Spiro (1,3-dioxolane-4,3') quinuclidines,their preparationand pharmaceutical compositions comprising them

This PDF First Page has been artificially created from the Israelian Abstracts

ספיר ו( ו,3-דיאוקםול\ן“4,'3)קוינוקלידינים, הכנתם ותכשירי רוקחות המכילים אותם

Spiro(1,?-*dioxolane-4,3 *)quinuclidines, their preparat ion and pharmaceutical compositions comprising them

The Purdue Frederick Company

The present invention relates to novel spiro(1,3-dloxolane

4,3')quinuclidine compounds of the general formula

STTWIARY OF THE INVENTION;

<img file="IL48452A_D0001.tif" />

wherein H. and , which may ־be identical or different, each _t^{1 Z} phenyl designates hydrogen, alkyl to a process for the production of these and to pharmaceutical preparations containing these novel compounds as active ingredient♦

The compounds of the above formula I can be produced by a ring-closure reaction. Two routes of synthesis for the production of such compounds ares

a. First preparing 3-hydroxymethyl-3-quinuclidlnol by reacting 3-carbomethoxy-3-quinuclldlnol with a reducing agent, such as metallic hydrides (as for example lithium aluminum hydride) in a suitable reaction medium, such as a high ether (for example in tetrahydrofuran ), under reflux; treating the reaction mixture with a lower alkyl acetate (such as methyl acetate or ethyl acetate) in an atmosphere of an inert gas, followed by treatment with an aqueous base (such as sodium hydroxide), followed by washing with water, to give the desired product;

b. Preparing quinuclidine 3-epoxide by reacting dimethylsulfoxonium methylide with qulnuclidin-3-one;

The- products of each of the above reaction steps (a) and (b) can be reacted with an aldehyde ( R^-CHO) or with a phenyl ketone ( Rj-CO-Rg), wherein and R₂ are each alkyl or a»yl., to result in the desired compounds of Formula 1.

The novel compounds of Formula I are characterized by interesting and valuable pharmacological properties. They can be used as active ingredients of pharmaceutical preparetlons to be used in human and in veterinary medicine.

For example, the oompound 2-methyl-spiro(l,3-dioxolane4,3’)qulnuclidlne is a specific and powerful cholinergic Btipiulent- and it has a high degree of specificity towards autonomic / , ganglionic and central muscarinic red&amp;ptors Ideated in the peripheric sympathetic ganglia or in th(/, Central nervous system. Due to its high degree of spebifici^ for th&amp;be sites, it can be used to activate these receptors Uftder conditions when acetylcholine is lacking at the sites.

Amongst conditions in which this compound can be used there may be mentioned those requiring treatment with acetylcholine-like drugs, such as Huntingtons chorea, tardive dyskinesia or hyperkinesia and also in mental disturbances due to a deficiency of central acetylcholine resulting in mental disorder. Such deficiencies may be spontaneous or these may be drug-induced. The above compound is also of use for the treatment of disorders requiring the application of a long-lasting cholinergic agent of mild local activity. Such agent is needed in disorders such as glaucoma, as the compound is not destroyed by the enzyme which desactivates acetylcholine♦

The compound 2,2-dlphenyl-spiro(l,3-dloxolane-4,3’)quinuclidlne is a powerful anticholinergic agent and it may be used for the treatment of disorders due to an excess of acetylcholine, whether this be spontaneous or drug-induced. It is of use in the treatment of various diseases, such as Parkinson’s diseases, of mental depression and it can also be used as adjunct in surgery instead of atropine,scopolamine etc. It may also be used in ophthalmology when prolonged mydriasis is required for diagnostic or for therapeutical purposes.

The present invention consists also in pharmaceutical compositionscontaining as active ingredient a spiro(l,3dioxolane-4,3') quinuclidine according to general formula I.

'10

Such pharmaceutical preparations are, inter alia, ophthalmogical preparations for inducing sustained mydriasis or for the treatment of glaucoma as well as preparations for the treatment of disorders characterized by an excess of central or peripheral acetylcholine—like activity; of Parkinson's diseases of mental depression; and as adjustment of surgery. They also serve in' the treatment of myaestenia gravis.

The preparation of compounds according to the present invention is illustrated by way of example ־with ¢0 reference to the following examples, which are to be construed in a non-limitative manner . Degrees are degrees centigrade.

Example 1: Preparation of 2-Methyl spiro (1,3-dioxolane-

4,3 )Quinuclidine.

To a stirred suspension of 17.5 g. lithium aluminum hydride in 100 ml dry tetrahydrofuran there was added ,during 1 hour a solution of 3-carbomethoxy-3-quinuclidinol tetrahydrofuran, 50 g in 100 ml. This vzas prepared according to Grob. Helv.Chim.Acta, 22, 1 689 (1954). The reaction mixture vzas refluxed during 4 1/2 hours, treated with 20 ml ethyl acetate under'nitrogen, then with vzater (17 ml) then with 15/״ aqueous sodium hydroxide (17 ml.), and again vzith water, 51 ml. The resulting mixture was filtered and the filtrate vzas evaporated under reduced pressure, leaving as residue a syrup, 35 g., comprising 3-hydroxymethyl-3quinuclidinol. A quantity of 5 g. of this syrup vzas treated with 20 ml. acetaldehyde and 20 ml. of methylene chloride. The resulting emulsion was cooled to 0°C and treated under agitation vzith 20 ml boron trifluoride ethereate for 1 hour. The resulting mixture was then poured on water containing an excess of potassium hydroxide and stirred until a complete decomposition of boron trifluoride had taken place. The mixture was extracted with ether end the extract vzas subjected to evaporation under reduced pressure. The residue consisted of crude 2-methyl spiro (1,3-dioxolane-4,3') quinuclidine^ B.P.=63-72° at 0.2 mm-Hg , R_f on neutral alumina (ethyl acetate) = 0.6; M⁺. This product consists of a mixture of the two isomers wherein ׳the methyl group is in one case in the cis-position (70/־), the other in the trans-position (30¢) respective to the nitrogen of the ring. The mixture was resolved into the two isomers by column chromatography on neutral alumina with ethyl acetate. The hydrochlorides of these ;;ere prepared by treatment of the two substances in dry acetone with gaseous hydrogen chloride, M.P. (cis-isomer) 233.8° (dec.); of rhe mixture : 234.2° (dec.).

Example : 2,2-dimethyl spiro (1 ,3־dioxolane-4,.3'-) tjuinuclidine himethylsulfoxonium methy.Lide was prepared by the method of Corey et al., Organic Jynth. 49., 78 (1969) from

17.2 g; sodium hydride, 88 g. trimethylsulfoxonium iodide in 455 ml of dimethylsulfoxide in a 1 liter reaction flask equipped with a mechanical stirrer, reflux condenser and gas inlet tube, protected from moisture. After completion of the reaction, the gas inlet tube was replaced with a pressure compensated dropping funnel containing quinucluline-3-one, 39 g. in dry dimethylsul0 !־oxide, 129 ml. Tais was added to the dimethylsulfoxinium methylide during a period of ל minutes , followed by stirring during a further 15 minutes at ambient temperature, followed by heatinr to 55-60° during 2 hours on a water bath. The reactio?! mixture was poured into 200 ml. of cold water and extracted with five portions of 200 ml each of benzene. The extracts were combined, washeo with water (100 ml), uith 100 ml of saturated aqueous soaium chloride; dried over anhydrous magnesium sulfate and evaporated, yielding crude quinuclidine-3- epoxide, 3.1.=55-60° at 0.5 mm/Hg. The crop was 21 g., i.e. a yield' of 49/. on neutral alumina (ethyl acetate) 0.5; M⁺ = 139; hydrochloride salt: 200. 7-202°.

3.5 g of the epoxide were treated with 50' ml acetone and 30 ml boron trifluoride ethereate at 0°, with stirring. The stirring was continued during. 48 hours at ambient temperature and after this decomposed by pouring into cold water containing an excess of potassium hydroxide. The organic phase was extracted with 100 ml ether, separated and dried over anhydrous, magnesium sulfate. After evaporation of the solvent there was obtained a clear syrupy substance, 5g, 2,2dimethyl spiro(1,3-dioxolane-4,3')quinuclidine, 3.1.=60-70° at 1 mm Hg, yield 4 g (80/); hydrochloride salt: M.P. = 245-245.5°.

Example 3: 2,2-diphenyl spiro (1,3-dioxolane-4,3¹)quinuclidine.

This compound was prepared via both the routes of Example 1 and of Example 2, using benzophenone. The M.l. = 105.5-105.6°. The yield //as 10-20 per cent. Hydrochloride salt: M.P. = 204-206°. R^ TLC on alumina with chloroform: 0.4(free base).

Various other compounds within the ambit of Formula I were prepared by these routes, either via 3-hydroxyme+hyl-

3-quinuclidinol or quinuclidine-3-epoxide by reaction with an aldehyde I^-CHO or with a ketone where R₁ and

R₂ ere as defined with respect to Formula I.

Compound.« of Formula I, whorein differ« from R₂, ' as exist two stereoisomers, namely a cis- and a trans-isomer׳These can be resolved by conventional moans, such as for example by^ column chromatography. The compound, wherein R.=mothyl and. R״=H was resolved and it was found that the mixture consisted of about by weight trans- and about ?0^ ci s4־|j|omer. The cis-isomer has a greater biological activity, and in the following Tables the activity of the substantially pure c’s-isomer of this compound Is given.

The compounds of the present Invention can be formulated into pharmaceutical compositions of matter by conventional means and. by the use of.conventional diluents, adjuvants and the Hire. They can be administered per os, by injection, by infusion ete. The dosage of the compound of Formula 1,' wherein R|=methyl,R₂=H is about 02׳. mg to 3.0 mjj/kg per day for adults, if given by injection; the oral dosage has to be about 2 to 3 times as large. The diphenyl compound, by parenteral administration. is to be given in dosages of from about 1 to 5 mg per day for adults.The diphenyl compound, can be effectively used in the form of ophthalmologlcal preparations, together with suitable adjuvants, buffers or the like, Vnd compositions of 0.5;? to about 2/ by weight give satisfactory results.

It is clear that the dosage and the route of anm'.nl;.tret.*.׳.« . have to be adjusted according to the disease or disorder to bo e treated and according to the sevrity of same.

The following tables׳ indicate some of the uses of the novel compounds and of pharmaceutical preparations containing these,and these are compared with some conventional compounds used for similar applications.

It is clear that the description Is by way of example only and. that these merely serve to illustrate the invention.

-. 6 ;::.!StMbTO ACTIVITY OF VARIOUS COMPOUNDS

COHWD;

IN VIVO'

SCO STIMULATION oat

Ei\״ (la) ug^umole)

IN VITRO

INDUCED TRMS ?ALL BLOOD PRESSURE EPNR Guinea pig ileum mice. cat induced contract!}#

ED,״ (ip)״ ED,״ ( iv ) EC,״( N) EMR mg/fe umole/kg ug/tfg nmole/kg ^ג

Acetylcholine 0.16

Acetyl- β-methyl choline! $0 022׳

<td> not applicable 0M</td><td> 0*16</td><td> 1</td><td> --------3----- 5*10</td><td> 1</td>

<td> not applicable</td><td></td><td></td><td> 1.8 ΊΟ⁷־</td><td> 3-6</td>

<td> 3-Acetoxyquinuclidine</td><td> 50</td><td> 0-2L</td><td> ?5</td><td> )6.5</td><td> 0.2</td><td> 1</td><td> 6.25 7'ΐθ''</td><td> 1¢</td>

<td> Cri^ ,11C1--^ ן £1- ^11R</td><td> 50</td><td> 0.2j</td><td></td><td> 2ϋ»5</td><td> f f סיס</td><td> 1 י 30</td><td> 188 1.2 10'5</td><td> 240</td>

, with 95ί confidence limlte (Litchfield et al.19^9)

Ή

EmR: equipotent molar ratio relative to ACh. nmole: nannomoleL!

<td></td><td> ?Acute Toxicity, trenorlgenlc ond eialigrenlc Activity in Pice____________________________</td>

<td> COMPOUND</td><td> Acut# Toxicity Tremors. Salivation 1 , שj_S/k? EL'״: (In) ' ng/1־g umoleAg mg/lc.g 1unole/fc5</td>

<td> 3-Acetoxyquinuclidine !,RpHiR^Cn/HCl</td><td> 112.5 («1 5־36 5־7 (־.Β» δ.8 2.9 220 (_yc) Μ 20-5 3&lt;0 13.7</td>

<td> Oxotremoririe</td><td> 5 (_i?) 0.14 0.?3 0.12 0.63</td>

with 95¾ confidence limits Litchfield i. Wilcoxon, 19^9) .

Chinn? &amp; Leaders, 1971

TABLET: fhe Activity of Compound I,R. =Rp=phenyl,^: HC1 and ־ of Atropine sulfate In various ^systems

I ^R^-R^aphenyl, HC !Atropine Sulphate»*

Guinoa-pig ileum, log Ki -0.6 - 0

SCG (cat).

<td> antagonism to McN-A-343 induced contraction of NM ED_S(J, pinole (ia)</td><td> ' 0.5</td><td> 1.4</td>

<td> Mice</td><td></td><td></td>

<td> LD₅₀, mg/kg (sc)</td><td> 40(34.5-46.5)</td><td> &gt;100</td>

<td> Relative mydriatic activity</td><td> l.S .</td><td> 1</td>

<td> Antagonism to Osotromorine induced salivation** ED_g(J? pmole/kg (sc)</td><td> ’ *t 0.28(0.2-0.35)</td><td> ++ 0.039(0.026-0.053)</td>

<td> Antagonism to Oxotremorine induced tremors⁰*⁰EDcn? pmole/kg (sc) M v</td><td> 0.31(0.27-0.35)¹</td><td> ++ 1(0.75-1.40)</td>

<td> CNS/PNS activity⁰,fl</td><td> 1.1(0.77-1.56)</td><td> 25.9(15.5-43.5)</td>

<td> Antagonism to Physostigmine## induced lethality ED ₀°, pnele/kg (sc)</td><td> + 0.20(0.19-0.23)</td><td> 6.05(6.7-8.9)4+</td>

* With 95¾ confidence limits (Litchfield and Hilcoxcn, 1949), ⁰⁰ Ozotro11OTi.no, 170 pg/kg, ip (1.1S EDgg) induced salivation.

⁰⁰⁰ OKBtsOJsorino, 200 pg/kg, ip (1.15 EDjjq) induced tremors.

Obtained by dividing ΕΟ^θ for blockade of tremors by ED§q for blockade of salivation.

Physostigmine salicylate 3 mg/kg, ip (2 LDj₀) induced lethality.

t R?=R2=־i/> ,HOI ig injected 20 min. prior to OKOtrewcrine or physostigmine salicylate.

Atropine Sulphate is injected 15 min. prior to osotiorajvine or physostigmine salicylate.