DE1938546A1 - Novel quinuclidine derivatives and processes for their preparation - Google Patents

Description

DR. -ELISABETH JUNG, DR. VOLKER VOSSJUS, DIPL.-ING. GERHARD COLDEWEY

8 MDNCHEN 23 SIEGESSTRASSE 26 TELEFON 34SO67. TELEGRAM ADDRESS: INVENT / MDNCHEN

TELEX 5 29β8β

July 29, 1969

u.z. a 8 475 (ho / To / Äii)

SGS-D-5.

Societe Generale de Recherches et ä ¹ Applications Seientifiques (SOGERAS) SoAo

Paris _t France "New Chinucl idinderivate \ mä ITerfaiurea to

Priority: I ₀ August 1968 ₈ Great Britain, No. ₀ 36 843

The invention relates to new chiuuclidine derivatives and their salts and quaternary ammonium salts according to general formula I.

in which R and R ₂ each represent an unsubstituted or halogen-substituted phenyl radical, an alkyl radical or an alkoxy radical with 1 to k

ο C atoms or © ine TrdfluorraethylgrupiDe mean ^ where the Stelo

<o lung of the side chain and a value χ chosen so that the sina _B An-00

^ Number of G ~ Ätome _B η which the nitrogen atom by the oxygen atom _ »separate ,, 2 or 3 _s b®trägt with the proviso that when χ = O ₉ is> η Φ 3 and R is a Wasserstoffaton" or "if χ Φ O ₉ R is a hydrogen atom or an alkyl radical with 1 to h carbon atoms, _{B is} their S'alze and

quaternary ammonium salts "

The invention also relates to processes for preparing the compounds of the general formula I «

It, procedure

_k If H means a hydrogen atom, taan works according to the following reaction sequence

! / "r ~ ^ ⁵ x - ^X - ^VT " ° ζ. '. - ~~ * ^(I)

In the formulas toa, X denotes a hydroxyl group and Ii sin halogenated or a residue of a reactive ester _t ζ · Β «denotes methaesulfönyloxy- csder p-toluenesulfonylose. Gegelsenenfalle the reaction is conducted in the presence of a Kondensationezsittels and in the presence or absence of a solvent performed ₀ The presence of a solvent is unerläBlich, w rm K = O "

Examples of Komensafcionsmittsl used according to the invention are alkali metals and their salts, such as di & aroide, üfartüm or _; Hydro3Eyde ₀ As Eaee particular a Alkal.tsali See, either in situ or top of the 'XonäfiauatieB can einge- ^s put Äroinoalkohols be used. will be produced.

Examples of solvents used in örfiMun ^ sgeraäS are po- '

■ '■. ■ ■■■■.' *

,. ,,, C - ,. ^ 009813/1822. BADORiQiNAL

clear solvents, trie dimethylformamide or hexamethylphoephortriamld, or non-polar solvents such as benzene, toluene or xylene, or their mixtures <»

The reaction is expediently carried out at the boiling point of the solvent, if this is not more than 10 ° C. If the reaction is carried out in the absence of a solvent, the reaction participants are intimately mixed and heated in an inert atmosphere to a temperature between about 130 ° C - 170 ° C. This process is described below in Examples 2 _9, 13, 15, 16, 18 and 19 explained

2 · Procedure

If the process described above is used for the preparation of compounds of the general formula I, in which R is a hydrogen atom and χ «0, in some cases, as byproducts, Xsosere of the desired product has the same structure as the quinuclidine aufweigen _g laaft that in allften- «eisieii chromatographlsoli ab | jsfcr © must be with · The formation of these by-products is surprisingly avoided if one uses the following procedure:

Sah uses the elitgeee ^ sfeen Ässiiuealkohol in the form of a salt with a strong organic or inorganic acid "%" B, the ChimclidinoX-3-hydro-chloride. In this case, the reaction is carried out in the presence of an alkaline condensing agent which contains the amino alcohol

0 0 9 8 13/1822

does not set free from the salt and under reaction conditions with the compound of the general formula

- Y

does not react, examples of such condensing agents are Alkali carbonates "such as potassium carbonate. .

The process is carried out in the presence of an inert solvent which enables at least partial dissolution of the aroino alcohol salsa at the reaction temperature. It is expedient to use aprotic polar solvents for this purpose, such as dimethylforroamide, at a temperature generally above 100 ° C.

Different variations of the first method are shown below Table I based on the production τοη DiphenylmethoxyO « quinuclidine illustrated ·. In the table, Ch means Ghlnuclidlnol-3,

j

D diphenylbrosethane and W the reaction product,

0 0 9 813/1822 _b ad OBlGiNAL

Table I.

Used reaction participation under conditions Product received

yield

' With

received Qh-Na-

trium salt in toluene + '''I 1 equivalent 1>

1 hour reflux »H + 2 isomers boil in toluene

IO

Same! © Aktionteilneh- msr in He & amethylphosphor * trlamid. ■

1 hour, 45 minutes at 100 ° C 19

ό Cfo-Ifaas made with HaH » tyiiamsals in hexameter). «O phosphoptriasaid + ι

* ·· * i @ ut D

manufactured Gh-

Sodium salt la xylene + 1 equivalent of D.

Hours at 25 ° C

4 hrs, reflux H + 2 isomers boil in

Ch + 0.5 equivalent equivalent

CJh + 1 equivalent D + i equivalent K MBethylformaraicl

in

Ch + 1 equivalent of D in dimethylformamide

3 hrs. Reflux- M + 2 isomers boil in xylene

5 hours 30 min. H + 2 isomers reflux in
Dimethylformamide

1 hour 30 minutes
Reflux
in dimethylformamide

M + 2 isomers

after chromatography

6 * +

39

72

CD CO OD

% of the product: M

ί-Ι

60 «rf

ί

-6-

ί-

O «9

I s

do

0 * 09813/1822 BAD OBlG (NAL

Dleaes second method 1st below in Examples 3, ΊΥ 6, 7, _f 8, 9, 10, and ii explained 12th

3 * procedure

If R means hydrogen a toss and χ «0 ISt ₁ you can also work on the following reaction topic;

Γ J - + - OH

The gas release is carried out in the presence of an inert solvent , such as binsol or toluene, in aiig @ isaists at a temperature below 100 ° C. This process is explained in Example 1 below.

It * procedure

V "nn R denotes an alkyl radical who operates according to folg.nden

Cn)

In the formulas, X denotes a halogenated or a residue of an ester capable of conversion, e.3 · a Hethanesulfonjloxy- or p »Toluenesulfonrloxyrbit and ϊ a hydroxyl group. The cast is optionally in the presence of a basic condensing agent

009813/1822

-8th- and eweoknäeig carried out in the presence of a solvent

Examples of erfindungegetääe Kondensationßmittel used are alkali metals or their derivatives, such as d \ t Anirte, hydrides or hydroxides * · As Kondensationsmlttel particular a Alkallderlvat of compound II itself is used, either in situ or ▼ or the condensation is produced.

Examples of solvents used in the invention are polar Solvents, never Dlmethylforeanid, or non-volatile solvents, such as benzene, toluene or xylene, or their ice

The UasetEung is sweeping at the boiling temperature of the teit carried out

This procedure is in Examples 20 and 21 below explained

The offered establishment of the connections to the general Forael XX required Auegangsaaterlallen are sub part in the chemical Literature in the case of processes for the preparation of analogous known Pro ducts described. This is the case with the compounds of the following general formulas:

ORIGINAL JKSPECJTED 009813/1822

The quinuolidine derivatives of the general formula

In which X is a halogen atom or a residue of a reactive -Esters means / can be derived from the corresponding alcohols Produce (X »OH) by any known method, in which the hydroxyl group is replaced by a halogen atom or a radical a reactive ester is replaced.

There are four compounds in which X is an OH group; their production is described below ο

The quinuclidinol-3 can be, for example, by catalytic reduction des Chinnclidinol-3 according to the method of Grob and Hitarb, HeIv “Chira · Acta, 40 (1957), string 2170.

The hydroxymethyl-3-ohinuclidine can be prepared by reducing an ester of Chlnuclldincarbonsäure, especially the methyl ester, with lithium aluminum hydride by the method of Orob and Hltarb *, Hölv. ChIm ₀ Acta, ^ Z, page 1689ο

The ffydroxymethyl-2-ohinuelidine can be prepared by heduction of an ester of 2-gluclidinoarboxylic acid with lithium. aluminum hydride or by reduction of 2-quinucldine carboxylic acid Ethyester with sodium in ethanol according to the method of Prelog

009813/1822

■ * »■

and Hitarb., Ann., 5 ^ 5 (19W, page 259 · ·

The _(r 2 hydroxy-ethyl) -2-quinuclidine can be prepared NaOH Each "any known method in which an aminoalcohol of the general formula R ^ N-CH ^1-CH ₂ OH

R " into a homolog of the general formula R'-N-CH-CHg-CHgOH

R

is converted. In particular, the following procedure can be used:

a) Conversion of hydroxy methyl 1-2-quinuclidine into a reactive ester, such as a halide or methanesulfonate, according to a known process whereby a hydroxyl group is replaced by a halogen atom or the remainder of a reactive ester. In particular, the chlorine t hy 1 -2-quinuclidine by the method of Prelog et al., Ann .. 5 ^ 5 (1940), page 259,

b) reaction of the derivative obtained with a Alkalioyanid in an inert solvent at a temperature which is depending on the type of the petitioner used and the solvent used, between 80 ° Q ° and 100 ° C "One can, for example, chloromethyl-2-ohinuclidin with Natrlumoyanid react in methyl sulfoxide at 80 ° G /

o) Conversion of the nitrile obtained into the methyl or ethyl ester according to a known process in which a nitrile of the formula H-CN is converted into an ester of the formula R-COOR ¹ »Man for example, the nitrile obtained can be reacted with a concentrated

009813/1822

ι trated mineral acid at room temperature cur carboxylic acid eliminated, and aneohlieSend the carboxylic acid methyl or ethyl ester ester, in particular by conversion of a saturated formation of hydrogen chloride la kethanol or ethanol at room temperature, ·

d) Beductios of the Kstere sun alcohol produced on these catfish, ε · Β · Using LithiUDaluBinluahydrid »in an inert solution agents, such as diethyl ether

The preparation of Ifrdroxjrathjrl-2-ehinuolidine according to the process described above is also the subject of the findunfc

The connections te? Srf i ^ teng Juanen physlkallsoh, beiapiel -

wise by 9isÜilt% iom _s crystallization or chromium, topraphle, or etienie & ti, for example duroh transfer to a sals and Winting of the base through treatment of a strong fase cleaned winds

For the production of a 4-way sale, the connections of the general

Pornel I is neither an organic nor an inorganic acid In the presence of a suitable chemical agent, such as an alcohol, Ether ·, ketones or chlorinated hydrocarbons, uogesetst · The «Tartarian Aoaonlunealse become an alky by tJaseteung old«

organic or inorganic sets with a lubricating effect, given- -4, - ■ - ■ -

^: fall in the presence of a solvent, at Bauateeiperatur or

with a slight smack. obtain·

009813/1822

BAD ORfQfMAt

1338146

Examples of suitable mineral acids are salt ~ ₈ hydrobromic, Methanaulfon "·, sulfuric and phosphoric acid _e Examples of geeigne. "■ te organic acids are acetic, Proplon = ,, succinic, maleic, fumaric, tartaric, Cltronen-, oxalic acid, benzoic acid or salicylic acid and anthranilic _S their substituted derivatives",

Examples of suitable alkylating agents are methyl »,, propyl, butyl, allyl or benzyl chloride or ₀ » bromide, iodide, sulphate or benzene sulphonate and their substituted derivatives »

The invention also relates to the use of the compounds of general formula I for the production of medicinal preparations for the treatment of Parkinson's disease, as antihlstaminics, neurosedativa and tranquilizers.

The examples illustrate the invention

1. Compounds of the general formula I " in which η" 2 iat

example 1 Manufacture of l ^ Diphenylmethoaar-chlnuclldln

A solution of 0.85 g of quinuclidinol-3 and 1.3 g of diphenyldiazomethane in 30 ml of anhydrous benzene is refluxed for 21 hours and, after cooling, 30 ml of ether are added. the organic solution is mixed three times with a total of? 0 ml of an aqueous

009 813/18 22

• 1938548

gen 2 η methanesulfonic acid solution extracted «The acidic solutions

Ice • are combined and in a water bath with 16 ml of 10 η sodium hydroxide solution made alkaline. The oil which separates out is extracted three times with a total of 90 ml of ether dried and eingedampfto the residue (0 "8 g) is transferred under the conditions described in example 2 in the Rydrochlorid" is obtained O ₉ 75 g of 3-diphenylmethoxy-quinuclidine hydrochloride, mp, 198 ° C.

The diphenydiazomethane used as the starting material can be produced by the oxidation of benzophenone hydrazone with yellow mercury oxide according to Smith & Mitarbo, 0rg _e Synth _Of 24, page 53s «,

Example 2 Production of 3 ° diphenylmethoxy-chlnuclidine

A solution of 25 g of quinuclidinol 3 in 300 ml of anhydrous dimethylformamide is mixed with 9 g of diphenyl bromomethane. The resulting solution is refluxed for 1 1/2 hours and then left to stand at room temperature overnight. The solvent is reduced under reduced pressure in a water bath at 80 ° C., the residue is suspended in 300 ml of anhydrous toluene and the toluene is evaporated off in a water bath at 80 ° C. under reduced pressure. The crystalline residue is mixed with 200 ml of distilled water and 150 ml of an aqueous 2. η methanesulfonic acid solution ₀ The insoluble product is mixed three times with ins-

009813/1822

1938549

extracted 600 ml of ether. The ether solutions are combined and extracted twice with a total of 150 ml of an aqueous 2 η methanesulphonic acid solution. The acidic solutions are combined and made alkaline with 80 ml of 10 η sodium hydroxide solution in a water bath. The oil that separates out is extracted four times with a total of 480 ml of ether.The ether solutions are combined and washed three times with a total of 600 ml of distilled water, dried over sodium sulfate and evaporated.The residue (42 g) is dissolved in 2 liters of cyclohexane and added to neutral aluminum oxide chromatographed »The by-products / are first eluted with cyolohexane and then with benzene _e then eluted with methyl acetate. The solution of the product in ethyl acetate is evaporated. The residue (24.9 g) is dissolved in 45 ml of isopropanol and 19 ml of a 4.4 molar solution of hydrogen chloride in anhydrous ether are added Washed mixture of 36 ml isopropanol and 16 ml anhydrous ether. Wan receives 21.3 g of 3-diphenylmethoxy-quinucldin hydrochloride with a melting point of 193 ° C *

Example 3

Production of 3-Diphenylmethoxy-Ohlnuolldln «·

Bine solution of 48 ₉ 3 g of diphenylbromomethane in 320 ml water-free "* dimethylformamide is 3-hydro0 Chinuolldinol-) slGriä and then mixed with 32 g with 27 g of anhydrous potassium carbonate. The suspension obtained is refluxed for 2 hours. That

Solvent is under reduced pressure (20 torr) in water f

0 09813/1 ft OO

ORlGiNAU

bath evaporated at 80 ° C, and the oily residue obtained is stirred with 250 ml of distilled water and 250 ml of ether The grainy solution is Äbdeka & Lert and extracted twice with a total of 500 ml of ether · The ether solutions are combined and twice with a total of 500λΙ of an aqueous 2 η Hydrochloric acid solution extracted. The acidic solutions are combined and extracted with 300 ml of ether, cooled in an ice-water bath and made alkaline with 100 ml of 10 η sodium hydroxide solution.The oil that separates is extracted twice with a total of 1 liter of ether dried anhydrous magnesium sulfate and evaporated. The oily residue (32 g) is dissolved in 62 ml of anhydrous isopropanol and 25 ml of a 6.2 molar solution of hydrogen chloride in ether are added to an Elswasserbad. After cooling to 3 ° C above power, the crystals obtained are centrifuged , a mixture of isopropanol and ether ml twice by suspending it in 80 washed containing 33 <ether, then ait twice a total of 200 ml of ether g- ■, incinerate and thereupon under reduced Druok dried at room temperature "is obtained 31 g of 3-Diphenylaethoxy -quinuclIdin hydrochloride from m.p. 198 ° C to 200 ° C.

The Cnlnuclidlnol-3-hydroohlorid invites calibration used as AuBgangßmaterial prepared by reaction of Chinuolidinol-3 in solution in a mixture of 80% isopropanol and 20% anhydrous ether old hydrogen chloride. The quinuclidinol-3 can be produced by catalytic reduction of the quinuclidinol-3 according to CA. Grob and Hitarb., Helv.Chim.Aota feO (195?), Page 217Ü _O D »s

009813/1822

Diphenylbromomethane is produced by converting hydrogen bromide acid with benzhydrol according to Courtot, Ann «, Ch im«, (1916), page 80o

Example 4 Manufacture of 3-diphenylmethoxy-ohinuclldln

Wan works according to the procedure of Example 3 but using of 2 moles of diphenyl bromomethane and 2 moles of potassium carbonate to 1 pint of quinuclide inol "= 3-hydrochloride, orido

From 3.3 g of quinucldinol-3-hydrochloride, 9 »6 g of diphenylbromomethane and 5 * 6 g of potassium carbonate in 35 ml of dimethylformamide are obtained ^, 4 g the oily base, the 3-diphenylmethoxy-quinuelidine hydrochloride from m.p. 198 ° C to 200 ° C results in »

Example 5

Manufacture of 1-methyl-B-Qlphenylmethoxy-Ehlnuclldinium-Methylsulfat

By reacting 9.3 g of 3-diphenylmethoxychlnuelidia hydrochloride in an alkaline medium 7.8 g of the oily base are obtained, of which 6.8 g in a mixture of 40 ml of anhydrous ether and 10 ml of anhydrous ether «Ethanol can be dissolved. The solution obtained is 6.6 ml of dimethyl sulfate are added dropwise within 5 minutes, After cooling to 3 ° C. for 2 hours, the obtained Crystals centrifuged, washed with an ice-cold mixture of 8 ml

ι 0 0 9 813/1822 ^8AD

193854a

= 47 *.

Ser-free ether and 2 ml of absolute methanol and then washed with 20 ml of anhydrous ether and dried at 55 ° C. under reduced pressure (1 Torr). 8 ₉ 5 g of the product with a melting point of 165 ° C. are obtained.

Example 6

Production of 3 ° phenyl ~ p ° chlo r pfaenyl ° methoxy- »quinuclidine

A solution of 45 g Phe ^ l ^ p-chlorophenyl-bromomethane in 265 ml of anhydrous Dimethylforifiamia is 26 _p 5 g quinuclidinol-3-hydro chloride and then treated with 22, 5 g anhydrous potassium carbonate "The resulting suspension is gekochtö 23 hours under reflux the dimethylformamide is removed under reduced pressure (25 torr) evaporated in a water bath at 75 ° C to 80 ° C the residue is treated with 100 ml of distilled water and 100 ml of ethyl acetate stirred, the aqueous solution is decanted off and extracted three times with a total of 300 ml of ethyl acetate _P the organic Solutions are combined and extracted three times with a total of 525 ml of an ice-cold aqueous 1 η methanesulphonic acid solution. The acidic extracts are combined and washed with 300 ml of ether, cooled in an ice-water bath and made alkaline by adding 6Q ml of 10% sodium hydroxide solution dropwise extracted three times with a total of 900 ml of ethyl acetate, the organic extracts are combined and twice with a total of 400 ml distilled

009813/1822 o _Rie , _{NAL INSPECTE0}

1938548

. -18 »

Washed with water, dried over anhydrous sodium sulfate and evaporated. The oily residue (18.2 g) is dissolved in 30 ml of anhydrous ethanol and the solution is added to a boiling solution of 6.3 g of fumaric acid in 70 ml of anhydrous ethanol. The mixture is Cooled to 3 ° G overnight, and the crystals obtained are centrifuged, suspended in 25 ml of ice-cold ethanol and then washed with 25 ml of ice-cold isopropanol and then twice with a total of 80 ml of ether. The product obtained (Ik- g) is made from 60 ml Recrystallized from boiling isopropanol and cooled to 3 ° C. overnight. The crystals obtained are centrifuged, washed with 30 ml of ice-cold isopropanol and then three times with a total of 120 ml of ether, dried at 45 ° C. under reduced pressure (5 torr) and left to stand at room temperature "This gives 11.6 g of the acid 3-phenyl-p-chlorophenyl» raethoxy-quinuclidine funiarat "monohydrat8 _e, mp 136 ° C"

The phenyl ~ p-chlorophenyl ~ bromo ~ methane used as the starting material is produced by reacting phenyl-p-chlorophenylmethanol with phosphorus tribromide according to British patent specification No. ₀ 670 622 «

Example 7 ' Preparation of 3-phenyl-fluorophenyl-methoxy-quinucldin ORfQINAL INSPEGTEO

009813/18 22

The procedure of Example 6 is followed, but only refluxed for 4 hours. From 19.6 g of quinuolidinol-3-hydrochloride, 32.8 g of phenyl-p-fluorophenyl-bromoethane and 16.5 g of potassium carbonate in 200 ml of dimethylformamide, 17 g of an oil is obtained which is converted into the hydrochloride in the following way: A solution of 17 g of this oil in 40 ml of anhydrous isopropanol is treated in a bis water bath with 9.5 ml of a 6 _s 2 molar solution of hydrogen chloride in ether. After cooling to 3 ° C. overnight, the crystals obtained are centrifuged, twice with a total of 60 ml a mixture of 50 ml of isopropanol and 10 ml of ether, then washed with 50 ml of ether and dried under reduced pressure at tree temperature ° C ».

? k @ sqrl- »p-fluorphonyl-Bromm @ th & n is made Naeh the United ·

fistespsa from Q ₀ Kohnsfcam »J ₀ Gh © ü _a S © e _Q i960 . Since © 2066 "

3 »(Phenyl ~ p-MetSigrlph3nyi)» metho «r-» chliBi © lldln

Mesa. Gs? ^ © l ^ © t E £ ®h the procedure © ¥ on example 6, but becomes 41

cooked,. From 21 g of quinuelidinol-3-hydrO '

3% g phenyl-p-metSjylpMei ^ l-brooHHstlmii and 17.7 g Kaliiie-

009813/1822

* carbonate in 220 ml of anhydrous dimethylformamide gives 21 g

»■

of an oil _{f converted} to fumarate by the method of Example 6. 22.8 g of acidic 3- (phenyl-p-raethylphenyl) <- 'Dethoxy-quinuclidine-fumarate-monohydrate with a temperature of 146 ° C to 1 * 1-8 ° C are obtained.

Phenyl-p-methylphenylbromomethane is produced by reacting hydrobromic acid with the corresponding alcohol after Ao Singh and Mitarbo, J «Am. Cherö. Soc. 8ff (1962), page 1179 »

“ J

Example 9 '.

Production of 3 ~ (phenyl ° -p-methoxyphenyl) ° methoxy °° chlnuolldln

The procedure of Example 6 is followed: “However, the mixture is refluxed for only 100 minutes and the basic products are extracted with 10% aqueous acetic acid solution instead of methanesulphonic acid”. From 26.5 g of quinuclidinol-3-hydrochloride _t 37 g of phenyl-p-methoxyphenylchloromethane and 22.5 g of potassium carbonate in 265 ml of dimethylformamide, 22.8 g of the crude oily product are obtained, of which 19.4 g by the process from Example 6 to be converted to pumarate ₀ 19.5 g of acidic 3- (phenyl-p-methoxyphenyl) methoxy-quinuclidin-fuiBarate with a melting point of 172 ° C. to 173 ° C. are obtained

The phesyl-p-inethoxyphenyl-chloromethane is produced by

009813/1822

Settlement of Pheiayl ^ p ^ methoaypfieisyl ^ iaethanol with hydrogen chloride according to the method of S _a HiShIcLa ₈ J ₀ Orgo Ghem *. J2 (1963) ;, page 2692 ο

Example 10

Preparation of 3 ° (I ^> heg} .yI- = 'P ° broraphenylc _a methQ3O ^ chiimelidin

One works Bach won the method Example 6 _S but is <refluxed only 6 hours, 20 g Ms öhims © liaiaol "3 = = hyäro · ehlopid _D 40 g Fheayl-p-bPCMnplMaayl-lnOBanethan wa & 1β _0? g of potassium carbonate in 210 ml of anhydrous DisBethjlfopmaraid obtained 23.4 g of an oil _s Example 6 reen according to the method of R & marat It is reacted ο receives 19 ₁ 7 g saiares 3 = (Phewl "P ^m bPomphei ^ l)". methozy- ohinuclidist fumarate, mp 15 _o ^ G ° to 155 ° C for ₈

The Pheiiyl --- p-toomphenyl ~ brora? Nethan is produced according to the procedure of the British patent office Mr ₀ 6? O 622ο

009813/1822 bad original

= 22 =

Example 11

Production of_3- (Phenyl-OHnethylphenyl ) «inetho: xy-quinuclidine

O-CH

Prepare by the method of Example 6, but 65 hours is taster reflux boiled from 21 g quinuclidinol-3 ~ hydro »chloride * 3 ^ g P! Ienyl" o = methylphenyl "brOmraethan and 17 _S 7 S Kaliuracarbonat in 220 ml of anhydrous dimethylformamide to obtain 17.2 g of an oil, which is reacted according to the procedure of example 6 for Pumarat * Kan obtained 18 g of acidic 3- (phenyl »o» methylphenyl) ~ me <= tho ^ r-chinuclldin fumarate, mp 149 _e ° C to 151 ° C «

The phenyl = o-methylphenyl bromine ethanol is produced by setting the corresponding alcohol with hydrobromic acid according to the method of A ₀ Ho Wragg and colleagues. _R J ₀ Chem · See 1958, page 4057

Example 12

Production of 3 "(phenyl ^ p-trlfluoromethylphenyl) ° .methoxy ° -chinu clidine

009813/1822 BADORIOfNAL

1938548

The procedure followed is Example 6, except that the mixture is refluxed for 136 hours. From 4.1 g of quinuolidinol-3-hydrochloride, 6.9 g of phenyl-p-trifluoromethylphenylchloromethane and 3.5 B potassium carbonate in 45 ml of anhydrous dimethylformamide, 1.6 g of an oil are obtained. 1 g of this base is mixed with 5 ml of a saturated solution from Pier ins äure in ethanol and with 5 ml of distilled water. One obtains ϋβ, β picrate with a melting point of <> 270 ° C ₀

The phenyl-p ^ trifluoromethylphenyl-chloromethane is produced by reacting phenyl-p-trifluoromethylphenyl-methanol with Thionyl chloride according to the method of Ss Rossi and Mitarbο, Farmaco Ed. Sol. 16 (1961), page 326 "

Example 13 Production of 2-Dlphenylmethoxymethy! -Quinuclidine

CH ₂ -O-CH (CgHc)

Bin Oemlech made from 4.8 g of 2-hydroxymethylquinuelidine, 8.4 g of diphenylbromomethane and 4.7 g of anhydrous potassium carbonate is heated to 150 ° C. for 4 hours and 45 minutes. After cooling the reaction mixture with 100 ml of distilled water, 14.5 ml of 2 η sodium hydroxide solution and 50 ml of ethyl acetate is added _e The aqueous solution is decanted and exträniert twice with a total of I50 ml of ethyl acetate. The organic solutions are combined and twice

009813/1822

1936548

extracted with a total of 200 ml of an aqueous 2 η hydrochloric acid solution. The acidic solutions are combined and made alkaline with 60 ml of 10 η sodium hydroxide solution in an ice water bath. The oil which separates out is extracted three times with a total of 180 ml of ether. The ether solutions are combined and washed twice with a total of 200 ml of distilled water, dried over anhydrous magnesium sulfate and evaporated The residue (5 _f 2 g) is distilled under reduced pressure. "5 g of 2-Dlphenylmethoxymethylquinuclidin, which _{passes over at 162 ° C (O 6} I Torr)" The corresponding Rjrdroehlorld melts at 210 ° C ₀

Used as a starting material 2-Hydroiye "ttayl-chinuö: iJ.din is prepared by reduction of 2-Chinuolldincarbonsäureäthylester with lithium aluminum hydride in ether · obtained from 32 g ^ -Chinuclidincarbonsäureäthylester 18.4 g 2 ~ hydroxymethyl _{p is} at 115 ° C to 116 ° C (16 Torr) passes «,

The ethyl 2-quinuclidine carboxylate can also be reduced with sodium in ethanol by the method of Prelog and MiteFb ₀ , Ann., 545 (1940), page 259i «/

The 2-Chlnuclidincarbonsäureäthy! Ester can be prepared by catalytic hydrogenation of l-AzabioyclOo / ^^ f ^ ooot-a-en-aoarbonsäureäthyleeter according to Braschler and coworkers ,, HeIv <, Chin. Aota, 46, (1963). Page 2646 «

009813/1822

= 25-

Example l } Λ Production of 1 « bromide

IJO g of 2-Diphenylmethojym8thyl <= ohimielidin is dissolved in 25 ml of a 2 molar Lösimg of methyl bromide dissolved in methanol »© The obtained solution is evaporated under reduced pressure _f in a water bath at 70 ° C * a." the residue was dissolved in 25 ml of anhydrous benzene and the benzo], evaporated under the same conditions. The residue is dissolved in 2 ml of anhydrous acetone and the solution obtained gekühlt- 16 hours at 3 ° C, the crystals obtained are zen "trifuglertj, washed twice with 8 ml ice-cold anhydrous acetone and dried under verminüeTtem pressure at room temperature to give 0 _B 8 g of product from m.p. 199 ° C to 201 ° C ₀

slli vag from 3c, piphen, ylmethoaymethyl ° ohii mclldin

A solution of 25 g of 3-hydroxymethyl-quinuclidine in 270 ml of anhydrous dimethylformamide is mixed with kh g of diphenylbromomethane and refluxed for 7 hours. The solvent is dissolved

evaporated in the water bath at 80 ° G under heated pressure. The residue is mixed with 250 ml of ether and 500 ml of an aqueous 1 η

MethänaulfonsäurelösuHg added *, The solid _a , in suspension Ter «

¹ )

C 2,. -. . 2 2 "SAD ORiQt _NAL

= 26 »

The remaining product is filtered off. The piltrate is decanted and the ether fraction is extracted with 100 ml of an aqueous 1 η methanesulfonic acid solution. The acidic solutions are combined, washed twice with a total of 500 ml of ether and added to the filter. The resulting suspension is made alkaline in an ice-water bath with 126 ml of 10 η sodium hydroxide solution dried and evaporated on a water bath at 70 ° C under reduced pressure. The residue (24 g) is dissolved in 100 ml isopropanol and 35 ml of a 3s9 molar solution of hydrogen chloride in anhydrous ether are added in an ice-water bath. After cooling to 3 ° C for 2 hours, the crystals obtained are centrifuged with an ice-cold mixture washed in 60 ml of isopropanol and 30 ml of anhydrous ether at room temperature and dried under reduced pressure to give _o

33 g of the hydrochloride of mp 230 ° _o Co

The 3 = hydroxymethyl quinuclidine used as the starting material is prepared by reducing 3 = quinuclidine carboxylic acid methyl ester with lithium aluminum hydride according to the method of and Mitarbo ,, HeIv. ChIm ₀ Aeta, 21 (W, page 1689. '

Example 16 Preparation of 3-Dlphenylmethoxyniethylquinuclldin

A mixture of 1.4 l g of 3-hydroxymethyl-ehinuclidine, 2 ₉ w g of di-

009813/1822

phenylbromraethan and 1.38 g of anhydrous potassium carbonate under nitrogen at 140 ° C 2 45 STDE Hin, and then at l60 ° C for 3 l / Z heated hours After cooling, the Reaktionsgemisoh with 20 ml of distilled water _e is 2 5 ml sodium hydroxide solution and η 50 ral ethyl acetate taken up. The aqueous fraction is decanted and extracted with 30 ml of ethyl acetate. The organic solutions are combined and extracted twice with a total of 80 ml of an aqueous 2 η hydrochloric acid solution. The acidic solutions are combined and made in an ice water bath with 20 ml of 10 η sodium hydroxide solution alkalis ohο

The oil which separates out is extracted twice with a total of 100 ml of ethyl acetate »The organic solutions are combined and

washed with 50 ml of distilled water, over anhydrous water dried nesium sulfate and evaporated. The residue (1.3 g) / ge ro according to example 10 into the Hydrochloric! transferred 1.1 g, mp Rydrochlorid ₀ 230 ° C ₉

Example 17

Preparation of 1-methyl-3-dlphenylroethoxymethyl-ohlnaclldinlniibronid

By reacting 14 g of 3-diphenylmethoxymethyl-ehinuelidln hydrochloride in an alkaline medium, 11.1 g of an oily one is obtained Base, of which Hg in 60 nl of a 2 molar solution of methyl bromide To be dissolved in methanol «The solution obtained is 2 hours at

009813/1822

Room temperature, allowed to stand datin evaporated under reduced pressure in Masserbad at 70 ° C. The residue is dissolved in a Gemisoh of isopropanol and anhydrous ether containing 75% ether corresponds ¹ holds, crystallized. 10.1 g of product with a melting point of 180 ° C. are obtained

Example 18

Production of 2 ° (Dlphenylmethoxyäthy1) -quinuclidine

A mixture of 8.5 g of 2 = hydroxyethyl-quinuclidine, 13.6 g of diphenylbromomethane and 7.6 g of anhydrous potassium carbonate are heated under nitrogen in a metal bath at 125 ° C for 3 hours is cooled and taken up with 100 ml of distilled water and 100 ml of ether. The ether phase is decanted, and the aqueous Phase is extracted with 100 ml of ether. The ether solutions are combined and twice with a total of 150 ml of an aqueous 2 η Methanesulfonic acid solution extracted The acidic solutions are combined and alkaline in an ice water bath with 25 ml of 10 η sodium hydroxide solution made"

The oil that separates out is washed twice with a total of 200 ml of ether

■ t -

extracted »The ether extracts are combined and twice with

009813/1822

washed a total of 150 ml of distilled water, dried over anhydrous magnesium sulfate and evaporated. The oil obtained
(10 g) is dissolved in 25 ml of anhydrous acetone and added to a boiling solution of 3 g of anhydrous oxalic acid in 6 ml of anhydrous acetone. After cooling for two hours to 3 ° C, the crystals obtained are centrifuged, with 10 ml of ice-cold anhydrous acetone and then with 20 ml of ether washed and dried at room temperature under reduced pressure. 11.8 g of the acidic oxalate with a melting point of 235 ° C. are obtained.

8 the recovered from the oily base oxalate g can be with Puraarsäure 8 ^ g acid, mp Pumarat "1 ^ 9 ° C to 150 ° C to produce ₀

Example 19 Production of 3 ° (phenyl ~ p ~ chlorophenyl) -methoxymethyl-chlnuclldin

However, E-! Aa operates according to the method VOA Example 15 "is, the time of refluxing 5 hours * From 21 g Phesjyl ° p ~ ehlorpheny] bromine than and 10" 5 g 3 = ^ dro3qrffiethyl ~ öhiaaeli & in in 50 ml of di me thyIforaiaraid do you get 1? The warm solution can be a g öligea Bas © ^ which 15.2 g in 10 ml of boiling ethyl acetate is dissolved _o

QQ 9 R 1 - * / 1 p 7 2

193854Q

to a boiling solution of 5 »15 g of sharkic acid in 10 ml of ethyl acetate, after 2 hours of cooling to 3 ° C, the crystals obtained are centrifuged, washed with 5 ml of cold ethyl acetate and then washed twice with a total of 30 ml of ether and under verffilsdertesi pressure (1 torr) at 40 ° C »dried to give 8.7 g of acid of mp Haleinat ₀ 111 ° C to 112 ° Co

The phenyl-p-chlorophenyl = bromomethane is described as in Example 5 manufactured

Example 20
. Production of 3 ° (1 ^t r, l ^> -Dlphenyläthoxy) -methyl-chlnuclldin

Qr-

CH,

A solution of 19 _B 8 g of 1,1-diphenylethanol in 300 ml of anhydrous xylene is slowly mixed with 9.8 g of 3-chloromethylquinuclidine hydrochloride, 11.6 ml of a 30% sodium amide suspension in xylene and 6 ml of anhydrous dimethylformamide After boiling under reflux for hours, most of the solvent is distilled off under reduced pressure. 200 ml of distilled water are added to the oily residue, and the insoluble oil is extracted three times with a total of 200 ml of ethyl acetate. The organic solutions are combined and four times with a total of 400 ml one

009813/1822

aqueous, ice-cold 0.5 tl hydrochloric acid solution. The acidic extracts are combined, filtered through paper and made alkaline in an ice-water bath by adding 20 ml of 10N sodium hydroxide solution. The oil which separates out is extracted three times with a total of 50 ml of ethyl acetate} "The organic extracts are washed over magnesium sulfate and evaporated under reduced pressure in a water bath at kO ° C. 5.9 g of an oil are obtained. By reaction with fumaric acid, one obtains the fumarate with a melting point of 150 ° C - 152 ° C.

The 3-chloromethylchinuolldin hydrochloride can be obtained by reacting 3-hydroxyraethylquinuclidine hydrochloride with thionyl chloride by the method of C ₀ A. Grob and Hitarb ·, HeIv. Chin. Aota 21 (195 ¹ O. page 1689, manufacture »

The 1,1-diphenylethanol can be converted into ethyl acetate with phenylbronide according to the method of A.Dieriohs and co-workers, Ber. 20 (1957), page 1208 »produce.

Example 21

· » Division of 2- (Γ «phenyl-1'-p-chlorophenrlethoxy) -quinuclidine

, -CHg-O-

Xn 100 al of anhydrous toluene are 9.2 g of l-phenyl-l-p-chlorophenyl-ethanol, 2 g of sodium amide, 4.2 g of 2-chloroethyl-quinucliÄfB-

009813/1822

hydrochloride and 1 ml of anhydrous dimethylformamide was suspended ₀ The suspension obtained 15 hours refluxed "After cooling to room temperature, 15 ml of distilled to give ₁ -Ser to, decanted and the aqueous phase extracted twice with 80 ml of ethyl acetate · The organic phases combined and washed three times with a total of 225 ml of distilled water and extracted three times with a total of 300 ml of an aqueous, ice-cold O ₈ 5 η methanesulfomic acid solution »The acidic extracts are combined and filtered through a paper filter and made alkaline in an ice water bath with 20 ml of 10 η sodium hydroxide solution The oil which separates out is extracted three times with a total of 300 ml of ethyl acetate; the organic solution is washed three times with a total of 300 ml distilled water, evaporated, dried over sodium sulfate and concentrated under reduced pressure _a is obtained ^, 5 g of an oil, of which 1.5 g are dissolved in 10 ml of anhydrous ethanol * The solution obtained is treated with 15 ml of a saturated solution of pluric acid in ethanol. After cooling for 2 hours to 3 ° C., the crystals obtained are centrifuged, washed with 5 ml of ethanol and then twice with a total of 20 ml of ether and dried under reduced pressure at tree temperature. 1.9 g of the Piorat from m.p. 150 ° C.

Du l-phenyl-l-p-chlorophenyl-ethanol can be converted into of p-chlorobenzaldehyde with Me thy! magnesium chloride according to the German Patent No. 952 715 produce. The 2-chloroethylquinuclide hydrochloride can be obtained from the 2-hydroxyethylquinuclide (the preparation of which is described in Example 18) using the following process:

009813/1822

1938548

• A ^{solution of 10 g of 2-hydroxyethylohinuolidine, cooled to O 0} C - in 80 ml of anhydrous chloroform is loaded with hydrogen chloride

. acts, and then 50 ml of thionyl chloride are added «. The fteäktionsgemisch 3 hours, refluxed for "Excess thionyl chloride and chloroform are removed under reduced pressure in a water bath at ⁰ C. The evaporated SO pike stand is purified by washing with anhydrous Ither. The suspension is filtered and the crystals obtained are dried under reduced pressure at room temperature to give 12 g of 2-CMoräthylchinuclidin hydrochloride mp "202 ⁰ C ₀

The compounds of the invention have valuable pharmacodynamic properties, making them suitable for use in human medicine. They are valuable as cholinolytics, antihistamines and neurosedatives. ₀ While all of the compounds of the invention possess these properties, but the results of the pharmacological tests in two groups according to the meanings of η in the general formula I were divided

A) Compounds of the general formula I in which η = 2 1st The pharmacological properties of these compounds were compared with diphenhydramine in the form of its hydrochloride (hereinafter referred to as DC) and its methyl sulfate (hereinafter referred to as DH) *

acute toxicity

The acute toxicity was determined according to the method of Deichmann and ieBlano, J ₀ Ind "Hyg, Toxicol, 2 £ (1943h S ₀ 415-417". The approximate values for the lethal dose are given in the following

Table II given in mg / kg Table II

link
(Example
Sr ₀ ) Mouse, I ₀ Vo Mouse, SoCo Rat, SoC. Mau8 _f PO DC 30th 130 475 180 SM 8th 175 280 1 22nd 54 210 132 5 3 140 265 13th 10 180 420 14th 2.4, 80 230 6th 30th 120 520 7th 30th 80 230 8th 24- 100 280 9 16 80 150 10 46 350 940 11th 16 55 280

in vitro test

The in vitro test was carried out according to the method of Magnus. Activities were measured against the following agonists: J.

Acetylcholine, on the duodenum of the batte. , Barium chloride, on the duodenum of the rat Histamine, nicotine on the ileum of the guinea pig, and the ileum of the guinea pig Serotonin, on the Hatteo colon

The concentrations that lead to a 50 # reduction in the

Agonist evoked contractions are necessary in ^

009813/1822 '

Table III below

Table III

Connect
manure
Example
Mr. Acetyl
choline ^ Barium-
ohlorid histamine Nicotine Serotonin DC 3xlO "* ⁷ 2x10 * " ⁶ 8xlO " ⁹ IxIO " ⁶ DM 5XlO " ⁸ 9XlO " ⁸ lxlO " ⁸ 9x10 ~ ⁸ 1 9XlO " ⁸ 3xlO ~ ⁶ 9x10 ~ ⁹ 5xlO ~ ⁸ IxIO " ⁶ 5 lxlO "" ⁸ O 8xlO ~ ⁸ 6xlO "* ⁶ 6xlO " ⁶ 13th 5x10 " ⁹ 6xlO " ⁶ 8xlCf ⁹ 4xlO ~ ⁹ 3xlO " ⁶ 14th 5xlO ~ ⁹ 6xlQ " ⁶ 2x10 ^y 2x10 * " ⁹ 4xlO " ⁶ 6th 7XlO " ⁸ 5xlO ~ ⁶ 7XlO " ⁸ IxIO " ⁶ IxIO " ⁶ 7th 2x10 ~ ⁹ 8xlO " ⁷ 4xlO " ⁸ 2XlO " ⁶ IxIO " ⁶ 8th 3xlO " ⁷ lxlO " ⁶ 8XlO " ⁸ 5 x 10 " ⁷ 2x10 " ⁶ 9 2x10 ~ ⁷ 3xlO " ⁶ 3xlO " ⁷ 7xlO ~ ⁷ 7xlO " ⁷ 10 7xlO " ⁷ 2XlO " ⁶ 2xlO " ⁷ IxIO "* ⁷ IxIO " ⁶ 11th 2XlO " ⁸ 4xlO " ⁷ IxIO " ⁸ 4xlO " ⁷ . 2xlO " ⁷

Effect on behavior

The effect on behavior was measured by means of a dews actimeter that works with crossed electromagnetic radiation beams,

measured

The compound to be investigated becomes suboutan to the Hausen half an hour before they are placed in the Actimeter and the activity of the test animals has been reduced for 15 minutes. «Eat« Each connection is in 6 different, logarithmic • Increasing doses were studied, and each dose was given to 6 animals

administered

0 0 9 813/1822

The effect was rated as follows:

++ Strong increase in activity '

+ Increase in activity + no significant effect

- decrease in activity - sharp decrease in activity

The results are given in Table IY below »

009813/18 22

/ I

Table IV

link
Example no " dose
ffi £, / & g, SoOo effect I. DC 1 to 5 DM 10 to 20 - 1 5 13th 0.3 to 10 + 14th 10 to 30 + 6th 3 to 10 + 7th 10 bie 50 - 8th + 9 10 3 Me 10 + 11th 10 to 30 - 1 big 3 3 to IG + + 0j, 3 to 10 + 10 to 30 0 _f 3 Mg 3 10 to 30 + ■ +

813/1822

Anticholinergic effect

The peripheral anticholinergic musoarin-like effect is based on the Had based on the inhibition of acetyl-ß-methylcholine 1st precalled chromodacryorrhea measured «, (Explanation! Den 5Pi Χ'βη a dye is administered that is also in the tear fluid & old o This makes it easier to observe the flow of tears become o)

The results © ® are evaluated as follows:

+ Little effect

+ strong performance
++ very strong effect
+++ very strong ρ long-lasting effect (e.g. atropine) «

The central anti-coXinergic effect is measured in the mouse on the basis of the inhibition of the anaigesia caused by oxotremorine. The effect is indicated by the EDc ₀ , ie the dose which, when administered subcutaneously, suppresses the analyzing effect of oxotremorine injected 15 minutes later in 50 # of the treated feathers »

The antinicotinic action is measured in the mouse at the end of the inhibition of the twitches caused by the administration of the Ni cotins. The test compounds are administered subcutaneously and are considered active against nicotine when they suppress caused by nicotine convulsions at 50 $ of animals {EDrq) ₀

The results are given in Table V ₀

009813/1822.

6AD OBIGtNAL

Table V

link
(Example Qr.) Peripheral anti
cholinergic we
kung central anti
cholinergic we
kung Antinicotin
effect DC + 16 11.5 SH ++ inactive 54 1 ++ 1.5 11.5 5 - ++ inactive weakness
effect 13th ++ 5 5.5 • 14 ++ inactive 9.5 6th inactive ^: 9 11th 7th inactive 3 inactive 8th + weakness
effect -inactive
• 9 weakness
effect inactive 10 inactive 24 17th 11th 4 · 0.5 3

Effect on the vegetative nervous system

This effect was given to anesthetized with sodium pentobarbital
male dogs. Both vagus nerves of the animals were measured
and the blood pressure in the carotid artery was cut
by means of a Ludwig manometer (i.e. a mercury aanome-
ter ait volume shift) or a Statham pressure camera
COebnungsmeßetreifen-principle without Volunenverschielrang) measuredo

S) The effect of the products is determined on the basis of the increase in adrenaline and horadrenaline blood pressure, acetylcholine lowering of blood pressure and that caused by irritation of the peripheral end of the vagus

009813/1822

Blood pressure reduction measured ο Xn the table VZ the actual effect of the intravenously administered product is given in mm HG, 'where the sign + indicates an increase in blood pressure and the sign a reduction in blood pressure of the base value.

Table VI

Dose,
mg / kg
IV
i ♦ I.
change
the vagus
Blood pressure
Lowering »j6 change
the acetyl
eholin-
Blood pressure
lowering, i> Changes
tion of the
Adrenaline-
Blood pressure
increase link
(Example
No.) 3 change
of blood
pressure,
mm Hg, - 20th - 20th + 20 SC - 10 DM 3 - - 100 - 100 + 20 1 3 - 30 - 100 - 100 + 20 5 3 + 10
then - 30 - 70 - 100 0 13th 0.3 - 30 - 100 - 100 0 14th 3 - 30 - 100 - 100 0 6th 3 - 50 ' - 80 - 80 0 7th 1 - 80 0 0 0 8th 3 - 40 0 0 0 9 3 - 30 - 10 - 15 0 10 1 - 40 - 50 - 75 0 11th - 20th

Antinistamine activity in vivo

Male awake guinea pigs are injected subcutaneously with 25 mg / kg of a compound to be examined, 30 minutes afterwards, a certain number of lethal doses of histamine are injected intravenously. The number of lethal doses of histamine which the animals survive is determined and the mortality _{0 is determined at the same time}

The results are given in Table VII below.

009813/1822

- 41 Table YII

link Number of survived le (Example no.) talen cans. DC : 85 DM 40 1 105 5 . "., ■". 4th 13th 5 14th 10 6th 30th 7th 400 8th 30th 9 .40 "". 10 10 11th '. ^: -; ■ ίο

Phenothiagin catalytic suppression

The administration of Neuroleptiea in sufficiently high doses in humans causes psychomotor symptoms produced ₉ see the symptoms of Parkinson's disease · remember _e These symptoms .werden by the compounds of the invention effectively suppressed ·

In the saturated, a subeutane injection of 12.5 mg / kg proehlorperazine causes catalepsy of more than 6 StO ₀ duration "which is prevented or alleviated by the simultaneous administration of a compound of the invention",

■ The "presence of a catalepsy wtei iiiHsend % Stei, examined every 3p. Minutes among other things the proaentes & s des? S4 € * vä% © fall, len © n animals we determined; egg © Bvm & e d @ r 10 received -5a:? Ä , tilaiüe @ is divided by 10 * »so that you get a @ & IHsrohsolmittswe ^ t fär ü®n percentage- rate of the total ix iiere i ^ -d üie we] D; mgsdar :: v & m

0Ό S S1 3/1 B 2 2. · 'Bad original

Product receives «

Haoh the above method were tested compounds Wirlcung against oxotremorine comprise ₀ Results are given in Table VIII below. A group of animals that showed 100% no catalepsy symptoms for 5 hours was rated 100 «

Table VIII

Ver
am
manure
(At
game
Mr,) 1 B © S €
3 SoCo kg
30th 100 orally I.
1 loose, ι
3 mg / kg
10 30th 100 300 Gust 21 > n, mg /
10 60 6th 28 43 1 36 37 52 76 14th 38 44 43 71 100 13th 18th 29 60 6th 54 94 100 7th 19th 61 73 4th 6th 30th 56 100 8th 50 39 10 30th 59 100 U '· 32 87 - 82

B) Compounds of the general iOnael I. In ler η »3 iat you p & armakoXogisehen properties of these compounds was with (^ (0hlor-4-pbenyl) -l-ethoxy7-2-ethyl) -2-methyl-l-pyrrolidine baw. Keolaeti »compared.

Me akut · Saxisität became üacii the process »by Beichsann &

"J. lad ο Hyg. Toxiool, 2% (1943), pp. 415-417, determined."

Θ09813 / 18 22

BATH ORIGINAL

The approximate values for the lethal dose are given in Table IX below in mg / kg

Table IX

link
(Example
Mr.) Chew, ioYo House, BoC Rat, βοΟο Heolastine 67 420 940 * 16 12th 80 280 17th 2.0 120 420 18th 16 67 120 19th 24 120 · 420

in vitro test

The in-yitro test was carried out according to the Magnus method. The activities were agonized against the following measured

Aoetylcholine, ant duodenum of the had Barium chloride, on the duodenum of the rat histamine, on the ileum of the guinea pig Hicotin "on the ileum of the guinea pig Serotonin" as the colon of the rat

The consentrations which aur 50 pounds diminution in by the Eontractions evoked by agonies are necessary Specified in table X below »

009813/1822

link
(Example no.) Acetyl
choline Barium-
ohlorid histamine Nicotine Serotonin Heelastin 4x1 Cf ⁷ 9x10 " ⁶ ~ · .Ο,
3x10 ^J 5x1O " ⁷ 9x10 ~ ⁸ 16 2xl (T ^ö 6x1 (T ⁷ 2x10 " ^G GxIO " ⁸ 6xlO " ⁶ 17th 4XlO- ⁸ MO " ⁸ 3xlO " ⁷ 1x10 ° ⁷ 9xlO ^ ⁶ 18th 2x10 ⁷ 9xlO " ⁷ ωο ~ ⁸ 7xlO ^ ⁷ 2xlO- ⁶ 19th ixlCf ' ⁶ §Χΐρ " ⁶ GxlO "" ⁸ inactive 3xlO " ⁶

Effect on behavior

The effect on behavior was measured by means of a Dews-Aetimetero, which worked with crossed, electro-magnetic radiation rods. The compound to be examined is administered to the mice eubcutaneously half an hour before they are placed in the Actimeter _f and the activity of the test animals was 15 minutes Each compound is investigated in 6 different, logarithmically increasing doses / and each dose is administered to 6 animals.

The effect was rated as follows:

++ Strong increase in activity + Increase in activity + no significant effect

- decrease in activity - sharp decrease in activity "

The results are given in Table XI below «,

009813/1822

BATH ORIGINAL

• Dftbe.Ue XI

link I) OBOH effect Möolastin 0.1 to 10 ± 16 30 to 100 17th 0 _λ 1 Ms 3
3 Ma 10 18th 1 to 10 19th 30th £ 1 to 10 30th + 1 to 3 10 + +

AJ & tlohoXinergic effect

The peripheral anticholinergic musoarin-like effect is demonstrated in the rat on the basis of the inhibition of acetyl-Q-methyieholin
Chroiaodacryorrhea induced - the results are assessed as followsί

+ Little effect
+ strong effect
ψ * very strong effect
+ ■ «■ + very strong j long-lasting effect (e.g. ₀ B ₀ atropine)«

The central anticholinergic effect is measured on the basis of the inhibition of the analgesia induced by oxotremorine. The effect is indicated by the ED ^ ₀ ,, d _o h _e ρ the dose for subcutaneous administration, the effect of anaigesierende 15 minutes later injected oxotremorine $ 50> the

009813/1822

BATH ORIGINAL

treated animals mi ί, οΓί) .click t,

The antiniootin effect is measured in the mouse on the basis of the inhibition of the twitches caused by the administration of the nicotine. ₃ JDLe ^ and unfcer-seeking compounds are administered subcubaneously and are considered to be active against nicotine if the twitches caused by the nicotine are at 50 $> the ver-Qucho suppress animals (ED _t - ₀ ) <,

The results are given in Table XII below »

Table XII

link peripheral anticho "
linergic effect central anticho-
linergic effect Antinicotin
effect Meclastin S. 43 14th 16 2.6 1.6 17th
18th ++
± inactive
30th 1.4
4.3 inactive inactive
I.

Effect on the autonomic nervous system

This effect was with sodium pentobarbital anesthetized male dogs intersected measured ₀ vurden Both vagus nerves of animals and blood pressure was in the carotid artery by means of a pressure gauge or einer'Statham Ludwig-pressure chamber "

measured

The effect of the products is determined by the increase in adrenaline »and noradrenaline blood pressure, the acetylcholine lowering of blood pressure and. the blood pressure caused by irritation of the peripheral end of the vagus

009813/1822

BATH ORIGINAL

pressure reduction measured _o In Table XIII, the actual effect of eating intravenous product in mm Hg _t specify where the character · * · a BXutdruuksteigerung and the sign ~ ■ line. Marking blood pressure lowering, The change in the effect of acetylcholine bi? W _{t of} the vagus irritation on the blood pressure are given in 96 of the base value?

Table XIIl

link
Meclastin D08iss _f
mg / kg
i, Vo change
of blood
prints t
mm Hg 0 change
the vagus--
Blood pressure
Lowering _f $ change
the acetyl
en oil in
Blood pressure
Lowering, £ Changes
tion of the
Adrenaline-
Blood pressure
increase
/ ° 16 1 - 20th 0 0 0 0 17th 1 0 - 100 - 100 + 30 18th 1 'O - 80 - 100 0 19th ι ■ 0 0 0 1 0 - 30 + 20

AntihiBtaminffektun ^ in viv o

Male conscious guinea pigs are subcutaneously 25 mg / kg one to the test compound injected 30 Hinuten then are injected intravenously with a certain number of lethal doses Histaminο It determines the number of lethal doses of histamine _f the _f survive the animals and at the same time determines the mortality * Results are given in Table XIV below

0 9-8 1 3/1 8 2 2

BATH

Table XIV

link
(Example Mr.) Number of over *
lived lethal doses Meclastin 900 16 20th 17th 5 18th 19th 60

In therapy, the new compounds can be used in dose ranges for oral administration from 10 to 200 mg / day and for parenteral Administration of 1 to 50 mg / day can be used.

The new compounds are used for medicinal purposes either in the form of bases or in the form of pharmacologically acceptable acid addition salts or quaternary ammonium salts used

The new compounds, in the form of the bases, salts or quaternary ammonium salts, can be used therapeutically either alone or together Bit additives (accompanying substances) »such as thinners, enveloping gowns, preservatives, humectants, Lubricants, solution agents, dyes or fragrances, are used that are pharmacologically acceptable and suitable for the type of application.

For oral administration, the new compounds can be in the form of tablets, coated tablets, powders, granules or gels, emulsions ,. Suspensions, solutions or syrups are used «.

009813/1822

For parenteral administration, sterile, aqueous or non-aqueous solutions ₈ suspensions or emulsions or powders can be used, »which are dissolved before use»

Suppositories can be used for rectal administration and solutions »emulsions, suspensions or ointments _{3 for external use}

The following is an example of the composition of a tablet containing a compound of the invention as an active ingredient

(Diphenylmethoxy <-2 ~ ethyl) ~ 2-

quinuclidine base 10 mg

Mannitol 100 mg

Corn starch 20 mg

Talcum 5 mg, 135 mg tablet.

009813/1822

Claims (1)

Claims Io quinuclidine derivatives of the general formula I. (I) R ₂ R r in which E ₁ and R ₂ are each an unsubstituted or halogen-substituted phenyl group, an alkyl »or Alfcoxyrest having 1 to 4 carbon atoms or a Trifluorraethylgruppe mean _s wherein the Stel development of the side chain and a value χ bq are chosen such that the number η of G atoms, which separate the nitrogen atom from the oxygen atom, are 2 or 3 »with the proviso that» if χ «0, η 4 · 5 and R is a hydrogen atom or, if Xj * 0, E is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, _{9 is} their salts and quaternary ammonium salts » 2 ο method for the preparation of the compounds according to claim 1, characterized by »that if R a hydrogen atom means a quinuclidine compound of all common formula with an ester of the general formula Y ~ CHv (A) 009813/182 2. _ommMm inspected in which T is a halogen atom or a radical capable of acting on an octlonus Beters means condensed in the presence or absence of a basic condensing agent and optionally converting the compound obtained into that salt or "quaternary ammonium salt" by reaction with an acid or an alkylating agent 3. The method according to claim 2, characterized in that the reaction is carried out in the presence of a solvent if χ * is o 4 »Method according to claim 2 and 3, characterized know without knowing that one * quinuclidinol-3 in the form des SaIseβ is used with a strong acid in the presence of a condensation agent that does not remove the ghinuolidinol from its SaIs in freedom sets and with the ester of the general formula I ^R l not responding * 5. Process for the preparation of the compounds according to claim 1, daduroh gekennseichnet that when H is a hydrogen atom and χ = 0, a 2- or 3-quinuolidinol of the formula with a slide «ο connection of the general formula 009813/18 22 condenses and if the compound obtained falls through Reacting with an acid or an alkylating agent into the Salt or quaternary aniflonium salt transferred 6- A process for the preparation of the compounds according to claim l characterized £ _f e k e η η ι, calibratable et η that is ,, if a H st Alky Ire bedevtet, - a Ghinun3idinverbindung the
my formula in which X means a halogen toin, i ^r it an alcohol of the general form ^ HO - C _x ■ Sx, K ^c KnndBiert and ' givenfq3: .b the connection obtained by converting with a St.ure ^ the one ::. AAki'-ation center}. transferred into the salt bsv., quaternary aninonium salt- 0098 13/1522 BAD OBlGiNAL