FI56533C - SAETT ATT FRAMSTAELLA NYA 4ALPH CARBAMYLOXY-8-ALCOXY-10-METHYLENE-3-METHYL-2,9-DIOXATRICYCLO (4,3,1,03,7) -DECANER - Google Patents

Description

Public notice of publication

Α§Γα lbj (11) utläggningsskrift 56533 (^ 45) Patent aySnnr Ity - -1930

Patent EiTi ^ Elat V '^ (51) Kv.lk.' / Int.CI. * C 07 D 493/08 FINLAND —FINLAND (21) Petentihememu »- PatMUiueknlng 3983/73 (22) HakemUpilvl - Ansflknlngadag 27.12.73 ( 23) The beginning of the cloud - Giltlghettdag 27.12.73

(41) Made public - Bllvlt offwtlig Qg qQ

National Board of Patents and Registration ^ Nihttvik, date of entry and issue

Patent · OCh registerstyrelsen Antökan utlagd och utl.ikrlftan publkarad 31.10.79 (32) (33) (31) Pyydetty atuolkaui —Begird prlorltet 08.02.7 3

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2306ll8-9 (71) Kali-Chemie Pharma GmbH, Hans-Böckler-Allee 20, 3000 Hannover,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Peter Willibrord Thies, Hannover, Federal Republic of Germany-Förbunds-republiken Tyskland (DE) (7 ^ 0 Oy Borenius & Co. Ab (5 * 0 The way to make new 4a-carbamyloxy-8- alkoxy-10-methylene-3-methyl-2,9-dioxatricyclo [1.3.1.0 7,7] decanes - Stained in the form of Uct-carbamyloxy-8-alkoxy-10-methylene-3-methyl-2 , 9-dioxatricyclo [4.3.1.0 3,7] decane

The invention relates to a process for the preparation of novel 4α-carbamyloxy-8-alkoxy-? 3,10-methylene-3-methyl-2,9-dioxatricyclo [4.3.1.0 7,7] decanes of the general formula

R10 H

* "· 'Fe 0C0NHR2 H

in which formula represents a methyl or ethyl group, and R 2 represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkyl, cyclohexyl or phenyl group.

The process according to the invention is characterized in that 8-alkoxy-3-methyl- is 10-methylene-2,9-dioxatricyclo [4.3.1.0.9-7] decan-4-one of the general formula 2,56033 in which formula has the same meaning as above, is reduced by means of metal hydrides in a manner known per se to 4α-hydroxy-8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 °] -7-decane, whose general formula is

R1 ° SC1 H

CH (III)

ψ /// OH H

wherein the compound of formula III obtained is reacted in a manner known per se a) with an isocyanate of the formula R2NCO, in which R2 is as defined above, or b) with a carbamic acid ester of the formula R2NHCOR2, in which R2 is as defined above and R 3 is an alkoxy group, after which the resulting carbamyloxy compound of formula I is isolated.

The preparation of the 8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 °] -7-decan-4-ones of the formula II used as starting materials is described in DE-A-20 27 890. These the compounds are reduced in a manner known per se (Tetrahedron Letters, No. 35 (1970), 3087-3090) by means of metal hydrides to the formula IIIa 4α-hydroxy-8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4], To 3,10 ° -7-decanes, after which these compounds are reacted in a manner known per se with isocyanates or carbamic acid esters to give the new 4α-carbamyloxy-8-alkoxy-3 to 3 rrr τ τ

D03J J

3 to 7-methyl-10-methylene-2,9-dioxatricyclo [4- (3,1,0 °) to 7-decanes.

These new 4α-carbamyloxy compounds of the formula I have a novel, highly sedative or even narcotic effect, while the related 46-hydroxy and 4β-acyloxy compounds known from DE 19 61 433 have central nervous system and vasodilatory effects.

This novel sedative and even narcotic effect occurs both intravenously and intraperitoneally and when administered orally, acting rapidly and reliably when the compounds are administered in doses that are only a fraction of their LDgg. The narcotic effect differs from the effect of known para-pulmonary narcotic agents in the effective dosage range as follows: 1) faster onset of action when administered orally 2) absence of anticonvulsant effects 3) absence of barbiturate-enhancing effects after administration of narcotic doses of the compounds, 4) rapid elimination and biotransformation 5) especially in the absence of a depressive effect on vasomotor and respiratory centers at doses capable of inducing anesthesia lasting up to an hour without the use of other medications.

Anesthesia conditions induced at low doses resemble physiological sleep state because experimental animals remained aroused. The substances according to the invention thus meet the conditions which, according to the latest results of sleep research, are set for an ideal sleeping pill.

Good oral resorption and rapid onset of action are conditions that nowadays must be applied especially to sleeping pills and sedatives. To the best of our knowledge, however, no hypnotic or sedative is known to date which, moreover, would have the advantage of not enhancing the effect of barbiturates. Despite the large number of parapulmonary narcotic, sleeping and sedative drugs on the market, the barbiturate group still has the largest share of the market, and there is a real need for barbiturate-free sleeping pills, narcotic drugs, and sedatives.

56533 μ

The narcotic activity and toxicity of the two compounds prepared according to the invention are shown in the following Table 1, in which these values are also compared with 4'-hydroxy-8-methoxy-3-methyl-10-methylene-2,9-? 3-dioxatricyclo / 4.3 , 1.0 'to the corresponding values for 7-decane.

Table 1 ΙΛ) ςη oral LD.f, Abdominal Anesthesia

Compound R. R0. "V. ^ u,. ... EDcn through the abdomen 1 2 inside the cavity- 50,. ...

,. . . ,,. . to the cavity in mg / kg Q / t · mice mg / kg f. .

_ & hiin mg / kg

Reference compound 4 * * - hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 3,7] decane 774 300 <300

Eg 2a CH 2 C 2 H 5 1025 527 <100

Eg 2b 944 802 <100

It is clear from the values shown in the table that the compounds prepared by the process of the invention have lower toxicity and are considerably more advantageous than the previously known compound.

Using 4c * -N-ethylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxa-37 tricyclo [4.3.1.0 * 7] decane (e.g. 2a), an additional experiments in cats and dogs. The cat was 226 mg / kg given intravenously. When administered intravenously at 5 mg / kg, the length of anesthesia was 10 min. and 10 mg / kg intravenously for 25 minutes, and 15 mg / kg 60 minutes for intravenous anesthesia. The dog developed an hourly anesthesia using 17.5 mg / kg intravenously.

The sedative and hypnotic effect of the compounds according to the invention could already be observed in experiments performed on white mice. The following Table 2 shows by way of example 4 <* - N-allyl- (e.g. 3a) and 4c * -N-propylcarbamyloxy-8-methoxy-3-5 56533-3 37 methyl-10-methylene-2,9-dioxatricyclo [ Corresponding experiments with 4,3,1,0'-decane (Example 3b).

Table 2

Example 3b Example 3a

You use as experimental animals. mice = CH ^ R-j = CH ^ r2 = ch2-ch2-ch3 r2 = ch2-ch = ch2 LD ^ q oral 619 mg / kg 970 mg / kg LDgg intraperitoneally 516 mg / kg 444 mg / kg

Land at 100 mg / kg to 50 mg / kg

Reduced mobility 100 mg / kg 50 mg / kg

Side position (narcosis) 100 mg / kg 50 mg / kg

The Haffner reflex is missing 200 mg / kg 100 mg / kg

Climbing test EDgg 75 mg / kg 112 mg / kg

Equilibrium test EDj-q 39 mg / kg 50 mg / kg

The invention is explained in more detail below by means of examples. All speeds reported in the examples are determined in methanol. The melting point was determined on a Kofler melting point apparatus.

Example 1 a) 4α-Hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 °] -7-decane

- O H

9.56 g of 8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 3,7] decan-4-one was dissolved in 150 ml of dry ether, and the solution was slowly added dropwise to the slurry under nitrogen gas. with 2.2 g of lithium aluminum hydride (LiAlI) in 150 ml of dry ether. After refluxing for 1 hour, the mixture was cooled to 20 ° C and the reaction mixture was poured into ice water. Ammonium sulfate was added and extracted several times with ether. The combined ether extracts were dried over sodium sulfate, clarified using a little charcoal, filtered and evaporated in vacuo. Yield: 9.3 g of crystals, corresponding to 96.4% of theory.

C11H16 ° 4 'M: 212> 25 (calculated)

Sp. 63 ° C / α7p °: + 30 ° The starting 8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 °] -7-decan-4-one was prepared as described in DE-A-6 56633 20 27 890.

b) 4 * -Hydroxy-8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 2,7] decane

In the same manner as in Example 1a), 8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0-7] decane-4- prepared according to DE patent 20 27 890 was prepared as a starting material. onion 4 * -hydroxy-8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.3.0 2,7] decane.

C12H18 ° 4 M: 226.28 (calculated)

Sp. 36 ... 38 ° C / 'ft7p °: + 35 °

Example 2 a) 4 * -N-Ethylcarbamyloxy-8-methoxy-3-methyl- 3,710-methylene-2,9-dioxatricyclo [4.3.1.0,7] decane 5 g of 4λ-hydroxy-8- methoxy-3-methyl-10-methylene-2,9-dioxatri-3,7-cyclo [4,3,1,0'-7-decane was dissolved in 50 ml of dry benzene, 2.5 ml of ethyl isocyanate was added to the mixture, and 3 drops of glacial acetic acid, followed by stirring for 1 1/2 hours at 60 ° C. The reaction mixture was allowed to stand overnight at room temperature, after which the benzene was evaporated in vacuo, whereupon the residue crystallized. 6.7 g of crude product were obtained, which was N- [N-ethylcarbamyloxy-e-methoxy-5-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0] d-decane, corresponding to 99.5 % of theoretical amount. For analysis, recrystallization from a mixture of ether and n-hexane.

C14H21NO5, M: 282.32 (calculated)

Sp. 123 DEG-124 DEG C. [.alpha.] D @ 20 = + 30 DEG C. b) 4 * -N-ethylcarbamyloxy-8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1], 0 '_7-decane

In a similar manner to Example 2a) was prepared using 4 * -hydroxy-8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [3,7] -4,3,1,0-7-decane as starting material and ethyl isocyanate 4'-N-ethylcarbamyl-3'-oxy-8-ethoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 7,7] decane.

M: 297.35 (calculated) 56533 7

Sp. oil / ~ α7γ) °: + 17 °

Example 3 a) 4α-N-allylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 2,7] decane 5 g of 4α-hydroxy-8-methoxy- 3-Methyl-10-methylene-2,9-dioxatricyclo-ε 3,7 l 4,3,1,0 ° -7-decane and 6.5 g of allyl isocyanate were dissolved in 70 ml of dry benzene and refluxed for 24 hours. -jäähdyttäen. The reaction mixture was then evaporated in vacuo, 50 ml of ethanol were added to the residue to remove excess allyl isocyanate, followed by re-evaporation in vacuo. The residue was then taken up in 150 ml of water and extracted four times with 100 ml of ether. The combined ether phases were dried over magnesium sulphate, clarified with charcoal, filtered and evaporated in vacuo. 7.5 g of crystalline crude product were obtained. Recrystallization from a mixture of ether and hexane (1: 9 v / v) gave 4.5 g of white crystals, corresponding to 71.5% of theory.

C 18 H 9 N 2 O 3, M = 295.35 (calculated)

Sp. 98-101 ° C (+ 38 ° b) 4a-N-propylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-

- · O H

dioxatricyclo / 4,3,1,0 * V-decane

In a similar manner to Example 3 a) was prepared starting from 4α-hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo- [3,7,3,3,1,0] -7-decane and propyl -isocyanate compound 4α-N-propylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 2,7] decane.

^ 15 ^ 23N ^ 5 '^ 97.35 (calculated)

Sp. 51-53 ° C (+ 35 ° C) 4α-N-Isopropylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0] '^ 7-decane

In the same manner as in Example 3a), 4a-hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo-L 4,3,1,0 * -7-decane and isopropyl isocyanate were prepared as starting material 4a- N-isopropylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxa-tricyclo-4,3,1,3,7-p-decane.

56533 8 C. rH, gNOr, M: 297.35 (calculated) Ί 3 & Ο Ο ΛΑ (Sp.) Oil / ä_7p: + 33 °

Example 4 4α-N-Cyclohexylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 7,7] decane 6.5 g of 4α-hydroxy-8-methoxy-3- methyl 10-methylene-2,9-dioxatricyclo [3.3.4.1.0,7] decane and 15 g of cyclohexyl isocyanate were reacted in benzene and treated as described in Example 2. Since the obtained product could not be crystallized, it was purified by chromatography on silica gel using thick-layer plates (17 plates 20 x 20, solvents: n-hexane-ethyl acetate, n-propanol, 70: 24: 6 by volume).

Yield: 5.5 g of a colorless oil, corresponding to 59% of theory. C18H27NO5 »M = 337.40 (calculated) (m.p.) oil /" a7p1: + 62 °

Example 5 4α-Carbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 3,7] decane 6 g of 4α-hydroxy-8-methoxy-3-methyl- 10-Methylene-2,9-dioxatricyclo [4.3.1.0,7] decane was mixed with 7 g of ethyl urethane and 0.4 g of aluminum isopropylate, and the reaction mixture was heated at 145-154 ° C for 5 hours. at 200 Torr pressure. Completion of the reaction can be seen from the amount of ethanol distilled. At the end of the reaction, most of the excess ethyl pyrethane was removed by distillation under reduced pressure (50 Torr) to leave a high-viscosity yellowish residue. This was purified by chromatography on silica gel, and the desired carbamate was crystallized from a mixture of ethanol and carbon tetrachloride. The yield of 4α-carbamyloxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0-7] decane was 87% of theory.

C12H17NO5 M: 255.27 (calculated)

Sp. 184 ° C Z-7p3: + 48 °

Example 6 4α-N-Phenylcarbamyloxy-8-methoxy-3-methyl-10-methylene-2,1 g-dioxatricyclo [4.3.1.0 3,7] decane 56533 9 10 g Ha-hydroxy-8 -methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.3.0.0,7] decane was dissolved in 300 ml of benzene and refluxed for 10 hours with 10 ml of phenyl isocyanate as a catalyst. spatula pointed phenylmercuric acetate.

The solution with ethanol was then evaporated to dryness several times.

The residue was poured into 300 ml of water and extracted four times with 300 ml of ether. The combined organic phases were dried over MgCO 4, filtered and evaporated in vacuo. This gave 13.5 g of crude product. The product was purified on n-hexane / ether on silica gel to give 7 g of pure N, N-phenylcarbamyl- * 37 oxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [3.1.1], 0 '_7-dean.

C18H21NO5 M: 331.37 (calculated) (mp) oil / cx_7 °: + 42 °

Claims (1)

A process for the preparation of sedative 4α-carbamyloxy-8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 7,7] decanes having the general formula R10 in which formula represents a methyl or ethyl group and R 2 represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an allyl, cyclohexyl or phenyl group, characterized in that 8-alkoxy-3-methyl-10-methylene-2,9 -dioxatricyclo [4.3.1.0.0,7] decan-4-one of the general formula V 0 H CH2 ^ (II) in which R1 is as defined above is reduced by means of metal hydrides in a manner known per se 4a- hydroxy-8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4.3.1.0 3,7] -decane of the general formula R 1 ° H -Γ'H OH H (III) 56533 11 in which formula has the same meaning as above, after which the compound of formula III obtained is reacted in a manner known per se a) with an isocyanate of formula R2NCO in which R2 has the same meaning as above, or b) with a carbamic acid ester of the formula R2NHCOR2, in which R2 represents the same as above and R1 is an alkoxy group, after which the carbamyloxy compound of the formula I formed is isolated. For the further preparation of α-α-carbamyloxy-5-methyl-10-methylene-2,9-dioxatricyclo [3,11,0 °] -decaner with the addition of a solid, bold alloy form R1 ° \ H e -Ipv // oconhr2 H is R, j is a methyl or ethyl group and R2 is a hydrogen, an alkyl group of 1 to 4 cholera, an allyl, cyclohexyl or phenyl group, the parent compound being treated with an alkyl group reducing agents for 8-alkoxy-3-methyl-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ° * __-7-decan-U-one with the following formula