AU594972B2 - N-substituted-arylalkyl and arylalkylene aminoheterocyclics as cardiovascular antihistaminic and antisecretory agents - Google Patents

Description

CO,12ONTWEALTH OF AUST P-P-LIA Form Requlation 13 2) PATENTS ACT, 1952 COrMPLErnE SPEC IFICATION

(ORIGINAL)

FOR OFFICE USE4 Short Title; Int. Cl.- Aplication Numzber- C-14-1 J~ Lodged- Complete Specification-Lod'ged; Acceptedi Lavsed: Published: 59497 tPriority- S. It .5 t S I It 0 *5

S

*0 S IS o 5 S IS I C I 5* 4*5* 0 5 0

S

55,5*

SO

Related Art: TO BE COMPLETED BY APK.!2C'1T Nam~e of Applicant; Address of Applicant: Actual Inventor-, Address for Service: A. H ROBINS COPI]?AtY, INCORPORATED 1407 Cummings Drive, Richmond, Virginia 23261-6609, U.S.A.

James Robert SHANKLIN, Jr Anthony George JROAKIS ARTHUR S. CAVI11' CO. Patent and, Trade Mark Atto.%-neys, 1 Alfred Street, Sydney? New South Wales, Australia, 2000.

Complete Specification for the invention entitled: "IN-SUBSTITUTED-ARYLALKYL AND ARYTJAIKYLENE AMINOHETEROCYCLICS A$ CARDIOVASCULAR ANTIHISTAMINIC AND ANTISECRETORY AGENTS".

The following statement is a full description of this invention, including the best method of performing it known to me3- -1- ASC-4 9

J

AHR-438A la BACKGROUND OF THE INVENTION 1. Field of Invention.

The present invention relates to certain Nsubstituted arylalkyl and arylalkylenepyrrolidines, piperidirne 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 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 ,0 32 6 42 disclose pertinent compounds, Samong which some would fall within a generic structure as follows:

A

f 15 Ar-C CH Ar-C

RA

wherein Ar is phenyl, p-fluorophenyl or m-trifluorophenyl; R is phenyl, p-fluorophenyl or cyclohexyl and A is hydrogen 20 or hydroxy, the compounds having utility as anti-inflammatory agents, sedatives and 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 from formulas representing novel 25 compounds.

U. S. Patent 3,922,276 discloses compounds, among which would fall within a generic structure as follows: f 438A 2 Ar--C: N-(CH,)n,-O

R

wherein Ar is phenyl or p-fluorophenyl and R is phenyl, p-fluorophenyl, m-trifluorophenyl or cyclohexyl, the compounds having utility as anti-inflammatory agents and 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 from formulas representing novel compounds.

U. S. Patent 4,16 3 ,790 discloses compounds which fall withil a generic structure as follows:

A

Ar-C N-Z

R

wherein Ar and R are phenyl and p-fluorophenyl and Z is hydrogen, acetyl, p-fluorobenzoylpropyl, carbamoyl, Nmethylcarbamoyl, N,N-dimethylcarbamoyl, phenylcarbamoyl, or N-(w-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 other 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.

l-Benzyl-(a,. -diphenyl~-4-benzylidinepiperidines of the formula (phenyl)a= N-CH -phenyl are disclosed in Gar. Offen. 2,800,919 as having anticonvulsant and vasodilating properties. Similar 1-benzyl- 4 4 t *9 t4.

r 4 4 i 4 6 ff 4*4 *I .444 rea t 44

U

i 438A 3 (aa-diphenyl-4-benzylidinepiperidines of the formula (phenyl) -CH N-CH NR1 R are disclosed in U. S. 4,0 3 5, 3 72 as having vasodilating properties. The compounds are excluded from the present invention by proviso.

1-Benzyl-(a a-diphenyl)-4-benzylpiperidines of the general formula 0 R (phenyl)2-C

-(CH

2 )n-C are disclosed in U. S. 3,965,257 as having antihistamine activity. The compounds are ketones and, as contrasted to the ethers, useful in the present methods.

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

R

C= N-CH2 Shaving hemodynamic, antiarrhythmic and antihistaminic 20 activities are disclosed in U. S. Patent 3,759,928 and are excluded from the present invention by proviso.

S S. Patent 3,984,557 discloses compounds which fall S**4 within a generic structure as follows: 25 o 4

C

0

R

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, I 71 438A 4 arylamino or an aryl group other than phenyl on the alkyl chain. (now US 0.,o,713) An application, Serial No. 811,799,4directed to the use of certain compounds of Formula I as anti-allergy agents wherein (B)z is confined to oxygen and A is hydrogen, hydroxy, cyano or forms a double bond has been filed on December 20, 1985, the specification of which is hereby incorporated by reference.

SUMMARY OF THE INVENTION The present invention is concerned with methods of correcting cardiovascular disturbances, and as 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: Ar C(Q)n- :4.o20 )n N-(CH2)m-(B)z-D Formula I wherein; p is zero, one or two; O 0 II

I

0 A is hydrogen, -0-R 1

-CNRR

2

-C-R

1 -C-O-R S" 25 -O-C-R -CHaOR 1

-CH

2

NRR

2 *o m is zero to six inclusive;

OH

Q is -CH- or

H

d and n are selected from zero or one and the dotted 3, 0 lines represent double bonds which may form consistent with the valence of carbon; Ar, D and R mse selected from the group consisting of or -Z <syorc

I

438A and in addition, R may have the values: CHe-, cycloalkyl or loweralkyl, and z D may have additionally the values: 0 0 SN or Ar(CHa)i-4, X, Y and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 0 11 -N02, -O-R 1

-C-R

1 -CFs, -CN, -C-N(R -(Ra, -C(o)OR, 1 SaR 2 -S2R -S(o)R 2

-N-C-R

1 -CHCOOM, -SONe R S02 I 6 I R 2 0 R 1 0

R

-NSOaCH 3 -NC-N"R or -NC-OR 2 B is selected from O, S, R R R t 20 0 0 o S and -N-C-0-R1; z is one or zero with the Sproviso that z cannot be zero at the same time n is zero when c" 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 aminering; R is selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R 2 is selected from loweralkyl, phenyl a.P* and phenylloweralkyl; M is a pharmaceutically acceptable metal ion and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and Sa hydrates and alcr olates 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.

I}

438A .1 The tean "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 formula -O-loweralkyl.

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 methylcyclohexyl and the like.

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

The term "central heterocyclic amine ring" refers to that portion of Formula I represented by 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" includes phenyl connected by hydrocarbon chains exemplified by loweralkyl above and wherein phenyl may be substituted by non-reactive or non- 25 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 30 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, 438A 7 antihistaminic and antisecretory agents. As stated above, an application directed to use of certain compounds of Formula I as antiallergy agents wherein (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 compounds as antiallergy agents.

Pharmacological testing methods used for screening in support of methods of treatment of this invention excluding antiallergy method of treatment are described hereinbelow.

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

Ar (d c -(CH Ia wherein p, m, d, Q, n, A, Ar, D, R, R' R 2 Ar M, B, z, S X, Y 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.

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, III, IV and V in the description of intermediate preparation, the preparations and examples t hereinbelow. One of the general methods used is outlined by equations in Chart 1, 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 L i- 438A 8 reaction time may vary from a few hours to 24 hr, depending on reactivity of the halide and temperature. Temperature may vary from 80°C. to 125 0 C. Products are usually isolated by partitioning in a solvent such as methylene chloride, chloroform or benzene and the like and a weak basic 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 free base and a salt is typically described in Example 4.

Alternate Method C is shown by equation in Chart III.

Mesylation or tosylation with such as mesyl or tosyl chloride is conducted in the presence of an acid receptor such as a tertiary amine; triethylamine, while tooling. The final reaction of the mesylate or tosylate with the DOM is conducted in a suitable organic solvent 20 and the free base is isolated by conventional means such as washing, extracting with an acid solution and an organic S« solvent and evaporating the solvent. Salts may be o prepared as described hereinabove.

0000 Alternate Method D is shown by equation in Chart IV.

When the halo compound is reacted with the DO(4 compound, a suitable solvent is dimethylsulfoxide and a suitable a# temperature is about 250C. When the halo compound is reacted with the HN-D compound, excess HN-D compound may R R be used as solvent and a temperature of about 100 C. or above is suitable.

Alternate Method E is shown by equation in Chart V.

The method is limited to preparation of certain derivatives such as wher.in D is 2-pyridinyl or 2-quinolinyl. Dimethyl sulfoxide is a suitable solvent and 60°C. is a suitable temperature for the reaction.

~43 8

A

9 CHART I Preparation of Compounds of Formula 1: Method A.

r Ar(d I d Acid Solvent, Receptor, e.g., tanol, DMF,

NB

2

CO

3 etc.14 NaHCOs, iT(I Catalyst (optional) (Ciii zD Optionally when A=OH and n=zero

H

4 4 44 4* 4 44 44 4 44 4 4' 4 4* 4* 4 44 4444 4 4 44

R

444, 4 4 44 -X halide -J Ii 43 9A CHART II Alternate Preparation of Compounds of Formula I: Method B.

(R Ar, n of (Q)n is zero)

E

ArJ (CH2 )m-(B)ziD Ar/ \-4p Ar" H 2 Pt.- Ar, CH2 Z -D A pp N D 2ArMgX EtO 2 C p +M

I_

Ar

C~

halor (C m\B)zD CHART III Alternate Preparation of Compounds of Formula I: 4 4 '4 S4 P *440g 04 4 0 491 40i 4 4444) 4 44 00 4 01 44 Method C.

(A)d Ar I d C4 C 1; (Cn2l))m-M

R)

when no other hydroxyl is 2reseni acid raceptor 0 Ar:

R/

4 4t 4 4 44 (A)d R v 7ootno:ea: Ox halo.

k*w 0 mexyl, toyl, *t alkali-metal.

d 1 4~38A 11 CHART IV Metc Alternate Preparation of Comnpounds of Formula I: )d D.

C n -(CH,)m-O-D

R

7

Z

A~ (A)p/ R N (CH 2

)M-X

H-ND

Ar,, NCz(Q)n p 444 p p 4 p p 44 4 I ~4 4,44 44 4- 4 4* .44,4 4 4, 'p 4*: p 4, *4 =X halo alkal.i metal CHART V Alternate Prepar',Rtion of Certain Compounds of Formula I: Method E.

Ar(A)da C (Q nE-E RZ 9N

X

d A 11 *M alkali metal cation pyridiri-2-yl or quinolin-2-yl halo (Br, Cl) 438A To prepare acid addition salts, 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 concentration 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, glutamic and stearic acid and the like. Exemplary of such inorganic salts are those formed with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

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

Precursors (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 10 sets of equations S" which are also applicable to pyrrolidinyl and homopiperidinyl S derivatives: See also U. S. Patents 3,922,276 and 3,956,296.

A t ~438A 19 @-CEt A ZMg X

OH

N@ rMgX 0 r11 I NXC -A r

OH

1 2 HI P, HOAC HO~Ar Pd/C CHA r 2 HC1

H

2 Pd/C HOA C, A HNaCIIA r

H

2 Pd/C HOAC, &k PhCH2 Naj'C02Et SArMgX

OH

?hCH 2 N(I)C-Ar 2 I

H,

2 Pd/c 44 44 4 4 4 4 44 4 P~ $44CU 4,44 4 44,4 44 4 04 4 4* 4 4* 44 4 4,4, 44 4* 1 444' 4 4A 44 1 4 LI 4411 1' 41 HNaCz2):- PhCH2N C HA r 2 I H2, Pd/C HND CHA r 2 4 PhCH 2

X

(x Cl, Br) P, HOA C 112; Pd/C; HOAC;AL or HI, P, HOAC; *r L HciOH H2, Pd/C, c 4 t I c HOAC, A Ph phenyl

U

HDX2E t PhSO 2 Cl Pyridine PhS0 2 -~NOjCO2Et LiA1H 4

O

09 /H

OH

C -A r2 H~>aC-Ar 2 A r c .11 ""Ar lqHBr (48%) Phenol PhS0 2 410 I P P, A MO-CHtr.

(4) HNciaCo2 Lt Ar HNorC -Ar CHeO 0 cn 2 (Kji.CO2Et)2 IJ-ArM)X HNO-CHr 2 HCl1, FH O a 00 a 4 0$ a4 JHI, P,

HOAC

0-.

Ar,-H N &j L;Mr2 Ha, ,PD /C BOAC C [aHr or Aalcohol mHZIa CO2Et I-O-(CH2)n-X 'p D--C2)-N C-',E X- C1, Br 1410 4 0I '4 Ph phenyl.

I I ~438A (7) O=C-Hi -RArCH~M 3 +0 e R Ar

CH

OH

CH

0

H

H t$ 4; 44 4 44 4 .4, 44 4 44 4 04 '~4 04 0 0444 w)R Y" Ar R Ar O)Ar

CH

2 Ha 0 Pd,A (high pressure, T high tamrp.) 25 4 We 444 4 4$ 41 C SoI~t )m Li (D r mor 4l38A~ (8) Ar

P

0

N

Ph-0-C-Cl INOH

A/

Be se L.Ph L-Ph PP'hS .Hc LPh Pt Ar 0

C-H

Ar' ICr03 Ar %CHCH,2OH Ar/ I P1 A ro Ar "CHCH- NH Ar b", Pt Ar ~CHCH K Ar/

H

2 IN&OHPt 44 44 4 4 4 4 .4 4 4 444 o 4444 44 4 4 44 o *4 44 44 4 4444 4444 4 4* 44 4 44 44*4 4 .4 4.44( C 4 .4 PPh3 Base '%CH-cmM3~h Ax/r 0 IPh -0-C-C 1

CHCH~~P

A rod *commnercially available Ph phanyl -1 438A )d Ar-~-(Q)nl )I R d (CH2) M-OH X halo.

0 0

C=-N

(C112)M-C-(-Q-)2 to A Oa 0A a p=0, 1, 2 m 0, 1 01-) CH 3 0

CEN

(CH

2 mCi~~) p 1 c=O 0 H0,NaOH or H® 'tAI ~1

H

At .1 438A 18 The method of preparation of certain starting materials wherein D is phenyl. substituted by hydroxy is illustrated by the following equations:

OH

Na 2

COS

0 The preparation of other hydroxyphenyl intermediates and compounds is illustrated by the following equation: @OCHe I Na

ICH

2 as in Chart I 0**6

CH

2 1 2 444' 94 4* 4 4 41 -phenyl.

*4 1 4 9A I ~438A 19 The preparation of certain substituted phenol starting materials is illustrated by the following equation

OCH

2 O Q -NH2 C iS;,,H )I -CH-.9 Q iS0 2

CH

3 CHsN=C=O j1 -CH 2

HC-NHICH

3 (3)

I,

'20 9, 9, 9 990 999.9 9 4999 90 9 .9 90 (Pd/c HO Q NHS0 2

CH

3 HO rUNIM O 0 HO-0 C-OEt 0= phenyl 9~ 0~ 49 9 0g 00 4 9440 4* 9 .4 The preparation of chemical intermediates is further illustrated in the following Preparations 1 to 814. Examples 1 to 147 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.

14$ I 4 I I I 4 r 4'- 438) Preparation 4-Diphenylmethylenepiperidine.

A solution of 7.0 g of l-acetyl-4-diphenylhydroxymethylpiperidine in 30 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 4.0 g of white crystals, m.p. 85-86 0 c.

Analysis: Calculated for CleHieN: C,86.70; H,7.68; N,5.62 Found c,86.70; H,7.83; N,5.73 Preparation 2 C[,a-Bis(p-fluorophenyl) -4-piperidinemethanol hydrochloride hydrate This compound was prepared by the method described in S, Preparation 1 of U. S. Patent 4,032,642, m.p. 243-243.5°C.

Sfrom the Gricnard reagent formed with p-fluorobromobenzene 20 and 1-acetyl-4-(p-fluorobenzoyl)piperidine followed by .o hydrolysis and conversion to the salt.

j 1 Preparation 3 -(Phenylmethyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride r[:l.

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 4 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 tit" dried over magnesium sulfato 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 ethanolether to give 89.33 g of white crystalline solid, m.p. 154-155 0

C.

1 i i 438A 21 Analysis: calculated for CisHa 2 NOaCl: C,63.48; H,7.81; N,4.94 Found C,63.07; H,7.82; N,4.91 Preparation 4 a.y-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-bromot'". orobenzene in 125 ml of tetrahydrofuran. The temperature )f the reaction was kept below 10°C. by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 24.7 9 (0.10 mole) of l-(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 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 S" 20 over magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane r* to give 19.87 g of the title compound, m.p. 113-115 0

C.

Analysis: calculated for C 2 sHs 5 NOF2 C,76.31; H,6.40; N,3.56 Found C,76.24; H,6.38; N,3.50 4o44o I. 44"" 4)(c 4444 *f L re_paration [a ,p-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 0 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 crystalized. 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 isopropyl ether- 2 -prtpanol, m.p. 159.5-160.5 C.

438A 22 Analysis: Calculated for C 18

H±

9

BF

2 N0: C,71.27; H,6-31; N,4-62 Found .C,70.93; H,6-71; N,4-38 Preparation 6 l-4Phenylsul fonyl) 2 4-piper idinecarboxyl ic 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 retnoved 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 to give a solid. This was recrystallized from ethanolether to give 4.59 g of crystalline solid, m.p.

85-86.5.

,Analysis: Calculated for C1 4 H19NO 4 S: C,56-55; H,6.44; N,24-71 Found C,56-53; H16-55; N,24.67 in another preparation, 100 g.(0.634 mole) of ethyl nipecotate and 130.4 g (0.724 mole) of benzene sulfonyl chloride were reacted by the above procedure for 4-1/2 hr.

to give the title product in 78.1% yield.

Preparation 7 (,a-Bis(4-fluorophenyl),-l-(phenylsulfonyl)-4-piperidine- 0 n4 a a methanol.' 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 N 2 and cooled in an ice bath wis added dropwiae a solution of 214).25 g (1.39 mole) of p-bromofluorobenzene in 150 ml of tetrahy"drofuran. The mixture was stirred for 2 hr after the addition was completed.

To this mixture was added 103 g (0.3246 mole) of 1.-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr.

The reaction was poured into ar icy aqueous solution of amnmonium chloride. The phases were separated, and the solvent was removed in vacuo from, the organic phase. The 4 38, 23 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 Vl liter volume. The title compound was obtained by adding hexan and cooling, recrystallizing the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130 0C. for 45 min. at which time the product had partially melted, m-p. 14l2.5-J14 0 c.

Analysis: Calculated for C 2 4

H

2 3 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 A-[s4 -fluiorophenyl )me thylene]j-l.-( phenylsu lfon~yl) piperidine, A solutiorn of 5.23 g (0.0118 mole) of a,cx-bis(4-fluorophenyl)-l.-(phenylsulffonyl)-i4-piperidine methanol in 100 ml of *Ott, acetic acid and 20 ml of 2M sulfuric acid was refluxed for 2-1/2 hr and then was poured over ice. The mixture was made 4 basic with 50% sodium hydroxide and the basic mixture was 20 extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodiu4m sulfate), and the ~::solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g (614.14%) of white crystalline solid, m.p. 90-92.5 0

C,

Analysis: calculated for C2 4

H

2 iN0 2

SF

2 C,67.7!i; H, 1 4.98, 00 N,3.29 to'Found :Co67.73: H1, 5.00; Preparation N,.2 4-rBis(4-fluorophenyl)methylenelpiperidine hydrobromide 1:1.

A Mixture of 1614 g (0.3142 mole) of a,,c-[bis(14-fluorophenyl) )-l-(phenylsilfonyl)-J4-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 hydrobroiic, acid solution was decanted from a gum in the bottom of the reaction Iftask. Ttje gum was triturated with'-i1 liter of ether, and a tan o,-)did Itormed.

438A 24 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 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 CIBH 1 8 NBrF 2 C,59.03; H,4.95; N,3.82 Found C,58.96; H,4.98; N,3.76 Preparation 4-[Bis( 4 -fluorophenyl)methyl]piperidine fumarate hydrate [1:1:0.53.

A mixture of 30.6 (0.99 mole) of phosphorous and 15.1 g (0.059 mole) of iodine in 90 ml of glacial acetic acid was strrred for 20 min at room temperature. 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 25 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 tan solid was collected from the warm solution. Fumaric acid (22 g, 0,190 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. 208-209 0

C.

Analysis: Calculated for Coa 2 2 NOa.sF 2 C, 67.78; H,6.26; N,3.95 Found c,67.86; i1,6.12 N,3.81 94 40 4 4 9 4 II I 44 a 4 4 4 444 0004^ 4 0004 a t 4 4 I 44" 4 o 4 0 g 04440 9 4 44 4 9't I t 44

I

I

11

I

Vt ii '9 I I Vt .4 *4 4944 4 .4 44 4 1438A Preparation 11 4 -[ae-(CP-Fluorophenyl) -a -phenylmethyl lpiper idin hydrochloridp, rai:li, This con'~pounC was prepared as described in U. S. Patent 4,032 ,64i2 by hydrogenation of ce-(p-fluorophenyl)benzylidinepip .ridine over palladium charcoal catalyst, m.p. 81-82 0

C.

Analysis: Calculated for CieH21ClFN: C,70.69; H,6.92; N,'4.58 Found C,70.69; H,6.93; N,4-52 Preparation 12 -chloropropoxy)-3-methoxyphenyl]ethanone.

To a mixture of 15.15 kg (96.26 mole) of l-bromo-3chloropropane and 25 liter of water heated to 86 0 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 A15 89 liter of water over a 2.5 hr period. The mixture was heated at 80-.85 OC. for 2-5 hr after additl-., was complete.

The mixture was cooled and extracted twice with 149 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 weater. The toluene layer was dried over 3 lb of anhyd3rous sodium sulfate and concentrated under reduced p~essure. The residue was heated to ref lux in 15 gal of diisopropylether, filtered, and the filtrate cooled. The crystallized title compound obtained by 25filtration together with ,ddil-tonal compound obtained by concentrating the filtrate to 25% of its original volume amounted to 4.2 k(q Acetovanillone recovered was 3.14 kg. The product was recrystallized twice from cyclohexane and twice fromn ligroin, m-P- 57.8-58.5 0 Analysis: Calculated for C1 2 Ha 5 ClO.3; C,59-39- H1,6-23; Found C,59-07' H1,6.22 *44' 4, 44 4 41 $4 I 438 A 2 6 Prepration 13 II 1- (3-Phienoxypropyl) -14 -iperidinecarboxyl ic acid ethyl aster oxalate rl:l:.

mixture of ethyl isonipecote (35.5 g,0.2moe 3-phenoxy-1-bromopropane (51.6 g, 0,,P,4 mole) and sodium II 5 carbonate (25.14 g, 0.214 mole) in 500 ml of absolute ethanol was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was r~ried over anhydrous sodium sulfate and the volvent was removed in 110 vacuo to give a liquid. The liquid was dissolved in I absolute ethanol, and a solution of oxalic acid mole) in absolute ethanol was added. The product 73.43 g precipitated as a white, crystalline solid, m.p.

18o-18l.5 0 c.

Analysis: calculated for Cj 9

H

2 7 N0 7 C,59.83; H,7.14; N,3.67 Found C,59.76; H,7-17; NO361 *Preparation 14 4-[Bis(4-fluorophenyl)methylenel--l.-(phenylmethyl)piperidine maleate A mixture of ct c-bis(14-fluoroplienyl)-l-(phenylmethyl)- 4-piperidinemethanol (5.09 9, 0.013 mole) in 200 ml of ~I acetic acid and 10 ml of 2M'sulfuric acid was refluxed for ii 2 hr. The solvent was removed in vacuo, and the residue ii was partitioned between methylene chloride and dilute ft .*25 sodium hydroxide. The methylene chloride solution was &U dri.ed o~ver magnesium sulfate and the solvent was removed in vacuc, to give the free base of the title compound as a A, solid. The free base was dissolved in methanol-diethylether and maleic acid (excoss) was added. The product 5.24 g precipitated as a white, crystalline so~lid, m-p. 180-181-5 C.

Analysis: calculated for C 2 9H2'rNF2O 4 C,70.86; :4 Found :C,70.80; H,5.J45; Ns,2 .79 4 3 84 Preparation a ,a-Bis(4-fluorophenyl)-4-pyridinemethaniol.

The Gri~inard reagent was prepared from 4-bromofluorobenzene (66.6 0.381 mole) and magnesiurn (9.13 g, 0.381 mole) in tetraliydrofuran (ice bath). The Grignard reagent was stirred at room temperature for 1-1A hr. mind 'transferred (un'der N 2 to an addition funnel. This solution was added dropwise to a tetrahydrofuran solution of ethyl isonicotinate (25.0 9, 0.165 mole) (ice bath cooling). The reaction mixture was stirred 3 hr at roo-m temperature and poured onto ice containing ammonium chloride (28 g, 0.-5 mole).

The mixture was allowed tc stand overnight. The reaction mixture was diluted to 3 liter with water and extracted with chloroform. The chloroform layer was back extracted with dilute sodium hydroxide. Removal of chloroform gave a gummy brown solid. The brown solid was tritL'rated with methanol-diethyl ether (10-120 v/v) and placed in the refrigerator freezer. Solid was filtered off and dried overnight in vacquo at 8 0 0C. to give 11.86 g of white crystalline product, m.p. 185-189 0

C.

20 Analysis: Calculated for C 1 8H, 3 N0F 2 C,72-72; H,4.J411 N,4.71 Found :c,7'2-76; T' -3091 N,4.67 ii n

I

it

I]

S I 5*1 4 @5 as S a it 4.4 *4

S

4.

a, a ass a es a a a 4 .5 a's;

S

a. S 44 it It is Preparation 16 4-r Bis (4-f luorophenyl) me th~I,,1-1- (phenylmethyl) piperidine, fumarate rl:1i.

25 A mixture of 4.3 g (0.139 mole) of phosphorous, 44 g (0.196 mole) of a 57% aqueous volution of hydrogen iodide and 4.15 g (0.0106 mole) of 4-Cbis(4-fluorophenyl)methyleneJl-(phenylmethyl)piperidine in 60 ml of glacial acetic wa, refluxed for 1 hr. The mixture was poured over ice and was 30 made basic with 50% sodium hydroxide. The aqiueous mixture was extracted with methylene chloride,. The methylene chloride solution was extracted with an aqueous solution of sodium muif ite and was dri#-4R over magnesium sulfate.

The solvent was removed in give 3.89 g of the free base of the title compound. The free base was converted to the fumarate salt, and the malt was recrystallized from methanol-ether to give 3.62 g white

I

i I 438.A 28 solid, m.p. 201-202 0 c.

Analysis: Calculated for C29HesNO 4 Fa: 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 role) of l-bromo-2-chloroethane, 83.1 g (0.5 mole) of ethyl p-hydroxybenzoate and 69.1 g (0.5 mole) of potassium carbonate in 200 ml of acetone was heated at reflux for 40 hr. The solids were 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 5% sodium hydroxide solution and filtered.

1 The filter cake was washed with water (100 ml) and dried to give 42.4 g (37.2 of a solid. A sample was recrystallized from benzene-petroleum ether (30-60 0 c) to give white solid, m.p. 74-76 0 c.

Analysia: Calculated for C 1 1 HisC 1 0 O: C,57.78; H,5.73 Found C,57.87; H,5.82 SThe filtrate pH was adjusted to 2 with concentrated hydro- 1 20 chloric acid. The resulting solid was collected by filtration, washed with water (100 ml) and dried to give 44.4 g of D" ethyl p-hydroxybenzoate.

Preparation 18 25 l-r4-(2-Chloroethoxy)-3-methoxyphenyl ethanone.

To a solution of 12.7 g (0.55 mole) of sodium metal in S 7.50 ml of absolute ethanol was added 83.1 g (0.5 mole) of acetovanillone to give a slurry, This slurry was then added o'-er a 3 hr period to a solution of 107.6 g (0.75 mole) l-bromo-2-chloroethane in 500 ml of absolute ethanol at r**q 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 extracted with 500 ml of benzene and the combined organic layers were washed successively with L i r ii r i i i

B

\i rir c":-d 29 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 2-propanol to yield 48.5 g of off-white solid. An analytical sample was prepared from isopropyl ether, m.p. 69-71 0

C.

10 Analysis: Calculated for C 11 3 HsC10 3 C,57.78; H,5.73 Found C,57.55; H,5.74 Preparation 19 1- -Bromobutoxy)-3-methoxyphenyllethanone.

To a warm solution of 12.7 g (0.55 mole) of sodium 15 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 a 3 hr period to a solution at reflux 20 of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was 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 layer was washed with four 300 ml portions of a 5% sodium hydroxide solution once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced 30 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 (466) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52-54 0 c.

Analysis: Calculated for C 1 sH 1 7 BrOs: C,51.84; H,5.69; Found c,52.03; H,5.76 4 1 t 4 .4 *@cz C9 C C

SOI

IC

C 4 44 44 4 Ix i-i i -3 3P- Preparation 4-(Diphenylmethyl)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 added, and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was recrystallized from a mixture of methylene chloride-ether-hexane to give two crops of crystalline solids: Crop I, 40.87 g m.p. 124-126; Crop II, 25.38 g m.p. 123-125.

Analysis of the mixture of the Crops I and II was as follows: Analysis: Calculated for C 1 8 sH 1 N: C,88.13; H,6.16; N,5.71 Found C,87.67; H,6.01; N,5.56 Preparation 21 S* -Chloropropoxy) -4-methoxybenzene.

20 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 So". 300 ml of dioxane 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 25 overnight at 80 0 C. The lower layer was separated and the aqueous layer extracted with hexane. The lower layer and hexane layer were combined, dried, and solvent was removed t in vacuo. The residue was dissolved in chloroform and extracted with 5% sodium hydroxide; removal of chloroform by evaporation gave a yellow oil. A 10 g sample of the oil 4 t t was subjected to column chromatography on silica gal with an elution series composed of hexane-methylene chloridemethanol. This furnished 9.64 g (79.3% based on the aliquot taken)of pure clear oil.

Analysis: Calculated for CoHi 0 2 Cl: C,59.86; H,6.53 Found c,59.39; H,6.56 I I- ns IRIII I~ 43 8

A

k Preparation 22 l-r4-(3-Chloropropoxy)phenyllethanone.

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 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 chloride-methanol. Fractions with similar TLCs were combined and solvent removed. The oil from the column did not analyze, therefore a short-path bulb-bulb distillation was carried out. This produced 4.38 g of clear oil.

Analysis: Calculated for C 1 1 HisOaCl: C,62.12; H,6.16; 20 Found C,61.70; H,6.17 1*1 a ra*o oC a a,+ U 4 *040 4C U 'a at 'H NMR (CDCl3) 18.1 66.8-7.0 4 1-4.3 SJ 36-3.8 6 2.:5 t 2-2 .4 Analysis: doublet doublet triplet triplet singlet triplet aromatic portons aromatic portons

CH

2 -CH 9-CHs or COCH 3 0 Preparation 23 4-(Diphenylmethyl)piperidine hydrochloride 1:1i.

A mixture of 62.69 g (0.296 mole) of diphenyl-4-pyridyl- 30 methane 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 85° for 4 days. 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. The methylene chloride solution was dried over I 438A 32 magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanol and acetonitrile, and excess ethereal hydrogen chloride was added. A precipitate was collected to give 59.13 g (80.3%) of slightly impure title compound as a white crystalline solid, m.p. 273-274 C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, m.p. 275.5-277 0 c.

Analysis: Calculated for C 18

H

22 NCI: C,75.11; H,7.70; N,4.87 Found c,75.03; H,7.73; N,4.93 Preparation 24 a-(4-Fluorophenyl) phenyl-4yridinemethanol.

To a suspension of 18.5 g (0.761 mole) of magnesium turnings and several crystals of iodine in 800 ml of anhydrous diethyl-ether, cooled in an ice bath and under an atmosphere of argon was slowly added a solution of p-bromofluorobenzene in 200 ml of diethyl-ether. The solution was stirred for 2 hr at 25°C. and 97.02 g (0.530 mole) of 4-benzoylpyridine was added as a solid. An 20 additional 1 liter of anhydrous diethyl-ether was added, and the solution was stirred at 250C. for 3 hr. The a 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 methanol-methylene chloride.

The solution was filtered and the solvent was removed in 0 vacuo. The residue was crystallized from chloroformhexane to give 66.68 g of title compound as a white, crystalline solid, m.p. 189-192 C. Part of this was recrystallized from methylene chloride-acetonitrile-hexane, m.p. 190-192 0

C.

Analysis: Calculated for CiesH4NOF; C,77.40; H,5.05? N,5.02 Found C,77.24; H,5.03; N,4.90 -4 14 38A 733 Preparation o ,a-BiS 4-chlorophenyl) -1.(phenylsulfonyl)-4-piperidinemethanol.

Following the procedure of Preparation 7, but substituting p-bromochlorobenzene for p-bromofluorobenzene, the title compc~und was prepared.

Preparation 26 4-Bis( 4 -chlcrophenyl)methylenelpiperidine hydrobvomide hydrate rl:l:lJ.

A mixture of 69.33 g (o.1146 mole) of c,a-bis(4-chlorophenyl)-l-(phenylsulfonyl)- 1 4-piperidinemethanol and 26 g (027mole) of phenol in 400 ml of 48% hydro.'omic acid was refluxed for~ 6 hr and then was stirred at room I! temperature for 10 hr. The reaction solution was decanted from a gum which had formed in the bottom of the reaction flas)R. The gum was washed with several portions of water ftand then was crystallized from ether to give a solid. The solid was recrystallized from a mixture of methanol- U diethyl ether to give 26,52 g of white crystalline n0 solid, m.p. 106-109 C.

Analysis: Calculated for C 18 BH2 0 NBrCl 2 0: C,51.83; H,14.83; Found :C,52-13; H,4.62;- N,3.38 Preparation 27 a 1-Chloro-14-(3-'chloropropoxy)benzene.

iF4425 A mixture of 77.2 g (0.60 mole) of p-chlorophenol, 2 189 g (1.2 mole) of l-bromo-K5-chl'ocopropane, 2149 g (1.8 mole) 44t of anhydrous potassium c~bnt~ and1 600 ml of acetone was stirred vigorously and heated to rei1ux for 16 hr under a nitrogen atmosphere. The potassium carbonate was removed by suction filtration, and the acetone and excess bromochioropropane were removed by heating under reduced pressure. The residue was dissolved in 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 I 43 8

A

under vacuum at ambient temperature to yield 107 g (87%) of white, flaky solid, m.p. 35-36 0

C.

Analysis: Calculated for CeHioOC12: 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 mole) of l-bromo-3-chloropropane, and potassium carbonate (1.5 mole, 207.3 g) were 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.

20 The solution was stirred and cooled in an ice bath. White crystals were collected by filtration, washed with cold o o petroleum ether and dried under vacuum at room temperature, m.p. 24-250C.

Analysis: Calculated for ClaHisOsCl: C,59.39; H,6.23; Found C,59.69; H,6.30 Preparation 29 1-(3-Chloropropoxy)-4-nitrobenzene.

A mixture of 7.0 g (0.05 mole) of 4-nitrophenol, 15.7 g (0.1 mole) of l-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 was cooled, filtered, and the filtrate was concentrated to give an oil which 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. 37-39o.

Analysis: Calculated for C 9 HioCNOs: C,50.13; H,4.67; N,6.50 Found C,49.95; H,4.71; N,6.51 U 43 8

A

[I Preparation lI-[Bis( 4-fluorophenyi)methyll-ipprdnpoao oxalate monohydrate.

A mixture of 10.67 g (0.0372 mole) of 4-[bis(4-fluorophenyl)methyllpiperidine, 5.42 g (0.039 mole) of 3-bromo-lpropanol 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 vacua, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesiumn sulfate and the solvent was removed in vacuo to give 8.88 g (67.3%) of oil, the fres. base of the title com~pound. A small sample of this oil was converted to the oxalate salt, and the salt was recrystallized from methanol-ether to give a white solid, m.p. 89-9I4 0 c. Overall yield was calculated to be 75.1%.

Analysis: Calculated for C 2 3

H

2 9 N0 8

F

2 c,60.92; H,6.45;' N,3-09 Found C,61-49; H,6:15; Preparation 31 20 4-3Clrpooy) mtoyezi acid methyl U A mixture of 100 9'(0,549 mole) ofnethylvanillate, 172.8 g (1.1 mole) of 1-bromo-3-chloropropane and 228 g *4*(1.65 mole) of anhydrous potassium carbonate in 1 liter of acetoae was heated at reflux for 20 hr. The mixture was cooled, filtered, and the filtrate concentrated to g~ve a white solid as residue. The solid was triturated with petroleum ether, collected by filtration, and dried to yield 137.8 g of white powder which was recrystallized from isopropyl alcohol, m.p. 104-105 0C.

Analycis: Calculated for C1 2

H

3 5 C10 4 Co55.71; 'H,5.84 IFound :C,55-871 NR,5.91 '1

U

I rrra~nr~ ~-n 438A 36 Preparation 32 4-[B is(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 ice bath. The temperature rose to 55 C. The reaction was then cooled in the ice bath.

To this solution was added 4-pyridine carboxaldehyde, 53.5 g (0.5 mole). The temperature rose to 950C. 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.

I

1 *z I i II II 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 furnished 1.08 g (48.6% yield based on the aliquot taken) of white crystalline product in 4 9 yield, m.p. 111.5-113.5°C.

Analysis: Calculated for CaoHisNOa: C,78.66; H,6,27; N,4.59 Found c,78.14; H,6.24; N,4.54 1 *i 1

III.

4 II *Ii I 44 *411 41 II $4tt 4 44 It ~4 38,z 37 Prepiration 33 '4-rBis(4-methoxphenyl)methyllpiperidine hydrochloride 'hydrate rl:1:1J.

The precursor pyridine derivative kI-.bis-4-mrethoxyphenyl) methyllpyridine 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-4methoxyphenyl)methyljpyridine (70.8 go 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 roomt 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 5% 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 wao then converted to the hydrochloride salt by dissolving it in methanol and treating with ethereal 9,44 hydrogen chloridoo. The white solid was filtered off and dried overnight at 800c. in vacuo in the amount of 2.08 g Mn-p. 132-1350C.

Analysis: Calculated for C 20 H2 8 N0sCl: C,6 H$7.71; N,3.83 Found. .c165.63; H,7.53; N,3.90 Preparation 34 4-[Bis(4-1Tethlphenyl)rethllpiperidine hydrochloride .a The free base of the title compound was prepared by hydrogenation of l-(bI.B-4-methylpheny1)methyl~p! ridine in acetic acid using palladium on carbon as catalyst and converted to the hydrochloride salt in nmethanol.-diethyl ether. The salt was recrystallized~ from methanol-diethyl ether and isopropanol-.diethyl ether and dried overnight ina vau at 800c. White solid amounting to 46% yield, nm.p.

232 0 C. was obtained.

Analysis: Calculated for C 30 Ii 36 NC1: C#76#051 ii,8-3o, No,4.43 Found c.75-5l; H,8.33; N, 1 4-33

I.

-ri 438A 38 Preparation N-r 4-'3-Chloropropoxy)phenyl lacetamide.

A mixture of 4-acetamidophenol, 182.2 g (1.2 mole), bromochloropropane, 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 refrigerated overnight and white crystals formed. This white solid was filtered and washed with acetone. The filtrate was stripped to dryness and the residue was dissolved in chloroform and extracted with 5% sodium hydroxide. 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 were recrystallized twice from acetone. A 5 g sample of the white crystals was recrystallized from acetone. This furnished 1.76 r (after drying in vacuo overnight at 80°C.) of white crystalline product, m.p. 125-127 0

C.

20 Analysis: Calculated for C 1 1 H14NOTCl: C,58.03; H,6.20; N,6.15 Found C,58.21; H,6.28; N,6.15 a -a aaa 0# La a a a.

a a aa, *I a a a a atrc a1a Preparation 36 3-Chloropropoxy)-3, 25 A mixture of 3,5-dimethoxyphenol, 100.0 g (0.6486 mole), chlorobromopropane, 148.0 9 (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 m-ixture was cooled to room temperature, filtered, and stripped to dryness 30 via a rotary evaporator. The resulting oil was dissolved in chloroform and the solution extracted with 5% aqueous sodium hydroxide; removal of chloroform gave 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' (CDC1s): 12-2.4 (quintuplet, center methylene protons, 2H), 3.6-4.2 aliphatic protons, 4H), 3.8 OCH 3 6H), i 39 6.1 aromatic protons, 3H).

Analysis: Calculated for C 11

H

1 5 0 3 C1: C,57.27; H,6.56; Found C,56.96; H,6.49 Preparation 37 3-Chloropropoxy)benzonitrile.

A mixtur8 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 mixtre was filtered and stripped to dryness. The resulting residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Removal of chloroform gave an oil which crystallized to give a white solid. A 5 g sample was recrystallized from isopropyl ether.

This furnished 1.22 g (24.11% based on 5 g sample) of white solid, m.p. 40-44 00C which contained a dimer iwpurity.

Analysis: Calculated for CioH 2 oNOCl: C,61.39; H,5.15; N,7.16 Found C,61.57, H,5,14 N,7.20 Preparation 38 l-4-(3-Chloropropoxy)--methyphenyllethanone.

A mixture of 25 g (0.166 mole) of 4-hydroxy-3-methylacetophenone, 45.8 g (0.33 mole) of l-bromo-3-chloropropane and 69.lg (0.5 mole) of anhydrQus potassium carbonate in S 500 ml of acetone was heated at reflux for 20 hr. The 0 0 25 mixture was cooled, filtered, and the filtrate concentrated under reduced pressure tou give an oil as residue. The oil o was crystallized in oetroleum ether, The solid was collected by filtration, washed with petroleam ether and dried to yield 35.8 g of an off-white powder. An analytical 0Oi 44 smpe sample r.p. 41.5-42.5 0 was prepa:ed from petroleum ether.

4 40' Analysis: Calculated for C 12

H

15 C10 2 C,63-58; H,6.67; Found C,63.40 H,6.64 4040 *I 0

II

Ii

U

N

dA Preparation 39 4-(2 'horopropoxylbenzamide.

A mixture of 50 g (0.365 mole) of 4-hycroxybenzamide, 1124.8 g (0.729 mole) of l-bromo-3-chloropropane nnd 151.3 g (1.1 inole) of anhydrous potassium carbonate in 1 liter of 5 acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was stirrecq with 1.2 liter of water to remove inorganic solids.

The mixture was filtered and the filter cake was washed with water aind petroleum ether and dried to yield 75.5 g of a white solid. The solid was recrystallized from, ethyl acetate, m.p. 142-143 0

C.

Analysis: Calculated for C 10 1-1 2 C1N0 2 C,56.22; H,5.66; N,6.56 Found :C,55.92; H,5.61; N,6-56 Preparation 240 1- r 4 (-Chloropentox) -3-methoxyp",henyl Ietha none.

,A mixture of 59.7 g (0.36 mole) of acetovanillone, 100 g (0 "19 mole) of l-bromo-5-chlcropentane and 138 g (l mole) of anihydrous 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 81.24 g 4(814%) of fluffy, white solid. The solid was recrystallized 25 from isopropyl ether, M-p. 57-580C.

Analysis: Calculated for C 1 4 fl 1 9 C10 3 C,62.11; H,'r.07; Found c,62.14,- H,7.10 Preparation 141 4 4 Ign4-(3-Chloropropoxv -3-methoxvbenzeneacetic ncid Fithvl .4 44 4 4 4 6 4 4 4 a 4444 6 *4 ester.

A mixture of 50 g (0.238 mole) of ethyl homovanillate, g (o.476 mole) of 1-bromo-3-chloropropane and 98.7 g 64 (0.71 mole) of anhydrous potassium carbonate in 1 liter of 3acetone was heated at refliux for 2~4 hr. The mixture was filtered and the filtrate was concentrated, under reduced

I

pressure to give an oil which graduE 41y crystallized to a semi-solid. The solid was recrystallized from ethyl etherpetroleum ether (30-60 0 to yield 44.14 g of white solid, m.p. 356-38 0

C.

Analysis: Calculated for C 1 4

H

1 9 C10 4 C,58.64, H,6.68 Found C,58-74; H,6.74 1-(-Chopropoxy) -4-(methylsulfonyl)benzene.

To a solution of 21. g 01ml)o -j-chloropropoxy) 4-(methylthio) benzene in 100 ml of chloroform was cautiously added a slurry of 51.8 g (0.75 mole) of m-chloroperbenzoic acid in 450 ml of chloroform. The mixt-ure was stirred at 4ambient temperature for 2 days and then filtered. The 4 filtrate was washed with four portions of a solution comprised Of 110 Ml of saturatpd sodium bicarbonate, 110 ml of water, 4 and '0 ml of 20% sodium hydroxide, once with brine, dried (sodium sulfate) and concentrated under reduced pressure to give a solid as residue. The solid wvas triturated with petroLeum ether, collected by filtration and air dried to yield 24 .3 g of white solid. An analytical sample, rn.p. 84-86 c. was recrystallized from 2-propanol.

Analysis: Calculated for C1oHisClO 3 S: c,48.29, H,5,27 44 Found C,148.738; H,5.30 F, P:,eparation 143 wo: 25 r-oxo-l-(phenylmethyl) -3-pyrrolidinecarboxylic acid methyl eater.

Q 4 A solution of 158.2 g (1.0 mole) of dime thy! ita conate 14 and 107.2 g (1.0 mole) of benzy3.amine in 750 ml of methanol.

1.1 ,was let stand at ambient temperature over the weekend. The 30 sol, tion was filtered and the filtrate was concentrated 4 under reduced pressure to give an. oil as residue, The oil crystallized when it was tritLurated with petroleum~ ether (30-60 0 The solid was collected by filtration and dried to yield 225.5 g if white powder. An analytical sample, m.p. 63-65 0 C. was prepared from diisopropyl ether.

Analysis: Calculated for C 1 3

H

1 5N03: C166.94; H,6.48; N,6.ol Found 66.82 H,6.48, N,6.01

I

i Cl i I---i 42 Preparation 44 1-Benzyl-3-hydroxymethyl-pyrrolidine oxalate rl:11.

A solution of (60.0 g, 0.2553 mole) 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 mixture was then stirred overnight at room temperature, then quenched by the slow addition of ethyl acetate. More ethyl acetate was added and the use of celite allowed the solid material to be separated from filtrate by filtration. The filtrate was stripped to dryness and dissolved in chloroform. The chloroform layer was extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered, and solvent removed to give an oil. A portion of the oil was converted tc the oxalate salt. The salt was recrystallized from methanol-diethyl ether and dried at 0 c. in vacuo overnight to give 2.27 g (39.4% yield based on aliquot taken) of white crystalline solid, m.p. 98-102 C.

Analysis: Calculated for C 14

H

9 eNOs: C,59.78; H,6.81; N,4.98 Found C,59.43; H,6.79; N,4.95 S Preparation 1-r 4 -(6-Chlorohexylox v)--methoxyphenyl ethanone.

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

Analysis: Calculated for CisHa1Cl0 3 C,63.26; H,7.43; Found c,63.50; H,7.60 I I i 438A 43 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 0 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 combined and concentrated under reduced pressure to yield 12.2 g (345) of white solid, m.p. 106-107.5 on recrystallization from 2-propanol.

Analysis: Calculated for CsH 1 2 N0 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 l-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 25 under reduced pressure to give a solid residue. The solid was triturated with petroleum ether collected by .filtration, and dried to yield 19.1 g of fluffy, C, OC white solid. An analytical sample, m.p. 100-102 was obtained on recrystallization from 2-propanol.

Analysis: Calculated for C 12 HlnC10 3 C,60.39; H,4.65 1 1 Found C,60.335; H,4.68 rv:' 4 t It 4 3 8

A

414 Preparation 48 7-(3-Chloropropoxy) -4--oxo-14H-1 -benzopyran-2 -carboxyl ic acid ethyl ester.

I A mi~xture of 23.14 g (0.1 mole) of 7-hydroxy-4-oxo-4H- 1-benzopyran-2-carboxylic acid ethyl ester, 31.6 g t:0.2 mole) of l-btiomo-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 (30-600c.), collected 1 by filtration, and recrystallized from 2-propanol to yield 22.-5 g of white solid, m.p. 107-1080c.

Analysis: Calculated for Cj 5

H

1 5 C10 5 C,57.98; H,14.87 Found .C,58.21; H,14.88 Preparati6n 142 1- 1 4 -(3-Chloropropoxy)-2-methoxyphenyl~ethanoile.

A mixture of 10.6 g (0.637 mole) of 1-( 1 4-hydroxy-2methoxyphenyl)ethanone, 20 g (0.127 mole) of l-bromo-3if :20 chloropropane and 26.~4 g (0.19 mole) of anhydrous potassium carbonate in 250 ml of acetone was heated at reflux for hr. The mixture was cooled, filtered and the filtrate concentrated under vacuum pump pressure at 90 C. to give an oil which gradually crystallized. The solid was I ,~25 triturated with petroleum ether (30-60 0 collected by filtration and dried to yieldt 14.6 g (914%) of white solid, 0~ m.p. 47-149 0C. on recrystallizing from isopropyl ether.

Analysis: Calculated for C1.

2

H

15 ,Cl0 3 C,59.39; H,6.23 Found :C,59.32; H,6.26 Preparation ,'3-Chloropropoxy) -4-su lf inylbenzene.

The, title compound is prepared by treating i-(3chioropropoxy) -4-met%.'hyl thiobenzene with sodium perborate in glacial acetic acid.

438A 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 r 500 ml of acetone. The reaction mixture was 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 in vacuo to give a brown oil (80.09 A ten gram portion of this oil was subjected to flash chromatography on silica gel with 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 0 C. in vacuo. This furnished 5.24 g (50.0% yield based on aliquot taken) of clear oil.

'H NMR (CDCal s )7 2.1-2.5 2, -CHi 2 2, -ClCH 4.2 2, -OCHa), 6.9 2, aromatic protons ortho and para to ether), 7.5 2, aromatic protons ortho and para 20 to CN group).

Analysis: Calculated for CloHoNOCl: C,61.39 H,5.15; N,7.16 Found C,61.27; H,5.15; N,7.14 Preparation 52 l-Phenylmethyl-3-pyrrolidinemethanol methanesulfonate (eater) mxalate 4' .A solution of 113.80 g (0.596 mole) of l-benzyl-3hydroxymethylpyrrolidine and triethylamine, 66.6 g (0.66 S' 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 stirring. The solution was allowed to stir overnight at room temperature. A solid precipitated and the solution was filtered. The solvent was removed by rotary 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), -1 i 13 438A 46 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 80 0

C.

in vacuo overnight, 181.63 g of white crystalline solid was obtained. A five gram sample was recrystallized again from methanol-diethyl ether and dried at 0°oc. 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.

1C Analysis: Calculated for Ca 2 Ha 5 N0 7 S: C,57.92; H,5.79; N,3.22 Found C,57.62; H,5.82; N,3.22 Preparation 53 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 10% palladium-on-charcoal catalyst at 75 0

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 20 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 o 'residue crystallized and was recrystallized twice from isopropanol-ether. The material was dried at 110°C./0.1 mm for 3 hr, m.p. ll0-145 0 C. (softens and turns liquid). The material appears to be an amorphous solid.

Analysis: calculated for Cae 2 2 4 NOs: C,66.65; H,6.10; N,7.07 Found c,66.79; H,6.05; N,7.04 a 30 Preparation 54 S,-Diphenyl-3-pyrrol idineacetamide N-cyclohexylsulfamate hydrate rl:1:1.51.

S

I t A 1.15 g sample of free base of the above compound obtained by proportioning a,a-diphenyl-3-pyrrolidineacetamide maleate in chloroform and aqueous basic solution and evaporating the chloroform layer and 0.735 g of hexamic acid 438A 47 were dissolved in 10 ml of ethanol. The solvent was evaporated, the residue crystallized, and then was recrystallized from ethanol, m.p. 103-106 0

C.

Analysis: Calculated for Ca 4

H

3 3

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 Preparation l-(Phenylmethyl)-4-piperidinol ester with 4-methylbenzenesulfonic acid maleate rl:l].

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 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 0 converted to the maleate salt, which was recrystallized 9. from methylene chloride-diethyl ether to give white crystalline solid, m.p. 159-160°C.

Analysis: Calculated for C 2 3

H

2 7 NOS: C,59.86; H,5.90; N,3.04 Found C,59.79; H,5.86; N,2.95 OB° °5 Preparation 56 1-2 -(Phenylthio)ethyll-4-piperidinecarboxylic acid Sethyl ester hydrochloride rl:ll.

A mixture of 69.3 g (0.40 mole) of 2-chloroethylphenyl- 4« sulfide, 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 4w 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.

f 438A 48 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. 125- 126°C.

Analysis: Calculated for C 1 6 Ha 4 NOaSCl: C,58.26; H,7.33; N,4.25 Found C,58.11; H,7.32; N,4.20 Preparation 57 l- (4-Methylphenyl)sulfonyll-4-piperidinol ester with 4-methylbenzenesulfonic 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°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 1 M sulfuric acid followed by 1 M sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from methylene chloride-diethyl ether to give 4.82 g (73.3) of the product, m.p. 140.5-141 0

C.

Analysis: Calculated for CisHa3NOsS 2 C,55.73; H,5.66; N,3.42 Found s C,55.60; H,5.64, N,3.39 Preparation 58 S* l-r 1(4-Methylphenyl)sulfonyll-l ,fy-diphenyl-4-piperidine- S* 25 acetonitrile.

The sodium salt of diphenylacetonitrile was formed in toluene from diphenylacetonitrile, 94.5 g (0.488 mole) and I 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 l nitrogen at room temperature. The solution became green in color. The solution/mixture was stirred overnight at 100 0

C.

The mixture was filtered and the toluene was removed by rotary evaporation.

I

A

438A 49 The filter cake and the residue from removal of toluene were combined and dissolved in chloroform. The chloroform was extracted several times with 5% sodium hydroxide followed by extraction with IN sulfuric acid and sodium hydroxide.

The chloroform was removed in vacuo to give a reddish-'-rown oil.

A sample of the oil was crystallized from toluene and washed with isopropyl ether. The solid obtained was then recrystallized from methylene chloride-hexanes and dried at 80 C in vacuo overnight to give white solid title compound in 26.7% yield based on aliquot taken, m.p. 183-184 0

C.

Analysis: Calculated for C 2 asHa6eNOS: C,72.53; H,6.09; N,6.51 Found C,72.11; H,6.07; N,6.45 Preparation 59 u,u-Diphenyl-4-piperidineacetonitrile oxalate A solution of l-[(4-methylphenyl)sulfonyll-a,o-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 S 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 anhydrous sodium sulfate and solvent removed *45 to furnish a red oil. This oil, the free base of the title compound, was converted to the oxalate salt using methanoldiethyl ether mixture. A sample of the oxalate salt was recrystallized from methanol-diethyl ether to give white crystalline product in 17.9% yield, m.p. 275-276 0

C.

Analysis: Calculated for C 2 a0liNaOa: C, 7 4.

7 4; H,6.59; N,8.72 Found C,74.51; H,6.52; N,8.60 *t 88 8r *0 8i 84i 8 8 8D a 1 88 8 84E'i 8 8J 88 9 8 9 4 84 4 -L r 438A Preparation uca-biphenyl-4-piperidineacetamide fumarate r 2 :31.

a-a-Diphenyl- 4 -piperidineacetonitrile oxalate [2:1] 60.34 g (0.165 mole) was converted to the free base by partitioning in 5% sodium hydroxide and 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 stirred overnight at 900C. The reaction mixture was poured into ice and carefully made alkaline with 50% sodium 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 which cyrstallized. A two gram sample of the oil was converted to the fumarate salt and the salt was recrystallized from methanol-diethyl ether. A white solid was obtained yield based on aliquot taken) which was dried overnight in vacuo at 80 0 24-2535°C.

Analysis: calculated for C 2 5 sHaN 2 0 7 C,64.09p H,6.02i N,5.98 Found C,63.82; H,6.14; N,5.82 20 4 Preparation 61 4 -Methylphenyl) sulfonylj -Q -diphenyl-3-piperidinei

H

f t propanenitrile.

The sodium salt of diphenylacetonitrile was formed in S400 ml of dimethylsulfoxide from sodium hydride 39.0 g, 25 0.975 mole) and diphenylacetonitrile (188.90 g, 0.975 mole).

The resulting solution was stirred under nitrogen for one hr at room temperature. A 90-10 mixture of 3-(chloromethyl)-l- (4-methylphenyl) sulfonyllpiperidine and 4-methylbenzenesulfonic acid l-[(4-methylphenyl)sulfonyl]piperidin-3-yl 30 methyl ester, 921.42 g (0.975 mole) dissolved in 400 ml of dimethylsulfoxide was added. The reaction mixture was heated to 85°c. 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 IN sulfuric 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 Uiff'*, J AmI 438A 51 ether to give a brown solid. A, five gram sample was recrystallized from ethyl acetite-isopropyl ether. This provided four grams (56.8% yield based on aliquot taken) of white solid, m~p. 136.5-131 0

C.

Analysis: Calculated for C 27 HIiBN 2 0 2 S: C,72.94; H,6.35; N)6.30 Found .C,72.82, 11,6.36; N,6,28 kreparation 62 cr,c-Diphenyl-3-Piperidinepropanenitrile fumarate Fl:l>, A mixture of 302.111 g (0.68 mole) of 1-C(4methylphenyl) sulfonylJ--x,ca-diphenyl-3-Piperidinepropanenitrile, hydrogen bromide (148%6, 750 ml), and phenol (260 g, 2.76 mole) was stirred vigorously while heating at reflux for 3-112 hr.

The reaction mixture was cooled to room temperature and made alkaline with 50%6 sodium hydroxide-ice, The aqueous phase was extracted several times with chloroform) and the chloroform layer was back extracted with 5% sodium hydroxide, The chloroform layer was dried, filtered, and solvent removed. NMR analysis showed about 80% product was obtained, so the same reaction sequence was repeated, The chloroform layer gave a brown oil which was converted to the oxalate salt. 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 and converted to the fumarate salt. The salt was ~f 25 recrystallized from methanol-diethyl ether and dried in vacuo at 8 0 0C. overnight to give 6.53 g of white crystalline product, m.p. 181-182 0 Oc.

Analysis: Calculated for C2 4

H,,

6

,N

2 0 4 C,70.92; H,6.45. N1,89 Found C,7.J46; H,6.,41; N1,6.86 0 Ot 30 Prep~aration 63, 44#tt ,cy-Diphenyl-3-Piperidinepropanamide maleate rl:l1, A solution of 52.01 g (0.179 mole) of a,cr-diphenyl-3piperidinepropanenitirile was stirred overnight at 85 0 C. inl 280 ml of 90% sulfuric acid. The reaction mixture was allowed to cool to room temperature and then poured into 50/0 sodium hydroxide/ice mix. The basic layer was extracted with 4hloroform. The chloroform layer was dried, filtered, and the solvent removed to give a fluffy solid, the. free base of 4 38A V 52 IIthe title compound. A 3 g pcrtion of the free base was converted to the maleate salt and recrystallized from rnethanol-diethyl ether. The salt obtained was dried in vacuo overnight at 8o C. This furnished 2 .15 g of 0 whit:e crystalline product, m-p. 177-179 C.

I Analysis: C-alculated fo'r C 2 4

H

2 8

N

2 0 5 C,67-91; H,6.65; N,6.60 Found .c,67.85; 11,6-85; N,6.55 Preparation 64 1-r(2-Chloroethyl)sulfonyll-4-fluorobenzene.

A solution of 300%hydrogen peroxide (153 go 1.34 mole) in 400 ml of glacial acetic acid was prepared. To this ice cooled solution was added a solution of 2-cbloroethyl p-fluorophenylsulfide (70.11 g, 0,369 mole) in 200 ml of Iglacial acetic acid. The resulting solution was stirred 72 hours at room temperature. The volume of acetic acid I was concentrated on a rotary evaporator, The residual I material was dissolved in chloroform and extracted with a 1 solution of sodium bicarbonate and sodium sulfite. The chloroform layer was then dried, filtered, and solvent removed to give a white solid A 5 g portion of this white solid was recrystallized from methylene chloride-isopropyl :00~ ether. The white solid was dried in vacuo at 80%0,C overnight. This furnished 1.84 q (32,6% yield base on aliquot 4~Q Itaken) of white crystalline solid, m-jp. 72,5--7~4 C.

25 Analysis: Calculated for C 5 HeS0eFC1: C)43.15; H0,62; jFound c,43.521 H,5.66 Preparation 685 4-Flu-oro-.o-(4-fluorophenyl)benzeneacetonitrile.I 4-luorophenylaceton it rile (70.0 go 62.2 ml, d=1.126, 0.518 mole) was heated to 120 0C. Bromine (83.0 go 26,6 ml 1 &-3.1l9, 0.525 mole) was added dropwise over I hr while maintaining a temperature of 12000C. The solution was stirred for 1A2 hr at 120 0 and then flushed vigorouisly with nitrogen for 3/4 hr (solution A).

in a separate 2-liter flaskX was placed aluminum ch~loride (85.0 9, 0.644 mole). Fluorobenzene (200 g, 2.08 mole d=1.0241 195.) 211) Was added dropwise With stirring over 43 8A I53 1/A hr while flushing with nitrogen (Mixture B).

Solution A was aadded aropwise to Mixture B starting at 0 room temperatui i. The temperature rose to 50 C. The reaction was stirred at this temperature for 1/3 hr. The temperature was raised to 7000C. and maintained there for ii 1/5 hr. The reaction became vigorous and a part of the Vmaterial was lost. The mixture which could be recovered was added tci ice/75 ml of concentrated hydrochloric acid.

The aqueous phase was extracted several times with chloroform. The solvent layer was dried, filtered, and solvent vremoved to give a green solid. The solid was recrystallized V from iscopropanol; the solid was washed with cold isopropaniol 0 11 twice and dried in vacuo at 55 C. overnight, This produced 29.72 g of light yellow solid, rn.p. 62-63.5 0

C.

H 15 Analysis: Calculated for C 1 4H9NF 2 CJ73.36; 11,3.96; N,6.11 Found C,73.55; H,3,88; N,6.10 Preparation 66 a -Bis(4-fluorophenyl)-l-F (4-methylphenyl.)sulfonyll- 4-piperidineacetonitrile.

The sodium salt of 4 floo, 4flurpey)bnee it acetonitrile was prepared in dimethyl sulfoxide from its free base, 28.0 g (0.1223 mole) and 4i.90 g of 60'9 sodium hydride (0.13227 mole). The salt was stirred for 1 hr at Uroom temperature, To the mixture was added 50.0 g (0,1223 mole) o! 1-[(i4-methiylphenyl)sulfonyl)-4-piperi.dinol ester with 4-rethylbenzeresulfconic acid over five minutes iii solid form while stirring under nitrogen. The resulting solution was stirred .15 hours at 6500,. and then allowed to atroeprte fresidhurs dis soledinwa ato ross pante fres72uhours Thessolutdinwa chlrofrmandextracted several times with 53% sodium hydoxie. hechloroform layer dried (anhyd~rouxi sodium sulfate), filtered, and solvent: ve-muved to give 111.36 g of.

solid. The solid was triturated With isopropyl ether and placed in the freezer. After washing the solid several, times with isopropyl ether, 55.143 g of white solid was obtained.

A 3 g sample was then triturated wlth 50-50 hot 544 isopropyl alcohol-mn~thano. an(! placed in the frcezer. The white solid collectee washed with isopropyl ether arid dried in vacuo at 80 0 C. overnight. This produced 2.28 g p of white oryrtlline product, M.P. 190-191 0

C.

Analysis: Calculated for C 2 8H 2 4

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 Preparation 67 c~-Bis(4~-fluorophenyl)J4-piperidineacetonitrile oxalate, diethyl ether [1:1:0J.51.

A solution of 52.41 g (0.1125 mole) of u,cu-bis-(4fluoropheiiyl) 4 -methylphenyl)sulfonyl)-24-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 itii;:ture. The alkaline phase was extracted several times with chloroform.

The chloroform layer was back extracted with 5% sodium hydroxide. The ihloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give 314.2'4 g I of dark brown oil. The entire oil was converted to the fj oxalate salt and recrystallized from methanol-diethyl ether.

The sailt obtained was dried in vacuo overnighta I 0 .t I give 34.24 g of whito cryEstalline solid, m.p.

124-127 C.

4 Analysis: Calcula3ted for C23HesN 2 F2O 4 c,62,86; H,5.73; IFound :c,62.30 ,6 .3y N,6.17 Preparation 68 44 N-r3-( 3-ChloroproPoxy) phenyl urea.

A mixture of 45.6 g (0.3 mole) of 1-(3-hydroxyphenyl%/ urea, 914.5 g (0.6 mole) of 1-bromro-,-3-chloropropane, 12; .4 g (0.9 mole) of anhydrous potassium carbonate and I liter of acetone was heated at reflux with mechanical stirring for ll rs.' Vhe mixture was concentrated and the residue was slurried with 1.5 liter of water. The mixture was filtered and the filter caKa was recrystallized from isopropanol to Ofthm.- 1 -1 AN 438A yield 57.0 g (83%)of off-white solid, m.p. 141-143°C.

Analysis: Calculated for CloH1sClN 2 Oa: C,52.52; H,5.73; N,12.25 Found C,52.37 H,5.79; N,12.17 Preparation 69 N-[4-(3-Chloropropoxv)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-.'hloropropane, 13.8 (0.10 mole) of anhydrous potassium carbonate and 150 ml of acetone was heated at reflux for 21 hours. 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 1 2 HlaClNO: C,55.93; H,6.26; N,5.43 Found C,55.93; H,6.28; N,5.46 Preoaration 2 -(4-Fluorophenyl)-2-pyridineacetonitrile.

A sample of sodium hydride 1.60 g, 0.04 mole) was washed with dry hexanrs. After removal of hexanes a :j 100 ml portion of dimethyl sulfoxide was added. To this 0 0 mixture was added a solution of 4-fluorophenylacetonitrile So. o (5.41 g, 0.04 mole). The mixture was stirred 3 hours S 25 at room temperature under nitrogen. 2-Bromopyridine (6,32 g, 0.04 mole) was added to the mixture, and the reaction S.*mixture was then stirred overnight at 65C. The reaction mixture was poured into 1.2 liters of wa-ter and the aqueous phase was extracted several times with chloroform (the 30 chloroform layer was filtered using Celite). The coTmbined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a red oil.

The oil was subjected to flash chromatography on silica gel using 10% ethyl acetate-90% hexanes and 20% ethyl i 438A 56 hexanes for elutioni. Fractions of similar purity were 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.

1 H (CDCl 3 ):Jf 8.5 proton adjacent to N in pyridine nucleus), 6.8-7.8 (in, 7, aromatics), 5.3 1, inethine).

Analysis: Calculated for CI 3

H

9

N

2 F: C,73.57; H,4.27; N,13.20 Found .C,73.23; H,14.23, N,13.12 Preparation 71 n-(-Fluoropenl)---rl-(4-methylphenvl)sulfonvl1- 4 niierid invl 1-2 -pyid inpa ceton it rile hemihvdrate.

The sodium salt of the free base of a-(14-fluorophenyl)- 2-pyridineacetonitrile was formed in dimethyl sulfoxide from sodium hydride 5.16 g, 0.129 mole) and the free base of cx-(4-fluorophenyl)-2--pyridifleacetonitrile (27,36 g$ 0.129 mole). The salt was stirred in dimethylsulfoxide 4-1/g hr at room temperature. Next, 4-mathylphenylsulfzonic acid ester with l-[(4+-methylbenzene)sulfonyl]l4-piperidilol, (52,8 g$ 0.129 mole) was added and the reaction a~ixture was stirred 2 hours at room temperature. The reaction mixture was stirred overnight at 8 0 0C. The solvent was A 4 304 removed in 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 dark brown residue. This material was triturated with acetone to give 36.2 g of white solid. A one gram portion was triturated with acetone and then recrystallized from miethylene chloride-acetone. The solid was dried in vacuo overnight at 80 to give 0.74 g (62.14% based on aliquot taken) of white crystals, m.p. 228-229 0

C.

Analysis: Calculated for C 2 5

H

2

SN

3 0 2 5 SF: C,65.90; H,5.

1 49; N,99.16 Found C165.86; H,5.27, N9. 16 III I A A A AA I A A Al Al A

I

1 10 20 43 8A 57 Prearation 72 ci-e4-Fluorophenyl)-a-(4-piperidinyls-2-pyridineacetonitrile oxalate [2:33.

A solution of U-4furpey)--[-(-ehlhnl sulfonyli- 1 1-piperidinyl)-2-pyridineacetonitrile, (30.86 9P 0.0687 mole) and phenol (75 g, 0.8 mole) in 200 ml of 48tb hydrobromic acid was heated at reflux for 3 hours. The mixture was cooled in ice and made alkaline with ice sodium hydroxide. The aqueous layer was extracted with chloroform and the chloroform layer was extracted with sodium hydroxide. The chloroform layer was dried over sodium sulfate, filterad, and solvent removed to give a darlk brown oil. 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 0 C. overnight. This furnished 0.90 g (80.2% based on aliquot taken) of white crystalline, m.p. 98 0 C. (softened 70 0 Analysis: Calculated for C 21 Fk.IN301F: C,58.60; H,J4.92,- N, 9,76 Found .C,5e.77; F1,5.01 N.Jo.0 1 4 44 Preparation 7,3 T-(8-Quinolinyloxy -1-propanol.

A solution of 8-hydroxyquinoline (36.0 g, 0.25 mole) and potassium tert-butoxide (28.0 g, 0.25 mole) in 80 ml dimethyl sulfoxide was stirred for 1 hour at room temperature. 3-Chloro.-l-propanol (24i.0 g, 0.25 mole) was added and the solution was hezited overnight at 70 0C.

The solution was poured into 500 iml of water. A brown .4'solid/mass was obtaineJ. The solid was washed with several portion8 of water and then triturated with acetone. The solid was filtered and dried in vacuo at 8 0 0C. overnight to give 35.67 g of light brown solid, m.p. 126.-127 0

C.

Analysis: Calculated for Ci 2 HisN0 2 C,70.92; H,6.J45; Found C,70.94; H,,6:49; N16.87 I 438A 58 Preparation 7 8-(3-Chloropropoxv)quinoline.

A solution of 3-(8-quinolinyloxy)-1-propanol (32.0 g, 0.158 mole) and thionyl chloride (24.0 g, 0.20: 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 g in 500 ml of water). The gummy residue was dissolved in chloroform and the solution was extracted with the potassium carbonate solution. The chloroform layer was dried over anhydrous 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. The solid was dried in vacuo at room temperature overnight to give 26,69 g of white crystalline solid, m.p. 69-71°C, Analysis: Calculated for Ca 2

H

1 2 NOCl: C,65.02, H,5.45; N,6.32 Found C,65.19; H,5.51 N,6.27 20 Preparation a ,-Bis(4-fluorophenyl) (4-mthylphenyl) sulfonyllj 3-piperidineacetonitrile.

I The sodium salt of 4-fluoro-a-(4-fluorophenyl) S benzeneacetonitrile was formed in 500 ml of dimethylo 25' sulfoxide 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.

l-i 4-Methylphenyl)sulfonyl -3-piperidinol,-4-methylphenyl- So: sulfonate ester (70.4 g, 0.172 mole) was added and the solution was stirred overnight at '65C. 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 chlorofort gave a dark brown oil. An eight gram portion of this oil was subjected to flash chroinatography on silica gel using 15% ethyl acetate-85 hexane for elution. Fractions of similar purity were combined 438A 59 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.

3H NMR (CDCls): 6.9-7.6tf(m, 12, aromatic), 3.7-4.0 (m, 2, protons adjacent to sulfonamide nitrogen), 2.

4 3, methyl), 1.3-2.9 7, aliphatics).

Analysis: Calculated for C 2 eHa 4

N

2 0 2

SF

2 :,66.93; H,5.18; N,6.00 Found :C,66.62; H,5.20? N,5.89 Preparation 76 aa-Bis(4-fluorophenyl)-3-piperiineacetonitrile maleate f;1:1.

A solution of a,a-bis(4-fluorophenyl)-l-[(4-methylphenyl)sulfonyl]-3-piperidineacetonitrile (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/ 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 ektracted with two 150 ml o portions of IN sodium hydroxide. The chloroform layer I "was dried over anhydrous sodium sulfate, filtered, and oo solvent removed to give a light brown oil. The oil was 0 4o25 converted to the maleate salt which was recrystallized from methanol-diethyl ether. The precipitate was dried in vacuo overnight at 800C. to give 13.05 g of white crystals, m.p. 115-118 0

C.

4 Analysis: Calculated for Cas3H2N 2 0 4 F2: C,64.48; H,5.18; "N,6.54 Found C,64.04; H,5.15; o. N,6.50 4 4 ooI i i I 3SI- ii 17 lllU C-L-4CIS: 438A Prepl. -tion 77 4-rBis(4 fluorophenyl)methyl-l--(3-chloropropyl) piperidine.

A solution of 4-[bis(--fluorophenyl)methyl]-lpiperidinepropanol (40.27 g, 0.117 mole free base) and thionyl chloride (17.90 g, 0.150 mole) in 350 ml of chloroform was stirred at room temperature for 1/2 hour.

The 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 dried (anhydrous sodium sulfate), filtered, and solvent removed to give a 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 iH 2 4

NOF

2

C

2 C,69.32; H,6.65; N,3.85 Found C,69.09; H,6.60; oN,3.84 I o Preparation 78 7-Hydroxy-4-oxo-4H-l-benzopyran-2-carboxyl ic acid ethyl ester.

S°To a warm, stirred solution of 18.4 g (0.8 mole) of 25 sodium metal in 250 ml of absolute ethanol was added dropwise a solution of 30.4 g (0.2 mole) of 2,4-dihydroxyacetophenone and 58.5 g (0.4 mole) of diethyloxalate in ml of absolute ethanol and 50 ml of absolute ethyl ether S over a 30 min period. The mixture was heated at reflux 30 for 4 hours and then poured into a solution of 200 ml of concentrated hydrochloric acid and 1.8 liter of water. The mixture was extracted with two 500 ml portions of ethyl zo.« ether and the combined extracts were 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 438A 61 heated tt reflux for 2 hours. he mixture was concentrated under reduced pressure and the solid residue was triturated with ethyl ether, collected by filtration, and recrystallized from 95% ethanol to yield 28.1 g of a tan powder, m.p. 217-221 0

C.

Analysis: Calculated for C 12 HloOs: C,61.54; H,4.30 SFound C,61.68; H,4.34 Preparation 79 Sa,-Diphenyl-l-(phenyhymetyl)-4-piperidineacetonitrile hydrochloride [1:11.

To a prewashed slurry of 8.00 g (.19 mole), 57% sodium hydride in 300 ml of dimethylsulfoxide was added 32.80 g (0.17 mole) diphenylacetonitrile. Th solution was heated at 65 0 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 600C. 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 cf sulfuric acid which caused a gummy residue to precipitate. Th- residue was taken up in a mixture of methylene chloride and 10% sodium hydroxide. The layers were l separated, the aqueous layer extracted with methylene °25 chloride and the combined extracts dried over magnesium sulfate. Concentration gave 35.0 g of a tan solid, ji m.p. 138-142 0 c.

j f A small portion was converted to the hydrochloride salt o«o* which was recrystallized from methanol/diethyl ether to give white powder, m.p>250 0

C.

Analysis: Calculated for C2eH 2 aClN 2 C,77.50; H,6.75; N, 6.95 Found C,77.09; H,6.76; N,7.04

I

438A

I

Ii

I

Preparation a,a-Diphenyl-l-(phenylmethyl)-3-piperidinepropanenitrile hydrochloride l1:11.

A mixture of 7.25 g, (0.025 mole) of a,a-diphenyl-3piperidinepropanenitrile, 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. 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 800C. overnight. A yield of 15 7.04 g of white solid, m.p. 243-246 0 C. with decomposition was obtained.

Analysis: Calculated for C 2 7

H

2 sN 2 C1: C,77.77; H,7.01; N,6.72 Found C,77.36; H,6.97; N,6.67 ii Preparation 81 Qa, a-Diphenyl-l-(phenylmethyl )-4-piperidineacetamide *o fumarate r:1 (a A solution of 5.88 g, (0.02 mole) of Q,a-diphenyl-4piperidineacetamide in acetonitrile was prepared by warming with a hair dryer. 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 overnight L at room temperature and then heated at reflux for 5 hours.

The reaction mixture was stripped to dryness, and the 30 residue obtained was partitioned between chloroform-water and chloroform-5% 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 methanol-diethyl ether and dried overnight at 243 8A 63 in vacuo. A yiel'64 of 1.65 g of white crystalline material, m.p. 218-220 0 C. was obtained, Analysis: Calculuted for CS 0

H

3 2

N

2 0 5 C,71.98; H,6.4P4; N,5.60 Found :C,71.60; H,6,J47; N,5-51 Preparation 82 a,U.-Diphenyl-l-(phenylmethyl).-3-Piperidinepropanamide hydrate A mixture of 7.70 g (0.025 mole) of cU,o-diphenyl-3piperidinepropanamide, 4.28 g (0.025 mole) of benzyl bromide and potassium carbonate (55 g, m.04 mole) was heated overnight at gentle reflux in 300 ml of acetonitrile containing potassium iodicae (0.3 The reaction mixture was stripped to dryness and partitioned between chloroformwater and chloroform 5% sodium hydroxide. Removal of chloroform gave an oil. This oil wa~s rubjected to column chromatography on silica gel. using dimethoxyethane and ethyl acetate for elution. A yield of 3.514 g of yellow amorphous solid after combining column fractions and drying at 8 0 0C. in vacuo overnight was obtained.

H 19MI (CDC13)6'7,1-7.6 (in, 15, aromatic), 5.-5-6.0 (br s, (mn, 11, alphatic).

Analysis: Calculated for C 2 7

H

3 1

N

2 0 1 5 C,79.57 H,7.67, N, 6.8y Found 73-65; H~,7.416; N,6.88 .rk t 4 P-rearation 82 a ,c-B is(4-f luorophenyl) -1.(phenylmethyl) -4 -piper idineacetonitrile .hydrochloride hydrate rl:1:0.51.

A mixture of acx-,bis(4-flUorophenyl)-11-piperidinezcetonitrile, 6.05 g (0.019 mole), benzyl bromide, 3.32 g (0.019 mole), and potassium carbonate, 5.53 g (0.041 mole) was heated overnight at gentle reflUx in 350 ml of acetonitrile containing potassium iodide. The reac.tion mixture was stripped to dryness and part~itioned between chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and solvent removed to give 7.55 g of light yellow oil. The oil was 4 38A 64 converted to the hydrochloride salt using ethereal hydrogen I chloride and the salt was recrystallized from methanoldiethyl ether. The white solid obtained by filtration was washed with diethyl ether and dried in vacuo overnight at 800C. A yield of 3.85 g of white crystals, Mn.P. 283 C. with decomposiltion was obtained.

Analysis: Calculated for C 2 6 1 2 8N 2 0 0 5

F

2 C1: C,69.71; H-,5-85; VFound :C,70.07; H',568;5 rearation 841N62 a.-s(4-fluorophenvl)-l-(Phenylmethyl)Y3prroli inepropanenitrile hydrate FQ:. I-.

The sodium,~ salt of 4 -fluoro-cx-(4-fluorophenyl) V 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 hI for 3 hrs, a solution Qf 63.18 g (0.183 mole) of 1-phenyl- If methyl-3-pyrrolidinemethanol methanesulfonate ester in dimethylsulfoxide was added. The resulting solution was stirred overnight at 60 C. The solvent was removed in vacua via a rotary evaporator. The oil obtained was dissolved in chloroform and extracted several times with 1N sulfuric acid.

it The chloroform layer was extracted with 5% sodium hydroxide.

4, dried over anhydrous sodium sulfate, filtered, aiid solvent I removed to give 59.6 g of dark brown oil. A 10 g fraction 2'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 solvent was removed in vacua. A dark brown oil was obtained and dried at 80 0 C. in vacua overnighit A yield of 41.13 g 30~ (33.5% based on aliquot used) of dark brown oil was obtained.

1 H NM (CDC1l 3 cf6A.-y.

4 (mo 13 aromatic),, 3.5 2, N-CR2- -K'6j) 1.1-2.8 9, aliphatic) 6 t Analysis: Calculated for Cz~eH 2 5

N

2 0 5

F

2 C,75.89; H,6.12; N 6.81 Found C,75.93" H:6.007 N,6 4384k It Example 1 4-(Diphenylmethylene) -l-(3-phenoxypropyl)piperidine oxalate rl:13.

A 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 (o.b5 mole) of anhydrous sodium carbonate El in 100 ml 'of 1-butanol wa's 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 Nodium sulfate and concentrated under reduced pressure to give Ail oil ats residue, the free base of the tit]le compound. The fr?' base was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 4.3 g of the title product as a white powder, m-p. 175-178%C.

Analysis: Calculated for C 2 9

H

3 1 N0 5 C,73-55, H,6.60; N,2-96 Found :C,73.59; H,6.64; N,2.83 Example 2 Ce,U-Bis-(4-fluorophenyl)-l-(3-phenoxypropyl)-4-piperidine- 20 met'lianol oxalate hydrate [1:1:0.5 J.

A mixture of 3.37 g (0.011 mole) of [ax,a-bis(p-fluoro- 4 to phbenyl)1-l4-piperidinemethanol, 2.52 g (0.011 mole) of(3-bromop ropoxy)benzene and sodium. bicarbonate (0.92 g, 0.011 mole) in 200 ml of 1-butanol was heated overnight, at reflux. The butanol was removed by the rotary evaporator, and the residue partitioned between chloroform and water. Removal of the o chloroform in vacuo, gave a dark brown oil, the free base of the title compound. The free base was converted to the oxalate salt and the salt was recrystallized from methanol-diethyl ether to give 1.41 g of white solid, m.p. 1530C.

Analysis: Calculated for C 2 9

H

3 2 !N0 8 9 5

F

2 C,6 1 4.92; H,6.ol; Ilea Found -C,65.27; ,58761 N,2 .61 .1 43 66 Example 3 4-[Dis(4-fluorophenyl)methylene]-l-(3-phenoxypropyl)piperidine oxalate Cl:l'.

A solution of 7.37 g !0.0168 mole) a,ca-bis(J4-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, mtade alkaline with ice/50% sodium hydroxide, and diluted to 1 liter with water. The aqueous phase was extracted with chloroform, and remov~al 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 V solid, rn.p. 190-192 0

C.

Analysis: Calculated for C 29 1- 29 N0 5

;F

2 c,68.36; H,5.7 4 N)2 Found .c,68.43; H,5,75; N,2 .69 Ex a 1.;p 1e 4 piperidin-rnethanol oxalate rl:l1.

V To a mixture of 5.10 g (0.21 rr ,le)of magnesium turning8 and a crystal of iodine in 800 m! o.f dry tetrahydrofuran (distilled from lithium aluminuim hydride) was added a solution of 36.75 g (0-21 mole) of p-bromofluorobenzene in 100 ml of tetrahydrofuran. The xeaction flask was cooled in an ice bath during this addition, and the reiction 425 mixture was under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hr. A solution o 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 temp~erature for 16 hr. The mixture was poured into an icy solution of ammonium chloride and the o aqueous mixturewas extracted with methylene chloride. The mnethylene chloride solution was extracted with dilute sodium hydroxide and was dried over mnagnesium sulfate. The solvent was removed in vacuo to give a gummy residue. The residue was treated with a solution of oxalic acid in mtethaniol and the salt was recrystallized from methanol-ether 24 38A 4 67 tt to give 224.17 g of white crystalline solid, m-p.

4 153-155C C.

4Analysis: Calculated for C 2

E

6

H

3 1 N0 6

F

2 c,66.02; H, 5.92; N, 2.66 Found .C,65-78; H,5.935; II_ 4(DiphenylmethylY.1(4-phenoxybutyl)piperidine fumarate rl:l].

A solution of 6.99 g (0.0278 mole) of 4-diphenylraethylpiperidine, 6.624 g (0.029 mole) of (4-bromobutoxy) benzene and 5 g (0.060 mole)of sodium bicarcbonate in 400 ml of 1-butanol was refluxed for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene Ichloride and dilute sodium hydroxide. The methylene chloride 415 solution was dried over magnesium sulfate, and the solvent was removed in varlic to give an oil, the free base of the title compound. The free base was dissojvNed 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 Isolid, m.p. 146.-147 0

C.

Analysis: Calculated for C 3 2Ii 3 -rN0 5 C745;H7.23; N,2 -72 I Found C,724.6 8 Hi,7.24; N,2.68 Example 6 4-(Diphenylmethyl 3-phenoxypropvl)piperidine ii fumarate rl~l1.

4 a Following the procedure of Example 5, Ii-(diphenylmethyl) piperidine and (3-bromopropoxy) benzene were reacted to give 4A430 the free base of the title compound which was reacted with fumaric acid in methanol to give the white fumarate salt in t 71% yield, m.p. 171.-172 0

C.

Analysis: Calculated for C 3 1 HsSN0 5 C,74-231 H,7-03; N,2-79 Found :C,724.62; H,7.03; N,2-73 438A 68 Example 7 4 -rBis (J4-f luoropbenyl) me thyl 3-phenoxypropyl) piperidine oxalate 11:13, Following the proce6ure of Example 2, 4-[bis(J4f luorophenyl)rmethyl ]piper idine and (3-bromojpropoxy) benzene were reacted to give the free base of the title compound which was reacted with oxalic acid recrystallizing from methanol -diethyl ether to give the white oxalate salt in yield, xn.p. 178-1810C.

Analysis: calculated for C 2 9H 3 lN0 5

F

2 c,68.09; 11,6.11;, N,2.74 Fo~und c,68.37; 11,6.13; N,2.76 Example 8 4 ipherwlmethyl) -phenoxye t.iyl) piper id ine Following the procedure of Example 5, 4-(diphenylmethyl) piperidine and (2-brorno'thoxy) benzene were reacted to give the free base of the title compound which was reacted with furnaric acid in ether-methanol mixture to give the white fumarate salt in 85% yield, m.p. 189-190 0%.

Analysis: Calculated for C 3 0

H

3 3 N0 5 C,73.90; H1,6.82; N,2.87 20 Found :C,7 1 4.07; H,6.91; N,2.85 Example 9 4-rBis(4-fluoro2henyl)methvlm-l-(2-phenoxvethvyl) piperidine oxalate rl:l>.

A mixture of- 5.83 g (0.02 mole) of 4-Cbis(4-fluorophenyl) 210 n. mthyl ]piper idine, 4[.02 g (0.02 mole) of (2-bromoethoxy)benzene an6, sodium carbonate (3.18 g, 0.03 mole) was heated overnight at gentle reflux in 300 ml of 1-butancl. The reaction was filtered and solvent removed in vacuo. The residue was dissolved in chloroform and extracted with water and sodium hydroxide. Removal of chloroform gave an oil which.

was converted to the oxalate salt. The salt was recrystallized from methanol-dietbyl ether to give 6.0 g of white crystalline product, m.p. 180-1820C.

Analysis: Calculated for C 2 8 H2 9 N0 5

F

2 C,67.6o; H,5.88,- N,2.& 82 Fpund c,67.68; H,5.871 N02.81

S

I..

IjI4 .4* 4 4, 44 4, 4 4 .4" #4 44 4 444* 44 4 I 44 4.4, 4 It 4. I

II''

4 Ic (S t 4 438A I 69 Example 4-[Bis( 4-fluorophenyl)methyll-l-( 4-phenoxybutyl) piperidine oxalate Following the procedure of Example 2, 4-[bis(4- {t 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 methanol-diethyl ether), in 4+8% yield, m.p. 206 0

C.

Analysis: Calculated for C 3 0

H

3 3 N0.

5

F

2 c,68-56, 11,6-33; N,2.67 Found .c,68.79, H,6.35; N,2 .67 Example 11 4 -r&4-Fluorophenl)-phenlmethll-l-(3-phenoxypropvl)_ piperidine fumarate r1:1 j.

A mixture of 5.14 g (0.02 mole) of 4-fe-(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 hr and concentrated under reduced pressure to give a residue. The residue was purified by column on 160 g of FlorisilV and the product was eluted with 2% acetone in benzene to give an oil, the free 4 base of the title compound. The free base was reacted with fumaric acid and the salt was recrystallized from isopropyl Alcohol to give 4.0 g of white solid, m.p. 169-171'C, (with decomposition).

4 Analysis: Calculated for Cs 1

H

3 4 FN0 5 c,71-66; H,6.60;- N,2.70 ij '.',Found C,71.37; H,6.55, N,2'.66 14-r~is(Example 12 4-1s4-f luorophenyl)me thyll-l-f2-(2 .6-dichlorophenoxy) ethyllpipeeridine.

4 4 4 4A 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-dichlorobenzele 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 ii 438A 1 If hydroxide solution. The oil which was obtained was chrornatographed on 300 g of silica gel using hexane-ethyl acetate i{ (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 0 c. This furnished 5.99 g of product oil.

Analysis: Calculated for CaH 5 O~l:c,65.55; H,5.29; N)2 .94 IFound :c,65.43 H,5-34 N 2 .77 The 1H NMR spectrum of the subject compound was obtained in CDCl 3 containing tetramethylsilane and is consistent with the structure indicated by the title, I aliphatic protons (cyclic) 7H J2.8 -or triplet CH- 2 next to N 2H cr2 1 Hydrogen next to N 2H 63.5 doublet inethine proton 1H d 4.1 triplet CH2 next to oxygen 2H V 66.8-7.4 aromatic protons 11H I Examle 17 1-r3-(4-Chlorohenoxy)propyl> ,c-bis(4-fluorophenyl)- 1 4-piperidinemethanol.

A mi.xture of 3.0 g (0.01 mole) of [c,a-bi:(p-fluoropheyl)-4-ipeidiemehanl,2.0 g(01 ol)f1-hr- 4-(3-chloropropoxy)benzene, 5.5 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g Of Potassium iodide in 100 ml of 2,1-butanol was refluxed for 20 hr to give, after working -up as in Example 1 (recrystallizing the free base from 4 isopropyl alcohol), 1.7 g of white solid, m.p. 92-930C Analysis: Calculated for C 2 -H2 BClF 2 N0: c, 68.71; H1, 5.98, 6 A aN,2-.97 Found c,68-66; 1H,5.99; N, 2 .92 4 t t 4 t 9 71 Example 14 4-r'Bis( 4-fluorophen~l)methv1]-l-r3-(2 -fliuorophenoxy) propyllpiperidine oxalate, rl:l].

A mixture of 5.85 g (0.02 mole) of 4-Ebis(4-fluorophenyl) me thyl ]piper id ine, 3.76 g (0.02 mole) of 2-(3-chloropropoxyl-l-fluorobenzene, and sodium carbonate (4.80 g, 0.045 mole) in 300 -Il of 1-butanol containing 0.3 g of potssim-iodide waig heated overnight at geterfu.The reaction mixture was stripped to dryness and the resulting oil partitioned between chloroform-5;1 sodium hydroxide and then between chloroform-water. Removal of chloroform gave an oil which was converted to the oxalate salt. The salt was recrystallized from rethanol-diethyl ether. The salt was subsequently triturated with isopropanol, and was it dried overnight at 80 C. to give 5.82 g of product, m.p. 182-183 0

C.

Analysis: Calculated for C 2 9H 3 0 N0 5

F

3 c,65.78; H,5.71; N,2.65 Found .c,66.0,5; H,5.79; N,2.59 Example Ii 4-rBis( 4-fluorophenl)methl-l-r3-(3-fluorophenoxL-j propyllpiperidine mandelate r1:11.

Following the procedure of Example 14, 4-.bis(4-fluorobenenewer recte togive the free base of the title comoun whch asreacted with mandelic acid to give the (recrystallizing from isopropyl alcohol) in 62% yield, m.p. 145 1147.5 C.

Analysis: calculated for CS 5

H

3 eN0 4 FS: C,71.05; H,6.137 N~,2-37 Found C,71.10; H,6.20, 'N,2.36 4 4 Example 16 4-rBis(4-fluorophenyl)methyl1-l,-r3-(4-chlorophenoxy) propyllpiperidine fumarate rlai Following the procedure of Example 14, 4-[bis(±i-fluoro~ phenyl)methyljpiperidine and 1-[4-(3-chloropropoxy) )chlorobenzene were reacted to give the free~ base of the title compound. The free base was chromat.-graphed on silica gel eluting with hexane-ethyl acetate and reacted with fumaric

I

438 A 72 acid (recrystallizing from methanol-diethyl ether) in 9% yield, rap. 169-170 OC.

Analysis: Calculated for C 31

H

3 2 N0 5

F

2 C1: c,65.10; H,5.64; N,2 Found c,6 2 4.85; H,5.63; N,2.4+6 Example 17 propylilpiperidine.

Following the combined procedures of Examples 124 and 16, 4 -[bis(4-fluorophenyl)methyl~piperid,ine and 4-(3chloropropoxy)-l-fluoroberizene were reacted and worked up by chromatography in Example 16, to give the free base in 53% yield as a yellow oil after drying in vacuo at 80 0

C.

4 overnight.

A-nalysis: Calculated for C 2 7 H2 8

NOF

3 C,73.78; H,6.2427 N,3.19 Pound C,73.64, H,6.39; N,3.14 h Example 18 pyljpeine fmaat the procedure of Example 124, 4-[bis(24fluorophenyl~methyl~piperldine and 1-(3-chloropropoxy)- 24-methoxyloenzene 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- 0 ether) in 624% yield, m.p. 172-173 C.

Analysis: Calculated for C 32

H

55 N0 8

F

2 c,67.71; H,6.22; N,2.247 ,Found c,67.89; H,6.25; N,2.39 Example 19 4 -rBis( 4 -fluorophenyl)methyll-l-r--(2-methoxyphenoxy) tit*A mixture Of 5.99 g (0.021 mole) of 4-[bis(24-fluorophenyl)methyljpiperidine, 4.35 g (0.022 mole) of 2-(3-chlcoropropoxy)-l-methoxyber~zene ether, and sodium carbonate (0.18 go 0.03 mole) in l-"butano. k, was heated overnight at gentle reflux.

The reaction mixture was filtered and stripped to dryness.

The residue was dissolved in chloroform and the solution was 436A 73 extracted with water and 5% sodium hydroxide. Removal of chloroform gave a dark brow n 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 8 0 C. overnight. This gave 3.18 g of title product.

Analysis: Calculated for C 2 sHZaN0 2

F

2 C,74.

1 48; 11,6.92; 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 tetramethyl silane and is consistent with the structure indicated by the title, S66.8 singlet7 or protons on ring 4 containing methoxy group.

d6.8-7.3 aromatic protons on fluoro- 8 phen~yl rings.

d4.otriplet CH2-0. 2H or 3.8 singlet 0-C13. 3H Z 3.4 doublet; methine proton. 1H d- 0.8-3.1 mnultiplet. 13H Example 40 4 aU,a-Bis(J4-fluorophenyl)-l-[3-(2-methoxyphenoxy)propyl..

4 0 4-piperidinemethanol.

Following the procedure of Example 1, £a,a-bis(p-fluoro- 4 phenyl) J-4-piperidinemethanol. and l-chloro-3-(2-methoxy- 4 phenoxy)propane were reacted using in addto oasu 4 ddtonptasu iodide catalyst to give the title com~pound in 66% yield, (recrystallizing~ from isopropyl alcohol), m~p. 127-218"c.

Analysis: Calculated for C 2 8

N

31

F

2 N0 3 C,71-93, H-,6.68, N,3.00 Found .C,71.88; ni,6.67; N,.9 Example 21 propyl]piperidine oxalate [1:13.

Following the procedure of Example 14, 4-[bis(4-fluoro- 0 phenyl)methylenejpiperidine and 2-(3-chloropropoxy)-l- 44 t niethoxybenzene 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 ialt (recrystallizing frbm ruethaxnol-dfehyl.ither) in.

73% yield, mn.p. 184-1860c.

1 438 H 74 {I Analysis: Calculated for C 30

H

3 )43 6

F

2 c,66.78; H,5.79; N,2 Found .C,66.74;.HI,5.79 N,2 .61 Example 22 '-Bis( 4 -fluorophgenyl)methyvl r-34dmtoy phenoxy)propylltpiperidine oxalate r1:12.

A mixture of 6.02 g (0.021 mole) of 4-[bis( 1 4-fluoro- 4 phenyl)methyljpiperidine, 4.83 g (0.021 mole) of 413.

chloropropoxy) 2-dime thoxybenzene, and potassium carbonate (5.52 g, 0.04 mole) was refluxed overnight in 300 ml of 1-butanol containing potassium iodide (0.3 9) The reaction mixture was stripped to drynes's 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 I rec rystallized from methanol -diethyl ether and methanol I isopropanol ether. This furnished 7.77 g of white solid, M.P. 188 0 c.

Analysis: Calculated for CslH 35 N0 7

F

2 C065.14; H1,6.17; N~,2.43 ii Found :C164-78; H1,6.14; N,2.44 Example 23 4 4 -r Bis (4-methylphenyl)me thy 1 r3- 6-d ime thoxyphenoxy)propylipiperidine fumarate r1:11.

Following the procedure of Example 22, 4-[bis(4-methyldimethoxybenzene were reacted to givo~ the free base of the title compound which was reacted with fumaric acid~ to give the white fumarate salt (recrystallizing from methanol- 4440 diethyl. ether) in 66% yield, ni.p. 206-207 C.

Analysis: Calculated for C 3 5

H

4 3 N0 7 C,71.29; Hi,7.35; N,2.38 FoUxr,d :C071.211; H,7.38; N,2.36 -1 Exampie 214 phenoxy)propyll piperidine oxalate rl:lJ.

Following the procedure of Example 22, bis( 1 4-fluorophenyl)methylenejpiperidine and 4-(3-chloropropoxy)-l,2dime thoxybenzene 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 methanoldiethyl ether) in 51% yield, rn.p. 173-176 0 c.

Analysis: Calculated for C 3

H

3 0F:c,65.37; H,5.84; N,2.146 Found C,65.2 H,.3 Example 4-rBis( 4-fluorophenyl )methylm-l-r3-(2 .6-dimethoxyphenoxy) propyllpiperidine oxalate hydrate rl:l:ll Following the procedure of Example 22, but substituting dimethoxy ethane for butanol, 4 -[bis(4-fluorophenyl)methyl] piperidine and 2-(3-chloropropoxy)-l,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 rnethanol-diethyl ether) in 9% yield, m.p. 132"134 0

C.

Analysis: Calculated for C 3 1.H 3 7 N0 8

F

2 C,63,15,' H,6.32,1 N02.38 Found :c,62.89; H,5.98; N,2.141 Example 26 4 -rBis(4-fluorophenl)methylJ-l-E3-(3,5-dimethoxyphenoxv) :4 25 propyllpiperidine, A mixture of 5.51 g (0.019 mole) of 4-bis(4-fluorophenyl)methyl,]piperidine, 4.142 g (0.019 mole) Of' l-(3chloropropoxy) 3, 5-dime thoxybenz ene and potassium carbonate (5,53 .,14 molek was heated overnight at reflux in 350 m!J of 1-butanol containIngj potassium iodide (0.3 The reaction mixture was stripped to dryi~ess and the residue partitioned between chloroform-5% sodim hydroxide and chloroform-water. Removal of chlorof orm gave a 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 -d imethoxyethane. After combining proper fractions eluted from the column and removing solvent$ 4 ii

U

ii Ii 4 38A the residual oil was dried in vacuo overnight at 80 0 C. This produced 2.61 g of brown oil.

Analysis: Calculated fbr C 2 6 9

H

3 3 N0 3

F

2 C,72.33; H,6.91; N,2.91 Found C,71.62; H,6.80; N,2.98 The 1 H NM?. spectrum of the subject compound was obtained in CDCls containing tetramethylsilane and is consistent with the structure indicated by the title: _ey.0 (multiplet, aromatic protons on fluorophenyl ring, 6.0 (singlet, aromatic protons on rethoxyphenyl ring, 3H), 2.8 (triplet, methylene next to ether oxygen, 2H), 3.75 (siunglet, 0CH 3 6H), 3.4 (doublet, methine attached to two aromatic rings, 1H), 0 .75 2.6 (multiplet, remaining aliphatics, 13H).

Example n 4-[Bis(4-methoxvphenvl'imethvll-l-r3--(3,4-dimethoxvphenoxy) Propyl Ipiper idine.

A mixture of 5.58 g (0.02 mole) of 4-[bis(4-methoxyphenyl)methyljpiperidine, 4.83 g (0.021 mole) of 4-(3-chloropropoxy)-l1, 2-dime thoxybenzene, 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 20 mixture was stripped to dryness, and the i-esidue partitioned between chloroforn-.5% soi.'-ium hydroxide, and chloroform-water.

Removal, of chloroform gave a dark brown oil. The oil was subjected to column chromatography on a silica gel column, with elution via ethyl a-c~tate-dimethoxy ethane. Thl-t *produced 4.72 g of dark brown oil.

Analysis: Calculateei for CSfI 3 9NO.S: C 73.64; H)7-77; N,2.77 Found C,7t2.38; H,7,7O; N$2-72 The 111 ITM? spectrum of the subject compcoand was obtainaed in CLC13 containing tetrametliylsilane and is consistent with the structure indicated by the ti.tle: Hd Lf 71 (multiplet, aromatic protons ortho to methine of 5H), 6.14 (nultiplet, aromatic proto.ns ad 4 ;%Nrnt to ether linkageo 2H)p 3.9 (triplet, metbiv" xt to ether 355 Iirikoge, 2H1), -7 (Qclia, 3 (doublet, methine attached to arontatic r .O (multiplet, aliphatic protons, 13H).

o

I

0 0 S 0

I

'555

I

o o

I

o '5 54

I

~5 0 '5.0 41 4 4 4 it 1' 4 ~438A 77 Example 28 ±4 B is 4-netoxyphenyl)methyl 3(4me thoxyphenoxy) Propyll-piperidine fumarate hyd r ate Following the procedure of Example 22, 4-[bis('4-methoxyphenryl methylJpiperidine and 4-3clrpoox)imtoy benzen~e were reacted to give the free base of the title compound which was separated by extracting with sodium hydroxide-chloroform and reacted with fumaric acid to give the title salt (recry,,':allizing from mnethanol -die thyl ether several times as well as isopropyl alcohol) in 15% yield, nm,p. 163-165 0 c.

Analysis: Calculated for C 3 4

H

4 2 N0 8 3 5 C,67.98; H,7.05; N,2.33 Found c,68.16; H,6.97; N,2.34 Example 29 1-4r-4ri(-loohny~ehlnllpprdnl propoxylphenyllethanone cxalate F1:l1.

Following the procedure of Example 2, 4-[b.s(4-fluorophenyl)methylenelpiperidine and l. I-(3-chloropropoxy)phenylI Pethanone, substituting sodium carbonate for sodium bicarbonate, IN a were reacted~ to give the free base of the title compound which V 20 was reiacted with oxalic acid to give the oxalate salt 0600 (recrys tall iz ing from rethanol-diethyl ether) in 59% yield, zn.p. 196-198 0 c.

c*0 4 0 Anal~ysis: Calculated for C 3 1

H

3 3N0pF 2 c,67.26, H,6.01; N,2-53 Found c,66.94; H,6.0l,- N,2.

1 Example 1-F'4-r3-r4-rBis( 4-fluorophenyl)metyJlllpieridinvl] ipr22oxylphenyllethanone, oxalate r1:11.

Following the procedure of Example 2, 4~-[bis(iI-fluorophenyl)niethyljpiperidine and l-[4-(3-chloropropoiy)phenyl] ethanone and substituting sodium carbonate for sodium bicarbonate were reacted to give the free base of the title compou~nd which was reacted with oxalic acid to give the oxalate salt (recrystallizing from methanol-diethyl ether) in 75% yield, m.p. 141-143 0 c.

33Analyais: calculated~ for CsIHasNOeF 2 c,67.26; H,6.0l; N12.53 Found c,66.94; H,6,01; N,2.40 .0 1 438A 78 Example 31 i-4r- -Bi 4- urpey~yrxmtv piperidinyllpropoxy]-phenyllethanone compound with, 2-propanol Following the procedure of Example 1, [a,.k-bis(pf luorophenyl)J]- 1 4 -piper idineme thanol and l-[4~-(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 compound in 71% yield, m 72-84 0 c.

Analysis: Calculated for C 2

SIH

31

F

2 N0 3

.C

3 HeO :C,71.22; H,7.28 Found C,71.26, H,7.34,- N,2 .56 NMR indicated that the solid contained one mole of 2-proparol as a solvate.

Example 32 lC 3-[4-[Bisfluorophenyl)hydroxy.ethyl-l piperidinyllpropc;xy-3-methylphenyl~ethanone.

Following the procedure of Example 1, Ca,cz-bis(pf luorophenyl)J-4-piper idineme thanol and l-[4-(3-chloropropo<y)- 1K1 3-methyiphenyijethanone were reacted using, potassium iodidr catalyst to give the white title compsi...l (recrystallizing from isopropyl alcohol) in 76% yield, m.p. 116-.117 0 c.

Analysis: Calculated for CS 0

H

3 31F 2 N0 3 C,73.00; Ho6.74; N,2.84 0 4 Q 4Found .C,72.90, Hi,6.80; N,2.78 0 0 0 Example _3_3 4-r3-f4-[Bis(4l-fluorophenyl)hydroxymethyl]-l-piperidinyl] propoxy] benzonitrile, Following the procedure of Example 1, [U.-js(p-fluoro- 4A phenyl) 3-4-piperidine methanol and I4-(3-chloropxropoxy) 4 benzonitrile were reacted using potassium iodidie as catalyst to give the white title compound (recrystallizing from isopropyl alcohol- ljopropyl ether) in 30% yield, M.P. 107.-108 0

C.

Analysis: Calculated for C 2 8 11 2 8

F

2 N2O 2 C)72-71; H,6.10; N,6.0 6 Found C,~72.82; H,6.11; N,6-05 438A 4 79 Example 3~4 4-3r-~s4furpeylmty]ipprdnl propoxy~benzonitriie fumarate [1:11.

'1 Following the procedure of Example 22, 4-[bis(4-fluoro- 0 5 phenyl)methyllpiperidine and 4-(3-chloropropoxy)cyanobenzene were reacted using potassium iodide catalyst to give the free base of the title compound which was reacted with fumaric acid to give the fumarate salt which was (recrystallized from methanol-diethyl ether) in 5396 yield, ni.p.

167'C.

U Analysis: Calculated for C 3 2

H

3 2

N

2 0 5

F

2 c,68.32, H,5.73; I N, 1 4.98 Found c c68.1o; H,5.70; (1 N,4.94 'I ExaM~2e propoxylbenzoic acid ethyl ester hydrochloride r1:11.

A mixture of 6.0 g (0.02 mole) of [ce,cQ.bis(pfluorophenyl]- 4-piperidinemethanol,5.0 g (0.02 mole) of 1 4-(3-chloropropoxy)benzoic acid methyl ester, 7.4 g (0,07 mole) of a 0 'nhydrous sodizum carbonate, 0.3 g of potassium iodide and 150 ml of~ dimethylformamide was heated on a steam bath for If 20 hr and then poured into 1.5 'liter of ice-water. A gum 0 precipitated and the aqueous solution was decanted. The gum 4 :1 was dIssolved in benzene awnd the solution was washed with water and dilute sodium hydroxide solution, dried over anhydrous sodium sulfate and concentrated under reduced iJ pressure to give 9.2 g Of gum as residue. The gum was purified by column chromatography on 200 g of Florisil'Z and the desired product was eluted with 20% acetone in benzene.

The fractions containing the free base of the title compound 30 were~ combined and concentrated under reduced pressure to give .4 a gum, -,he 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. 19.3.5- 194-.59d- Analysis: Calculated for CSOH 34 ClF 2 NOt: c,65.99; H,6.28; N,2.57 Found :c,66.16; H,6.32; N,2-56 4 38P, Example 3 4 -rE3-r 4 -rBis(4-fluorophenyl)hydroxmethylm-l-piperidinyl] propox Ibenzoic acid hydrochloride hydrate rl:l:0.51.

A solution of 2.7 g (0.005 mole) of -3[[bs4 fluorophenyl)hydroxymethylJ-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 and the solution was poured into 500 ml of ice water and the mixtur-e was allowed to stand at ambient temperature overnight. Sodiu2' 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 30 ml of ethereal hydrogen chloride. The salt which gradually crystallized was collected {j 15 by filtration, washed with ethyl ether and dried to g..ve 0.2 g of white powder, m.p. 148-158 0 C. with decomposition.

Analysis: Calculated for Ci 6

H

3 0ClF NO 4 0.5 H120: C,63 V2;H,5.93; N,2.66 Found c,63:97; H,6.25; N,2.51 fiExamgle 37 I4-r3-r 4 -r Bis (4 -f luorophenyl) methylene I 14yiper idinylI 4 propoxylbenzoic a4cid ethyl ester hyvdrobromide rl:li.

00 A mixture of 6.09 q (0.021 mole)of 4,Eb-s( 1 4-fluorophenyl) 4 methylenelpiperidine, 5.20 g (0.02 mole) of l-CJ+-(3z-chloro- 0 04 propoxy)-phenylicarbethoxybenzene 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 4. reaction mixture vyas stripped to dryness and partitioned between chloroform water and chloroform %sdu ydoie Removal of chloroform gave an oil. The oil was conv'erted 30 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 methanol -die thyl ether. The salt was washed with water to remove acetamide present as an impurity. The salt wag washed with diethyl ether and dried in~ vacuo overnight at 80 A yield of 6.81 g of whitoe solid, m.p. 192-1940C., was 438A obtained.

Analysis: Calculated for C 3 0

H

3 2

NO

3

F

2 Br: c, 62.94; H, 5.63; N,2 UFound c,62.83; H,5.58; Ni,2.45 Example 38 I: 4-r3-v 4-rBis( 4-fluorophenyl)methyll-l-piperidinyll propoxylbenzoic acid ethyl ester hydrobrornide rl:l1.

Following the procedure of Example! 14, 4-[bis(4- I 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 cil was stripped to dryness and the solid obtained was recrystallized from isopropyl alcohol-diethyl ether to give the white salt in 20% yield, m.p. 1142-1J44%.

(j Analysis: calculated for CS 0 fl 3 4

NO

3

F

2 Br: C,62.72; H,5.97; N,2 .44 Found C,62.66; H,5.95; N,2.145 Example 39 4 -[3-E4-fBis(4-rnethoxyphenyl)methyl ]-l-piperidinyl] propoxylbenzoic acid butyl ester.

A mixture of 6.22 g (0.02 mole) of 4-[bis(4-methoxy- 464.phenyl)methyl~piperidine, 4.84 g (0.02 mole) of I4-(3-.

chloropropoxy)benzoic acid ethyl ester, and potassium carbonate, 5.60 g (0.04 mole) in 350 MI of l-butanol was refluxed overnight with potassium iodide. The reaction mixture was stripped to dryness and the residue partitioned between chloroforr-5% sodium hydroxide then chloroformwater. Removal of chloroform gave an oil. This oil V'as chromatographed on a 200 g silica gel comumn packed in 50/50 v/v hexane-ethyl acetate. The material was eluted with hexane-ethyl acetate mixtures and finally 1% methanol-ethyl.

acetate.

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

Analysis: Calculated for C 3 4

H

4 3 N0 5 c,7 1 4.81 H,7.94; N,2.57 Found C,74.1.9; H07-91; V,2-53 't 1438A The 1H NMR spectrum was obtained in tetramethylsilane and is cnsisentwiththestructure indicated by the title, (H's ortho to C0 2 2H), 6.8 (mn, aromatic, l0H), 4.2 (mn, CH2 alpha to o, 4H), 3.7 Ocu,3, 6H), 0.9-3.5 aliphatics, 21H).

EEamle 140 4 -[3-E 4 -rBis( 4 -iethoxyphenyl)methylj-l-piperidinyl] propoxyjbenzoic acid ethyl aster fumarate hydrate [1:1:0.51.

Following the procedure of Example 22, but substituting dimethylformainide at 73 0 C. for butanol, 4-bis(4-methoxy-.

h phenyl)inethyl~piperidine and 4-(3-chloropropoxy)benzoic V acid ethyl ester 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 methanoldiethyl ether) in 27% yield, rn.p. 147.5 -85 0 c.

Analysis: Calculated for CsBH 4 4 N0 6 5 C,67.27; H,6-90; N,2.18 Found .c,7.6 H,6.7, N,2.19 U Example 141 Following the procedure of Example 35, cea-bis(p-fluoro- U phenyl)- 1 4-piperidine methanol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is Example 42 04 4-r3-r[I-rBis( 4 -fluorophenvl)hydroxymethyl-l-piperidinylI propoxyl-3-inethoxybenzeneacetic -acid ethyl ester hydrochloride.

Following the procedure of Example 35, [a,a-bis(pf loo n l) ppid imhno and 4-(3-chloropropoxy)- 3-mehoxbeneneceti Acd ehylester are reacted and ft 438A Example 43 ethyl"Jphefoxylpropylipiperidine fumarate rl:l1.

phenyl)methylenelpiperidinQ and -(3-chloropropoxy)-(l,ldimethylethyl)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 furnaric acid to give the white fumarate salt (recrystallizing from isopropyl alcohol-diethyl ether) in 40% yield, m.p.

2o8. 5-209.5oc.- Analysis: Calculated for C 3 5

H

3 9 N0 5

F

2 C,71-05; H,6.64; N,2.37 Found C,70-91; H1,6-57; N,2.38 Example 44 4 -rBis(4-fluorophenyl)methyll-l-r3,'-r4l-(1,1-dimethylethyl) phenoxylpropyl lpiperidine fumarate hydrate rl:1:0.5-1.

Following the procedure of Example 9, 4-.rbis(4--fluorophenyl)methyl~piperidine and 4-(3--chloropropoxy)-(l,Idimethylethyl)bp-nzene 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 salt (recrystallizing from methanol-diethyl ether and isopropyl alcohol-diethyl ether) in 55% yield, m.p. 194-196 0 c. with decomposition.

2Analysis: calculated for C 35

H

42 N0 5 5

F

2 C,69.75; H1,7-02; Founc .C,7'0.01; 11,6.89; Example 4-rLs(4-methoxyphenyl)methyll-l-r3-r4-(1,1-dimethy a ethyl)phenoxylpropyllpiperidine oxalate E~1 Following the procedure of Example 22, 4-[bis(4-methoxyphenyl)rnethyljpiperidine and 4-(3-chloropropoxy)-(l,ldiniethylethyl)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 nethanol-diethyl ether) in 35% yield, m.p. 212 0

C.

Analysis: Calculated for C3 5

H

45 N0 7 c,71.o4; H1,7.67; N,2-37 Found C,70.91; H1,7.70; N,2.35 84 Example 46 1-[3 [4-(1,1-rimethylethyl)phenoxy~propylJ-.(-,a-bis(4fluorophenyl)-J4-piperidinemethanol.

Following the procedure of Example 1, [U,U-bis(p-fluoropheny1)]-i4-piperidinemethanol and 4-(3-chloropropoxy)- (1,J-dimethylethyl)benzene were reacted using potassium iodidte catalyst to give white powder (recrystallizing from isopropyl alcohol) in 41% yield, m.p. 126-127 c.

Analysis: Calculated for C 3 1

H

3 7

F

2 N0 2 C,75.

1 43; H,7.56; N,2.84 Found C,75.21; H,7.58, N,2 .82 Example 47 4-rBis(4-fluorophenyl)methyll-l-r3-r3-( trifluoromethyl) phenoxylpropyllpiperidine oxalate r 1:11.

Following the procedure of Example 9, 4-[bis-(4-fluorophenyl)methyl)piperidine and l-[3-chloropropoxy]-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-diethy1 ether) in 39% yield, m.p.

185-186 0

C.

Analysis: Calculated for Cs 0 Hs 0 N0 5

F

5 C,62.17; H,5.22; N,2.42 Found :c,62-54; H,5.27; N,2-52 Example 48 propoxylphenyll Acetamide fumarate hydrate rl:1:0. t Following the procedure of Example 22 but substituting dimethylformamide at 73 0 c. for refluxing butanol, 4-Cbis-(4methylphenyl)methyljpiperidine and N-[4-(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 methanol-diethyl ether), M.P. 149-152 0 c.

Analysis: Calculated for C 3 5

H

4 3

N

2 0 6 5 :4 C,70-57; H,7.23; N, t AtFound :C070.80O; H,7.28; N,.6 .0 438A Example 49 N- 4 E3- E 4 -[Bis(4 -fluorophenyl) me thyl ]l -p ipe rid inyl3 propox lphenylacetanide hydrobronide A mixture of 25-683 g (0.089 mole) 4-bis(4-fluorophenyl) methyljpiperidine, 20.3 g (0.089 mole) of N-[i4-(3-chloropropoxy)phenyl~acetamide, arnd potassium carbonate, 21.4 g, (0.155 mole) was stirred overnight at 70-.80 0 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 acetic acid, and the hydrabromide 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 (43,55Q of pale-white solid, m.p. 223-225 0 C. was obta ined.

Analysis: Calculated for C 2 9

H,

3 3

N

2 0 2

F

2 Br: c,62.26, H,5.95; .01 Found :C,61.99; H,5.94; Example _50N,-0 goo propxybneneimine fumarate hydrate [1:100.51 0 .oA solution of 11.8 g (0.02709 mole) of N-EJ4-E3-Cbis o(4-f luorophenyl) me thyl -piper idinyl ]propo~.y ]ace tamide was heated at gentle reflux for four hours in 500 ml of methanol containing 500 ml of 6N hydrochloric acid. The reaction was stopped and allowed to cool overnight. The reaction mixture was evaporated to a small volume on the rotary evaporator, diluted with water and made alkaline with 5% sodium hydroxide.

6 4. The reaction mixture was then partitioned between the alkaline phase and chloroform. The chloroform layer was dried, ~0 filtered, and solvent removed to give an oil. The oil was converted to the funiarate salt and the salt was recrystallized from methanol-diethyl ether. The white solid obtained war, dried overnight in vacuo at 8 0 0c. to give 8.49 g of white crystalline product, m.p. 121.,5-121.0 0

C.

Analysis: Calculated for C 3 1

H

3 5

N

2 0 5 5 sF 2 c,66.30; H 6.28; N, 99 Found :c,,66.49; H,6.13; N, 4.92 -1 438A Example 51 N- 3-[4 -Bis(4-fluorophenyl)hydroxymethyl -1piperidinyljpropoxy]phenyl]acetamide hydrochloride hydrate 11:1:11.

A mixture of 3.0 g (0.01 mole) of [a,U-bis(p-f.uorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 mole)of N-[4- (3-chloropropoxy)phenylacetamide, 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 product was eluted with 20% 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 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 0 c. (with decomposition).

Analysis: Calculated for c 2 9

H

33 ClF 2

N

2 0 3 .Had0: C,63.44; H,6.43; No5.10 Found c,63.32; H,6.56, 20 N,4.92

U

U

U

I I I 4 I

II

0DiExample 52 Ott, c, r-Bis( 4 -fluorophenyl)--r3-(4-nitrophenoxy)propyl1-4piperidinemethanol.

*Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 9.1 g (0.03 mole) of Ca,a-bis (p-fluorophenyl)]-4-piperidinemethanol and 6.7 g (0.03 mole) of 1-(3-chloropropoxy)-4-nitrobenzene were reacted to give 4 4 10.5 g of the title compound which was recrystallized from It isopropyl ether, m.p. 95.5-94.5oC.

Analysis: Calculated for CZ 7 H2eF 2

N

2 0 4 c,67.21l H,5.85; N,5.83 Found C,67.05; H,5.83; N,5-7 1 4 Itt 3 ~438A Example 53 4-r3-r-Bis(4-fluorophenyl)hydroxymethyl-l-pieiiy propoxylbenzamide.

Following the procedure of Example 1 and using potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) of ~Ca,a-bis (p-fluorophenyl)3-.4-piperidinemethanol, 1 g (0.01 mole) of 1 -(3-chloropropoxy)benzamide and 6.9 g (0.05 mole) of anhydrous potassium carbonate in 100 ml of 1-butanol were reacted to 1,Lve 3.0 g of whi-te powder, rn~p., 200-2041 0

C.

The recrystp~1lizing solvent used was absolute ethanol.

Analysis: Calculated for C 2 8

H

3 0

F

2

N

2 0 3 c,69.981- 14,6.29; N,5.83 Found :c,69.61; H06.

1 49; N,5170 Example 54l 4- Bis (4-fluorophenyl) me thl 1-r2 2-(1-naphthalenyloxv) lethyl2piperidine hydrochloride rl:lJ.

A mixture of 2 .8 4 g (0.0099 mole) of 4-aabs~-loo phenyl)methyljpiperidine, 3.01 g (0,012 mole) of l-(2-bromoethoky) naphthalene and'5.0 g (0.080 mole) of sodium bicarbonate in 4{00 ml of 1-butanol was refluxed for 16 hr. The solvent was removed in vacuo and the residue was partitioned between mnethylene 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 25was collected to give 3.13 4 of white crystalline solid, m-P- 155-158 0 c.

Analysis: Calculated for C 5 0

P

3 0 M0F 2 C1: C,72.94; H06.12; N02.84 Found C,73.20; H,6.10,- N)2-78 1 III 4,4 .4 4 4.

I 44 4 II 4 4 44*, 4 .4 I 4' 4 4*~I I 41

LI

ltlt 4 t

J

4{38A~ 88 Example 4-Bs4f ,rpey~ehyllr-2nptaeyoy ethyllpiperidine oxalate rl:lj.

,Following the procedure of Example 514 and substituting 2-(2-bromoethoxy)naphthalene and oxalic acid for hydrogen chloride, the title compound was obtained in 61.9% yield as white. cryst~alline solid, m.p. 168-171 O.

Analysis: Calculated for C 32

H

3 lN0 5

F

2 C,70.19; H,5.717 N,2.r56 Found .C,70.26, H,5.75; Ni,2.63 Example 56 i-4[-4[i(-furpey ehyllpprdnl propoxy)-3-.methoxyphenyllethanone oxalate [1 :11.

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-[acmbis(p-fluorophenyl)methyljpiperidine, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ral of dimethylformamide was heated at 80 0 C. for about 2 hours. TLC showed no product at this po~int. The temperature was raised t20 to 100 0 C. for 1 hr, at which time TLC showed the reaction Vo to be complete. After cooling, the reaction mixture was 4 filtered and the. dimethylfortiamide was removed under reduced pressure. The crude product was dissolved in chloroform and filtered and the filtrate was concentrated under reduced prsuet 'ive 7.7 g (914%) of crude product. The solid was dissolved in benizene and placed on a FlorisilM column.

Upon eluting with an :acetone-benzene gradient, 5.5 g of 414 product was obtained. ThL, oxalate malt was prepare and upon recrystallization from isopropanol-.methanol gave 3.8 g of salt, m.p. 164.5-166 0 c.

Analysis: Calculated for C 3 2

H

3 SFRN0_ 7 C,6.6 .5 N12.140 Found :C,66.1l; Ho6.13; N02-39 4~3 8

A

89 propoxy]-3-methoxyphenyl~ethanone furnarate Amixture of 58.26 g (0.203 mole) of 4-[bis(4-fluorophernyl)methyl)piperidine, 54.5 g (0.225 mole) of 1-chloro- 3-(4 -acetyl-2 -methoxyphenoxy) propane, 18.7 g (0.223 mole) hot reaction mixture was filtered, and the solvent was removed in vacuo from the filtrate. The residue was between methylene chloride and dilute sodium hydroxide, The methylene chloride solution was dried over magn(osium sulfate, and the solvent was removed in vacuo to gz,ve an oil. T~be oil was dissolved in 600 ml of anhydrous ethcr, and 4.91 g of a solid was collected at room temperatu,' e. 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 0 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 too$ 2 crops of title compound. [Crop I 44.15 g, m.p. 163..

04 4 164.50C.; Crop II 38.75 9, m.p. 161-163'.]. An additional 10.00 g m.p. 159-162 of title compound collected from the original ether-n~ethanol filtrate.

Analysis: calculated for C 34 .sHs 7 .eN0 7 r.

8 F C,66-05, N,6.21 :.~.sowdFound c,65.96,# H,6.18:.

NMRshoedthat the salt contained 1.2 equivalents N02.16 of fumaric acid. Example 58 ropxyJ~3~ethoxyphenyl')ethanone oxalate [1:11.

The title compound was prepared by the method described in U. S. Patent 3,922,276 (See Ex. 12 of that patent) as follows: A mixture of 4.7 g (0.0165 mole) of -4-[a~ca-bis(pfluorophenyl)methylefle)piperidine, 4 .0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphefloxy)Propyl hiori~e and 1.4 g of sodium bicarbonate in 60 mi of dimethy1formatnide %ras heated -t at 100 OC. overnight. After cooling, the reaction mixture was filtered and the dimetbylformamide was removed at reduced pressure. The residuel oil was dissolved in benzene and placed on a FlorisilOD column. Elution with a gradient of acetone-benzene gave 5.7 g (70) of a viscous brown oil.

The free base was reacted wi,th oxalic acid to give the oxalate salt, m.p. 169-170 0 C. after recrystallization fr-om isopropyl alcohol and drying under nitrogen.

Analysis: Calculated for C 3 2 11 3 3

F

2 N0 7 c,66.o8; H,5.72; N,2.41 Found .c,66.01; H,5.67; N,2 Example 59 P iper idinyl 1propoxy I 3-me thoxyphenyl Ie tha none oxalate r1:11i.

The title compound was prepared by the method described in U. S. 3,922,276 (See Ex. 12 of that patent) as follows: A mixture of 7.1 g (0.027 mole) of 4-a(-lorpey)q phenylmethylenelpp eridine, 6.5 g (0.027 mole) of 3-(P,,acetyl-o-methoxyphenoxy)pro~yl chloride and 2.3 g, (0.027 mole) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100 c. for approximnately 8 hours. The mixture was filtered and the dimethylfornmamide was removed under re'luced pressure, The residual oil was dissolved in chloroform and the mixture was filtered, The filtrate was concentrated un~der 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-l145 0

C.

after recrystallization from methylisobutyl ketone.

Analysis.6 Calculated for C 3 2 1J 3 4 FN0 7 r: C,68-19; H06-08; N,2.J49 ~o Found :c,68.1 1 Hi,6.12; 1 *1

A

14 3Ek 91 Example l-[3-Methoxy- 1 4-[3-[4-phenyl[3-(trifluoromethyl)rhlenyli methylene J-l-piperidinyllpropoxy~phenyllethanone oxalate 22111 The title compound was prepared by the method described in U. S. Patent 3,92?,276 (See Ex. 10 of that patent) as follows: A mixture of 5.0 g (0.0157 mole) of 4 -a-phenyl-ce- (m-trifluoromethylPhenyl)methylenejpiperidine, 3. 82 g (0.0157 mole) of 3-(p-acetyl-o-rnethoxyphenoxy)propyl 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-lg* hrs.

The mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. The g1~ssy residue obtained weighed 4.25 g and was dissolved in benzene and placed on a Florisilt colhrnn. Using an acetone-benzene gradient elution, product was obtained as a glassy res~ldue.

This residue was dissolved in ether and tl,'e oxalate salt was obtained. The salt has a glassy appearance, M.P.

12 0 -125C 0 c Analysis: Calculated foi C 33

H

34

F

3 N0 7 c,614.59; H,5.58, N,2.28 Found -c,64.34; H,5.72; N,2.04 Example 61 4-r3.2X 14Cyc-lohexylphenylmethylene) -1-piperidinyl 1 prop2oxy1-3-me'thoxyphenvllethanone oxalate [1:1] The free base of the title compound was obtained as in Example 1 of U. S. Pate'Li ,152,276 by reacting 4f.(a-cyclohexyla-phenyl)nmethylenepiperidine with 3-(p-acetyl-o-methoxyphenoxy) propyl chloride in a mixture with sodium bicarbonate in dimethylformAmide and converted to the oxalate sawlt, M.P.

Analysis: Calculated for C 3 2

H

4 1 N0 7 r: c,69.67; H,7.49; N,2-54 Found c,69..83; H,7.58; N,2-56 94 ~4 .4 4 4 94 A 4* 9 4, 4~ 4 *449 .4 4* 9 *4*4 S 44 9 9 A 44 4444 9 9 9* 4 4*44 9 4 44 4 i} 438A 92 ExaMple 62 -[4-r3-r4 -(cyclohexylphenylmethyl) -1-piper id inyl I D"OPDXYI 3-me thoxyphenyl 3e tna none oxalate hydrate 11:1:0-5.

A mixture o 1 5.2 g (0.02 mole) of 4.[(-cyclohexyl-a- II phenyl)methyljpiperidine,4.9 g (0.02 mole) of 3-(p-acetylo-methoxyphenoxy)propyl chloride 4 IAd 1.7 g (0.02 mole) of sodium bicarbonate in 100 ml of dimethylformamide was ij stirred and heated at 100 C. for 14 hrs. The reaction mixture was cooled, filtered, and the dimethylfor~mamide was removed under reduced pressure. The residual rn-'Zerial was dissolved in benzene and placed on a FlorisilS column.

Elution using an acetone-benzene gradient gave 7.0 g (714.5%) of free base of the title compound. The oxalate salt was prepared and recrystallized from isopropanol, mp15-160kC.

Analysis: Calculated for C(3 4

H

8 8

N

2 0 1 5 C,68-31; H,7.88; N,2.)49 Found .C,68.60; H,7.78; N,2.42 The free base of the title compound was obtained by iireacting 4 (-cyclohexyl-ai-phenyl)methyl ]piper id iie and 3-(p-acetyl-o-methoxyphenoxy)propyl chloride in a mixture 4 with sodium bicarbonate, isolated tnd reacted withn oxalic acid. The oxalate salt was recrystallized from isopropanol, m-p. 155-160 0

C.

4.Af Example 63 4 4 -r3-r4-EBis( 4-fluorophenv. .)methylene]-1-pip-eridinylI 'j propoxyl-alpha-methylbenzeniemethanol oxalate r1:11.

A solution of 1-[4-[3-[l4-[bis(4-fluorophenyl)methylene)- 11 1-piperidinyl~propoxy~phenyllethanone, 3.56 g (0-0077 mole) 4 and sodium borohydride, 1.51 g (oxo4 mole) was stirred 6 hrs at roo~m temperature. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide, Removal of chloror orm gave an oil which was converted to the oxalate salt. Recrystallization from methanol-diethyl ether gave 2.67 g of white crystalline product, m.p. 142-145 Analysis: Calculated for C 3 1

H

3 3 N0 6

F

2 c,67.26; H,6.01;N,~5 Found C,67.17; H,5-92; N,2.

14 7 438A Example 614 4 -E3-[ 1 4-[Bis( 4-fluorophenyl)methyl]-l-piperidinyl] prpoy-3-.nethoxy--a-methylbenzenemethanol.

Sodium borohydride (3.0 g, 0.079 mole) was added to 250 ml of 95% ethanol. To the mixture was added 4.14o g (0.00885 mDole of l-[3-(p-acetyl-o-methoxyphenoxy)propyl] 4 -rc,-bis(p-fluorophenyl)methyl]piperidine in 100 ml of ethanol over 15 minutes. The resulting solution was stirred 2-1112 hr at room temperature. The reaction mixture was stripped to dryness and partitioned between chloroform 1o and 5% sodium hydro.-dde. 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 chioride-diethyl ether.

This furnished 2.16 g of white solid, M.P. 132-135 0C.

Analysis: Calculated for C 30

H

35 N0 3 9F 2 C,72.r72? H,'7.12; N, 2.83 Found :C,72.28; H,7.21;- N,2 .52 Example 653 20 1-[ 4 -r3-[I4-(Diphenylmethyl)-l-piperidinyllpropoxy3-~ ri 44 tt 4 4 4 'it "4 Pt, 44,4 O ~t4 $4 44 44 44 4 4<444 methoxyphenyllethanone (cxalate rl:li.

9 4* 4 4 44,.

44 44 4 44 44' 4 @4 44 4 lit 4 it A mixture of 5.0 g 02 mole) of 4-(a-phenyl'benzyl) piperidine, 4.85 g (0.02 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride, and 3,1 g (0.04 mole) of sodium 25 bicarbonate in 100 ml of dimethylfornamide was heated at 100 0 C. for about 3 hrs. The reaction mixturi was cooled, filtered and the filtrate was concentrated under reduced pressure. The residual oil was dlas:lved 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 uk,7n standing and trituration in -hnr gave 8.4 g of salt melting at 149-155%.- Recrystalliza.~..:, from isobutyl methyl kcetone gave 7.0 g of the salt,, m.p. 153-155 0C. (See Ex. 11, U. S.

4 38A If 94 1 3,956,296).

I Analysis: calculated for C 32

H

37 N0 7 c,70.l87 H,6.81; N,2.56 Found C,70.00; ji,6.76; N,2.56 h Example 66 1-r 4 -r3-r4-Bis(4-fluorophenyl)hydrox (-.ethyllpiperidinyllpropoxy1-3-methoxyphenyllethanone.

A mixture Of 5.0 g (0.0165 mole) of U,cU-bis(p-fluoro- 11 phenyl)-J4-piperidinemethanol, 4.o g (0.0165 mole) of 3-(Pif acetyl-o-metLhoxyphenoxy)propyl chloride and 1.4 g (0.165 mole) of sodium bicarbonate in 60 ml of dime thylf ornamide was stirred and heated a oC. for two hours. The temperature was raised to 100 C. for one hour. After cooling, the reaction mixture was filtered and the dimnethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil' column. Usinga grad4.ent elution of a ce tone -benzene, 1.8 g of product was obtained from the column, m.p. 141.5-1J43 C.

(See Ex. 12, U.S. 3,956,296).

I 20 Analysis: Calculated for C 3 0

H

3 3

F

2 N0 4 C,70.71; H,6.53; 4fFun N, 2 Found C,70.49; H,6:58; SN N2 .59 Example 67 [I :l-r'-r3 -rr(4-Fluorophenyl)hydroxyphenylmethylI 1 piperidinyllpropoxy)-3-methoxyphenyllethanone.

A mixture of 6.5 g (0.023 mole) of a-(p-fluorophenyl)c. -phenyl-4-piperidinenethanol, 5.5 g (0.023 mole) of 3-(pacetyl-o-methoxyphenoxy)propyl chloride and 1.92 g (0.023 mole) of sodium bicarbonate in 80 ml, of dixnethylformamide 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%c. A sample was dried over refluxing toluene and submitted for analysis. (see 438A Ii ~c 14,U.S. 3,956,296).

Analtysis: 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 i-r4'-r3-r4-(Diphenylhydroxvrnethyl) ,l-piperidinyl] p2ropoxyl-3-methoxyphenyl~ethanone oxalate rl:l.fl A mixture of 5.2 g (0.0194 mole) of cxadphnl4 piperidinemethanol, 4.7 g (0.0194 mole) of 3-(p-acetyl-omethoxyphenoxy)propyl chloride and 1.6 g (0.0194 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100 OC. for 3 hrs. After cooling, the reaction mixture was filtered and the dime thyl fo rmamide 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 benzene-isooctane. 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 off-white solid melting at 174-176 0 c. (See Ex. 15, U.S. 3,956,296).

000 Analysis: Calculated for C 3 2

H

3 7 rN0 8 C,68-19, Hi,6.62; N,2.49 Found :c,68.34; 11,6.75; N,2.42 00 0 Example 69 l-[4-[3-[J4-[Hydroxyphenyl [3-(trifluoromethyl)phenyll :00methyl] -l-piperidinyl~propoxy]-3-methoxyphenyl~ehnn hydrochloride hydratz [1:1:0.53.

0 0 A mixture of 7.0 g (0.021 mole) of a-phenyl-u-(m-trifluorometlhylphenyl)-4-piperidinemethalol, 5.1 g (0.021 mole) of 3-(pacetyl-o'methoxyphenoxy)propyl chloride and 3.0 g (0.036 mole) of sodium bicarbonate in 125 ml of dry dirnethylformamide was stirred and heated at 90.-95 Oct for 5 hours. The mixture was cooled and filtered. An excess of water was added to the reaction mixture. The mixture was extracted several times with benzene and the collected extracts were dried ovrer a*nhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The ii

A

I

i I-*IC)IPOU I" 438A 96 crude solid which was obtained was dissolved in benzene and placed on a Florisil® column. Elution using an acetonebenzene 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 0 C. (See Ex. 16, U.S. 3,956,296).

Analysis: Calculated for Ce 2

H

72 cl 2 FeN 2 a0.: C,63.

4 2; H,6.18; N,2.39 Found c,63.68; H,6.03; N,2.33 Example 1-[4-[3-[4-(Cyclohexylhydroxyphenylmethyl)-1-piperidinyl] propoxy -3-methoxyphenyl ethanone 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-omethoxyphenoxy)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 (74.5%) I was obtained. The solid was dissolved in ether, and the ether solution was treated with an 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. 152-155°C. (See Ex. 17, U.S. 3,956,296).

Analysis: Calculated for CsoH 42 C1N0 4 C,69.82; H,8.20; N,2.71 *30 Found c,69.50; H,8.31; N,2.62 4r I

'U

Ii ~438A 11 97 1 Example 71 1_-[4-[2-14I-Bis(4--fluorophenyl)hydroxymethyll-lpiperidinyliethoxyl-3-methoxyphenyl~ethanone.

Following the procedure of Example 1 and utilizing potassium iodide catalyst, a mixt-.ire of 3.0 g (0.01 mole) of a, -b is (p-f luorophenyl) -4 -piper id ine methanol, 2'.3 g (0.01 mole) of l-[I4-(2-chloroethoxy)-3-methoxyphenyl) ethanone and sodium carbonate in butanol, the title compbund Il was prepared in 22% yield, M.P. 131-1350C. after recrystallization from isopropyl alcohol.

010 Analysis: Calculated for C 2

E

9

HS

1

F

2 N0 4 C,70.29, H,6.31; N,2.83 Found C,70-00; H,6.-39 N,2 I Example 72 1-r 4 -r 4 -r4-rBis(4-fluorophenyl)hydroxyethyl...- N 15 piperidinyllbutoxyl-3-methoxyphenyllethanone.

This compound was prepared according to the procedure~ used to synthesize the compound of Example 35. A mixture if of 3.0 g (0.01 mole) of ot,a-bis(p-fluorophenyl)-4- 1 piperidine methanol, 3.0 g (0.01 mole) of l-[ 1 4-(4-bromobutoxy)-3-methoxyphenyljethanone, 5.3 g (0.05 mole of Ianhydrous sodium carbonate and 0.3 g of potassiuu,, iodide in 100 ml of dimethylformamide gave, after purifio:ation by 0 column chromatography on Florisil® (acetone-benzrane)..

0.8 g of off-white powder, m.p. 104-10 5 'oC. after from 2-propanol--isopropyl ither.

I 2~ Analysis: calculated for Cs 3 HssF 2 N0: C,71.11; H,6.74; N,2.68 Found C,70.84, H,6.71; N,2-65 Founde 7 4 4 t peintoxyJ-3-methoxyphenyl~ethanone.

Following the procedure of Example 1 arnd utilizing potassium iodide catalyst, a mixture of 3.0 g (0.01 mole) 6f cr,a -bis (p-f luorophenyl) -4 -piper id ineme thanol, 2.7 g (0.01 mole) of 1-4(-hooetx)3mtoyhnlehnn and sodium carbonate in butanol, thie title compound was prepared in 65% yield as white solid after recrystallization 438 98 from isopropyl alcohol, m.p. 117.5-118.5 C.

Analysis: Calculated for C, 3

?H

3 7

F

2

NO

4 C,71.149; H,6.94; Found .C,71.51; H,7-06; Example 714 ethoxYj-3-methoxyphenyl]ethanone.

A mixture of 4-rbis(4-fluorophenyl)methyl~piperidine, The reaction mixture was filtered and stripped to dryness.

The dark brown oil obtained was dissolved in chloroform and extracted with 1Ni sulfuric acid and 5% sodium hydroxide.

acetate for elution. A white solid was obtained by 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 129-1310C. was obtained.

Analysis: Calculated for Cr, 9

H

3 1 N0 3

F

2 C,72.63; H,6.52; N,2.92 *Found C,72.52;H,.5'N28 Example 1 -r4l-r3-r4-rBis(4-chlorophenyl)methylenel-l-piperidin'lI propoxy1-3-methoxyyhenyllethanone.

A mixture of 3.96 g (0-01305 mole) of 4-Ebis(4-chlorophenyl)methylenelpiperidine, 3.16 g (0.013 mole) of 1-f 14 (3-chloropropoxy)-3-methoxyphenyljethanone 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 chloroformwater and chloroforn-5% sodium hydroxide. Removal of 1 i i 438A 99 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 0

C.

Analysis: Calculated for Cso 30

H

31 N0 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-r4-r3-r4-r (4-Fluorophenyl)phenylmethyll-l-piperidinylI propoxyl-3-methoxphenylpethanone oxalate r1:1].

A solution of 4.42 g (0.0164 mole) of 4-fluorophenyl)phenylmethyljpiperidine, 4.11 g (0.0170 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, and 0.01 g of potassium iodide in 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 0 c. was obtained.

Analysis: Calculated for C 32

H

38

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-r4- 3- r4-rBis(4-methoxyphenyl)methyl -l-piperidinyll propoxyl-3-methoxyphenyllethanone oxalate r1:11.

A mixture of 7.78 g (0.025 mole" of 4-[bis(4-methoxy- 4, phenyl)methyl]piperidine,' 6.05 g (0.0i25 mole) of 1-4-(3chloropropoxy)-3-methoxyphenyliethanone, and potassium carbonate (553 g9, 0.04 mole) in 300 mi 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 chloroform and watery removal of chloroform in vacuo gave a dark bnown 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 ~4 38A 100 and reacted with oxelic acid. Recrystallization of the salt from methanol-diethyl ether gave 4.16 g (2 7 of white h solid, m.p. 163.5-165 C.

A~nalysis: Calculated for CsHi~:c6.0 ,.31 Found c,66.76; H,6.84; N,2.26 Example 78 1-r4-r3-r4-Bis(4-methylphenyl)methyll-l-piperidinylI propoxyp.3-methoxyphenyl]ethanone.

A mixture of 5.10 g (0.018 mole) of i4-fbis(4-methylphenyl)methyljpiperidine and 4.4 g (0.018 mole) of 1-[I4- (3-chloropropoxy)-3-methylphenyllethanone in 350 ml of 1-butanol was heated overnight at gentle reflux with U 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 partitioned between sodium hydroxide and chloroform-water.

Removal of chloroform gave a dark brown oil. The oil was subjected to column chromatography on a silica gel column with a gradient elution series of hexane-ethyl acetate ii :20 and ethyl acetate-dimethoxy-ethane. The proper fractions from the column were combined. This resulted in 2.60 g of oil (after drying in vacuo at 80 0 c.overnight).

Analysis: Calculated for C 3 2

H

3 9N0 3

C,

79 l1 4 H,8.09; N,2.88 ,:Found :C,78-70; H,8.08; NY2.80 *4*625 IH NMR (CDC1s): (iultiplet, aromatic protons next to ketone, 2H), 4 44 6.7-7.6 (multiplet, aromatic proton, 9H1), 4.0 (triplet, methylene adjacent to ether oxygen,2H), 3.8 (singlet, OCH 3 3H), 3.3 (doublet, methine next to rings, 1H1), 2.5 (singlet, methyl of ketone, 3H1), 2.2 (ainglet, methyl groups attached to aromatic rings, 6H), 1.0-3.0 (multiplet, remaining aliphatic protons, 13H1).

4 38A 101 Example 79 1-1 4 4-[B is(4-f luorophenyl) me thyl]-1-piperidinyl~ butoxy I-3-niethoxyphenyl Jetha none.

A mixture of 6.15 g (0.021 mole) of 4-[bis(4-fluoropheny1)methyllpiperidine and 6.45 g (0.02 mole) of 1-[4- (4-bromobutoxy) methoxyphenyljethanone 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 The mixture was then heated five hours at reflux, The reaction mixture was stripped to dryness on a rotary evaporatl. r, and the residue was partitioned between sodium hydroxide and chloroform-water.

Removal of chloroform gave a dark brown oil. The oil was subjected to chromatography on a silica gel column and eluted with a hexane-ethyl acetate-dimethoxyethane series.

Fractions from the column were combined and solvent removed by pumping in vacuo overnight at 80 0 C. This provided 3.34 g (31.3/1, of brown~ oil.

Analysis: Calculated for C 3 1H 35 W0 3

F

2 C,73.35, H,6-95; P.Found .C,72-34; 112 6.62 N,2 20 NMR ahalysis'wag obtained as follows: 4 0 0 H NMR (CDcls): d'6.8-7.6 (multiplet, aromatics, 11H), 4.1 (triplet methylene next to ether linkage, 2H), 3.4-3.6 (doublet, methine it attached to two fluorophenyl rings, l1H), 3.8 (singlet, OCH 3 .25 3H), 2.5 (singlet, COCH 3 1.1-3.0 (multiplet, remaining 1, 4 4"Example 4-r3-r4-rBis(4-fluorophenl)hvdroxMethl1-l-piperidinvl] propoxyl-3-methox3vbenzoic acid methyl ester.

Following the procedure of Example 1 and utilizing potassium iodide catalyst and substituting dime thylf ormamido 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 ~Crac-bis (p-f luorophenyl) -4 -piper idiraemethanol, 7.4 g (0;07 mole) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 150 ml of dlmethylformamide was 143 8

A

102 reacted to give 5.7 g of white solid, m.p. 131-132.50C.

after recrystallization from isopropyl alcohol.

;rnalysis: calculated for CS 0 H1 3 3

F

2

NO

5 c,68.56; 11,6.33; N,2.67 Found c,68.23; H,6-35; N,2.6o Example 81 of cr-B is (4-f luorophenyl) 1-1-r3:1l4- (me thylthio)phenoxy I propyl).

4 -piperidinemp-thanol.

Following the procedure of Example 1, a mixture of g (0.01 mole) of Ca,cx-bis(p-fluorophenyl)14piperidi~e-.

methanol, 2.2 g (0.01 mole) of I-chloro-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 (8)ofwtepdr 7

M.P.

113-115 0 C. after recrystallization from isopropyl ether.

Analysis: Calculated for C2eH~lF2NO2S: c,69.54, 11,6.

1 46; Found .C,69,57; H)6-.10 N,2 Example 82 phenoxylpropyl -4 -piper idineme thanol f-umarate r1:11.

Following the procedure of Example 1, a mixture of g (0.01. mole) of [Cc-bis(p-fluorophenylb-14.piperidine.

methanol, 2.5 g (0.01 mole) of 1-(3-chloropropoxy)-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.

4. The gummy residue was reacted with fumaric acid and the fumarate salt obtained was recrystallized from acetonitrile to give 3.0 g (148%) of white solid, xn.p. 176-.178 0 c.

30 Analysis: Calculated for CS 2 R3! 5 F2Ns: c,60.85 7 H,5.59; N,2i.22 Found .C,60.72; H,5-54; N02 i 1- 438A 103 Example 83 4- 3-r4-rBis( 4-fluorophenyl)hydroxymethyll-1-piperidinyl propoxyl-3-methoxybenzeneacetic acid ethyl ester hydrochloride.

Following the procedure of Example 45, [a,c-bis(pfluorophenyl)]-4-piperidinemethanol and 4-(3-chloropropoxy)- 3-methoxybenzeneacetic acid, ethyl ester are reacted and the hydrochloride salt is prepared.

Example 84 Bis(4-florophenyl)hydroxmethyll-l-piperidinvyl] ethoxylbenzoic acid ethyl ester hydrochloride.

Following the procedure of Example 45, ,ze-bis(p-fluorophenyl)-4-piperidinemethianol and 4-(2-chloroethoxy)benzoic acid ethyl ester are reacted and the hydrochloride salt is prepared.

Example 4-r3-[4-rBis(4-fluorophenyl )hydroxymethyl]-l-piperidinyl] propoxyl-3-methoxybenzeneacetic acid sodium salt hemihydrate.

This compund was prepared according to the procedure of Example 1. A mixture of 3.0 g (0.01 mole) of Ca,a-bis(pfluorophenyl)J-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 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 0

C.

Analysis: Calculated for C 30

H

32 F NNa0s.0.5 c,64.7 4H5.98; N,2.52 Found c,6 4 .507 H,5.97: N,2.39 14 I 64d S It I *6 *I 4 S S S. 438A 1024 Example 86 7-E3- 2 4 B is(4 1 -fluorophenyl) hydroxymethyl J1 -p ipe rid inyl 1propoxyj 2H-1-be nzopyran-2 -one.

This compound was prepared according to the procedure of Example 1. A mixture of 3.0 g (0.01 mole) of loi,cx-bis (p,-fluorophenyl)j-4-piperidinemethanol, 2.~4 g (0.01 mole of 7-(3-chloropropoxy) -2 H-l-1erzopyran-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 (711/a of pale yellow crystals, 99-120 0 C. with decomposition.

Recrystallizing solvent used was 2-propanol.

Analysis: Calculated for Cs 0

H

2 9F 2 N0 4 C,71.27; H,.5.78,- N02 .77 ItFound .C,71.02, H,5.89, Example 87 dinyllpropoxylbenzoic acid ethyl ester fumarate 4I ii This compound is prepared according to the procedure of Examrple 1. A mixture of 3.0 g (0.01 mole) of [cx,cx-bis (p-fluorophenyl)J-4-piperidinemethanol, 2.4 g (0.01 mole) Of 2-(3-chloropropoxy)benzoic acid ethyl eater, 5.3 g (0-05 1~20 mo~le) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of dirnethylformamide gave 5.7 g of gum as to residue. The guiq was purified by column chromatography on 100 g of silica gel. F.ractiond eluted vith 35% acetone in benzene were combined and concentrated to give 3.0 g of pale yellow gum as residuL. The gum was conv'erted to the 4444 fumaric acid salt and the solid was recrystallized twice from 2-propanol to yield 2.0 g of 41ite solid, m.p.

138-141 0 C An,'alysis: Calculated for C 3 3 HSOF2N10 7 c,66,143; 11,6.08; N12.35 'A0 Found :c,66.25; H,6.08; N$2.27 Example 88 2-3r-~s4furpeylmtyllp~eiiy.

propoxylbenzoic acid ethyl eater., A mixture of 32.79 g (0.116 mole) of 4-[bin(4-fluorophenyl)methyl)piperidine, 27.0~4 g (0.114 mole) of 2-(3-1 chloropropoxy)benzoic acid mthyl enter, and potassium -4

I

438A carbonate, 19.140 g (o.114o mo1a) was heated overnight at reflux in 500 ml of diethoxy-ethane containing potassium iodide (0.14 The reaction was filtered and stripped to dryness. Tha residue obtained was dissolved in chloroform and extracted with 5% sodium hydroxidle, sodium sulfite, and water. The chloroform layer was Oried (anhydrous sodium sulfate), filtered, and solvent removed to furnish a dark brown oil (56.20 The oil was subjected to flash chromatography on an 83.5 g silica gel column (eluted with ethyl acetate). Fractions were comb~ined with similar purity.

One sample of 6.149 g was dried in vacuo at 800~c.

overnight and analyzed.

NMR d7.8 (in, 1, aromatic proton ortho to ester) (in, 11, aromatic), 4.3 2, C-O-CH 2 )i 4.1 2,

-OCH

2 3.5 1, methinC-), 1,3 3,9 CH 3 1.7-3.0 (in, 13, aliphatic).

Analysis: Calculated for CS 0

H

3 3 N0V 3

F

2 C,73.00; H,6-74; N,2 .814 Found :C,72-98; H-$6.70; N,2.93 Example 89 pentoxvl-3-methoxyphenyllethanone hemihydrate.

A mixture of 6.03 g (0.021 mole) of 4-[bis(4-fluo.-ophenyl)inethyl~piperidine, 5rI*_9 g (0.021 mole) of chloropentoxy) -3-methoxyphenyl~ethanone, and potassium carbonate (5.53 g, u.014 mole) was heated overnight at gentln reflux in 350 ml of 1-butanol contining potassium iodide (0.2 The reaction mixture was cooled at room tempera-, ture, fil.tered, and stripped to dryness. The residue 30 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 vising ethyl acetate and 2% methunol-c-thyl acetate for elution.

Fractions of similar purity were combined and solvent, removed.

I

4 414 44 I 4 14' I 44 4,4 4 4~ ~r '4 4 -0 1 438A, The sample was dried in vacuo at 70 0 C. overniight after being U exposed to the atmosphere for 24 hours. A yield of 2.7 g of brown oil was obtained.

1 H NMR (CDCl 3 d" 6 8 -7.

6 (mn, 11, aromatic), S4.1(t, 2, -OCH 3 d3.9 3, OCH 3 13.4-7.6 inethine of difluorophenyl group), 3, -CCsvd'1-3.0 (in, 18, aliphatics 0 and 0.5 Analysis: Calculated for C 32 H3 8 N0 3 5

F

2 C,72.43, H,7.22; N,2.64 Found .C,72.75; H,7-23; N,2 .57 Example 4-[3-r4-EBis(4-fluorophenvl)methyl]-1-piperidiniyl 1propoxylbenzanide fumarate [2:31.

V A mi,"ture of 6.10 g (0.02125 mole) of 4-bis(4-fluoro- I phenyl)n 1 athyljpiperidine 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 overnight at gentle reflux. The reaction was filtered and stripped to dryness. The residue ~I obtained was 4tissolved in chloroform and extracted with S water. The chloroform layer was dried, filtered, and j solvent removed to give an oil. This material was converted 11 *25 to the fumarate salt and recrystallized from methanol- 444 diethyl ether. The white crystalline solid obtained was dried in vacuo overnight at 65 0 C. A yield of 5.47 g (4o.3%) 44 of white crystalline product was obtained, m.p. 193-1940c.

"14 Analysis: Calculated for Cs 4 H38N20BF2: c,63.94; Hi,5.68; N,4,39 Found .c,64-03; H,5-73; N,4.37 f 438-A 107 Example 91 4-[Bis('{-fl'.uorcphenyl)methyl1-l-E3-[ 1 -(methylsulfonyl) phenoxy~propyllpiperidine oxalate A mixture of 6.02 g (0.021 mole) of 4-rbis(4-fluorophenyl)methyljpiperidine and 5.22 g (0.021 mole) of l-(3-chloropropoxy)-4(methylsulfonyl)benzene in 350 ml of 1-butanol containing potassium carbonate (5-53 9, 0.0 4 mole) and potassium iodide (0.2 g) was heated overnight at gentle reflux. The 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. The dark brown oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether to give a white solid.

This material was dried in vacuo ovrnight at 65 0 C. A yield of 6.21 g of white crystalline solid, m.p.

202-204 0 C. was obtained.

Analysis: Calculated for CS 0

H

33 NS0 7

F

2 C,61.11; H,5.64; N,2.38 Found c,60.99; H,5.64; N,2.36 Example 9 2u, 1-r4 4-r6-,r4-rr]2is 4 i,,',Iorophenyl)hydroxymethyl 1-lpiperidinyllhexyloxyl-3" rnethoxyphenyllethanone.

Following the procedure of Example 1 and utilizing, potassium iodide catalyst, a mixture of [a,a-bis(p-fluorophenyl)3-4-piperidnemethanol and 1-[4-(6-chlorohexoxy)-3- 25 methoxyphenyiethanone and sodium carbonate in butanol, the title compound is prepared.

Ott Example 9 1-E 4 -r3-r4-rBis(J4 -fluc.rophenylhydroxmethx11 -l- 1 iperidinvl propoxyv-l2-met'hoxvphetyllethanone.

3Q Following the pro-edure of Examples I and 66, [ocabis (p-fluorophenyl) 1 t-piperidinemethanol and 3-(p-acetyl-mmethoxyphenoxy)propyl chloride are reacted to give the title Ic mpu compound., '108 Example 914 CeC- urpey)--3(-yrxpeoypoy 4 -p iperid ineme thanol Following the procedure of Example 2 and using potassium Iodide catalyst, [ce,a-bis(p-fluoropheny)]-J4-piperidinemethanol and 2-(3-chloropropoxy)-l-benzyloxybenzene are reacted to give 1-[3-(2-benzyloxypheanoxy)propyl]-,-bis(14-fluorophenyl)- 4-piperidinemethanol ich is reacted with hydrogen over palladium on carbon catalyst to give the title compound.

Example crvc-[Bis(4-fluorophelyl) J-1-[3-[14-(methylsulfinyl) phenoxy 3propyl 3-J4-piper idine methanol fumarate.

Following the procedure of Examples 1 and 82, [cx,cx-bis (p-fluorophenyl)J- 1 4-piperidenemethanol and l-(3-chloropropoxy) -I4 -(methylsulf inyl) benzene are reacted to give the free base of the title compound which is then reacted with fumaric acid to give the title compound.

Exampple 96 4-3-r4-rBis(4-fluorophenyl)hydroxymethyl]-l-piperidinylI propoxylbenzenesulfonamide hydrochloride [1:11i.

This compound was prepared according to the procedure of Example 1. A mixture of 3.0 g (0.01 mole) of Ca,a-bis A4 4441 (p-fluorophenyl))-4-piperidinemethanol, 2.5 g (0.01 mole) of 4-(3-chl"oropropoxy)benzenesulfonanide, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.3 g of potasiumn iodide in 100 ml of 1-butariol gave a gum as residue. The gun', was U converted to the hydrochloride with ethereal hydrogen chloride and the solid was recrystallized from absolute ethanol to 't t 0 yield 3.5 g (614%) of white solid, m.p. 152-1750C.

Analysis: calculated for C2 7 HsjClF 2 N2O 4 S: C,58.64; H,5-65; Foun ,58.43~N,5.o6 Fon ,5.3 ,5.68; N,5.06 N ~4387A 109 ft Example 97 p N-r 4-r3-r4-rBis( 4-fluorophenyl)hydroxymethyl1-lpiperidinyllpropoxylphenyllmethanesulfonamide.

b Following the procedure of Example 1, [U,a-bis(p- (I fuorphenl) -4-piperidinemethanol and N-[4-(-bromopropoxy)phenyl]methanesulfonamide are reacted to give the title compound.

Example 98 N-r4-r3-ri4-Bis(4-florophenyl)hydroxymethyl]-lp-iperidinyllpropoxylphenylp-N'-methylurea.

Following the procedure of Example 1, [ae,c-bis(pfluorophenyl)]-4-piperidinemethanol and N-rJ4-(3-bromopropoxy)phenyl]-NI-methylurea are reacted tog give the title compound.

Example 99 r4-r3-r 4 -rBis(4-fluorophenyl)hydroxvmethyl]-l-pi~eridinvl] p~ropoxylphenylicarbamic acid ethyl ester.

Following the procedure of Example 1, Ca,a-bis(pfluorophenyl)J-4-piperidinemethanol and [4-(3-bromopropoxy) phenyljcarbamic acid ethyl ester are reacted to give the title compound.

Exantle 100 't N-r3-[3-rJ4-rBis( 1 4-fluorophenyl)hydroxymhethylJ-l- Following the procedure of Example 1, Ca,ai-bis(fluorophienyl)]-4-pipericlinemethanol and N-3-(3-bromopropoxy) phenyl~urea are reacted to give the title compound.

Example 101 4 4 44-[ 3-r 4-rBis (4-fluorophenyl)hvdrox'nnmethylj-l-piperidinv1] 4*4 propoxyl-3-methoxybenzoic acid sodium salt.

Following the procedures of 'rxamples 1 and 85 but substituting l4-(3-chloropropoxy) -2-methoxyberizoic acid for me the corresponding 3-methoxy compound,, the title compound is 4 44 prepared.

~438A 1-r4-[3-rL-rBis(I-fluorophenyl)hydroxymethyl]piperidinyllpropoxyl-2-hydioxyphenyllethanone.

Following the procedure of Example Ca,cx-bis(pfluorophenyl)-4-piperidinei.-ethanol and l-[4-(3-brombpropoxy)- 2-hydroxyphenyllethanone are reacted to give'the title I? compound.

Exmlel103 lj 7-r3-r'4-[Bis (i-fluorophenyl)hydroxymethyl]-l-piperidinyllpropoxyl- 1 4-6xo-4H--benzopyran-2-carboxylic acid ethyl ester hydrochloride.

A mixture of 3.0 g (0.01 mole) of [a,a-bis(p-fluorophenyl)3- 1 4-piperidinemethanol, 3.1 g (0.01 mole) of7-- I chloropropoxy)- 1 4-oxo-4H-l-benzopyran-2-carboxylic 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 gum as residue. The gum was purified by column chromatography on 120 g of Florisil.

U The desired fractions eluted with 10% acetone in benzene were combined and concentrated under reduced pressu7,e to give a glass as residue. The glass was dissolved in etlierisopropanol and treated~ with ethereal hydrogen chloride.

The solid which precipitated was collected by filtration and recrystallized from ak.oltte ethanol to give 1.9 g I of white solid, z.p. 191 0 C. with decomposition.

Analy;5is: Calculated for C 3 3

H

3 4 C1F 2 N0 6 c,614.55; H,5.58 7 IFound :c,6 1 4.

1 H,5-51; 1Example 104 N,2.26 7-r3-E4-[Bis(J4-fluorophenyl)hydroxymethyl~llpiperi diny11propoxyl-2 3dhdo4--bnoya--n hydrochloride.

Fallowixog the procedure of Example 103, Ccx,c-bis(pfluo,'rophenyl.) -4 -piper!, d ineme thanol1 and 7-(3-bromopropoxy) 2)3-dhdoIHl noya -one are reacted to give the title compound.

43 8

.A

Example 105 1-r4- -4(Diphenylmeth ylene) -l-piperidinyllpropoxyl 3-methoxyphenyl~ethanone oxalate hydrate rl:1:0.51.

A mixture of 7.5 g (0.030 mole) of 4-dipheny'lmethylenepiperidine, 6.3 g (0.032 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl bromnide, 25 g of potassium carbonate and 150 ml of toluene was heated at reflux for 16 hrs, 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 isopropanol 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 isopropanol-methanol mixture. The product weighed g m.p. 186-188 0

C.

Analysis: Calculated for C 32

H

38 N0 7 5 C,69.29; H,6-54, N,2.53 Found .c,69-20, H,6.49; N,2-71 Example 106 1-4r-4(ylhxlhnlehl-,,,-erhdo pyridin-1-yllpropoxyl-3-methoxyphenyllethanone oxalate hydrate [1:1:0.51.

The free base of the title compound was obtained by reacting 4-(c-cyclohexylphenylrnethyl)-l,2,3,6-tetrahydro- *to with 3-(p-acetyl-o-metlioxyphenoxy)propyl chloride in a mixture with sodium bicarbonate in dimethylformamide 44 25and isolated on a Florisil®& column eluting with benzene.

The title salt was prepared, m.p. Lo 0

C.

Analysis: Calculated for C84H84N201!5: C,68.55; H,7-55; N,2:50 Found ,87;H76;N24 tti t C ~I .112 Example 107 1-r 4 4 -[Bis(4-fluorophenyl)hydroxymethyl -lpiperidinyl propoxy] -2-methoxyphenyl ethanone hydrochloride 1l:1].

This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of g (0.01 mole) of[u,a-bis(p-fluorophenyl)]-4-piperidinemethanol, 2.4 g (0.01 mole) of l-[4-(3-chloropropoxy)-2methoxyphenyl3ethanone, 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 CoHs 4 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 N,2 20 4-rBis(4-fluorophenyl)methyl-l--r3-(2,6-dichlorophenoxy)propyl piperidine.

S* A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine o" (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate 25 (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.2 g).

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 2 THaT 7 NOCl2F C66.13; H,5*.55; N,2. N,2.8 __e j 113 Example 109 4-TBis( 4-fluorophenyl)methyll-l-[3-(2, 6)-dichiorophenoxy)propyllpiperidine oxalate Free base of the compound of Example 108 was converted to the oxalate salt and recrystallized from methanoldiethyl ether and dried in vacuo at 8 0 C. overnight, 0 m-p. 158-161 C.

Analysis: Calculated for C 2

EH

2 EN0 5 Cl 2

F

2 C,60.0l; H,5.014; N)2.*414 Found C,60.02; H,5.07;- N,2 .46 Example 110 2-r3-r 1 4-rBis( 4-fluorophenyl)methyl1-l-piperidinvlD propoxylbenzonitrile.

A mixture of 7.41 g (0.025 mole) of 4-[bis(4-fluorophenyl)methyllpiperidine, 4.90 g (0.025 mole) of 2-(3chloropropoxy)benzonitrile, and potassium carbonate, 5.514 g (0.014 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 a 4 oil was triturated with diethyl ether and placed in a freezer overnight. White crystals were obtained and dried in vacuo overnight at room temperature. A yield of 5.15 g (46.15%) of analytically pure material, m.p. 88.5-90 C. was obtained.

Analysis: Calculated for C2sH2abN20F2: C,75-31; H,6.32,- Fud.C75.16; H,16.314; 4* N,6.26 4 a G 4 0 4444 4 4 4 44 4 438A 114 Example 111 a,a- Bis(4-fluorophenyl)-l-[2-(phenylthio)ethyl-4piperidinemethanol 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 transferred to a 500 ml addition funnel (under nitrogen). This solution was added dropwise to a tetrahydrofuran solution of l-[2-(phenylthio)ethyl]-4-piperidinecarboxylic acid ethyl ester, 29.10 g (0.1 mole) in about 200 ml of tetrahydrofuran. 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 oH 3 iNO 5 SFa: C,64.85; H,5.62; N,2.52 Found c,64.80; H,5.62; S N,2.45 4#4 Example 112 4-rBis( 4 -fluorophenyl)methylenel-l-r2-(phenylthio) S" ,25 ethyl piperidine.

a a-Bis(4-fluorophenyl)-l-[2-(phenylthio)ethyl-4piperidinemethanol maleave, 26.13 g (0.047 mole) was converted 0 0,4 0 to the free base by partitioning with methylene chloride and weak alkaline solution and evaporating the organic layer 41 to give an oil. The oil was dissolved in 150 ml of methanol 4 1 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 icer 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, 43 8A 115 m-P. 101.5-103.5 C. in 60% yield K Analysis: Calculated for C 2 eH2 5

NSF

2 C,74.08, H,5.98, N,3.32 Found C,714.12, H,5.96; N,3.25 Example 113 thvl-2:::ZZf r2oroph hl r-o4henlorpensulfonylI phienyl)- 1 4--piperidinemethanol, 4.76 g (0.020 mole) of 2chloroethyl-p-chlorophenylsulfone and 4.90 g (0.0462 mole) of sodium carbonate in 600 ml of acetonitrile was heated at U 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 from a mixture of methylene chloride (1400 ml), methanol (5o ml) 4and hexane (200 ml) to give 6.99 g of white crystalline solid,, m.p. 211-212 0

C.

Analysis: Calculated for C 2

,BH

2 eN0 3

SF

2 Cl: C,61-72; H,5-18, N,2 .77 Found :c,61-511 H,5-16; N,2 .81 ]2heyl~methylenepiperidine.

k\ mxixture of 2.74 g (0.0054 mole) of ux,cx-b.s(4-fluoro- 5 phenyl)-',-[2-E (4-cI orophnyl) sulf onyl ]ethyl]4pp~iie methanol in 100 ml of glacial acetic acid and 40 ml of 2 M sulfuric acid was refluxed for 6 hr. The solvent was 0 4 removed in vau and the resulting solid was recrystallized from methylene chloride-hexane to give 1.95 g of white crystalline solid, mn.p. 152-153 0CO Analysis: Calculated for C 2 8H.

2 4 N0 2 SC1F 2 Co63.99; H,14-96; N12 .87 Found :C,64.24; H,4:9

J

43 8A 116 Example ll 4 -rBis(4-fluorophenyl)methyl1-l-r3-(penylsu-lfonyl) propyllpi-eridine fumarate rl:1.51.

A mixture of 5.74 g (0.02 mole) of 4-Cbis(4-fluorophenyl) methyljpiperidine, 4.36 g (0.02 mole) of 3-chioropropyl phenyl sulfone, 3.18 g (0.03 mole) of sodium carbonate, and potassium iodide (0.3 g) in 300 ml of n-butanol was refluxed overnight.

The reaction mixture was stripped to dryness and the residue partitioned between chloroform-55% 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 (25.7%) of white solid, m.p. 172-173 C.

Analysis: Calculated for CR 2

H

35

NOBF

2 S: c,61,58, H,5.48; N'2 .18 N;2.l14 Example 116 4-rBis(4-fluorophenl)methll-l-r2-r(4-chlorophenyl) sulfon 3et -lpperidine maleate [1;11.

it A mixture of 4.22 g (0.0147 mole) of 4-[bis(4-flvoro- 20 pheny1!)methyllpiperidine, 3.63 g (0.0152 mole) of 2-chioroethyl-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 :225 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 :4 salt was recrystallized from methanol-diethyl ether to give 4220 6.84 g of white crystalline sl.,mp15-.186 0

C.

Analysis;- Calculated for CSoH 3 oN0eSF 2 Cl: C,59.45; H,4.99; Found :C,59.57 H,.991 N 0 2 .32, Ii a

'I

471 438A 117 Example~ 117 il.[Bis(4-ifluorophenvl)methyL]-1-r2-(phenlsulfonyl) ethyllpiperidine raleate E~] A mixture of 5.20 g (0.016 mole) of 1-[bis(4-fluorophenyl)methyllpiperidine, 3.32 g (0,0162 mole) of 2-chloroethyl phenyl. sujlfone, and 500 g (0.0362 mole) of potassium carbonate in 500 ml of acetonitrile was refluxed for 19 hr.

The solvent, was removed in va cuo, and the residue was partitioned between methylene 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 maleate salt, and the salt was recrystallized from methanol-ether to give 4.82 g of white crystalline solid, m~p. l8 .5-18t.5 0C.

Analvsis- Calculated for C 30

H

31 N0aF 2 C163.04; H,5.147; N,2 .145 Found :C,62.88; 11,5,140, N,2 Example 118 11(2 3-.Dihvdro-l1,4-benzodioxan-2-vlmethl)-Y.rydiphenl-4-piperidirlacetonitrile.

A mixture of 6.214 g (0.027 mole) of 2-(bromomethyl)l,4-benzodioxal, 0.027 mole of acx-dip~ienyl-14-piperidineacetonitrile and potassium carbonate (6.91 g) 0.05 mole) was stirred overnight at room temperature. The reaction was refluxed for 5 hours and then stirred overnight at room temperature. The reaction mixture was stripped to V425 dryness. The residue was dissolved in chloroform and the solution was extracted with water and 5% sodium~ hydroxide.

Removal of chloroform gave an oil. NM showed a 2/1 ratio 4 of product to starting material. The reaction was then ref luxed overni.ght in 350 Ml of 1-butanol containing 4 t 3 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 chioroform-water and chlorofori-5% sodium hydroxide. Removal of chloroform gave an oil which was crystallized from methanol and dried in. yacuo- at 80 0 C, overnight, A yield 438A 118 of 7.18 g of white crystalline product, m.p.

130-131.5 0 C. was obtained, A'n:alysis: Lilculated for C 28 aseN 2 0a: C,79.22; H,6.65; N,6.60 Found C,7888; H,6.62; N,6.55 Example 119 1-F3-(4-Acetyl-2-methoxyphenoxy)piopyl-a ,ce-diphenyl- 4-piperidineacetonitrile oxalate rl:1].

A mixture of 6.78 g (0.05 mole) of 1"-4-(3-chloropropoxy)-3-methoxyphenylethanone 7.72 g (0.028 mole) of ca,-diphenyl-4-piperidineacetonitrile was heated overnight at reflux in 350 ml of 1-butanol containing potassium iodide (0.4 The reaction mixture was strippecd L dryness, and the residue was dissolved in chloroform. The chloroform layer was extracted with lN sulfuric acid and then with 5% sodium hydroxide. The chloroform was removed in acuo to give a brown oil. The oil was converted to the oxalate salt, and the salt crystallized from methanol.

The salt was dried in vacu at 80c. overnight. A yield of 8.36 g (52t12) of white solid, m.p. 226-927C. with decomposition was obtained.

Analysis: Calculated for C 3 i 38 N$e0 7 C,69.21? IH,6,34.

N44.89 Found c,68,78; H,6.32s No 4.84 Example 120 -(4-Acetyl-2=ethoxphenoxy)propyll-r dipheayl- 3-piperidinepropanenitrie.

A mixture of 5.80 g (0.02 mole) of ca-diphenyl-3piperidinepropanenitrile, 4.84 g9 (0o02 mole) of l-c4- (3-chloropropoxy) -methoxyphenyl)ethanone, and potassium "carbonate, 5.60 g (0.04 mole) was heated overnight at 68 0

C.

in 400 mi of dimethyiformamide containing potassium iodide (o.3 The reaction mixture was stripped to dryness and partitioned between chloroform-water and sodium hydroxide. The chloroform layer was dried, filtered r and solvent remSVed to give an oil. The oil was subjected to column chromatography on a sitica gel column with elution 438 via ethyl acetate. Frac~tions containing the product were combintid and t'nsferred to brown glass bottles with acetone. The oil was triturated with diethyl ether and pumped to dryness in vacuo at 80 0 C. overnight, A yield of 2.37 g (23.9Q) of oil was obtained.

Analysis: Calculated for C3 2

H

3 6 3N 2 03n c,77.39; H,7.31; N,5.64 Fcound .C,7'7.00; H,7.35, Example 121 1-4(-ctl2mtovhnovttl-uc-ihnl p iperidinepropane nit rile, 6.02 a (0.02 mole) of 1-fl 4 bromobu toxy)-3 -me thoxyphenyl Ie tha none, anid 5.60 9, (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 echloroform- 5% sodium hydroxide., The chloroform layer was dried, filtered, and solvent removed to give a dark yellow oil.

The oil was subjected to col~umn chromatography on silica gel with elution vi.a ethyl acetate. Pure fractions were combined, and the oil was trituraLed with dietbyl ether.

*42 5 The oil was dried in vacuo at 80 0 c. overnight. A yield of 5.96 g 5 8.J4%) of light yellow oil was obtained. 1 H NMR (CDC1,S)LP7.2 7.8 (Mn, 12, aromatic), 6.9 1, aromatic), 1. 1 2 .4 (mn, 17, al1ipha tic).

Analysis: Calculated for C 3 ,sH 3 eN 2 0 3 C,77.61; H,7.50; N,5,48S round C,76.961 H,7.55; N,5.35 438A If 120 Example 122 1F 3- (4-Acetyl-2 -methoxyphenoxy) propyl .a,-diphenyl.

3-pyrrol idinea(,etamide.

A mixture of 5.00 g (.018 mole) of a,a-diphenyl-3pyrrolidineacetamide, 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 fi18 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 di2,ute hydrochloric acid, and 100 ml dilute sodium hydroxide, dried over magnesium sulfate mnd concentrated to yield 7.70 g of yellow glass. The glass was crystallized frQm methylene chloride-diethyl ether: to yield 5.70 g of a fine tan powder which o~ontained ether. The powder was recrystallized from ethyl acetate and acetcnitrile to give an cff-white powder, m,p., l'c5.5-148.5c.

Analysis: Calculated for C 3 0

H

3 4

N

2 0 4 C,74-05; H, 7 .04; N 5-76 Found C,73.80;H,0l Example 123 I- -(4-Acetyl-2-methx rheno v~ro 1 m~-di hen 1- 0 4 -piper idineacetamide fumarate hydrate [l:0.5:11.

A mixture of 5.88 g (0.02 mole) of cx,c-diphenyl-4piperidineacetaie 48 (0.02 mole) of 1-[4~-(3chro p propoxy) -3-me thoxyphenyl 3e th anone, and 6.91 g (0.05 mole) potassium carbonate was heated a.t reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.3 g).

0 4 4 8 The reaction mixture was stripped to dryness. The resielue *kt 30 obtained was partitioned between ohloroform-water and sodium hydroxide lay*er. The chloroform layer ws dried) filtered, and solvent removed by rotary evaporator. The residue obtained Was converted to the fumarate salt. The salt was recrystallized from methanol- 235 diethyl ether. The white solid obtained was dried in vacuoovernight at 80 0 C. A yield of 3.71 g of white solid, 438A 121 m.p. 211-2130C. was obtained.

Analysis: Calculated for C 3 Sfl 4 oN 2 0 7 C,68.73; H,6.99;- Found C,68.56, H,6.72; 51 Example 124 (5.60 gi 0.04 mole) was stirred overnight at room temperature in 300 ml of acetonitrile containing potassium iodide (0.2 The mixture was then heated overnight at gentle reflux. The mixture was stripped to dryness and the residue obtained was partitioned between chlorofo~rm m.p. 169-1710C.

Analysis: Calculated for C3 4

H

42

N

2 0 7 C,69.13; H,7.17; NT,4.74 PFound .C,69.22; H,6.89, 25- Example 129 ~j qca- iphenyl- 3-pperdinproanaidebydrate rl:0.51.

A mixture of 7.00 g (0.0227 inole)' of axca-diphenyl-3piperidinepropanamide, 5.50 g (0.0227 mole) of chloropropoxy)-3-methoxyphenyl)ethanone and potassium carbonate (11.2 g, 0.08 mnole) 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 resulting residue was partitioned between chioroform-water and chloroform-5 oimhdoie 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- 2.

4138A 122 ethyl acetate. Fractions of pure material were combined andI dried in vacuo at 80 0 C. overnight. A yield of 3.75 g of a light yellow amorphous solid was obtained, HNMR (CDC1 3 4P 7. (in, 12, aromatic), 6.9 1, aromatic), 5.8 6.4 (br s, 2, 5.1 (1r s, 1-1/2 3.9 2, C-HO), 3.9 3, oc11 3 2 .5 3, C-CH 3 1.1 2.4 (m.l 15, aliphatic).

Analysis: Calculated for C 3 9 2

H_

39

N

2 0 4 5 C,73.40; H 7.51; Found C,73.42; H,7-47; N,5.22 Exam-ele 126 4-rBis(4-fluorophenvl)methyl]-l-r(2. dhro14 benzodioxan-2-l)rnethyllpiperidine oxalate r1:11.

A mixture of 1.53 g (0.019 mole) of 4-[bis(J4-fluorophenyl)inethyllpiperidine, 4.39 g (0.019 mole) of 2-(bromomethyl)-2,3-dihydro-l,4-benzodioxan, and potassium carbonate 7.80 g (04056 vwale) was stirred overnight at r-oom temperature in 250 ml of acetonitrile. The reaction mixture was stripped to dryness and partitioned between chloroform and water. Removal of chloroform gave a lit$ yellowish brown oil which was converted to the oxalate it salt. The salt was recrystallized from methanol-diethyl ether. A yield of 3.63 g of white solid, 4 *40m.p. 142-145 C. was obtained.

~.25.Analysis: Calculated for C 2 9 I129N~eF 2 C,66.28,- H,5-56; N,2 .61 VFound C ,66.06; H,5-50; Examn-le 127 N26 1.-r2- (2.6-Dichlorophenoxy) ethyll-t. .nr-diPhevl'3 #ou piperidinepropanenitrile.

A mixture of 6.09 g (0.021 mole) of cr,a-diphenyl-3- ~pipexridinepropanenLt rile and 5.63 g (0.021 mole) ofT2-2 bromoethoxy)-l,3-dichlorobenzene in 350 ml of acetonitrile was stirred overnight at room temperature with potassiumci 35carbonate, 5.53 g (0.04 mole) and 0.2 g of potassium iodide.

35 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 438A 123 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 brown oil was dried overnight in vacuo at 80 0 C. A yield of 5.49 g (54.5%) of brown oil was obtained.

1H NMR (CDCLa)e 6.8-7.4 13, aromatic), 4.1 2, -OCHa),0.7-2.9 13, remaining aliphatic) Analysis: Calculated for C 2 eH 2 8

N

2 OC1 2 C,70.14; H,5.89 N,5.84 Found C,70.08; H,5.88 N,5.76 Example 128 1-r5-(4-Acetyl-2-methoxyphenoxy)pentyl-a, -diphenyl- 3-piperidinepropanenitrile hydrate rl:0.51.

A mixture of 5.80 g (0.02 mole) of a,a-diphenyl-3piperidinepropanenitrile, 5.42 S (0.02 mole) of 1-[ 4 (5-chloropentoxy)-3-methoxyphenyl]ethanone, and potassium carbonate, 553 g(0.0 4 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassium iodide (0.3 The reaction mixture was stripped to S' I" 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 25 by rotary evaporation following filtration. The oil Sobtained upon removal of chloroform was subjected to column chromatography (flash chromatography) on silica gel with methanol-ethyl acetate (4:96 v/v) for elution.

S" Similar fractions were combined and removal of solvent 30 gave a clear brown oil. The oil was dried in vacuo overnight at 80 0 C. The oil was triturated with diethyl ether and dried in vacuo again, at 800C. overnight. A yield of 6.37 g of clear brown oil was obtained, 1H NMR (CDCls) 12, aromatic), 6.9 1, 35 aromatic), 4.1 2, CH~g), 3.9 3, CHas), 2.5 3, 0

C-CH

3 1.1-2.4 19, aliphatic).

Analysis: Calculated for C 3 4

H

4 1 NOs.s 5 C,76.52; H,7.7; N Found C,76.37; H,7.65; N,5.19 438A 124 Example 129 I-r-3-(4-Pcetyl-2-methoxVphenoxy)propyl-t (Y-bis(4~ijfluorophenvl)- 4 -piperidineaceton4trile maileate rl1:1.

A mixture of cr i(4furohnl)4ppeiie acetonitrile, 6.45 g (0.021 mole), 1[4->)chloropropoxy)- 3-methoxyphenyij]etha none (5.00 g, 0.021 mole), and potassium carbonate, 5.53 g (0.011 mole), was heated overnight at gentle reflux in 350 ml of 1-butarliol containing potassium iodide (0.2 g) The reaction mixture -was stripped to dryness and then partitioned several times between chloroandsolentremoved to give a dark brown oil. The oil Iwa converted to the maleate salt. The salt was recrystallie from methanol -dieth. l ether and dried in vacuo C. overnight. A yield] of 6.8o g of 1 white crystals, m.p. l58-l60oCwsoband Analysis: Calculated for C 3 5 H_,8N 2 0 7

F

2 C,66.24; Hs5.72; Found, C,66.13; H,5.69; 4 N,4 1 Example 130 -(2,6-Dichlorophenoxy)propyl.,cbis(4fuoro..

pheny:l)-{-acetonitriie maleate rl:l1.

A mixL-.%-xe of 5.99 g (0.0192 mole) of Q,,a-bis(4f luorophenyl) -J4 pipor id ineaceton it rile oxalate and 1,3- 0% 14 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 pcitassium iodide, 0.2 g. The reaction mixture was stripedto drynes:rand the resulting residue was II partitioned severztl times between water and chloroform.

The hloofom lyerwas dried (anhydrous sodium sulfate), filtered, and solvent removed to give a light brown oil.

The entire oil was vcnverted to the maleate salt. The salt was 4ecrystallized from methanol-diethyl ether, t'nd dried 4 ~in vacuo overnight at 8 0 C. A yield of 4.55 g (37.5%) oi white rystals, m.p. 162-'163 0 C. was obtained.

351

-I

4 3 8A 125 Analysis: Calcul~ted for C 3 2

H

3 0

N

2 0 5

F

2 C1 2 C,60.83; 11,4.79; N,4 .14 Found C, 60.89; H, 4 .82; N,4 .44 Example 131 1-[3-(2.6-Dichlorophenoxv)Propylj- c-diphenvl-3piperidinepropanenitrile oxalate rli.2, A mixture of 5.80 g (0.02 mole) of cy,c-diphenyl-3piperidinepropanenitril'Ae and l,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 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 rec-rystal),ized from methanol-diethyl ether, and was dried in vacuo )vernight at 800C. A yield of 7.23 g of white crys;tals, m-p. 159-161 0 was obtained, Analysis: Calculated for Cs 1

H

3 2

N

2 0 5 C1 2 C,63.81, H,5.53;- ~Found .c,64.02, 1,54.80, N, 4.86 Example 132 25 f luoronhenyl) -4 -P iperidinea ceton it rile fumarate [1:13.

94 A mixture of 5.38 g (0.0172 mole) of c,ca-bis(11- -004 fluoropbenyl)-4-piperidineacetonitrile and 5.20 g (0.0172 mole) of 1 -bromobutoxy) -3 -methoxyphenyl Ietha none 4 was heated overnight at reflux in 350 ml of acetonitrile containing potasaium carbonate, 5.54 g (0.04 mole) and potassium iodide) 042 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 S35 solvetat removed to give an oil. The oil was converted to 0. 1 the fumarate Aalt. The salt was recrystallized from mnethanol -dief.hyl ether, and was dried infl macuo overnight at 438A 126 8 0 0C. A yield of 5.78 g of white crystals, M.P. 181.5-182 C. was obtained.

Analysis: Calculated for C 36

H

3 8

N

2 0 7

F

2 C,66 .66; H,5.90; oun C,6.56;N, 4.32 Fnd C: 6-6 H,5.92; ~Example 133 N42 1-r2-(2,6-Dichlorophenoxy)ethyll--a ,cx-diphenyl-3piperidinepropanamide.

A mixture of 7.65 g (0.025 mole) of a,cu-diphenyl-3piper idinepropanen it rile, 2-(2 -bromoethloxy) 3-dichlorobenzene (6.70 g. 0.025 mole), and potassium carbonate, 5.514 g (0.04 mole) was stirred overnight at reflux in 350 ml of acetonitrile containing potassium iodide, (0.2 g).

The reaction mixture was stripped to dryness and the was paritioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and solvent removed to give K 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.

4 Similar fri-ctions were combined and solvent was removed.

0 The resulting oil was dried'in vacuo overnight at 65 C.

A yield of 6. 98 g of clear oil was obtained.

3.H NM4R (CDCl,) d 6.9-7o5 (in, 13, aitomatic), 6.0 (br 2, 25N4) 1. Ct 2, 0-cH2), 2.7 2, N-.CH2), 1.0-2.3 b 0 Cm, 11, aliphatics).

Analysis: Calculated for C2eHsoNeO2Cl2: c067.6i; H,6.08,.

Found~ c,6.52,N,5.63 Foun c,6-52;H,6.08; N,5.63 Example 134 4, t a-[l-[3-(4-Acetvl-2-methoxvphenoxv)Pzonvyl>14- Piperidinyl -fluorophenvl) -2 -pyrid inea ceton it rile 4 It t fumarate r1:1).

A mixture of a-C14-fluorophenyl)-.c-(4-piperidi'nyl)- 2-pyridineacetonitri4le (7.18 g, 0.024 mie), 1-t14-(3chloroProPoxy)-3-methoXyphenyllethahone (5.89 g, 0.024 mole), and potassium carbonate (55 g, 0.04 mole) was -0 1 127 heated overnight in 350 ml of 1-butanol containing potassium iodide (0.15 9i). The reaction mixture was stripped to dryness and the residue obtained was partitioned between chloroform and water. The chloroform layer was extracted with 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 cv~nverted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo overnight at 80 0 C. to give 9.143 g (62.7%) of white crystals, m.p. 166-167 0

C.

Analysis: Cal~culated for C 2 4

H

3 8N 3 Oj" c,66.11, H,5.87,- N, 6.80 Found C,65-57, H,5.89,-

H

2 0 found by NMR) N,6.70 Example 13tj a-rl-r114-Acetl-2-methoxyphenoxv)rP~l- P iperidinv]-f-y luorophenl) -2-Pyr idinea ce tonit rile fumarate hydrate A portion of the compound prepared in Example 1)4 was exposed to the air for 3 days, m.p. 166-167 0

C.

Analysis: Calculated for C3 4

H

3 6N, 3 0 8 F: C,6 1 4.214, H,6.02; N,6.61 Found C,614-07; H$,5.82 7 N,6-58 4.44 44 4 44 4 4.

444 4, 4444 4444444 44 44.4444 4444 44 4444 44 4444 44 44* 4444 44 £44444 44 44.

44 4444 44 444 4 t~ 444 4 44 If 25 Example 13b a ,a-Diphenyl-l-r 8-ctuinolinyloXy) Propyv.-3piperidinepropanenitrile-hydrate r1:0.9,., A mixture of a,ca-diphenyl-3-),.iperidinepropanenitrile (8.12 g, 0.028 m-le), 8-(3chloropropoxy)quinoline (6.18 g, 0.028 mole) and potassium carbonate (5.53 g, 0.m4 mole) was heated at reflux overnight in 350 ml of 1-butanol 30 containing potassaium 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 ove= anhydrous sodium sufate, filtered, and solvent removed to g ive a darlt red mass.

This material was sUbiected to flash. chromatography on a 438A 128 silica gel column using 10% methanol-ethyl acetate, methanol-ethyl acetate, and 50% methanol-ethyl acetate Ii for elution. Fractions of similar purity were combined and solvent was removed by rotary evFaporator. The residue obtained was dried in vacuo at 8o 0 c. overnight to give 5.29 g (39961 of a dark black residue.

1 H NMR (CDCl 3 9 (in, 1, proton ortho to N in ring), 7.9-8.1 (mn, 1, proton para to N in ring), 6.9-7.6 (in, 1~4, aromatics), 41.2 (to 2, methylenes adjacent to oxygen atom), 1.1-2.7 (mn, 16, aliphatic protons and 1H from Analysis: Calculated for C 32

H

3 3

N

3 0 1 5 C,79.31; H,7.07; p N, 8.67 Found C,79.47; H,7.19; N.8.69 Example 137 8-F 3-r4-rBis(4-fluorophenyl )iethyll-l-piperidinylI propoxylquinoline hydrate rl:0.53.

A mixture of 4-(c-p-fluorophenyl)-p-fluorobenzylpipa~ldine (8.03 g, 0.028 mole), 8-(3-chloropropoxy) quinoline (6,18 go 0,028 mole), and potassium carbonate (5.53 go 0,04 mole) was heated overnight at gentle reflux p in 350 inl of 1-butanol containing potassium iodide (0.3 g).

The reaction mixture was fi:ltered through activated charcoal and solvent was remnoved by rotary evaporator.

V 25 The 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 darik red mass. This mnateriLal wdas subjected to flash chromatography on silica gel using 20 and 50% methanol in ethyl acetate for elution. Fractions with similar purity were combined and solvent removed, 4 4 1 aThe residue was dried at 80 0 C in vacuo overnight to give 4 3.741 g of a dark red product.

I-H NM.R (CDCl3):J98.9 (mn, 1, proton ortho to N in ring), 7.9-8.1 1, proton para to N in ring) 6.8-7.41 (mn, 12, 4 4aromatic), 41.2 2, Cfl2 attached to 3.5 (dI,1, inethine attachel to two aromatic rings), 1.0-3.2 (in, 14o, aliphatic protona and 111 for 0.5 H2eo)- 438A 129 Analysis: Calculated for C 30

U!

3

O.

50

N

2

O

7 f.F 2 :,75.53; H,6.44-, N, 5.87 Found 75.66; H, 6 -56; N, 5.86 Example 138 52-r3-r4-rBis( 4-fluorophenyl)methyl1-l-piperidinylI propoxylbenzoic acid hydrate Fl:0.51.

A solution of -C3-.[4-[bis(4-flaorophenyl)methyl]- ],-piperidinyljpropoxyjbenzoic acid ethyl ester (25.3 9, 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 nwixture was made acidic with 1N 6ulfuric acid. The acidic layer was extracted with Chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered 1 and solvent removed to give a gummy residue. The mraterial was subjected to flash chromatography using 20% methanolethyl acetate and 5096 mnethanol..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 0 c. to give 5.72 g (2316%) of material.

Ili NMP. (CDC1 3 )009.2 (br 2, C00U and 0.5 H 2 7.8 (inA 1, Vt:: ~H next to CoOOH), 6-7-7.3 (in, 11, aromatic), 4,1 (mn, 2,

CH-

2 next to 165-3#66m, 114, aliphatics).

Analysist Calculated for: C 2 8 11 3 oN 3 5

F

2 C,70-87; H,6.37 N 2-95 Found :C171.1424- H,631; N,3-01 Example 139 r4-Bis(4-.fluor -ey)iehlN-tihen l..piperidine- Rp~aamine-malente rl:22.

A solution of 4-Ebis(14-fluorophenyl)mthyl1>1-(3chloropropyl)piperidine (35.27 g, 0.097 mnole) in 200 mlt of aniline (204.4, 2.2 Mole) was stirred overnight at 10000. The solution was cooled to room temperature and then extracted several times with 1N sulfuric acI44 The chloroform layer was extracted with 5% sodium hydroxide 438A 130 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 to give 29.84 g of light brown solid, m.p. 153-154°C.

Analysis: Calculated for Ca 2 HaoN 2

OF

2 C,64.4l1 H,5.87; N,4.29 Found C,64.36; H,5.87; N,4.39 Example 140 N-r3-r4-rBis(4 fluorophenyl)methyl j-1-piperidinyll propyvl -N-methylbenzeneamine.

A solution of 4-[bis(4-fluorophenyl)methyl]-l-(3chloropropyl)piperidine (8.43 g, 0.023 mole) in 100 ml of N-methylaniline was stirred )0 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 lN sulfuric acid (each neutral to litmus paper). The fourth 100 ml portion of 14I sulfuric acid used for extraction was strongly acidic to litmus paper. This fourth fraction was made alkaline with ice and 50% sodium hydroxide and then extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and dried over j 25 anhydrous sodium sulfate. Chloroform was remoeed by S 6tary evaporation to give a reddish brown oil. This oil S 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.

H NMR (CDCIs): d'6.6-7.2 13, aromatic), 3. 1, methine attached to aromatic nuclei), 3.3 2, methylene attached to aromatic 2.9 3, N-CHs),'1.1-2.7 (m, t 5 13, aliphatics).

Analysis: Calculated for Ca 2 HsaN 2

F

2 C,77.39; H,7.42; Found C,77.141 HN,6.44 N,6.42 j 438A 131 Example 141 l-[3-(4-Actvl-2-methoxvphenoxy)propy1]-xu bis lfluorophenyl)-3-piperidineacetonitrile oxalate hydrate El:1:11.

A mixture of a,a-bis(4-fluorophenyl)piperidineacetonitrile (6.55 g, 0.02 mole), l-[4-(3-chloropropoxy)- 3-methoxyphenylethanone (5.08 g, 0.02 mole), and potassium carbonate (5-53 g, 0.04 mole) was heated overnight at gentle reflux in 350 ml of 1-butanol containing potassii;m 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 dried over anhydrous sodium sulfate, filtered, and solvent removed to give a darx brown oil. This oil was converted to the oxalate salt which was recrystallized twice from methanol-diethyl ether. The salt was dried in vacuo overnight at 80 0 c. to give 2,28 g of white crystalline solid, m.p. 108-109 0

C.

Analysis: Calculated for C 3 3

H

3 8 eN 2 0F 2 C,63.25, H,5.79 N,4.47 20 Found C,63.08; H,5.48; ,4.39 .4D Example 142 Opel* 1-r3-(4-cyanophenoxy)propyll--a,a-bis(4-fluorophenyi)- 3-piperidineacetonitrile.

25 A mixture of 4-(3-chloropropoxybenzonitrile (6.39 g, 0.0327 mole), a ,-bis(4-fluorophenyl)piperidineacetonitrile (10.22 g, 0.0327 mole), and potass 4 urn carbonate (5.54 g, 0.04 mole) was heated overnight iAt reflux in 350 ml of i 1-butanol containing potassium iodide (0,2 The reaction mixture was stripped to dryness and the residue obtained rt was partitioned between chloroform 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% hexaneethyl acetate and 75% ethyl acetate-25% hexane for elution. Fractions of similar purity were combined and

M_

438A 132 the resulting oil was dried in vacuo overnight at The material crystallized while 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 800C. to give 5.84 g (37.9) of white crystalline product, m.p.

132-133 0

C.

Analysis: Calculated for CeHa 2 7

N

3

OF

2 C,7).87; H,5.77 N,8.91 Found C,73.56; H,5.75; N,8.85 Example 143 4-[5-[4-[.:is((4-fluorophenvl)methyll--piperidinvyl Propoxy--3-methoxybe i jn it r ile.

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 solution had a cloudy white color, but shortly (about 10 minutes) after stirring, the solution had a clear brown color. The reaction mixture was stirred for 30 minutes at room temperature. A dimethylsulfoxide solution of 4-[bis(4-fluorophenyl)methyl]-l-(3-chloropropyl)piperidine (7.26 g, 0.02 mole) was added and the S resulting solution was stirred overnight at 50 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% methanol-ethyl acetate for elution.

Fractions of similar purity were combined and solvent Sremoved in vacuo. The residue was dried in vacuo over night at 80°C. to give 4.40 g of brown oil.

1H NMR (CDCls):'6.8-7.3 11, iromatict), 4.1 2, -CHO0 methylenes), 3.8 3, _QCHs), 1, methine attached to carbon containing two fluorophenyl groups), 1.2-3.0 13, aliphatict).

i 438A~ 133 Analysis: Calculated for C2 9 1H 3 ON20 2

F

2 C,73.09; H,6.34; N,5.88 Found C,72.38; H,6.34l; N,5.78 *NMR shows 1/4 H20 aid a trace of ethyl acetate.

Example l4~4 4-Bis(4-fluorophenyl)methyl_1-1-F3-(l-naphthalenyloxy) piropyl ]piperidine hydrobromide hyd rate rl :1:51 The sodium salt of c-naphtho1 was formed in 300 ml of dimethyl sulfoxide from a-naphthol (2 .59 g, 0.018 mole) and sodium hydride 0.72 g, m.18 mole). The sodium salt was stirred 2-1/g hcu2-s at room temperature.

4-[bis(4.Jfluorophenyl)methyl>Nl(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 at 65 C. The solvent was removed in vacuo and the residue obtained was partitioned between chloroformwat-ar, chloroforn-lN sulTfuric acid, and 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 recrystallized. from methanol-diethyl ether.

The white salt obtained was dried in vacuo at 80 0 C. overnight. The crystaline 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 CSI3 3 NO1.5F 2 Br: C,66.31; H,5.92;~ N,2 .49 Found :C,66.46; H,5:84,1 N,2 .49 Example 145 2...r3,:r4-rBis(4i-fluorophenyl)methy.2 1-1-piperidinylpropoxylquinoline hydrate rl:0.51.

t The sodium salt of 4-bis(4-fluorophenyl)methyli-1piperidinepropanol was formed in 300 ml of dimethyl mulfoxide from its~ free base (6.90 g, 0.02 mole) and sodium hydride 0. g, 0.02 mole). 2-Chioroquinoline g, 0.02 mole) was added and the reaction mixture was heated at 600C. over the weekend. The reaction mixture'Wau 134 stripped to dryness and the residue obtained was dissolved in chloroform. The chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodi.um sulfate, filtered, and solvent removed to give an oil. The oil was subjected to flash chromatography on silica gel using ethyl acetate for elution.

Fractions of similar purtiy were combined and solvent removed. The residue was dried in vacuo overight at 800C.

to give 5.16 g of clear brown oil.

1 H NMR (CDC13):0d6.8-7.9 14, aromatics), 4.

5 2, -OCHa), 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

31

N

2 0 1 aO F 2 C,74.82 H,6.49; N,5.82 Found C,4.56; H,6.36; N,5.69 438; Si! j7i 4

I

4 9, 49* 0 rs 25 9 9 9, 9*o 49 9l 4499 rrr 3Q 41 4i f 1, 4 Example 146 4-rBis(4-fluorophenyl)methyl-l-1-3-(2-naphthalenyloxy propyllpiperidine hydrate ri:0.51.

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 hour at room temperature and had a clear brown color. 4-[Bis(4-fluorophenyl)methyl]-l-(3-chloropropy~)piperidine (7-55 9, 0.0208 mole) in 100 .ml of dimethylsulfoxide was added. The resulting solution was stirred overnight at 60°C. 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 anhydrous sodium sulfate, filtered, and solvent removed to give a brown oil. The oil (free base) was subjected to flash chromatography on silica gel using 50-50 ethyl acetate-hexanes and 75-25 ethyl acetate-hexanes for elution. Fractions of similar purity were combined and solvent removed to give an oil.

The oil was dried in vacuo at 80°C. overnight to give 2.97 9 of a dark brown glass after being exposed overnight to laboratory air.

438A 135 H NMR (CDC1s):6 6.8-7.8 15, aromaties), 4-4.3 2, -OCH2), 3.4-3.6 1, methine attached to two fluorophenyl groups), 1.1-3.0 13, aliphatics).

Analysis: Calculated for CsoH31NOF2: C,7748; H,6.71; N,2.91 Found 1: C,7786; H,6.65; N,2.94 Example 147 3-[3-[4--Bis(ii-fluorophenyl)methyl]1T-piperidinyl propoxylbenzonitrile hydrate rl1:0.51.

A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (7.85 g, 0.027 mole), 3-(3-chloropropoxy)-l-benzonitrile (5.33 g, 0.027 mole), and potassium carbonate (5.84 0.027 mole) was heated overnight at reflux in 350 ml of i-2utanol containing potassium iodide (0.2 The reaction mixture was filtered and stripped to dryness.

The residue obtaine- was dissolved in chloroform and extracted with water and 5% 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 acetatehexanes for elution. Fractions of similar purity were combined and solvent removed. The residue was dried in vacuo overnight at 80 0 c. to give 5.65 g (45.9) of dark brow %n oil.

H NMR (CDC13):' :6.7-7.3 12, aromatics), 3.8-4.1 (t, 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 CaeH 2 eN 2 0i.0s C 73.83;H ,6.42; N',6.15 Found C,74 1 .05 t, 6.27 S 30 N,6.09g tCt *0 S S Table 1 (page 1)

(CH

2 )m-(B)z-D Ex.

p. Ar 1 1 CaH 5 !s- 2 3 14 6 7 8 9 11 12 13 141 16 17 18 19

I-F-CSH

4 4-F-C 8

H

4 1t-F-CaH 4

C@H

5 4-.F-CBH 4 CaHs 14-F-cBH& 1I-F-CaH 4 14-F-COH 4 1-F-CeH4-

-F-COH

4 14 -F -C 6 H 4 li-p-COH 4 1I..F-CH 4 l-F-COH 4 4-F-C 8

H

4

R

COH!

5 4-F-CSH 4 4-F-CaH 4 CeSH 5

CBH

5 s 4-.F-CH 4 CaH 5 4-F-Ca4 14-F-CaH 4 14-F-CaH4- 1-F-COH 4 14-F-C 8

H

4 14 -F*CeH4 14-F-CaH4- 4-F-C eH4 Ring Pos i- (Q)h t ion 14 OH 4 14 OH 4 H 4 H 4 H 4 H 4 H 4 H 4 H 4 H 4 OH 4 H 4 H 4 H 41 H 4 H 4 H 4 z 0 3 0 3 0 3 0 3 0 3 0 3 0 3 0 2 0 2 014 0 3 O 2 0 3 0 3 0 3 0 3 0 3 0 3 0 3 D Salt CeH-_-oxalate COH!5-oxa late Cell 5 oxalate CISH5 -fumarate CsH! 5 fumarate

COH

5 oxalate

CIMH

5 oxalate 2,6-C1 2

-COH

3 4-Cl-COH4-- 2-F-CeH 4 oxalate 3-F-CSH 4 mandelat 4-Cl-C 6 11.- fumarate 4-F-CISH 4 4-OCH 3 -CesH4- fumarate 2-0CH 3

-CSH

4 ).c5 H 2 0 e Table 1j (Page 2) *9 -o *9-9 *09 a e 9 *0 0 5 4 9 *0 9 9 9 9* 0 9 0 a 9

NO.

21 22 23 214 26 27 28 29 31 Ar 4-F-CSH 4 4-F-Cf5H 4 4-F-c 6

H

4 4-CH 3

-CGH

4 4-F-C 8

SH

4 1! H 4 4-F-C8H 4 4-0CH 3

.C

6

'H

4 4-ocHi 3

-CH

4 4-F-CSH 4 4-F-C 8

H

4 4-F-CSH 4

R

4-F-C 8

H

4 4-F-C 8

H

4 4-F-CsH 4 1 1-CH 3

-CGH

4 1 t-F-C 6

H

4

L-F-CSH

4 4I-OC-CH 4 4-OCH 3

-CSH

4 4-FC-CH 4 4-F-C 8

H

4 4-F-C 8

H

4 4-F-CSH 4 4-F-C 6

H

4 4-F-CSH 4 14-F-C 6 1 4 4-OCH 3

-COH

4 4-OCHS-CSH 4 j

OH

H

H

H

H

H

H

H

OH

OH

OH

H

OH

OH

H

H

H

Ring Posi- Q)n t ion 4 4 4 I 4

(B)

7 01 0 0 0 0 0 0 (1 0 0 0 0 2 -OCHS-C 8

H

4 2 -OCH 3 -C8H 4 13,4l-(OCH 3 2

-COH

3 2 ,6-(OCH 3 2 -CeH 3 3, k-(oCH 3 2 -CeH 3 2,6-(OCH 3 2

-CSH

3 3,5-(0CH: 3 2 -C6H: 3 3, 4-(OCH 3 2

-C

6

H

3 4-OCHS-C 6 H4k-c(o) CH ;-C.H 4 4-c(O)CHS-CH 4 4-C(O)CH3-C 6

H

4 Salt oxalate oxalate fumarate oxalate, H2 0 fumarate, 0.5 oxalate oxalate 2 -propanolfumarate

HCI

HC 1,

H

2 0 HB r HBr fumarate,

H

2 0 32 1 4-F-CsH 4 4-F-c8H 4 4-F-C 6

H

4 4-F-CSH 4 4-F-C 8

H

4 4-F-C8H 4 4 4-OCH 3

-C

6

H

4 4 4 4 4 4 4t 4 4 4 0 3 2-CH 3 -4-C(O)cHs-

CSH

3 0 3 4-CN-C 8

H

4 0 3 4-CN-COH 4 0 3 4-C(O)OC 2

H

5 -C8H 4 0 3 4-C(O)OH-COH 4 4-C(O)OC 2

H

5 -Cf3H 4 4-C(o) 0C 2

H

5 -Cj5H 4 4-C(o) OC 4 Hq-CeH 4 4-C(O) 0C 2

H

5 -C8H 4

S

a a a S. a a S 0 0 .5*0 S 5. S 0 0 Table 1 (Page 3) Ex.

No. p Ar 4:1 1 4-F-C8H 4 42 1 4-F-C 8

H

4 43 1 44 1 49 1 1 4-F-C 8

H

4 4-F-CsH 4 4-OCH 3

-C

8

H:

4 4-F-CiSH 4 4-F-CSH 4 4-CH 3

-C

8

H

4 4-F-C 8

H

4 4-F--CSH 4 4-F-CsH 4 4-F-CsH 4 4 -F -C3,1 4 4-F-C 8

H

4 4-F-C8H 4

R

4-F-CSH 4 4-F-C8H 4 4-F-CeH4- 4-F-CSH 4 4-OCE- 3

-CSH

4 4-F-C8H 4 4-CH 3

-C

6

H

4 4-=F-C 8

H

4 4-F-CeH 4 4-F-C 6

H

4 4-F-C 8

H

4 4-F-CSH 4 (A)pj

OH

OR

(Q)

Ring Pos it ion 4 4 z 0 0 0 0 0 0 0 0 0 0

D

4-c(o) 0C 2

H

5

CH

4 2 -OCHs-4-CHa c( 0) C 2

H

5

-CSH

4 4-t--butyI-C 6 3H 4 4-t-butyl-COH 4 4-t-butyl-C 6

H

4 1 t-t-butyl-CH 4 3-CF 3

-C

8

H

4 4-NHC(o) CH 3

-CSK

4 4-rmc(o)CH 3 -c 8

,H

4 4-NH 2

CBH

4 Salt HC 1 HC1 fumarate fumarate,

H

2 0 oxalate oxa late fumarate,

H

2 0 HBr fumarate,

H

2 0 HCl, H120 HC1 oxalate oxalate 1.2 fumarate oxalate 4 0 3 4-NHC(o)C11 3 -Cfi 4 4 0 3 4-NO 2

-CSH

4 4 0 3 4-c(o)N1 2

-C

6 11 4 .4 0 2 -1-C 10

H

7 4 0 2 2-C- 0

H

7 4 0 3 2-OCH 3 1 4_c(o)CH 3 Cj,3H 3 4 0 3 2-OCH 3 -4-c(o)CH 3 C8H 3 4 0 3 2-ocH: 3 -4-c(o)CH.- Cj 6

H

3 1 4-F--CsH 4 58 1 4-F-cSH 4 Table 1 Ex.

No. -P_ 59 1 1 61 1 62 1 63 1 614 1 1 66 1 (Paga 1)7- Ar 1 -F-C 6

H

4 3-CF 3

-C

6 5H 4

C

6

H

5 4-F-C84 4-F-CSH 4 4-F-CSH 4 CeaHs 3-CF 3

-C

8

H

4

CGH

5 1 -F-C8H 4 4-F-c 6

H

4

R

CSH!

5 4-F-C8H 4 4-F-CSH 4

C

8

SH

5 4-F-CSH 4 CeHS

CGH

5

C

8

H

1 1 14-F-C 8

H

4 4-F-C 8

H

4 4-F-C 8

H

4 l

H

H,

OH

OH

OH

OH

OH

OH

OH

(Q)n Ring Pos it ion 4' 14 14 14 14 14 14 14 m D 0 3 2-OCH 3 -4-c(O)CH 3

CSH

3 O 3 2-OCH 3 -14-c(o)CH 3

COH

3 o0 3 2-ocH 3 -14-c(O)CH 3

C

8

H

3 o 3 2-OCH 3 -14-CMuICH 3

CSH

3 O 3 4-COHCH 3

-C

8 H1 4 O 3 2-OCHS-14-COHCH 3 CE5H 3 0 3 2-OCH 3 -14-C(O)CH 3 CaH 3 O 3 2-OCH 3 -4-c(o)CH 3

C

6

H

3 O 3 2-OCH 3 -14-C(o)CH 3 C43H 3 O 3 2-0CHS-14-c(o)CH 3

CSH

3 O 3 2-OCH 3 -14-c(o)CE_ 3 O 3 2-OCH 3 -4--c(O)CH 3

C

8

H

3 O 2 2-OCH 3 -14-C(O)CH! 3 C3H.

3 O 14 2-OCH 3 -14-c(o)CH 3 O 5 2-OCH 3 -14-C(O)CH 3 Salt oxalate oxalate oxalate oxalate, 0 .5 H 2 0 oxalate oxaiate oxalate HC1, 0 .5 H120

HCJ

4 4 4 4 4 4 4 p 0* p 0 0 *fl 000 Ca *40 0 0 0~ C 00 Ce 0 0 0 0 Table 1 Ex.

No. p 741 1 1 76 1 77 1 78 1 75:1 8o 1 81 1 82 1 83 1 841 1, 1 86 1 87 1 (Page 5) Ar 4-c-c 6 4- 4-Q-CH 4 4-CH 3 .c 6 1 4 4-CH-CH 4 4-..F..CH 4 14-F-C8H 4 4-F-Ce614- 14-F-CSH 4 4-F-C8H 4

R

4-F-CSH 4 4-Ci-CSH 4 4-OCH 3 -CeH 4 4-CH 3

-C

8

H

4 4-F-C8H 4 1 l-F-C 6 11 4 11-F-C 6

H

4 4-F-CSH 4 l-F-CGH 4 14-..F..CH 4 4-F-COH 4 d

H

H

H

H

H

OH

OH

OH

OHl

OH

OH

OH

H

(Q)

Ring Pos 1tion 14 14 14 14 14 14 14 14 4~ 14 14 '4 14 14

(B)

0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2-OCH 3 -14-c(O)CH 3

CSH

3 3 2-OCH 3 ,-4-C(0)CH 3 3 2-OCH,-14-c(O)CH 3

C

6

H

3 3 2-OCHi 3 -14-C(O)CH 3

CGH

3 3 2-OCH 3 -4-c(C)CHs-

CSH

3 14 2-OCH 3 -4-C(O)CH 3 CS613- 3 2-OCH 3 -14-C(0)OCH 3

COH

3 3 4-SCHS--COH 4 3 4-S(o) 2 C1 3

-C

6

H

4 3 2-OCHs-14-CH 2 c(o) 0C 2

H

5 -CeH 3 2 4-C(O)0c 2 Hs-CsH 4 3 2 -0CH 3 -4 -CH 2 C(0) ONa-C,6H 3 0 3 2-C(O)0C 2

H

5 -C11 4 Salt oxalate oxalate fumarate

HCJ

HC 1 0.5 H120 0 fumarate 0.5 H 2 0 88 1 1-F-ceH 4 14 0 3 2-(C)0C 2 Hs-Cf3H 4 89 1 II-F-CaHt- 4-F-CS 6 11 4 H 4 0 5 2-0c11 3 -4-c(o)cH 3

C

6

H

3 ft.

S ft 4* S -ft ft. ft *0 0 0 ft ft ft.

Table 1 (Page 6) Ex.

bfo P Ar 1 4F-C 8

H

4

R

II-F-CSH

4 4-F-CSH 4 t- 4.-F-CH 4 4-.F-CeH 4 4-F-CSH 4 93 1 4-F-C 8

H

4 lj-F-CaH 4 14-F-C 8

H

4 4-F-C 8

H

4 14-F-C 6

H

4 99 1 4-F-CsH 4 4 C6H 4 14-F-C 8

H

4 4-F-C 6

H

4 4-P-C 6 11 4 4-F-C 6

H

4 4-F-CeH 4 14-F-C8H 4 4-F-Cf3H 4 14-F-Ce3H 4 14-F-CeH 4 d

H

H

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

n Ring Pos ition 14 z 0

D

4-C(O)iH 2

CSH

4 14 0 3 4-S(O) 2

CH

3 -CeH*- 14 0 6 2-o-H--4-c(O)CH 3 3 14 0 3 3-OCH 3 -4-C(O)CH 3 C8H 3 14 0 3 2-OH-CeH 4 14 0 3 4-S(O)CHs-C 8

H

4 14 0 3 4-S(O) 2

NH

2

-C

8

H

4 14 0 3 4-NIS(0) 2

CH

3 -CfsH 4 14 0 3 4-NHC(O)NHCH 3 C6H 4 14 0 3 4-NHC(o)OC 2

H

5 14 0 3 3-NHC(O)NH2-C8H 4 14 0 3 2-OCHS-4-CO0H- 4 0 3 3-OH-14-C(O)CH.

3 0 14 0 3 jgn Salt furnarate oxalate funiarate

HCI

sodium Hc1 100 101 4-F-CeH 4 14-F-CeH 4 102 1 4-F-C.

3

H

4 103 1 4-F-CCH4- 104. 1 -IF-C 8

H

4 a o a a a a a flO 0 00* *Oe a a a a a 4 a a a a a 'Table 1 (Page 7) Ex.

NO. P- Ar 105 1 CSH 5 106 1 CaHs- 107 1 4-.FC 8

H

4

R

C

8

H

5 C3HI3n lo8 109 110

III

112 113 1141 115 116 117 4 -F-CeH 4 4-F-C 8 11 4 4-F-c~a 4 1' -F-C 8

H

4 4-.F..CH 4 4-F-C8H 4 4-F-CgSH 4 4-F-CeH 4 4~-F-C8H4I- 4-F-C 6

H

4 ,4-F-CSH 4 4-F-CBH 4 4-F-C 6

SH

4 4-F-C 6

H

4 4-F-C 6

H

4 4-F-C8H 4 4-F-C 8

H

4 4-F.C 8

H*-

4-.FCOH 4 4-F-C 8 3H 4

H

OH

H

,H

H

-OH

-OH

H

Ring Position (B) 2 m D 14 0 3 2-OCH 3 -4-C(O)CH 3

C

6

H

3 4* 0 3 2-0CH 3 -14-C(O)CH, 3

CBH

3 4 0 3 3-OCH:T 3 -4-c(o)CH 3

COH

3 4 0 3 2,6-c1 2

-C

6

H

3 4 0 3 2,6-C1 2

-C

8

H

3 4 0 3 2-CN-CSH 4 4 S 2 CeH 5 4 S 2 CsH 5 14 -S(0) 2 2 4-C1-C8H 4 4 2 2 4-c1-cGH 4 4 -S(0) 2 3 C8H 5 Salt Oxalate 0.5 H 2 0 oxalate 0.-5 HC1 oxalate ma lea te fumarate ma lea te maleate -4 -4 2 4-cl-c11 4 2 CsHs- 118 3.L c,,Yt- 119, 1 CSH 5 120 1 C8H 5 121 1 C8H 5 122 0 C 6 11 5

-CN

CSHS- -CN 4 0 3 2-OCH 3 -4-C(O)CH 2 C 6

H

3 Cells- -CN -CF! 2 3 3 2-OCH 3 -14-C(O)CH 3

COH

3

CSH

5 -CN -Cl! 2 3 0 4 2-0CH 3 -4-C(0')CH 3

C

6

H

3 es -C(o)NH 2 -0 3 2-OCH 3 -14-C(o)CH 3 Cj3H 3 oxalate

-A

(Page 8) Table 1

EX.

P_

Ar 123 1 C 8 11 5 d 9Q) Ring Posi-~ tion 14 0

D

2-ocH 3

C

3 CoH 2 1214 1 CeH 5 12,5 1 CsHsj- 1-26 1 4-..F...CsH 4 Cell 5

NH

2

-CH

2 4 0 14 2-0C11 3 -'I-C(0)C11 3

CESH

3 3 0 3 2-OCH 3 4 4-F-CSH 4 127 128 CfSH 5 CaHs-

-CN

-CK

129 1 krcR- 130 132 133 134 4-F-CSH4a 4 Z-pyridinJ.

-4CN

-CN

-C NH, -ci:

-CN

H

H

H

-Cl-la- 3 0 2 2,6-C1 2 -CeH 3 -Cfl 2 3 0 5 2 -OCH 3 -4-(0)CH 3

C

6

H

3 4 0 3 2-0C11 3 -4-C(0)CH 3

C

8

SH

3 4 0 3 2,6-C1 2

-C

8 1{ 3

-CH

2 3 0 3 2,6-C1 2

-C

8 11 3 4 0 14 2-OCH, 3 -4-C(0)C11 3 Cf 8

H

3

-CH

2 3 0 2 2,6-C1 2

-CSH

3 4 0 13 2-OCH 3 -4-C(G)CH 3

C

6

H

3 4 0 3 2-OCH 3 CEll 3

-CR

2 3 0 3 8-quinolinyl 4 0 3 8-quinolinyl 4 0 3 2-C(0)OH-C 8

,H

4 -NH- 3 Cells- Salt Ofumara te,

H

2 0 funtarate 0.5 H120 0.5 H120 oxalate 0.5 P,_2 maleate nialeate oxalate fumarate fuma rate f uxnarate H120 0 .5 0.5 1120 0.5 11 a 0

O

2 maleate 135 1 4-Z-CeI1 4 136 1 %ll 5 137 1 4-F-calT 4 138 1 4-F-C6H 4 139 1 4-F-cHE 4 S-pyridinyl

C

8 11 5 1pF..FcH 4 4-F-C 6 5H 4 8

R

4 I S S Table 1 Ex.

No. p~ 140 1 141 1 142 1 143 1 144 1 (Page 9) Ar 4-F-CSH 4 4-F-CSH 4 4-F-CSH 4 4-F-C 6

H

4 4-r-CH 4 4-F-C 8

H

4 4-F-CaHs- 4-F H4-

R

4-F-CSH 4 4-F-C 6 Rl 4 4-F,-C84 4-F-C8H 4 4-F-CSH 4 4 -F-CSH 4 4-F-C 8

H

4 4-F-C 6 3H 4 d

H

-CN

-CN

Ring Posi- -4 -NCH, 3 .3 3 0 3 3 0 3 4 0 3 -4 0 13

D

C

6

H

5 2-ocH 3 -4-C(o)cH 3 4-CN-C 8

H

4 2 -OCH 3 -4-CN-C8H 3 1-C-I Off- Salt oxa late hydrate HBr, 0 .5 H 2 0 0 .5 H 2 0 0.5 0.5 H 2 0 145 146 147 4 0 3 2-quino>.inyl 4 0 3 ?2-Ci)H- 4 0 3 3-CN-CsH 4 Footnote: *1,2 ,3,6-tetrahydropyridine.

t:i Ii 438A 145 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 of Furchgott, R. and Bhadrakom, S. (1953), J. PHARMACOL. EXP. THER. 108: 129-43. The strips ar suspended in water-jacketed, 10 ml, organ baths that are kept at 37C. and aerated with a mixture of 95% oxygen and 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 min is allowed for maximum relaxation to occur, and during this time the bath is changed at 15 to 20 min intervals. The bath contains a physiological solution, hereafter 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 potassium chloride 5.6 calcium chloride 2.6 magnesium chloride 6-hydrate 1.2 ~sodium dihydrogen 25 phosphate hydrate S.4 sodium bicarbonate 25.0 'to* glucose 9.1 Strips are first checked for viability based on their A 4,4 response to norepinephrine at a final bath concentration 30 of 0 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 r, 35 composition 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 1 438A 146 solution is exchanged by fresh physiological (calcium-free) solution three times.

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 glucose 9.1 The solution is prepared in g.ass-distilled water and adjusted to pH 7.4. If the strips contract, they will be washed with physiological solution and then reincubated 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. (1963), 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 25 Godfraind, T. Kaba, A. (1969) BRIT. J. PHARMACOL. 36: 549-60). Responses are allowed to reach a plateau before tadding the next increment of calcium chloride.

After control responses are obtained, the strips are washed with normal bath solution containing test drug S, 30 (Formula I) at 10-7 molar concentration for about one hour "t at 15-20 min intervals.(See Broekaert, A. and Godfraind, T.

(1979)). During this time the tissues have returned to resting tension.

The strips are then incubated in the physiological 35 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 ICL-~~ i

I

U

ti i2 i i i

H

ii 15 I t 41 4 25

J

1;41 1 4 4o 4 4

I'

438A 147 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 u-blocking activity is present, the strips are washed with the normal bath solution containing the research compound until the resting tension is again at baseline. The strips are then retested for their response to norepine- -5 phrine at a final bath concentration of 10 5 molar.

In the foregoing primary screen, a minimum of 2 strips _'7 are used to test each drug at 10 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 PAa 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 Druas to Unanesthetied Snontane-io v HvDertensive Rats.

6 4* 4 64 4 6444 I 4 44 6 4 44 6644t 4 44 44 4 I44i 4 4 44 Surgical Preparation of Rats Charles River, spontaneously hypertensive rats are 30 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 skin diagonally down the animal's back and around to the right side of the lower abdomen of the rat.

438A 148 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 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 1.5 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 I 25 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 Ss.uturing the ligature tied around the cannula to the dorsal 30 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 Swall and skin sutured in separate layers with blanket stitch.

The animal is given 0.2 ml Combiotic (procaine penicillin G 35 and dihydrostreptomycin sulfate).

S| 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 438A 149 cement (Purdy and Ashbrook, 1978), J. PHARM. PHARMACOLOGY 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 the 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 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 P253D) creating a continuous saline-arterial connection. Continuous tracings from the direct aortic blood pressure are recorded on a Grass polygraph (Model 7).

Heart rate is determined from the blood pressure pulse.

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 S averaged for a i-min period and measurements of blood pressure and heart rate is printed on a Texas Instruments 25 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 r. infused with beparin in sterile saline (2 mg/ml) at a rate ,30 of .05 to .06 ml/hr. Purina Mouse Chow and water are 4 4$ available ad libitum. A solution containing 5% dextrose and terramycin- is given once weekly. Surgically prepared rats may be used more than once during a study. A minimum of 3 days must lapse before rats are used again. A rat is 35 used only once in a dosage group.

-i 438 150 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 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 heart rate are measured in each rat prior to and at 30, 60, 90, 120, 180, 240, 300, 360 minutes and 2 4 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 Determining Effect of Compounds on Coronary Blood Flow.

20 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 surgically exposed, a tracheal tube was inserted and the dog was artificially 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 30 left anterior descending coronary artery was exposed and a Statham electromagnetic blood 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.

o os o O 00 040 00* 4P* C Cr 0 0 0*

CC

C b CC p u Ciii: 0 *C Cdr C

CCO

Ci II- a 151 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 showed an increase in coronary arterial blood flow at 0.5 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 9 9 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 25 test compound is other than water, its effect is established 6 4by testing an equal amount as a control. The dose :protecting 50% of the animals (PDso) from death may be *9 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 Pvloric-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 arranged into groups of 9 rats each for treated animals and 8 rats for controls.

Each group was injected intraduodenally at the time of I i c 152 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 l served as controls. Four )ours following ligation, rats were killed, the stomachs removed, gastric juice collected 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 Sorm 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

I

I II Il I I I I* It 153 of preferred dosage forms. It is only necessary that the active ingredient constitute an reffective amount such that Ii a suitable effective dosage will be consistent with the dosage form employed, in multiples if necessary. The exact individual dosages, as well as daily dosagez, will of course be determined according to standard medical prii-,ciples under the direction of a physician or veterinarian. Generally, the following guide to projected human oral dosageis 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 d 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 40O-300 mg/day divided into 2 or 3 doses. Thus, for example, two capsules each containing it10-50 mg active agent of Formula I could be administered 2-3 times daily for blood pressure lowering.

Oral dosages projected for use in the treatment of angina for an adult human are of the order of 60-1400 mg/day divided into 2 or 3 doses. Thus, for example, two capsules each containing 10-30 mg active agent of Formula I could be Oraldosgesprojected for use as antihistamines for an aulthuma ar ofthe order 10-120 mg/dny divided into 2 o 3 ose. Tusfor example, one or two capsules each conainng 0-4 mgactive agent of Formula I could be adiitrd23tmsdaily for temporary relief of cough due to minor throat and bronchial irritation which may occu wih th comoncold or with inhaled irritants.

Oraldosgespro4jected ior use as antisecretory agents 4OV, for an adult human are of the order of 4~ to 150 mg/day divided into 2 or 3 doses. Thus, for example, one or tw~o doses each containing 0.5 to 50 mg active agent of Formula I could be administered 2-3 times daily for temporary relief 4 1 154 due to excessive acid release in the sNtomach.

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 compositions of the present invention without departing from the spirit or scope thereof, ind it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

I

I 4 s I 4 4 I 4 4 fnt i <1 t «i 6 t 1 4t 4

I(

Claims (5)

1. A compound selected from the group having the formula: (A) Ar' wherein; p is zero, one or two; 0 0 1 1 2 11 A is hydrogen, -O-R -CNR Rj2 -C R" ,CO- 0 01 -O-C R -CH OR 1 i.CH2NR'R 2 mn is zero to six incl1five; Qi~i -2 -C-or-- d and r- are selected from zero or one and the dotted lineis repros(,'nt double bonds which may form consistent with the valence of carbon; Ar, D and R are selected from the group consisting of zF j and in addition, R may have the values; cH 2 cycloalkyl or loweralkyl; and D may have additionally the values; 1,56 0 0 OI I (CH 2 0 2 00 So)r2 -r(H 2 x, 2C, and2 are selecd 9 0R 1 0-C-R2 R1$ 2 -NC-N' or -NC-O 2 B is selected from 0, S, -S-1 and -N-C-0-R 1 0 R. z is one or zero with the proviso tha .t z cannot be Z~nro 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 amino- carbonyl, or a double bond forms between the a carbon and a carbon of the central heterocycl-ic amine ring;- R1 is selected from hydrogen, loweralkyl, phenyl and phenylloweralklyl; fl 2 is selected from loweralkyl, phenyl and phenyl- a 4o25M is a pharmaceutically acceptable metal ion, and 0*4* the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and that cannot represent oxygen at the same time D is phenyl or substituted phenyl when n is zero and (A )d is hydrogen or hyd.Ixyl or when d is zero and a dauble 'bond forms between the a carbon and a carbon of a saturated central hetezrocyclio; amine ring. 157

2. A compound as claimed in claim 1 which. is: fluorophenyl)hydroxymethyJ...1..piperidiny1lpropoxy)-2H-1- benzopyran-2-one or a pharmaceutically acceptable salt thereof; or

7-[3-El4-[bisC 4- f luoropheniyl )hydroxymethyl -1 -piper idinyl propoxy] -4 -oxo- N 1 4H--benzopyran-2-carboxylic acid ethyl ester or a pharmaceu-tically acceptable salt thereof or 7-[3-E'4-Ebi*(14-. f luoropb enyl) hydroxymethylj pipe rid inyl ]propoxy 1-2, 3- dihydro-4H-l-benzopyran-4 -one or a pharmaceutically acceptable salt thereof; or a ,u-bis 4-fluoro- phenyl)-l-[2-(phenylthio)ethyllJ4-piperidinemethanol or a pharmaceutically acceptable salt thereof, or 'h-[bis (4-fluoro- phenyl)methylene)-l-[2-(phenylthio) eth-,llpiporidine or a pharmaceutically accepta~ble salt thereof? or c,a-bis(4-fluoro- phenyl)--[2-[ (4-chlnrophenyl)sulfonylJ ethyl,'j-4-piperidine- methanol or a pharmaceutially acceptable salt thereoff or (4-chloro- phenyl)sulfonylethyJ 4 bis(4-fluorophenyl)iethylene] piperidine or a pharmaceutically acceptable salt thereof; or 4-[bis(4J-fluoro- .~ophenyl)methyl)-1-[3-[(4corphee yt.llfnyl)suoyliethleo ppinora pharmaceutically acceptable salt thereof o 4-[bis( 4-f luoro- pienyl)methyl-l-2-(pheloulfofl)ethy1Jpiperiifle or a It" pharmactkutically acceptable salt thereuf; or 158 1-(2 ,3-dihydro- 1, 1 4-benzodioxan-2-ylmethyl)-,a-dipheny-}-pi~eridine- acetonitrile or a pharmaceutically acceptable salt thereof; or methoxynhenoxy)propyl]-rM,U-diphenyl-l4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof; or 2-methoxyphenoxy)propylj-a,cx-diphenyl-3-piperidinepropane- nitrile or a pharmaceutically acceptable salt thereof; or 4-acetyl- 2 -methoxyphenoxy) but yl I-,a -d irhenyl -3-piper id inepropa ne nitrile or a pharmaceutically acceptable salt thereof? or 2-methoxyphenoxy)propylJ-4x,a-diphenyl-3-pyrrolidineacetamide or a pharmaceutically acceptable salt thereof; or 1-f 3-(4-acetyl- 2-methoxyphenoxy)propyl ,c-diphenyl-4-piperidinoacetamide or a pharmaceutically acceptable salt thereof; oj,: 2-methoxyphenoxy)butyl]--u,a-diphenyl-4-piperidineacetamide or a pharmaceutically acceptable salt thereof; or 2-methoxyphenoxy)propyl]-a,a-dipigenyl-3-piperidine- propanamide or a pharmaceutically acceptable salt thereof; or 4-lbis( 4-fluoro- phenyl)methylJ-l-C (2 ,3-dihydro,-l,4-benzodioxan.-2-yl)methyl] pipreridine or a pharmaceutically acceptable Bait thereofj or 1-r2-(2 ,6- dichlorophenoxy)ethy1J-u nitrile or a pharmaceutically acceptable salt thereof; or l-[5-(4-acetyl- 2-inethoxyphenoxy)pentyll-,c,-dipheny1-3-Piperidinepropane- nitrile or a pharmaceutically acceptable salt thereof'A cr 0 #1 4* 4 0464 4 40 .4 4 159 4-acetyl- 2 -methoxyphenoxy)propyl.-r,u..bis (4-.fluorophenyl) -4 piperidineacetonitrile or a pharinaceutically acceptable salt thereof; or 6 -dichloro- phenoxy)proyi..a,az-bis(i4-fluorophenyl).J-acetbnitrile or H a pharmaceutically acceptable salt thereof;or dichlorophenoxy)propl~la,adiphnyl3-Piperidinepropae. acnitrile or a pharmaceutically acceptable salt thereof or ,-ct dichophenoxy)btyl -a,a -is (4 -yluoop3y -piperididopaamid actnieor a pharmaceutically acceptable salt thereof; or pihryl)-2- yiirectoytll or aa -ihnl3praceically i orapar0etial acceptable salt thereof; or acetyl-2-methoxypenoxy)propyl-4-piperidinyla(J4.fluoro- *phernyl)-2-pyridineacetonitrile or a pharmaceutic ally salt thereof; or actl2-etoyhnx)25pl3- -ieiiy a4 -a-diphenyl- p 3-8qunliyoxeropyl]-3-pipeidinepropannitrile o hrae .al o aphratclyacceptable salt thereof or *03 fluoroihenyxymethyI eridihyJd inpopunon ra or pharmaceutically acceptable salt thereof; or 000 1 0 -[3is[4-[biuoro 00. flrphenyl)methyl ]hey-l-piperidinen~poanam oine or tO' pharmaceutically acceptable salt thereof; or tt 16o 4-[bis (4- fluorophenyl)methy1J-l-piperidinyl~propyl I--methylbenzene- amine or a pharmaceutically acceptable salt thereof; or 2-methoxyphenoxy)propylJ-u,c-bis(Li-.fluorophenyl) -3- piperidineacetonitrile or a pharinaceutically acceptable salt thereof; or l-[3-(4-cyano- phenoxy)propylj-.x,a-bis(4-fluorophenyl)-3-piperidine- acetonitrile or a pharmceutically acceptable salt thereof; or 4-Cbis (4-fluoro- phenyl)rnethylj-l-[3-( 1-naphthylenyloxy)propyl~piperidine or a pharmaceutically acceptable salt thereof; or f luorophenyl) methyl 1-1 -piper id inyl 3propoxylqu inol ine or a pharmaceutically acceptable salt thereof, or 4 is (4-f luoro- phenyl~methylj-1-[3-(2-naphthalenyloxy)propyl~piperidine or a pharmaceutically acceptable salt thereof, 3. A method of treating hypertension which comprises administering an effective amount of a compound 1i~i -selected from the group of compounds having the formula: (A )d *4 Ar whren 9)nv(B)z-D p .540 p is zero, one or two; 0A is hydrogen, -0-R -gNRlR2 c-R, -C-0-.R tt -0c-R"-CHeO0RI, -CH2NR 1 R 2 4 4~ I m is zero to six inclusive; OH Q is -CH2- or 1~ i 161 d 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 *O7Y or Ms and in addition, R may have the values: X x Ha, yloalyl or loweralyl and (H 2 cycloalkyl or loweralkyl. and D may have additionally the values: 0 o (cH 2 o-2 6 e 6 4 e a S 40 a« 9 sl 9 94 9 4 or Ar(CH 2 4 X, Y and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 0 -NOs, -0-R -C-R -CF3, -N(R -C(O)OR 1 0 R 1 -SQR 2 -SR 2 -S(0)R 2 -R i -CH 2 COOM, -S02N -NSOzCHs, 0 9 R 2 R -NC-N' or -NC-OR R 1 e R^ 0 I I B is selected from 0, S, -vR, and -N-C-0-R 7 0 R z is one or zero with the proviso that z cannot be 35 zero at the same time n is zero when one of the following occurs at the same time that D is phenyl or substituted 4t 162 P.phenyl: (Ad is hydrogen, (Ad is cyano, (Ad is amino- carbonyl,'or a double bond korms between the ar-carbon and a carbon of the central heterocyclic amine ring; R1 is selected from hydrogen, loweralkyl, phenyl, and phenylloweralkyl; R 2 is selected from loweralkyl, phenyl and phenyl- loweral'kyl; M is a pharmaceutically acceptable metal ion, and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. 4. The method of claim 3 wherein the compound is 4-(diphenylmethylene)-l-.(3-phenoxypropyl)piperidine or a pharmaceutically acceptable salt thereof; or ce,c-bis(4fluorophenyl)l3.phenxypropyl)-4-piperidine- methanol or a pharmaceutically acceptable salt thereof; or 4-[bis(4-fluorophenyl)methylenel(3...phenogypropyl). piperidine or a pharmaceutically acceptable salt thereof; or 4-(diphenylmethyl)-l-(4,-phenoxybutyl)piperidjfle or a p harmaceutically acceptable salt the~reof; or 4 -(diphenylmethyl)-l-.(3-phenoxypropyl)piperidine or a pharmaceutically acceptable salt thereof F or 4-bis (4 -fluo rophenyl) me thyl 1- (3-phenoxypropyl) pipe rid ine 0 4, or a pharmaceutically acceptable'salt thereof; o~r 4-(diphenylmethyl)-1-(2-phenoxyethyl)piperidine or pharmaceutically acceptable salt thereof; or 163 4-bs4furpey~et l--2peoyty)piperidine or a pharmaceutically acceptable'salt thereof; or 4-[bis(4-fluorophenyl)methyl--(4-.phenoxybutyl)piperidine or a pharmaceutically acceptable salt thereof; or (4-fluorophenyl)phenylmethyl)-l-(3-phenoxypropyl) piperidine or a pharmaceutically acceptable salt thereof; or 4-bis( 4 -florophenyl)methyl1l-C2(2,6-.dichlorophenoxy) ethyl]piperidine or a pharmaceutically acceptable salt thereof or 1-[3-(4-chlorophenoxy)propyll..a,a-bis(4-fluorophenyl)-4-J piperidinemethanol or a pharmaceutically acceptable salt thereof or 4-bs4furpey~ehl--3(-loohnx~rpi piperidine or a pharmaceutically acceptable salt thereof; or 2 I-Cbis(4fluorophenyl)methylJ-l-[3-(3-fluorophenoxy) propyllpiperidine or a pharmaceutically acceptable salt thereof; or 4 piperidine or a pharmaceutically acceptable salt thereof; or 16i4 piperidine or a pharmaceutically acceptable salt thereof; or 4-piperi-dinemethanol or a phainn.aceutically acceptable salt thereof or 4-bs4furpey~ehlee--3(-ehxpeoy propyl]piperidine or a pharmaceutically acceptable salt thereof; or it 25 0 A I I 4 -bis(4-fluorophenyl)methyl]-1-E3-(3,14-dimethoxyphenoxy) propyljpiperidine or a pharmaceutically acceptable salt thereof.; or I4-bis(4-methylphenyl)methylJ-l-[3-(2,6-dimethoxyphenoxy) propyljpiperidine or a pharmaceutically acceptable salt thereof; or 4-bis(4-fluorophenyl)rethylenel-l-C3-(3,4-dimethoxyphenoxy) propyljpiperidine or a pharmaceutically acceptable salt thereof or 4-Cbis(I4-fluorophenyl)rnethyl3-1-[3.-(2,6-dimethoxyphenoxy) propyl]_piperidine or a pharmaceutically acceptable salt thereof; or l4-bis(4-fluoropbenyl)methyl)-l-[3-(3,5-dimethoxyphenoxy) propyljpiperidine or a pharmaceutically acceptable salt thereof or 4-bs4mto~pey~ehl--3(,-iehxpeoy propyl ]piper idine or a pharmaceutically acceptable salt thereof; or 4. 4. 0 4.44' 0 4* 4.4. 49 44 435 9 9' 04 165 4-Cbis(4-methoxyphenyl)methyil-l-[3-(J4-methoxyphenoxy)propyl] piperidine or a pharmaceutically acceptable salt thereof; or 1-4[-4Ci(-loohny~ehlnllppidnl propoxy~pheny1)ethanone or a pharmaceutically acceptable salt thereof; or 4-CbI-s(4 1 -fluorophenyl )ethyll-l-piperidinylipropoxy] phenyl~ethanone or a pharmaceutically acceptable salt thereof;~ or l-Eif-[3-[4-bis(4-fluorophenyl)hydroxynethyl>-l-~piperidinyl] propoxylphenyllethanone or a pharmaceutically acceptable salt thereof; or l.-[4-[3-[4-Cbis(4-fluorophenyl)hydroxymethylJ-l-piperidinyl] propoxy)-3-methylphenyl )ethanone or a pharmaceutically acceptable salt thereof; or 4.-3-[4-[bis -fluoropheny1 )hydroxymethylj -1-piperidinylI propoxyllbenzonitrile or a pharmaceutically acceptable salt thereof; or 25 4-3[-bs4furpey~ety31pprdnlpooy benzonitrile or a pharmaceutically acceptable salt thereof; or 9 it 4 4 t -[3-bis(bs4-fluoropn.nyl)hydoxymthyl-l-piperidinyl] 1%4 1A 0 a, t propoxy~benzoic acid etyleser, a pharmaceuticallytbesl atthereof 4 or o t~ 166 4[3-[4-[bis(4-fluorophenyl)methylenel.piperidinylI propoxy]benzoic acid ethyl ester or a pharmaceutically acceptable salt thereof; or 1 4-[3-[l4-bis(l-fluorophenyl)methyl)..lpiperidinyl~propoxyI benzoic acid ethyl ester or a pharmaceutically acceptable salt thereof; orI 4 -[3-[I4-rbis(4-methoxyphenyl)methyl>.l..piperidinyl]propoxy] benzoic aci~d butyl ester or a pharmaceutically acceptable salt thereof; or 4-3[-bs4mtoyhnlmty)lpprdnlpooy benzoic acid ethyl ester or a pharmaceutically acceptable salt thereof; or ethyl)phenoxy]propyllpiperidine or a pharmaceutically acceptable salt thereof; or 4-bs4furpey~ehl--3[-11dmtyehl phenoxylpropyllpiperidine or a pharrna~euticallyacceptable salt thereof; or phenoxy~propyl]piperidine or a pharmaceutically acceptable salt thereof; or w tt ~4-piperidinemn;thanol or a pharmaceutically acceptable salt thereof; or It, 4 -rbis( 4 -fluorophenyl,)methyl]-1-c3-[3-(trifluoromethyl) pherioxy~propyl~piperidine or a pharmaceutically acceptable salt thereof; or propoxy~phenyl~acetamide or a pharmaceutically acceptable salt thereof; or N-C4I[3E[4-[bis(4..fluorophenyl)methyl]-lpiperidinylJ propoxyjphenyllacetamide or a pharmaceutically acceptable sait thereof; or 1 4-3-r-[bis(4-fluorophenyl)methyl3-1-piperidinyl~propoxyJ benzerieamine or a pharmaceutically acceptable salt thereof or N-4[-4[i-\-loohnl~yrxmty31pprdnl propoxy~pheriyllacetamide or a pharmaceutically acceptable salt thereofp or a,a-bis(4-fuorophenyl)-l-3-(-nitrophenoxy)propyl 4. piperidinernethanol or a pharmaceutically acceptable salt thereof; or 4 C3C4-[bs( floohnl)hdoyehl)--ierdiy propoxylbenzarnide or a pharmaceutically acceptable salt thereof; or ethyl )piperidine or a pharmaceutically acceptable salt thereof; or .4 4 4 t ~~rpoy methoxypepiperida nne or a pharmaceuticallyacetbesl thaceteof or tteropo 163 4 [,l-[bis 4-fluorophenyrl )methyl l-1-piperid inyl J propoxyJ-3-methoxyphenyl~ethanono or a pharmaceutically acceptable salt thereof; or 4 bis(4fluorophenyl)rethylene]-l-piperidinyl] propoxyj-3-rnethoxyphenyljethanone or a pharmaceutically acceptable salt thereof; or 4 -[(4-fluorophenyl)phenylrethylene)-l-piperidinyl) propoxy>-3-nethoxyphenyl)ethanone or a pharmaceutically acceptable salt thereof; or l-C3-metboxy--1[3-[4-[phenyl[3-( trifluoromethyl )phenyl] rethylene)-l-piperidinyl~propoxy~phenyllethanone or a pharmaceutically acceptable salt thereof; or l-[4-[3-[-(cyclohexylphenylrethylene)-l-piperidinylI propoxy]->4methoxyphenyl~ethanone or a pharmaceutically acceptable salt thereof; or 1-[4-[3-[4-(cyclohexylphenymethyl)-l-piperidinyl),propoxy]- 3-methoxyphenyijethanoie or a pharmaceutically acceptable salt thereof; oX 4. 4-[3-[4-bis(4-fluoropheny)metylene-l-piperidinyl) propoxy)-,a-mrethylbenzenemethanol or a pharmaceutically acceptable salt thereof; Or~ '44 o4 '4-3-[4-bis(4-fluorophenyl)methyl)-1-piperidinyl]propoxy) 3-rnethoxy--methylbenzetemethanol or a pharmaceutically 4 acceptable salt thereoff or to 41 169 1-C 4-(diphenymethyl) pipe rid inyllpropoxy]-3- methoxypheriy1jethanone or a pharmaceutically acceptable salt thereof; or propoxy]-3-methoxyphenyl~ethanone or a pharmaceutically acceptable salt thereof; or 1-['4-r3-E4-(4-fluoropheny1l)hydroxyphenylmethylJ-l- p iperid inyl jpropoxyj 3-methoxyphenylj]et--ha none or a pharmnaceutically acceptable salt thereof; or l-[4-[-4-(diphenylhydroxymethyl)'-l-piperidinyl]propoxy>- 3-nethoxyphenyllethanone or a phiarmaceutically acceptable salt thereof; or 1--[3-4-hydroxypenyl[-3-(trifluoronethyl)phenylI methyl) -1-piper id inyl ]propoxy 3-3-methoxyphenyl 3etha none or a pharmace~~itically acceptable salt thereof; or l-[4-'-[4-(cyclohexylhydroxyphenylniethyl)-1-pipPeridinylI propoxyj3-3-methoxyphenyl~ethanone or a pharmaceutically acceptable salt thereof; or 4-[bis(4J-fluoropheyl)hydroxymethylJ-l-piperidiny1J ethoxy) -3-methoxyphelyl )ethanonle. or a pharmaceutically acceptable salt thereof; or butoxy ]-3-methoxyphehyl ]etha none or a pharmaceutically acceptable salt thereof; or 170 pentoxy>-3-methoxyphenyljethanone or a pharmaceutically acceptable salt thereof; or l-r 4 -[2-[4-Ebis(4-fluorophenyl)methyl]-1-piperidinyl] ethoxyJ-3-methoxyphenyllethanone cr a pharmaceutically acceptable salt thereoifj or -3C-bs4choohnlmtyen)lpprdnl propoxyJ-3-methoxyphienyllethanone or a pharmaceutically acceptable -salt thereof; or 1-4r-4C4furpey~heymty31pprliyl propoxy3-rnethoxyphenyljethanone or a pharmaceutically acceptable salt thereof; or -methoxypheyl)methyl-l-piperidinylI propoxyl-3-nmethoxyphenyllethanone or a pharmaceutically acceptable salt thereof: or 1-E4-r3-E 1 4-[bis(4-methylphenyl)nlethylj-l-piperidinyl] or a pharmaceutically V acceptable salt thereof j or 1i4t 4-bs4fuoohnlmehl--iprdnl butoxyl-3-metho~yphenyli -thanone or a pharmaceutically 4" acceptable salt thereof; or propoxy]-3-inethoxybenzoic acid methyl ester or a pharmaceutically acceptable salt thereoff or Ci pot-bis(4-f luorophelyl) (methylth io)phenoxyl propyl]-4-.piperldiflemethano1 or a pharmaceutically acceptable salt thereof; or 171 U,-bi 4-loohnl [-4(ehlufnlpeoy propy1]- 1 4-piperidinemethanol or a pharmaceutically acceptable salt thereof; w:- fbis( Lhfluorophenyl)hydroxymethyl] -l-piperidinylI propoxyl-.3-methoxybenzeneacetic acid izr a pharmaceutically acceptable salt thereof; or 7-[3-[4-rbis('4-fluorophenyl)hyaroxymethyl3-l-piperidinyl] propoxy3 -2 -i-l-benzopyran-2 -onie or a pharmaceutically acceptable salt thereof; or 0-3[-bs4furpey~yrxmtyllpprdnl propoxylbenzoic acid ethyl ester or a pharmaceutically acceptable salt thereof; or 2-r3-[E4-[bis(4l-fluorophenyl)met'li-l-piperidiny1Jpropoxy] benzAc acid ethyl ester or a pharmaceutically acceptable salt thereof or l-4[-4[i 4floohnlntyllpprdnl pentoxy] 3 -me thox.yphenyl Ietha none or a ph~rmaceutically t acceptable salt thereof; or 4-[3-r4-Cbis( 4-fluorophenyl)methylp-l-piperidinyljpropoxy] berizarnide or a pharmaceutically accteptable salt thereof; or pentoxy]propyllpiperidine or a pharmaceutically acceptable salt thereof; or 4 172 propox~ 'benzenesulfonamide or a pharmaceutically acceptable salt thk.reof; or 7-3[-bs4furpey~yrxmtyllpprdnl propoxyj- 1 4-oxo-J4H-l-benzopyran-2-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof; or 1-[4-3-Ei-(diphenylmethyene)-l-piperidinyllpropoxy]-3- methgxyphenyllethanone or a pharmaceutically acceptable salt thereof; or 1-.4[-4(ylhxlhnlehl-,,,-erhdo 15pyridin-l-yl~.propoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereoff or 1-,4[-4Ci -furpey~yrxmty)l piper' 4..iyl~propoxy-2-methoxyphenyllethanone or a pharmaceutically acceptable salt thereofj or l-[3-(2,6-dichlorophenoxy)propyl-4--bis(4-fluorophenyl) methylipiperidine or a pharmaceutically acceptable salt thereof; or 1 4 4252-[3-c4-[bis(4-fluorophenyl)methyl]-l-pip&~ridinyl~propoxy] benzonitrile or a pharmaceutically acceptable nalt thereof, 1 &c,Q-bis(4-fluorophefyl)-l-2(phelylthio)ethyl)-4- piperidinemethanol or a pharmaceutically acceptable salt thereof; or a piperidine or a pharmaceutically acceptable salt thereof?. or cr,c-bis(4-fluorophenyl)-l-[2-[(4-chlorophenyl)sulfonyl] ethyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof;F or l-[2-[(4-chloroplienyl)sulfonyl)ehyl-4-rbis(lF-fluorophenyl) methylerielpiperidine or a pharmaceutically acceptable salt thereof; or 4-bs4fuzpey~ehl-l[-peysloy~rpl piperidiie or a pharmaceutically acceptable salt thereofF. or 4-bs4furpey~ehl--2[,-hoohnl sulfonyljethyljpiperidiie or a pharmaceutically acceptable salt thereof; or 4-Cbis(4-fluorophenyl)methylJ-l-[2-.(phenylsulfonyl)ethyl] piperidine or a pharmaceutically acceptable salt thereoff ox l-(2,3-.dihydro-l,4..benzodioxan-2-ylmethyl)-r,c-diphenyl- 4-piperidirieacetonitrile or a pharmaceutically acceptable salt thereof f or t4 a 4 4 044 44 l-[3-(4-acetyl-2-methoxyphenoxy)propyl-,-diphenyl-4- piperidineacetonitrile or a pharmaceutically acceptable salt thereof F or 1-3(-ctl2mtoyhnoypoylac-ihnl3 piperidi~nepropanenitrile or a pharmaceutically acceptable salt thelzeof; or 1-4(-ctl2mtoyhnoybtl-xr-ihnl3 piperidiriepropanenitrile or a pharmaceutically acceptable salt thereof; or 4t~ 174 1-3(-ctl2mtoy eoy~r~II-,a-ihnl_ pyrrolidirleacetamide or a pharmaceutically acceptable salt thereof;~ or l-r3-( 4-acetyl-2-methoxyphenoxy)propyl3--a cU-diphenyl-4- piperidi-Lneacetamide or a pharmaceutically acceptable Bait thereof; or l-[4-(4-acetyl-2-methoxyphenoxy)butylCrao-diphenyl-i- piperidineacetamide or a pharmaceutically acceptable salt thereof; or 1-[3-(4-acetyl-2-methoxyphenoxy)propyl]--q,(:;,-diphenyl-3- piper id inepropa nanide or a pharmaceutically acceptable salt thereof; or 4- bis (4-f luorophenyl) methyl 3-dihydro-1, 4- benzodioxan-2-yl)mnethyl3rpiperidine or a pharmaceutically acceptable salt thereof; or l-[2-(2,-6-dichlorophenoxy) ethylJ]-cx,c-diphenyl-3-Piperidine- propanenitrile or a phari-,; ceutically acceptable salt thereoff or *Go 1-[5-(4-acetyl-2-nethoxyphenoxy)pentyll-a,af-diphenyl-3- p iperid ineplropanen it rile or a pharmaceutically acceptable *4 4 salt thereof; or l-[3-(4-acetyl-2-methoxyphenoxy)propyl-a,-bis(4-fluoro- phenyl) -~4-pipe ridinea ceton itrile or a pharmaceutically acceptable salt thereof; or 0 44 1-[3-(2,6-dichlorophenoxy)propy1l--a,a-bis(4-fluoropheny1)- .44 :1 .435 4-acetonitrile or a pharmaceutically acceptable salt thereof ~or 175 (2,6-dichlorophenoxy) propyl] r-,cj-diphenyl-3-piperidine- propanenitrile or a pharmaceutically acceptable salt thereof; or 1-4(-ctl2mtoyhnoybtl-~-i(-loo phenyl)-l4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof; or 1-[2 -(2,6-dichlorophoethxy)--q, a iphenyl3-Piperidine- propanamide or a pharmaceutically acceptable salt thereof; or 4 lC-4aetl2mtoyheoypoy]4-ieiiy] at-(J4-fluorophenyl)-2-pyridineacetonitrile or a pharmaceutically acceptable salt thereof; or a,ca-diphenyl-1-13-(8-quinolinyloxy)propyl>,'3-Piperidine propanenitrile or a pharmaiceutically acceptable salt thereof; or

8-3[-bs4furpey~ety]lpprdnlpooy quinoline or a pharmaceutically acceptable salt thereof4 or 2-L3-[4-[bis(4-fluoropheny:')methyl3-1-piperidinyl~propoxyI benzoic acid or a pharmaceutically acceptable salt thereofq or propanamine or a pharmacetically acceptable salt thereof;~ or 444 N-methylbenzeneamine or a pharmaceutically a ccepit able salt thereof; or a 4* 0 176 l-[3-(J4-acetyl-2-methoxyphienoxy)propyll-a ,a-bis(14-fluoro- phenyl)-3-Piperidineacetonitrile or a pharmaceutically acceptable salt thereof;or 1-3(-ynpeoypoyluubs4furpey)3 piperidineacetonitrile or a pharmaceutically acceptable salt thereof ;or 4-3[-bs4furpellmehl--ieiiy~rpx] 3-methoxybenzonitrile or a pharmaceutically acceptable salt thereof;or ~4-[bis(4-fluorophenyl)nmethyll-l3-(l-laphthaleflyloxy) propyllpiperidine or a pharmaceutically acceptable salt thereof; or 4-fluorophenyl )methyl]-l-pipe'ridinyl~propoxyJ quirioline or a pharmaceutically acceptable salt thereof.; or 4-bs4furpey~ehlll[-2nptaeyoy propyl~piperidine or a pharmaceutically acceptable salt thereof or 3-E3-r'4-[bis (4-fluorophenyl)n:.,i-tyl)-1-piperidinyl~propoxyJ benzonitrile or a pharmaceutically acceptable salt thereot. *Ott 5. A method for treating angina by increasing 11, 1 coronary blood flow which comprises administering a compound selected from the group having the formula: 350 (A)d t *Z Q n IN-Cl 2 )m-(B)Z-D Whierein; 177 p is zero, one or two; O A is hydrogen, -0-R1, -CNR -C-R 1 -C-O-R, -CH2R', -CH2NR 1 R; O m is zero to six inclusive; OH Q is -CH 2 or d 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 x Y 3 or and in addition, R may have the values: X Y CH, cycloalkyl or loweralkyl and Z D may have additionally the values: 0 0 0 (CH2 0 -2 4 4 25 o oo 0*00 B040 or Ar(CHa) 1 4 -7 X, Y and Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 6 0. 0 *l O -NOa, -0-R -CF, -CN, -I-N(R -N(R1)2, -C(0)0R', So R' -SR -SR 2 -S(O)R 2 N--R -CH 2 CO0M, -SO2N"R, -NS0 2 CH 3 44 0 R 0 -NC-N" or -Nt-OR 2 R 4 t II ij--ii~ 178 o II I B is selected from O, S, and -N-C-O-R1 0 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 amino- carbonyl or a double bond forms between the a-carbon and a carbon of the central heterocyclic amine ring; R is selected from hydrogen, loweralkyl, phenyl and phenylloweralkyl; R 2 is selected from loweralkyl, phenyl and phenyllower- alkyl; M is a pharmaceutically acceptable metal ion, and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. F. The method of claim 5 wherein the compound is l-[4-[3-[4-[bis(4-fluorophenyl)methyl]-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereof; or i 0 4 4 r t. 0! 04 4 Sa I 11L 25 1-[4-[3-[4-[bis(4-fluorophenyl)methylene]-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereof; or 1-[3-methoxy-4-[3-[4-[phenyl[3-(trifluoromethyl)phenyl] methylene]-l-piperidinyl]propoxy]phenyl]ethanone or a pharmaceutically acceptable salt thereofi or l-[4-[3-4--(cyclohexylphen ethlene)-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereoffor l-[4-[3-r4-(cyclohexylphenylmethyl)-l-piperidinyl)propoxy]- 3-methoxyphenyl]ethanone or a pharmaceutically acceptable salt thereof or 179 l-E4-E3-.4-hydroxyphenylE-3-(trifluoromethyl)phenyl) rethyl)-l-piperidinyllpropoxy-3--methoxyphenyl~ethanoie or a pharmaceutically acceptable salt thereof;. or 4-(cyclohexylhydroxyphenylmethyl)-l-piperidinyl] propoxy)-3-methoxyphenyljethanone or a pharmaceutically acceptable salt thereof; or 1-[4-[2-[4~-[bis(4-fluorophenyl)methylJ-l-.piperidinylI ethoxy]-3-rnethoxyphenyljethanone or a pharmaceutically acceptable-salt thereof; or 1-4[-4[4furpey~peymty]lpprdnl propoxy)-3-methoxyphenyllethanone or a pharmaceutically acceptable salt thereof; or pentoxy)-3-mrethoxyphenyllethanone or a pharmaceutically acceptable salt thereof; or 1-[4-[3-[4-(diphenylmethylene)-l-piperidinyljpropoxy]- 3-rethoxyphenyllethanone or a pharmaceutically acceptable salt thereof; or 9 00 0 Co 0 04 0 0 0 1-[-[3-I4-(cyclohexy'Lphenymethyl)-l,2,3,6-tetrahydro- pyridin-1-yl~propoxy-3-inethoxy~phanyllethanone or a pharmaceutically acceptable salt thereof; or 1(2 ,3-dihydro-l, 4-benzodiox an-2-ylmethyl) -u,a-diphenyl- 4-piperidineacetonitrile or a pharmaceutically acceptable salt thereoff or o ~4# p 4 04 0*94 9 44 p. i -7 II r i i 180 1-[3-(4-acetyl--methoxyphenoxy)propyla(xdpenl4 piperidineacetonitrile or a pharmaceutically acceptable salt thereof or 1-[-(4-acetyl-2 -methoxT.enoxy )propyl)-cr ,a-diphenyl-3- piperidinepropanenitrile or a pharmaceutically acceptable salt thereof; or 1-[4-(-acetyl-2-methoxypenoxy)butyl] a,-diphenyl-3- piperidinepropanenitrile or a pharmaceutically acceptable salt thereof; or 1-[2-(2,6-dichorphenoxy)ethyl -aca..diphenyl-3- piperidinepropanenitrile or a pharmace-t ically acceptable salt thereof; or 1-[5-(4-acetyl-2-methxyphenoxy)pentdp l piperidinepropanen itrile or a pharmaceutically acceptable salt thereof. 7. 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: it I a 4 00 100~ 0$ 4 460*" 0P 4 44 0 o 5, 54$ I 40 40 4 (A )d Ar R, N-(CH2)m-(B)-D k/ 'yjp wherein; p is zero, one or two; 0 0 OA is hydrogen, -0-R NR'R -C-R -C--R -CHe-OR', -CH 2 NR 1 R 2 m is zero to six inclusive; 9H Q is -CH- or -Y H 181 d 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 or and in addition, R may have the values: CH,2, cycloal) yl or lowerallkyl, and D may have additionally the values: 0 Q 0 (CH 2 0 2 ~01 0 43 44 a 0 44 N ~or Ar(CH2) 1 4 X, y and~ Z are selected from the group consisting of hydrogen, loweralkyl, halogen, 0 -sck2, -$R 2 )R 2 -CH 2 COOM, -SORI)2 -CSO)CH 3 R' \R' B isAR, _Sectd rom, S, and N0R 1 0 R 0 is oneed r from wit the prois ta annot beCO- zero at the same time n is ~Zero when one of the following occurs at the same time that D is phenyl, or substituted 444~ 4 4 44 182 phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is amino- carbonyl, or a double bond forms between the a-carbon and a carbon of the central heterocyclic amine ring; R 1 is selected from hydrogen, loweralkyl, phenyl, and phenylloweralkyl; R is selected from loweralkyl, phenyl, and phenyl loweralkyl; M is a pharmaceutically acceptable metal ion, and the h pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. 8. The method of claim 7 wherein the compound is 1-[4-[3-[4-bis(4-florophenylmethylene-1-pipeidinyl propoxy])3-methoxyphenylethanone or a pharmaceutically acceptable salt thereof; or 1-4--4-(diphenylmethylene)-1-piperidinyl propoxy)- 3-methoxyphenylethanone or a pharmaceUitically acceptable salt thereof.

9. A method of decreasing gastric secretion and acid release in an animal which coprises administering a compound selected from the group having the formla: (A)d Ar wherein; 4 -r 30 p is zero, one or two; 0 A is hydrogen, -ON, -gNRR2, 0 1 CH 2 0R, -CH 2 NRlR 2 m is zero to six inclusive; Q is -CH 2 or r 44 35 H tt J 183 d and n are selected from zero or one and the dotted lines represent double bonds which may form consi,stent with the valence of carbon; Ar, D and R are selected from the group consisting of x y or and in addition, R may have the values: x y CH2, cycloalk~yl or loweralkyl and D may have additionally the values: 0 0 20 c:)0 (CH 2 0 2 2 0 0 O'0 0 Nor Ar(i) 1 4 X Y and Z are selected from the group consisting of hydrogen, 1l;,weralkyl, halogen, 0 0 -SC R 2, -SR 2 -s(o)R 2 CH 2 C00M, -S0N -NSO 2 CH3) jQ. ~2 00 R0 0 B is oelecteO from 0, S, nd -N-C-0-R' 0 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 lbi phenyl: (A)d is hydrogen, (A)d is cyano, (A)d is amino- carbonyl, or a double bond forms between the a-carbon and a carbon of the central heterocyclic amine ring; R 1 is selected from hydrogen, loweralkyl, phenyl, and phenylloweralkyl R 2 is selected from loweralkyl, phenyl, and phenyl- loweralkyl; M is a pharmaceutically acceptable metal ion, and the pharmaceutically acceptable salts thereof, including acid addition salts, quaternary salts, and hydrates and alcoholates thereof. The method of claim 9 wherein the compound is 4-[bis(4-fluorophenyl)methylene -1-piper idinylj propoxy -3-methoxyphenyl)ethanone or a pharmaceutically acceptable salt thereof: or l-4-3-[4-(diphenylmethylene)-l-piperidinyllpropoxyl3- methoxyphenyllethanone or a pharmaceutically acceptable salt thereof. 1 A1 F1 novel mpon ild ati-d interme dia teZmpun set forth herein or any novel method or method step set "fort the said compound, e 4ed-ser-s p-b e inbstrtilly--as-heren de DATED this 5th cday of September 1986. to a 444 4 4 4 4 A.H. ROBINS COMPANY, INCORPORATED 13y Its Patent Attorneys ARTHUR S. CAVE CO. 4 4 44 $44't 4 4 4.~