FI58776C - SAETT ATT FRAMSTAELLA NYA 4ALPH CARBAMYLOXY-8-ALCOXY-3,10-DIMETHYL-2,9-DIOXATRICYCLO- (4,3,1,03,7) -DECANER WITH A DRUG NETWORK - Google Patents

Description

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Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2306ll8.9 (71) Kali-Chemie Pharma GmbH, Hans-Böckler-Allee 20, 3000 Hannover 1,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Peter Willibrord Thies, Hannover, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7 * 0 Oy Borenius & Co Ab (5 * +) A way of making new sedatives and narcotics i + o-carbamyloxy-8-alkoxy-3,10-dimethyl-2,9-dioxatricyclone *, 3,1,03 * '] -decanes - Sätt att framställa nya-n-carbamyloxy-8-alkoxy- 3,10-Dimethyl-2,9-dioxatricyclo- [1+, 3,1,0 ^ '_ / - decane with luggage and narcotic network (62) Separated from application 3983/73 (patent 56533) -Avdelad frän ansökan 39Ö3 / 73 (patent 56533)

The present invention relates to a process for the preparation of novel 4α-carbamyloxy-8- to 3-alkoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decanes having the general formula R1 ooe ^ - ^ liiu oconhr2

B

wherein R1 represents a lower alkyl group and R? means hydrogen, lower alkyl, allyl, cyclohexyl or phenyl.

The process according to the invention is characterized in that 4α-hydroxy-8- [3,7-alkoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decane of the general formula 2 58776 R1 ° n CH3 v / »yCU« 3

"-bit u OH

wherein a is as defined above, is reacted with a) isocyanates of the general formula R 2 NCO, wherein R 2 is as defined above, or b) carboxylic acid esters of the general formula R 1 HCl, wherein R 2 is as defined above, and R 3 is an alkoxy group, or c) carbamic acid chlorides of the general formula R 2 NHCOCl, wherein R 2 is as defined above, after which the carbamyloxy compound (I) thus obtained is isolated.

The starting 4a-hydroxy-8-alkoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 2,7] decanes of formula II can be prepared according to Tetrahedron Letters 35 (1970), p. 3087-3090 by reducing with metal hydrides the 8-alkoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 2,7] decan-4-one disclosed in DE 2027890.

The novel 4α-carbamyloxy compounds of the formula I obtained from the 4α-hydroxy compounds of the formula II by the process according to the invention have a novel highly sedative or even narcotic effect, while the close 4g-hydroxy or 48-acyloxy compounds known from DE 1961433 have vasodilating 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 LD 2. The narcotic effect differs from the effect of known para-Pulmonary narcotic drugs in the effective dosage range as follows: 3,577,7 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 need to be imposed especially on 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.

Disorders of motor coordination, i.e., the ataxic effect, prolongation of hexobarbital-induced anesthesia, and anesthesia, were selected as well-detectable and evaluable criteria for the novel effect of the compounds of the invention.

The following Table 1 shows the demonstrative effects of some compounds using 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 * 7] decane as a reference.

58776

table 1

Compound ^ D50 ^ 50 Narcosis Hexobarbital- p.o. p.m. Ataxia EDS0 i'P · »Roosin pite- nemmen

Eg R. R- mice mice mice mice mice _ _mg / kg mg / kg mg / kg mg / kg_mg / kg_ 1 a) CH3 C2H5 51 8 297 68.1 1 00 31, 6 2 c) CH3 CH (CH3) 2 156 118 12 46.4 31.6 1 b) C2H5 C2H5 1470 527 - 100 ng

Comparison of 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 4,7] decane> 1500 1600 200 800 68 = no effect n.g. = not measured

As can be seen from the above values, the compounds according to the invention are more advantageous than the reference compound due to their ataxic and narcotic effects and the prolonging effect of hexobarbital anesthesia. Although the compounds of the invention have lower toxicity values, they still have a more advantageous dose-effect relationship than the reference compound.

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 the results of experiments performed with Ha-allyl and 4a-N-propyl compounds.

58776 5 Example 2 b Example 2 a m, R1 = CH ~ R- = CHq

Table 2 13 13

You use as experimental animals. mice ^ 2 = ^ 2 ~ ^ s ^ 2 oral LDcn 327 mg / kg 339 mg / kg

0 U

Intraperitoneal LDcn 244 mg / kg 279 mg / kg

Settle 100 mg / kg to 100 mg / kg

Reduced mobility 50 mg / kg 25 mg / kg

Side position (anesthesia) 100 mg / kg 100 mg / kg

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

Climbing test ED5Q 44 mg / kg 75 mg / kg

Equilibrium test ED, -q 38 mg / kg 62.5 mg / kg Preparation of starting material 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo / 4,3,1,0-7decane 4 g of DE patent 8-Methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0.0.0 7,7-decan-4-one prepared according to 2,027,890 was dissolved in 100 ml of dry ether and the solution was slowly added dropwise under nitrogen gas. to a slurry of 1 g of LiAlHl + in 100 mL of dry ether. It was refluxed for 1 hour, then cooled to 20 ° C and 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: 4 g, corresponding to 99% of theory. the oily product rotation / ot7 ^ was -61 °.

In the same manner as above, 8α-hydroxy-8-ethoxy-3,10-dimethyl-3,7,9-dioxatricyclo [4.3.1.0,7] decan-4-one was prepared from 4α-hydroxy-8-ethoxy- 3.10-Dimethyl-2,9-dioxatricyclo [4.3.1.0 * 7] decane. the rotation of the oily product was / ä_7p = -63 °.

The invention is explained in more detail below by means of examples.

All rotations mentioned in the examples have been measured in methanol. Melting points are measured with a Kofler melting point apparatus.

6 58776

Example 1 a) 4α-N-Ethylcarbamyloxy-8-methoxy-3,1O-dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane 5.0 g of 4α-hydroxy-8-methoxy-3,10-dimethyl -2,9-Dioxatricyclo [m] * 4,3,1,0 ° -decane and 5 ml of ethyl isocyanate were dissolved in benzene and a small amount of acetic acid was added to the solution as a catalyst. After a few hours, the ethyl isocyanate was practically quantitatively attached to the alcohol so that The corresponding carbamate was formed, which was then neutralized with sodium bicarbonate, washed with water and dried, after which the benzene was evaporated to give white crystals of 4α-N-ethylcarbamoyl-? 3-oxy-8-methoxy-3,10-dimethyl-2,9- dioxatricyclo / 4,3,1,0-7decane was obtained quantitatively.

C14H23NO5, H: 285.33. Mp 103-105 ° C. / ά_7 ^ ° -31 °.

b) 4α-N-Ethylcarbamyloxy-8-ethoxy-3,1O-dimethyl-2,9-dioxatricyclo [-4.3.1.0 2,7] decane

In the same manner as in Example 1a, 4α-hydroxy-8-ethoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 4,7] decane and ethyl isocyanate were prepared by adding acetic acid, neutralizing, washing and purifying. by separating crystalline 4α-N-ethylcarbamyloxy-8-ethoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1,00,7] decane.

C15H25NO5 M: 299'37 · S.P · 73 ... 75 ° C / "a7 ^ 3 -17 °

Example 2 a) 4α-N-Allylcarbamyloxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 2,7] decane 4.5 g of 4α-hydroxy-8-methoxy-3, 10-Dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decane and 4 g of allyl isocyanate were heated for 24 hours in benzene to which a few drops of glacial acetic acid had been added at 50-60 ° C, followed by the treatment was continued as described in Example 1. The crude product (6.0 g) was recrystallized from a mixture of n-hexane and diethyl ether (1: 9 v / v) to give 4.2 g of white crystals, corresponding to 67% of theory.

C15H23NO5 'M = 297> 35 7 58776

Sp. 56-58 ° C. B) 4α-N-propylcarbamyloxy-8-methoxy-3,10- ** 3 7 dimethyl-2,9-dioxatricyclo [4,3,3,10-] decane

In the same manner as in Example 2 a), 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0] decane and propyl isocyanate were prepared by adding acetic acid and heating H-N-propylcarbamyloxy- 8-Methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decane as an oily product.

C15H25NO5 'M: 299> 37 S.p. - [α] 220 -20 ° C) 4α-N-Isopropylcarbamyloxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane

In the same manner as in Example 2 a) was prepared by heating 4-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane and isopropyl isocyanate in the presence of acetic acid 4a-N -isopropylcarbamyloxy-8-methoxy-3,10-dimethyl-2,9-dioxa-tricyclo [4.3.1.0 3,7] decane as an oily product.

C1 5H2 5NO5 M: 299'37 S.p. - / -a720 -27 °

Example 3 4α-N-Cyclohexylcarbamyl-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane

Option 1 • . . - 3 7 5 g of 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0] decane and 5 g of cyclohexyl isocyanate were boiled for 6 hours in 70 ml of benzene, to which 3 drops of glacial acetic acid had been added, using a vertical condenser. The treatment was performed as described in Example 1a). First, the crude product obtained as an oil was crystallized from n-hexane. Yield: 6.2 mg of white crystals, corresponding to 78% of theory.

ClflH9qNO2, M: 339.43

Sp. 109-110 ° C / α721 -26 ° β 58776

Option 2

A solution of 4.45 g of cyclohexylamine and 50 ml of benzene was bubbled with dry HCl gas until precipitation was complete. To the benzene suspension of cyclohexylamine hydrochloride was added, with stirring, 50 ml of a 20% toluene solution of phosgene, and the mixture was refluxed for 6 hours to form clear cyclohexylcarbamic acid chloride. The reaction mixture was cooled, carefully neutralized with 20% benzene solution of triethylamine, followed by the addition of 3.31 g of 4α-hydroxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decane dissolved in 20 ml. to benzene. A couple of drops of acetic acid were added to the mixture, followed by boiling with stirring and refluxing for 36 hours. The mixture was then allowed to cool, the separated precipitate was filtered off and the filtrate was evaporated to dryness several times with benzene until the pungent odor of cyclohexyl isocyanate had disappeared. The crude product, 7.15 g of a tan oil, was purified by column chromatography on silica gel using ether-n-hexane (15:85) as eluent. 4.1 g of pure white crystals (78% of theory) with a melting point of 110-112 ° C were obtained.

Example 4 4α-Carbamyloxy-8-methoxy-3,10-dimethyl-2,9-q7-dioxatricyclo74,3,1,0-7-decane-q7 5 g of 4α-hydroxy-8-methoxy-3,10-dimethyl- 2,9-Dioxatricyclo [4.3.1.0 7,7] decane was mixed with 5 g of ethyl urethane and 0.4 g of aluminum isopropylate, and the reaction mixture was heated at about 150 ° C for 5 hours at 0.27 bar. pressure. 2 and 4 hours from the start of the reaction, 5 g of methane were added. At the end of the reaction, most of the excess urethane was removed under reduced pressure (0.067 bar). The residue was purified on silica gel using ether-n-hexane solution. The yield was 2.6 g. C12H19NO5 M: 257.28 M.p. 157-158 ° C "39 °

Example 5 a) 4α-N-phenylcarbamyl-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 7,7] decane - 3,7 3 g of 4α-hydroxy-8-methoxy-3, 10-Dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane and 5 ml of phenyl isocyanate were dissolved in 50 ml of benzene to which a couple of drops of glacial acetic acid had been added. After a reaction time of 6 hours, 9,577,76 of the mixture were evaporated with benzene several times in vacuo. The residue was poured into 50 ml of ice water and extracted three times with 50 ml of benzene. The combined organic phases were dried over Na 2 SO 4, filtered and evaporated in vacuo. The product was purified on silica gel with n-hexane / ether to give 3.8 g of an oily product.

C 9 H 23 NO 5, M: 333.3

Sp. (oily) [α] D 7 23 ° b) 4α-N-phenylcarbamyloxy-8-ethoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 3,7] decane

In the same manner as in Example 5 a) 4a-N-hydroxy-8-ethoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0] 7-decane and phenyl isocyanate were prepared from oily 4a-N -phenylcarbamyloxy-8-ethoxy-3,10-dimethyl-2,9-dioxatricyclo [4.3.1.0 °] decane.

C19H2 5N05 'M: 347'41 S.p. (oily) [α] 25 D -16 °

Claims (1)

58776 1 o Claim A process for the preparation of new sedative and narcotic-acting • 4'-carbamyloxy-8-alkoxy-3,10-dimethyl-2,9-dioxatricyclo-3,7 / 4,3,1,0'-decanes of the general formula is R10 U-OCONHR2 H in which R1 represents a lower alkyl group and R1 represents hydrogen, a lower alkyl group, an allyl group, a cyclohexyl group or a phenyl group, characterized in that 4α-hydroxy-8-alkoxy-3,10-dimethyl-2,9 -dioxatricyclo-__ 3 7 / 4,3,1,00-7-decane of the general formula R 10 ° - min OH H in which R 1 is as defined above is reacted with a) isocyanates of the general formula R 2 NCO, wherein R 2 is as defined above, or b) with carbamic acid esters of general formula R 1 NHCOR 8, wherein R 2 is as defined above and R 3 is alkoxy, or c) with carbamic acid chlorides of general formula R 2 NHCOCl, wherein R 2 is as defined above, whose ice The carbamyloxy compound (I) thus obtained is isolated. A 4-carbamyloxy-8-alkoxy-3,1O-dimethyl-2,9-dioxatricyclo [-4,3,1,0] 7-decane with a mixture of drugs and a narcotic network with the formula H 1 0C0NHR2 H is added. Formula R 1-4 alkyl and alkyl groups and R 1-4 alkyl derivatives, alkyl groups, allyl groups, cyclohexyl groups or phenyl groups, inverted compounds, but not α-hydroxy-8-alkoxy-3,1O-dimethyl-2,9-dioxatricyclo / 4,3, 1, 0 ', 7-decane with the formula - ^ o,' --Am OH H 1 wilts the formula R ^ betecnar decamma som ovan, bringas att reagera med a) isocyanater with the form of R2NCO rär R2 betecknar detsamma som ovan, eller