DE2410982A1 - 8-N-METHYLPIPERAZINYL-N'-CARBONYLDIBENZOBICYCLO SQUARE BRACKET ON 3,2,1 SQUARE BRACKET TO OCTADIENE - Google Patents

Description

The invention relates to O-III-methylpiperazinyl-l-i'-curüonjlüicenzobicycloQ3,2,1] octadiene and its pharmaceutically acceptable salts and a process for the preparation of the compounds and their use as pharmaceutical gowns.

Compounds in which the Diben3obicyclo [| 3,2, i] oGtadienkern in the 8 ~ position via a carbonyl or alkylene group to a Amino group is bound are known. In DT-OS 1 955 334 are different derivatives of 5-ίΙ droxydibenzobicyclo ^, 2, T] -octadiene and three derivatives of the dibenzobicyclo £ 3 »2.1] octgdienkernea indicated, including S-carboxauiidodibensobicycloQ ;; , 2.1] oct.adiene and G-AuinoQeth / ldibenzobicycloQ ^, 2,1] octadiene. The connections They are also referred to as 5 »10-Iiethan-5H-dibenzo ^ a , dJcyclohöptGtidei'ivate · These compounds are al3 Diuretics are described.

A09839 / 1022

In an older proposal (I) T-OS 2 216 884) AiiLidc ^ reasiva and anticonvulsants are described in which an amino residue (-1TRAi ₀ ) in G-Slolluri £ is bound to a Dibenzobicyclop?, 2, 1jjoctadicnkerii.

Ia none of these VerüfferiGlioliuuscii i:; t the use of compounds, iait a Dibeiizobicyclooctadienkerii al «Sedaciva and Tranquilizer described. As such, however, the c-round connections are suitable. IDs are also no ir-Kethylpiperazinylaaidderivate described ηουίι the unique and unexpected activities of the inventiin ^ s _(: ; em sufficient compounds.

Nowhere in the prior art is the importance of the geonetrical isonry of the dibenzobicyclo [| 3i2,1] octadiene compounds substituted in the 8-position erv / ähnt. It has been found that the anti-isomeric compounds of the present Invention of a much better therapeutic ratio possess as the corresponding syn isomer ,. and lib? the invention For this purpose, the compounds with anti-configuration are preferred.

The invention relates to compounds of the formula

which are given here (in anti-configuration), ie 8-anti ( ¹ -methylpiperazinyl-IT 1 -carbonyl) dibenzobicyclo [[3> 2,1 ^ JoctadiGn and its pharmaceutically acceptable salts. The invention also relates to processes for the preparation of these compounds and their use as pharmaceutical agents.

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The compounds according to the invention are prepared in Form of the free base by converting IT-IIethyloipc ^ aain with an acyl halide, preferably dcai clilorid, of o-syn- or 8-mrti-Cfirboxydibetizobicyclo £ 3 »2,1] octaäieii, in solution in an in-place solvent such as Diclilor.nethan, Chloroiora, Benzene, hexane or the like. The reaction runs in quickly less than 1 h at 20 to -30 ° C completely. The product can easily be isolated by removing the solvent and is purified by urocrystallization or other common processes

The necessary intermediates, O-ayn- and 8-anti-carboxydibensobicyclop, 2,1]] octadiene, are prepared from the popular compound 8-anti-Chlordibenzoeyclo £ 3.2, i3octadiene (J. Am. Cheia. Soc. 87, 2877 (1965)). The Cfclorverbiauung is by a Grignard reaction into the Hagnesiura-Grignard reagent converted and then reacted with carbon dioxide, ui-i the enäspre— to obtain corresponding 8-syn- and 8-anti-carboxylic acids.

The carboxylic acid is by reaction with an inorganic Acid halide is converted into the corresponding acyl halide. It has been shown that ihionyl chloride does not scijnell 8-eyn- or 8-antl-carboxydibenzobicyclo £ 3 »2.1] octadiene reacts, when the reactants are mixed and heated briefly to reflux temperature (up to an hour). That Acid chloride can be obtained by evaporation of excess ihionyl chloride obtained and used without further purification as described above.

The resulting free base can easily be converted into an acid addition salt can be converted by treatment with an appropriate equi-polar amount of an acid. That will be common carried out by treating the free base in isopropyl alcohol with the acid, the resulting salt precipitating out. If necessary, the precipitation can through. Adding one

Non-solvent can be facilitated. Suitable according to the invention pharmaceutically acceptable acid addition salts

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can organic or inorganic salts 3ei: i and uuiaasen the llydrochlorid, Ilydrobromid, maleate, sulfate, phosphate, acetate, Lactaü ', tartrate, oitrate, organic sulfonates such as Hethanauliüonate etc.

It has been shown that the compounds according to the invention in pharrnukologincue »! Standaruuntersuclrangen ά \ ιλ LlaciVvieii- the calming or tranquilizing effectiveness in mammals are active. It has been shown that the invention

u .qη m ι π η 1 r> hρ π. '

,,. Z u .qη m ι π η 1 r> hρ π. '

Proper connection of the aortaIi caused by narrow SYRONUSES counteracts the administration of arrphetamine in an experiment described by Lasagna, L. and McCaη £, W.P. Science 125: 1241 (1957); Burn, J. II. And ilobbs, II., Arch. Int. Fharmacodyn 112: 290 (1958) et al.

In this test, male mice (17 to 27 g) ^»70 ~ 'are at 10 mice in each cage, the administered at unüersuchen" e 7erbindung, and the mice v / earth v / ieder 30 sin placed in a cage long before they are injected intraperitoneally with 10 ng / kg d, l-Ampiietar-iiasuliat Immediately after the administration of amphetamine, the group of 10 laus cn ir, a rectangular glass vessel of approximately 15.2 χ 12.7 χ 25.4 ν - ^ e . The group treated only with the carrier (comparison) is similarly placed in another vessel. The agglomeration or the close coexistence of the animals in an area of approximately 194 cm leads to mortality after the administration of the amphetamindo3is, acting in mice in the individual cages not lethal,! times 5 h occurs a mortality of more than 70 #, usually 90 to 100 fi in the control mice on the narrow coexistence. Control mice were pre-treated with the carrier and then loaded with Amphetauiin. Effective Compounds protect against the occurrence of group mortality, the mortality being often reduced to 0 in 5 h with effective doses.

The compounds of the invention also have a tranqulisierende effect on mammals by their iPlihigkei z,

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BAD ORSGiNAL

to inhibit spontaneous movement activity. At this Vcrsuoh a single Mau3 (16 to 24 g) is weighed and the compound to be examined is placed in a suitable container geometric distance administered. Immediately after administration each treated group, consisting of 15 houses, given in the counting Koranier by V / oodv / ard-iiktivibäißkfiii ^ cn. The cumulative activity counts, which are observed by interrupting infrared rays through the Mice in the count kaumer, will be 15, 30, 45, 60 µl; 3 S-O min after <3era bringing the house into the Zälilkauuner noted. That Ratio of the mean of three cages per treatment to the mean of three treated only with the vehicle Hausen * is "determined" and means a value less than 1 a dampening effect. Other experiments that have been used and that the tranquilizing effect of the invention Connection include the Sidman Veriaeiüungs- or alternative attempt in rats and the antagonistic effect compared to the movement atiniulation induced by caffeine in mice.

The compounds of the invention can be administered intraperitoneally or orally. Mena they are administered intraperitoneally, they come in solution in a pharmaceutical grade. appropriate solvent in doses of about 1 to 30 µg / kg body weight of the test animal. It is preferred to administer doses of 2 to 20 mg / kg of the anti isomer since doses in this range have been shown to be well effective in animal studies. Such doses give good therapeutic ratios since the intraperitoneal ^> cq * u has been determined to be approximately 282 mg / kg for the hydrochloride.

When the Hydrochloride is administered orally, doses of 10 to 50 mg / kg are used to ensure a tranquilizing effect to achieve. Since the oral LD ^ Q is greater than 800 mg / kg, possesses the anti-isomer therapeutic ratios of 40 and more,

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When a test animal or a person is treated with the compound of the invention, the dose must be post-response of the patient and the age, weight, general health and the like can be varied · A regulation of the respective The dose is within the usual knowledge of the person skilled in the art.

The compound of the present invention and its salts are used in any the usual dosage forms for drugs administered. The salts are easily soluble in water and solutions in the known pharmaceutical carriers or pills or capsules can be prepared and used as desired. Both the compound itself and its salts are solids and can be easily mixed with diluents and excipients Can be used together to make pharmaceutical dosage forms of various types.

It has been found that the compound and its salts generally contain some water of crystallization.

The following examples show the most favorable manufacturing process for the compound of the invention and its salts.

example 1

29.5 g (0.126 mol) of 8-anti-chlorodibene obicyclo 3.2,1joctadiene were added to a suspension of 3-15 g (0.13 mol) of magnesium turnings in 20 ml of tetrahydrofuran, the solution being kept at reflux temperature. Five drops of 1,2-dibromomethane were added. The mixture was held at reflux temperature for approximately 1 €> h. The mixture was then cooled with a dry ice-acetone bath to -25 ⁰ C and quickly passed through carbon dioxide. The addition of carbon dioxide was continued for 1.5 hours and then the mixture was warmed to room temperature. The mixture was then carefully added to an aqueous solution saturated with ammonium chloride. The aqueous layer was separated and extracted with dichloromethane and then combined twice with dietary ether and the organic layers combined. The united organic

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Layers were evaporated under reduced pressure (3 m pressure to a non-volatile residue. Diethyl ether was added and the ether solution was washed twice with an equal volume of 5% aqueous sodium hydroxide liquid. The aqueous solution was then acidified, washed with dichloromethane and the dichloromethane extracts combined and dried over magnesium sulfate. This solution was filtered and the piltrate evaporated under reduced pressure to give 8-carboxydibenzobicyclo [] 3,2,1] octadiene. This solid product was fractionally crystallized from benzene to give a white plague, pp. 175 to 180 ⁰ C. Dos nuclear magnetic resonance spectrum of this isomer showed that substantially pure it was (more than 95 ° />) anti-isomer.

Analysis:

calculated for Cj, found:

The mother liquors from the recrystallization of the anti isomer were evaporated to give a residue which was fractionally crystallized from benzene or ethanol. The essentially pure syn-d, l-isomer, pp. 218 to 222 ^° C., was obtained. The purity was excellent
Nuclear magnetic resonance spectrum confirmed.

C. foil 81 , 5 5.64 81 ,8th" 5.60

218 to 222 ⁰ C. The purity was determined by the magnetic

It should be noted that the amount of syn-I.somer obtained can be reduced significantly if the temperature of the solution at which carbon dioxide is added is used -55 ° C until the aqueous ammonium chloride solution is added.

Example 2

A solution of 50 ml of thionyl chloride and 7.8 g (0.052 mol) of anti-8-carboxydibenzobicyclo [J3,2,1 [] octadiene was brought to reflux temperature heated and kept 1 Ii at this temperature. The superfluous thionyl chloride was

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evaporated temp pressure. Benzene (approximately 50 ml) was added and the mixture was again evaporated to dryness under reduced pressure. The solid product was anti-O-Carbo;: / - dibenzobicyclo [[: 5.2, i3octadiene chloride, ^ p. 102 to 104 ⁰ C.

Example 3

The anti-8-carboxydibenzobicyclooctadiene chloride (0.032 Hol) according to Example 2 was dissolved in dichloroethane and 10 g (0.10 mol) of H-methylpiperazln were added with stirring. After 30 min, the mixture was washed successively with equal volumes of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was then dried over anhydrous sodium sulfate and filtered. The piltrate was evaporated in vacuo to give an oil which solidified on washing with hexane. The solid product was λ with hexane verriebe · and filtered. The solid free base 8-anti ~ (IM-Ie thylpiperazino-IT'-carbonyl) dibenzobicyclo £ 3.2, i [joctadiene, melting point 172 ° to 174 ° C. (not corrected) was obtained. The structure was confirmed by the infrared spectrum.

Example 4

7 ml of 7N hydrogen chloride in isopropanol were added to a suspension of 8.5 g (0.039 mol) of 8-anti- (1Meth / lpiperazine-li'-carbonyl) dibenzobicyclo [] 3J, 2, iloctadienbaoe in 100 ml of ioopropanol, the hydrochloride being added originated. The solution was then treated with diisopropyl ether, whereupon the salt precipitated, which was filtered off. The pesticide was recrystallized from a mixture of isopropyl alcohol and diisopropyl ether. ! Octadiene hydrocLlorid, Pp 265-267 ⁰ C. - einon tan Peststoff of 8-anti- (li-meth ~ _t 7lpiperazin Ji ^f carbonyl) dibenzobicyclo [] 5,2,1 [] was obtained.

409819/102?

Analysis: "' % 0 ' / Oil> ίϊΤ

for C ₂₂ H ₂₄ N ₉ O «HCl-1/2 H ₂ O: 69.4 6.8 7.4 found:" 69.9 6.9 7.4

example 5

After the process described in Examples 2, 3 and 4, S-syn-Carboxydibensobicyclofp, 2.13 ° ^C radii, turned into white, solid Ö-syn- (iT-Meth / lpiperazine- iT ^t -cartonyl) dibenzobicyclo [[3.2, I ^ octadiene hydrochloride, pp. 265 to 267 ⁰ C,

Analysis: #C ^ H, 'IT

for C ₂₂ H ₂₄ IT ₂ O-IICl-1/4 H ₂ O: 70.8 6.9 7.5 found: 70.9 6.9 7.3

- patent claims -

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Claims (2)

I) H. ING. K. WÜKSTIIOFK DK. E. τ. ΡΚΟΙΙΜΑΝΝ DK. ING. D. 1! KIIHKNS DIPt ,. ING. H. GOKTZ PAT IXTiVWlLTI 8 UßNOIIKW 9O SCUWEI (JEBHTBUiKI X nunw (ββΐΐΐ Μ Μ 31 TSLVOIAUMX ι ΜΟΤΙΟΤΓΛΤΚΚΤ M0 «CMBK 1Δ-44 567 Patent claims 1. 8-H-methylpiperazinyl-II. ^1- carbonyldibenzobicyclofp »2, octadiene, preferably in the arifci configuration, and its acid addition salts. 2. A process for preparing the compound according to claim 1, characterized in anti-form, that 3j2,1] octadienchlorid converts 8-anti-CarboxydiLenzobicyclo £ K-methylpiperazine in an inert solvent at a temperature of 20-30 ⁰ G. 62VI 409839/1022