DE2253377A1 - NEW ARYL-4-PIPERIDYLKETONE DERIVATIVES AND PROCESS FOR THE PREPARATION - Google Patents

Description

2153377

LIGHT ANALYSIS DR-JUR-UiL-CHEM-WALTERBEIT

ALFRED HOIPPf "ε". ■. -,.

DR. JUH. DIPL-CM EM. ! {.- J. WOLFF ^ H Ω kl 1972

DR-JUEHANSCHk-BtJL dU.UKI. WL

it ?. FRANKFURT AM MAIN-HDCHS!

Our No. 18 229

Richardson-Merrell Ine.
New York, NY », V.Sfc.A.

New aryl ^J l-piperidyl ketone derivatives and processes for their

Manufacturing / -

The present invention relates to new aryl-4-piperidyl ketone derivatives and their acid addition salts, which are suitable as anaigics and anticoagulants, as well as a process for their production. ">

The new aryl-il-piperidyl ketone derivatives according to the invention can be expressed by the following general formula

Formula I.

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where η is an integer from 1 to 3 and R eirx-n Phenyliv.; U, a straight or branched all: ylr <:.; t with 1 to H carbon atoms or a bifunctional 1, 'I-butadienylene radical which together with the phenyl ring forms a nnphthyl ring, where η is 1 when H is a bifunctional 1,4-butadienylene radical.

LOispiele of the radical R of the formula T are a phenyl group, a ro wheel or verzweißtkettiger Allcylrest 1 to ¹ I carbon atoms wherein the alkyl group in an ortho, meta or para position on the phenyl ring gubundenen methyl, ethyl, Propyl, isopropyl, butyl, isobutyl or tert. Hutyl radical, or a bifunctional 1,4-butadienylene red which, together with the phenyl ring, forms a ⁰ ^ - or ß-riaphthyl ring.

From the above formula I it can be seen that the compounds according to the invention are substituted phonyl-'l-piperidyl ketone derivatives, as represented by the following formula 17 , "£ -iiaphthyl-'l-piperidy. Iketone derivatives, uio they are represented by the following formula III or β-naphthyl-1-piperidyl ketone derivatives, as they are represented by the following formula IV, can be.

(R ¹ )

Formula ET

C = O

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BATHROOM OBiQINAL

mm * ϊ -

Formula III

Formula IV

In the above formula II, R denotes a phenyl radical or a straight-chain or straight-chain alkyl radical with 1 to H carbon atoms in the ortho, meta or para position on the phenyl chain and is an integer from 1 to

The connections according to the invention are made by Formula V below is shown

U ir

Formula V

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SAD ORIGINAL

ρ
in which R denotes a phenyl radical or a straight or branched lower alkyl radical with 1 to k carbon atoms bonded to the phenyl ring in the ortho, meta or para position.

Pharmaceutically acceptable acid addition salts of the invention Compounds are the salts of any suitable inorganic or organic acid. Suitable inorganic Acids are, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid and the like. Suitable organic acids are, for example, carboxylic acids such as e.g. acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, fumaric acid, Malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid and dihydroxymaleic acid, benzoic acid, Phenylacetic acid, 4-aminobenzoic acid, ^ -hydroxybenzoic acid, Anthranilic acid, cinnamic acid, salicylic acid, 4 "-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid and like that.

Examples of the compounds according to the invention are 4-piperidyl-o-tolyl ketone, 4-piperidyl-p-tolyl ketone, iJ-piperidyl-2,3, i-trimethylphenyl ketone, 3,4-diethylphenyl-4-piperidyl ketone, 4-isopropylphenyl- ⁱ 1-piperidyl ketone, 4-tert-butylpheny 1-4-piperidyl ketone, 3-ethylphenyl- ¹ 1-piperidyl ketone, p-biphenylyl-JJ-piperidyl ketone, cC-naphthyl-4-piperidyl ketone, 4-piperidyl-3,4 , 5-tri-n-propylphenyl ketone, 2-isobutylphenyl-4-piperidyl ketone, β-naphthyl-4-piperidylhetone, 4-piperidyl-4-n-propylphenyl ketone and the like.

The compounds of the invention are useful as analgesics and Anticoagulants suitable and. can in the form of pharmaceutical

themselves

chemical preparations for oral and parenteral administration suitable to be used. The amount of the compound in the dosage unit can be used to achieve the desired Effect within wide limits from about 0.5 mg / kg to about 50 mg / kg vary in patient body weight per dose. the

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225337?

The desired effect can be achieved in that 1-to 5 to 300 mg of the active ingredient can be administered 4 times a day. The compounds according to the invention can be used on warm-blooded animals and incbeijondere be administered to mammals.

The new connections can be used together with the conventional ones Carriers in dosage unit forms such as solids, e.g. tablets or capsules, or liquid solutions, suspensions or elixirs for oral administration or liquid solutions, suspensions, emulsions and the like for parenteral administration can be used. The amount of active ingredient in each dosage depends on the type of dosage unit , of the animal and its weight. So each dosage can be about 5 to about. 300 mg of active ingredient .Contained in a substantial amount of a pharmaceutical carrier.

The utility of the compounds of the invention will. explained below. The compound of Example 5 showed in vitro a 100 % inhibition of by adenosine diphosphaj; induced platelet aggregation in platelet-rich human plasma when 100 µg of the compound was used per ml of plasma. In the standard hot plate test · {cf. J. Pharm. Exp. Therap. Vol. 107, p. 385 (19-53)] with mice, the compound of Example 4 inhibited the heat stimulus. When administered orally, the EDf-Q of this compound in mice was 33 »5 mg / kg.

The compounds according to the invention can be used alone or in Association with other analgesics such as acetylsalicylic acid or p- ^ ftthoxyacetanilide with or without a stimulant such as caffeine, administered to achieve the desired analgesic effects. When a compound of the invention is used in conjunction with other analgesics, the ratio can be the amount of compound to the amount of other analgesics about 1: 1 bi; 3 1:10, preferably 1: 5 concerned, 'being a stimulant like caffeine in connection with an inventive

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Compound and other analgesics used is the ! "tight dos used stimulant about half the amount the connection.

Pie compounds according to the invention can be made by Friedel-Crafts

Acylation of a suitable compound according to the following

Create scheme:

0 C- halo

(R) _n *

. HCl Lewis acid

In the above reaction, R and η have the meanings given above and halo means a halogen atom.

The reaction illustrated above can be carried out in a number of Solvents such as nitrobenzene, chlorinated hydrocarbons such as chloroform, tetrachloroethane and the like or in one Excess of the aromatic reactant, i.e. Compound 1, and catalyzed by a number of Lewis acids such as aluminum chloride, boron trifluoride, hydrofluoric acid, tin IV chloride and the like can be carried out. the The amount of the Lewis acid used in the reaction is 1 to 8 times, preferably 3 to 4 times the amount of the acid chloride, compound 2, on a molar basis. Preferably the reactants are using an excess of the aromatic reactant solvent in an ice bath and with stirring slowly mixed with an excess of aluminum chloride, during which time the reaction temperature is kept below 35 ° C. After the addition is complete, the reaction

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ioirperatur 10 minutes to 6 hours, preferably 10 to ⁷ ) 0 minutes increased to 25 to 90 ° C, preferably 50 to 70 ° C. The reaction mixture is decomposed with water and ice and then made strongly alkaline by treatment with a 50% sodium hydroxide solution while cooling. The reaction mixture is then extracted with a suitable solvent such as toluene, chloroform, chlorobenzene and the like. The organic extract is dried, filtered and concentrated "whereby a base of the formula I is obtained" which can be converted into an acid addition salt by generally known processes.

The compounds according to the invention can also by oxidation the suitable oC- (subst.) -aryl- * J-piperidinemethanol derivatives with a suitable oxidizing agent such as chromic acid, sodium dichromate, manganese dioxide, lead tetraacetate and the like in a suitable solvent such as acetic acid, sulfuric acid, Pyridine and the like can be produced. The reaction temperature can be 0 to 100 C; preferably the reaction is carried out at room temperature. The response time can take 10 minutes to 1 day, depending on the reaction conditions be. It is preferably 1/2 to 1 hour. the oC- (subst ») -Aryl-ij-piperidinm'ethanolderivate are by catalytic reduction of the corresponding substituted arylpyridine ketone or of the corresponding c6- (subst.) -aryl-il-pyridinemethanol derivative obtain. The substituted arylpyridine ketones are by reacting an appropriately substituted aryl Grignard reagent with isonicotinic acid nitrile and subsequent hydrolysis of the imine complex obtained. The oC- (subst.) .- aryl-4-pyridinemethanol derivatives are made by reacting an appropriately substituted Grignard reagent with pyridine-4-carboxaldehyde and subsequent decomposition of the complex obtained with. obtained from a saturated ammonium chloride solution.

The following examples illustrate a preferred embodiment of the invention serve to explain the

Invention. ""'"' ■ * ■ ·" = -.-

dücloZU / IU Ii

p-U-rt. -Butyl phenyl - ^ - piperidyl ketone hydrochloride

(/;) «150 ml of thionyl chloride were slowly stirred with 129 β (1.0 Hol) 'l-piperidinecarboxylic acid added. The mixture v: urdo heated to ^ 5 ° C for 15 minutes, after which the excess Thionyl chloride was removed at 50 C under vacuum. That obtained oil was poured into ether, and the obtained precipitate was collected, washed with ether and vacuum dried, leaving 168 g of JJ-piperidinecarboxylic acid chloride hydrochloride were obtained.

(Ii) A mixture of 168 g (0.915 mol) * i-piperidinecarboxylic acid chloride hydrochloride, 750 ml tetrachloroethane and 160 g (1.1.9 mol) tert-P / utylbenzene was slowly added to 370 g (2.78 mol) in an ice bath with stirring ) Aluminum chloride was added, the reaction temperature being kept below 25 C. The reaction mixture was slowly warmed to 65 ° C for 10 minutes and then decomposed by pouring it into water and ice and cooling to 20 ° C. The mixture was made strongly alkaline with 50% NaOH and chloroform was added. An equal volume of water was added and a small hence solid was filtered off. The organic phase was separated and the aqueous layer was extracted with methylene chloride. The methylene chloride and chloroform extracts were combined, dried over anhydrous magnesium sulfate, filtered and treated with ethereal HCl and ether. The precipitate obtained was .umkristallisiert butanone and dried to give the desired product of melting point 232.5 to 233.5 ° C.

Example 2

2-IJaphthy 1- * 1 -piperidylketonhydrochlorid

Kino slurry of 99 g (0.75 mole) naphthalene and Q6 g (0.5 Hol) A-piperidinecarboxylic acid chloride hydrochloride in tetrachloroethane was for 10 minutes with 200 g (1.5 mol) of aluminum chloride offset. The reaction mixture was left to stand for 10 minutes at room temperature, after which the above was added to ice water

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poured, made basic with a 50 # NaOH solution and extracted with diethyl ether. The ethereal layer was dried over magnesium sulfate, filtered and washed with.-ethereal Treated HCl. The resulting oil was dissolved in heated methanol, treated with charcoal, filtered and washed with Butanone diluted. The methanol was removed by distillation, adding more butanone than was necessary. The solution was cooled overnight and the solid obtained was filtered off and recrystallized from methanol-butanone, the desired product having a melting point of 251-253 ° C was obtained. ·

Example 3 He sity ^1-1 I-piperidyl ketone hydrochloride

A mixture of 20 g (0.11 mol) of Ij-piperid'tncarbonsäurechloridhydrochlorid and 50 ml of mesitylene Vmrde in an ice bath with stirring with 60 g (0.6 mol) of aluminum chloride. The reaction mixture was heated to 50 ° C over 1/2 hour and decomposed by pouring it onto ice and basified with a 50 % NaOH solution. The reaction mixture. 2 ml of toluene were added and the organic layer was separated and dried over anhydrous magnesium sulfate. The mixture was filtered, treated with ethereal HCl, and the precipitate obtained was washed with dry diethyl ether and recrystallized several times from methanol-butanone, the desired product having a melting point of 295-296 ° C. being obtained. ■ · .. '

example H.

p-Isopropylphenyl - ^ - piperidylketone hydrochloride '

In a mixture of 900 ml (3.22 mol) of cumene and 368 g (2.0 mol) of l-piperidinecarboxylic acid chloride hydrochloride on a Ice bath with stirring with 800 g (6.0 mol) of aluminum chloride ' offset. The reaction mixture rose for 10 minutes Heated to 50 C, cooled and poured into ice water by adding it vmrde, "decomposed and with a 50 $ NaOH solution" basic made. The mixture was cooled and extracted with toluene.

! Vi.ο 'i'dLu'o] lorning was dried over magnesium sulfate, rilt.rloTt. ur: <! treated with essential IfCl. The obtained: HL. "Ior; -. Chla _f '·, was recrystallized from methanol-butanone, v; oli (.; I IaG desired product of melting point 2 ^ 5.5-246 ° C was obtained.

Iic; ir, piel 5
p -Piphenylyl- ^j l-piperidyl ketone

A mixture of 15 '»g (1.0 mol) biphenyl, 92 g (0.5 mol) 'l-Piperidinecarboxylic acid chloride hydrochloride and 1 liter of methylene chloride was slowly stirred in an ice bath with 150 g (1.12 mol) aluminum chloride crosslinked, the reaction temperature being kept below 19 ° C. Another 500 ml of methylene chloride were added, after which the mixture was decomposed by pouring it into water. The reaction mixture was treated with ethanol and chloroform until a small amount of solid had gone into solution. The organic layer was separated, filtered through celite, and the solvent was removed by heating and gradually replaced with water. After cooling, the pesticide obtained was filtered off, washed with toluene, dissolved in chloroform and ethanol and filtered through celite. The product obtained became isolated from this solution and washed with ether, v / obei p-biphenylyl-'l-piperidyl ketone hydrochloride was obtained, then using methanol and sodium methoxide was converted into the free base. The product was recrystallized from heptane, p-biphenylyl-'lpiperidyl ketone obtained from melting point 116.5-119 ° C.

Example 6

> \ -Piperidyl-p-tolylketone hydrochloride

A cooled mixture of 96.5 g (0.4 mol); X- (p-tolyl) - * lpipei'idinmethanolhydrochlorid, 600 ml acetic acid, kO ml 2 ^liters (v / v) sulfuric acid and 72 ml water for 1 1/2 hours with stirring with 26.5 g (0.2 mol) of chromium trioxide

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iii * networks · 0 ml of acetic acid, v.'öhrend which time more ¹ O nil of water was added. The mixture was stirred for 1/2 hour at a temperature below 9 ° C. The solvent was removed in vacuo and the remaining residue was treated with an excess of sodium hydroxide and. then extracted successively with ether and chloroform. The combined extracts were washed with .Wasser, dried over anhydrous magnesium sulfate and filtered. Chloroform and ethereal HCl were added to the filtrate. The solid obtained was filtered off and recrystallized from isopropyl alcohol and V / as π er, the desired product having a melting point of 274-277 ° C. (decomp.) Being obtained.

movie 7 ■

Jl-piperidyl-p-tolyl ketone hydrochloride

A mixture of 1.47 g (0.8 mol) of 4-piperidinecarboxylic acid chloride hydrochloride "and" 300 ml of dry, toluene was added to a 320 g (2.4 mol) of aluminum chloride were added to the ice bath while stirring. The reaction mixture was then heated to 65 ° C. for 10 minutes, cooled and poured into an ice / water mixture was poured, decomposed. A solution of 800 ml of 50 mg NaOH was added while increasing the temperature was kept below 35 C. This material was extracted with toluene, dried over anhydrous magnesium sulfate, filtered through celite and treated with ethereal HCl. The resulting precipitate was washed with ether and recrystallized from methanoi-butanone, the 'desired Product of melting point 274-277 ° C (dec.) Was obtained.

Example 8 '

3, H -Diethylphenyl-4-piperidyl ketone hydrochloride

Following the procedure of Example 6, the title compound was obtained using a suitable amount of OL - (3,4-diethylphenyl) -4-piperiäinothanolhyorochlorid instead of OC - (p-tolyl) -4r-pipericunmethariolli.V'irochlorici .

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ORIGINAL

! '<"■ i ry i ol 9

The following formulation is an example of a tablet an effective compound according to the invention:

Per tablet

(a) p-Tertiary rutylphenyl-iJ-piperidyl kotone hydrochloride 50.0 mg

(b) Strength ijO, 0 mg

(c) lactose 160.0 mg

(d) magnesia urastearate 3.0 mg

That by mincing lactose with the active compound Granules obtained and a part of the starch and granulated with starch paste were dried, sieved and with Hafnernum tearate mixed. The mixture became tablets of 253 mg each pressed.

f'.eir.piel 10

The following formulation is an example of a tablet an effective compound called according to the invention in connection with other analgesics, e.g. acetylsalicylic acid:

Per tablet

(a) Mesityl - ^ - piperidyl ketone-

hydrochloride 50.0 mg

(b) acetylsalicylic acid 250.0 mg

(c) Strength JjO, 0 mg

(d) lactose 120.0 mg

(e) Magnesia stearate 5.0 mg

] javj through Munich of lactose with hesityl-'l-pipcridylketonh; / droch3oricl and part of the starch oriialtene granules

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8ADORiQfNAL

was made with / iStcirkepaste. granulated, dried, sieved / and mixed with acetylsalicylic acid and magnesium stearate. That Mixture was compressed into tablets of 465.0 mg each.

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Claims (1)

- in - Γα U '■ ntanr.pi'i'iche 1. Compound of the general formula v.'orin η is an integer from 1 to 3 and R is a phenyl radical, a straight or branched chain lower alkyl radical 1 to 't carbon atoms or a bifunctional 1,4-buta * dienylenrerjt, which together with the phenyl ring to which he is attached bound int, forms a cC- or ß-haphthyl ring, mean, where η is 1 when R is a bifunctional l, * l-butaclienylene radical means, and their pharmaceutically acceptable acid addition calcins. 2. A compound according to claim 1, wherein R is a straight or branched lower alkyl radical with 1 to U carbon atoms means. 3.; les Ltyl-'l-piperidyl ketone as a compound according to claim 2, or dc.-CLen acid addition salt. ^l \ . Compound according to Claim 2, v / orin η 1 means. 5. p-tert-butylphenyl-it-piperidyl ketone aln compound according to claim h, or desr.en iWiureadditionscalz. 6. p-Isopropylphenyl-'l-piperidyl ketone as a compound "Claim ¹ \, or its acid addition as. 309820/1012 __ BATH ORIGINAL ','. 'i-riperidyl-p-tolylkoton as a compound according to claim ¹ I, or its acid addition :; sal ζ. fi. A compound according to claim 1, wherein R is phenyl '·. A compound of Claim 8 wherein η is 1. 10. p-Biphenylyl- ^ i-piperidyl ketone as a compound according to claim 9 »or its acid addition salt. 11. A compound according to claim 1, virorin R is a 1,4-butadienylene radical means. '? .. 2-naphthyl - ^ - pi _i peridyl ketone .as a compound according to claim 11, or its acid addition salt. , 13. A method for producing a compound according to claim 1, characterized in that there is a substituted aromatic Vcrrindane of the formula in a gcr>ip; neten Lönungaradttel and in the presence of a] /, ··. ·. ' i π -ίϊΰ ure rait a ^ -J'iperidinearbonsnurehalogenderivat the formula " C-halo . Ιϊ-halo v; oriii η and R have the meanings according to An ;; 3iruch 1 and ^r : Qlo means an Ilalogenatom, converts the Vcri.-indun; "-; ^r '£; level fa31r> in a manner known per se into the pharmaceutically acceptable acid additionoaalz transferred. For: Richardson-Mefrell Inc. New York, N.Y., V.St.A. BATH