CA1067902A - 4-diphenylmethane-4-diphenylmethylene and 4-diphenylmethanol-piperidine derivatives - Google Patents

Abstract

Abstract of The Disclosure Compounds of the following general formula are useful as antihistamine agents antiallergy agnets and broncho-dilators:
wherein R represents hydrogen or hydroxy; R1 represents hydrogen; or R and R1 taken together form a second bond between the carbon atoms bearing R and R1; n is the integer 4 or 5; Y represents -?-, or

Description

~i7~32 Field of the Invention This invention relates to novel compounds and their use as antihistamine agents.
Background of th__Invention Compounds which may be represented by the following formula are described as antihistamine agents, antiallergy agents and bronchodilators in Belgian patents 794,595, 794,596, 794,597 and 794,598 whlch correspond respectively to U.S. Patents Nos.
3,806,526, issued April 23, 1974; 3,829,433, issued August 13, 1974; 3,878,217, issued April 15, 1975; and 3,862,173, issued January 21, 1975. ~ ~

~ R7 ~:

~NJ
. .

wherein R6 represents hydrogen or hydroxy; R7 represents hydrogen;
or R6 and R7 taken together form a second bond between the carbon atoms bearing R and R7; p is an integer of from 1 to 3; Y' O NOH OH :
represents -C-, -C-, or -CH-; Z' represents thienyl, phenyl or `;~ substituted phenyl wherein the substituent on the substituted phenyl may be attached at the ortho, meta, or para position of the phenyl ring and is selected from halogen, a straight or : branched lower alkyl chain of from l to 4 carbon atoms, a lower .
` alkoxy group of from 1 to 4 carbon atoms, di(lower)alkylamino, ., ~
~' `~ 30 ,.,!j; ~ ; r ~ ~:
'''''''''~ .
~ -2-~ . ,, '7~ 0 2 M-787 or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, morpholino or N-(lower)alkyl-piperazino; and pharmaceutically acceptable acid addition salts and individual optical isomers.
Additionally compounds of the above formula wherein O OH
t~ I
Y' is -~- or -CH- and Z' is naphthyl or substituted phenyl wherein the substituent on the substituted phenyl ... is straight or branched alkyl of 5 or 6 carbon atoms, alkoxy of 5 or 6 carbon atoms, or cycloalkyl or 3 to 6 carbon atoms attached at the ortho, meta, or para position of the phenyl ring are disclosed as antihistamine agents antiallergy agents and bronchodilators in U.S. Patent Nos. 3,941,795, issued March 2, 1976, and 3,931,197, issued January 6~ 1976. ~
The compounds of the present invention are distinguish- :
- able over the above-cited U.C. applications in that the. -;
alkylene chain between the piperidine ring and the func-tional group;as represented by Y in the compounds of the ~ .
present invention is longer, containing 4 or 5 carbon atoms, resulting in compounds with unexpected superior ..
: ~ utility.
`Summary oF Invention The nove;l~-substituted piperidine derivatives of this ¦
. ~ invention are useful as antihistamines, antiallergy`agents ~ -and:bronchodilators and are represented by.the fbrmula .

~. l t: ::

:~ . . ... .-.. . . .
.

: ~ :

~ ~ M-787 ~o~ao~

~\~
C R

Formula I

(CH2)n~~Y~Z
- wherein R represents hydrogen or hydroxy; R1 represents hydrogen; or R and R1 taken together form a second bond between the carbon atoms bearing R and R'; n is the ~ NOH ~H
integer 4 or 5; Y represents -C~ , or -CH-Z represents phenyl or a substituted phenyl ring wherein the substituent on the substituted phenyl ring is attached at the ortho, meta or para position of the phenyl ring and is selected from halogen, a straight or branched alkyl '~ -~'group of from~1~to 6 carbon atoms, an alkoxy group of from '' 1 to 6 carbon~atoms3~a cycloalkyl group of from 3~to 6 '; ;~
carbon atoms,~a di(~lower)alkylamino group~ or a saturated monocyclic h~eterocycli~c group se~ected from pyrrolidino~
piperidino7~morpholino, or N-(lower)alkylpiperazino.~'~
Pharmaceutically acceptable~acid addition salts and individual`'~o'ptical isomers of eompounds of Formula I
. :~ - ~ , ~ are also inçluded in the scope of this invention. ~' :: , : , - ~
Detail~ed Description of Invention Compounds of this inv~ention are 4-substituted-'~ 20 ~ ~ piperidi~noalka~none derivatives, ~-substituted-piperi-dinoalkanone oxime~derivatives, or 4-substituted piperi-dinoalkanol~ derivatives as further represented by the ' ` ~4-.: ." .,. .., ,..: ,.. ,,, ,,. ,,:. ~ , ....

~ C M-787 1~7 90 ~Z

following repsective Formulas 11 to IV.

C - R
,~
Formula 11 . . ' C - R

Formula 111 N NOH
(cH2)n--C--Z , .':

'; ' ' R1 Formula IV .- -N J . OH ;
(CH2)n -CH -Z

I:n ~he above~Formulas i~l to IV the substituent groups as represenèed~by R, R~ n~and Z have;the meanings defTned in~Formul~a ~
The~substituent;on the substituted phenyl ring as represented:by~Z in~Formulas 1 to IV may be attahced at ` -IC ~' be or~ho, meta,~or p-r- positiol of the phenyl ring ~nd ~ ~

, \ ~ M-787 ~06790Z

is selected from halogen, for example, chlorine, fluorine, bromine, iodine, preferably chlorine or fluorine; a straight or branched alkyl group of from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, and _-hexyl; an alkoxy grou~ of from 1 to 6 carbon atomsJ for example, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexyToxy; a cycloalkyl group of from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; di(lower)alkylamino wherein the (lower)-alkyl contains from 1 to 4 carbon atoms and may be straight or branched, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl; or a saturated monocyclic heterocyclic group such as pyrrolidino, piperidino, mor-pholino or N-(lower)alkylpiperazino wherein the (lower)-alkyl group contains from 1 to 4 carbon atoms and may be ¦~
straight or branched, for example, methyl, ethyl, n-propyl, t isopropyl, n-buty.l~ isobùtyl, and tert-butyl. -:
Preferred compounds of this invention are those , 1~ qH
wherein Y is -C- or -CH- and of these compounds those wherein R~is hydroxy~or R and R1 taken together f~orm a second~bond between the carbon atoms bearing R and R1 are more preferred.
-This invention also includes the pharmaceutically acceptable~acid addition salts of the compounds o.f the ,.
hereinbefore~set~ forth formulas, optical isomers and ~`
salts thereof.: Pharmaceutically acceptable acid addition 'E
salts of the compounds of this invention are those of ."~
any suitable inorganic or organic acid. Illustrative ~ I .

~ :
~ , , .

( ( M-787 ~ 9 ~'~

examples of suitable inorganic acids are hydrochloric, hydrobromic, sulphuric, and phosphoric acids Illustra-tive examples of suitable organic acids include carboxylic ! :
acids, such as, acetic~ propionic, glycolic, lactic, pyruvic, malonic, succinicJ fumaric, malic, tartaric, citric, ascorbic, maleicJ hydroxymaleic, and dihydroxy-maleic, benzoic, phenylacetîc, 4-aminobenzoic, 4-hydroxy- .
benzoic, anthrani.lic, cinnamic, salicylic, 4-aminosalicylic, ~ :
. 2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid;
10 ~ and sulfonic acids, such as, methanesulfonic, ethanesulfonic, and ~-hydroxyethanesulfonic acid. .. ..
Iliustrative examples of compounds of this invention are 4-(~ diphenylmethyl)-a-(p-N-methylpiperazinophenyl)-1-piperidinehexanol, 4~ .-diphenylmethylene)-~-(p-cyclo- ~ -butylphenyl)-1-piperidinepentanol, 4-(~-hydroxy-~-phenyl- .~ .
benzyl)-a-(p-ethoxyphenyl)-1-piperidinepentanol, 4-(~
diphenylmethyl)-a-(p-chlorophenyl)-1-piperidinehexanol, -5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]-4'-bromovalero- ::
phenone, 6-[4~ hydroxy-~-phenylbenzyl)piperidino]capro- ~:.
phenone, 5-[4-(~,~-diphenylmethyl)piperidino]-4'-morpho-linovalerophenone, 4'-dimethylamino-6-[4~ -diphenyl-methylene)piperidino3caprophenone, 6-[4-(~,~-diphenyl- . .
me~hyl)piperidino]caprophenone oximeJ 5-[4-(a,~-diphenyl- :
- methylene)pi:peridino]-4'-isopropylvalerophenone oxime, 4'-ethyl-6-[4~ hydroxy-a-phenylbenzyl)piperidino]capro- . .
:: .. phenone, 6-[4~ hydroxy-a-phenylbenzyl)piperidino~-4'-~: ~ neopentylcaprophenone, 5-[4-(~,~-diphenylmethyl)piperidino]-: 4'-hexyloxyvalerophenone, and 5-[4-(~-hydroxy~ phenyl- :.
: benzyl)piperidino]-4'-piperidinovalerophenone.
o ~ The novel compounds of this invention are useful as ( ~ M-787 ~ ~ ~ 9 ~ Z

antihistamines, antiallergy agents and ~ronchodilators~
and are further characterized by minimal central nervous system stimulant and depressant effects which are commonly found in commerclal antihistamines. The compounds may be administered alone or with suitable pharmaceutical carriers to warm blooded animals, mammals such as felines, canines, porcine, bovine, equine, and humans and can be in solid or liquid form such as, for example tablets, capsules, powders, solutions, suspensions, or emulsions.
10 ` The compounds of this invention can be administered orally, parenterally, for example, subcutaneously~ intra-venously/ intramuscularly, intraperitoneally, by intra-nasal instillation or by application to mucous membranes such as that of the noseJ throat, and bronchial tubes, for example, in an aerosol spray containing small particles of a compound of this invention in a spray or dry powder fo,mc The quantity of novel compounds administered will vary. Depending on the patient and the mode of adminis-tration, the quantity of novel compound administered may vary over a wide range to provide in a unit dosage of from about 0.01 to 15 milligrams per kilogram of body I weight of the patient per dose to achieve the desired effect.- For example the desired antihistamine, anti- ¦
allergy and bronchodilator effects can be obtained by consumption of a unit dosage form such as, for example, a tablet containing 1 to 40 mllligrams of a novel com-pound of this invention taken 1 to 4 times daily.
The solid unit dosage forms can be of the conven-tional type. Thus, the solid form can be a capsule which .

( ( M-787 ~06~790JZ

can be of the ordinary gelatin type containing a novel com-pound of this invention and a carrier, for example, lubri-cant and inert fillers such as lactose, sucrose, corn starch, and the like. In another embodiment, the novel compounds are tabletted with conventional tablet bases such as lactose, sucrose, corn starch, and the like in combination with binders such as acacia, corn starch or gelatin, disintegrating agents such as corn starch, ?
po~ato starch, or alginic acid, and a lubricant such as io stearic acid, or magnesium stearate.
The novel compounds may also be administered as injectable dosages by solution or suspension of the com-pounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and/or oils~ with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
Illustrative of oils there can be mentioned those of petro-leum~ animal, vegetable or synthetic origin, for exam~le, peanut oil, soybean oil, mineral oil~ and the iike. Water, saline, aqueous dextrose, and related sugar solutions, ethano~s and glycols such as propylene glycol or poly-ethylene glycol are illustrative of liquid carriers for injec~table solutions.
For use as aerosols the novel compounds in solution - or suspension may be pac~aged in a pressurized aerosol container together with a gaseous or liquified propellant, for example~ dichlorodifluoromethane, dichlorodifluoro-methane with dichlorodifluoroethane, carbon dioxide, nitrogen~ propane, etc. with the usual adjuvants such as co-solvents~ and wetting agents~ as may be necessary or .
: ~; , 9 : . -~ ( M-787 16)6'7g(~

desirable. The compounds may also be administered in a non-pressurized form such as in a nebulizer or atomi7er.
The compounds of this invention possess unexpected superior utility as antihistamine agents compared to the corresponding lower homologs. To illustrate the utility of the compounds of this invention the following tabula-tion indicates the amount of certain representative co~-pounds of this invention required to reduce by 50% wheals ; induoed by intradermal injections of ly of histamine into guinea pigs as compared to the direct lower homolog.
Each compound was orally administered one hour prior to the histamine injection.
Compound_ of invention~ÇL~9 4'-fluoro-5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]-valerophenone hydrochloride0.8 5-[4~ hydroxy-a-phenyl-benzyl)piperidino]valero-~ phenone hydrochloride 0.7 Lower hom~loqs 4'-fluoro-4-~4~ hydroxy-a-phenylbenzyl)piperidino]-~butyrophenone hydrochloride 3.5 4-[4-(~-hydroxy-~-phenylbenzyl)-piperidino]butyrophenone hydro-chloride ~ ~ 6.1 The compounds of this invention may be prepared by ~several methods, and~some of the compounds of this inven-. ~ -10-~ . . . .
~ ., , . : .
: ~" .. ' ~
~ .

( ~ M-787 ~ 0~7 g ~ Z
tion are used to prepare other compounds of the invention as will be apparent from the following.
O .:
The compounds of Formula I wherein Y represents -C~
may be prepared by reacting a 4~substituted piperidine, compound 1, with an w-haloalkyl aryl ketone, compound 2, as indicated by the following:

~C~ + halo-(CH~In~~~Z~ ~C~

2 ~ 0 . H (CH2)n~e-Z
1 Formula ll In the above reaction halo represents a reactive halogen - atom, and R, R1, n, and Z have the meanings defined in general Formula I
. ~. . .
. ~he above reaction is carried out in alcoholic sol-vents, such as, methanol, ethanol, isopropyl alcohol, and n-butanol; in ketone solvents, such as, butanone, and . . . . .: , methyl isobutyl ketone; in hydrocarbon solvents such as :
, ~
benzene and toluene; or in halogenated hydrocarbons, such :as, chlorobenzene; in the presence of an inorganic base , such as sodium bicarbonate or potassium carbonate, or in the presence of an organic base such as triethylamine, or an excess of compound 1. In some cases it may be desirable ~:
to add catalytic amounts of potassium iodide to the re^ .:
action mixture. The reaction time is usually about 48 ~: . . hours, but may vary from about 4 to 175 hours at a ~ :
. :::
- 11 -' ' .
': ~
' ' . .

( M-787 79~2 temperature of from about 70~C to the reflux temperature of the solvent.
The w-haloalkyl aryl ketone derivatives, compound 2, may be prepared by reacting the appropriate w-halo-alkanoyl halide and an aromatic compound in thé presence of aluminum chloride. They may also be prepared by reacting a substituted phenyl Grignard reagent with an w-haloalkanonitrile, followed by the usual work up. I -; The 4-diphenylmethylpiperidine and ~,~-diphenyl-4-piperidinemethanol starting materials as represented by compound 1 wherein R is hydrogen or hydroxy~ and R1 is hydrogen are commercially available, 4-Diphenylmethylene-piperidine as represented by compound 1 wherein R and R1 form a second bond between the carbon atoms bearing R and R1 may be prepared by dehydration of ~ diphenyl-4-piperi-dinemethanol by generally known procedures. i O ~ .
The compounds of Formula I wherein Y represents -~may also be prepared by the reaction of an appropriately 4-substituted 1-piperidinealkanonitrile with an organo-metallic compound such as an aryl Grignard or an aryl-lithium compound in a solvent such as diethyl ether or tetrahydrofuran-followed~by isolation and purification ~l of the aryl 4-substituted piperidinoalkyl ketone deriva- ¦
, . 1 ' tive by generally known procedures. The nitrile deriva- , tive is obta~ined by the reaction of an appropriately sub-~sti~tuted piperidine compound with a haloalkylnitrile.
The compounds of Formula I wherein Y represents ~-O
-C- and Z represents a substituted phenyl wherein the .
: 1 `- ' I ''' ' , ( ( M-787 ~ ~'79 ~ Z

substituent on the substituted phenyl is selected from a di(lower)alkylamino group or a saturated monocyclic heterocyclic group and is attached at the ortho or para position of the phenyl ring may also be prepared from ..
the corresponding halogen substituted phenyl derivative, preferably a fluoro derivative, using an excess of the dialkylamine or the heterocyclic amine. When volatile .
amines are employed the amine may be bubbled through a ~ .....
solution of the halogen substituted phenyl derivative in 10` dimethylsulfoxide at about 100C for about 4 to 8 hours.
When higher boiling amines are employed such as, for ,~-exampleg piperidine, excess amounts of the amine are used as base, reactant, and solvent for the reaction which ts carried out at the reflux temperature of the amine for ~ -about 4 to 24 hours.
The compounds of general Formula I wherein Y represents NOH
-C- may be prepared by the addition of a hydroxyl.amine salt . .
to the corresponding aryl 4-substituted-piperidinoalkyl ketone, that is, oompounds of general Formula I wherein 0 - . ~:' Y represents:--C- as;represented by the following; : -C R NH2OH X ~ R ~ -~RI ~R I .

O NOH .:
( CH2 ) n-~ -Z ( IH2 ) n C _Z
Formula 1I Formula 111 ;.. -.

~` - 3 . .
::

: ~ , ( ~ M-787 ~C~679C~

In the above reac~ion R, Rl, n and Z have the meanings define~ in general Formula I, and NH20H X represents an acid addition salt of hydroxylamine.
. The above reaction may be carried out in lower alco-~ holic solvents or water, or a combination of a lower al-coholic solvent and water in the presence of a mineral base such as sodium hydroxide, potassium hydroxide, or sodium acetate, or an organie base such as pyridine. The . reaction time varies from about 1 to 8 hours, and the 10~ reaction temperature varies up to 100C. Depending on the amount of base used, the strength of the base used and/or .
the method employed to isolate the product as represented by Formula III, the product is obtained as the free base or the acid addition salt as is exemplified in the specific ~.
examples.
- The compounds of general Formula I wherein Y represents .:
OH
, . . .
-CH- may be prepared by redueing the corresponding aryl ..
4-substituted-piperidinoalkyl ketone, tha~ is, compounds : :
: - l '~
of general Formula I wherein Y represents -C- as illustrated below~
- . ' -:, . ' - R Redu-ct ~n~ C ~ R
R~ ~ Rl ~

~: (CHz)n- -Z (CHz)n~CH -Z .: .

: Formula II ~Formula IV

: ' - 1 ~ - . . ' , . .

~ ( M-787 - ~06~7~0~

In the above reaction RJ R~, n and Z have the meanings defined in general Formula 1.
Preferred reducing agents such as sod hlm borohydride '' may be employed in the above reaction using a lower alco-hol solvent such as methanol, isopropyl alcohol, and tert-butanol. The reaction is carried out at temperatures ranging from about 0~ to the reflux temperature of the solvent, and the reaction time varies from about 0.5 to about 8 hours. Other hydrides as reducing agents such 1'0` ' as lith'ium aluminum hydride and diborane may also be ' used in an appropriate solvent such as diethyl ether.
This reaction may also be achieved by catalytic reduc-tion using Raney nickel, palladium, platinum or rhodium cat-alysts in lower alcohol solvents, acetic acid, or their ' aqueous mixtures~ or by aluminum isopropoxide in isopropanol. '-The aryl 4-substituted-piperidinoalkyl ketone deriva- ' tives as represented by Formula ll in the above two reactions may be prepared by methods described hereinbefore.
The optical isomers of the compounds of this inven-tion may be separated by using a (+) or (-) binaphthyl-phosphoric acid derivative or a salt of said derivative ' ' - ~ , .
and an assymetric base by the method described by R. Viterbo-et~al., in Tetrahedron Letters No. 48, - pp. 4617-4620 (1~71). ' 4'-tert-Butyl-5-[4-(~-hydroxy -phenylbenzyl)piperidino]- "
valerophenone hydrochloride _........................................... : .
A mixture of 32.0 g (0~.12 mole) of ~J~-diphenyl-4~
piperidinemethanol, 38.0 9 (0.15 mole) of 4'-tert-butyl-5-chiorovalerophenone, 27.8 9 (0.2 mole) of potassium bicar-15- "
''' ' , ( M-787 ~ ~67~ ~ Z

bonate, and 200 mg of potassium iodide in about 500 ml of toluene i 5 stirred and refluxed for 142 hours then filtered while hot. About 50 ml of ether is added to the filtrate which is then made acidic using ethereal HCl. The result-ing precipitate is recrystallized from methanol-butanone to give 4'-tert-butyl-5-~4-(~-hydroxy-~-phenylbenzyl)-piperidino]va1erophenone hydrochloride, M~P 209.5-211C.
EXAMP_E 2 4'-Fluoro S-r4-(~-hydroxy-~-phenylbenzyl)pieeridin 10` valerophenone hydrochloride A mixture of 19.~ g (0.07 mole) of ~,~-diphenyl-4- ~ -piperidinemethanol~ 17.1 9 (0.08 mole) of 5-chloro-4'-fluorovalerophenone, 20.0 g (0.2 mole) of potassium bicar- ~ -bonate) and 0.1 9 of potassium iodide in 250 ml of toluene and 35 ml of water is stirred on a s~eam bath for 70 hours.`
The organic layer is separated and combined with two 50 ml toluene extracts of the aqueous layer. The combined organic material is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate is diluted with about 20~ ml of ether then made acidic with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 4'-fluoro-5-~4~ hydroxy-~-phenylbenzyl)piperidino]- -valerophenone hydrochloride~ M.P. 177-179C.
EXAMPLE ~_ .
5-~4-(~-Hydroxy-~-phenYlbenzYl)piperidinol-4'-methoxy-valerophenone hydrochloride A mixture of 41.5 9 (0.15 mole) of ~ diphenyl-4-piperidinemethanol~ 38.6 9 (0.17 mole) of 5-chloro-4'-methoxyvalerophenone, 30 9 of potassium bicarbonate, and -16-.
~" ~

.

1~679~)2 0.19 9 of potassium iodide in 500 ml of toluene and 70 ml of water is stirred and refluxed for 136 hours.
The organic layer is separated and combined with toluene extracts of the aqueous layer. The combined organic materia1 is washed with water and saturated sodium chlo-ride solution, dried over mag~esium sulfate and filtered.
The filtrate is diluted with ether and made acidic with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 5-[4~ hydroxy-~-phenyl-10` benzyl)piperidino]-4'-methoxyvalerophenone hydrochloride, M.P. 211-213C.
EXAMPLE_4 5-[4-~-Hvdroq~ 9 ~sL~lben ~ nolvalerophenone hydrochlo de A mixture of 27.6 g (0.1 mole) of ~,a-diphenyl-4-- piperidinemethanol, 21.~ g (o.ll mole) of 5-chlorovalero-phenone, 20 9 of potassium bicarbonate, and 0.1 9 of potassium iodide in 300 ml of toluene and 25 ml of water - is stirred and refluxed for 1~6 hours then worked up by -20 the procedure described in Examples 2 and 3 to give 5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]valerophenone hydro-chloride~ M o P ~ 162-164~C.
- : ,:

4'-tert-Butyl-6-[4~ hydroxy-~-pheny1ben~yl)piperidino]-caprophenone hydrochloride A~ mixture of 22.4 9 (O.Oô mole) of ~ diphenyl-4- -piperidinemethanol, 23.8 9 (0.09 mole) of 4'-tert-butyl-~6-chloroc~aprophenone, 20 9 (0.2 mole) of potassium bicar-~- bonate, 0.1 9 of potassium iodide in ~00 ml of ~oluene ~and 45 ml of water is stirred on a steam bath for about ~; ~ 17 .
~ .~ ; . ~ .
- : : ' . ' ~ . " :' \ ~ M-787 79~)2 96 hours after which the organic layer is separated and combined with toluene extracts of the aqueous layer.
The combined organic material is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate is diluted with ether and made acidic with ethereal HCl. The resulting precipi-tate is recrystallized from methanol-butanone to give 4'-tert-butyl-6-[4~ hydroxy-~-phenylbenzyl)piperidino]-caprophenone hydrochloride.

4'-tert-Butyl-6-[4~ diphenylmethylene)piperidinoJ-caprophenone hydrochloride A mixture of 20.0 9 (o.o8 mole) of 4-(~,~-diphenyl-methylene)piperidine, 23.8 g (0.09 mole) of 4'-tert-butyl-6-ehlorocaprophenone, 20 9 of potassium carbonate, and 0.1 9 of potassium iodide in ~00 ml of toluene and 45 ml of water is stirred vn a steam bath for about 96 hours and worked up by the procedure described in Example 5 to give 4'-tert- -butyl-6-[4~ diphenylmethylene)piperidino]caprophenone hydrochloride.

6-~4-(-Hydroxy-~-phenylbenzyl)piperidinol-4'-methoxy-caprophenone hydrochloride ~.
A mixture of 27.6 9 (0.1 mole) of ~ diphqnyl-4-.
piperidinemethanol~ 26.5 9 (:0.11 mole) of 6-chloro-4'-;methoxycaprophenone, 20 9 of potassium bicarbonate~ and 0.1 9 of potassium iodide in 300 ml of toluene and 45 ml of water is stirred on a steam bath for about 82 hours then worked~up by the procedure described in Example 5 ~; 30 to g~ive 6-[4-(~-hydroxy-~-phenylbenzyl)piperidinol-4 ,. . . :, ~ ( M-787 ~6~79~ 1 methoxycaprophenone hydrochloride.

When in the procedure of Example 2 appropriate amounts of the 4-substituted piperidine and haloalkyl aryl ketone each listed below are substi~uted respectively for ~ diphenyl-4-piperidinemethanol and s-chloro-4'- ~ :
fluorovalerophenone, the respective products listed below ~ :
are obtained.

;, ::

' ..

.

':

.
1 9 ~
., , , : .
~: ' ' , .... . .
:

.
~067~z a) o . . c c ~ ~ o Q Q -- O
c.~ a.) C -- o ~ ~
Q O1) ~ I`J Q
._ c -- ~ I ~ ~ r~, Q O cL c) c _ c .~ ~ .Q O
Q) _ C ~ > -- ~
r >~ O
c Q c ' I O C
v o v Q ~ r a) --~ L ~ ~ ._ ._ ,c ~ L
E O E ~-) I ~ ~ Q O O
v ~ ) I Q _ >~ X -c > c O o ~ Q ~
O -- O ~ c Q O >~ I O
O ~ -C ~ ~ 'E ~ O
-- ~ ~-- Q ~ ~--~ U
-- ~ 1 -- a) o ~ ~ c E ` I ~ ~ >- O -0ti I O ~ ~ C r r ~.~ c ~ C
E -C -- ~ - c ~ O l ~ O ~ O
:~. O L ~ O ~ 11 0 3` ~U C
~ ~ C ~ ~ C ~ I E O ~ Q a~
._ ~ I ._ ~ _ _ r I .-- c l ~ _C ~ ~ _C ~ ~ O ~O Q Q

- . , c~ ' .
O
~ O
c O ~ l Q ~ O Q
o O
c O O ~ E O
v _ ~
X _ ._ v > O ~ ~
_ v _c ._ _ ~
~ v Q E Q
a~ , ._ ._ :
~ , , ~ ~ .:
v ~ =~
_ cl: O O O O O
c o o c o a~ o ~
o _ r _ O
r c r ~ c c au ~ o Q ~ O Q
, .
a~ a Q) ~
c ._ ._ . ._ ~
~._ ._ ,. .
._ ~ ~ ..
Q.Q .Q ", ~ :
._ Q c Q ~
L ;.
c c ~ ~ ::

3 ~ a) a) Q
~ E E E Q - ..
._ _ _ _ .
o s c ~ ::
-- -- -- c a.~ ' ; ' _ ,c _ .::
rJ Q O `: :
B da) i ~ :
_, Q d ~
d E 1~::
~`;~' : ' .

( M-787 ~LQ1679~

~-(p-tert-Butylphenyl)-4-(~-hydroxy-c-phenylbenzyl)-1-- piperidinepentanol (A) To 62.3 9 (0.12 mole) of 4'-tert-butyl-5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]valerophenone hydro-chloride dissolved in about 1200 ml of methanol is added methanolic potassium hydroxide until the solution is basic. The solution is cooled in an ice bath with stirring and 5 9 (0 13 mole) of sodium borohydride is added por-tionwise. The mixture is stirred an additional half hour, allowed to warm to room temperature then heated on a steam bath for half an hour. The solven~ is removed at reduced pressure and the remaining residue is washed with water and recrystall;zed from acetone to give ~-(p-tert-butylphenyl)-4~ hydroxy-~-phenylbenzyl)-1-piperidine-pentanol.
(B) The title carpound may also be prepared by reducing the corrPsponding valerophenone derivative dissolved in methanol at 2 atmospheres of hydrogen pressure In the presence of rhodium on charcoal catalyst for about 3 hours.
Following the reduction reaction the catalyst is removed by filtration, and the remaining material is concentrated to a solid which is purified by recrystallization to give ~-(p-tert-butylphenyl)-4-(~-hydroxy-~-pheny1benzyl)~
piperidinepentanol as the hydrochloride.

When in the procedure of Example 9 an appropriate amount of the compounds of Examples 2 through 8 is respectively substituted for 4'-tert-butyl-5-~4-(~-hydroxy-~-phenylbenzyl)piperidino]valerophenone hydrochloride, -21~
:
. .,,',.

the following compounds are obtained.
-(~-fluorophenyl3-4-~-hydroxy-~-phenylbenzyl)-1-piperi~
dinepentanol, : -(p-anisyl)-4~ hydroxy-~-phenylbenzyl)-1-piperidine-pentanol,

4-(c-hydroxy-~-phenylbenzyl)-:L-piperidinepentanol~
~-(p tert-buty1phenyl)-4-(~-hydroxy--phenylbenzyl)-1-piperidinehexanol, ; ~-(p-tert-butylphenyl)-4-(~-diphenylmethylene)-1-piperi-10` - dinehexanolg ~-(p-anisyl)-4-(~-hydroxy--phenylbenzyl)-1-piperidine-hexanol~ .
4-(,~-diphenylmethyl)-c-(p-tolyl)-1-piperidinepentanol, 4-(~-diphenylmethyl)~-(p-n-pentoxyphenyl)-1-piperi-dinehexanol, ~-(p-dimethylaminophenyl)-~ -diphenylmethylene)-1-piperidinepentanol, and 4-(~-hydroxy--phe-nylbenzyl)-~-(p-piperidinophenyl)-1-piperidinehexanol.
. . . EXAMPLE 11 4' tert-Butyl-5-[4-(~-:hydroxy-~-phenylbenzyl)piper_dino]- :
valeroPhenone oxime h~roch~oride A mixture of 15 9 (0.028 mole) of 4'-tert-butyl-5- 3,~ ;
`. [4-(-hydroxy--phenylbenzyl)piperidino]valerophenone ~ .
hydrochloridé and 15 g of hydroxylamine hydrochloride in : 120 ml ctf pyridine in heated on a steam bath for about 5 hours after which the pyridine is removed at reduced 3 pressure. The remaining residue is dissolved i.n methanol :
and added to excess iced 10% H~l. The resulting solid ~, ;
~ is filtered, washed with water, and recrystallized from ~ ~ :
-22- :
.
~ , ."

~ ( M-787 ~lt6'~9~

isopropyl alcohol to give 4'-tert-bu~yl-5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]valerophenone oxime hydrochlo-ride.

4'-Fluoro-5-~4-(~-hydroxy~ henylbenzyl~eiperid-n val_rophenone oxime - A mixture of 15 9 (0.033 mol~) of 4'-fluoro-5-~4-(~-- hydroxy-~-phenylbenzyl)piperidino]valerophenone hydro-chloride and 15 9 of hydroxylamine hydrochloride in 120 ml 10 ` of pyridine is stirred on a steam bath for about 4 hours . then cooled to room temperature. The pyridine is removed at reduced pressure on a steam bath, and the residue is triturated with a dilute sodium hydroxide solution and extracted with chloroform. The chloroform extract is washed with water, dried over magnesium sulfate, fil-; tered and concentrated to a residue which is trituratedwith hexane. The resulting solid is filtered off and re-crystallized from ethanol to give 4'-fluoro-5-[.4-(~-.
hydroxy-~-phenylbenzyl)piperidino]valerophenone oxime.
~ ~ L~
: When in the procedure of Example 11 an appropriate amount of~the compounds of Examples 3 to 8 is respectively :~ substituted for 4'-tert-butyl-5 ~4-(~-hydroxy-~-phenyl-. benzyl)piperidino]valerophenone hydrochloride~ the following compounds are ~btained: ~-

5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]-4'-methoxy-~: : valerophenone oxime hydrochloride, -5-[4~(~-hydroxy-~-phenylbenzyl)piperidino]valerophenone oxime hydrochlorideg ~
0 4'-tert-butyl-6~-[4-(~-hydroxy-~-phenylbenzyl)piperidino]- `.
~: -23-- ~
' ,' ~ ( M-787 ~6'~9t~2 caprophenone oxime hydrochloride, 4'-tert-butyl-6-[4~ .-diphenylmethylene)piperidino]-caprophenone oxime hydrochloride,

6-[4-(~-hydroxy-~-phenylbenzyl)piperidino]-4'-methoxy-caprophenone oxime hydrochloride, 5-[4-(~,a-diphenylmethyl)piperidino]-4'~methylv31ero-phenone oxime hydrochloride, 6-[4~ c-diphenylmethyl)piperidino]-4'-n-penoxy-caprophenone oxime hydrochloride, I
4'-dimethylamino-5-[4-(~ diphenylmethylene)piperidino]-valerophenone oxime dihydrochloride, and 6-[4-(~-hydroxy-c-phenylbenzyl)piperidino]-4'-piperidino- :~ :
caprophenone oxime dihydrochloride. ~: .
EXAMPLE 14 :
. .
4'-Cyclopentyl-6-[4-(~ diphenYlmethy.lene)piperidi-n - caprophenone hydrochloride When ~n the procedure of Example 2 appropriate amounts : ;
of 4-(~ diphenylmethylene)piperidine and 6-chloro-4'-cyclopentylcaprophenone are substituted resepctively for ~ -diphenyl-4-piperidinemethanol and 5-chloro-4'-fluoro- .. . . ;
valerophenone, 4'-cyclopentyl-6-[4-(~ -diphenylmethylene)-piperidino]caprophenone hydrochloride is obtained~

~-(p-Cyclopentylphenyl)-4-(~,~-diphenylmethylene)-1-piperidinehexanol '~
When in the procedure of Example g (A) an appropriate ~ ::
amount of 4' cyclopentyl-6-[4-(~ diphenylmethylene)- `:.~
~ - .. . ..
piperidino]caprophenone hydrochloride is substituted for . 4'-tert-butyl-5-[4~ hydroxy-~-phenylbenzyl)piperidino]- - .
3 valerophenone hydrochloride, ~ -cyclopentylphenyl)-4- .

: -24- . . . :
`''i' . '"' :'' ""
, :,. .. .
~` . ....
' "' ': ' ' ' ~' ' ' ~

3 ~ ~

diphenylmethylene)-1-piperidinehexanol is obtained.

5-~4~ ydroxy-~-phenylbenzyl~piperidinol-4'-piperidino-valerophenone A mixture of 15.6 g (0.035 mole) of 4'-fluoro-5-[4-(~-hydroxy-~-phenylbenzyl)pip~ridino]valerophenone, the - free base of the compound of Example 2~ and a small amount of potassium iodide in 100 ml of piperidine is refluxed for about 22 hours. The unreacted piperidine is removed under vacuum, and the remaining residue is triturated with water. The water is decanted and the residue is dissolved in methanol and then added to a large amount ; of water. The resulting precipitate is dissolved in a large volume of ether, dried over magnesium sulfate, and filtered. The filtrate is concentrated and -~
cooled yielding a product which is recrystallized from ether to give 5-[4-(~-hydroxy-~-phenylbenzyl)piperi-dino]-4'-piperidinovalerophenone.
EXAMPLE 1l An illustrative composition for hard gelatin capsules is as follows: -(a) 4'-tert-butyl-5-[4~ hydroxy-- ~-phenylbenzyl)piperidino]-- valerophenone hydrochloride 10 mg (b) talc 5 mg ~(c) lactose 100 mg The formulation is prepared by passing the dry powders of (a) to (c) through a fine mesh screen and mixing them ., well. The powder is then filled into hard gelatin capsules 3o at a net fill of 115 mg per capsule.
:: , ''.~ -25- ~?
~ !

( ( M-787 _,~
106~902 _ An illustrative composition for a tablet is as follows:
(a) ~-(P-tert-butylphenyl)-4~
hydroxy-~-phenylbenzyl)-L-piperidinepentanol 5 mg (b) starch 43 mg (c) lactose 60 mg (d) magnesium stearate 2 mg The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried~ screened, and mixed with the magne-sium steara~e. The mixture is compressed into tablets weighing 110 mg each.

An illustrative composition for an aerosol solution ~
is the following: -~ ~ e~ .: .' (a) 4'~tert-butyl-5-[4-(~ .
hydroxy-~-phenylbenzyl)-..
piperidino]valerophenone oxime hydrochloride 5~o (b) ethanol~ ~ 35.0 (c) dichlorodifluoromethane 60.0 The materials (a), (b) and (c) are packaged in 15 ml ,; . .. .
stai~nless steel containers equipped with a metering valve ~ `-designed to meter~0.2 gram per dose, an equivalent of 10 mg of~noYel compound (a).
: ~ ~ : . ,.

-~;- : : ' ' : ,~.. ,.,"
~ ~ -26- ;
.
: ' '."".
.
.
.

C ~ M-787 10~ 0~

An illustrative composition for an aerosol suspen-sion is the fol lowing:
We i qht per cent (a) 4'-fluoro-5-[4-(~-hydroxy-~-phenylbenzyl)piperidino]-valerophenone hydrochloride (particle size <10~) 20.0 . (b) sorbitan trioleate 0.5 (c) dichlorodifluoromethane ~9.75 (d) diehlorodifluoroethane 39.75 The materials (a) to (d) are packaged in 15 ml stainless steel containers equipped with a metering valve designed - .
to meter 50 mg per dose, an equivalent of lO mg of novel compound .(a).
EXAMPLE 21 l - -An illustrative composition for an injectable sus-- pension is the following 1 ml ampul for an intramuscular ¦.
. ` injection.
Weiqht per cent .
~ ~ (a) 5-[4-(~-hydroxy-~-phenyl- :~
: : ~ benzyl)piperldino]valero- : ~
phenone hydrochloride ~ .
(particle size <10~) 1.0 (b) po~iyvinyl ~pyrrolidone (M.W. 25000~) ~ o.5 (c~): lecithin : ~ 0.25 (d)~wat:er:for injec:tion~to make 100.0 ~ The~materials (a) to (d):are mixed~ homogenized~ and filled -~ 30 ~ into~ ml ampuls which~are sea:led and autoclaved 20 minutes ~: ~ :: :

1O~r7 9 ~)Z M - 7 87 at 121C. Each ampul contains 10 mg per ml of novel compo-nd ( a ) .

~ ' '' : ., . .
, .. . . . .

.

: , ~ ~ , :; ~ !` :

28- . :
~;: ` , .
:: .'. :'

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound selected from a base of the formula:

wherein R is selected from hydrogen or hydroxy; R1 is hydrogen;
or R and R1 taken together form a second bond between the carbon atoms bearing R and R1; n is the integer 4 or 5; Y is , Z
is selected from phenyl or a substituted phenyl ring wherein the substituent of the substituted phenyl ring is attached at the ortho, meta or para positions of the phenyl ring and is selected from halogen, a straight or banched alkyl group of from 1 to 6 carbon atoms, an alkoxy group of from 1 to 6 carbon atoms, a cycloalkyl group of from 3 to 6 carbon atoms, a di(lower) alkylamino group, or a saturated monocyclic heterocyclic group selected from pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino;
which comprises reacting in a suitable solvent an aryl 4-substituted piperidino alkyl ketone of the formula wherein R, R1, n and Z have the meanings defined hereinabove, with a ketone reducing agent for from 0.5 to 8 hours at a temp-erature of from 0°C to the reflux temperature of the solvent.

2. A compound selected from a base of the formula:

wherein R is selected from hydrogen or hydroxy; R1 is hydrogen;
or R and R1 taken together form a second bond between the carbon atoms bearing R and R1; n is the integer 4 or 5; Y is ; Z
is selected from phenyl or a substituted phenyl ring wherein the substituent of the substituted phenyl ring is attached at the ortho, meta or para positions of the phenyl ring and is selected from halogen, a straight or branched alkyl group of from 1 to 6 carbon atoms, an alkoxy group of from 1 to 6 carbon atoms, a cycloalkyl group of from 3 to 6 carbon atoms, a di(lower) alkylamino group, or a saturated monocyclic heterocyclic group selected from pyrrolidino, piperidino, morpholino, or N-(lower)alkylpiperazino, whenever prepared by the process of claim 1.

3. The process of claim 1 wherein R is hydroxy.

4. A compound selected from a base of the formula:

wherein R1, n and Z have the meanings defined in claim 2, whenever prepared by the process of claim 3.

5. The process of claim 1 for the preparation of .alpha.-(p-tert-butylphenyl)-4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)-1-piperidine-pentanol which comprises reacting 4'-tert-butyl-5-[4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)piperidino]valerophenone with a ketone reducing agent in a suitable solvent for from 0.5 to 8 hours at a temp-erature of from 0°C to the reflux temperature of the solvent.

6. .alpha.(p-tert-Butylphenyl)-4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)-1-piperidinepentanol, whenever prepared by the process of claim 5.

7. The process of claim 1 for the preparation of .alpha.-(p-anisyl)-4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)-1-piperidinepentanol which comprises reacting 4-[4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)piperidino]-4'-methoxyvalerophenone with a ketone reducing agent in a suitable solvent for from 0.5 to 8 hours at a temperature of from 0°C to the reflux temperature of the solvent.

8. .alpha.-(p-Anisyl)-4-(.alpha.-hydroxy-.alpha.-phenylbenzyl)-1-piperi-dinepentanol, whenever prepared by the process of claim 7.

9. The process of claim 1 for the preparation of .alpha.-(p-cyclopentylphenyl)-4-(.alpha.,.alpha.-diphenylmethylene)-1-piperidinehexanol which comprises reacting 4'-cyclopentyl-6-[4-(.alpha.,.alpha.-diphenyl-methylene)piperidino]caprophenone with a ketone reducing agent in a suitable solvent for from 0.5 to 8 hours at a temperature of from 0°C to the reflux temperature of the solvent.

10. .alpha.-(p-Cyclopentylphenyl)-4-(.alpha.,.alpha.-diphenylmethylene)-1-piperidinehexanol, whenever prepared by the process of claim 9.