DE2362396C2 - 3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0 → 3 →, → 7 →] decane - Google Patents

Description

in which Ri is an alkyl group with 1 to 4 carbon atoms and one of the two radicals R2 and R3 is a hydrogen atom and the other is a carbamyloxy group of the formula -OCONHR5, where R _{5 is} a hydrogen atom or an alkyl group with 1 to 4 carbon atoms according to Patent 23 06118, characterized in that in the compounds of the formula I R3 is a hydrogen atom and R _{2 is} a carbamyloxy group of the formula -OCONHR ₅ , in which R _{5 is} an unsaturated aliphatic radical having up to 6 carbon atoms.

The invention relates to a further development of the 3-methyl-10-methylene-2,9-dioxatricyclo [4,3 _> l, O ^ jdecane of the general formula I.

RiO " H

H, C =

CH,

(D

in which Ri is an alkyl group with 1 to 4 carbon atoms and one of the two radicals R2 and R3 is a hydrogen atom and the other is a carbamyloxy group of the formula - OCONHR ₅ , where R5 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms according to Patent 23 06 118 , S-Me & yl-10-methylen - ^ - dioxatricycloTjW.OWjdecane are known per se from DE-OS 19 61 433

The known compounds wear in the 8-position an alkoxy group in the 4a-position (corresponding to R2 of general formula I) a hydrogen atom and in 4 /? position (corresponding to R3 of general formula I) a hydroxy group. The known compounds have novel CNS depressants and vasodilators Effects.

Patent 23 06 118 describes the corresponding 4 ″ -hydroxy compounds (corresponding to R2 = OH and R3 = H of the general formula I) and patent 23 06 118 describes the carbamyloxy compounds derived from the 4 ″ or Aβ-hydroxy compounds (Ri, R2 and R3 as defined above for general formula I)

The 4λ resp. 40-carbamyloxy compounds are distinguished by sedative or already narcotic effects.

Surprisingly, it has now been found that the sedative or narcotic effect is increased, if in the 4'-carbamyloxy compounds protected by the patent 23 06 118 the nitrogen of the Carbamyloxy group-substituting alkyl radical is replaced by an unsaturated aliphatic radical.

The present invention therefore relates to 3-methyl-10-methylene-2,9-dioxatricy-

clof ^ Al.O ^ ldecane of the general formula I in which Ri has the meaning given above, R3 is a hydrogen atom and R _{2 is} a carbamyloxy group of the formula —OCONHR5, in which R5 is an unsaturated aliphatic radical with up to 6 carbon atoms

Table 1 below shows the starting compounds according to the invention and known or analogous to them substances used with which tests were carried out on the effect, their Results are summarized in Table 2. As well assessable criteria for the pharmacological Effects became the ataxia, the hexobarbital anesthesia prolongation and the anesthetic chosen.

Tabel

Fp [ ⁰ C] (Kofler) reference ¹ )

(Methanol)

CH ₃
CH ₃
CH ₃

H
OH

OCONH-AUyI

OH

Oil 63 98-101 + 42 ° + 30 °

+ 38 °

981
2090
2286

') Substance number internal to the applicant, see for

981: DE-OS 19 61433, example 2.

2090: DE-PS 23 06 118, example la or the present application, example a). 2286: present application, example b).

Table 2

Connection ¹ )

ρ. ο.

mouse
mg / kg

LD ₅ ,, ip

mouse
mg / kg

Alaxia

Mouse mg / kg

Anesthesia hexobarbital anesthesia

ED ₅₁ ) ip extension

Mouse mouse

mg / kg mg / kg

610
774
970

600
300
444

') See footnote to Table 1.
- = not effective.

<300
55

15.5

The values in Table 2 show that in comparison with the known 4j3-hydroxy compound 981 or the to this epimeric 4 ″ -hydroxy compound 2090 the 4 ″ -N -allylcarbamyloxy compound according to the invention 2286 as a representative representative of the compounds claimed here with comparable or improved Toxicity has a comparable or improved effect in ataxia, also better in narcotic Effect is and finally shows a very good effect in the hexobarbital anesthesia extension in the the comparison substances are ineffective.

The preparation of the compounds of the invention are characterized in that a 3-methyl-10-methylene-2,9-dioxatricyclo [4,3, l, 0 ^37] decane of the formula II

clo [4,3, i, 0 ³ '] decan-4-one of the general formula IJI

R ₁ O

H ₂ C =

CH ₃

(U)

in which Ri has the meaning given above, R2 'is a hydroxyl group and R ₃ ' is a hydrogen atom, is reacted in a manner known per se with an isocyanate of the general formula R5NCO, in which R5 has the meaning given above.

It is also possible to react the OH compound with an appropriately substituted carbamic acid ester or chloride. The preparation of the carbamates according to the invention phosgene is carried out by reaction of the 4 "-hydroxy-8-alkoxy-2,9-dioxatricyclo [4,3, l, 0 ^37] decanes with phosgene to Chlorameisensäureester from which by reaction with the appropriate amine R5NH2 , in which R5 has the meaning given above, the desired carbamate is obtained.

For the preparation of the 4 <x -hydroxy compounds of the general formula required as starting materials II one proceeds in such a way that one 2,9-Dioxatricy-

CH ₃

(III)

in which the remainder Ri has the meaning given above, in a manner known per se with a metal hydride to form a 4'-hydroxy compound of the general formula II in which Ri, R2 'and R3' have the above meaning, reduced.

Compounds of the general formula III are known from DE-OS 20 27 890. The reduction of the The keto compound concerned is carried out analogously to that described in Tetrahedron Letters No. 35 (1970), p. 3090 Way.

example

a) 4 "-hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3, l, 0 ^37] decane (2090)

9.56 g of S-methoxy-S-methyl-10-methylene ^ -dioxatricyclo [4.3, 1.0 ³ - ⁷ ] decan-4-one were in 150 ml of dry

Dissolved ether and slowly dripped the solution under nitrogen into a slurry of 2.2 g of lithium alanate (L1AIH4) in 150 ml of dry ether. Now, an hour, it was refluxed, then cooled to 20 ⁰ C and the mixture poured onto ice water. After adding

of ammonium sulfate was extracted several times with ether. The combined ether extracts were over Dried sodium sulfate, clarified with a little animal charcoal, filtered and concentrated in vacuo. Yield: 9.3 g Crystals, that is 96.4% of theory.

h ^r i The 8-methoxy-3- used as starting compound

methyl-10-methylene-2,9-dioxatricyclot4,3, l, 0 ^37] decan-4-one is prepared according to the DE-OS No. 20 27 890th

b) 4ot-N-Allylcarbamyloxy-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3, l, O ³⁷ ] decane (2286)

5 g of 4'-hydroxy-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4 _r 3, ^{1.0 3} - ⁷ ] decane (2090) and 6.5 g of allyl isocyanate in 70 ml! Dissolved dry benzene, the mixture was refluxed for 24 hours. Then the reaction mixture was first evaporated in vacuo, the residue was admixed with 50 ml of ethanol to remove excess allyl isocyanate and again concentrated in vacuo.

The residue was then taken up in 150 ml of water and extracted 4 with 100 ml of ether each. The combined ether phases were dried over magnesium sulfate, clarified with a little charcoal and, after filtration, evaporated in vacuo. 7.5 g of crystalline crude product were obtained. After recrystallization from ether / hexane (1: 9; v: v) was added 4.5 g of the title compound as white crystals, melting at 98- 101 ⁰ C (Kofler, uncorrected), [α] '+ obtain 38 ° (methanol) ίο. The yield was 71.5% of theory.

Claims (1)

Claim: Further development of the 3-methyl-10-methylene-2,9-dioxatricyclo [43,1.0 ³ ' ⁷ ] decanes of the general formula I. RiO _Λ Η (D