0 00 0 0 00 .0 0 O .0.0 0 ~00 0 0.0 0*04 0 0 0044 .0 00*000 0 0

'I

-135- AHR-438A-CIP Analysis: Calculated for C 3 jH 3 3 N0 6

F

2 67.26; H, 6.01; N, 2.53 Found 66.94; H, 6.01; N, 2.40 Example 31 l-[4-[3-14-Bis(4-fluorophenyl)hydroxymethyll-l-piperidinyllpropoxy]phenyllethanone compound with 2-propanol Following the procedure of Example 1, Qi,a-bis(p-fluorophenyl)-4-piperidinemethanol and 1-14-(3-chloropropoxy)phenyllethanone were reacted using potassium iodide catalyst to give the free base of the title compound which when recrystallized from isopropyl alcohol gave the white title compund in 0 0 71% yield, m.p. 72-84'C.

Analysis: Calculated for C 2 9

H

3 lF 2 N0 3

'C

3

H

8 0 71.22; H, 7.28; N, 2.60 Found 71.26; H, 7.34; N, 2.56' 000 Example 32 00 0 0 1-[4-134-Bis(4-fluorophenyl)hvdrox-Ymethyl-l1-pi peridinylipropoxy]- 3-methylphenvlilethanone.

Following the procedure of Example 1, cL~a-bis(p-fluorophenyl)-4-piperi- 0 0 0 dinemethanol and 1-14-(3-chloropropoxy)-3-methylphenyllethanone were 00 reacted using potassium iodide catalyst to give the white title compound (recrytallizing from isopropyl alcohol) in 76% yield, m.p. 116-117C.

o 0 Analysis: Calculated for C 30

H

3 3

F

2 N0 3 73.00;HI, 6.74; N, 2.84 Found 7 2.9 0; H, 6.8 0; N, 2.7 8 0.,**Example 33 4- F 3 4 4-lBis( 4- flu oropheny1) hvdroxvmethvI] 1 piperidin yl1propoxy] benzonitrile.

Following the procedure of Example 1, a,ci-bis(p-fluorophenyl)-4-piperidinemethanol and 4-(3-chloropropoxy) benzonitrile were reacted using potassium iodide as catalyst to give the white title compound (recrystallizing from isopropyl alcohol- isopropyl ether) in 30% yield, m.p. 107-108'.

Analysis: Calculated for C 2 8

H

2 8

F

2

N

2 0 2 72.71; H, 6.10; N, 6.06 Found 72.82; H, 6.11; N, 6.05 -136- AHR-438A-CIP Example 34 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzonitrile fumarate Following the procedure of Example 22, 4-[bis(4-fluorophenyl)methyl]p.peridine and 4-(3-chloropropoxy)cyanobenzene were reacted using potassium iodide catalyst to give the free base of the title compund which was reacted with fumaric acid to give the fumarate salt which was (recrystallized from ethanol-diethyl ether) in 53% yield, m.p. 167 0

C.

Analysis: Calculated for C 32

H

32

N

2 0 5

F

2 C, 68.32; H, 5.73; N, 4.98 Found C, 68.10; H, 5.70; N, 4.94 Example S34-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzoic acid S, *ethyl ester hydrochloride A mixture of 6.0 g (0.02 mole) of a,a-bis(p-fluorophenyl-4-piperidinet methanol, 5.0 g (0.02 mole) of 4-(3-chloropropoxy))benzoic acid methyl ester, 7.4 g (0.07 mole) of anhydrous sodium carbonate, 0.3 g of potassium iodide and 150 ml of dimethylformamide was heated on a steam bath for 20 hr and S, then poured into 1.5 lite;r of ice-water. A gum precipitated, and the aqueous solution was decanted. The gum was dissolved in benzene, and the solution was washed with water and dilute sodium hydroxide solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 9.2 g of gum as residue. The gum was purified by column chromatography ,n 200 g of Florisil®, and the desired product was eluted with 20% acetone in 4 benzene. The fractions containing the free base of the title compound were combined and concentrated under reduced pressure to give a gum, the free base, as residue. The free base was converted to the hydrochloric acid salt which was recrystallized from 2-propanol to give 5.3 g of white powder, m.p. 193.5-194.5°.

Analysis: Calculated for C 30

H

34 C1F 2 N0 4 C, 65.99; H, 6.28; N, 2.57 Found C, 66.16; H, 6.32; N, 2.56 -137- AHR-438A-CIP Example 36 T 4-[3-[4-[Bis(4-fluorophenyl)hydroxvmethyl-1-piperidinyl]propoxy]benzoic acid hydrochloride hydrate A solution of 2.7 g (0.005 mole) of 4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]benzoic acid ethyl ester and 1.2 g (0.022 mole) of potassium hydroxide in 50 ml of ethanol and 20 ml of water was heated on a steam bath for 2 hr. Acetic acid, 10 ml, was added the solution was poured jinto 500 ml of ice water, and the mixture was.allowed to stand at ambient temperature overnight. Sodium chloride was added to the mixture to give a coagulated solid. The solid was collected by filtration and air dried. The solid was dissolved in 20 ml of isopropyl alcohol, and the solution was poured into ml of ethereal hydrogen chloride. The salt which gradually crystallized was collected by filtration, washed with ethyl ether and dried to give 0.2 g of white powder, m.p. 148-158 0 C with decomposition.

SAnalysis: Calculated for C 19

H

3 1 C1F 2 NO4.

5 C, 63.82; H, 5.93; N, 2.66 SFound C, 53.97; H, 6.25; N, 2.51 Example 37 4 j 3-[4-[Bis(4-fluorophenyl)methylene-1-piperidinyl]propoxy]benzoic I acid ethyl ester hydrobromide SA mixture of 6.09 g (0.021 mole) of 4-[bis(4-fluorophenyl)methylene]piperidine, 5.20 g (0.02 mole) of 1-[4-(3-chloropropoxy)-phenyl]carbethoxyiI benzene and sodium carbonate 4.30 g (0.04 mole) in 230 ml of 1-butanol containing potassium iodide (0.3 g) was heated overnight at gentle reflux.

The reaction mixture was stripped to dryness and partitioned between Schloroform water and chloroform 5% sodium hydroxide. Removal of chloroform gave an oil. The oil was converted to the hydrobromide salt using hydrogen bromide in glacial acetic acid. The acetic acid and excess hydrogen bromide were removed in vacuo. The salt was recrystallized from ethanoldiethyl ether. The salt was washed with water to remove acetamide present as an impurity. The salt washed with diethyl ether and dried in vacuo overnight at 80°C. A yield of 6.81 g of white solid, m.p. 192-194°C, was obtained.

Analysis: Calculated for C 3 oH 32

NO

3 F2Br C, 62.94; H, 5.63; N, 2.45 Found C, 62.83; H, 5.58; N, 2.45 i r -138- AHR-438A-CIP Example 38 4-[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]benzoic acid ethyl ester hydrobromide Following the procedure of Example 14, 4-[bis(4-fluorophenyl)methyl]piperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted using potassium iodide as catalyst to give the free base which was reacted with hydrogen bromide in glacial acetic acid. The oil was stripped to dryness and the solid obtained was recrytallized from isopropyl alcohol-diethyl ether to give the white salt in 20% yield, m.p. 142-144 0

C.

Analysis: Calculated for C 3 oH 34

NO

3

F

2 Br C, 62.72; H, 5.97; N, 2.44 S' Found C, 62.66; H, 5.95; N, 2.45 S Example 39 4-[3-[4-Bis(4-methoxyphenyl)methyl]-1-piperidinyl]propoxbenzoic acid butyl ester.

A mixture of 6.22 g (0.02 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 4.84 g (0.02 mole) of 4-(3-chloropropoxy)benzoic acid ethyl ester, I and potassium carbonate, 5.60 g (0.04 mole) in 350 ml of 1-butanol was refluxed overnight with potassium iodide. The reaction mixture was stripped to dryness and the residue patitioned between chloroform-5% sodium hydroxide then chloroform-water. Removal of chloroform gave an oil. This oil was chromatographed on a 200 g silica gel column packed in 50/50 v/v hexane-ethyl acetate. The material was eluted with hexane-ethyl acetate mixtures and finally 1% methanol-ethyl acetate.

I From the chromatography was obtained 5.09 g of an oil.

Analysis: Calculated for C 34

H

4 3

NO

5 C, 74.83; H, 7.94; N, 2.57 Found C, 74.19; H, 7.91; N, 2.53 The 'H NMR spectrum was obtained in CDC1 3 and is consistent with the structure indicated by the title, 6 8.0 (H's ortho to CO 2 2H), 6.8 aromatic, 4.2 CH 2 alpha to 0, 4H), 3.7 OCH 3 6H), 0.9-3.5 aliphatics, 21H).

-139- AHR-43 8A- CII' p p p p a p a 'p p a a 0.44 p '40 p a a a pj 04 ~4 4 a p p a 'a A0P~ k 'a a Example L- 3-[4-[Bis(4-methoxyphenyl)methv ii- -pi peridinyllpropoxylbenzoic acid butyl ester fumarate hydrate 1: 1:0.51.

Following the procedure of Example 22, but substituting dimethylformamide at 73'C for butanol, 4-[bis(4-methoxyphenyl)methyllpiperidine and 4-(3-chloropropoxy)benzoic acid ethyl ester were reacted to give the free base of the title compound which was reacted with fulmaric acid, to give the white fumarate salt (recrystallizing from meth anol-di ethyl ether) in 27% yield, m.p. 147.5-148.5'C.

Analysis: Calculated for C 3 6

H

4 4 N0 9 5 67.27; H, 6.90; N, 2.18 Found 67.26; H, 6.78; N, 2.19 Example 41 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]- 1-piperi dinyllethoxy]benzoic acid ethyl ester hydrochloride.

Following the procedure of Example 35, Q,a-bis(p-fluorophenyl)-4piperidine methanol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is prepared.

Example 42 443- [Bi s(4fluorop henyl) hydroxymethyll- 1- piperi di nvl] pro poxyl- 3methoxybenzeneacetic acid ethyl ester hydrochloride.

Following the procedure of Example 35, a.,a-bis(p-fluorophenyl)-4piperidinemethanol and 4-(3-chloropropoxy 3-methoxybenzene acetic acid ethyl ester are reacted and the hydrochloride salt is prepared.

Example 43 4-lIBis(4-t-luorophenyl)methylene]- 1, 1-dimethylethy lDhenoxy Propylipi Peri dine fumarate Following the procedure of Example 9, 4-Iibis(4-fluorophenyl)methylenelpiperidine and 4-(3-chloropropoxy)-( 1, 1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give an oil which was dissolved in ethyl acetate and filtered through silica gel to give the free base of the title compound. The free base was reacted with fumaric acid to give the

J)-

-a.

-140- -40-AHR-438A-CIP

I

tt t t I t I t Ii

I

'I

white fumnarate salt (recrystallizing from isopropyl alcohol-diethyl ether) in yield, m.p. 208.5-209.5'C.

Analysis: Calculated for C 3 5

H

39 N0 5 F2: C, 71.05; H, 6.64; N, 2.37 Found 7 0.9 1; H, 6.5 7; N, 2.3 8 Example 44 4-[Bis(4-fluorophenyl)methyll-13-[4-( 1,1-dimethylethyl)phenoxylpropylipiperidine fumarate hydrate [1:1:0.51.

Following the procedure of Example 9, 4- [bis(4-fluoropheriyl)methylenelpiperidine and 4-(3-chloropropoxy)-( 1, 1-dimethylethyl )benzene were reacted using potassium iodide catalyst to give the free base title compound which was reacted with fumaric acid to give the white fumarate salt (recrystallizing from meth anol- di ethyl ether and isopropyl alcoholdiethyl ether) in 55% yield, m.p. 194-196'C with decomposition.

Analysis: Calculated for C 3 5

H

4 2 N0 5 5

F

2 C, 69.75; H, 7.02; N, 2.32 Found C, 70.01; H, 6.89; N, 2.44 Example 4-[Bis(4-methoxyphenyl)methyl-l-[3-II4-(1.1-dimethylethyl)pheoxy1- Propyl i pperi dine oxalate Following the procedure of Example 22, 4-Ilbis(4-methoxyphenyl)methylipiperidine and 4-(3-chloropropoxy)-( 1, 1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give the free base which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 35% yield, m.p. 212'C.

Analysis: Calculated for C 35

H

45 N0 7 C, 7 1.0 4; H, 7.6 7; N, 2.3 7 Found 7 0.9 1; H, 7.7 0; N, 2.3 Example 46 1- 4- 1 -Dimethylethyl)ph enoxyl pro pyl I-q, a-bi s(4- fluorophenyjL)piperidinernethanol.

Following the procedure of Example 1, a,ci-bis(p-fluorophenyl)-4piperidinemethanol and 4-(3-chloropropoxy)-( 1, 1-dimethylethyl)benzene were reacted using potassium iodide catalyst to give white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126-127'C.

-141- -141- AHR-438A-CIP Analysis: Calculated for C 3 lH 37

F

2 N0 2 C, 75.43; H, 7.56; N, 2.84 Found 75.21; H, 7.58; N, 2.82 Example 47 4-[Bis(4-fluorophenyl)methyl]-l-[3-[3-(trifluoromethyl)phenoxy]propylipiperidine oxalate Following the procedure of Example 9, 4-fjbis-(4-fluorophenyl)methyllpiperidine and 1-[3,chloropropoxyl-3-trifluoromethylbenzene were reacted using potassium iodide catalyst to give the free base of the title compound which was reacted with oxalic acid to give the white oxalate salt (recrystallizing from methanol-diethyl ether) in 39% yield, m.p. 185-186'C.

*Analysis: Calculated for C 30

H

3 ON0 5

F

5 C, 62.17; H, 5.22; N, 2.42 Found 6 2.5 4; H, 5.2 7; N, 2.5 2 Example 48 N-14-[3-14-[Bis(4-methylphenyl)methvll- 1-piperidinyllpropoxyipheny] acetamide fumarate hydrate [1:1:0.51.

Following the procedure of Example 22 but substituting dimethylformamide at 73'C for refluxing butanol, 4-!bis-(4-methylphenyl)methyl]piperidine and N-14-(3-chloropropoxy)phenyllacetamide were reacted using potassium iodide catalyst to give the free base of the title compound which was reacted with fumaric acid to give the white fumarate hydrate (recrystallizing from inethanol-diethyl ether), m.p. 149-152'C.

Analysis: Calculated for C 3 5

H

4 3

N

2 0 6 5 C, 7 0.5 7; H, 7.2 8; N, 4.7 0 Found 70.80;H, 7.2 8; N,4.6 Example 49 N-14-13-14-[Bis(4-fluorophenyl)methyll--piperidinylIpropoxyhelacetamide hydrobromide [1:11, A mixture of 25 .68 g (0.089 mole) 4-[bis(4-fluorophenyl)methylene]piperidine, 20.3 g (0.089 mole) of N-f 4-(3-chloropropoxy)phenyllacetamide, and potassium carbonate, 21.4 g, (0.155 mole) was stirred overnight at 80'C in 350 ml of dimethylformamide. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform and water; removal of chloroform gave a dark red oil. The oil was dissolved in glacial

L

-142- AHR-438A-CIP acetic acid, and the hydrobromide salt was formed with hydrobromic acid in glacial acetic acid. Solvent was removed in vacuo, and the residue was recrystallized from methanol-diethyl ether. A yield of 21.68 g of palewhite solid, m.p. 223-225'C, was obtained.

Analysis: Calculated for C 29

H

33

N

2 02F 2 Br: C, 62.26; H, 5.95; N, 5.01 Found C, 61.99; H, 5.94; N, 5.01 Example 4-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzeneamine fumarate hydrate o A solution of 11.8 g (0.02709 mole) of N-[4-[3-[bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]acetamide was heated at gentle reflux for four Shours in 500 ml of methanol containing 500 ml of 6N hydrochloric acid. The 0" 0 reaction stopped and allowed to cool overnight. The reaction mixture was Sevaporated to a small volume on the rotary evaporator, diluted with water o and made alkaline with 5% sodium hydroxide. The reaction mixture was then partitioned between the alkaline phase and chloroform. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was S' converted to the fumarate salt and the salt was recrystallized from methanol- Sdiethyl ether. The white solid obtained was dried overnight in vacuo at to give 8.49 g of white crystalline product, m.p. 121.5-124.0 0

C.

Analysis: Calculated for C 3 1

H

35

N

2 0 5 5

F

2 C, 66.30; H, 6.28; N, 4.99 Found C, 66.49; H, 6.13; N, 4.92 o p Example 51 N-[4-f3-[4-[Bis(4-fluorophenyl)hydroxvmethyll- 1piperidinvl]propoxy]phenyllacetamide hydrochloride hydrate A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of N-[4-(3-chloropropoxy)phenyl]acetamide, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column Schromatography on 80 g of Florisil® and the product was eluted with acetone in benzene. The combined fractions containing product were concentrated under reduced pressure to give a glass as residue. The glass was dissolved in ethyl ether, filtered through cotton, and the filtrate treated -143- AHR-438A-CIP with ethereal hydrogen chloride. The resulting solid was collected by filtration, washed with ethyl ether and dried to yield 2.1 g of white' solid, m.p. 135-170'C (with decompositon).

Analysis: Calculated for C 29

H

3 3 C1F 2

N

2 0 3

.H

2 0: C, 63.44; H, 6.43; N, 5.10 Found C, 6 3.3 2; H, 6.5 6; N, 4.9 2 Example 52 a,a-B is(4-fluo roph en-yl)- I- 3-(4-ni troph enoxy) pr~jpyl pi peri dinemethanol.

Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 9.1 g (0.03 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol and 6.7 g (0.03 mole) of 1-(3-chloropropoxy)-4-nitrobenzene were reacted to give 10.5 g of the title compound which was recrystallized from isopropyl ether, m.p. 93.5-94.5'C.

Analysis: Calculated for C 2 7

H

2 8

F

2

N

2 0 4 C, 6 7.2 1; H, 5.8 5; N, 5.8 1 Found C, 6 7.0 5; H, 5.8 3; N, 5.7 4 Example 53 f" 3 4[ i(-luoohenlhdox-et yll-1 -pi peridinyljpro poxy]- 0 benzamide.

Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of Q,a-bis(p-fluorophenyl)-4-;J,,iperidinemethanol, 1 g (0.01 mole) of 4-(3-chloropropoxy)benzarnide an'd 6.9 g (0.05 mole) of anhydrous potassium carbonate in 100 ml of 1-butanol were reacted to give 3.0 g of white powder, nip., 200-204'C. The recrystallizing solvent used was absolute ethanol.

Analysis: Calculated for C 28

H

30

F

2

N

2 0 3 C, 69.98; H, 6.29; N, 5.83 Found C, 69.61; H,6.4 9; N,5.7 0 Example 54 4-[Bis(4-fluorophenyl)methyl]- 1-!2-(-naphthalenyloxy)ethyll- $Piperidine hydrochloride [1:11.

A mixture of 2.84 g (0.0099 mole) of 4-IIQ,-bis(p-fluorophenyl)inethyl]piperidine, 3.01 g (0.012 mole) of 1-(2-bromoethoxy)naphthalene and 5.0 g (0.060 mole) of sodium bicarbonate in 400 ml of 1-butanol was refluxed for 16 -144- AHR-438A-CIP r t S r 5 f: S SFI hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in a mixture of ether and methanol, an excess of ethereal hydrochloride was added, and a white precipitate was collected to give 3.13 g of white crystalline solid, m.p.

155-158 0

C.

Analysis: Calculated for C 30

H

30

NOF

2 C1: C, 72.94; H, 6.12; N, 2.84 Found C, 73.20; H, 6.10; N, 2.78 Example 4-[Bis(4-fluorophenyl)methyl]-l-[2-(2-naphthalenyloxy)ethyl]piperidine oxalate Following the procedure of Example 54 and substituting 2-(2-bromoethoxy)naphthalene and oxalic acid for hydrogen chloride, the title compound was obtained in 61.9% yield as white crystalline solid, m.p. 168-171°C.

Analysis: Calculated for C 32

H

3 1

NO

5

F

2 C, 70.19; H, 5.71; N, 2.56 Found C, 70.26; H, 5.75; N, 2.63 Example 56 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]-3methoxyphenvl]ethanone oxalate The title compound was prepared by the method described in U.S.

Patent 3,956,296 (see Example 13 of that patent) as follows: A mixture of 4.75 g (0.0165 mole) of 4-[a,a-bis(p-fluorophenyl)methyl]piperidine, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was heated at 80°C for about 2 hours. TLC showed no product at this point. The temperature was raised to 100°C for 1 hr, at which time TLC showed the reaction to be complete. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The crude product was dissolved in chloroform and filtered and the filtrate was concentrated under reduced pressure to give 7.7 g of crude product.

The solid was dissolved in benzene and placed on a Florisil® column. Upon eluting with an acetone-benzene gradient, 5.5 g of product was obtained. The I t r i;l;

L.

-145- AHR-438A-CIP oxalate salt was prepared and upon recrystallization from isopropanolmethanol gave 3.8 g of salt was obtained, m.p. 164.5-166°C.

Analysis: Calculated for C 3 2

H

3 5

F

2

NO

7 C, 65.86; H, 6.05; N, 2.40 Found C, 66.11; H, 6.13; N, 2.39 Example 57 1-[4-[3-[4-[Bis(4-fluorophenyl)methyl]- 1-piperidinylpropoxy]-3methoxyphenyl]ethanone fumarate A mixture of 58.26 g (0.203 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 54.5 g (0.225 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)propane, 18.7 g (0.223 mole) of sodium bicarbonate and 1.2 g (0.0072 mole) of t" potassium iodide in 800 ml of 1-butanol was refluxed for 16 hr. The hot reaction mixture was filtered, and the solvent was removed in vacuo from the S, filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. The oil was dissolved in 600 ml of anhydrous ether, and 4.91 g of a solid was collected at room temperature. The ether solution was then treated with a solution of 30.2 g (0.26 mole) of fumaric acid in methanol. Anhydrous ether was added and 99.88 g m.p. 160-163°C, of title compound was isolated. This was recrystallized from isopropanol-diethyl ether, (2.5 g, 0.0216 mole of additional fumaric acid was added) to give 2 crops of title compound. [Crop I 44.15 g, m.p. 163-164.5°C; Crop II- 38.75 g, m.p. 161-163 0 C] An additional 10.00 g m.p. 159-162°C of title compound collected from the original ether-methanol filtrate. NMR showed that the salt contained 1.2 equivalents of fumaric acid.

Anaysis: Calculated for C 3 4.8H 37 8

N

7 O.8F 2 C, 66.05; H, 6.02; N, 2.21 Found C, 65.96; H, 6.18; N, 2.16 Example 58 1; 1-[4-[3-[4-[Bis(4-fluorophenyl)methylene]-l-piperidinyl]propoxylmethoxyphenyllethanone oxalate The title compound was prepared by the method described in U.S.

Patent 3,922,276 (see Example 12 of that patent) as follows: A mixture of 4.7 g (0.0165 mole) of 4-[a,a-bis(p-fluorophenyl)methylene]piperidine, 4.0 g -146- AHR-438A-CIP

I

Sr t I r

LI

ft I I (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g of sodium bicarbonate in 60 ml of dimethylformamide was heated at 100oC.

overnight. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in benzene and placed on a Florisil® column. Elution with a gradient of acetone-benzene gave 5.7 g of a viscous brown oil. The free base was reacted with oxalic acid to give the oxalate salt, m.p. 169-170 0 C after recrystallization from isopropyl alcohol and drying under nitrogen.

Analysis: Calculated for C 32

H

33

F

2

NO

7 C, 66.08; H, 5.72; N, 2.41 Found C, 66.01; H, 5.67; N, 2.40 Example 59 1-[4-[3-[4-[(4-Fluorophenyl)(phenyl)methylene]-1-piperidinyl]propoxy]- 3-methoxyphenyllethanone oxalate The title compound was prepared by the method described in U.S.

3,922,276 (see Example 12 of that patent) as follows: A mixture of 7.1 g (0.027 mole) of 4-[a-(p-fluorophenyl)-a-phenylmethylene]piperidine, 6.5 g (0.027 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.3 g (0.027 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100°C for approximately 8 hours. The mixture was filtered, and the dimethylformamide was removed under reduced pressure.

The residual oil was dissolved in chloroform, and the mixture was filtered.

The filtrate was concentrated under vacuum to give 11.5 g of crude free base The free base was reacted with oxalic acid to give the oxalate salt, m.p. 143-145°C, after recrystallization from methyl isobutyl ketone.

Analysis: Calcualted for C 32

H

34 FN0 7 C, 68.19; H, 6.08; N, 2.49 Found C, 68.14; H, 6.12; N, 2.54 Example 1-[3-Methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl]methylene]-lpiperidinyl]propoxy]phenyl]ethanone oxalate The title compound was prepared by the method described in U.S.

Patent 3,922,276 (see Example 10 of that patient) as follows; A mixture of g (0.0157 mole) of 4-[a-phenyl-a-(m-trifluoromethylphenyl)methylene]piperidine, 3.82 g (0.0157 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl r* -147- AHR-438A-CIP 'It tt rr t I t t r I I chloride and 2.52 g (0.03 mole) of sodium bicarbonate in 75 ml of 1-butanol was stirred and heated at reflux for 17.5 hrs. The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The glassy residue obtained weighed 4.25 g and was dissolved in benzene and placed on a Florisil® column. Using an acetone-benzene gradient elution, product was obtained as a glassy residue. This residue was dissolved in ether and the oxalate salt was obtained. The salt has a glassy appearance, m.p. 120-125 0

C.

Analysis: Calculated for C 3 3

H

34

F

3 N0 7 C, 64.59; H, 5.58; N, 2.28 Found C, 64.34; H, 5.72; N, 2.04 Example 61 1-[4-[3-[4-(Cyclohexylphenylmethylene)-1-piperidinyl]propoxy]-3methoxyphenyl]ethanone oxalate The free base of the title compound was obtained as in Example 1 of U.S. Patent 3,922,276 by reacting 4-[(a-cyclohexyl-a-phenyl)methylene]piperidine with 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethylformamide and converted to the oxalate salt, m.p. 184-185°C.

Analysis: Calculated for C 32

H

41 N0 7 C, 69.67; H, 7.49; N, 2.54 Found C, 69.83; H, 7.58; N, 2.56 Example 62 1-[4-[3-[4-(Cvclohexhexv nvlmethvl)-l-iperidinvlproDoxv]- 3 methoxyphenyllethanone oxalate hydrate A mixture of 5.2 g (0.02 mole) of 4-[(a-cyclohexyl-a-phenyl)methyl]piperidine, 4.9 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride ai.d 1.7 g (0.02 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100°C for 4 hrs. The reaction mixture was cooled, filtered, and the dimethylformamide was removed under reduced pressure.

The residual material was dissolved in benzene and placed on a Florisil® column. Elution using an acetone-benzene gradient gave 7.0 g of free base of the title compound. The oxalate salt was prepared and recrystallized from isopropanol, m.p. 155-160 0

C.

a~: 2 L J -148- AHR-438A-CIP Analysis: Calculated for C 64

H

88

N

2 0 15 C, 68.31; H, 7.88; N, 2.49 SFound C, 68.60; H, 7.78; N, 2.42 The free base of the title compound was obtained by reacting cyclohexyl-a-phenyl)methyl]piperidine and 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture with sodium bicarbonate, isolated and reacted with oxalic acid. The oxalate salt was recrystallized from 2-propanol, m.p.

155-160 0

C.

2xample 63 4-[3-[4-[Bis(4-fluorophenyl)methylene]- -piperidinyl]propoxy]-amethylbenzenemethanol oxalate A solution of 1-[4-[3-[4-[bis(4-fluorophenyl)methylene]-l-piperidinyl]propoxy]phenyl]ethanone, 3.56 g (0.0077 mole), and sodium borohydride, 1.51 g (0.04 mole), was stirred 6 hrs at room temperature. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which was converted to the oxalate salt. Recrystallization from methanoldiethyl ether gave 2.67 g of white crystalline product, m.p. 142- 1450C.

Analysis: Calculated for C 31

H

33

NO

6

F

2 C, 67.26; H, 6.01; N, 2.53 Found C, 67.17; H, 5.92; N, 2.47 Example 64 4--3-[4-lBis(4-fluorophenyl)me thvl)- -piDeridinvl]TroDoxv]-3-methoxva-methylbenzenemethanol.

Sodium borohydride (3.0 g, 0.079 mole) was added to 250 ml of ethanol. To the mixture was added 4.40 g (0.00885 mole) of 1-[3-(p-acetyl-omethoxyphenoxy)propyl]-4-[a,a-bis(p-fluorophenyl)methyl]piperidine in 100 ml of 95% ethanol over 15 minutes. The resulting solution was stirred 2.5 hr at room temperature. The reaction mixture was stripped to dryness and partitioned between chloroform and 5% sodium hydroxide. The organic layer was back extracted with 5% sodium hydroxide and water; removal of chloroform gave an oil. The oil formed a white solid in diethyl ether. The white solid was filtered off and recrystallized from methylene chloridediethyl ether. This furnished 2.16 g of white solid, m.p. 132-135 0

C.

-149- AHR-438A-CIP Analysis: Calculated for C 30

H

35

NO

3 F2: Found C, 72.72; H, 7.12; N, 2.83 C, 72.28; H, 7.21; N, 2.52 0 *0 0 t f Example 1-[4-[3-[4-(Diphenylmethyl)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate A mixture of 5.0 g (0.02 mole) of 4-(a-phenylbenzyl)piperidine, 4.85 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, and 3.4 g (0.04 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100°C for about 3 hrs. The reaction mixture was cooled, filtered and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in chloroform, and the chloroform was filtered to remove insolubles.

The filtrate was concentrated under reduced pressure to give 8.6 g of a red oil The oil was dissolved in a mixture of 4:1 ether-isopropanol and treated with 2.3 g of oxalic acid dihydrate. The oxalate salt crystallized upon standing and trituration in ether gave 8.4 g of salt melting at 149-1550C.

Recrystallization from isobutyl methyl ketone gave 7.0 g of the salt, m.p. 153- 155°C. (See Example 11, U.S. 3,956,296).

Analysis: Calculated for C 32

H

37 N0 7 C, 70.18; H, 6.81; N, 2.56 Found C, 70.00; H, 6.76; N, 2.56 Example 66 1-r4-F3-r4-rBis(4-fluoroDhenvl)hvdroxvmethvl]-l- iDeridinyl]propoxl- 3-methoxvDhenvllethanone. ci:

F

f (lr A mixture of 5.0 g (0.0165 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred and heated at 80°C for two hours. The temperature was raised to 100°C for one hour. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil® column. Using a gradient elution of acetonebenzene, 1.8 g of product was obtained from the column, m.p. 141.5- 143°C. (See Example 12, U.S. 3,956,296).

~4i AHR-438A-CIP -150- Analysis: Calculated for C 30

H

33

F

2 N0 4 Found C, 70.71; H, 6.53; N, 2.75 C, 70.49; H, 6.58; N, 2.59 tr *4 SO Q 4r 4 St r i 'S rr t( t Example 67 1-[4-[3-[4-[(4-Fluorophenyl)hydroxyphenylmethyl]-1-piperidinyl]propoxy]- 3-methoxyphenyl]ethanone.

A mixture of 6.5 g (0.023 mole) of a-(p-fluorophenyl)-a-phenyl-4piperidinemethanol, 5.5 g (0.023 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml of dimethylformamide was heated at 100-110°C for 2 hrs. The reaction mixture was cooled and filtered, and the dimethylformamide was removed at reduced pressure. The residual oil was dissolved in chloroform and filtered. The chloroform was removed at reduced pressure. The solid residue which remained weighed 8.6 g and was recrystallized from ethanol to give 3.1 g of material melting at 147-148 0 C. A sample was dried over refluxing toluene and submitted for analysis. (See Example 14, U.S. 3,956,296).

Analysis: Calculated for C 30

H

34 N0 4 F: C, 73.30; H, 6.97; N, 2.85 Found C, 73.15; H, 7.05; N, 2.77 Example 68 1-[4-[3-[4-(Diphenylhydroxymethyl)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxalate A mixture of 5.2 g (0.0194 mole) of a,a-diphenyl-4-piperidinemethanol, 4.7 g (0.0194 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.6 g (0.0194 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100°C for 3 hrs. After cooling, the reaction mixture was filtered and the dimethylformamide was removed under reduced pressure. The residual oil weighed 8.3 g Some of the product crystallized upon trituration in anhydrous ether and was collected by filtration. The filtrate was evaporated to dryness and the residue was dissolved in hot benzeneisooctane. Upon cooling, the crystalline product was obtained. A total yield of 6.3 g of solid product was obtained. The solid free base was converted to the oxalate salt. Recrystallization from isobutyl methyl ketone gave the offwhite solid melting at 174-176°C. (See Example 15, U.S. 3,956,296).

I

I

t

I

-151- AHR-438A-CIP Analysis: Calculated for C 32

H

37 NOg: C, 68.19; H, 6.62; N, 2.49 Found C, 68.34; H, 6.75; N, 2.42 Example 69 1-[4-[3-[4-[Hydroxyphenyl[3-(trifluoromethyl)phenyl]methyl]- 1piperidinyl]propoxy]-3-methoxyphenyl]ethanone hydrochloride hydrate A mixture of 7.0 g (0.021 mole) of a-phenyl-a-(m-trifluoromethylphenyl- 4-piperidinemethanol, 5.1 g (0.021 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 3.0 g (0.036 mole) of sodium bicarbonate in 125 ml of dry S dimethylformamide was stirred and heated at 90-95"C for 5 hours. The mixture was cooled and filtered. An excess of water was added to the reaction r mixture. The mixture was extracted several times with benzene, and the collected extracts were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude solid which was obtained was dissolved in benzene and placed on a Florisil® column. Elution using an acetone-benzene gradient gave a gummy solid. The gum was dissolved in ether, and the hydrochloride salt was prepared. The hydrochloride salt weighed 3.1 g and became a clear melt at 95°C. (See Example 16, U.S. 3,956,296).

Analysis: Calculated for C 62

H

72 C1 2

F

6

N

2 0 9 C, 63.42; H, 6.18; N, 2.39 J Found C, 63.68; H, 6.03; N, 2.33 I Example t I I t 1-[4-[3-[4-(Cyclohexylhydroxyphenylmethyl)- 1-piperidinyl]propoxy]-3methoxyphenyllethanone hydrochloride A mixture of 3.9 g (0.143 mole) of a-cyclohexyl-a-phenyl-4-piperidinemethanol, 3.5 g (0.143 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 2.35 g (0.28 mole) of sodium bicarbonate in 100 ml of dimethylformamide was heated at 100°C for 4 hrs. After cooling, the reaction mixture was diluted with about 600 ml of water and extracted with benzene. The collected benzene extracts were washed with water and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. A crude solid weighing 5.1 g was obtained.

The solid was dissolved in ether, and the ether solution was treated with an -152- AHR-438A-CIP 6000 00 0 a 0 oGo 00 C 0 0 000 excess of ethereal hydrogen chloride. The hydrochloride salt obtained was recrystallized from isobutyl methyl ketone to give 4.0 g of the salt, m.p. 152- 15500. (See Example 17, U.S. 3,956,296).

Analysis: Calculated for C 3 0 11 4 2 C1N0 4 C, 69.82; H, 8.20; N, 2.71 Found C, 69.50; H, 8.31; N, 2.62 Example 71 1-f 4-[2-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]ethoxyj-3methoxyphenyllethanone.

Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of QL,o-bis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-14-(2-chloroethoxy)-3-methoxyphenyllethanone and sodium carbonate in butanol, the title compound was prepared in 22% yield, rn.p. 131-135'C after the recrystallization from isopropyl alcohol.

Analysis: Calculated for C 2 9

H

3 lF 2 N0 4 C, 70.29; H, 6.31; N, 2.83 Found C, 70.00; H, 6.39; N, 2.60 Example 72 1-f 4.44-[4-[Bis(4-tfluorophenyl)hydroxymethyll-l-piperidinvl]butoxy-3methoxyphenyllethanone.

This compound was prepared according to the procedure used to synthesize the compound of Example 35. A mixture of 3.0 g (0.01 mole) of a,Qi-bis(p-fluorophenyl)-4-piperidinemethanol, 3.0 g (0.01 mole) of bromobutoxy)-3-methoxyphenylllethanone, 5.3 g (0.05 mole of anhydrous sodiumn carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide gave, after purification by column chromatography on Florisil® (acetone-benzene), 0.8g of off-white powder, m~p. 104-105'C, after recrystallization from 2-propanol-isopropyl ether.

Analysis: Calculated for C 3 jH 3 5

F

2 N0: C, 71.11; H, 6.74; N, 2.68 Found C, 70.84; H, 6.71; N, 2.65 0 00 a a -153- AHR-438A-CIP Example 73 1-[4-[5-[4-Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]pentoxy]-3methoxyphenyl]ethanone.

Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 2.7 g (0.01 mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl] ethanone and sodium carbonate in butanol, the title compound was prepared in 65% yield as white solid after recrystallization from isopropyl alcohol, m.p.

117.5-118.5 0

C.

Analysis: Calculated for C 32

H

37

F

2 N0 4 C, 71.49; H, 6.94; N, 2.61 0 Found C, 71.51; H, 7.06; N, 2.50 S, Example 74 1-[4-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]ethoxy]-3methoxyphenyl]ethanone.

A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.88 g (0.017 mole), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]e.hanone, 3.86 g (0.017 mole), and potassium carbonate, 5.53 g (0.04 mole), was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was filtered and stripped to dryness. The dark brown oil obtained was dissolved in chloroform and extracted with 1N sulfuric aci and sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed. This furnished a brown oil which was subjected to flash chromato- Sgraphy on silica gel using hexane-ethyl acetate for elution. A white solid was obtained by evaporating the fractions containing the product. The solid was extracted with diethyl ether, and the mixture was placed in the freezer overnight. A white solid was obtained which was dried at 80°C in vacuo overnight. A yield of 2.2 g of white crystalline solid, m.p. 129-131°C was obtained.

SAnalysis: Calculated for C 29

H

31 N0 3

F

2 C, 72.63; H, 6.52; N, 2.92 Found C, 72.52; H, 6.45; N, 2.87 j 1 -154- AHR-438A-CIP Example 1-[4-[3-[4-[Bis(4-chlorophenyl)methylene]-l-piperidinyl]propoxy]-3methoxyphenyl]ethanone.

A mixture of 3.96 g (0.01305 mole) of 4-[bis-(4-chlorophenyl)methylene]ethanone in 300 ml of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform-water and sodium hydroxide. Removal of chloroform gave an oil which crystallized from isopropyl alcohol. The solid was again crystallized from isopropyl alcohol to give 4.16 g of light yellow solid, m.p. 143-144°C.

Analysis: Calculated for C 3 0

H

31

NO

3 C1 2 C, 68.70; H, 5.96; N, 2.67 Found C, 69.11; H, 6.02; N, 2.55 Example 76 1-[4-[3-[4-[(4-Fluorophenyl)phenylmethyl]:- -piperidinyl]propoxy]-3methoxyphenyl]ethanone oxalate A solution of 4.42 g (0.0164 mole) of 4-[(4-fluorophenyl)phenylmethyl]piperidine and 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxy- St phenyl]ethanone, 0.01 g of potassium iodide and 1-butanol was refluxed for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give an oil. A solution of the oil in methanol was treated with an equivalent of oxalic acid, ethyl ether was added, and 6.39 g of white crystalline solid, m.p. 161-163°C was obtained.

Analysis: Calculated for C 32

H

36

NO

7 F: C, 67.95; H, 6.42; N, 2.48 Found C, 67.92; H, 6.42; N, 2.44 Example 77 1-[4-[3-[4-[Bis(4-methoxyphenyl)methyl]-l-piperidinyl]propoxy]-3methoxyphenyl]ethanone oxalate A mixture of 7.78 g (0.025 mole) of 4-[bis(4-methoxyphenyl)methyl]piperidine, 6.05 g (0.025 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and potassium carbonate (5.53 g, 0.04 mole) in 300 ml of 1-butanol containing potassium iodide (0.3 g) was refluxed overnight. The reaction mixture was stripped to dryness, and the residue was partitioned between -155- AHR-438A-CIP chloroform and water; removal of chloroform in vacuo gave a dark brown oil.

The oil was subjected to column chromatography on silica gel using a gradient elution composed of methanol and ethyl acetate. The corresponding fractions from the column were combined and reacted with oxalic acid.

Recrystallization of the salt from methanol-diethyl ether gave 4.16 g (27.4%) of white solid, m.p. 163.5-165°C.

Analysis: Calculated for C 34

H

41 N0 9 C, 67.20; H, 6.80; N, 2.31 Found C, 66.76; H, 6.84; N, 2.26 Example 78 1-[4-[3-[4-[Bis(4-methylphenyl)methyll-1-piperidinyl]propoxy]-3o methoxyphenyl]ethanone.

,oOo A mixture of 5.10 g (0.018 mole) of 4-[bis(4-methylphenyl)methyl]piperidine and 4.42 g (0.018 mole) of 1-[4-(3-chloropropoxy)-3-methylphenyl]- "ethanone in 350 ml of 1-butanol was heated overnight at gentle reflux with potassium carbonate (5.53 g, 0.04 mole) and potassium iodide (0.3 The reaction mixture was stripped to dryness, and the resulting residue was o, partitioned between chloroform-5% sodium hydroxide and chloroform-water.

Removal of chloroform gave a dark brown oil. The oil was subjected to °o column chromatography on a silica gel column with a gradient elution series of hexane-ethyl acetate and ethyl acetate-dimethoxyethane. The proper fractions from the column were combined. This resulted in 2.60 g of oil (after drying in vacuo at 80°C overnight).

°oo- Analysis: Calculated for C 32

H

3 9 N0 3 C, 79.14; H, 8.09; N, 2.88 Found C, 78.70; H, 8.08; N, 2.80 1H NMR (CDC1 3 8 (multiplet, protons on ring next to ketone, 2H), 6.7-7.6 (multiplet, aromatic proton, 9H), 4.0 (triplet, methylene adjacent to ether oxygen, 2H), S: 3.8 singlet, OCH 3 3H), 3.3 (doublet, methine next to rings, 1H), 2.5 (singlet, methyl of ketone, 3H), 2.2 (singlet, methyl groups attached to aromatic rings, 6H), 1.0-3.0 (multiplet, remaining aliphatic protons, 13H).

-156- AHR-438A-CIP Example 79 4' 1-[4-[4-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]butoxy]-3methoxyphenyl]ethanone.

A mixture of 6.15 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine and 6.45 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone in 350 ml of acetonitrile was stirred overnight at room temperature with potassium carbonate, 5.53 g (0.04 mole) and potassium iodide (0.3 g).

The mixture was then heated five hours at reflux. The reaction mixture was stripped to dryness on a rotary evaporator, and the residue was partitioned S1between chloroform-5% sodium hydroxide and chloroform-water. Removal of S *chloroform gave a dark brown oil. The oil was subjected to chromatography 11 on a silica gel column and eluted with a hexane-ethyl acetate-dimethoxy- .ethane series. Fractions from the column were combined and solvent removed by pumping in vacuo overnight at 80°C. This provided 3.34 g of brown oil.

Analysis: Calculated for C3135NO3F2: C, 73.35; H, 6.95; N, 2.76 Found C, 72.34; H, 6.92; N, 2.70 NMR analysis was obtained as follows: 1H NMR (CDC13): 6.8-7.6 8 (multiplet, aromatics, 11H), 4.1 (triplet methylene next to ether linkage, 2H), 3.4-3.6 (doublet, methine attached to two fluorophenyl rings, 1H), 3.8 (singlet, OCH 3 3H), 2.5 (singlet, COCH3, 3H), 1.1-3.0 (multiplet, remaining aliphatics, Example 4-[3-!4-[Bis(4-fluorophenyl)hydroxymethyll-1-piperidinyl]propoxy]3methoxybenzoic acid methyl ester.

Following the procedure of Example 1 and utilizing potassium iodide catalyst and substituting dimethylformamide for butanol, a mixture of 5.4 g (0.021 mole) of 4-(3-chloropropoxy)-3-methoxybenzoic acid methyl ester, 6.0 g (0.02 mole) of [a,a-bis(p-fluorophenyl)]-4-piperidinemethanol, 7.4 g (0.07 S mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of dimethylformamide was reacted to give 5.7 g of white solid, m.p. 131- 132°C after recrystallization from isopropyl alcohol.

d -157- -157- AHR-438A-CIP Analysis: Calculated for C 30

H

33

F

2 N0 5 T'o-nd C, 6 8.5 6; H, 6.3 3; N, 2.6 7 C, 68.23; H, 13.35; N, 2.60 Q t 4 t, It 4 I II Example 81 a,a-[Bis(4-fluorophenyl)]-l-[3-[4-(methylthio)phenoxylpropyll-4piperidinemethanol.

Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of [,-bis(p-fluorophenyl)-4-piperidinemethanol, 2.2 g (0.01 mole) of 1-chioro- 3-(4-methylthiophenoxy)propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was reacted to give 2.3 g of white powder, m.p. 113-115'C after recrystallization from isopropyl ether.

Analysis: Calculated for C 2 8

H

3 jF 2 N0 2 S: C, 69.54; H, 6.46; N, 2.90 Found C, 6 9.5 7; H, 6.5 1; N, 2.8 Example 82 a,a- Bi s(4- fluorophenyl)1- 1- 3- 4- (methvlsulfonyl)phenoxy] propyl]-4piperidinemethanol fumarate [114.

Following the procedure of Example 1, a mixture of 3.0 g (0.01 mole) of [o,c-bis(p-fluorophenyl)-4-piperidinernethanol, 2.5 g (0.01 mole) of 1-(3chloropropoxy)-4-(methylsulfonyl)benzene, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of'potassium iodide in 100 ml of 1-butanol was reacted to give a brown gum as residue. The gummy residue was reacted with fumaric acid, and the fumarate salt obtained was recrystallized from acetonitrile to give 3.0 g of white solid, m.p. 176-178'C.

Analysis: Calculated for C 3 2

H

3 5

F

2 N0 8 S: C, 60.85; H, 5.59; N, 2.22 Found C, 60.72; H, 5.54; N, 2.20 Example 83 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyll-l-piperidinylpropoxy.3 methoxybenzeneacetic acid ethyl ester hydrochloride.

Following the procedure of Example 45, Q,-bis(p-fluorophenyl)-4piperidineinethanol and 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid, ethyl ester are reacted, and the hydrochloride salt is prepared.

L t 1) -158- AHR-438A-CIP Example 84 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl--piperidinyl]ethoxy]benzoic acid ethyl ester hydrochloride.

Following the procedure of Example 45, a,a-bis(p-fluorophenyl)-4piperidinemethanol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is prepared.

Example 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyll-1-piperidinyl]propoxy]-3methoxybenzeneacetic acid sodium salt hydrate ,This compound was prepared according to the procedure of Example 1.

a o A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 2.9 g (0.01 mole) of 4-(3-chloropropoxy)-3-methoxybenzeneacetic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of acetonitrile gave the ester as a gum. The gum was converted to the hydrochloride with ethereal hydrogen chloride to give a white solid. The solid could not be recrystallized so it was partitioned between methylene chloride and a 5% sodium hydroxide solution. An i emulsion resulted which was let stand until the layers separated. During this time a solid precipitated. The mixture was filtered. The filter cake was recrystallized from ethyl acetate to yield 0.7 g of fluffy, white solid, m.p. 102-112°C.

Analysis: Calculated for C3nH 3 3F2NNa05.

5 C,64.74; H,5.98; N,2.52 Found C,64.50; H,5.97; N,2.39 Example 86 7-[3-[4-[Bis(4-fluorophenyl)hydroxymethyll-1-piperidinyl]propoxy]-2H- 1-benzopyran-2-one.

This compound was prepared according to the procedure of Example 1.

A mixture of 3.0 g (0.01 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole of 7-(3-chloropropoxy)-2H-1-benzopyran-2-one, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.6 g of pale yellow crystals, m.p. 99-120°C with decomposition.

L J 44- i -159- AHR-438A-CIP Analysis: Calculated for C 30

H

29

F

2 N04: Found C, 71.27; H, 5.78; N, 2.77 C, 71.02; H, 5.89; N, 2.63

SI

4 0 4 *4 I l f Example 87 2-[3-[4-[Bis(4-fluorophenyl)hydroxymeth:y!]-1-piperidineyl]propoxy]benzoic acid ethyl ester fumarate This compound is prepared according to the procedure of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of 2-(3-chloropropoxy)benzoic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide gave 5.7 g of gum as residue. The gum was purified by column chromatography on 100 g of silica gel. Fractions eluted with 35% acetone in benzene were combined and concentrated to give 3.0 g of pale yellow gum as residue. The gum was converted to the fumaric acid salt and the solid was recrystallized twice from 2-propanol to yield 2.0 g of white solid, m.p. 138-141 0

C.

Analysis: Calculated for C33H36F2NO 7 C, 66.43; H, 6.08; N, 2.35 Found C, 66.25; H, 6.08; N, 2.27 Example 88 2-[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyllpropoxy]benzoic acid ethyl ester.

A mixture of 32.79 g (0.116 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 27.04 g (0.114 mole) of 2-(3-chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 19.40 g (0.140 mole) was heated overnight at reflux in 500 ml of diethoxyethane containing potassium iodide (0.4 The reaction was filtered and stripped to dryness. The residue obtained was dissolved in chloroform and extracted with 5% sodium hydroxide, sodium sulfite, and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to furnish a dark brown oil (56.20 g).

The oil was subjected to flash chromatography on an 83.5 g silica gel column (with ethyl acetate). Fractions were combined with similar purity. One sample of 6.49 g was dried in vacuo at 80°C overnight and analyzed.

c 4 4 44 1<1 *4,O r -I 1

L

1

I

-160- AHR-4,8A-CIP i

I

II

.1 #r -o Gc Pt t I II I I U (It* ~tI

XI

1 II L9I CE C t r f\ 17 1H NMR (CDC13): 7.8 8 1, aromatic proton ortho to ester), 7.0 8 11, aromatic), 4.3 8 2, C-O-CH 2 4.1 8 2, -OCH 2 3.5 8 1, methine), 1..3 8 3, CH 3 1.7-3.0 8 13, aliphatic).

Analysis: Calculated for C 30

H

33 N0 3

F

2 C, 73.00; H, 6.74; N, 2.84 Found C, 72.98; H, 6.70; N, 2,93 Example 89 1-[4-[5-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyl]pentoxy]-3methoxyphenyl]ethanone hydrate A mixture of 6.03 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 5.69 g (0.021 mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl]ethanone, and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

The reaction mixture was cooled at room temperature, filtered, and stripped to dryness. The residue obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried (sodium sulfate), filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel using ethyl acetate and 2% methanolethyl acetate for elution, Fractions of similar purity were combined and solvent removed. The sample was dried in vacuo at 70°C overnight after being exposed to the atmosphere for 24 hours. A yield of 2.7 g of brown oil was obtained.

1H NMR (CDC1 3 6.8-7.6 8 11. aromatic), 4.1 8 2, -OCH 2 3.9 8 3,

OCH

3 3.4-3.6 8 1, methine of difluorophenyl group), 2.5 8 3, -C-CH 3 1-3.0 8 18, aliphatics and 0.5 H 2 0) II Analysis: Calculated for C 32

H

3 8N03.

5

F

2 Found

O

C, 72.43; H, 7.22; N, 2.64 C, 72.75; H, 7.23; N, 2.57 Example 4-[3-[4-[Bis(4-fluorophenyl)methyl]- -piperidinyl]propoxy]benzamide fumarate A mixture of 6.10 g (0.02125 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine and 4.53 g (0.02125 mole) of 4-(3-chloropropoxy)benzamide in 350 ml of 1-butanol containing potassium carbonate (5.53 g, 0.02125 mole) and potassium iodide (0.2 g) was heated ovrnight at gentle reflux. The

L

-161- AHR-438A-CIP reaction was filtered and stripped to dryness. The residue obtained was dissolved in chloroform and extracted with water. The chloroform layer was dried, filtered, and solvent removed to give an oil. This material was converted to the fumarate salt and recrystallized from methanol-diethyl ether. The white crystalline solid obtained was dried in vacuo overnight at A yield of 5.47 g of white crystalline product was obtained, m.p.

193-194oC.

Analysis: Calculated for C 34

H

36

N

2 0 8

F

2 C, 63.94; H, 5.68; N, 4.39 Found C, 64.03; H, 5.73; N, 4.37 Example 91 4-IBis(4-fluorophenyl)methyl]-1-[3-[4-(methylsulfonyl)phenoxy]propvl]piperidine oxalate 1:1].

SA mixture of 6.02 g (0.021 mole) of 4-[bis(4-fluorophenyl)methyl]- 09 piperidine and 5.22 g (0.021 mole) of 1-(3-chloropropoxy)-4-(methylsulfonyl)benzene in 350 ml of 1-butanol containing potassium carbonate (5.53 g, 0.04 mole) and potassium chloride (0.2 g) was heated overnight at gentle reflux.

The reaction was filtered and stripped to dryness. The residue obtained was yield of 6.21 g of white crystalline solid, m.p. 202-204'C, was obtained.

0. Analysis: Calculated for C30H33NS0F2 C, 61.11; H, 5.64; N, 2.38 Example 92 1-[4-[6-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]hexyloxy- 3-methoxyphenyl]ethanone.

Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixture of [a,a-bis(p-luorophenyl)-4-piperidinemethanol and 1- [4-(6-chlorohexoxy)-3-methoxyphenyl]ethanone and sodium carbonate in butanol, the title compound is prepared.

0 Analsis Calulaed or Co~sNS072 1.11 H,5.64 N,2.3 -162- AHR-438A-CJEP Example 93 1-[4-[3-[4-IIBis(4-fl orophenyl)hydroxvymethyl-l-piperidinylpropokcv]- 2-methoxyphenjyljethanone.

Following the procedure of Examples 1 and 66, [a,a-bis(p-fluorophenyl)]-4-piperidinemethanol and C $.(p-acetyl-m-methoxyphenoxy)propyl chloride are reacted to give the title compound.

Example 94 a,a-Bis(4-fluorophenyl)- 1-[3-(2-hydroxyphenoxy)propyl]-4-piperi dinemethanol.

Following the procedure of Example 2 and using potassium iodide catalyst, a,a-bis(p-fluorophenyl)-4-piperidinemethanol and 2-(3-chloropropoxy)-1-benzyloxybenzene are reacted to give 1-[3-(2-benzyloxphenoxy)pro pyllI-a, a-bi s(4-fl uoroph enyl) -4-pi pe ridi nemeth an ol which is reacted with hydrogen over palladium on carbon catalyst to give the title compound.

Example I ai,a-[Bis(4-fluorophenyl)]-l-[3-[4-(methylsulfinyl)phenoxylpropyll-4piperidine methanol fumarate.

d Following the procedure of Examples 1 and 82, [a,a-bis(p-fluorophenyl)l-4-piperidenemethanol and 1-(3-chloropropoxy)-4-(methylsulfinyl)benzene are reacted to give the free base of the title compound which is then reacted with fumaric acid to give the title compound.

Example 96 V 4-[3-[4-[Bis(4-fluorophenyl)hvdroxvmethvll- 1-piperidinyl ]proroxvlbenzenesulfonainide hyvdrochloride[1:11.

This compound was prepared according to the procedure of Example 1.

A mixture of 3.0 g (0.01 mole) of [Qa,c-bi s(p-fluoroph enyl)]I-4-pi peri dinemethanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy)benzenesulfonamide, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was converted to the hydrochloride with ethereal hydrogen chloride and the solid was recrytallized from absolute ethanol to yield 3.5 g of white solid, m.p. 152-175TC.

L

-163- AHR-438A-CTEP Analysis: Calculated for C 27

H

3 1 C1F 2

N

2 0 4 S C, 58.64; H, 5.65; N, 5.06 Found 58.4 3;LI, 5.6 8; N,5.0 6 Example 97 N-[4-[3-[4-[Bis(4-fluorophenyI)hydroxymethll1-piperidinylipropoxy]phenyllmeth anesulfonamide.

Following the procedure of Example 1, [Qi,a-bis(p-fluorophenyl)1-4piperidinemethanol and N-[4-(3-bromopropoxy)phenyllmeth anesulfonamide are reacted to give the title compound.

Example 98 N-I!4-3-14-[Bis(4-fluorophenyl)hydroxvmethyl]-l-piperidinyllpropoxy]t t t phenyl]-N'-methyvlurea.

Following the procedure of Example 1, [E,a-bis(p-fluoropheny)1-4piperidinemethanol and N-[4-(3-bromopropoxy)phenyll-N'-methylurea are reacted to give the title compound.

Example 99 [4-[3-[4-IBis(4-fluorophenyl)hydroxymethyll-l-piperidinyllpropoxylphen yll carbamic acid ethyl ester.

Following the procedure of'Example 1, [,QL-bis(p-fluorophenyl)1-4piperidinemethanol and [4-(3-bromopropoxy)phenyllcarbamic acid ethyl ester are reacted to give the title compound.

Example 100 N- 13-[3-[4-[Bis(4-fluoro phen yl)h ydrox ymethvl 1-1-pip eridinyl ]propoxy 1- Phenyllurea.

Following the procedure of Example 1, [,a-bis(fluorophenyl)]-4-piperidinemethanol and N-13-(3-bromopropoxy)phenyllurea are reacted to give the _____title compound.

L

00 00 p p p 0 0 0# 4 4 e 49 P 90*0 04 *4 4 04 t p 9 p 0 ft I-pot I I I~*1 t

I-~

I- P it p p -164- AHR-438A-CrEP Example 101 4- [34[4-[Bis(4- fluorophenyl)hydroxymethyll- I- piperidinyl Ipropgxyi3 methoxybenzoic acid sodium salt.

Following the procedures of Examples 1 and 85 but substituting 4-(3chloropropoxy)-2-methoxybenzoic acid for the corresponding 3-methoxy compound, the title compound is prepared.

Example 102 4 3 [Bis(4- fl uorophenyl)hydroxymethyl] pi peri di nyll pro poxy.2.

hydroxyphenyllethanone.

Following the procedure of Example 1, ,a-bis(p-fluorophenyl)-4-piperidineinethanol and 1-f 4-(3-bromopropoxy)-2-hydroxyphenyl jethanone are reacted to give the title compound.

Example 103 7-f3-[4-[Bis(4-t-luorophenyl)hydroxymethyll-l-piperidinyllpropoxy-4oxo-4H-1-benzopyran-2.-carboxylic acid ethyl ester hydrochloride [1:11.

A mixture of 3.0 g (0.01 mole) of [,-bis(p-fluorophenyl)i-4-piperidinemethanol, 3.1 g (0.01 mole) of 7-(3-chloropropoxy)-4-oxo-4H- 1 -benzopyran-2carboxylic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of acetonitrile heated at reflux for 48 hr gave a gulm as residue. The gum was purified by column chromatography on 120 g of FlorisilO, The desired fractions eluted with 10% acetone in benzene were combined and concentrated under reduced pressure to give a glass as residue. The glass was dissolved in ether- 2-propanol, and treated with ethereal hydrogen chloride. The solid which precipitated was collected by filtration and recrystallized from absolute ethanol to give 1.9 g of white solid, m.p. 191"C with decomposition.

Analysis: Calculated for C 3 3

H

34 C1F 2 N0 6 64.55; HI, 5.58; N, 2.28 Found 64.41; H, 5.51; N, 2.26 Pr~ ~nRP~

I'

-165- -65-AHR-438A-CIEP to 00 0 0 0 0 f 0 t 0* t q.* t Example 104 7 -[3-Ii4-[Bis(4-fluorophenyi)hydroxymethyll 1-piperidinyl]propoxy]-'2,3dihydro-4H-1-benzopyran-4-one hydrochloride.

Following the procedure of Example 103, [,-bis(p-fluorophenyl)]-4piperidinemethanol and 7-(3-bromopropoxy)-2,3-dihydro-4H- 1-benzopyran- 4-one are reacted to give the title compound.

Example 105 l-[ 4 3 4 -(Diphenylmethylene)-l-piperidinyl]propoxy-3-methox-y phenyllethanone oxalate hydrate [1:1:0.51.

A mixture of 7.5 g (0.030 mole) of 4-di phenylmethyle nepiperi dine, 6.3 g (0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromide 25 g of potassium carbonate and 150 ml of toluene was heated at reflux for 16 hr, cooled, filtered and the solvent evaporated at reduced pressure. The residual oil was taken up in benzene, washed with water, dried over magnesium sulfate and then the solvent was evaporated. The free base was dissolved in 2-propanol and treated with 3.8 g (0.03 mole) of oxalic acid dihydrate in dry ether. The white salt which separated was recrystallized from an 2- prop anol -methanol mixture. The product weighed 8.5 g m.p. 186-188'C.

Analysis: Calculated for C 32

H

3 6 N0 7 5 69.29; H, 6.54; N, 2.53 Found 69.20; H, 6.49; N, 2.71 Example 106 1-[4-[3-t4-(Cyclohexylphenylinethyl)- 1.2,3 .6-tetrahydropyri din- 1-yllpropoxyl-3-methoxyphenyllethanone oxalate hydrate The free base of the title compound was obtained by reacting 4-(Q-cyclohexyiphenylmethyl)- 1, 2,3 tetrahydropyri dine with 3-(p-acetyl-o-methoxyphenoxy)pro'pyl chloride in a mixture with so 'ium bicarbonate in dimethylformamide and isolated on a FlorisilO column eluting with benzene. The title salt was prepared, m.p. 110 0

'C.

Analysis: Calculated for C 6 4

H

84

N

2 0 1 5 C, 68.55; H, 7.55; N, 2.50 Found 68.79; H, 7.64; N, 2.47

I

-166- AHR-438A-CIP

I

:1 4 4.

0* 44 0~ 'iI 4 L I Example 107 1-[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyll-1-piperidinyl]propoxy]- 2-methoxyphenyl]ethanone hydrochloride This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of[a,abis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-2-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of Florisil® and the fractions eluted with 20% acetone in benzene were combined and concentrated under reduced pressure to give a solid as residue.

The solid was converted to the hydrochloride and this solid was recrystallized.

from 2-propanol-isopropyl ether to yield 2.2 g of white powder, m.p.

196-197 0

C.

Analysis: Calculated for C 30

H

34 C1F 2 N0 4 C, 65.99; H, 6.28; N, 2.57 Found C, 65.87; H, 6.31; N, 2.54 Example 108 4-[Bis(4-fluorophenyl)methvl]-1-[3-(2,6-dichlorophenoxy)propyllpiperidine.

A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassi:ra carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80°C. A yield of 3.26 g of white crystalline solid, m.p. 101.5-103°C was obtained.

Analysis: Calculated for C 27

H

27 NOC1 2

F

2 C, 66.13; H, 5.55; N, 2.85 Found C, 66.12; H, 5.56; N, 2.88 t tC t -167- AHR-438A-CIP Example 109 4-[Bis(4-fluorophenyl)methyl]-1-[3-(2,6-dichlorophenoxy)propyl]piperidine oxalate Free base of the compound of Example 108 was converted to the oxalate salt and recrystallized from methanol-diethyl ether and dried in vacuo at overnight, m.p. 158-161°C.

Analysis: Calculated for C 29

H

29 N0 5 C1 2

F

2 C, 60.01; H, 5.04; N, 2.44 Found C, 60.02; H, 5.07; N, 2.46 Example 110 2 -[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]benzonitrile.

A mixture of 7.41 g (0.025 mole) of [4-[bis(4-fluorophenyl)methyl]piperidine, 4.90 g (0.025 mole) of 2-(3-chloropropoxy)benzonitrile, and 0 1 potassium carbonate, 5.54 g (0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The mixture was stripped to dryness, and the resulting residue was partitioned several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a brown oil. The oil was triturated with diethyl ether and placed in a freezer overnight. White Scrystals were obtained and dried in vacuo overnight at room temperature. A yield of 5.15 g of analytically pure material, m.p. 88.5-90°C was obtained.

Analysis: Calculated for C 28

H

2 8.N 2 0F 2 C, 75.31; H, 6.32; N, 6.27 Found C, 75.16; H, 6.34; N, 6.26 Example 111 a,a-Bis(4-fluorophenyl)- -[2-(phenylthio)ethyl]-4-piperidinemethanol maleate A Grignard solution was prepared in tetrahydrofuran (ice bath) from magnesium, 5.81 g (0.242 mole) and p-fluorobromobenzene, 42.4 g (0.242 mole). This Grignard reagent in about 350 ml of tetrahydrofuran was stirred about 3 hr at room temperature. The reaction mixture was then transferred to a 500 ml addition funnel (under nitrogen). This solution was added dropwise to a tetrahydrofuran solution of 1-[2-(phenylthio)ethyl]-4-piperidineicarboxylic acid ethyl ester, 29.10 g (0.1 mole) in about 200 ml of tetrahydro- I I Li >j 1 -168- AHR-438A-CIP oi r 0 ~t 0r 0 00 0 i f 0 I I

I

I

i

F

furan. The solution was stirred overnight at room temperature, then poured onto ice containing 35 g of ammonium chloride. The solution was extracted with chloroform and the chloroform back extracted with 5% sodium hydroxide. Removal of chloroform gave a dark brown oil. The oil was converted to the maleate salt and recrystallized from methanol-diethyl ether to give 5.0 g (56.5% yield based on aliquot taken) of white crystalline product, m.p. 171-173°C.

Analysis: Calculated for C 3 0

H

3 1

NO

5

SF

2 C, 64.85; H, 5.62; N, 2.52 Found C, 64.80; H, 5.62; N, 2.45 Example 112 4-[Bis(4-fluorophenyl)methylene]-l-[2-(phenylthio)ethyl]piperidine.

a,a-Bis(4-fluorophenyl)- -[2-(phenylthio)ethyl-4-piperidinemethanol maleate, 26.13 g (0.047 mole) was converted to the free base of partitioning with methylene chloride and weak alkaline solution and evaporating the organic layer to give an oil. The oil was dissolved in 150 ml of methanol containing 100 ml of 6 N hydrochloric acid, and the solution was heated 4-1/2 hr at gentle reflux. The reaction mixture was cooled to room temperature, made alkaline with an ice-50% sodium hydroxide mixture and extracted with chloroform. The chloroform layer was evaporated to leave an oil which crystallized. Trituration of the solid in methanol followed by refrigeration and filtering gave the title compound, m.p. 101.5-103.5°C, in 60% yield.

Analysis: Calculated for C 26

H

25

NSF

2 C, 74.08; H, 5.98; N, 3.32 Found C, 74.12; H, 5.96; N, 3.25 Example 113 a,a-Bis(4-fluorophenyl)- -[2-[(4-chlorophenyl)sulfonyl]ethyl]-4piperidinemethanol.

A mixture of 5.85 g (0.0193 mole) of a,a-bis(4-fluorophenyl)-4piperidinemethanol, 4.76 g (0.020 mole) of 2-chloroethyl-p-chlorophenylsulfone and 4.90 g (0.0462 mole) of sodium carbonate in 600 ml of acetonitrile was heated at 65°C for 18 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give a solid. This was recrystallized ii 4

I

1 -169- AHR-438A-CIP .9 99 *a 9 4 *4 9 49P 0 4 14 44 4 4 11 I' I I *5*4 I S I Ir from a mixture of methylene chloride (400 ml), methanol (50 ml) and hexane (200 ml) to give 6.99 g of white crystalline solid, m.p. 211-212°C.

Analysis: Calculated for C 26

H

26 N0 3

SF

2 C1: C, 61.72; H, 5.18; N, 2.77 Found C, 61.51; H, 5.16; N, 2.81 Example 114 1-[2-[(4-Chloropheayl)sulfonyl]ethyl]-4-[bis(4-fluorophenyl)methylene]pi peridine.

A mixture of 2.74 g (0.0054 mole) of a,a-bis(4-fluorophenyl)-1-[2-[(4chlorophenyl)sulfonyl]ethyl]-4-piperidinemethanol in 100 ml of glacial acetic acid and 40 ml of 2 M sulfuric acid was refluxed for 6 hr. The solvent was removed in vacuo, and the resulting solid was recrystallized from methylene chloride-hexane to give 1.95 g of white crystalline solid, m.p. 152- 153 0

C.

Analysis: Calculated for C 26

H

24

NO

2 SC1F 2 C, 63.99; H, 4.96; N, 2.87 Found C, 64.24; H, 4.95; N, 2.84 Example 115 4-[Bis(4-fluorophenyl)methyl]-l-[3-(phenylsulfonyl)propyl]piperidine fumarate A mixture of 5.74 g (0.02 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 4.36 g (0.02 mole) of 3-chloropropyl phenyl sulfone, 3.18 g (0.03 mole) of sodium carbonate, and potassium iodide (0.3 g) in 300 ml of nbutanol ws refluxed overnight. The reaction mixture was stripped to dryness, and the residue partitioned between chloroform-5% sodium hydroxide and then between chloroform-water. Removal of chloroform gave an oil which was converted to the fumarate salt. Recrystallization from isopropyl alcohol-diethyl ether gave 3.31 g of white solid, m.p. 172-173°C.

Analysis: Calculated for C 2 2

H

35 N0 8

F

2 S: C, 61.58; H, 5.48; N, 2.18 Found C, 61.69; H, 5.54; N, 2.14 -170- -70-AHR-438A-CIEP Example 116 4-[Bis(4-fluorophenyl)methyll--12-[(4-chlorophenyl)sulfonyllethylpiperidine maleate [1:11.

A mixture of 4.22 g (0.0147 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 3.63 g (0.0152 mole) of 2-chloroethyl-p-chlorophenyl sulfone, and 4.1 g (0.039 mole) of sodium carbonate in 400 ml of acetonitrile was refluxed for 22 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried (magnesium sulfate), and the solvent was removed in vacuo to give an oil. This was converted to the maleate salt, and the salt was recrystallized from me th anol-di ethyl ether to give 6.84 g (76.9%) of white crystalline solid, m.p. 185-186'C.

Analysis: Calculated for C 3 0

H

3 ON0 6

SF

2 Cl: C, 59.45; H, 4.99; N, 2.31 Found 59.5 7; H,4.99;N, 2.3 2 Example 117 4-[Bis(4-fluorophenyl)methyl]-l-[2-(phenvlsulfonyl)ethyl]piperidine maleate A mixture of 5.20 g (0.016 molp,) of 4-[bis(4-fluorophenyl)methyl]piperidine, 3.32 g (0.0162 mole) of 2-chloroethyl phenyl sulfone, and 500 g (0.0362 mole) of potassium carbonate in 500 ml of acetonitrile was refluxed for 19 hr. The solvent was removed in vacuo, and the residue was partitioned between tiiotb vlene chloride and dilute sodium hydroxide. The organic solution was dried (magnesium sulfate), and the solvent -was removed in vacuo to give an oil. This was converted to the male ate salt, and the salt was recrystallized from methanol-ether to give 4.82 g(52.4%) of white crystalline solid, m.p, 183-5-184.5'C.

Analysis-. Calculated for C 3 0

H

3 lN0 6

F

2 S: C, 63.04; H, 5.47; N, 2. Found 62.88; H, 5.40; N, 2.45 Example 118 1-(2 ,3-Dihydro-1 ,4-benzodioxan-2-ylmethyl)-a,a-diphenyl-4-piperidineacetonitrile.

A mixture of 6.24 g (0.027 mole) of 2-(bromomethyl)-1,4-benzodioxan, (7.45 g, 0.027 mole) of cL,a-diphenyl-4-piperi dine acetonitrile and potassium 1 i

I

K

;1 -171- AHR-438A-CIP q# *y p q t, tL tt I I i IIr I i i

I

CI I

I

IIt It .1C carbonate (6.91 g, 0.05 mole) was stirred overnight at room temperature. The reaction mixture was refluxed for 5 hours and then stirred overnight at room temperature. The reaction mixture was stripped to dryness. The residue was dissolved in chloroform and the solution was extracted with water and sodium hydroxide. Removal of chloroform gave an oil. NMR showed a 2/1 ratio of product to starting material. The reaction was then refluxed overnight in 350 ml of 1-butanol containing potassium iodide (0.3 g) and potassium carbonate (6.91 g, 0.05 mole). The reaction mixture was stripped to dryness, and the resulting residue was partitioned between chloroformwater and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which was crystallized from methanol and dried in vacuo at overnight. A yield of 7.18 g of white crystalline product, m.p. 130- 131.5 0 C was obtained.

Analysis: Calculated for C 28

H

2 8

N

2 0 2 C, 79.22; H, 6.65; N, 6.60 Found C, 78.88; H, 6.62; N, 6.56 Example 119 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-diphenyl-4-piperidineacetonitrile oxalate A mixture of 6.78 g (0.05 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 7.72 g (0.028 mole) of a,a-diphenyl-4-piperidineacetonitrile was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.4 The reaction mixture was stripped to dryness, and the residue was dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric acid and then with 5% sodium hydroxide. The chloroform was removed in vacuo to give a brown oil. The oil was converted to the oxalate salt, and the salt crystallized from methanol. The salt was dried in vacuo at overnight. A yield of 8.36 g of white solid was obtained, m.p.

226-227°C (with decomposition).

Analysis: Calculated for C 33

H

36

N

2 0 7 C, 69.21; H, 6.34; N, 4.89 Found C, 68.78; H, 6.32; N, 4.84 hL

-U

8 i~r-i -172- AHR-438A-CIP It II *a r II I rP 0 it it t Example 120 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-diphenyl-3-piperidinepropanenitrile.

A mixture of 5.80 g (0.02 mole) ofa,a-diphenyi-3-piperidinepropanenitrile, 4.84 g (0.02 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and potassium carbonate, 5.60 g (0.04 mole) was heated overnight at 68°C in 400 ml ofdimethylformamide containing potassium iodide (0.3 g).

The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was subjected to column chromatography on a silica gel column with elution via ethyl acetate. Fractions containing the product were combined and transferred to brown glass bottles with acetone. The oil was triturated with diethyl ether and pumped to dryness in vacuo at 80°C overnight. A yield of 2.37 g of oil was obtained.

Analysis: Calculated for C 3 2H 36

N

2 0 3 C, 77.39; H, 7.31; N, 5.64 Found C, 77.00; H, 7.35; N, 5.63 Example 121 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl]-aa-diphenyl-3-piperidinepropanenitrile.

A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropanenitrile, 6.02 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone, and 5.60 g, (0.04 mole) of potassium carbonate was stirred overnight at room temperature in 400 ml of acetonitrile containing potassium iodide (0.3 The mixture was then stirred overnight at reflux, then stripped to dryness, and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give a dark yellow oil. The oil was subjected to column chromatography on silica gel with elution via ethyl acetate. Pure fractions were combined, and the oil was triturated with diethyl ether. The oil was dried in vacuo at 80°C overnight. A yield of 5.96 g of light yellow oil was obtained. 1H NMR (CDC13) 5 7.2-7.8 12, aromatic), 6.9 1, aromatic), 4.1 2, CH 2 3.9 3, -OCH 3 2.5 3, C-

CH

3 1.1-2.4 17, aliphatic).

I

I

-173- AHR-438A-CIP Analysis: Calculated for C 3 3

H

38

N

2 0 3 C, 77.61; H, 7.50; N, 5.48 Found C, 76.96; H, 7.55; N, 5.35 Example 122 1-[3-(4-Acetyl-2-methoxypenoxy)propyl]-a,a-diphenyl-3-pyrrolidineacetamide.

A mixture of 5.00 g (.018 mole) ofa,a-diphenyl-3-pyrrolidineacetamide, 4.14 g (.018 mole) of 3-chloro-l-[(4-acetyl-2-methoxy)phenoxy]propane and 1.91 g (.018 mole) of sodium carbonate in 100 ml of 1-butanol was refluxed 18 hrs. The solution was cooled and concentrated in vacuo. The residue was taken up in 300 ml of methylene chloride, washed with 100 ml dilute sodium hydroxide, 100 ml dilute hydrochloric acid, and 100 ml dilute sodium t: hydroxide, dried over magnesium sulfate and concentrated to yield 7.70 g of yellow glass. The glass was crystallized from methylene chloridediethyl ether to yield 5.70 g of a fine tan powder which contained ether.

SThe powder was recrystallized from ethyl acetate and acetonitrile to give an Soff-white powder, 143.5-148.5°C.

Analysis: Calculated for C 3 0

H

34

N

2 0 4 C, 74.05; H, 7.04; N, 5.76 I Found C, 73.80; H, 7.01; N, 5.80 Example 123 1-[3-(4-Acetyl-2-methoxyphenoxy)provl-a.a-diDhenvl-4-piDeridineacetamide fumarate hydrate A mixture of 5.88 g (0.02 mole) of a,a-diphenyl-4-piperidineacetamide, 4.84 g (0.02 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and 6.91 g (0.05 mole) potassium carbonate was heated at reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was stripped to dryness. The residue obtained was partitioned between chloroform-water and chloroform-5% sodium hydroxide layer. The chloroform layer was dried, filtered, and solvent removed by rotary evaporator.

S~The residue obtained was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether. The white solid obtained was dried in vacuo overnight it 80°C. A yield of 3.71 g of white solid, m.p.

211-213°C was obtained.

r1, -174- AHR-438A-CIP Analysis: Calculated for C 33

H

4 0

N

2 0 7 Found C, 68.73; H, 6.99; N, 4.86 C, 68.56; H, 6.72; N, 4.60 oo q 9a 9 o p o 99a *Q 9 II 9 99 9 99 9~ if *999a 99 9 o *o 99O p 8 99a 9 9 o~999 9 9 Example 124 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl]-a,a-diphenyl-4-piperidineacetamide fumarate hydrate A mixture of 6.0 g (0.02 mole) of a,a-diphenyl-4-piperidineacetamide, 6.02 g (0.02 mole) of 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone and potassium carbonate (5.60 g, 0.04 mole) was stirred overnight at room temperature in 300 ml of acetonitrile containing potassium iodide (0.2 g).

The mixture was then heated overnight at gentle reflux. The mixture was stripped to dryness, and the residue obtained was partitioned between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give a gummy residue. This material was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether and was dried in vacuo overnight at 80°C to give 5.91 g of white solid, m.p. 169-171 0

C.

Analysis: Calculated for C 34

H

42

N

2 0 7 C, 69.13; H, 7.17; N, 4.74 Found C, 69.22; H, 6.89; N, 4.44 Example 125 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a.a-diphenvl-3-piperidinepropanamide hydrate A mixture of 7.00 g (0.0227 mole) ofa,a-diphenyl-3-piperidinepropanamide, 5.50 g (0.0227 mole) of 1-[4-(3-chloropropoxy)-3.methoxyphenyl]ethanone and potassium carbonate (11.2 g, 0.08 mole) was heated cvernight at reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g).

The reaction mixture was stripped to dryness, and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide.

The chloroform layer was dried, filtered, and solvent removed to give an oil.

The oil was subjected to column chromatography on silica gel and eluted with dimethoxyethane-ethyl acetate. Fractions of pure material were combined and dried in vacuo at 80°C overnight. A yield of 3.75 g of a light yellow amorphous solid was obtained, 1H NMR (CDC13): 8 7.7 12,

C,

.7 V

L.

-175- AHR-438A-CIP ft rf D 4 4 44 4r 4 4$O aromatic, 6.9 1, aromatic), 5.8 6.4 (br s, 2, NH 2 5.1 (br s, 1-1/2 H 2 3.9 2, CH20), 3.9 3, OCH 3 2.5 3, C-CH 3 1.1 2.4 15, aliphatic).

Analysis: Calculated for C 32

H

39

N

2 0 4 5 C, 73.40; H, 7.51; N, 5.35 Found C, 73.42; H, 7.47; N, 5.22 Example 126 4-[Bis(4-fluorophenyl)methyl]-1-[(2,3-dihydro-1,4-benzodioxan-2yl)methyl]piperidine oxalate A mixture of 5.53 g (0.019 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine (4.39 g, 0.019 mole) of 2-(bromomethyl)-2,3-dihydro-l,4benzodioxane, and potassium carbonate (7.80 g, 0.056 mole) was stirred overnight at room temperature in 25,0 ml of acetonitrile. The reaction m-Ature was stripped to dryness and partitioned between chloroform and water. Removal of chloroform gave a yellowish brown oil which was converted to the oxalate salt. The salt was recrystallized from methanoldiethyl ether. A yield of 3.63 g of white solid, m.p. 142-145°C was obtained.

Analysis: Caluclated for C 29

H

29 N0 6

F

2 C, 66.28; H, 5.56; N, 2.61 Found C, 66.06; H, 5.50; N, 2.61 Example 127 1-[2-(2.6-Dichlorophenoxy)ethyl]-Q,a-diphenyl-3-piperidinepropanenitrile.

A mixture of 6.09 g (0.021 mole) of a,a-diphenyl-3-piperidinepropanenitrile and 5.63 g (0.021 mole) of 2-(2-bromoethoxy)-l,3-dichlorobenzene in 350 ml of acetonitrile was stirred overnight at room temperature with potassium carbonate (5.53 g, 0.04 mole) and 0.2 g of potassium iodide.

The mixture was then heated overnight at gentle reflux. The mixture was then stripped to dryness, and the resulting residue was dissolved in chloroform. The chloroform was extracted with 5% sodium hydroxide and water.

The chloroform layer was then dried, filtered, and solvent removed to give 12.2 g of oil. The oil was subjected to flash chromatography on silica gel using 20% ethyl acetate-hexane and 50% ethyl acetate-hexane for elution.

Fractions of pure material were combined and solvent removed in vacuo. The i

I

iC -ill -176- AHR-438A-CIP brown oil was dried overnight in vacuo at 80°C. A yield of 5.49 g of Sbrown oil was obtained.

1H NMR (CDC13) 8 6.8-7.4 13, aromatic), 4.1 2, -OCH 2 0.7-2.9 13, remaining aliphatic) Analysis: Calculated for C 2H 28

N

2 0C1 2 C, 70.14; H, 5.89; N, 5.84 Found C, 70.08; H, 5.88; N, 5.76 Example 128 1-[5-(4-Acetyl-2-methoxyphenoxy)pentyl]-a,a-diphenyl-3-piperidinepropanenitrile hydrate A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropaneo nitrile, 5.42 g (0.02 mole) of 1-[4-(5-chloropentoxy)-3-methoxyphenyl]- ,b ethanone, and potassium carbonate (5.53 g, 0.04 mole) was heated overnight S,,at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 g).

SThe reaction mixture was stripped to dryness, and the residue dissolved in chloroform. The chloroform layer was extracted with water and then dried with anhydrous sodium sulfate. The chloroform was removed by rotary evaporation following filtration. The oil obtained upon removal of chloroform t t twas subjected to column chromatography (flash chromatography) on silica gel with methanol-ethyl acetate (4:96 v/v) for elution. Similar fractions were t' combined and removal of solvent gave a clear brown oil. The oil was dried in vacuo overnight at 80°C. The oil was triturated with diethyl ether and dried in vacuo again, at 80°C overnight. A yield of 6.37 g of clear brown oil was obtained, 1H NMR (CDC13) 8 7.2-7.8 12, aromatic), 6.9 1, 0 aromatic), 4.1 2 CH20), 3.9 3, OCH3), 2.5 3, C-CH 3 1.2-2.4 19, aliphatic).

Analysis: Calculated for C 34

H

41

N

2 03.

5 C, 76.52; H, 7.74; N, 5.25 Found C, 76.37; H, 7.65; N, 5.19 Example 129 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis(4-fluorophenyl)-4piperidineacetonitrile maleate A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (6.45 g, 0.021 mole), 1[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.00 g, 0.021 -177- AHR-438A-CIP mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness and then partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give a dark brown oil. The oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80°C overnight. A yield of 6.80 g of white crystals, m.p. 158-160OC was obtained.

Analysis: Calculated for C 35

H

36

N

2 0 7

F

2 C, 66.24; H, 5.72; N, 4.14 Found C, EG.13; H, 5.69; N, 4.41 Example 130 1-[3-(2,6-Dichlorophenoxy)propyll-a,a-bis(4-fluorophenyl)-4-piperidine- Sacetonitrile oxalate A mixture of a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile (5.99 g, 0.0192 mole) and 1,3-dichloro-2-(3-chloropropoxy)benzene (4.76 g, 0.02 mole) was heated at reflux overnight in 350 ml of 1-butanol containing potassium carbonate, 5.53 g (0.04 mole), and potassium iodide, 0.2 g. The reaction S' mixture was stripped to dryness and the resulting residue was partitioned t several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give a light brown oil. The entire oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether, and dried in vacuo overnight at A yield of 4.55 g of white crystals, m.p. 162-163°C was S...obtained.

Analysis: Calculated for C 32

H

30

N

2 0 5

F

2

C

2 C, 60.83; H, 4.79; N, 4.14 Found 60.89; H, 4.82; N, 4.44 Example 131 1-[3-(2,6-Dichlorophenoxy)propyl]-a,a-diphenyl-3-piperidinepropanenitrile oxalate A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3-piperidinepropanenitrile and 1,3-dichloro-2-(3-chloropropoxy)benzene (4.76 g, 0.02 mole) in 350 ml of 1-butanol was heated overnight at reflux with potassium carbonate (5.54 g, 0.04 mole) and potassium iodide (0.2 The reaction mixture was i -178- AHR-438A-CIP *s Ir I rr S r St t *t t Iy It stripped to dryness, and the residue partitioned several times between water and chloroform. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give an oil. The entire oil was converted to the oxalate salt. The salt was recrystallized from methanol-diethyl ether, and was dried in vacuo overnight at 80 0 C. A yield of 7.23 g of white crystals, m.p. 159-161°C was obtained.

Analysis: Calculated for C 31

H

32

N

2 0 5 C1 2 C, 63.81; H, 5.53; N, 4.80 Found C, 64.02; H, 5.61; N, 4.86 Example 132 1-[4-(4-Acetyl-2-methoxyphenoxy)butyl]-a,a-bis(4-fluorophenyl)-4piperidineacetonitrile fumarate [1:11.

A mixture of 5.38 g (0.0172 mole) of a,a-bis(4-fluorophenyl)-4piperidineacetonitrile and 5.20 g (0.0172 mole) of 1-[4-(4-bromobutoxy)-3methoxyphenyllethanone was heated overnight at reflux in 350 ml of acetonitrile containing potassium carbonate (5.54 g, 0.04 mole) and potassium iodide, 0.2 g. The reaction mixture was stripped to dryness and the residue obtained was partitioned several times between chloroform and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give an oil. The oil was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether, and was dried in vacuo overnight at 80°C. A yield of 5.78 g of white crystals, m.p.

181.5-182 0 C was obtained.

Analysis: Calculated for C 36

H

38

N

2 0 7

F

2 C, 66.66; H, 5.90; N, 4.32 Found C, 66.56; H, 5.92; N, 4.28 Example 133 1-[2-(2,6-Dichlorophenoxy)ethyl]-a,a-diphenyl-3-piperidinepropanamide.

A mixture of 7.65 g (0.025 mole) of a,a-diphenyl-3-piperidinepropanenitrile, 2-(2-bromoethoxy)-1,3-dichlorobenzene (6.70 g, 0.025 mole), and potassium carbonate (5.54 g, 0.04 mole) was stirred overnight at reflux in 350 ml of acetonitrile containing potassium iodide, (0.2 The reaction mixture was stripped to dryness, and the residue was partitioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium t ee L. -179- AHR-438A-CIP sulfate), filtered, and solvent removed to give 12.91 g of brown oil. The entire oil was subjected to flash chromatography on silica gel using 75-25 v/v ethyl acetate-hexane and 100% ethyl acetate for elution. Similar fractions were combined and solvent was removed. The resulting oil was dried in vacuo overnight at 65°C. A yield of 6.98 g of clear oil was obtained.

1H NMR (CDC13): 6 6.9-7.5 13, aromatic), 6.0 (br 2, NH 2 4.0 2, 0-

CH

2 2.7 2, N-CH 2 1.0-2.3 11, aliphatics).

Analysis: Calculated for C 28

H

30

N

2 0 2 C1 2 C, 67.61; H, 6.08; N, 5.63 Found C, 67.52; H, 6.08; N, 5.63 Example 134 a-[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-a-(4fluc rophenyl)-2-pyridineacetonitrile fumarate SA mixture of a-(4-fluorophenyl)-a-(4-piperidinyl)-2-pyridineacetonitrile S(7.18 g, 0.024339 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.89 g, 0.024339 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight in 350 ml of 1-butanol containirg potassium iodide (0.15 g).

SThe reaction mixture was stripped to dryness, and the residue obtained was Spartitioned between chloroform and water. The chloroform layer was i extracted in 1N sulfuric acid, 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered, and the solvent removed to give an oil. The oil was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C to give 9.43 g of white crystals, m.p. 166-167 0

C.

NMR indicated 0.25 H 2 0 was present.

Analysis: Calculated for C 34

H

36

N

3 0 7 F C, 66.11; H, 5.87; N, 6.80 Found C, 65.57; H, 5.89; N, 6.70 Example 135 a-[l-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]-a-(4fluorophenyl)-2-pyridineacetonitrile fumarate hydrate A portion of the compound prepared in Example 111 was exposed to the air for 3 days, m.p. 166-167°C.

Anaysis: Calculated for C 34

H

3 8

N

3 0 8 F C, 64.24; H, 6.02; N, 6.61 Found C, 64.07; H, 5.82; N, 6.58 1i -180- AHR-438A-CIP ta a a a t aE t I t t t t tf ft 1 it Example 136 a,a-Diphenyl-l-[3-(8-quinolinyloxy)propyll-3-piperidinepropanenitrile hydrate A mixture of a,a-diphenyl-3-piperidinepropanenitrile (8.12 g, 0.028 mole), 8-(3-chloropropoxy)quinoline (6.18 g, 0.028 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated at reflux overnight in 350 ml of 1butanol containing potassium iodide (0.3 The reaction mixture was filtered and stripped to dryness on a rotary evaporator. The residue obtained was dissolved in chloroform and extracted with 5% sodium hydroxide and water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark red mass. This material was subjected to flash chromatography on a silica gel column using methanol-ethyl acetate, 20% methanol-ethyl acetate, and 50% methanolethyl acetate for elution. Fractions of similar purity were combined, and solvent was removed by rotary evaporator. The red black residue obtained was dried in vacuo at 80°C overnight. This furnished 5.29 g of a dark black residue.

'H NMR (CDC13): 68 8.9 1, proton ortho to N in ring), 7.9-8.1 1, proton para to N in ring), 6.9-7.6 14, aromatics), 4.2 2, methylenes adjacent to oxygen atom), 1.1-2.7 16, aliphatic portions and 1H from 0.5 H 2 0).

Analysis: Calculated for C 32

H

33

N

3 0 1 5 C, 79.31; H, 7.07; N, 8.67 Found C, 79.47; H, 7.19; N, 8.69 Example 137 8-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy1quinoline hydrate [1:0.51.

A mixture of 4-[a-(p-fluorophenyl)-p-fluorobenzyl]-piperidine (8.03 g, 0.28 mole), 8-(3-chloropropoxy) quinoline (6.18 g, 0.28 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was filtered through activated charcoal, and solvent was removed by rotary evaporator. The dark red residue was dissolved in chloroform and then extracted with 5% sodium hydroxide and water. The chloroform layer was dried over anhydrous sodium, filtered, and solvent removed to provide a dark red mass. This material was subjected to flash chromatography on silica gel

II

i i,

L!.

I

t t ii -181- AHR-438A-CIEP O 0 It 0 i 04 it't it 0

(I

0f 00 0 0t 0 LI i 044 0400 0 1 using 10, 20 and 50% methanol in ethyl acetate for elution. Fractions with similar purity were combined and solvent removed to give dark black mass wich was dried at 80°C in vacuo overnight. This furnished 3.74 g of a dark red mass.

'H NMR (CDC13): 8 8.9 1, proton ortho to N in ring), 7.9-8.1 1, proton para to N in ring), 6.8-7.4 12, aromatics), 4.2 2, CH 2 attached to 1, methine attached to to aromatic rings), 1.0-3.2 14, aliphatic protons and 1H for 0.5 H 2 0).

Analysis: Calculated for C 30

H

32

N

2 0 1 5F 2 C, 75.53; H, 6.44; N, 5.87 Found C, 75.66; H, 6.56; N, 5.86 Example 138 2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinyl]propoxy]benzoic acid hydrate A solution of 2-[3-[4-[bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]benzoic acid ethyl ester (25.3 g, 0.051 mole) in 400 ml of 200 ethanol containing potassium hydroxide (16.8 g, 0.30 mole) was heated at reflux for 4 hours. The reaction mixture was concentrated to a volume of approximately 200 ml. The reaction mixture was made acidic with 1N sulfuric acid. The acidic layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give a gummy residue. The material was subjected to flash chromatography using methanol-80% ethyl acetate and 50% methanol-50% ethyl acetate for elution. Fractions of similar purity were combined. Solvent was removed in vacuo, and the residue was dried in vacuo overnight at 80°C to give 5.72 g of material.

1H NMR (CDC13): 8 9.2 (br 2, COOH and 0.5 H 2 7.8 1, H next to COOH), 6.7-7.3 11, aromatic), 4.1 2, CH 2 next to 1.5-3.66 14, aliphatics).

Analysis: Calculated for C 28

H

30 NO3.

5

F

2 C, 70.87; H, 6.37; N, 2.95 Found C, 71.42; H, 6.31; N, 3.01 4t''f^ ii ;i i.

ii i; it I

I

r i s -i a -182- AHR-438A-CIEP 44 44 *o 4 44e 0 o i

O

I

tar r e Example 139 4-[Bis(4-fluorophenyl)methyl]-N-phenyl-1-piperidinepropanaminemaleate A solution of 4-[bis(4-fluorophenyl)methyl]- -(3-chloropropyl)piperidine (35.27 g, 0.097 mole) in 200 ml of aniline (204.4, 2.2 mole) was stirred overnight at 100 0 C. The solution was cooled at room temperature and then extracted several times with IN sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide and then dried over anhydrous sodium sulfate. The solution was filtered, and then solvent removed in vacuo to give a dark brown oil. The oil was converted to the maleate salt which was recrystallized from methanol-diethyl ether. The solid obtained was dried in vacuo overnight at 80°C to give 29.84 g of light brown solid, m.p. 153- 154 0

C.

Analysis: Calculated for C 27

H

30

N

2 0F 2 C, 64.41; H, 5.87; N, 4.29 Found C, 64.36; H, 5.87; N, 4.39 Example 140 N-[3-[4-[Bis(4-fluorophenyl)methvl]-1-piperidinyl]propyl]-Nmethylbenzeneamine.

A solution of 4-[bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine (8.43 g, 0.023 mole) in 100 ml of N-methylaniline was stirred 30 hours at 100°C. The reaction mixture was cooled to room temperature and diluted with 300 ml of chloroform. The chloroform layer was extracted with three 100 ml portions of 1N sulfuric acid (each neutral to litmus paper). The fourth 100 ml portion of 1N sulfuric acid used for extraction was strongly acidic to litmus paper. This fourth fraction was made alkaline with ice and sodium hydroxide and then extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and dried over anhydrous sodium sulfate. Chloroform was removed by rotary evaporation to give a reddish brown oil. This oil was subjected to flash chromatography on silica gel using ethyl acetate for elution. Fractions of similar purity were combined and solvent removed. The residue was obtained and dried in vacuo overnight at 80°C to give 4.41 g of brown oil.

r; L _4 -183- AHR-438A-CIP 1H NMR (CDC13): 8 6.6-7.2 13, aromatic), 3.5 1, methine attached to aromatic nuclei), 3.3 2, methylene attached to aromatic 2.9 3, N-.

CH

3 1.1-2.7 13, aliphatics).

Analysis: Calculated for C 28

H

32

N

2

F

2 C, 77.39; H, 7.42; N, 6.45 Found C, 77.44; H, 7.44; N, 6.42 Example 141 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis(4-fluorophenyl)-3piperidineacetonitrile oxalate hydrate A mixture of a,a-bis(4-fluorophenyl)piperidineacetonitrile (6.55 g, 0.02 omole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.08 g, 0.04 mole) o twas heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness and the residue obtained was dissolved in chloroform. The chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was Sdried over anhydrous sodium sulfate, filtered, and solvent removed to give a dark brown oil. This oil was converted to the oxalate salt which was recrystallized twice from methanol-diethyl ether. The salt was dried in vacuo 0o0 overnight at 80°C to give 2.28 g of white crystalline solid, m.p. 108- S109 0

C.

Analysis: Calculated for C 33

H

36

N

2 0 8

F

2 C, 63.25; H, 5.79; N, 4.47 Found C, 63.08; H, 5.48; N, 4.39 Example 142 1-[3-(4-Cyanophenoxy)propyl-a,a-bis(4-fluorophenyl)-3-piperidineacetonitrile.

A mixture of 4-(3-chloropropoxy)benzonitrile (6.39 g, 0.0327 mole), a,abis(4-fluorophenyl)piperidineacetonitrile (10.22 g, 0.0327 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloro- Sform and water. The chloroform layer was back extracted with water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give an oil. The oil was flash chromatographed on 300 g of silica gel using 50% hexane-50% ethyl acetate and 75% ethyl -184- AHR-438A-CIP hexane for elution. Fractions of similar purity were combined and the resulting oil was dried in vacuo overnight at 80°C. The material crystallized while A drying overnight. The solid obtained was recrystallized from equal volumes of isopropanol and low boiling petroleum ether. The solid obtained was dried in vacuo overnight at 80°C to give 5.84 g of white crystalline product, m.p. 132-133°C.

Analysis: Calculated for C 29

H

27

N

3 0F 2 C, 73.87; H, 5.77; N, 8.91 Found C, 73.56; H, 5.75; N, 8.85 Example 143 S .4-[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperid vylpropoxy]-3o methoxybenzonitrile.

So The sodium salt of 4-hydroxy-3-methoxybenzonitrile was prepared by reacting sodium hydride 0.8 g, 0.02 mole), 4-hydroxy-3-methoxybenzonitrile (3.00 g, 0.02 mole), and 250 ml of dry dimethylsulfoxide. Initially, the 1' solution had a cloudy white color, but shortly (about 10 minuts) after stirring, the solution had a clear brown color. The reaction mixture was S' r, stirred for 30 minutes at room temperature. A dimethylsulfoxide solution of 4-[bis(4-fluorophenyl)methyl]l-1(3-chloropropyl)piperidine (7.26 g, 0.02 mole) was added, and the resulting solution was stirred overnight at 50 0

C.

The dimethylsulfoxide was removed in vacuo, and the residue obtained was dissolved in chloroform. The organic layer was extracted with 5% sodium hydroxide and also water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil. The oil was flash chromatographed on silica gel using ethyl acetate and 2% methanolethyl acetate for elution. Fractions of similar purity were combined and solvent removed in vacuo. The residue was dried in vacuo overnight at to give 4.40 g of brown oil.

1H NMR(CDC13): 8 6.8-7.3 11, aromatics), 4.1 2, -CH 2 0 Smethylenes), 3.8 3, -OCH 3 3.4-3.6 1, methine attached to carbon containing two fluorophenyl groups), 1.2-3.0 13, aliphatics). NMR also indicated 0.25 H20 and a trace of ethyl acetate.

Analysis: Calculated for C 2 9H 30

N

2 0 2

F

2 C, 73.09; H, 6.34; N, 5.88 Found C, 72.38; H, 6.34; N, 5.78 I

IL..

-185- AHR-438A-CIP Example 144 9 4-[Bis(4-fluorophenyl)methyl]-l-[3-(l-naphthalenyloxy)propyl]piperidine hydrobromide hydrate The sodium salt of a-naphthol was formed in 300 ml of dimethyl sulfoxide from a-naphthol (2.59 g, 0.018 mole) and sodium hydride 0.72 g, 0.018 mole). The sodium salt was stirred 2-1/2 hours at room temperature. 4- [bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine (6.52 g, 0.018 mole of free base) in 100 ml of dimethyl sulfoxide was added, and the resulting solution was stirred overnight at 65°C. The solvent was removed in vacuo, and the residue obtained was partitioned between chloroform-water, chloroform-lN sulfuric acid, and chloroform-5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and solvent removed to give a green oil. The oil was converted to the hydrobromide salt which was Srecrystallized from methanol-diethyl ether. The white salt obtained was dried in vacuo at 80°C overnight. The crystalline solid was left exposed to the air overnight to give 1.88 g of white crystalline solid, m.p. 220-223°C.

Analysis: Calculated for C 31

H

33

NO

1 5 F2Br: C, 66.31; H, 5.92; N, 2.49 SFound 66.46; H, 5.84; N, 2.49 Example 145 2-[3-[4-[Bis(4-fluorophenyl)methyl]-1-piperidinvl]propoxy]quinoline hydrate [1:0.51.

The sodium salt of 4-[bis(4-fluorophenyl)methyl-l-piperidinepropanol was formed in 300 ml of dimethyl sulfoxide from its free base (6.90 g, 0.02 mole) and sodium hydride 0.8 g, 0.02 mole). 2-Chloroquinoline (3.26 g, 0.02 mole) was added and the reaction mixture was heated at 60°C for approximately 72 hr. The reaction mixture was stripped to dryness, and the residue obtained was dissolved in chloroform. This chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give an oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate for 1 elution. Fractions of similar purity were combined and solvent removed. The residue was dried in vacuo overnight at 80oC to give 5.16 g of clear brown oil.

-186- AHR-438A-CIP 9I *9 *O 9 9 9, *9 it 1 H NMR (CDC13): 8 6.8-7.9 14, aromatics), 4.5 2, -OCH 2 3.4 and 3.6 1, methine attached to two aromatic rings), 1.2-3.1 13, aliphatics remaining).

Analysis: Calculated for C 30

H

3 1

N

2 07.

5

F

2 C, 74.82; H, 6.49; N, 5.82 Found C, 74.56; H, 6.36; N, 5.69 Example 146 4-[Bis(4-fluorophenyl)methyl-l--[3-(2-naphthalenyloxy)propyl]piperidine hydrate The sodium salt of 2-naphthol was prepared in 300 ml of dimethyl sulfoxide from 2-naphthol (3.00 g, 0.0208 mole) and sodium hydride 0.83 g, 0.0208 mole). The solution was stirred 1 hr at room temperature and had a clear brown color. Then, 4-[bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine (free base 7.55 g, 0.0208 mole) in 100 ml of dimethylsulfoxide was added. The resulting solution was stirred overnight at The solvent was removed in vacuo, and the residue obtained was partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. An oxalate salt could not be obtained in pure form so the oil (free base) was subjected to flash chromatography on silica gel using 50-50 ethylacetate-hexanes and 75-25 ethylacetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil. The oil was dried in vacuo at 80 6 C overnight to give 2.97 g (32.3% yield) of a dark brown glass after being dried overnight at room temperature.

1 H NMR (CDC13): 8 6.8-7.8 15, aromatics), 4-4.3 2, -OCH 2 3.4-3.6 1, methine attached to two fluorophenyl groups), 1.1-3.0 13, aliphatics).

Analysis: Calculated for C30H 3 1NO1.

5 F2: C, 77.48; H, 6.71; N, 2.91 Found C, 77.86; H, 6.65; N, 2.94 Example 147 3-[3-[3-[Bis(4-fluorophenyl)methyll-1-piperidinyl]propoxy]benzonitrile hydrate [1:0.51.

A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine, the free base of Parparation 10 (7.85 g, 0.027 mole), 3-(3-chloropropoxy)-l-benzonitrile I t, r 1 1 i?( -187- AHR-438A-CIP (5.33 g, 0 027 mole), and potassium carbonate (5.84 g, 0.027 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0,2 g).

The reaction mixture was filtered and stripped to dryneF. The residue obtained was dissolved in chloroform and extracted with water and sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a brown oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate-hexanes for elution.

Fractions of similar purity were combined and solvent removed. The dark brown oil obtained was dried in vacuo overnight at 80°C to give 5.65 g (45.9% yield) of dark brown oil.

H' NMR (CDC13): 8 6.7-7.3 12, aromatics), 3.8-4.1 2, methylenes adjacent to oxygen atom), 3.4-3.6 1, methine attached to two phenyl rings), 1.1-3.0 13, remaining aliphatic protons).

Analysis: Calculated for C 28

H

29

N

2 0 1 .5F 2 C, 73.83; H, 6.42; N, 6.15 Found C, 74.05; H, 6.27; N, 6.09 Example 148 a.a-Bis(4-fluorophenyl)- 1-[3-(4-methoxyphenoxy)propyl]-4-piperidinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,abis(p-fluorophenyl)-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4methoxyphenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 2.3 g (49% yield) of title compound as a white solid, mp 107-108°C.

Analysis: Calculated for C 28

H

3 1

F

2 N0 3 C, 71.93; H, 6.68; N, 3.00 Found C, 71.90; H, 6.70; N, 2.99 Example 149 a,a-Bis(4-fluorophenyl)-1-[3-(4-methylphenoxy)propyll-4-piperidinemethanol fumarate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,abis(p-fluorophenyl)-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(4methylphenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate -188- AHR-438A-CIP and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue, p> The gum was purified by column chromatography on 100 g of Florisil®.

a Fractions eluted with 10% acetone in benzene were combined and concentrated to give a gum. This gum was converted to the fumaric acid salt, and the solid was recrystallized from absolute ethanol to yield 3.2 g of title compound as a white solid, mp 193-194°C with decomposition.

Analysis: Calculated for C 32

H

35

F

2 N0 6 C, 67.71; H, 6.22; N, 2.47 Found C, 67.93; H, 6.25; N, 2.53 3 Example 150 1-[3-(4-Fluorophenoxy)propyl]-a,a-bis(4-fluorophenyl)-4-piperidinemethanol fumarate hydrate [11:11].

,t This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) ofa,abis(p-fluorophenyl)-4-piperidinemethanol, 1.9 g (0.01 mole) of 1-chloro-3-(4fluorophenoxy)propane, 5.3 g (0.035 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a solid as residue.

The solid was further purified by column chromatography on 60 g of Florisil®.

Fractions eluted with 2-10% acetone in benzene were combined and concentrated to give a solid residue. The solid was converted to the furmaric acid salt and this solid was recrystallized from isopropanol to yield 2.2 g of title compound as a white solid, mp 155-157°C.

Analysis: Calculated for C 3 1

H

34

F

3

NO

7 C, 63.14; H, 5.81; N, 2.38 Found C, 62.99; H, 5.64; N, 2.28 Example 151 1-4-[3-[4-[(4-Fluorophenyl)(2-pyridinvl)methyl]-1-piperidinyllpropoxyl-3-methoxyphenyl]ethanone.

A mixture of 2-[(4-fluorophenyl)(4-piperidinyl)methyl]pyridine (6.28, 0.0232 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.62 g, 0.0232 mole), and potassium carbonate (5.53 g, 0.04 mole) was heating overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

The reaction mixture was stripped to dryness and the residue obtained was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, r:w -189- AHR-438A-CIP *1 0 0s 4 4 00 4 9 44 4 Vt I '4~ I V V 4 4 4444 4444 filtered, and solvent removed to give a borwn oil. This oil was subjected to flash chromatography on silica gel using 10% methanol-ethylacetate, methanol-ethylacetate, and 30% methanol-ethylacetate for elution.

Fractions of similar purity were combined and solvent removed to give a brown oil. This material was dried in vacuo overnight at 80°C to give 6.89 g (62.3% yield) of dark brown oil.

H

1 NMR (CDC13): 8 6.8-7.8 15, aromatics), 4-4.3 2, -OCH 2 3.9 (s, 3, -OCH 3 3.6-3.8 1, C-H attached to pyridine ring), 2.6 3, C-CH 3 1.2- 3.6 9, remaining aliphaties).

Analysis: Calculated for C 29

H

33

N

2 0 3 F: C, 73.09; H, 6.98; N, 5.88 Found C, 72.51; H, 7.10; N, 5.81 Example 152 [4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]phenyl]carbamic acid ethyl ester oxalate hydrate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(4fluorophenyl)-4-piperidinemethanol, 2.6 (0.01 mole) of N-[4-(3-chloropropoxy)phenyl]carbamic acid ethyl ester, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dimethylformamide heated in a steambath for 24 hr gave a gum as residue. The gum was converted to the oxalic acid salt in ethyl acetate and the solid was recrystallized from 2-propanol to yield 32 g of title compound as a white solid, mp 0

C.

Analysis: Calculated for C 32

H

4 1

F

2

N

2 09.

5 C, 59.90; H, 6.13; N, 4.37 Found C, 59.69; H, 5.80; N, 4.21 Example 153 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis(4-fluorophenyl-3pyrrolidinepropanenitrile.

A mixture of a,a,-bis (4-fluorophenyl)-3-pyrrolidinepropanenitrile (5.00 g, 0.016 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.88 g, 0.016 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

The reaction mixture was cooled to room temperature and filtered. The L 1 i i i -190- AHR-438A-CIP i So o o 0 0 0 00g 0 r~ 0 0* 0 6040 0 0 0 00 00 4 00 4 00 0000 0 40 00 0 0 00 i04 0" 0 04 butanol was removed by rotary evaporator to produce a dark brown oil. This oil was dissolved in chloroform, and the organic phase was extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to provide a dark brown oil. The entire oil was subjected to flash chromatography on silica gel using ethyl acetate, methanol-biiyl acetate, and 10% methanol-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed in vacuo. A dark brown oil was obtained and dried in vacuo overnight at 80°C to give 4.33 g (52.2% yield) of a glassy brown residue.

H

1 NMR (CDC13): 8 6.8-7.7 11, aromatics), 4.0-4.25 2, -CH 2 3.9 3, -OCH 3 1.5-2.7 16, aliphatics).

Analysis: Calculated for C 31

H

32 NZQ3F 2 C, 71.80; H, 6.22; N, 5.40 Found C, 71.66; H, 6.29; N, 5.53 Example 154 2-[3-[4-[Bis(4-fluorophenyl)methylne]- 1-piperidinyl]propoxy]phenol.

A mixture of 6.0 g (0.02 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 5.5 g (0.02 mole) of 3-(2-benzyloxyphenoxy)propyl chloride, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol was heated at reflux for 24 hr. The mixture was concentrated, and the residue was partitioned between benzene and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was converted to a crystalline hydrochloride. The salt changed to an oil upon standing overnight. The oil was partitioned between methylene chloride and a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated to give a gum as residue.

The gum was dissolved in 500 ml of absolute ethanol and hydrogenated in a Parr apparatus over 5% palladium on carbon catalyst at 70°C overnight.

The mixture was filtered through Celite®, and the filtrate was concentrated to give a gummy solid as residue. The solid was triturated with ethyl ether, and the mixture was filtered. The filtrate was slowly evaporated, and a solid precipitated. The solid was collected by filtration and recrystallized from 4* .640 4 0

-A

I

-191- -9 1-AHR-438A-CI[P

Y

04 #4 04 0 0 0 4 0 90 0 04 0 9I~ 09 9 O 0~ Go o 40 0 0 00 0 00 0000 0 00 00 0 6 00 0 0 0 0 00 00 0 0 00 O 00 ~000

S

0460 GO isopropyl ether to yield 1.6 g (18% yield) of title compound as a white solid, mp 125-127'C.

Analysis: Calculated for C 2 7

H

2 7

F

2 N0 2 C, 74.46; H, 6.25; N, 3.22 Found C, 74.47; H, 6.29; N, 3.12 Example 155 1-13-(4-Ethyl-2-methoxyphenoxy)propyll-cL,a-bis (4-fluorophenyl)-4piperi dinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of Q,QLbis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 3-(4-ethyl-2methoxyphenoxy) propyl chloride, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave 3.7 g of title compound as a white solAid, mp 118-120'C.

Analysis: Calculated for C 3 0

H

3 5

F

2 N0 3 C, 72.70; H, 7.12; N, 2.83 Found 72.72; H, 7.43; N, 2.81 Example 156 1-(3-Phenoxypropyl)-cL-diphenyl-4-pi peridinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.0 g (0.015 mole) of ci,cidiphenyl-4-piperidinemethanol, 3.2 g (0.0 15 mole) of 1-bromo-3-phenoxypropane, 5.3 gr (0.05 mole) of anhydrous sodium carbonate and 0.4 gof potassium iodide in 100 ml of 1-butanol gave 3.2 g of title compound as a white solid, mp 87-88'C.

Analysis: Calculated for C 27

H

3 1N0 2 C, 8 0.7 6; H, 7.7 8; N, 3.4 9 Found C, 80.82; H, 7.79; N, 3.52 Example 157 ,c-Bis(4-fluorophenyl)- 1-[3-[4-(methylsulflnyl)phenoxypropyll-4piperidinemethanol oxalate hydrate compound with 2-propanol [1:0.51.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of Ql,Qbis(p-fluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-(3- -192- AHR-438A-CIP chloropropyl)-4-methylsulfinyl)benzene, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 120 g ofFlorisil.® Fractions eluted with 15-25% acetone in benzene were combined and concentrated to give the purified base as an oil. The oil was converted to the oxalic acid salt, and the solid was recrystallized from 2-propanol to yield 2.6 g (40% yield) of title compound as a white solid, mp 75-105 0

C.

Analysis: Calc'd for C 30

H

36

F

2 NOs, 5 S.0.5(C 3

H

8 C, 58.50; H, 6.23; N, 2.17 Found C, 58.32; H, 5.99; N, 2.05 Example 158 a.a-Bis(4-fluorophenyl)-1-[3-[4-(1-methylethyl)phenoxy]propyl]-4piperidinemethanol oxalate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) of a,abis(p-fluorophenyl)-4-piperidinemethanol, 3.2 (0.015 mole) of 1-chloro-3-(4isopropylphenoxy) propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a solid as residue.

S'The solid was converted to the oxalic acid salt, and this solid was recrystallized from ethyl acetate to yield 4.6 g (54% yield) of title compound as a white solid, mp 105-109 0 C with decomposition.

rI Analysis: Calculated for C32H37F2NO6: C, 67.47; H, 6.55; N, 2.46 Found C, 66.92; H, 6.61; N. 2.52 Example 159 3-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]- -piperidinyl]propoxy]benzoic acid ethyl ester fumarate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) ofa,abis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of dimethylformnamide gave a gum as residue. The gum was converted to the fumaric -193- AHR-438A-CIP acid salt, and the solid was recrystallized from acetonitrile to yield 4.2 g of title compound as a fluffy, white solid, mp 123-131 0

C.

Analysis: Calculated for C 34

H

37

F

2 N0 8 C, 65.27; H, 5.96; N, 2.24 Found C, 65.09; H, 5.95; N, 2.25 Example 160 1-[ 4 -[3-[4-[Bis(4-methylphenyl)methylene]- -piperidinyl]propoxy]-3methoxyphenyl]ethanone.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) of a,a-bis(4methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyllethanone, 5.3 g (0.05 mole) of anhydrous sodium 'carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a brown gum as residue. The gum was dissolved in ethyl ether and filtered to remove insolubles. The filtrate was treated with ethereal hydrogen chloride and a solid gradually crystallized. Attempted recrystallization of the solid from isopropanol failed, the solid was partitioned between methylene chloride and

S

t a sodium bicarbonate solution. The organic layer was dried over sodium 'sulfate and concentrated under reduced pressure to give a brown gum. The gum was converted to the f aric acid salt. The solid was recrystallized twice from 2-propanol but a satisfactory combustion analysis could not be obtained. This salt was partitioned between methylene chloride and a sodium bicarbonate solution as above to give a gum as residue. The gum crystallized after standing for several days. The solid was triturated with ,ti petroleum ether, collected by filtration, and recrystallized from 2-propanol to yield 2.2 g of title compound as an off-white solid, mp 92-95°C with decompositon.

Analysis: Calculated for C 32

H

37 N0 3 C, 79.47; H, 7.71; N, 2.90 Found C, 79.18; H, 7.88; N, 2.88 Example 161 1-[4-[3-[4-[Bis(4-methylphenyl)hydroxymethyl]-1-piperidinyl]propoxy]- 3-methoxyphenyl]ethanone oxalate hydrate [1:1:11.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.6 g (0.015 mole) ofa,a- -194- AHR-438A-CIP o 0 0 0 a 0a 0 0 a Q 00 0 0a 0 0 0 S0 0 t* 0 0s bis(4-methylphenyl)-4-piperidinemethanol, 3.6 g (0.015 mole) of chloropropoxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of anhydrods sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a brown gum as residue. The gum was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 5.3 g of title compound as an off-white solid, mp 92-95 0 C with decomposition.

Analysis: Calculated for C 34

H

4 3 N0 9 C, 66.97; H, 7.11; N, 2.30 Found C, 66.61; H, 6.79; N, 2.29 Example 162 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]benzoic acid methyl ester fumarate A mixture of 9.1 g (0.03 mole) of a,a-bis(p-fluorophenyl)-4-piperidinemethanol, 6.7 g (0.03 mole) of 4-(3-chloropropoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.6 g of potasium iodide in 125 ml of dimethylformamide was heated in a steambath for 25 hr. The reaction mixture was poured into 1.5 liters of ice-water. The resulting solid was collected by filtration, washed with water and dried. The solid was converted to the fumaric acid salt to yield 12.5 g of title compound as a white solid, mp 140-174°C with decomposition.

Analysis: Calculated for C 33

H

35

F

2 NO8: C, 64.80; H, 5.77; N, 2.29 Found C, 64.67; H, 5.80; N, 2.34 Example 163 1-[3-(4-Aminophenoxy)propyl]-a.a-bis(4-fluorophenvl)-4-piperidinemethanol oxalate A solution of 2.6 g (0,0054 mole) of a,a-bis(4-fluorophenyl)-1-[3-(4nitrophenoxy)propyl]-4-piperidinemethanol in 50 ml of tetraydrofuran was hydrogenated at ambient temperature over 5% palladium on carbon catalyst at 40 psi. The mixture was filtered, and the filtrate was concentrated to give a gum as residue. The gum was converted to the dioxalate salt, and the solid was recrystallized from 95% ethanol to yield 2.1 g of title compound as an off-white solid, mp 136-139 0 C with decompositon.

Analysis: Calculated for C 31

H

34

F

2 N20 1 0: C, 58.86; H, 5.42; N, 4.43 Found C, 58.73; H, 5.48; N, 4.43 L 2 1 -195- AHR-438A-CIP Example 164 4-[3-4-[Bis(4-fluorophenyl)methyiperidinyl]propoxy2 methoxyphenyllethanone oxalate 4r t 4 4 ft 4 (4 It A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (5.74 g, 0.02 mole), 1-[ 4 3 -chloropropoxy)-2-methoxyphenyl]ethanone (4.85 g, 0.02 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated at reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness, and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted with water, dried over sodium sulfate, filtered, and solvent removed to give a brown oil. The oil was converted to the oxalate salt. The oxalate salt was recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C to give 7.04 g (60.3% yield) of white crystalline product, mp 190.5-191°C.

Analysis: Calculated for C 32

H

35 N0 7

F

2 C, 65.86; H, 6.05; N, 2.40 Found C, 65.73; H, 6.05; N, 2.45 Example 165 4-[Bis(4-fluorophenyl)methyl]-l-[3-(4-ethyl-2-methoxyphenoxv)-

I

fT propyl]piperidine oxalate A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (5.74 g, 0.024 mole), l-[ 4 3 -chloropropoxy)-2-methoxyphenyl]ethanone (5.57 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was back extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give an oil. The oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried overnight in vacuo at 80°C to give 10.04 g (73.4% yield) of white crystalline product, mp 185-186°C.

Analysis: Calculated for C3 2

H

37

NO

6

F

2 C, 67,47; H, 6.55; N, 2.46 Found C, 67.41; H, 6.53; N, 2.50 -196- -96-AHR-438A-CIP Example 166 1-13-(Ij,1'-Biphenyl-4-yloxy)propyl]-a,a-bis(4-fluorophenyl)-4- PiPeridinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(pfluorophenyl)-4-piperidinemethanol, 2.5 g (0.01 mole) of 4-(3-czhloropropoxy)- 1,1'-biphenyl, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.5 g of title compound as a white solid, mp 108-109'C.

01 Analysis: Calculated for C 3 3

H

33

F

2 N0 2 C, 77.17; H, 6.48; N, 2.73 Found 7 6.8 0; H, 6.8 3; N, 2.7 2 4* Example 167 N -[4-[3-4-[Bis(4-fluorop~hen yl)h ydroxymethyll]-1- piperidinylpooxyl- Phenyll-N'-niethylurea.

To a solution of 4.5 g (0.01 mole) of 1-13-(4-aminophenoxy)propyl-o.,abis(4-fluorophenyl)-4-piperidinemethanol in 50 ml of benzene was added dropwise a solution of 0.6 g (0.01 mole) of methylisocyanate in 10 ml of benzene. The mixture was stirred for 1 hr during which time a solid precipitated. The mixture was diluted with 25 ml of cyclohexane, the solid was collected by filtration and recrystallized from 2-propanol to yield 1.6 g (31%) of title compound as a white solid, mp 177-178'C.

Analysis: Calculated for C 2 9

H

3 3

F

2

-N

3 0 3 C, 6 8.3 5; H, 6.5 3; IN, 8.2 j Found 68.69; H, 6.65; N, 8.29 14 Example 168 N-14-13-[4-Bis(4-fluorophenl)hydroxyrethyll-piperidinyllpropoxylphenyllmethanesulfonamide fumnarate 111:0.51 compound with 2-methoxyethanol 111:11.

It To a solution of 4.5 g (0.01 mole) of the base of 1-[3-(4-aminophenoxy)propylj-a,ci-bis(4-fluorophenyl)-4-piperidinemethanoI and 1.5 g (0.015 mole) of triethylamine in 50 ml of benzene and 100 ml of ethyl acetate was added dropwise a solution of 1.2 g (0.01 mole) of methanesulfonyl chloride in 10 ml of benzene. A gum immediately precipitated. The mixture was stirred at ambient temperature for 2 hr and then treated with a saturated sodium L -I -197- AHR-438A-CIP bicarbonate solution. The mixture was stirred for 0.5 hr during which time all solids dissolved. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from 2-methoxyethanol to yield 4.0 g of title compound as a tan solid, mp 153-156 0 C with decomposition.

Analysis: Calc'd for C 30

H

34

F

2

N

2 0 6

S.C

3

H

8 0 2 C, 59.62; H, 6.37; N, 4.21 Found C, 59.84; H, 6.59; N, 4.17 i o Example 169 1-[4-[3-[4.-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]phenyl]-l-propanone compound with 2-propanol o This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,a-bis(pfluorophenyl)-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-[4-(3-chloropropoxy)phenyl]-l-propanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.7 g 6(76%) of title compound as a white solid, mp 57-62 0

C.

Analysis: Calculated for C 3 0

H

33

F

2 NOs 3

C

3

H

8 0: C, 71.59; H, 7.46; N, 2.53 Found C, 71.42; H, 7.29; N, 2.63 Example 170 1-[4-[3-[4-[Bis(4-methoxvphenyl)hydroxyrnethyll-1-piperidinvl]- Oo, propoxyl-3-methoxyphenyllethanone oxalate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.2 g (0.01 mole) of a,a-bis(4methoxyphenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 100 g of Florisil®. Fractions eluted with 5-40% acetone in benzene were combined and concentrated under reduced pressure to give a brown glass as residue.

The glass was converted to the oxalic acid salt. The solid was recrystallized -198- AHR-438A-CIP 11 a a Ao A

A

AO 'r A Aa 1 from absolute ethanol to yield 3.3 g of the title compound as a white solid, mp 139-142°C with decomposition.

Analysis: Calculated for C 34

H

4 1NO0o: C, 65.48; H, 6.63; N, 2.25 Found C, 65.38; H, 6.70; N, 2.38 Example 171 1-[4-[6-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]hexyloxy]- 3-methoxyphenyllethanone hydrochloride This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,abis(p-fluorophenyl)-4-piperidinemethanol, 2.8 g (0.01 mole) of chlorohexyloxy)-3-methoxyphenyl]ethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 80 g of Florisil®. Fractions eluted with 2-5% acetone in benzene were combined and concentrated to give a glass as residue. The glass was dissolved in anhydrous ethyl ether, filtered, and the filtrate treated with ethereal hydrogen chloride.

A gummy solid precipitated. This solid was triturated with fresh ethyl ether until a fine, white solid resulted. The solid was collected by filtration and dried to yield 1.0 g of title compound as a white solid, mp 182-186°C with decomposition.

Analysis: Calculated for C 33

H

40 C1F2N04: C, 67.37; H, 6.86; N, 2.38 Found C, 67.17; H, 6.94; N, 2.37 Example 172 a.a-Bis(4-fluorophenvl)-l-[3-[4-(1-hvdroxvethyl)-2-methoxyphenoxy]-4piperidinemethanol oxalate hydrate To a stirred slurry of 0.6 g (0.015 mole) of lithium aluminum hydride in ml of dry tetrahydrofuran was added a solution of 5.6 g (0.015 mole) of 1- [4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3methoxyphenyl]ethanone in 100 ml of dry tetrahydrofuran. The mixture was stirred at ambient temperature for 2 hr and then cautiously treated successively with 1 ml of water, 1 ml of a 20% sodium hydroxide solution and 3 ml of water. The mixture was stirred for 0.5 hr, filtered and the filtrate concentrated to give a gummy solid as residue. The gum was converted to the oxalic

I.

L -199- AHR-438A-CIP 'a 1 0 04 II I .I I acid salt. The gum was recrystallized from 2-propanol and then from absolute ethanol-ethyl ether to yield 3.5 g of title compound as a white solid, mp 81-87°C with decomposition.

Analysis: Calculated for C 32

H

4 0

F

2 N09.

5 C, 61.14; H, 6.41; N, 2.23 Found C, 61.13; H, 5.97; N, 2.17 Example 173 4-[4-[4-[Bis(4-fluorophenyl)hydroxymethyll-1-piperidinyl]butoxy]benzoic acid methyl ester fumarate [1:11].

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 9.1 g (0.03 mole) of a,a-bis(pfluorophenyl)-4-piperidinemethanol, 7.3 g (0.03 mole) of 4-(4-chlorobutoxy)benzoic acid methyl ester, 10.6 g (0.1 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 125 ml of dimethylformamide gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile-dimethylformamide to yield 12.2 g of title compound as a white solid, mp 186-188 0

C.

Analysis: Calculated for C 34

H

37

F

2

NO

8 C, 65.27; H, 5.96; N, 2.24 Found C, 65.23; H, 6.00; N, 2.32 Example 174 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)-2-hydroxyethyl]-1-piperidinyl]proDoxy]-3-methoxvhenvllethanone fumarate hydrate A mixture of 4.52 g (0.0143 mole) of a,a-bis(4-fluorophenyl)-4-piperidineethanol, 3.75 g (0.0155 mole) of 3-(4-acetyl-2-methoxyphenoxy)-lchloropropane, 4.1 g (0.049 mole) of sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 ml of 1-butanol was refluxed for 8 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was treated with a small portion of activated charcoal and was dried over magnesium sulfate. The solvent was removed in vacuo to give the nonsalt form of the title compound. This was converted to the fumarate salt, and the salt was recrystallized from methanol ether to give 5.94 g of the title compound as a white crystalline solid: mp 135-136 0

C.

~1

I

i

I

2 -200- AHR-438A-CIP Analysis: Calculated for C 3 5

H

4 1 N0 9 F2: Found C, 63.92; H, 6.28; N, 2.13 C, 64.03; H, 6.07; N, 2.16 Example 175 1-[4-[3-[4-[2,2-Bis(4-fluorophenyl)ethyl]-l-piperidinyl]propoxy]-3methoxyphenyl]ethanone fumarate A mixture of 5.15 g (0.0148 mole) of 4-[2,2-bis(4-fluorophenyl)ethyl]piperidine hydrochloride hydrate 3.71 g (0.0153 mole) of3-(4-acetyl-2methoxyphenoxy)-l-chloropropane, 1.59 g (0.015 mole) of sodium carbonate, o. 2.30 g (0.0274 mole) of sodium bicarbonate and a 0.2 g (0.0012 mole) of potassium iodide in 400 ml of 1-butanol was heated at reflux for 12 hr. The r solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give the free base of the title compound as an oil. This was converted to the fumarate salt, and th salt was recrystallized from methanol-ether to give 5.87 g (63.6 g) of title compound as a white crystalline solid; mp 156- I 157 0

C.

Analysis: Calculated for C 35

H

39 N0 7

F

2 C, 67.40; H, 6.30; N, 2.25 Found C, 67.51; H, 6.34; N, 2.29 Example 176 1-[4-[3-[4-r2.2-Bis(4-fluorophenyl)ethylene]-1-piperidinyl]propoxy]3methoxyphenvl]ethanone fumarate t ,A solution of 3.89 g (0.013 mole) of 4-[2.2-bis(4-fluorophenyl)ethylene]piperidine, 3.20 g (0.013 mole) of 3-(4-acetyl-2-methoxyphenoxy)-l-chloropropane and 2.02 g (0.024 mole) of sodium bicarbonate in 400 ml of 1-butanol was heated at reflux for 14 hr. The solvent was removed in vacuo, and the Sresidue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was subjected to flash column chromatography (silica gel; eluted with 99/1 mixture of methylene chloride and methanol) to give the free base of the title compound.

This was converted to the fumarate salt, and the salt was recrystallized from

U

-201- AHR-438A-CIP at 5r tt r 1

II

i methanol ether to give 5.19 g of title compound as a white crystalline solid; mp 179-179.5 0

C.

Analysis: Calculated for C 3 5

H

37 N0 7

F

2 C, 67.62; H, 6.00; N, 2.25 Found C, 67.59; H, 6.00; N,2.23 Example 177 a-(4-Fluorophenyl)-a-[1-(3-phenoxypropyl)-4-piperidinyl]-2-pyridineacetonitrile oxalate A mixture ofa-(4-fluorophenyl)-a-(4-piperidinyl)-2-pyridine acetonitrile (11.30 g, 0.0383 mole), 3-phenoxypropyl bromide (8.20 g, 0.0383 mole), and potassium bicarbonate (4.0 g, 0.04 mole) was heated overnight at reflux in 350 ml of acetonitrile (dried over 4A molecular sieves). The reaction mixture was cooled to room temperature and filtered, and solvent removed by rotary evaporator. A dark brown oil was obtained and dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water, dried over sodium sulfate and filtered, and the solvent was removed to give a brown oil. A 0.55 g sample of the oil was converted to the oxalate salt in methanol-diethyl ether. A white crystalline solid was isolated and dried in vacuo overnight at 80 0 C, to give 0.35 g of product; mp 121-125 0

C.

Analysis: Calculated for C 30

H

31

N

3 0 7 F: C, 63.82; H, 5.53; N, 7.44 Found C, 63.78; H, 5.56; N, 7.67 Example 178 1-[4-[3-[4-fBis(4-chlorophenvl)methyl]-1-piperidinvl]propoxy]-3methoxyphenyllethanone oxalate hydrate A mixture of 4-[bis(4-chlorophenyl)methyl]piperidine (11.39 g, 0.0357 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (8.64 g, 0.0357 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 300 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was stripped to dryness, and the residue obtained was partitioned several times between chloroform and water. The chloroform layer was dried over sodium sulfate and filtered, and the solvent was removed to give a dark brown oil. This oil was converted to the oxalate salt and the salt was recrystallized from methanol-diethyl ether. A yellow solid was isolated and dried in vacuo overnight at 80 0 C. The yellow solid was next exposed to j -202- AHR-438A-CIP s the atmosphere for 24 hours and submitted for analysis. This procedure produced 6.65 g (30% yield) of light yellow solid; mp 169-171 0

C.

Analysis: Calculated for C 32

H

36 NO7.

5 C1 2 C, 61.44; H, 5.80; N, 2.24 Found C, 61.40; H, 5.71; N, 2.24 Example 179 1-[4-[3-[4-[Bis(4-chlorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]- 3-methoxyphenyllethanone oxalate SThis compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 2.5 g (0.0075 mole) of a,a-bis(4-chlorophenyl -4-piperidinemethanol, 1.8 g (0.0075 mole) of •chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous f' sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gummy solid as residue. This solid was converted to the oxalic acid salt, and the solid was recrystallized from absolute ethanol to yield 1.4 g of title compound as a pale-yellow solid, mp 89-113°C with decomposition.

Analysis: Calculated for C 33

H

36

C

1 2 N0 1 0 C, 58.50; H, 5.36; N, 2.07 Found C, 58.22; H, 5.32; N, 2.07 Example 180 4-[3-[4-[Bis(4-fluorophenyl)methyll-1-piperidinyllpropoxy]-3-methoxybenzoic acid tgthyl ester, The sodium salt of methyl vanillate was formed from methyl vanillate r(11.26 g, 0.062 mole) and sodium hydride 747 g, 60%, 0.062 mole) in 300 ml of dimethyl sulfoxide (dried over 4A moaV% lar sieves). During the formation of this sodium salt, the dimethyl sulfoxide solution turned light green. The salt was stirred 0.5 hr at room temperature under nitrogen atmosphere.

Next, 4-[bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine (21.32 g, 0.062 mole) in 100 ml of dimethyl sulfoxide was added dropwise. The resulting solution was stirred overnight at 60'C. The warm reaction mixture was stripped to dryness on a rotary evaporator. The residue was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil (31.35 The oil was dissolved in ethyl acetate and placed on an 800 g silica gel column. This column was eluted with ethyl acetate.

I mw-fp -203- AHR-438A-CIP Fractions of simil purity were combined and dried in vacuo at overnight to give 22.70 g (71.9% yield) of brown oil.

1 H NMR (CDC13): 6 6.7-7.7 11, aromatics), 4.0-4.3 2, -OCH 2 3.9 6, OCH 3 of ether and ester), 3.5 2, methine group attached to two fluorophenyl groups), 1.3-3.0 12, remaining aliphatics).

Analysis: Calculated for C 3 0

H

33

NO

4

F

2 C, 70.71; H, 6.53; N, 2.75 Found C, 70.48; H, 6.60; N, 2.71 Example 181 1-[4-[3-[4-[Bis(3-fluorophenyl)methyll-1-piperidinyl]propoxy]-3t i methoxyphenyl]ethanone fumarate A mixture of 5.32 g (0.019 mole) of 4-[bis(3-fluorophenyl)methyl]piperidine, 4.80 g (0.020 mole) of 3-(4-acetyl-2-methoxyphenoxy)-l-chloropropane, 2.4 g (0.029 mole) of sodium bicarbonate and 0.20 g (0.0012 mole) of Spotassium iodide in 400 ml of 1-butanol was heated at reflux for 23 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride Ssolution was dried over magnesium sulfate, and the sovlent was removed in vacuo to give an oil. This was dissolved in methanol and the solution was treated with an excess offumaric acid. Ether was added and a gum formed.

the gum was triturated with acetonitrile to give 1.75 g of the title compound as a white crystalline solid, mp 180-181°C.

Analysis: Calculated for C 34

H

37

NOTF

2 C, 66.98; H, 6.12; N, 2.30 Found C, 66.70; H, 6.11; N,2.32 The solvent was removed in vacuo from the filtrate and the residue was recrystallized from a mixture ofmethanol-ether-acetonitrile to give 2.83 g of title compound, mp 181-182 0

C.

Analysis: Calculated for C 34

H

37 N0 7

F

2 C, 66.98; H, 6.12; N, 2.30 Found C, 66.95; H, 6.09; N, 2.28 -217- AHR-438A-CIP Example 205 MM I I I -204- AHR-438A-CIP Example 182 4-[3-[4-[Hydroxy(diphenyl)methyl]- 1-piperidinyl]propoxy]benzoic acid methyl ester.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 5.3 g (0.02 mole) of a,adiphenyl-4-piperidinemethanol, 4.6 g (0.02 mole) of 4-(3-chloropropoxy)benzoic acid methyl ester, 7.4 g (0.07 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of dimethylformamide give 6.8 g of title compound as a fluffy, white solid, mp 146-147°C.

Analysis: Calculated for C 29

H

33 N04: C, 75.79; H, 7.24; N, 3.05 Found C, 75.68; H, 7.22; N, 3.11 Example 183 1-[4-[6-[4-[Bis(4-fluorophenyl)methyl]l--piperidinyl]hexyloxy]-3methoxyphenyllethanone.

A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (7.90 g, 0.0275 mole), 1-[4-(6-chl,.rohexyloxy)-3-methoxyphenyl]ethanone (7.82 g, 0.025 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 400 ml of 1-butanol containing potassium iodide (0.2 The mixture was cooled to room temperature and filtered. Butanol was removed by rotary evaporation. The brown oil obtained was dissolved in chloroform and the solution was extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a Sbrown oil. This oil was dissolved in ethyl acetate and subjected to flask chromatography on silica gel using ethyl acetate and 5% methanol-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed to give an oil. The oil was dried at 80°C overnight in vacuo to give 7.28 g (54.4% yield) of title compound as a light brown oil.

1 H NMR (CDC13): 8 6.7-7.5 11, aromatics), 4-4.2 2, -OCH 2 3.9 3, -OCH 3 3.4-3.6 1, methine on carbon attached to two fluorophenyl groups), 2.6 3, C-CH 3 1.5-3.0 13, remaining aliphatics).

11

O

Analysis: Calculated for C 33

H

39 N0 3

F

2 C, 73.99; H, 7.34; N, 2.61 Found C, 73.92; H, 7.54; N, 2.62 -218- AHR-438A-CIP es d) ,a-bis3-(trfluoromethyl)phenyl-4piperiineacetic acid ethyl ester, -ieridineacetic acid eth e) Q,a-bis[4-(triuoromethyl)phenyl] 4 pipe c acid ethyl ester.

-205- AHR-438A-CIP Example 184 4-[3-[4-[Bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]-3methoxybenzoic acid hydrate A solution of 4-[3-[4-[bis(4-fluorophenyl)methyl]-l-piperidinyl]propoxy]-3-methoxybenzoic acid methyl ester (18.58 g, 0.0365 mole) in 400 ml of ethanol was heated for 6 hr at reflux with potassium hydroxide (16.8 g) in 50 ml of water. The ethanol was removed by rotary evaporation. Next, IN sulfuric acid (-200 ml) was added. The aqueous phase was made neutral to litmus paper by the addition of 5% sodium hydroxide. The neutral aqueous layer was extracted several times with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a white solid.

The white solid was triturated with diethyl ether and cooled to about 0°C.

The white solid was then filtered out of solution and then dried in vacuo overnight at 80°C to give 11.38 g (61.8% yield) of white crystalline product, the title compound, mp 123-126 0

C.

Analysis: Calculated for C 29

H

32 N04.

5

F

2 C, 69.03; H, 6.39; N, 2.78 Found C, 69.18; H, 6.32; N, 2.78 Example 185 4-[Bis(4-fluorophenyl)methyl]-l-[3-(3-methoxyphenoxy)propyl]piperidine hydrate The sodium salt of I-methoxyphenol was prepared in dimethyl sulfoxide from sodium hydride 1.10 g, 0.027 mole) and m-methoxyphenol (3.36 g, 0.027 mole). The salt was stirred for 0.75 hr at room temperature, and a clear brown solution was obtained. Next, 4-fbis(4-fluorophenyl) methyl]-l-(3-chloropropyl)piperidine (9.34 g, 0.027 mole) in 100 ml of dimethyl sulfoxide was added. The resulting solution was stirred overnight at 55°C. The solvent was removed in vacuo, and the oil obtained was subjected to flash chromatography on silica gel using 50% hexanes-ethyl acetate for elution. Fractions of similar purity were combined and solvent removed.

A brown oil was obtained and dried at 80°C overnight in vacuo to give 3.96 g of brown oil.

'H NMR (CDC13): 8 6.3-7.3 12, aromatics), 3.8-4.1 2, -OCH 2 3.7 3, -OCH3), 3.4-3.6 1, methine attached to two fluorophenyl rings), 1.2-3.0 (m, 13, remaining aliphatic protons).

-206- AHR-438A-CIP Analysis: Calculated for C 28

H

32

NO

2 5 F2: C, 73.02; H, 7.00; N, 3.04 Found 72.66; H, 6.89; N, 3.06 Example 186 1-14-[3-[4-[Cyclohexyl(4-fluorophenyl)methyll-1-piperidinyl]propoxy]- 3-methoxyphenyllethanone.

A mixture of 4-[cyclohexyl(4-fluorophenyl)methyl]piperidine (5.71 g, 0.0207 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.03 g, 0.0207 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

The reaction mixture was cooled to room temperature and filtered. The 1o butanol was removed by rotary evaporation to give a brown oil. This oil was dissolved in chloroform, and the chloroform layer was extracted with S* sodium hydroxide and water. The chloroform layer was dried over sodium S, sulfate, filtered, and solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel. Elution was performed using ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate.

Separate fractions of similar purity were combined, and solvent was removed to give a yellow oil. This oil was dried in vacuo overnight at 80°C to give 7.36 g of title compound.

1H NMR (CDC 3 8 6.7-7.5 7, aromatics), 4.0 2, -O-CH2), 3.9 (s, 0

II

3, -O-CH 3 2.5 (s,3,-C-CH 3 1.0-3.0 25, remaining aliphatics).

t Analysis: Calculated for C 3 oHo4NO 3 F C, 74.81; H, 8.37; N, 2.91

M

Found C, 74.39; H, 8.36; N, 2.8i Example 187 4-[Bis(4-fluorophenyl)methyl]-1-[3-(phenylthio)propylIpiperidine citrate A mixture of 19.23 g (0.067 mole) of 4-[bis(4-fluorophenyl)methyl]piperidine, 16.0 g (0.069 mole) of 3-thiophenoxy-l-bromopropane, and 6.72 g (0.080 mole) sodium bicarbonate in 400 ml of 1-butanol was heated at reflux for 25 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydorxide solution.

The methylene chloride solution was dried over magnesium sulfate, and the -220- AHR-438A-CIP s Example 209 Qia-^Bis(4-flhnrnnI... 1 rn -207- AHR-438A-CIP solvent was removed in vacuo to give the non-salt form of the title compound as an oil. This was converted to the citrate salt, and the salt was recrystallized from methanol-ether to give 33.05 g of title compound as a white crystalline solid: mp 149.5-151°C.

Analysis: Calculated for C 33

H

37

NO

7 SF2: C, 62.94; H, 5.92; N, 2.22 Found C, 63.08; H, 5.94; N, 2.23 Example 188 4-[Bis(4-fluorophenyl)methyl]-l-[3-(phenylsulfinyl)propyl]piperidine S, oxalate A solution of 4.33 g (0.0099 mole) of 4-[bis(4-fluorophenyl)methyl]-l-[3- (phenylthio)propyl]piperidine and 7.70 g (0.050 mole) of sodium perborate S" tetrahydrate in a mixture of 150 ml of methanol and 100 ml of 30% sulfuric acid solution was stirred at room temperature for 2 hr. The reaction mixture S° *was poured over ice, and the mixture was made basic with 50% sodium hydroxide solution. The mixture was extracted with methylene chloride.

The extract was dried over magnesium sulfate, and the solvent was removed in vacuo to give the non-salt form of the title compound as an oil. This was converted to the oxalate salt, and the salt was recrystallized from methanolether to give 4.38 g of the title compound as a white crystalline solid; Smp 173.5-174 C (with decomposition).

Analysis: Calculated for C 29

H

31 N0 5

SF

2 C, 64.07; H, 5.75; N, 2.58 Found C, 63.91; H, 5.74;N,2.57 'In a similar procedure 3.46 g of the title compound was obtained; mp 169-170.5 0

C.

Analysis: Calculated for C 29

H

3 1 NOsSF 2 C, 64.07; H, 5.75; N, 2.58 Found C, 63.80; H, 5.75; N, 2.61 Example 189 2-[(4-Fluorophenyl)[l-(3-phenoxypropyl)-4-piperidinyl]methyl]pyridine hydrate A solution of a-(4-fluorophenyl)-a-[l-(3-phenoxypropyl)-4-piperidinyl]- 2-pyridineacetonitrile oxalate (2.34 g, 0.00545 mole) in 75 ml of glacial acetic containing 10 drops of concentrated hydrochloric acid was prepared.

To this solution was added 2 grams of platinum on carbon catalyst -221 -221- AHR-438A-CIP lized from 2 -propanol to yield 4.4 g of the title compound as a tan solid, I mp 95-100C.e compound as a tan so Analysis: Calrnitoa C- 1- -208- AHR-438A-CIP After reacting with hydrogen for 5 days at 80°C and 1000 psi, the reaction 4 mixture was allowed to cool to room temperature. The mixture was filtered through Celite®, and the filtrate washed with glacial acetic acid. The acetic acid was removed by rotary evaporation. The residue obtained was dissolved in chloroform, and the solution was extracted with 5% sodium hydroxide.

The chloroform was dried over sodium sulfate and filtered, and the solvent removed to give a brown oil. This oil was subjected to flash chromatography on silica gel using 5% methanol ethyl acetate for elution. Fractions of similar purity were combined, and solvent removed to give a brown oil. The oil was dried in vacuo overnight at 80°C, to give 0.35 g (15.5% yield) of brown oil.

1H NMR (CDC13): 8 8.5 1, proton adjacent to nitrogen atom in pyridine ring), 6.8-7.5 12, aromatics), 4.0 2, -OCH2-), 3.6 1, methine P proton attached to carbon bonded to fluorophenyl ring and also pyridine t ring), 1.0-3.0 13, remaining aliphatic protons).

Analysis: Calculated for C 26

H

30

N

2 01.F C, 75.52; H, 7.31; N, 6.77 Calculated for C 26

H

29 .5N201.

25 F C, 76.35; H, 7.27; N, 6.85 Found C, 76.28; H, 7.14; N, 6.85 t 4 Example 190 1-[4-[3-[4-[(3,4-Difluorophenyl)(4-fluorophenyl)methyl]-l-piperidinyllpropoxy]-3-methoxyphenyl]ethanone oxalate A mixture of 2.68 g (0.036 mole) of 4-[(3,4-difluorophenyl)methyl]piperidine, 2.50 g (0.110 mole) of 1-chloro-3-(4-acetyl-2-methoxyphenoxy)propane, 3.0 g (0.036 mole) of sodium bicarbonate, and 0.20 g (0.0012 mole) of potassium iodide in 300 ml of 1-butanol was heated at reflux for 30 hours.

The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. Methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give an oil. The oil was flash chromatographed (silica gel, elution with 95/5 methylene chloride methanol) to give the nonsalt form of the title compound. This was converted to the oxalate salt, and the salt was recrytallized from methanol-ether to give 3.85 g of the title compound as a white crystalline solid, m.p. 170 -171°C.

-222- AHR-438A-CIP Example 214 M n n1-[3-(2-Ethox henox opyl ]--aa-bis(4-fluorophen yl)-4- pi peridine- -209- AHR-438A-CIP Analysis: Calculated for C 32

H

34 N0 7

F

3 C, 63.89; H, 5.70; N, 2.33 Found C, 63.87; H, 5.71; N, 2.34 Example 191 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-a,a-bis (4-fluorophenyl)-3pyrrolidineacetonitrile.

A mixture of a,a-bis(4-fluorophenyl)-3-pyrrolidineacetonitrile (5.13 g, 0.0172 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.17 g, 0.0172 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

The butanol was removed by rotary evaporator. The residue obtained was 'dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed i vacuo to give a dark brown oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate and 25% methanol-75% ethyl acetate for elution. Fractions of similar purity were combined, and solvents removed.

SA dark brown oil was obtained and dried in vacuo 2 days at 80°C to give 5.85 g (57.5% yield) of the title compound as a dark brown gum.

'H NMR (CDC13): 5 6.8-7.6 11, aromatics), 4.3 2, -OCH 2 3.9 3,

OCH

3 2.6 3, -COCH 3 1.3-3.8 11, aliphatics).

Analysis: Calculated for C 30

H

30

N

2 0 3

F

2 C, 71.41; H, 5.99; N, 5.55 Found C, 70.94; H, 5.99; N, 5.51

LI

Example 192 1-[3-(4-Acetyl-2-methoxvphenoxy)propyl]-a.a-bis(4-fluorophenyl)-3piperidinepropanenitrile hydrate A mixture of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.45 g, 0.0184 mole), a,a-bis(4-fluorophenyl)-3-piperidinepropanenitrile (6.00 g, 0.0184 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux. The mixture was cooled to room temperature and stripped to dryness on a rotary evaporator. The residue was partitioned between chloroform and water. The chloroform layer was back-extracted with water and sodium hydroxide solution. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a dark brown oil. The oil was -223- AHR-438A-CIP Example 217 -210- AHR-438A-CIP subjected to flash chromatography on silica gel using 75% ethyl acetate hexanes and 100% ethyl acetate for elution. Fraction of similar purity were combined and solvent removed. A dark brown oil was obtained and dried in vacuo at 80°C to give 590 g (59.2% yield) of title compound as a yellowishbrown gum.

H

1 NMR (CDC13): 8 6.8-7.8 11, aromatics), 4.2 3, -OCH 3 4.2 (m, 2, -OCH 2 2.6 3, -O-CH 3 1.1-2.8 15, aliphatics).

II

O

Analysis: Calculated for C 32

H

35

N

2 0 3 5 F2: C, 70.96; H, 6.51; N, 5.17 Found C, 71.58; H, 6.49; N, 5.12 "Example 193 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-aa-bis(4-fluorophenyl)-4piperidineacetamide fumarate hydrate A mixture ofa,a-bis(4-fluorophenyl)-4-piperidineacetamide, (6.94 g, 0.021 mole), 1-[4-(3-chloropropoxy-3-methoxyphenyl]ethanone (5.09 g, 0.021 mole), and potassium carbonate (5.53 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The mixture was stripped to dryness. The residue obtained was partitioned Sbetween chloroform and water. The chloroform layer was dried over sodium sulfate and filtered, and solvent removed to give a yellowish-brown residue.

This material was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80°C to give 8.47 g of title compound as a white crystalline solid, mp 258-260°C (with decomposition).

Analysis: Calculated for C 33

H

37

N

2 0 6 5

F

2 C, 65.66; H, 6.18; N, 4.64 Found C, 65.88; H, 6.13; N, 4.65 Example 194 1-[4-[3-[4-[Bis(3,4-difluorophenyl)methyl]-l-piperidinyl]propoxy]-3methoxyphenyl]ethanone.

A mixture of the free base of 4-[bis(4-fluorophenyl)rethyl]piperidine hydrochloride (6.46 g, 0.02 mole), l-[4-(3-chloropropoxy)-3-methoxyphenyllethanone (4.84 g, 0.02 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 1-butanol (350 ml) containing -211- 11-AHR-438A-CIP potassium iodide (0.2 The mixture vscooled to room temperature and then stripped to dryness. The residue obtained was partitioned between.

chlorofor-m and 5% sodium hydroxide solution. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed in vacuo to 'give a yellow residue (11.17 The oil was subjected to flash chromatography on silica gel using ethyl acetate, 5% methanol-ethyl acetate and 10% methanolethyl acetate for elution. Fractions of similar purity were combined and solvent removed. A thick viscous oil was obtained and dried in vacuo overnight at 80'C. This procedure furnished 6.74 g of the title compound as a viscous oil.

1 H NMR CDC1 3 8 6.8-7.6 (in, 9, aromatics), 4.1-4.3 2, -O-CH2), 3.9 3, OCH3), 2.5 3, -C-OH 3 1.2-3.6 (in, 14, remaining aliphatics).

V 4 Analysis: Calculated for C 3 0

H

31 N0 3

F

4 C, 68.04; H, 5.90; N, 2.64 Found 67.49; H,6.0 6; N,2.5 6 Example 195 When in the procedure of Example 66 and substituting the following for a,a-bi s(p-fluorophenyl) -4-pi peri din emeth an ol: a) Qi,-bis(3 ,4-difluorophenyl)-4-piperidinemeth anal, b) ,a-bis(2 ,5-diflu-orophenyl)-4-piperidinemethanol, c) QL,c-bis(2,4-difl uorophenyl)-4-piperidinemeth anol, d) a~a-bis[3-(trifluoromethyl)phenyll-4-piperidi.nemethanol, and e) ,a-bis[4-(trifluoromethyl)phenyll-4-piperidinemethanol there are obtained: a) ,4-difluorophenyl)hydroxymethyl]- 1-piperidinyl]propoxyl-3-methoxyphenyllethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)hydroxymethyl]- 1-piperidinyl]propoxy]-3-methoxyphenyliethanone, c) 1-14-(3-[4-[bis(2,4-difluorophenyl)hydroxymethyl- 1-piperidinyl]propoxy]-3-methoxyphenyllethanone, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)phenyllhydroxymethyl]- 1piperidinyllpropoxyl-3-methoxyphenyllethanone, and -212- -12-AHR-438A-CIP e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyIlhydroxymethyl-1 piperi di nyl Ipropoxy] -3 -meth oxyph enyl Ieth anon e.

Example 196 When in the procedure of Example 56 and substituting the following for 4-[QL,a-bis(p-fluorophenyl)methyllpiperidine: a) 4-[a,a-bis(3 ,4-difluorophenyl)methyllpiperidine, b) 4- [a,QL-bis(2,5-diflu orophenyl)methylllpi pcri dine, c) 4-[a,-bisi3-(trifluoromethylphenyllmethyllpiperi dine, and d) 4- [a,-bi s[4- (trifl uoromethyl)phenyllmethyllpi peri dine.

there are obtained the following: 4 04 t 4 4 a) ,4-difluorophenyl)methyl]-1 -piperidinyllpropoxy]- 4, 3-niethoxyphenyllethanone oxalate salt, b) 1-1j4-[3-[4- [bis(2 ,5-difluorophenyl)naethyl]- 1-piperidinyllpropoxy]- 3-methoxyphenyl~ethanone oxalate salt, c) 1-14-[3-[4-[bis[3-(trifluoromethyl)phenyllrnethyll-1-piperidinyllpropoxyi-3-methoxyphenyllethanone oxalate salt, and d) [bis[4-(trifluoromethyl)phenyllmethyl]- 1-piperidinyl]- I tpropoxyi-3-rnethoxyphenyllethanone oxalate salt.

Example 197 When in the procedure of Example 58 and substituting the following for 4-[c,a-bis(p-fluorophenyl)methylenelpiperidine: a) 4- bi s(3 difluorophenyl)methyl en e Ipiperi dine, b) 4-II,-bis(2,5-difluorophenyl)methylenelpiperidine, c) 4- a-bi s(2,4-difluorophenyl)methyl ene Ipiperi dine, d) 4- [c,a-bis[3-(trifluoromethyl)phenyllmethyleneI piperi dine, and e) 4- [,-bis4- (trifluoromethyl)phenylmethylenelpiperi dine there are obtained: a) ,4-difluorophenyl)methylene]-1-piperidinyl]propoxy] -3 -methoxyphenylj eth anon e oxalate salt, -226- AHR-438A-CrP Examl e224 1-[4-[3-17-Bs34dfurnpu -213- -213- AHR-43 BA-CF-P b) 1-14-[3-[4-Ibis(2,5-difluorophenyl)methylenel--piperidinyllpropoxyl-3-mrethoxyphenyllethanone oxalate salt, c) 1-14-13-[4-[bis(2,4-difluorophenyl)methylenel-'i-piperidinyl]propoxyl-3-methoxyphenyllethanone oxalate salt, d) 1-14-3-[4-[bis[3-(trifluororethyl)phenyllmethylenel-1-piperidi nyl 1propoxyl -3 -methoxyphenyl Ieth anon e oxalate salt, and e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyllmethylene]- 1-piperidinyllpropoxy]-3-methoxyphenyllethanone oxalate salt.

Example 198 1-4-[3-14-l(ci-3 ,4-Difluorophenyl-a-4-fluorophenyl)hydroxvm .ethyl]lpipe ridinyl ]pro poxy 3 -methoxyphenyl Iethanone.

When in the procedure of Example 66 and substituting a-(3,4difluorophenyl)-a-(4-fluorophenyl)-4-piperidinemethanol for Q,a-bis(pt I fluorophenyl)piperidinemethanol, the title compound is obtained.

Example 199 l-14-[3-[4-[a-(3,4-Difluorophenyl)-a-(4-fluorophenyl)methylene]- 1piperidinvllpropoxy]-3-methoxyphenyllethanone oxalate.

When in the procedure of Example 58 and substituting difluorophenyl-QL-(4-fluorophenyl)methylenelpiperidine for 4-[CL,Q..bis(pfluorophenyl)methylenelpiperidine the title compound is obtained.

ExaMple 200 1-fj4-[3-14-[Bis(2.4-difluorophenyl)methyl1-l-piperidinylpropoxy-3methoxyphenyllethanone oxalate [1:11.

A mixture of 4-[bis(2,4-difluorophenyl)methyllpiperidine (7.30 g, 0.023 mole), 3-(4-acetyl-3-methoxyphenoxy)propyl chloride (5.57 g, 0.023 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.2 The reaction mixture was filtered and then stripped to dryness. The residue was dissolved in chloroform, and the solution was extracted with 5% sodium hydroxide.

The chloroform layer was dried over sodium sulfate and filtered. The removal of chloroform provided a dark brown oil. This material was converted to the oxalate salt in methanol-diethyl ether. A white solid was isolated and -227- AHR-438A..CIP Poy eh xp eylt a o e 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 4.0 g -214- AHR-438A-CIP dried in vacuo overnight at 80'C. This procedure furnished 8.23 g of white crystalline product, mp 151-153'C.

Analysis: Calculated for C 32 1{ 33 N0 7

F

4 C, 62.03; H, 5.37; N, 2.26 Found 62.10; H, 5.37; N, 2.33 ExaMple 201 Utilizing Methiod F, supra, and reacting the following compounds: a) 1 ,4-difluorophenyl)hydroxymethyl]-l1-piperidinyllpropoxy]-3-methoxyphenyllethanone, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)hydroxymethyl]-1-piperidinylpropoxy]-3-rnethoxyphenyllethanone, c) difluorophenyl)hydroxymethyll-1-piperidinyl]propoxy]-3-inethoxyphenyllethanone, d) 1-[4-[3-[4-[bis[3-(trifluoromethyl)phenyllhydroxymethyll- 1piperidinyllpropoxyi-3-methoxyphenyllethanone, and e) 1-14-[3-4-[bis[4-(trifluoromethyl)phenyllhydroxymethyl- 1piperidinylipropoxy]-3-methoxyphenyllethanone with potassium hydride and iodoethane; there are obtained: a) 1-14-[3-[4-[bis(3,4-difluorophenyl)ethoxymethyl]methyl]lpi peri dinyl Ipropyl]- 2-methoxypheno xyl eth anon e, b) 1-[4-[3-[4-[bis(2,5-difluorophenyl)ethoxymrrethyllnaethyl]- 1- £pi peri dinvI IpropylI- 2-methoxyp henoxyl eth anon e, c) 1-[4-13-[4-bis(2,4-difluorophenyl)ethoxyxnethyllmethyl]-1piperidinyllpropyl]-2-.methoxyphenoxylethanone, d) 1-[4-f 3- [4-[bis[3-(trifluoromethyl)phenyllethoxymethyllmethyl]- 1pipe ridi nyllpropyl]I- 2-methoxyph enoxyl eth anon e, and e) 1-[4-[3-[4-[bis[4-(trifluoromethyl)phenyllethoxymethyllinethyl]- 1piperidinyllpropyl]-2-methoxyphenoxy]ethanone.

Example 202 Utilizing the procedure of Example 129 and substituting the following for a,a-bis(4-fluorophenyl)-4-piperidineacetonitrile: a) ,a-bis(3,4-difluorophenyl)-4-piperidineacetonitrile, -228- AHR-438A-CIP elution system of 0-10% acetone in benzene. The fractions containing the desired product were combined and concentrated under reduced pressure to -215- -15-~A.HR-43 8A- CIP b) Q,a-bis(2 ,5-difluorophenyl)-4-piperidineacetonitrile, c) a a-bis(2,4-difl uorophenyl)-4-piperidineacetoni tri le, d) Q,a-bjs[3-(trifluoromethyl)phenyl]"-4-piperidineacetonitrile, and e) Q,a-bis[4-(trifl uorornethyl)phenyl]-4-piperidineacetoni trule there are obtained: a) 1-13-(4-acetyl-2-methoxyphernoxy)propyl]-a,at-bis( 3,4-difluorophenyl)-4-piperidineacetonitrile maleate, b) 1-[3-(4-acetylh2-methoxyphenoxy)propyll-a,a-bis(2,5-difluorophenyl)-4-piperidineacetonitrile maleate, c) 1-I3(4-acetyl-2-rnethoxyphenoxy)propyl-Qt,Q-bis(2,4-difluorophenyl)-4-piperidineacetonitrile maleate, d) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,Q-bisi3-(trifluoromethyl)phenyl]-4-piperidineacetonitrile maleate, and e) 1-13-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis[4-(trifluoroniethyl)phenyl]-4-piperidineacetonitrile rnaleate.

Example 203 Utilizing Method G, supra, and reacting the following compounds with lithium aluminum hydride: a) 1-[3-(2-rnethoxyphenoxy)propyll-a,Q-bis(3,4-difluorophenyl)-4pi peri dine acetonitri le, b) 1.[3-(2-methoxyphenoxy)propyl]-cl,Q-bis(2,5-difluorophenyvl)-4piperidineacetonitrile, c) 1-[3-(2-methoxyphenoxy)propyl]-o.,Q-bis(2,4-difluorophenyl)-4piperidineacetonitrile, d) 1-[3-(2-methoxyphenoxy)propyl]-a,Q-bisII3-(trifluoromethyl)phenyll -4-piperi dine ace toni tri le, and e) 1-[3-(2-methoxyphenoxy)propylJ-a,a-bis[4-(trifluoromethyl)phenyl]-4-piperidineacetonitrile there are obtained: a) 1-i3-(2-methoxyphenoxy)propyll-4-lbis(3 ,4-difluorophenyl)- (aminomethyl)methyllpiperidine, -229- ~..HR-438A-C1IP Eiijnemethanol.

-216- AHR-438A-CIEP b) 1 -13-(2-methoxyphenoxy)propyll-4-[bis( 2 (aminomethyl)methyllpiperidine, c) 1-[3-(2-methoxyphenoxy)propyll-4-ibis(2 ,4-difl uorophenyl)- (aminomethyl)methyllpiperidine, d) 1- [3-(2-methoxyphenoxy)propyl]-4- [bis[3-(trifl uoromethyl) phenyl I(amin omethyl)methyllIpiperi dine, and e) 1-13-(2-methoxyphenoxy)propyl]-4-Ibis[4-(trifluoromethyl)ph-enylj(aminomethyl)methyllpiperidine.

Example 204 Utilizing Method H, supra, and reacting the following compounds: a) 1-f 3-(4-acetyl-.2 zmethoxyphenoxy)propyl1-a,a-bis(3 ,4-difluorophenyl)-4-piperidineacetonitrile, b) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis(2 phenyl)-4-piperidineacetonitrile, c) 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-a,a-bis(2 ifluororelphenyl]-4-piperidineacetonitrile, an e) 1 -[3-(4-acetyl-2-methoxyphenoxy)propyll-a,ci-bis[4-(trifluoromethyl)phenyll-4-piperidineacetonitrile stepw'ise with potassium hydroxide, water and heating and acid; there are obtained: a) Q,Q-bis(3 ,4-difluorophenyl)- 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-4-piperidine acetic acid, b) a,a-bis(2,5-difluorophenyl)- 1-[3-(4-acetyl-2-methoxyphenoxy)pro)pyl]-4-piperidineacetic acid, 0c) ,a-bis(2,4-difluorophenyl)-1-[3-(4-acetyl-2-inethoxyphenoxy)propyl]-4-piperidineacetic acid, d) a,a-bisII3-(trifluoromethyl)phenyl]- 1-[3-(4-acetyl-2-methoxyphenoxy)propylj-4-piperidineacetic acid, and e) ,a-bis4(trifluoromethyl)phenyl]-1-[3-(4-acetyl-2-methoxyphenoxy)propyl]-4-piperidineacetic acid.

-230- AHR-438A-CIEP To a magnetically stirred solution of 3.88 g (0.01 mole) of 4-[2-amino-l,1.

41 -217- -17-AHR-438A-CIEP ExamplIe205 Utilizing Method I, supra, and reacting the following compounds: a) 1-1i4-[3-[4-Iibis(3 ,4-difluorophenyl)hydroxymethyl-1-piperidinylpropoxy]-3-methoxyphenyllethanone, b) 1-I4.i3[4bis(2,5difluorophenyl)hydroxymethyl-l-piperidinyllpropoxy]-3-methoxyphenyllethanone, c) 1-[4-[3-[4-[bis(2,4-difluorophenyl)hydroxyrnethyl- 1-piperidinyllpropoxyl-3-methoxyphenyllethanone, d) bis[-(trifluoromethyl)hydroxyme thyll 1-piperidinyllpropoxy 3-methoxyphenyll eth a -ion e, and e) 1-[4.13[4-[bis[4-(trifluoromethyl)hydroxymethyl]- 1-piperidinyl]propoxy]-3-methoxyphenyllethanone with acetic anhydride there are obtained: a) a,Q-bis(3 ,4-difluorophenyl)- 1-13-(4-acetyl-2-methoxyphenoxy)- 1< propyl]-4-piperidinemethanol ethanoate (ester), b) Q,a-bis(2,5-difluorophenyl)- 1-13-(4-acetyl-2-methoxyphenoxy)propyl]-4-piperidinemethanol ethaiioate (ester), c) ,-bis(2,4-difluorophenyl)- 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-4-piperidinemethanol ethanoate (ester), d) ,-bis3-(trifluorolethl)phenyljl-[3-(4-acetyl-2-methoxyphenoxy)propyll-4-piperidinemethanol ethanoate (ester), and e) a,-bis[4-(trifluoromethyl )phenyll- 1-[3-(4-acetyl-2-methoxyphenoxy)propyll-4-piperidinemethanol ethanoate (ester).

Example 206 Utilizing the procedure of Example 66 and substituting the following compounds for a,o-bis(p-fluorophenyl)-4-piperidinemethanol: a) a,a-bi s(3,4-di fluorophen i) -4-piperidine acetic acid ethyl ester, b) a,a -bi s(2,5-difluorophenyl)-4-pi peri dine acetic acid ethyl ester, c) ai,a-bis(2,4-difluorophenyl)-4-piperidineacetic acid ethyl ester, -231- AHR-438A-CTEP night. The solvent was removed in vacuo, and the residue was partitioned between chloroform and dilute sodium hydroxide. The organic layer was, -218- AHR-438A-C.EP d) ,-bis[3-(trifluoromethyl)phenyl]-4-piperidineacetic acid ethyl ester, e) ,c-bis[4- (trifluoromethyl) phenyl]- 4-piperi dine acetic acid ethyl ester, f) 1, 1-bis(3,4-difluorophenyl)- 1-(4-piperidinyl )-2-butanone, g) 1 ,1-bis(2,5-difluorophenyl)-1-(4-piperidinyl)-2-butanone, h) 1 ,1-bis(2,4-difluorophenyl)- 1-(4-piperidinyl)-2-butanone, i) 1 ,1-bis[3-(trifluoromethyl)phenyll- 1-(4-piperidinyl)-2-butanone, and j) 1,1-bisII4-(trifluoromethyl)phenyl]-1-(4-piperidinyl)-2-butanone there are obtained: 1. a) c,-bis(3 ,4-difluorophenyl)- 1-[3-(4-acetyl-2-methcoxyphenoxy)propyl] -4-pi peri dine acetic acid ethyl ester, b) u,a-bis(2,5-difl-uorophenyl)- 1-13-(4- acetyl-2-methoxyphenoxy)- V propyll-4-piperidineacetic acid ethyl ester, c) a,a-bis(2,4-difluorophenyl)- 1-[3-(4-acetyl-2-inethoxyphenoxy)propyll-4-piperidineacetic acid ethyl ester, d) ,-bisf3-(trifluorolnethyl)phenyl]- 1-13-(4-acetyl-2-methoxyphenoxy)propyll-4- piperi dine acetic acid ethyl ester, e) ,-bis[4-(trifluoromethyl)phenyll- 1-[3-(4-acetyl-2-rnethoxyphenoxy)propyll piperi dine acetic acid ethyl ester, 1. 1-bis(3 ,4-difluorophenyl)- 1- 3- acetyl- 2- metho xyp heno xy)propyll-4-piperidinyll-2-butanone, g) 1, I-bi s(2,5-difluorophenyl)- 1- 1- acetyl- 2-methoxyphe noxy)propyl]-4-piperidinylll-2-butanone, h) 1, 1-bis(2,4-difluorophenyl)- 1-[1-i3-(4-acetyl-2-methoxyphenoxy)propyl]-4- piperidinyl]- 2-butanone, i) 1 ,1-bis[3-(trifluoromethyl)phenyll- 1-[1-[3-(4-acetyl-2-rnethoxyphenoxy)propyl]-4-piperidinyl]-2-butanone, and j) 1 ,1-bisII4-(trifluoromethyl)phenyl-1-{ 1-13-(4-acetyl-2-inethoxyphenoxy)propyl]-4-piperidinyl]-2-butanone.

-219- AHR-438A-CIP Example 207 1-[3-(4-Acetyl-2-methoxyphenoxy)propyll-a,a-bis(3-fluorophenyl)-4piperidinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of 4- [a,a,bis(4-fluorophenyl)hydroxymethyl]piperidine, 2.4 g (0.01 mole) of 1-[4- (3-chloropropoxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrdus sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.6 g of the title compound as an off-white solid, m.p. 149-151 C (absolute ethanol).

Analysis: Calculated for C 3 0

H

35

F

2 N0 4 C, 70.71; H, 6.53; N, 2.75 i ,e Found C, 70.66; H, 6.53; N, 2.79 Example 208 11,o1* [[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]phenyl]amino]oxoacetic acid ethyl ester fumarate To a solution of 2.4 g (0.0054 mole) of the free base of 1-[3-(4-amino- 4 phenoxy)propyll-a,a-bis(4-fluorophenyl)-4-piperidinemethanol oxalate [1:2] I and 1.5 g (0.015 mole) of triethylamine in 50 mL of benzene was added dropwise a solution of 1.0 g (0.008 mole) of ethyl oxalyl chloride in 10 mL of Sbenzene, and the mixture was stirred at ambient temperature overnight.

The mixture was treated with 20 mL of water and vigorously stirred. The layers were separated, and the organic layer was washed with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give a gum as residue. The gum was dissolved in ethyl ether and filtered to remove insolubles. The filtrate was concentrated, and the gummy residue was converted to the fumaric acid salt. The salt was recrystallized from absolute ethanol-water to yield 1.1 g of the title compound as a white solid, mp 215-216°C (dec.) Analysis: Calculated for C 33

H

36

F

2

N

2 0 7 C, 64.91; H, 5.94; N, 4.59 Found C, 64.62; H, 5.90; N, 4.59 II o i c^~da S 3 -220- AHR-438A-CJIP Example 209 a,c-Bis(4-fluorophenyl)-l-[3-(2-methoxy-4-meth ylphenoxy)propyl]-4piperidinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.5 g (0.015 mole) of [Q,a-bis fl uorophenyl)] pipe ridi nemethanol, 3.2 g (0.0 15 mole) of 1chloro-3-(2-methoxy-4-methylphenoxy)propane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1butanol gave 5.4 g of the title compound as a white solid, mp 121-122'C (2-propanol).

Analysis: Calculated for C 29

H

33

F

2 N0 3 72.33; H, 6.91; N, 2.91 Found 7 2.3 4; H, 6.9 5; N, 2.9 0 4 It Example 210 1 -[2-[3-14-Bis(4-fluorophenyl)hydroxymethyHl-1-piperidinylipropoxylphenyllethanone.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of bis(4-fluorophenyl)!I-4-piperidinemethanol, 2.1 g (0.01 mole) of 2'-(3-chloropropoxy)acetophenone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.4 g of the title compound as a white solid, mp 113-114 0

C.

Analysis: Calculated for C 29

H

31

F

2 N0 3 72.63; H, 6.52; N, 2.92 Found 72.54; H, 6.56; N, 2.94 Example 211 1113-[3-14-[Bis(4-fluorophenyl)hydrox-ymethyl]- 1-piperidinylipropoxylphenyllethanone oxalate hydrate 1:1:1].

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of II,Gbis(4-fluorophenyl)I1-4-piperidinemethanol, 2.1 g (0.01 mole) of 3'-(3-chloropropoxy) acetophenone, 13.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue.

The gum was converted to the oxalic acid salt, and the solid was recrystal- 0)-0 C-0 M~ 4

W

-O A 0 '0

I

-221- AHR-438A-CIP lized from 2-propanol to yield 4.4 g of the title compound as a tan solid, mp 95-100 0

C.

Analysis: Calculated for C 3 1

H

35

F

2 NO C, 63.36; H, 6.00; N, 2.38 Found C, 62.94; H, 6.02; N, 2.20 Example 212 a,a-Bis(4-fluorophenyl)-l-[3-(3-methoxyphenoxy)propyl]-4-piperidinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of[a,abis(4-fluorophenyl)]-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(3methoxyphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.1 g of the title compound as a white solid, mp 107-108°C (2-propanol).

Analysis: Calculated for C 28

H

31

F

2

NO

3 C, 71.93; H, 6.68; N, 3.00 Found C, 71.90; H, 6.70; N, 3.01 Example 213 1-[3-(4-Ethylphenoxy)propyl)-a,a-bis(4-fluorophenyl)-4-piperidinemethanol oxalate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,abis(4-fluorophenyl)]piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(4v. ethylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a solid as residue. This solid was converted to the oxalic acid salt, and the salt was recrystallized from 2-propanol to yield 3.0 g of the title compound as a white solid, mp 132-135 0

C.

Analysis: Calculated for C 31

H

35

F

2

NO

6 C, 67.01; H, 6.35; N, 2.52 Found C, 66.60; H, 6.32; N, 2.31 J^.<y -T NOW-r- -222- AHR-438A-CIP Example 214 l-[3-2-Ethoxyphenoxy' propyli.Q,a-bis(4-fluorophenyl )-4-pi peri dinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [Q,Qbis(4-fluorophenyl)Ij-4-piperidinemethanol, 2.1 g (0.01 mole) of 1-chloro-3-(2ethoxyphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1.-butanol gave 3.6 g of the title compound as an off-white solid, mp 89-91'C (petroleum ether, 60-110'C).

Analysis: Calculated for C 2 9

H

33

F

2 N0 3 72.33; H, 6.91; N, 2.91 Found 7 2.3 9; H, 6.9 0; N, 2.9 6 Example 215 a.a-Bis(4-fluorophenyl)- 2-methylphenoxy)propyl]-4- piperidi nemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of tia,a-bis(4fluorophenyl)]-4-piperi'dinemethanol, 1.8 g (0.01 mole) of 1-chloro-3-(2methylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.5 g of the title compound as a white solid, mp 108.5-109'C (petroleum ether, 60-110'C).

Analysis: Calculated for C 2 8

H

3 jF 2 N0 2 74.48; Hi, 6.92; N, 3.10 Found 74.57; H, 6.92; N, 3.11 Example 216 a,a-Bis(4-fluorophenyl)-l-r3-(3-meth-ylphenoxv)propyl]-4-piperidinemethanol.

This compound was prepared according to the procedure used to j syntheisze the compound of Example 1. A mixture of 3.0 g (0.01 mole) of a,Qbis(4-fluorophenyl)I1-4-piperidinemethanol, 1.8 g (0.01 mole) of 1-.chloro-3-(3methylphenoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.8 g of the title compound as a white solid, mp 112.5-114'C (2-propanol).

Analysis: Calculated for C 2 8

H

3 jF 2 N0 2 74.48; H, 6.92; N, 3.10 Found 74.44; H, 6.95; N, 3.15 00 Cd 0 d 0 I IO -223- AHR-438A-CIP SExample 217 Sa.a-Bis(4-fluorophenyl)-l-[3-(2-phenylmethoxy)phenoxy propyl-4piperidinemethanol fumarate [1:11.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 7.6 g (0.025 mole) of Q,a-bis(4fluorophenyl)]-4-piperidinemethanol, 6.9 g (0.025 mole) of 1-chloro-3-(2benzyloxyphenoxy)propane, 8.5 g (0.08 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of 1-butanol gave a gum as residue.

The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile to yield 10.5 g of the title compound as an offwhite solid, mp 172-174°C.

Analysis: Calculated for C 3 8

H

39

F

2

NO

7 C, 69.18; H, 5.96; N, 2.12 Found C, 69.15; H, 5.92; N, 2.19 Example 218 a,a-Bis(4-fluorophenyl)- 1-3-(2-hydroxyphenoxy)propyl]-4-piperidinemethanol fumarate with ethyl acetate A solution of 6.1 g (0.011 mole) of a,a-bis(4-fluorophenyl)-1-[3-[2- (phenylmethoxy)phenoxy]propyl]-4-piperidinemethanol dissolved in 200 mL of absolute ethanol was hydrogenated in a Parr apparatus over 5% palladium on carbon catalyst at 60°C overnight. The cooled mixture was filtered through Celite®, and the filtrate was concentrated to give a gum as residue.

The dark gum was dissolved in ethyl ether and filtered to remove insolubles.

S The filtrate was concentrated to give 2.8 g of tan gum as residue. The gum It was dissolved in ethyl acetate and mixed with an equivalent amount of fumaric acid dissolved in ethyl acetate. The solution was filtered, and a solid crystallized from the filtrate. The solid was collected by filtration and dried to yield 2.3 g of the title compound as a white solid, mp 106-116°C (dec).

The presence of 1 mole of ethyl acetate was confirmed by 1H NMR.

Analysis: Calculated for C 3 1

H

33

F

2

NOTC

4

H

8 0 2 C, 63.92; H, 6.28; N, 2.13 Found C, 63.62; H, 6.08; N, 2.24 0) -224- AHR-438A-CIP Example 219 a,a-Bis(4-Fluorophenyl)-l-[3-[2-(l-methylethoxy)phenoxy]propyl]-4- Spiperidinemethanol.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,abis(4-fluorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-chloro-3-[2- (1-methylethoxy)phenoxy]propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.9 g of the title compound as a fluffy, white solid, mp 75-79 C (2-propyl ether).

Analysis: Calculated for C 30

H

35

F

2 N0 3 C, 72.70; H, 7.12; N, 2.83 Found C, 72.65; H, 7.47; N, 2.69 Example 220 34-[3-[4-[Bis(4-fluorophenyl)hydroxymethyll- 1piperidinyl]propoxy]benzeneacetic acid ethyl ester oxalate [1:11 with ethyl acetate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 7.6 g (0.025 mole) of [a,abis(4-fluorophenyl)]-4-piperidinemethanol, 6.1 g (0.025 mole) of 4-(3-chloropropoxy)benzeneacetic acid methyl ester, 9.5 g (0.09 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 150 mL of dimethylformamide gave a gum as residue. The gum was purified by column chromatography on 250 g of Florisil®. Fractions eluted with 5-25% acetone in benzene were combined and concentrated to give a gum as residue. The gum was I converted to the oxalic acid salt, and the solid was recrystallized from ethyl i acetate to yield 7.0 g of the title compound as a white solid, mp 93-98 C (dec).

Analysis:Calculated for C 32

H

35

F

2

NO

8 *0.5C 4

H

8 0 2 C, 63.44; H, 6.10; N, 2.18 Found C, 63.00; H, 5.99; N, 2.23 Example 221 4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl- 1-piperidinyl]propoxylr N,N-dimethylbenzamide fumarate [1:11.

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-

ICI

S 0,0 o6: i 2~ i 11 1,1 -225- AHR-438A-CIP bis(4-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of4-(3-chloropropoxy)-N, N-dimethylbenzamnide, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from acetonitrile-water to yield 4.0 g of the title compound as a white solid, mp 166-168 0

C.

Analysis: Calculated for C 34

H

38

F

2

N

2 0 7 C, 65.37; H, 6.13; N, 4.48 Found C, 65.21; H, 6.12; N, 4.45 Example 222 1-[3-(2,6-Dimethoxyphenoxy)propyl]-a,a-bis(4-iluorophenyl)-4piperidinemethanol.

This compound was prepared according to the procedure used to synt tI tthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,abis(4-fluorophenyl)J-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-(3-chloropropoxy)-2,6-dimethoxybenzene, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 2.0 g of the title compound as a white solid, mp 136-137 0 C (2-propyl ether/2propanol).

Analysis: Calculated for C 29

H

33

F

2 N0 4 C, 70.00; H, 6.68; N, 2.81 Found C, 70.15; H, 6.78; N, 2.85 Example 223 [4-f3-[4-[Bis(4-fluorophenyl)hydroxymethyl-1-piperidinvl]propoxvlphenyliphenylmethanone fumarate This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [a,a-bis(4fluorophenyl)1-4-piperidinemethanol, 2.7 g (0.01 mole) of [4-(3-chloropropoxy)phenyl]phenylmethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was converted to the fumaric acid salt, and the solid was recrystallized from absolute ethanol to yield 4.3 g of the title compound as a tan solid, mp 200-201'C (dec).

Analysis: Calculated for C 38

H

37

F

2 N0 7 C, 69.39; H, 5.67; N, 2.13 Found C, 69.36; H, 5.63; N, 2.17 ES N 0 00 co ed Cd Cd X c~ CI d Cd CZ XL2d EE 0 -226- AHR-438A-CrEP 1-[4-i13-[4-[Bis(3 ,4-difluorophenyl)hydroxymethyll-1-piperidinyllprpxv--,i~oxpeyltaoe The compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 1.4 g (0.004 mole) of a,abis(3,4-difluorophenyl)-4- pipe ridi nemethanol, 1.0 g (0.004 mole) of 1-14-(3chloropropoxy)-3-methoxyphenylljethanone, 1.6 g (0.015 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 1.lg of the title compound as an off-white solid, mp 143-146'C (2propanol).

4.Analysis: Calculated for C 30

H

3 jF 4 N0 4 C, 66.05; H, 5.73; N, 2.57 Found 66.03; H, 5.89; N, 2.50 Example 225 f 1 ~4413- [4-[Bi s(4-fl uorophenyl)hydroxymethylll-1 -pi peri di nyl)pro poxylbenzeneacetic acid hydrate (1:0.51.

t A mixture of 3.7 g (0.0073 mole) of the free base of 4-[3-i14-[bis(4-fluorophenyl)hydroxymethyll- 1-piperidinyllpropoxylbenzeneacetic acid ethyl ester oxalate [1:11, 0.8 g (0.0145 mole) of potassium hydroxide, 10 mL of water and mL of 95% ethanol was heated at reflux under a nitrogen atmosphere for hr. The solution was poured into a rnixture of 1.3 g (0.022 mole) of glacial acetic acid in 500 xnL of ice-water and let stand at ambient temperature over night. The solid which had precipitated was collected by filtration, washed with water, air dried, and recrystallized from 2-propanol to yield 2.9 g (78%) of the title compound as a white solid, mp 113-121'C (dec).

Analysis: Calculated for C 2 9

H

3 2

F

2 N0 4 5 69.03; H, 6.39; N, 2.78 Found 69.35; HI, 6.43; N, 2.74 Example 226 1-(4-[13-[3-[Bis(4-fluorophenyl)hydroxymethvll- 1-piperidinyllpropoxyl- 3-methoxyrphenyllethanone.

The compound was prepared according to the procedure user to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of Q,Q-bis(4fluorophenyl)-3-piperidinemethanol, 2.4 g (0.01 mole) of 1-14-(3-chloropro- C) M~ Ca cc~~ .WNC M CS M IdC 6 C M~ COE t L U -227- AHR-438A-CIP poxy)-3-methoxyphenyl]ethanone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 4.0 g of the title compound as an off-white solid, mp 100-105°C (2-propanol).

Analysis: Calculated for C 3 0

H

3 3

F

2 N0 4 C, 70.71; H, 6.53; N, 2.75 Found C, 70.62; H, 6.61; N, 2.77 Example 227 1-[4-f33-3-2,2-Bis(4-florophenyl)-2-hydroxyethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone fumarate This compound was prepared according to the procedure used to synthesize the compound in Example 1. A mixture of 3.7 g (0.012 mole) of the Sfree base of [a,a-bis(4-fluorophenyl)]-3-piperidineethanol hydrochloride 2.8 g (0.012 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 4.3 g (0.04 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 mL of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. Fractions eluted with 20-60% acetone in benzene were combined and concentrated to give a gum. This gum was converted to the fumaric acid salt, and the solid was recrystallized from ethyl acetate acetonitrile to yield 2.6 g of the title compound as white solid, mp 133-136 0

C.

Analysis: Calculated for C 35

H

39

F

2 N0 8 C, 65.72; H, 6.15; N, 2.19 Found C, 65.41; H, 6.15; N, 2.18 Example 228 1-[4-[3-[3-[Bis(4-fluorophenvl)hydroxymethyl]-1-vvrrolidinvl]propoxy]- 3-methoxyphenyl]ethanone.

A mixture of 2.9 g (0.01 mole) of a,a-bis(4-fluorophenyl)-3-pyrrolidinemethanol, 2.4 g (0.01 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenylethanone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 100 mL of 1-butanol was heated at reflux for 24 hr. The mixture was concentrated under reduced pressure, and the residue partitioned between 100 mL of benzene and 100 mL of water. The benzene layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown gum. The gum was purified by column chromatography on 80 g of Florisil® using a gradient i U\a) a) aO o _Z 0 o a Id L C L S -2 a 0 CI 0 -228- AHR-438A-CIP elution system of 0-10% acetone in benzene. The fractions containing the desired product were combined and concentrated under reduced pressure to give 3.2 g of a brown gum. This gum was further purified by high-pressure liquid chromatography (Waters Associates Prep LC/System 500A; Preppac 500 silica; 1% methanol in methylene chloride; fli w rate 150 mL/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 1.7 g (34% yield) of the title compound as a light-yellow, glassy solid, mp 44-46 0

C.

Analysis: Calculated for C 29

H

3 1

F

2

NO

4 C, 70.29; H, 6.31; N, 2.83 Found C, 69.60; H, 6.26; N, 2.86 t 4 .Example 229 [[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]phenyl]amino]oxoacetic acid ethyl ester.

To a solution of 4.5 g (0.01 mole) of the base of 1-[3-(4-aminophenoxy)propyl]-a,a-bis(4-fluorophenyl)-4-piperidinemethanol (free base obtained in Preparation 133), and 1.5 g (0.015 mole) of triethylamine in 50 mL of benzene is added dropwise a solution of 1.4 g (0.01 mole) of ethyloxolyl chloride in I mL of benzene. The mixture is stirred at ambient temperature for 3 hr and then treated with 50 mL of water. The layers are separated and the organic layer is washed with brine, dried over sodium sulfate, and concentrated to give the title compound.

Example 230 [[4-[3-[4-[Bis(4-fluorophenvl)hvdroxvmethvl--l-iperidinvylpropoxy]phenvlaminol-oxoacetic acid.

A solution of[[4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]phenyl]amino]oxoacetic acid ethyl ester in 50 ml of ethanol is treated with 20 ml ofa 2N sodium bicarbonate solution and the mixture is heated at reflux overnight. The mixture is cooled and poured into 500 ml of water containing 10 ml of acetic acid. The resulting solution is collected by filtration and dried to give the title compound.

41 C c 4 4 oCXM C Cd 3X 0 I Oe C 4 0 0s Cq LO 6 g C >1 ga j>g 1-M g w g-z

C;C

-229- HR-438A-ClIP Examnple 231 ac-Bis(4-fluorophenyl)- 1-13-[ 4-(dimeth-ylamino)phenoxylpropyll1-4piperidinemethanol.

A solution of 4.8 g (0.01 mole) of Q,a-bi-9(4-fluorophenyl)-1-13-(4-nitrophenoxy)propyl-4-piperidinemethanol (obtained in Example 52) and 2.0 g (0.025 mole) of 37% formalin in 100 ml of absolute ethyl alcohol is hydrogenated at ambient temperature over 5% palladium on carbon catalyst overnight. The mixture is filtered through Celite® and the filtrate is concentrated to give the title compound.

Example 232 1-f 4-f 3-[4-[Bis(4-fluorophenyl)hydroxymiethyll- 1-piperidinyl]propoxyl-.

Penl-2,2-dimethvl-1-propanone.

A mixture of 3.0 g (0.01 mole) of QL,c-bis(p-fluorophenyl)-4-piper; dinemethanol, 2.5 g (0.01 mole) of 4-(3-chloropropoxy) phenyll b utyl I ketone, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol is heated to reflux overnight. The mixture is concentrated and the residue is partitioned between benzene and water. The organic layer is dried over sodium sulfate and concentrated to give the desired tit'lemcmpound.

Example 233 hen yl)meth vii-1- piperidinyl -3-methoxyphenylI ethanone fumarate hydrate LI12:.

A mixture of 7.65 g (0.023 mole) of Qaa-bis(4-flu orophenyl)-4-piperi dineacetamide, 2.17 g (0.023 mole) of methyl chloroformate in 400 ml of methylene chloride at room temperature was stirred overnight. The mixture was extracted with dilute sodium hydroxide and was dried over sodium sulfate. The solvent was removed in vacuo to give 5.95 g of 4-[2amnino- 1, 1-bis(4-fluorophenyl)-2-oxoethyl 1 -pipe ridinecarboxylic acid methyl ester as a white solid, mp 126-129'C.

Analysis: Calculated for C 21

H

2 2

N

2 0 3

F

2 64.94; H, 5.71; N, 7.21 Found C, 64.83; H, 5.97; N, 6.92 -230- AHR-438A-CIP To a magnetically stirred solution of 3.88 g (0.01 mole) of 4-[2-amino-l,1bis(4-fluorophenyl)-2-oxoethyl]-1-piperidinecarboxylic acid methyl ester and g (0.05 mole) of 50% sodium hydroxide solution in 40 ml of methanol at room temperature was added dropwise a solution of 4.04 g (0.025 mole) of bromine in 25 ml of methanol. The mixture was heated at reflux for 16 h.

The solvent was removed in vacuo, and the residue was partitioned betweel chloroform and water. The organic layer was dried (sodium sulfate), and the solvent was removed in vacuo to give 3.60 g of 4-[bis(4-fluorophenyl)- (methoxycarbonyl) aminomethyl]-l-piperidinecarboxylic acid methyl ester.

A pure sample was prepared by subjecting 0.26 g of this material to flash chromatography (silica gel, elution with a 50/50 mixture of ethylacetate- Shexanes) to give 0.13 g of a white solid, mp 213°C.

Analysis: Calculated for C 22

H

24

N

2 0 4

F

2 C, 63.15; H, 5.78; N, 6.70 Found C, 62.64; H, 5.81; N, 6.53 S, A mixture of 2.98 g (7.1 mmole) of 4-[bis(4-fluorophenyl) (methoxycarbonyl) aminomethyl]-l-piperidinecarboxylic acid methyl ester and 20.0 g (0.25 mole) of 50% sodium hydroxide solution in 40 ml,of methanol was heated at keflux overnight. Water (10i ml) was added, and the mixture was extracted with chloroform. The organic phase was dried (sodium sulfate), and the solvent was removed in vacuo to give an 1.92 g of a,a-bis(4fluorophenyl)-4-piperidinemethanamine as a yellow oil: 1H NMR (CDC1 3 51.0-1.9 7H, CH2 at 3 and 5 position ofpiperidine ring, NH 2 and NH), 2.2- 3.3 5H, CH 2

NCH

2 and CH), 6.8-7.6 8H, aromatic); CIMvS, m+ 1/e 303, 286. A small sample was converted to the oxalate salt, and the salt was recrystallized from methanol'ether to give a,a-bis(4-fluorophenyl)-4-piperidinemethanamine ethanedioate hemihydrate as a white crystalline solid, mp 151-154 0

C.

Analysis:Calculated for C 22

H

24

N

2

F

2 0 8 *0.5H 2 0 C, 53.77; H, 5.13; N, 5.70 Found C, 53.39; H, 5.20; N, 6.04 A mixture of 7.34 g (0.0243 mole) of a,a-bis(4-fluorophenyl)-4-piperidinemethanamine, 5.88 g (0.0243 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone and 5.53 g (0.04 mole) of potassium carbonate in 500 ml of 1-butanol containing 0.2 g of potassium iodide was heated at reflux over- -231- AHR-438A-CIP night. The solvent was removed in vacuo, and the residue was partitioned Sbetween chloroform and dilute sodium hydroxide. The organic layer was' dried (sodium sulfate) and the solvent was removed in vacuo to give 12.94 g of the nonsalt form of the title compound. This was converted to the fumarate salt, and the salt was recrystallized from methanol/ether to give 11.25 g of the title compound as a pale yellow solid, mp 124-128 0

C.

Analysis: Calculated for C 3 8

H

44

N

2 0 12

F

2 C, 60.15; H, 5.84; N, 3.69 Found 59.84; H, 5.56; N, 3.56 Example 234 N-[[1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-piperidinyl]bis(4fluorophenyl)methyl]acetamide.

A mixture of 3.53 g (6.95 mmole) of 1-[4-[3-[4-[aminobis(4-fluorophenyl)methyl]-l-piperidinylj-3-methoxyphenyl]ethanone, 1.10 g (14.0 mmole) of acetyl chloride and 0.96 g (6.95 mmole) of potassium carbonate in 100 ml of acetonitrile was stirred at room temperature overnight. The reacton was then stripped to dryness, and chloroform was added. Water was slowly added. The chloroform layer was extracted with water and also sodium hydroxide. The chloroform layer was dried (sodium sulfate) filtered, and the solvent removed to give a fluffy brown residue (3.68 g, This material was subjected to flash chromatography on silica gel using ethyl acetate for elution. Fractions of similar purity were combined and solvent was removed to give a fluffy white residue. This material was dried in vacuo overnight at 80°C to give 1.63 g (42.6% yield) of fluffy white amorphous material (mp 98 0 C glass 128 0 C oil).

Analysis: Calculated for C 3 2

H

36

N

2 0 4

F

2 C, 69.80; H, 6.59; N, 5.09 Found 69.33; H, 6.60; N, 5.07 S. p

S

S.

a 232.

TablII(Page I)

S

0 00 0~S 0000 00 0 7 0 0 0 v 0 AHR-438A-Ci1' (A)d

I

Ex.

No.

1 2 3 4 6 7 8 9 11 12 13 14 16 17 18 Ar CE;i.I5- 4.Fi?t114- 4C 6 11-

C

6 "1 5 4-F-C(;11 4 4-F-C 6 ;11,1- 4.-F-C 6 I.1- 4-F-C 6 1 14- 4-F-C(;114- C6;LJ 5 4-F-C 6 114- 4-F-C 6 1-1 4 4-F-C 61-14- 6 "1 5

C

6 5 4-F-C 6 11 4

C

6 "1 5 4-F-C 6 11 4 4-F-C 6114-

C

6 "1 5 4-F-C(;11 4 4-F-C 6 i LI- 4-F-C 6 114- 4-F-C 6 114- 4-F-C 6 11 4

C

6 il1 1 (A)d Oil O il it 11 Oil R i ng LQ)n ltuwion~ -4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 (B)z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

D

C

6 i11-

C

6 115-

C

6

H

5

C

6

H

5

C

6 11 5

C

6 11 5

C

6

H

5

C

6 11 5 4-C 6 11-

-C

6 H 3C 6

H-

4-CI-C 6 114- 4-F-C(;11 4 4-0C11 3

-C

6 11 4 Salt oxalate oxalate, 0.5 1120 oxalate oxalate fumarate fumnarate oxalate funiarate oxalate oxalate fum ara te Oxalate mandelate fuinarate furnarate -233- IIR-438A-CIP Salt 'umarate Table 1 (Page Ex.

No. P 19 1 1 21 1 22 1 23 1 24 1 1 26 1 27 1 28 1 Ar 4-F-C 6 114- 4-F-CGH 4 4-F-C 6 11 4 4-C11 3

-C

6 114- 4-,F-Ca;114- 4-F-C 6 11 4 j- 4-OC II 3

-C

6 1*1 4 4-OCIJ 3

-C

6

H

4 4-F-C 1 114- 4-F,-C(;1l 1 j-

R

4-F-C 6 H1 4 4-F-C 6

H

4 4-F-C6fH4- 4-F-C 6 1L 1 4-CI1 3

-C

6 fI 4 4-F-C 614- 4-F- (61H 4 4-F-C 6 11 4 4- 0C11 3

-C

6 l14- 4-0C11 3

-C

6 11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-Cr11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C6H 4 4-F-C 6 11 4 e 11 il 11 il il Ring (Q)n Position 4 4 4 4 4 4 4 4 4 4 4 4 4 (B)z 0 0 0 0 0 0 0 0 0 0 0 0 0

D

2-OCH 3

-C

6 114- 2-OCH 3

-C

6 H4- 2-0C11 3

-C

6 11 4 3,4-(OCH3)2-C613- 2,6-(OCH3) 2 -C6HI 3 3,4-(0C11 3 2

-C

6

H

3 2,6-(0C11 3 2

-C

6 11 3 3 ,5-(0C11 3 2

-C

6

H

3 3,4-(0OC1 3 2

-C

6 1{ 3 4-OC11 3

-C

6 11 4 4-C(0)Cii 3

-C

6

H

4 4-C(O)C11 3

-C

6

H

4 4-C(0)CH 3

-C

6

H

4 AHR-438A-CJP Salt oxalate oxalate furnarate oxalate oxalate, 1120 fumnarate, 0.5 1120 oxalate ox ala te 2-propanolate fu,-arate IHcI, 1120 ~HBr LHBr 32 1 4-Fe-C 6 i1-4 33 1 4-1"-C 6 114- 34 1 4-F-C 6 tI 4 1 4-F-C0 6 114- 36 1 4-F-C 6 LJ1- 37 1 4-F-C 6 1 1 38 1 4-F~-C 6 II1, 1 39 1 4-OCI-1 3

-C

6 11 4 4 0 3 2-C11 3 -4-C(0)CH 3

C

6 11 3 4 0 3 4-CN-C 6 H1 4 4 0 3 4-CN-C 6 11 4 4 0 3 4-C(0)0C 2 H1 5 -C6114 4 0 3 4-C(0)0H-C 6 11 4 4-C(0)0C 2

H

5

-C

6 11 4-Ck'0)0C 2

H

5

-C

6 Hz 4 0 3 .4-C(0)0C 4 1 9

-C

6 11 4 AHR-438A-CIP ~-234- .AR48-I AHR-438A-CIP 00 AHR-438A-CIP Salt oxalate, 1120 oxalate fumnarate fumarate, with ethyl acetate oxa late, with 0.5 ethyl acetate fumarate fumnarate Table 1 (Page 3)1 Ex.

No. P Ar 40 1 4-0C11 3

-C

6 11 4 41 1 4-F-C 6 11 4 42 1 4-F-C 6 11 4 43 1 4-F-C 6 11 4 44 1 4--C6H 4 1 4-0C11 3

-C

6 114- 46 1 4-F-C;1-1 4 47 1 4 -F C 6 11 4 48 1 4-C11 3

-C

6 11 4 49 1 4-F-C 6 11 4 50 1 4-F-C 6 11 4 51 1 4-F-C,6II 4 52 1 4-F'-C 6 1 1 53 1 4-IF-C(31tJ 4 54 1 4-F-C 6 11 4 55 1 4-F-C 6 11 4 56 1 4-F-CjI~j-

R

4-OCH 3

-C

6

H

4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-0C11 3

-C

6 11 4 4-F-C 6

H

4 4-F-C 6114- 4-C11 3

-C

6 11I4- 4-F-C 6 H1 4

~I-F-C

6

H

4 4-F-C 6 H1 4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 H1 4 4-F-C 6 11 4 4-F-C 6 11 4 (A)d

H-

Ring (Q)n Position 4 o11 Oil Oil (B)z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

D

4-C(0)0C2H 5

-C

6

H

4 4-C(0)0C 2 1 5

-C

6

H

4 2-OC H 3 -4-CH 2 C(0)0C2H 5

-C

6 114- 4-t-butYl-C 6

H

4 4-t-butYl-C 6 11 4 4-t-butYl-C6114- 4-t-butYl-C 6 11 4 3-CF 3

-C

6 I1 4 4-NHC(0)CH 3

-C

6 11 4 4-NHC(0)C1 3

-C

6

H

4 4-NH 2

-C

6

H

4 4-N11C(0)C1 3

-C

6 11 4 4-NO 2

-C

6 H14- 4-C(O)N11 2

-C

6 11 4- 1-C 1 0

H

7 1-C 1 0117- 2)-0C1 3 -4-C(0)C11 3

C

6 11 3 Salt fumnarate, 0.5 1120

HCI

HCI

fumnara te fumnarate, 1120 oxalate oxalate fumnarate, 1120 HBr fumnarate, 0.5 H 2 0 HCI,1H 2 0

HCI

oxalate oxalate Oil 011 Oi

H

iR-438A-CIP -235- 409 Cc AHR-43 8A-r'TP Salt 1120 fumnarate T~able 1 (Page 4) Ex.

No. P Ar 57 1 4-F-C 6 1-1 4 58 1 4-F-C 6 11 4 59 1 4-F-C 6 11 4 1 3-CF 3

-C

6 11 4 61 1 C 6 11 5 62 1 C 6 11 5 63 1 4-F-C 6 11 4 64 1 4-rF-C 6 [Lj- 1 C(;11 5 66 1 4-F-C(6lI 4 67 1 4-F-C(jlj- 68 1 CO11 5 69 1 3-CF 3

-C

6 11 4 1 CG 11 5

R

4-F-C 6 11 4 4-F-C 6114-

C

6 11 5

C

6

H

5

C

6 H1 1 1 4-F-C 6114- 4-F-C 6 11 4

C

6 "1 5 4-F-C 6114-

C

6 11 5

C

6 11 5 06115- 061111e (A)d Of] Oil Oil Oil Oil Ring (Q.in Position 4 4 4 4 4 4 4 4 (B )z 0 0 0 0 0 0 0 0 0 0 0 0 0 0

D

2-OCH 3 -4-C(0)CH 3

C

6 "1 3 2-00113-4-0(0)0113-

C

6 11 3 2-0C1 3 -4-C(0)C1 3 06113- 2-OC}1 3 -4-C(0)C1 3 06113- 2-0C11 3 -4-C(0)C1 3 06113- 2-0C1 3 -4-C(0)C1 3 06113- 4-CHOHCH 3

-C

6 1 4 2-OCH 3 -4-

CHOIICH

3

C

6 11 3 2-0C1 3 -4-C(0)C1 3 06113- 2-0C1 3 -4-C(0)C1 3

C

6 H1 3 2-0011 3 -4-C(0)CH 3 06113- 2-0011 3 -4-C(0)011 3

C

6

H

3 2-0011 3 -4-C(0)C11 3 06113- 2-00H 3 -4-C(0)C1 3 06113- Salt 1.2 fumnarate oxalate oxalate ox ala te oxalate oxalate, 0.5 1120 oxalate oxalate oxalate 1101, 0.5 1120 1101 -236- -236- AHR-438A-CJIP 4.

AHR-438A-CIP Table 1 (Page Ex.

No. P Ar, 71 1 4-F-C 6 11 4 1- 72 1 4-F-C 6 11j- 73 1 4-F-C 6 1L 1 74 1 4-F-C(;H,-t 1 4-CI-C 6 11- 76 1 4-F-C 6 11 4 77 1 4-0C11 3

-C

6

H

4 78 1 4-CH 3

-C

6 11 4 79 1 4-F-C 6114- 1 4-F-C 6 1-1 4 81 1 4-F-C(;11 4 82 1 4-r--C 6 11 4 83 1 4-F-C 6 H1 4 84 1 4-F-C 6 1-1 4 1 4-1i-C 6 11 4

R

4-F-C 6 H4- 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-CI-C 6

H

4

C

6 H1 5 4-0C1 3

-C

6 11 4 4-CH 3

-C

6 11 4 4-F-C 6 11 4 4-F- C 614- 4-F-C 6 1-1 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 H1 4 4-F-C 6 11 4 e (A)d 01IL 0il 0i1 1-1 11 if

H

H

Oil1 Oi01 Oi01 Oil1* Ol01 Oil Ri ng (Q)n Position 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 (B)z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

D

2-OCH 3 -4-C(0)CH3-

C

6 H1 3 2-OCH 3 -4-C(0)CH 3

C

6

H

3 2-OCH 3 -4-C(0)CH 3

C

6 H1 3 2-OCH 3 -4-C(0)CH 3

C

6

H

3 2-0C11 3 -4-C(0)CH 3

C

6 11 3 2-OCH 3 -4-C(0)CH 3

C

6 11 3 2-0C11 3 -4-C(O)CH 3

C

6 H1 3 2-OCH 3 -4-C(0)CH 3

C

6 11 3 2-0C11 3 -4-C(0)CH 3

C

6

H

3 2-0C113-4-C(0)- 0C11 3

-C

6 11 3 4-SCII 3

-C

6 11 4 4-S(0) 2 C11 3

-C

6

H

4 2-OCH 3 -4-C11 2 C(0)0C 2

H

5

C

6

H

3 4-C(0)0C 2

H

5

-C

6

H

4 2-0C11 3 -4-CH 2 C(0)- ONa-C 6 11 3 Salt oxalate oxalate furnarate

HCI

HCJ

0.51H20 11 1 -1-11-1 -237- H-38~T AHR-438A-CT1? Table 1 (Page 6) Ex.

No. P Ring e kAAd (Q)n Position (B)z D j:9on 0 o1o -1- 0 w) w0 Ii ~)0 0* 0 c 0 86 1 4-F-C 6 11 4 87 1 4-F-C 6 1-1 4 4-F-C 6114- 4-F-C 6 1-1 4 4-F -C 6 1-1 4 4-F-C 6114- 93 1 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 11 4 4-F-C 6

H-

4 4-F-C 614- 4-F-C 6 1-1 4 4-F-C 6 11 4 4-F-C64 4-F-C 6 11 4 4-F-C 6 H1 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 H1 4 4-F-C 6 H1 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6114-

H

H

Oil Oil oil Oil Oi01 4 0 3 4-F-C 6114- 4-F-C 6 17 4 4-F-C)1-1 4 4.-F-C 6 114- 4-F-C 6 1L 1 4 0 3 2-C(0)0C 2

H

5

-C

6 H4- 4 0 3 2-C(0)0C 2

H

5

-C

6

H

4 4 0 5 2-0CH 3 -4-C(0)CH 3

C

6 H1 3 4 0 3 4-C(0)N11 2

-C

6 H4- 4 0 3 4-S(0) 2 C11 3

-C

6

H

4 4 0 6 2-0C11 3 -4-C(0)CH 3

C

6 H1 3 4 0 3 3-OCH 3 -4-C(0)CH 3 4 0 3 2-011-C 6 11 4 4 0 3 4-S(0)CH 3

-C

6 11 4 4 0 3 4-S(0)2NH 2

-C

6

H

4 4 0 3 4-NHS(0) 2

CH

3 4 0 3 4-NHC(0)NHCH 3

C

6 H1 4 4 0 3 4-NHC(0)0C 2 1 5

C

6

H

4 4 0 3 3-NHC(0)NH 2 4 0 3 2-OCH 3 -4-C(O)OH-

C

6

H

3 Salt 0.75 fumnarate 0.5 1120 1.5 fumnarate oxalate fumnarate

HCI

sodium 99 1 4-F-C 6 11 4 100 1 4-F-C(;11 4 101 1 4-F-C(;11 4 -238,- 9, 4* a 9, a-co C AHR-438A-CIP Table 1 (Page 7) Ex.

No. P Ar 102 1 4-F-C 6 1 114- 103 1 4-F-C 6 J-1 4 104 1 4-F-C6I 1 4- 105 1 C 6 115- 106 1 C0115- 107 1 4-1F-C 6 11 4 108 1 4-F-C 6 1-Lj4- 109 1 4-F-C 61-14- 110 1 4-F-C 6 1-1 4 111 1 4-F-C 6 H1 4 112 1 4-r--C(;11 4 113 1 4-F-C 6 11 4 114 1 4-F-C 6 11 4 115 1 4-F-C 6 11 4

R

4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6 11 4 (A)d 011 Oil 01l (Q)n Ring Position 4 (B)z 0

D

3-OIH-4-C(0)CH 3

C

6 114-

C

6 11 5

C

6 HI I- 11 40 3 0 m o I OOC 2

II

0 4 0 3 0 lO 4 0 3 2-OCH 3 -4-C(0)CH 3

C

6 H1 3 4* 0 3 2-OCIHs-4-C(0)CH3-

C

6

H

3 4 0 3 3-OCH 3 -4-C(0)CH 3

C

6 H1 3 4 0 3 2,6-C1 2

-C

6 11 3 4 0 3 2,6-C1 2

-C

6 11 3 4 0 3 2-CN-C 6

H

4 4 s 2 C 6 11 5 4 S 2 C 6 11 5 4 -S(0) 2 2 4-Cl-C 6

H

4 4 -S(0) 2 2 4-Cl-C 6

H

4 4 3 C 6 H1 5 Salt "Cl

HCI

oxalate, 0.5 oxalate, 0.51H20 HCl oxalate maleate 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6

H-

4 4-F-C 6

H

4 4-F-C 6 H1 4 4-F-C6114- 4-F-C 6114- 4-F-C 6 H1 4 4-F-C 6 11 4 Oil

H-

1-1 1H 011 Oil 1.5 fumnarate

NM----M

-239. -39.AIIR-438A-CWE Table 1 (Page 8) Ex.

No. P Ar 116 1 4-F-C 6 11 4 117 1 4-F-C 6 11 4 118 1 C6 1 11 5 119 1 C 6 1-1 5 120 1 C 6 1I15- 121 1 C6115- 122 0 C 6 1 t5- 123 1 C6115- 124 1 C 6 11 5 125 1 C6115- 126 1 4-F-C 6 11 4 127 1 C 6 L1 5 128 1 C6115- 4-F-C6Ht 4-F-C 6 f1 4 Ring e (A)d (Q)n Position H -4 H 4I -CN -4 -CN -4 (B)z -S(0) 2

D

4-CI-C 6 11 4 Salt maleate maleate -S(0) 2 2 06115 1 o

C

6 H1 5 C6115- 06115-

C

6

H

5

C

6 11 5 06115- 4-F -C 6 11 4 06115-

C

6

H

5 -CN -0112- 3 0 3 2-00113-4-C(0)CH3- 3 2-00113-4-C(0)0113- 06113-

-CN

-C(0)N11 2 -C(0)N11 2 11

-CN

-CN

-0112- 3 0 4 2-00113-4-0(0)0113- 3 0 3 2-00113-4-0(0)0113- C6113- 4 0 3 2-0C11 3 -4-C(0)CH 3

C

6

H

3 4 0 4 2-OCH 3 -4-C(0)011 3

C

6

H

3

-CH

2 3 0 3 2-0011 3 -4-C(0)CH 3

C

6 11 3 oxalate fumnarate, 1120 fumnarate, 0.5 H 2 0 0.5 H 2 0 oxalate -Cu 9 1 q

O

3 0 2 2,6-012-06113- 3 0 5 2-00H 3 -4-C()11 3

C

6

H

3 0.5 H 2 0

CH,)-

-24C-

A

Table 1 (Page 9) Ex.

No.

129 130 131 132 wCD C) t oo~ CD C C12' En

.C)

*0 CD C Ar 4-F -C 6 11 4 4-F-C 6 114-

C

6 "1 5 4-F-C (I14- 133 1 C(;11 5 134 1 4-F-C 6 114- 135 1 4-F-C 6 11 4 136 1 C 6 11 5 137 1 4-F-C 6 H14- 138 1 4-F-C 6 11 4 139 1 4-F-C 6 11 4 140 1 4-F -C 6 11 4 141 1 4T-F-C 6 1I14- 142 1 4-F-C 6 tl 4 143 1 4-F-C(;IL 4 144 1 4-F-C(;IJ4- 145 1 4-F-C 6 11, 1

R

4-F-C 6

H

4 4-F-C 6 11 4

C

6

H

5 4-F-C 6

H

4

C

6

H

5 2-pyridinyl 2-pyridinyl C6H 5 4-F-C 6 11 4 4-F-C 6 T1 4 4-F-C 6 H1 4 4-F-C 6

H

4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 11 4 4-F-C 6 1-1 4 4-F-C 6 11 4 (A)d

-CN

-CN

-CN

-CN

-CN

-CN

-CN

-CN

-CN

H

(Q)n Poosition m ID 4 0 3 2-OCHi 3 -4-C(0)CH 3 C6" 3 4 0 3 2,6-C1 2

-C

6 H3- 3 0 3 2,6-C1 2

-C

6

H

3 4 0 4 2-OCH 3 -4-C(0)C113-

C

6

H

3 3 0 2 2,6-C1 2

-C

6

H

3 4 0 3 2-0C113-4-C(0)CH3- C6" 3 4 0 3 2-0CH 3 -4-C(0)CH 3

C

6 3 3 0 3 8-quinolinyl 4 0 3 8-quinolinyl 4 0 3 2-C(0)OH-C 6 11 4 4 -NH- 3 C 6

H,

5 4 -NCH 3 3 C 6

H

5 3 0 3 2-OCH 3 -4-C(0)CH 3 C6" 3 3 0 3 4-CN-C 6 11 4 4 0 3 2-OCH 3 -4-CN-C 6

H

3 4 0 3 1-010117- 4 0 3 2-quinolinyl Ring AR1R-438A-C[P Salt maleate maleate oxalate fumarate fumarate fumarate

H

2 0 0.5 0.5 0.5 2 maleate oxalate, 1120 HBr, 0.5 H 2 0 0.51120 ~Einff~~ -241-L*- AHR-438A-CTiP Table 1 (Page Ex.

No. P Ar 146 1 4-F-C 6

H

4 147 1 4-F-C 6 114-

R

4-F-C 6

H

4 4-F-C 6 114- Ring e (A)d (Q)n Position (B)zm D Salt 11 4 0 3 2-CljI07- 0.5 1120 H- 4 0 3 3-CN-C 6 H4- 0.51H20

V

-24-1 -41AHR-438A-CJEP

CD

0 wa

CD

0 '1 0 0

CD

0 C-1-

CA,

1 0 cn i 0

CD

o CD Ca r (n

CL

CD

Cl- Table 1 (Page Ex.

No. P Ar 146 1 4-F -C 6 11 4 147 1 4-F-C 6 H5 4 148 1 4-F-C(;11 4 149 1 4-F-C 6

H

4 150 1 4-F -C6;11 4 151 1 4-F-C 6 11 4 152 1 4-F -C 6 11 4 153 0 4-F-C 6 11 4 154 1 4-F-C 6 1J 4 155 1 4-F-C 6 11 4 156 1 C611 5 157 1 4-F-C 6 11 4

R

4-F-C 6 H4- 4-F-C 614- 4-F-C 6 H-4- 4-F-C 6 11 4 4-F-C 6

H

4 2-pyridinyl 4-F- C 6 H14- 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 1:1 4

C

6 11 5 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6

H

4 4-C11 3

-C

6 11 4 e (A)d

-H

11

-CN

011 011 011 01l Ring (Q)n Position 4 (B)z 0

D

2-C 1 017- CI-2 4 0 3 3-CN-C 6 11 4 4 0 3 4-0C11 3

-C

6 114- 4 0 3 4-CH 3

-C

6 11 4 4 0 3 4-F-C 614- 4 0 3 2-OCI{ 3 -4-C(0)CH3-

C

6 11 3 4 0 3 4-NHC(0)0C 2

H

5 C 614- 3 0 3 2-0C11 3 -4-C(0)C113-

C

6 11 3 4 0 3 2-0H-C 6 H4-v 4 0 3 2-OCH 3 -4-C 2

H

5

C

6 11 3 4 0 3 C 6

H

5 4 0 3 4-S(0)CH 3

-C

6 Hj- 4 0 3 4-CH(CI1 3 2

-C

6

H

4 4 0 3 3-C(O)0C 2

H

5

C

6 11 4 4 0 3 2-0C11 3 -4-C(O)C11 3

C

6

H

3 Salt 0.5 1120 0.5 1120 fumnarate fumnarate, H120 oxalate, 1.5 1120 oxalate, 1120, 0.5 2propanolate oxalate furnarate 158 1 159 1 4-F-C 6 14- 4-F-C 6 114- 160 1 4-CI1 3

-C

6 11 4

I

-242- AIIR-43 8A-CIP Ca1 N~

CD

CD 0) (12 0-

(D

1 11 o o o L Cat 0- 0 CD CD a. 0 CL 0 D P) 0 0. Ca O 0 oD0 Ci) Table 1 (Page 1 1) Ex.

No. P Ar 161 1 4-C11 3

-C

6 11 4 162 1 4-F-C(5l14- 163 1 4-le-C 6 11 4 164 1 4-Fe-C(;11 4 165 1 4-F-C 6 1{ 4 166 1 4-r,-C(111 4 167 1 4-F-C 6 11 4 168 1 4-F-Clifl~ 1 169 1 4-F-C(,11l4- 170 1 4-0C11 3 -C6j11 4 171 1 4-F-C(11 4 172 1 4-F-C 6 11 4 173 1 4-le-C6 1 114- 174 1 4-F-C(;114-

R

4-C11 3

-C

6 11 4 4-F-C 6 11 4 4.-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 H1 4 4-F-C 6 H1 4 4-F-C 6 1I 4 4-F-C 6114- 4-0C1 3

-CP

6 1-1 4 4-F-C 6 H1 4 4-F-C 6 H1 4 4-F- C6114- 4-F-C 6 11 4 e (A)d Oil 0i1 0il .11 -Oil 011 Oil 01l 011 011 Ring (Q2! Position 4 (B)z 0

D

2-OCH 3 -4-C(O)CH3-

C

6 H13- 4 0 3 4-C(0)0CH 3 -C6114- 4 0 3 4-NI{ 2 -C61H 4 4 0 3 3-OCH 3 -4-C(0)CH 3

C

6 11 3 4 0 3 2-0C11 3 -4-C 2

H

5 4 0 3 4 0 3 4-NHC(0)NIICII- 3

C

6

H

4 4 0 3 4-NHS(0) 2

CH

3

C

6 11 4 4 0 3 4-C(0)C 2

H

5

-C

6

H

4 .4 0 3 2-OCH 3 -4-C(0)CH 3

C

6 11 3 4 0 6 2-0C11 3 -4-C(0)CH 3

C

6 H1 3 4 0 3 2-OCH 3 -4-CH(OH)

(CH

3

)-C

6 11 3 4 0 4 4-C(0)OCH3-C 6 1{ 4 4 0 3 2-OCH3-4-C(0)C11 3

C

6 H1 3 Salt oxalate, H120 fumarate 2.0 oxalate oxalate oxalate fumarate, 2-methoxyethanolate 2-propanolate oxalate

HCI

oxalate, 1.51H20 fuinarate fumarate, H120 C11 2 C11 2 -243- Table 1 (Page 12) Ex.

No. P 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 4-F-C 6 11 4 4-F-C 6 114- 4-F-C 6'-4- 4-Cl-C 6114- 4-CI-C 6 114- 4-F-C 6 11 4 3-F-C 6 11L 1

C

6 11 5 4-F-C 6 1-1 4 4-F-C 6 11 4 4-1F-C 6 11 4 4-F-C 6 1J 4 4-F-C 6 11 4 4-F-C 6 1-1 4 3,4-F 2

-C

6 11 3 4-F-C 6 1 14- 4-F-C 6 114- 2-pyri dinyl 4 -Cl-C6jH 4 4-F-c 6 114- 3-F-C 6 11 4

C

6 H1 5 4-F-CSIH 4 4-F-C 6

-H

4 4C 6 1 4-F-C 6 yH 4 4-F-C 6 H1 4 2-pyridiny!I 4-F-C 6 H7 4 4-F-C 6

H

4 e (A)d (Q)n

CN-

H

H-

H-

If ifH ifH

CN-

Ring Position 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 3 (B )z 0 0 0 0 0 0 0 0 0 0 0 0

S

SCO)

0 0 0

D

2-OCH, 3 -4-C(0)CH3

C

6 H1 3 2-0C11 3 -4-C(0)CI{3 C6113-

C

6 H1 5 2-0CIH 3 -4-C(0)CH3

C

6

H

3 2-0CH 3 -4-C(0)CH3

C

6

H

3 2-0C11 3

OCH

3

-C

6

H

3 2-OCHi 3 -4-C(0)CH3

C

6 H1 3 4-C(0)OCH 3

-C

6

H

4 2-0 C1 3 -4-C(0)CH3

C

6

H

3 2-0C11 3 -4-C(0J0H-

C

6

H

3 3-OCH 3

-C

6

H

4 2-0C11 3 0)CH3

C

6

H

3

C

6

H

5

C

6

H

5 2-0C11 3 -4-C(0)CH 3

C

6 H1 3 2-0C113-4-C(0)C11 3

C

6 H1 3 AHR-43 8A-CIP Salt fumnarate fumnarate 1.5 oxalate oxalate, 0.5 H 2 0 1.5 oxalate fumnarate 0.5 1120 0.5 1120 citrate oxalate 0.5 1120 -oxalate -244- AHR-43 8A-CIP T able 1 (Page 13) Ex.

No. P 192 193 194 195(a) 195(b) 195(c) 195(d) 195(e) 196(a) 196(b) 196(c) 196(d) 197(a) 4-rF -C 6 11 4 4-F-C 6 [,1 4 3 ,4-F 2

-C

6

H

3 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6

H

3 2,4-F 2

-C

6 11 3 3-CFP 3

-C

6 1-1 4 4-CFI-C 6 11 4 3,4-F 2 -Cd11- 2,5-F 2

-C

6 11 3 3-CF 3

-C

6 11 4 4-C F 3 -C;1,1 4 3,4-1 I' 2

-C

6 H1 3

R

4-F-C 6 11 4 4-F-C 6 11 4 3,4-F 2

-C

6 1J 3 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6

H

3 2,4-F 2

-C

6

H-

3 3-CF 3

-C

6 11 4 4-CF 3

-C

6 11 4 3 ,4-F 2

-C

6

H

3 2,5-F 2

-C

6 11 3 3-CF 3

-C

6 114- 4-CF 3

-C

6 114- 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6 11 3 Ring e (A)d (Q)n Positic CN CH 2 3 C(0)Ntt 2 4 H Oil* Oil Oi0l Oil1 O0l in (B)z 0 0 0 0 0 0 0- 0 0 0 0 0

D

2-OCH 3 -4-C(0)CH 3

C

6 H1 3 2-0C11 3 -4-C(O)C11 3

C

6

H

3 2-OCH 3 -4-C(0)CH 3 C 6

H

3 2-OCH 3 -4-C(O)C11 3

C

6

H

3 2-0C11 3 -4-C(0)C11 3

C

6

H

3 2-0C11 3 -4-C(0)C11 3

C

6 H1 3 2-OCH 3 -4-C(O)CH 3

C

6 11 3 2-0C11 3 -4-C(O)CH 3

C

6

H

3 2-OCH 3 -4-C(O)CH 3

C

6 11 3 2-0 CH13-4- C( 0)CH 3

C

6 113- 2-OCH 3 -4-C(O)C11 3 C 61'3- 2-OCH 3 -4-C(0)CH 3

C

6

H

3 2-OCH 3 -4-C(O)CH 3

C

6

H

3 Salt 0.5 1120 fumarate, 1120 oxalate oxalate oxalate oxalate oxalate oxalate 197(b) 1 2,5-1 2

-C

6 1-1 3 0 3 2-OCJ- 3 -4-C(0)CU1 3

.C

6 11 3 -245a 4 4 40* 0 4 0 4 S a a 0 a 4 4000 Ot 400 44 0 040 4 Table 1 (Page 14) Ex.

No. P Ring e (A)d (Q)pn Position 197(c) 197(d) 197(e) 198 199 200 201(a) 201(b) 201(c) 201(d) 201(e) 202(a) 202(b) 2 (c) 2,4-F 2

-C

6 11 3 4-CF 3

-C

6 11 4 3 4-F3-C 6 11-T- 3,4-F 2

-C

6 2,4-F 2

-C

6 11 3 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6 11 3 2,4-F 2

-C

6 11 3 3-CF 3

-C

6

H

4 4-CF 3 -C6H 4 3 ,4-F 2

-C

6 11 4 2,5-F 2

-C

6

H

3 2,4-F 2

-C

6 tJ 3

R

2,4-F 2

-C

6

H-

3 3-CF 3

-C

6 11 4 4-CF 3 -0 6 11 4 4-F-C 6 11 4 4-F-C 6

H

4 2,4-F 2

-C

6

FH

3 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6

H

3 2,4-F 2

-C

6

H

3 3-CF 3

-C

6 4-CF 3

-C

6 11 4 3,4-F 2

-C

6 fl 4 2,5-F 2

-C

6

H

3 2,4-F 2

-C

6 11 3 Oil1 if c 2 11 5 0

C

2 11 5 0

C

2 1I 5 0

C

2 11 5 0

C

2 11 5 0

-CN

-CN

-CN

(B)z M 0 3 o 3 o 3 o 3 o 3 o 3 0 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3

D

2-00H3-4-C(O)CHa

C

6 11 3 2-OCH 3 -4-C(O)CH3

C

6 11 3 2-0CH 3 -4-C(0)CH 3

C

6 11 3 2-OCH 3 -4-C(O)CH 3

C

6 11 3 2-0C11 3 0)C1-1 3

C

6 11 3 2-OCH 3 -4-C(0)CH 3 2-OCH 3 -4-C(O)C11 3

C

6

H

3 2-OCH 3 -4-C(0)CH 3

C

6

H

3 2-0C11 3 -4-C(0)CH 3 2-OCH 3 -4-C(O)CHf 3

C

6

H

3 2-OCIH 3 -4-C(0)CH3

C

6 11 3 2-0CH- 3 -4-C(0)CH 3

C

6

H

3 2-OCH 3 -4-C(O)CH 3

C

6 11 3 2-OCH3-4-C(0)CH 3 C61H 3 AHR-43 8A-CWT, Salt oxalate oxalate -oxalate -oxalate -oxalate maleate maleate maleate Table 1 (Page Ex.

No. P 202(d) 202(el 203(a) 203(b) 203(c) 203(d) 203(e) 204(a) 204(b) 204(c) 204(d) 204(e) 205(a) 205(b) 205(c) 205(d) 3-CF 3

-C

6

H

4 4-CF 3

-C

6

H

4 3 ,4-F 2

-C

6

H

3 2,5-F 2

-C

6

H

3 2,4-F2-C 6 F1 3 3-CF3-C6JH- 4-CF 3 -C6Hl 4 3,4-F" 2

-C

6 1{ 3 2,5-F 2

-C

6

H-

3 2,4-F 2

-C

6 I1 3 3-CF 3

-C

6

H

4 4-CF 3

-C

6 11 4 3,4-F 2

C

6 ii1 3 2,5-F2-C 6

H

3 2,4-F 2

-C

6 lJ 3 3-CF 3

-C

6 1 1

R

3-CF 3

-C

6 114- 4-CF 3

-C

6 114- 3 ,4-F 2

-C

6

H

3 2 ,5-F 2

-C

6 1{ 3 2,4-F 2

-C

6

H

3 3-CF 3

-C

6 11 4 4-CF 3

-C

6 1 4 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6 11 3 2 ,4-F 2

-C

6 11 3 3-CF 3

-C

6 11 4 4-CF 3 -C 614- 3,4-F 2

-C

6

H

3 2,5-F 2 -Cj1f 3 2,4-F 2

-C

6 11 3 3-CF 3

-C

6

H

4 Ring e (A)d (Q)n Position -CN 4 -CN 4 C11 2 N1-1 2 4 C11 2 N11 2 4 C11 2 NI1 2 4 C11 2 NI112 4 CI-1 2 NI1 2 4 -C(0)01i 4 -C(0)01I 4 -C(0)0O1 4 -C(0)0.11 4 -C(0)01I 4 4 C1I:3 4 CI 13 4 C11 3 4 C13 (B)z in 0 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 AHR-43 8A-CIP D Salt 2-OCH 3 -4-C(O)CH3- maleate

C

6

H

3 2-OCH 3 -4-C(O)CH 3 maleate

C

6 11 3 2-OCH 3

-C

6 11 4 2-OCH 3

-C

6

H

4 2-OCH 3

-C

6 11 4 2-0C11 3

-C

6

H

4 2-OCH 3

-C

6

H

4 2-0C11 3 -4-C(O)C11 3

C

6

H

3 2-OCE3-C(O)C11 3

C

6 H1 3 2-0C11 3

-C(O)CH

3

C

6 11 3 2-OCH 3 -C(O)C11 3 2-0C11 3 -4-C(O)CH 3

C

6 H1 3 2-OCH 3 -4-C(O)CH 3

C

6

H

3 2-0C11 3 -4-C(O)CH 3

C

6 11 3 2-0C1-1 3 -4-C(O)CIJ 3

C

6

H

3 2-0C11 3 -4-C(O)CH 3 -247-

C

p p p 4 o PC, 0 C S AIHR-438A-CIP 0 CD D a D 0) R

(D~

~D

:3 0 CD 0C) w CD H aiC Table 1 (Page 16) Ex.

No. P A r 205(e) 1 4-CF 3

-C

6 11 4 206(a) 1 3,4-F 2

-C

6

H

3 206(b) 1 2,5-F 2

-C

6

H

3 206(c) 1 2,4-F~ 2

-C

6

H

3 2106(d) 1 3-CF 3

-C

6 1-1 4 206(e) 1 4-CF 3

-C

6 11 4 206(f) 1 3,4-F 2

-C

6 11 3 206(g) 1 2,5-F 2

-C

6 11 3 206(h) 1 2,4-F 2

-C

6 11 3

R

4-CF3-C 6 11 4 3 ,4-F 2

-C

6 11 3 2,5-F 2

-C

6 11 3 2,4-F 2

-C

6

H

3 3-CF 3

-C

6 11 4 4-CF 3

-C

6 11 4 3 ,4-F 2

-C

6 14 3 2,5-F 2

C

6 11 3 2,4-F 2

-C

6 11 3 3-CF 3

-C

6 11 4 4-CF 3

-C

6

H

4 3-F-C 6

H

4 4-F-C 6 1-1 4 4-F-C 6 11 4 e (A)d

-OC(O)-

9113 0c 2 11 5 0C 2 1'15 0c 2 11 5 0C 2 11 5 0C 2 11 5

-C

2 5

C

2 115

C

2 1 5

C

2 11 5

C

2 "1 5 C20115 01-1 01o-1 Ring Position 4 4 4 4 4 4 4 4 4 4 4 4 4 4 (B )z 0 0 0 0 0 0 0 0 0 0 0 0 0 0

D

2-OCH 3 -4-C(0)CH3-

C

6

H

3 2-0C11 3 -4-C(0)CH 3

C

6

H

3 2-0C11 3 -4-C(0)CH3-

C

6

H

3 2-0C11 3 -4-C(0)C11 3

C

6 11 3 2-OCIHa-4-C(O)CH 3

C

6

H

3 2-0C11 3 -4C()C1 3

C

6

H

3 2-OCH 3

-C(O)CH

3

C

6

H

3 22,-C11 3 -C(0)CI{ 3

C

6

H

3 2-0C11 3 -4C(O)CH 3

C

6

H

3 2-OCH 3 -4-C(0)CH 3 c 6 T1 3 2-OCFHa-4C(0)CHi 3

C

6 11 3 4-NH[C(O)C(0)- 0-C 2 11 5

]-C

6 11 4 4-C11 3 -2-OCH 3 C6H Salt fumnarate 206(i) 2060j) 207 208 209 3-CF 3

-C

6 11 1 4-CF 3

-C

6 1{ 4 3-F-C 6 11.p 4-F-C 6 ;H~i- 4-F-C(;1L 1 kir 4 U i4-Utl 3 -2-UUH 3

C

6 11 3 39 1 rn- -248- AHR-438A-CWP Table 1,(Page 17) Ex.

No. P Ar 210 1 4-Fi-C 6 11 4 211 1 4-F-C 6 1{ 4 212 1 4-.F-C 6 t1 4 213 1 4-F-C 6

;H

4 214 1 215 1 4-F-C 6

H

4 4-F-C6I14-

R

4-F-C 614- 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6 f1 4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C611 4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6

H

4 e (A)d Oi01 Oi01 Oi01 Oi01 Oi01 Oil1* Oi01 Oi0l Ring Position 4 (B)z 0 216 1 4-F-C 6 11 4 217 1 4-1i-C 6 3!L 4 218 1 4-F-C 6 11 4 219 1 4-F-C 6 t-1 4 220 1 4-F-C6;t1 4 221 1 4-F -C(;11 4 222 1 4-F-C 6 11 4 223 1 4-F-C 6 11 4 224 1 3,4-F 2

-C

6 11 3 0il

D

2-C(0)C11 3

-C

6

H

4 Salt 4 0 3 3-C(0)CH 3 -C6H4- 4 0 3 3-CH 3

O-C

6 1-1 4 4 0 3 4-C 2

H

5

-C

6

H

4 4 0 3 2-(C 2 11 5 0)-C 6

H

4 4 0 3 2-C11 3

-C

6 11 4 4 0 3 3-CH 3

-C

6 11 4 4 0 3 2-(C 6 iEJ 5 -C12-0-)-

C

6

H

4 4 0 3 2-OH-C 6

H

4 4 0 3 2-[(CH 3 2

CH

2 -0-j- 4 0 3 4-[C11 3

CH

2 6 11 4 4 0 3 4-[(CI{ 3 2

C

6

H

4 4 0 3 2,6-(-0-CH 3 2

C

6

H

3 4 0 3 4-[C 6 11 5

C

6

H

4 4 0 3 2-0C11 3 -4-C(0)CH 3

C

6

H

3 fumarate fumarate, with ethyl acetate oxalate, with ethyl acetate fumarate oxalate, 1120 oxalate Oi0l 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6

H

4 3 ,4-F 2

-C

6 11 3 Oi01 Oi0l 011 011 fumar ate -249- AIIR-438A-CIP Table 1 (Page 18) Ex.

No. P Ring e (Ad Q Position (Bz m D Salt -249- AR48-L AHR-438A-CIEP Table 1 (Page 18) Ex.

No. P 0 0 Ii 01=0 0 0 225 226 227 228 229 230 231 232 233 234 4-F-C;1-1 4 4-FC(;11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 114- 4-F-C 6 11 4 4-F-C 6 1-1 4 4-F-C 6

H

4 4-F-C(;H 4 4-F-C 1 1 4- 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C 6 11 4 4-F-C 6

H

4 4-F-C 6 H1 4 4-F-C 6 11 4 4-F-C 6 1-1 4 Ring e (A)d Position 0O1.l 4 011l 3 011 CH 2 3 0il 3 011 4 011 4 011 4 01 l -4

-NI-

2 4 N11C(0)CI-1 3 4 (B)z m 0~ 3 0 3 o 3 o 3 o 3 o 3 o 3 o 3 o 3 0 3 D Salt 4-[-CH 2 0.51H20

C

6

H

4 2-OCH 3 -4-C(0)CH 3

C

6

H

3 2-0C11 3 -4-C(0)CH 3 fumnarate

C

6 H1 3 2-OCH 3 -4-C(0)CH 3

C

6 11 3 4-[NH[C(0)C(0)0-

C

2

H

5 6

H

4 4-[NH[iC(0)C(0)- Oil]]-6 4-N(CH 3 2

-C

6 11 4 4-IIC(0)C(CH3) 3 2-OCH 3 -4-C(0)CH 3 06114- 2-0C11 3 -4-C(0)CH 3 C6114- 1,2,3,6- tetra hyd ropy ridine.

-250- AHR-438A-CIP Screening Method for Calcium Channel Blocking Activity in Isolated Rabbit Aorta.

A non-fasted rabbit is killed by cervical dislocation. Spiral arterial strips are prepared from the thoracic aorta by the method ofFurchgott, R. and Bhadrakom, S. (1953), J. PHARMACOL. EXP. THER. 108:129-43. The strips suspended in water-jacketed, 10 ml, organ baths that are kept at 37°C and aerated with a mixture of 95% oxygen and 5% carbon dioxide. An isometric recording of tissue response is made with a Grass force-displacement transducer (Model FT03C) and a Grass polygraph.

The loading tension on the strips is about 1 g. About 90 min is allowed for maximum relaxation to occur, and during this time the bath is changed at to 20 min intervals. The bath contains a physiological solution, hereafter ,IT referred to as normal bath solution, prepared in glass-distilled water and adjusted to pH 7.4. The composition of the solution in millimoles per liter 'will be sodium chloride 120.0 potassium chloride 5.6 calcium chloride 2.6 magnesium chloride 6 hydrate 1.2 sodium dihydrogen phosphate hydrate sodium bicarbonate 25.0 'tr glucose 9.1 Strips are first checked for viability based on their response to norepinephrine at a final bath concentration of 10-5 M; then they are washed with the normal bath solution until resting tension has returned to baseline.

Following this, the normal bath solution is replaced with a physiological solution, hereafter referred to as a calcium-free bath solution, having the same pH and compositon as the normal bath solution except that the calcium is omitted. Strips are then incubated in this calcium-free solution for 10 min.

During this time the solution is exchanged by fresh physiological (calciumfree) solution three times.

263 AHR-438A-CIP or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, -251- AHR-438A-CIP Strips are then tested for completeness of calcium depletion by incubation for 15 min in potassium depolarizing solution. The composition of the depolarizing solution in millimoles per liter is sodium chloride 32.2 potassium chloride 100.0 magnesium chloride 6-hydrate 1.2 trihydroxymethyl hydrochloride 12.0 glucose 9.1 The solution is prepared in glass-distilled water and adjusted to pH 7.4. If the strips contract, they will be washed with physiological solution and then Sreincubated in the depolarizing solution. The process is repeated if necessary until the strips are unresponsive and thus calcium depleated. Alternatively, the strips may be rewashed with depolarizing solution until they are calcium depleted.

Cumulative concentration response curves (controls) are made with calcium chloride as the agonist by the method of Van Rossum, J. M. (19630, ARCH. INT. PHARMACODYN. 143:299-330. Final bath concentrations of calcium chloride will be 0.1 millimolar, 0.3 millimolar, and 1.0 millimolar (See Godfraind, T. Kaba, A (1969) BRIT. J. PHARMACOL. 36:549-60).

Responses are allowed to reach a plateau before addir g the next increment of calcium chloride.

After control responses are obtained, the strips are washed with normal i, bath solution containing test drug (Formula I) at 10-7 molar concentration for about one hour at 15-20 min intervals (see Broekaert, A. and Godraind, T.

(1979)). During this time the tissues have returned to resting tension.

The strips are then incubated in the physiological solution (calcium-free) for 10 min and finally in the depolarizing solution for 15 min, both of which solutions at this point contain Formula I test drug. If the strips contract in the depolarizing solution, they will be washed as mentioned above until unresponsive. The cumulative concentration response to calcium chloride is then made over the range of concentrations used for the control determination.

As a final test to determine selectivity and whether a-blocking activity is present, the strips are washed with the normal bath solution containing the 264 -252- AHR-438A-CIP research compound until the resting tension is again at baseline. The strips are then retested for their response to norepinephrine at a final bath concentration of 10'5 molar.

In the foregoing primary screen, a minimum of 2 strips are used to test each drug at 10'7 molar. Those compounds which consistently produce at least 20% inhibition of the calcium induced contractions will be tested further. For those test drugs giving interesting positive results, a PA 2 value may be obtained, see Van Rossum (1963) ibid. Reference articles which may be used for comparison are lidoflazine, diltiazem, verapamil, nifedipine or other appropriate drugs. In this test, the more active compounds such as those of Examples 56, 57 and 60 showed 100% change (reduction) in contraction at 10-7 molar concentration of these agents caused by 1 millimolar concentration of calcium. Compared to the reference calcium channel blocking drugs, these compounds were found to be superior.

Test Method for Antihypertensive Effect of Orally Administered Drugs to I Unanesthetized Spontaneously Hypertensive Rats.

Surgical Preparation of Rats I Charles River, spontaneously hypertensive rats are anesthetized with sodium pentobarbital (50 mg/kg, IP). The abdomen and the top of head are shaved and cleaned. A midline incision, approximately 5 mm long, is made in the skin of the dorsal surface of the animal's neck. Brass tubing, 22 cm long with a slight bend in the end, is passed through the incision, under the S*skin diagonally down the animal's back and around to the right side of the lower abdomen of the rat.

The animal is then taped to the table in a supine position. A midline incision approximately 4 cm long is made with scissors in the skin and another through the abdominal muscle wall. With small blunt hemostats, the skin is separated from the abdominal muscle at the midline to expose the tip of the brass tube. A small opening is made through the abdominal muscle at the appropriate angle with the blunt tips of the hemostats.

The distal end of a modified Week's cannula is inserted in the abdominal cavity and the other end is threaded through the brass tube until it exits at the base of the animal's neck. The brass tubing is removed and the 7 mm cured polyethylene tip of the cannula is aligned and positioned for insertion 265 AHR-438A-CIP m is zero to six inclusive; -253- AHR-438A-CIP into the abdominal aorta. The positioned cannula is filled with isotonic saline.

The abdominal viscera is gently moved to the side, exposing the aorta in the region of bifurcation. The aorta is isolated and 2 silk ligatures, 1 to cm apart, are placed around it. The ligatures are used to briefly and gently occlude blood flow. The abdominal aorta is punctured craniad to the bifurcation with the tip of a 23-gauge hypodermic needle, The needle is removed, and the tip of the cannula inserted through this opening toward the heart. Caution is taken to keep the tip vertically aligned in the aorta. Blood is allowed to flow back through the cannula to check correct insertion. The cannula is cleared of blood with a 0.4 cc flush of isotonic saline. The stability of the cannula in the artery is ensured by suturing the ligature tied around t o the cannula to the dorsal muscle layers lying directly beside the aorta. The cannula is also satured to the abdominal wall at the point of exit. The abdominal viscera is repositioned, and the abdominal wall and skin sutured in separate layers with blanket stitch. The animal is given 0.2 ml Combiotic® (procaine penicillin G and dihydrostreptomycin sulfate).

The end of the cannula exteriorized at the base of the neck is tied off and passed through an L-shaped piece of aluminum tubing fastened to the skull by screws and dental cement (Purdy and Ashbrook, 1978), J. PHARM.

PHARMACOLOGY 30:436-41.

For protection and attachment of the cannula to the cage, the cannula is inserted through a length of flexible metal spring, which is attached to th' aluminum tubing and to a part of a swivel device that permits the animal to move with relative freedom around the cage. During recovery, each rat is given a bottle of 5% dextrose containing terramycin (1 tsp. Pfizer Terramycin soluble powder/L 5% dextrose) to drink.

Blood Pressure Recordings On the day following surgery, the tied-off cannula is reopened and attached to the swivel device. One end of a saline filled length of polyethylene 50 tubing is attached to the swivel and the other to a Statham pressure transducer (Model P23ID) creating a continuous saline-arterial connection. Continuous tracings from the direct aortic blood pressure are recorded on a Grass polygraph (Model Heart rate is determined from the blood pressure pulse.

-254- AHR-438A-CIP The electrical output of the blood pressure signal from the polygraph is fed into a Buxco Channel Cardiovascular analyzer (Model 12). The blood pressure signals are averaged for a 1-min period and measurements of blood pressure and heart rate is printed on a Texas Instruments data terminal (Model 700 ASR).

Maintenance of Rats To maintain patency of cannula and to permit the animal to be used for maximum time, animals are continuously infused with heparin in sterile saline (2 mg/ml) at a rate of.05 to .06 ml/hr. Purina Mouse Chow and water are available ad libitum. A solution containing 5% dextrose and terramycin is given once weekly. Surgically prepared rats may be used more than once t' *during a study. A minimum of 3 days must lapse before rats are used again, A rat is used only once in a dosage group.

Experimental Procedure Each surgically prepared rat is individually housed in a separate cage.

Each cage is labeled with the lot number and sequential rat number. Single doses of 10, 20, and 30 mg/kg of the test drug calculated on free base content is administered orally by using a syringe and size 16 gavage tube. Control article is PEG-300: saline at ratio of 1:1. Reference articles are verapamil and nifedipine. The carrier for compounds of Formula I and verapamil is PEG-300: saline, 1:1, and for nifedipine, it is ethanol. The dosage volume for test and control articles is 1 ml/kg body weight. Arterial blood pressure and 11" heart rate are measured in each rat prior to and at 30, 60, 90, 120, 180, 240, 300, 360 minutes and 24 hours after drug administration.

The more active compounds such as compounds of Examples 56 and 57 are slightly less active in lowering blood pressure in hypertensive rats than nifedipine, but duration of action is longer.

Procedure for Determinating Effect of Compounds on Coronary Blood Flow.

The procedure used to determine the effect of the aforementioned compounds on coronary arterial blood flow is described as follows.

Mongrel dogs of either sex were anesthetized with phenobarbital sodium (100 mg/kg) and pentobarbital sodium (100 mg total dose). The trachea was

LI

-255- AHR-438A-CIP surgically exposed, a tracheal tube was inserted and the dog was artifically respired with room air using a Harvard Model 613 Respirator. The heart was exposed by a left thoracotomy at the fourth intercostal space. An approximately 1.5 cm segment of the left anterior descending coronary artery was exposed and a Statham electromagnetic blood flow probe was implanted around the vessel. The flow probe was implanted around the vessel. The flow probe cable was connected to a Statham Model 2201 Blood Flow Meter.

Continuous recordings of carotid arterial blood pressure, and of coronary arterial blood flows, were obtained using a Grass Model 5 Polygraph.

The compounds were administered via a femoral vein. Changes in both magnitude and duration of change in coronary blood flow from pre-drug levels were determined. Generally, multiple doses of the compounds tested were administered to a single dog. Appropriate intervals between doses were allowed to permit the blood flow to return to control levels.

Illustratively, the compounds of Examples 56, 57, 61, 62, 69, 74, 76, 89, 105, 106, and 128 showved an increase in coronary arterial blood flow at mg/kg of the compounds of about 75-120 ml/min.

Screening Procedure for Antihistamine Activity The compounds of the present invention exhibit antihistaminic activity in guinea pigs. The method of testing is a modification of the procedure of Tozzi et al (Agents and Actions, Vol. 4/4, 264-270, 1974) as follows: Guinea pigs are fasted 18-24 hrs in individual cages. Water is available ad libitum. On the test day, animals in groups of 3 are injected intraperitoneally with 30 mg/kg of the test compound prepared in an appropriate vehicle. Thirty minutes later histamine at a dosage level of 1.2 mg/kg 2 x the LD 99 is injected into a marginal ear vein. Survival of the guinea pigs for 24 hrs is positive evidence of antihistaminic activity. If the vehicle used for the test compound is other than water, its effect is established by testing an equal amount as a control. The dose protecting 50% of the animals (PD 5 o) from death may be established from dose-response curves. Compounds such as in Examples 58 and 105 were found to be active at dosages at least as low as 3 mg/kg.

Screening Procedure for Gastric Antisecretory Activity In Pyloric-Ligated Rats.

Female Sprague-Dawley rats weighing 130-180 g were starved 24 hours in individual screen-bottom cages with water ad libitum. Animals were -256- AHR-438A-CIP arranged into groups of 9 rats each for treated animals and 8 rats for controls.

4 Each group was injected intraduodenally at the time of pyloric-ligation with test drug in doses of 25.0 mg/kg (0.2 ml/100 g body weight). Rats dosed with deionized water (2 ml/kg) served as controls. Four hours following ligation, rats were killed, the stomachs removed, gastric juice colle, ed and the volume determined. Total hydrochloric acid output was determined by potentiometic titration to pH 7.0 endpoint using a Radiometer TTA-61 autopipetting titration system. Statistical analysis was performed by using the "Student's t-test" significance. Illustratively, at a dose of 25 mg/kg, significant reduction of secretion occurred of about 85% in volume and 98% in acid was obtained for the compound of Example 58. Similarly, reduction in volume obtained for the compound of Example 105 was about 65% for both volume and acid.

Pharmaceutical Compositions and Administration Compositions for administration to living animals are comprised of at least one of the compounds of Formula I according to the methods of treatment of the invention in association with a pharmaceutical carrier or excipient. Effective quantities of the compounds may be administered in any one of various ways, for example, orally as in elixirs, capsules, tablets or coated tablets, parenterally in the form of sterile solutions, suspensions and in some cases intravenously in the form of sterile solutions, intranasally and to the throat or bronchial region in the form of drops, gargles, syrups, powders, etc. or subcutaneously. Suitable tableting excipients include lactose, potato and maize starches, talc, gelatin, stearic and silicic acids, magnesium stearate and polyvinyl pyrrolidone.

For the parenteral administration, the carrier or excipient can be comprised of a sterile parenterally acceptable liquid, water or arachis oil contained in ampoules.

Advantageously, the compositions are formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredients. Tablets, coated tablets, capsules, ampoules, sprays and suppositories are examples of preferred dosage forms. It is only necessary that the active ingredient constitute an effective amount such that a suitable effective dosage will be consistent with the dosage form employed, in multiples if necessary. The exact individual dosages, as well as daily dosages, will of course be -257- AHR-438A-CIP determined according to standard medical principles under the direction of a physician or veterinarian. Generally, the following guide to projected h rman oral dosages is derived by knowledge of the activity obtained in animal screening tests for the various indications in the methods of the invention compared to activity of known agents in the field in the same animal screening tests. However, the amount of the active compounds administered need not be limited by these comparisons due to uncertainty in transposing comparative animal data to human treatments.

Oral dosages projected for hypertension for an adult human are of the order of 40-300 mg/day divided into 2 or 3 doses. Thus, for example, two f; <capsules each containing 10-50 mg active agent of Formula I could be o administered 2-3 times daily for blood pressure lowering.

Oral dosages projected for use in the tretment of angina for an adult human are of the order of 60-400 mg/day divided into 2 or 3 doses. Thus, for wo o example, two capsules each containing 10-30 mg active agent of Formula I 1 could be administered 2-5 daily to increase coronary blood flow.

Oral dosages projected for use as antihistamines for an adult human are of 4 the order 10-120 mg/day divided into 2 or 3 doses. Thus, for example, one or two capsules each containing 10-40 mg active agent of Formula I could be administered 2-3 times daily for temporary relief of cough due to minor 4 P throat and bronchial irritation which may occur with the common cold or with inhaled irritants.

Oral dosages projected for use as antisecretory agents for an adult human are of the order of 4 to 150 mg/day divided into 2 or 3 doses, Thus, for S400 example, one or two doses each containing 0.5 to 50 mg active agent of Formula I could be administered 2-3 times daily for temporary relief due to excessive acid release in the stomach.

Other routes of administration such as subcutaneous, intraperitoneal, intravenous, etc. are possible with dosage forms being adapted to the situation as will be obvious to one skilled in the art of medicine.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, methods of treatment and compositons of the present invention without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

270 AHR-438A-CIP (A)d n N-(CH2) m-(B)z-D C- Q)

Claims (15)

1. A compound selected from the group having the formula: Cr A)d C Q) nl, 7~ 2 R wherein: p is zero, one or two; o R 1 if A is hydrogen, -O-RI, -C N, -C-N /R 1 R1 R 0 0 0 If 11 11 -C-R1, -C-0-R1, -0-C-R 1 -CH 2 OR 1 -0H 2 -N R \R or -NHC(0)CH 3 *0 00 1 0 0 0 90 9 0 0090 IR 0 *0 0~ 0* 0 00 II 0 0011 01 ~11 04 I 00 I I I mn is zero to six inclusive; OH Q is -CH, -CH 2 or de and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of: ~0 S 0 or and in addition, R may have the values of cycloalkyl or loweralkyl; and D may have additionally the values: I, I I d 0286s :AB 272 J. 2 3 aeslce R R and R same or different, aeslce from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R 4 is selected from loweralkyl, phenyl and phenyl loweralky'l; M is a pharamceutically acceptable metal ion; and -259- -59-AHR-438A-CDP o" o 0 0 I (OH 2 02 o 0 0 00 g or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, II/ 0 R N -0H 2 2 R, -SR',-S(O)R 4 lowe-hydroxyalkyl, -N-C-R 4 -CH 2 )C(O)OM, -N-C(O)C(O)-O-loweralkyl, IIIH 9 R1 0 R 2 ,-NS(O) 2 CH 3 ,-N-C-N R9 RiR 1 R3 0 OH -N-C-R o-CH-Ioweralkyl; 0 0 0 11 11 1 11 B is selected from 0, S, or 11 1 0 RI z is one or zero wvith the proviso that z can not be zero at the same time n is zero when one- of the following occurs at the same time that D is phenyl or substituted phenyl.: (A)d is hydrogen, (A)d is cyano, (A)d is aminocarbonyl, or a double bond formns between the a carbon and a carbon of the central heterocyclic amine ring; :a~ 0286s:AB 260 R, R 2 and R 3 same or different, are selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R 4 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharamceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof, with the further proviso that cannot represent oxygen at the same time D is phenyl or substituted phenyl when n is zero and (A)d is hydrogen or hydroxyl or when d is zero and a double bond forms between the a carbon and a carbon of a saturated central heterocyclic amine ring, and subject to the additional proviso that at least one of the following-three conditions applies, namely, a) A is -NR R 2 or -NHC(O) CH 3 b) D is 4-phenylphenyl and I c) Ar, D or R is phenyl substituted by X, Y and Z where X 1 is -CH(OH)-lower alkyl or -NH-C(O) C(O)-O-lower alkyl.

2. A compound of claim 1 which is 1-[3-([1,l'-Biphenyl]-4- yloxy)propyl]-a,a-bis(4-fluorophenyl)-4-piperidinemethanol or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 which is fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]-phenyl] amino]oxoacetic acid ethyl ester or a pharamceutically acceptable salt thereof.

4. A compound of claim 1 which is fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]- phenylaminoloxoacetic acid or a pharmaceutically acceptable salt thereof.

A compound of claim 1 which is l-[4-[3-[4-[Aminobis(4- fluorophenyl)methyl]-l-piperidinyl]-3-methoxyphenyl]ethanone fumarate hydrate or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 which is N-[[l-[3-(4-Acetyl-2- methoxyphenoxy)propyl]-4-piperidinyl]bis(4-fluorophenyl) methyllacetamide or a pharmaceutically acceptable salt thereof. f ft -261- 7 ii I I .1 ft... ft ft. ,ft ft ft ft ft. ftft ft ft ft

7. A method of treating hypertension which comprises administering an effective amount of a compound selected from the group of compounds having the formula: Ar(A)d C N-Q)n(CH.,m(B)z-D R wherein: p is zero, one or two; 262 62 -AHR-438A-CF-P OR1 0 0 0 A is hydrogen, -0-111, RI R1 R2 -CH 2 OR 1 -CHI~N "R2 -N or NHC(O)CH 3 11R2 m is zero to six inclusive; Q is -CH 2 or H d, e and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of- N S 0- or 4 49 44 U 99 and in addition, R may have the values cycloalkyl or lowera-lkyl; and D mnay. have additionally the values: 0 0 "N X (OH 2 02 0 0 0 9 0 0 44 9 *4 *9 4 49 C I I N 00 263 AH-R-438A-CIP or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, -C-RI, -C N, -N C(0)0R', -S(O),R 4 0R, R 2 07''2 0 -S0R,-N-C-R 4 -CHC(0)OM, ,-NS(O) 2 CH,, -N-C-N ,-N-C-OR 2 I if I 3 RIO R 2 R 1 RI R3 OH -CH7-loweralkyl, lowerhydroxyalkyl or -N-C(O)C(O)-0-oweralkyl; 0 0 H 0 11 11 I fi B is selected from 0, S, or 0K' z is one or zero with the proviso that z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is aminocarbonyl, or a double bond forms between the a carbon and a carbon of the central heterocyclic amine ring; R 1 R 2 and R 3 same or different, are selected from hydrogen, lower- alkyl, phenyl and phenylloweralkyl; V. R4 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharmaceutically acceptable metal ion; and the pharmaceu- tically acceptable salts thereof, including acid addition salts, quaternary salts and hydrates and alcoholates thereof, -with- the further proviso that at least one of the following three conditions applies, namely, a) A is -NR R 2 or -NHC CH~ b) D is 4-phenylphenyl and 6) Ar, D or R is phenyl substituted by X, Yand Z where X is.-CH-(CH1)- lower alkyl or -NH-C(O) C(O)-o--lower alkyl. -264- b.

A method for treating angina by increasing coronary blood flow which comprises administering a compound selected from the group having the formula: 44 CI 44 .4 4 *1 U N (C H )m D R wherein: p is zero, one or two; RIO 0 0 A is hydrogen, -0-11 1 -C N, -C(0)N 2, C-0-RI, -0-C-R1, R1 RI I t -CH 2 OR', -CI{ 2 -N \R I -N Ior -NHC(O)CH 3 'V ,4~4' -"I 265 AHR-438A-CIP m is zero to six inclusive; OH Q is -CH, -CH2- or H d, e and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of: N S or 0. and in addition, R may have the values cycloalkyl or loweralkyl; and D may have additionally the values: ar 4 I Cr a s Ct C I II 0 00 0 ^(CH) 0 2 0 @J.D' 00^Q at' I I C I or Ar(CH 2 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 266 66 -AHR-438A-CI-P 0 R -CH 2 -C(O)0R 1 2 R, lowerhydroxyalkyl, -CH 2 C(O)OM, -N-C(O)C(O)-O-1oweralkyl, 111 1 R'O H -S(O) 2 N ,-NSCO) 2 CH 3 ,-N-C-N R2 1 1 \R RR 1 R 0 OH -N-C-OR 2 or -CH--Ioweralkyl; 0 0 0 B is selected from 0, S, or II I u R' z is one or zero with the proviso that z cannot be zero at the same time n' is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is aminocarbonyl, or a double bond forms between the a carbon and a carbon of the central heterocyclic amine ring; RI-, R 2 and R 3 same or different, are selected from hydrogen, lower- alkyl, phenyl and phenylloweralkyl; R 4 is selected from loweralkyl, phenyl and phenyllhweralkyl; M is a pharmaceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof, W.ith the further proviso that at least one of the following three conditions applies, namely, a) A is -NR 1R or -NH-C(Q) CH 3 b) D is 4-phenylphenyl and c) Ar, D or R is phenyl substituted by X, Y and z wherd x is -CH(OH)- lower alkyl or -NIU-C(O) C(O)-O-lower alkyl. #4 *4 *4 4 54 44

9. 4 ''44 4~ 44 44 4 4. 4 4 U 4444 4 4* 4 44 44 4 4 44 -267- 9 A method for countering the effects of histamine in a living animal body which comprises administering a compound selected from the group having the formula: (A)d Arx p O H 2 )e p R LI It wherein: p is zero, one or two; C t I C II I I 'Ft V V C C 0 0 A is hydrogen, -O N, *R 1 R 1 R -CH 2 OR 1 CH 2 N -N or -NHC(O)CH 3 IR 2 \R 2 mn is zero to six inclusive; 268 AHR-438A-CI? OH Q is -CH, -CH 2 or d, e and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of: I S 0 or and in addition, R may have the values cycloalkyl or loweralkyl; and D may have additionally the values: 0 Oxx 0 0 0 .~0 3 sa a. a a a. a a a a a a a a a a a a, a.a~ a a a a* a. a4 a a *a a ~a a a sa a S a a I. 5 4 54a4 a a aa a' a as S a a ft S sa I 00~ or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 269 AHR-438A-CIP -CF 3 -C r N, -N C(O)OR', -CHC(O)OR',-S(O),R 4 -SR 4 o R RR lowerhydroxyalkyl, -N-C-R 4 -CIIC(0)OM,-N-C(0)C(0)-O-loweralkyl,;(0) 2 N, I II I R'O H R 0 2 O OH II t II I -NS(O),CH 3 -N-C-N ,-N-C-OR 2 or -CH-loweralkyl R' R' R3 R 0 0 0 II I II B is selected from O, S, or -N-C-0-R 1 II I 0 R 1 z is one or zero with the proviso that z cannot be zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is aminocarbonyl, or a double bond forms between the a carbon and a carbon of the central heterocyclic amine ring; R 1 R 2 and R 3 same or different, are selected from hydrogen, lower- alkyl, phenyl and phenylloweralkyl; R 4 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharmaceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof, .with the #4 further proviso that at least one of the following three conditions applies, namely, a) A is -NR R or -NHC(O) CH 3 b) D is 4-phenylphenyl and c) Ar, D or R is phenyl substituted by';X, Y and Z where X is -CH(OH)- lower alkyl or -NH-C(Q) CXO)-O-lower alkyl. O*R"

10. A method of decreasing gastric secretion and acid release in an animal which comprises administering a compound selected from the group having the formula: -A 270 AHR-438A-CIP (A)d N-(CH 2 (jH2)e R wherein: p is zero, one or two; Rl 0 0 II II II A is hydrogen, -C N, ,-C-R I -C-O-R 1 /R 1 /R 1 \R2 -CH 2 0R 1 -CH 2 -N -N or -NHC(O)CH 3 R 2 R 2 m is zero to six inclusive; OH 1 Qis-CH, -CH2- or-C-; -H I€ ro 4 ft 9 a 9 4 9. 4,9, o t I t 4 9* 99 t (X 4 I I 4 44 d, e and n are selected from zero or one and the dotted lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of: NY S I F "1 01. or and in addition, R may have the values cycloalkyl or loweralkyl; and D may have additionally the values: "z"t' cN 271 AHR-438A-CrLP 0 0) N 00 or Ar(CH 2 1 4 X, Y, and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, IRI 0 R -N -CH 2 -C(O)OR',-SCO) 2 R, -SR 4 ,-S(O)R 4 lowerhydroxyalkyl,,, -IN-C-R 4 -CH 2 C(O)OM, -N-CCO)C(O)-O-Ioweralkyl, 11i R1O H 4 4 4 44 44 4 4 44 4 4 44 444$ 44 4 .4 44 44 44 4 4 44 4 4 4 4 44 44 4 44 4 4 44 R1 0 R -S(O) 2 N -NS(O) 2 CH 3 ,-N-C-N R2 I I \R R1 R1 0 O'H C-OR- or -Cdl-loweralkyl; 0 0 0 B is selerted from 0, S, or 0R' z is one or zero with the proviso that z cannot be zero at the sa-me time n is zero when one of the following occurs at the sa-me time that D is phenyl or substituted phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is aininocarbonyl, or a double bond forms between the a carbon and a carbon of the central heterocyclic am-ine ring; 44 44 4 4 4 0286s:AB 272 1 2 3selected R 1 R 2 and R 3 same or different, are selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R 4 is selected from loweralkyl, phenyl and phenylloweralkyl; M is a pharamceutically acceptable metal ion; and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof, with the further proviso that at least one of the following three conditions applies, namely, a) A is -NRR 2 or -NHC(O) CH 3 b) D is 4-phenylphenyl and c) Ar, D or R is phenyl substituted by X, Y and Z where X is -CH(OH)-lower alkyl or -NH-C(0) C(O)-O-lower alkyl.

11. A method of any one of claims 7 to 10 wherein the administered compound is 1-[3-([l,l'-Biphenyl]-4- yloxy)propyl]-a,a-bis(4-fluorophenyl)-4-piperidinemethanol or a pharmaceutically acceptable salt thereof.

12. A method of any one of claims 7 to 10 whei.n the administered compound is fluorophenyl)hydroxymethyl]-l-piperidinyl]propoxy]-phenyl] amino]oxoacetic acid ethyl ester or a pharamceutically acceptable salt thereof.

13. A method of any one of claims 7 to 10 wherein the administered compound is fluorophenyl)hydroxymethyl]-i-piperidinyl]propoxy]- phenylamino]oxoacetic acid or a pharmaceutically acceptable salt thereof.

14. A method of any one of claims 7 to 10 wherein the 04 administered compound is l-[4-[3-[4-[Aminobis(4- fluorophenyl)methy.]-l-piperidinyl]-3-methoxyphenyl]ethanone fumarate hydrate or a pharmaceutically acceptable salt S: °thereof.

15. A method of any one of claims 7 to 10 wherein the administered compound is N-[[l-[3-(4-Acetyl-2- methoxyphenoxy)propyl]-4-piperidinyl]bis(4-fluorophenyl) methyl]acetamide or a pharmaceutically acceptable salt thereof. DATED this 31st day of July, 1992.