IL44145A - Dioxatricyclodecanes and their production - Google Patents

Abstract

1436821 4 - Hydroxy - 2,9 - dioxatricyclo [4,3,1,0<SP>3,7</SP>]decanes KALI-CHEMIE PHARMA GmbH 18 Jan 1974 [8 Feb 1973] 02548/74 Heading C2C Novel compounds I in which R 1 is C 1-4 alkyl, R 2 is OCOR 4 or OCONHR 5 when R 3 is hydrogen and R 3 is OCONHR 5 when R 2 is hydrogen (R 4 is C 1-4 alkyl and R 5 is a C 1-6 alkyl, C 2-6 unsaturated aliphatic, C 3-6 cycloaliphatic or aromatic group) and the 10,11 bond may be hydrogenated are prepared by reducing a compound III in which the 10,11 bond may be hydrogenated preferably with a metal hydride to form a mixture of the corresponding 4α- and 4#- hydroxy compounds and reacting the 4α-OH compound with a carboxylic acid chloride R 4 COCl, a carboxylic anhydride (R 4 CO) 2 O, an isocyanate R 5 NCO, an ester or chloride of a carbamic acid R 5 NH-COR 6 (in which R 6 is chlorine or alkoxy) or with phosgene followed by an amine R 5 NH 2 to form compounds I (R 3 =H): compounds I (R 3 = OCONHR 5 ) are prepared from the corresponding 4#-hydroxy compound by the methods described above. Compounds I have sedative, hyprotic and narcotic properties and may be administered orally or parenterally. [GB1436821A]

Description

Novel dioxatricyclodecanes and their1 production1 ALI-CHEMIE PHARMA GMBH C. 42320 This invention relates to 4-hydroxy-2., 9-dioxatricyclo- 3 7 . [4,3,1,0 ' Idecane esters with lower .alkanoic and carbaitiic . acids of the general formula I wherein ¾ is an alkyl group containin 1 to k C-atoms, 1¾2 is an OCOR^ or OCONHR,. group when is a hydrogen atom, and is an OCONHR,. group when R is a hydrogen atom, and wherein R^ is an alkyl group containing 1 to 4 C-atoms and R5 is a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an ethylenically unsaturated aliphatic hydrocarbon radical containing 2 to 6 carbon atoms , cyclo-aliphatic hydrocarbon radical containing 3 to 6 C-atoms or a phenyl group, and the 10,11 double bond may be hydrogenated.

Israel Patent Specification No. 35768 describes certain 3 7 4-hydroxy-2 , 9-dioxatricyclo [4,3,1,0 ' ]decanes and their esters, in which the OH or the ester group is in β-position. These compounds have novel depressant effects on the central nervous system and they are vasodilatants.

It has now been found that the hitherto unknown C^ epimeric esters of these compounds have a powerful , quick and reliable sedative or even a considerable narcotic effect when intravenously, intraperitoneally, or perorally administered in doses which are only fractions of the LD^Q. Within their effective dosage range, their narcotic effects differ from those of 44145/2 1. a more rapid effect after peroral administration, 1~ 2. the absence of anticonvulsive effects, 3. the absence of barbiturate-potentiating effects after the administration of narcotic doses of compounds not hydrogenated in 10,11 position, k . rapid elimination and bio-transformation, and, 5. in particular, the absence of a depressant effect on the vasomotor and respiratory centre upon administration of doses capable of causing and, without supplementary medication, maintaining narcoses lasting up to one hour.

States of narcosis in tested animals brought about by low doses resemble the state of physiological sleep, since the tested animals can be awakened. The compounds according to the invention thus satisfy conditions which, according to the most recent research into sleep, an ideal hypnotic drug should fulfil.

Good oral absorption and rapid initiation of effects are conditions which are nowadays demanded, particularly of a hypnotic or sedative drug. However, we are not aware that a hypnotic or sedative drug has so far been proposed which offers the additional advantage of having no potentiating effect on barbiturates. Of the large number of parapulmonary narcotics, hypnotics and sedatives on the market, barbiturates represent the major proportion and there is a considerable potential demand for hypnotics, narcotics and sedatives that are not barbiturates and are free from barbiturate potentiation.

Whereas in the alcohols and esters described in Patent Specification No. 35768 the 4-hydroxy group or acyloxy group is in β-position the esterified hydroxy group in the present carboxylic esters is in a-position. This epimerisa- 44145/2 Epimerisation can be successfully accomplished f instance by oxidation of the C-k-β alcohols to the 2,9-dioxatricycl of formula II as described in the Israel Specification No. 35768 wherein R^ is an alkyl group containing 1 to k C-atoms and the 10,11-double bond may be hydrogenated, followed by reduction, for instance with hydrogen, in contact with a catalyst, such as Raney nickel, but preferably with a metal hydride, when the C-k-a alcohols are obtained in overall yields of 60 to 80 of theory. Esterification can be carried out in conventional manner with carboxylic anhydrides of the formula (R4CO)20 or carboxylic acid chlorides of the formula 4COCl. For the production of the carbamates, the -hydroxy compound is reacted with an isocyanate of the general formula R^NCO or with an ester or chloride of carbamic acid of the general formula R5 HCOR5, where R5 has the above specified meaning and R^ is a chlorine , atom or an alkoxy group. Alternatively the -hydroxy compound can be first reacted with phosgene to form the chlorofor ic acid ester and this then converted to the required carbamate by reaction with the corresponding amine R^NH^* Naturally the esters could also be obtained by transesterification.

It has further been found that esters of carbamic acid of the β-compounds also have a greater sedative effect than th . e S fication 5768 44145/2 The β-carbamic acid esters can t>c prepared in an 1 analogous manner to the a-carbamic acid esters, the starting material being a 4-p-hydroxy-2,9-dioxatricyclo [4,3,1,03 ' 7 ]decane as described in Israel Patent Specification No. 35768 and having the following formula where R-j^ is an alkyl group containing 1 to k C-atoms and the 10,11 double bond may be hydrogenated, this starting compound being esterified as above described.

A few physical data of the C-k epimers produced as, or in an analogous method to that, described in the Examples are collated in the following Table, those compounds which do not form part of the present invention being indicated by an asterisk.

• '· V. ■' .44145/3 Ψ 2a le_l .

Table 1 (continued) 1 a'est R mp. °C. r„ 720 C-4 substituents No. (Kofler) a-7D (methanol) 1246* CH3 oil - 36 0 β - OH, - H 1561* CH5 oil - 61 0 a - OH, β - H 2045* CH3 oil .0 0 β-OCOCH^ a - H j 2080 oil - 35 0 a-0C0CH3, β - H I j 2044* J1 CH5 49-52 0° β-θσθ0Η2ΟΗ3, a - H | i 2081 j CH5 ,oil - 32 0 a-0C0CH2CH3, β - H : j 1767 CH3 91-93 - 2 0 β-00Ο1«ΐσΗ20Η3, a - H j 2026 CH- 103-105 - 31 ° a-0C0NHCH2CH3, β - K i ! 2057 ! CH- ' j 128-132 j 0°■ > · β-000ΝΗ0Η(σΗ3)2, a - H 12065 CH3 j oil j - 27 a-0C0NHCH(CH3)2, β - H 2198 CH- j 130 ] - 5° .1 β-000 Η2, a - H j 2157 CH —CH3 73-75 - 17° a-0C0NHCH2,CH3 β - H ί 44145/2 The differences in the effect of some pairs of epimers and a-homologues a pair of a 10,11 hydrogenated and unhydrogenated compounds are illustrated in Table 2.

Table 2 Failure of muscular coordination, i.e. ataxia, the prolongation of hexobarbital narcosis and narcosis were chosen because they are readily observable and assessable criteria.

\ For instance, if the pair of epimers identified by the two test numbers 2067 and 2076' are compared it will be clearly' apparent that, despite substantially the same toxicity and the same dose causing ataxia, only the ct-compound 2076 itself has a narcotic effect without prolonging the hexobarbital narcosis ,' whereas the β-compound is not narcotic, but prolongs the hexobarbital narcosis. In the analogous pair of epimers bearing test numbers 2057 and 2065 which are hydrogenated at the C-10 atom the differences are even greater. However, in this case the β-compound neither produces narcosis nor does it prolong a hexobarbital narcosis, whereas the a-compound has a very pronounced narcotic effect besides prolonging a hexobarbital narcosis even in doses less than the narcotic dose. Whereas 147 mg./kg. of the β-compound are needed to cause ataxia, the a-compound needs only 12 mg./kg. to produce this effect.

However, this increase in effectiveness by a power of ten is in conformity with higher toxicity. Nevertheless, the relation (effective dose to lethal dose) remains constant. Furthermore, if the effective doses pf the C- -β alcohols listed in Table 2 are compared with those of their esters, a clear intensification of the depressant effect on the central nervous system, accompanied by a simultaneous reduction in toxicity by esterification, for instance with acetic, propionic, ethylcarbamic , and isopropylcarbamic acid can be observed. However, the intensification which ! 44145/2 cannot be achieved by such esterification does not produce narcotic effects, lipophilic properties of the esters are significantly greater than those of the alcohols.

The narcotic effectiveness of the present 2, 9-dioxatricyclo ,3,l,03'7] decanes is obviously stereospecific and tied to the C-¾-a-configuration, as is unambiguously borne out by comparisons between the pairs of C~¾ epimers listed in Table 2.

The sedative and hypnotic effectiveness of the, present compounds has been recognised in screening tests on white mice. The relevant tests performed with the k a-N-allyl- and the k a-N-propyl-carbamates are listed by way of example in the following Table. x The invention will now be further illustrated by the following Examples, of which Example 1 illustrates the production of a starting material Example 1 ^-a-Hydroxy-S-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo- l¾,3,l,03»7 decane (2090). \ 9.56 g. of S-methoxy-3-methyl-10-methylene-2, 9-dioxatricyclo-[k, 3, , prepared as described in Specification No. 1,290,828, were dissolved in 150 ml. of dry diethyl ether. The solution was added slowly under nitrogen dropwise into a suspension of 2.2 g. of lithium aliuminium hydride (LiAlH^) in 150 ml. of dry diethyl ether. This was then refluxed for one hour, cooled to 20^C. and poured onto ice water. After the addition of ammonium sulphate, the mixture was repeatedly extracted with diethyl ether. The combined ether extracts were dried over sodium sulphate, clarified with a little animal charcoal, filtered and concentrated under vacuum. Yield:- 9.3 g. of a crystallised product, being 96.4% of theory.

Example 2 'i-a-Acetoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo-^,3,l,03'7]decane (2117). 3.2 g. of the 4-a-hydroxy-8-methoxy-3-methyl-10-methylenc-2,9-dioxatricyclo- , produced as in Example 1, were dissolved in a mixture of 2 ml. of pyridine and 8 ml. of acetic anhydride and allowed to stand. for 2k hours at room temperature. Excess pyridine and acetic anhydride Were then distilled off under vacuum, the residue being taken up in ice water and extracted with diethyl ether. After the ether extract had been dired over sodium sulphate and concentrated in vacuo , the ¾-a-acetpxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo- -, 3, 1 , slowly crystallised. After 44145/2 Example 3 -a-Propionoxy-S-methoxy-3-methyl-10-methylene--2,9-dioxatricyclo 3i (2118). 3.2 g. of -a-hydroxy-8-methoxy-3-methyl-10-methylene--2,9-di oxatri eye 1o b , 3 , 1 , 05 > 7]decane produced as in Example 1 were reacted in the manner described in Example 2, with 15 ml. of propionic anhydride and 2 ml. of pyridine and worked up as described in- Example 2. After crystallisation from diethyl ether/n-hexane , 4.0 g. of 4-a-propionoxy-8-methoxy-3-methyl-10-methylene-2, 9-dioxatricyclo [4, 3, 1,Ο^» T^decane, representing 98.7 of theory, were obtained.

Example 4 4-a-Ethylcarbamoyl-8-methoxy-3-methyl-10-methylene-2 , 9-dioxatricyclo [4 , 3 , 1 , 03 ' 7] decane (2076). 5 g. of 4-a-hydroxy-8-methoxy-3-methyl-10-methylene-2, 9-dioxatricyclo {j¾,3,l, produced as in Example 1 were dissolved in 50 ml. of dry benzene and, after the addition of .2.5 ml. of ethyl isocyanate and 3 drops of glacial acetic acid, stirred at 60°C. for 1½ hours.. After having been allowed to stand overnight at room temperature, the benzene was distilled off in vacuo. This caused the residue to crystallise. The yield of 4-a-ethylcarbamoyl- 3 7 8-methoxy-3-methyl-10-methylene-2 , 9-dioxatricyclo [4 , 3 , 1 , 0 ' ]-decane was 6.7 g. or 99.5% of theory. For analysis the product was recrystallised from diethyl ether/n-hexane.

This compound was also used for additional tests on cats and dogs. At an i.v.LD^g oi 226 mg./kg. in the case of cats, the duration of the narcosis after the administration i.v. of 5 mg./kg. was 10 minutes, after the administration i.v. of 10 mg./kg., 25 minutes, and after the administration In the case of dogs a narcosis lasting one hour could be produced with 17.5 mg./kg. i.v.

Example 5 3 , 10-Dimethyl-4-B-isopropylcarbamoyl-8-methoxy-2 , 9- 3 7 dioxatricyclo[4,3,l,0 ' Jdecane (2057) . k.5 g. of ½- -hydroxy-8-methoxy-3,10-dimethyl-2,9- dioxatricyclo^.,3,l,o5»7]decane (1246) prepared by the method described in Specification No. 1,309,928 were added to a solution of 10 ml. of isopropyl isocyanate in 50 ml. of "benzene and, after the addition of 5 drops of acetic acid, the clear solution was allowed to stand at room temperature. The solution was repeatedly evaporated in vacuo after the addition of "benzene to remove excess isopropyl isocyanate, the residue was poured onto ice water, and extracted with benzene. After washing the benzene phase with water, drying over sodium sulphate and concentrating, in a vacuum, . a yellowish oil resulted which crystallised when triturated with diethyl ether/n-hexane. The yield of pure 3,10-dimethyl-4-6-isopropylcarbamoyl-8-methoxy-2 , 9-dioxatricyclo- ' 3 7 [4,3,1,0 ' Jdecane (2057) was 4.7 g., i.e. 75% of theory.

Example 6 -a-Hydroxy-8-methoxy-3, 10-dimethyl-2, 9-dioxatricycloid , 3, 1 , 03» 7] decane (156I). k g. of 3, 10-dimethyl-8-methoxy-2, 9-dioxatricyclo ^, 3, Ι,Ο5»7}-decan-4-one prepared by the method described. n Specif cation No. 35768 were reduced in a manner analogous to that described in Example 1 with lithium aluminium hydride in dry diethyl ether. 4-a-Hydroxy-3 , 10-dimethyl-8-methoxy-2 , 9-dioxatricyclo- 3 7 [4,3,1,0 ' ]decane (1561) was obtained in a practically quantitative yield (4.0 g.).

Example 7 ; ' 'i-a-Acetoxy-S-methoxy-S, 10-dimethyl-2, ^dioxatricyclo- h.O g. of ½-a-hydroxy-8-methoxy-3, i0-dimethyl-2,9-dioxatricyclo i , 3, 1 , 0^> 7 decane were dissolved in 1^2 ml. of acetic anhydride and Ί ml, of pyridine and the clear solution was kept for k hours at room temperature. After the excess , acetic anhydride and pyridine had been distilled off, the residue was poured onto ice water and extracted with diethyl ether. The ether phase was washed ,with a IN sodium hydroxide and water and dried over sodium sulphate before being concentrated in vacuo until the weight remained constant. 4.5 g. of colourless oily ¾-a-acetoxy-8-methoxy-3, 10-dimethyl-2,9-dioxatricyclo [¾,3,1, 05»7 decane (2080), equivalent to 9k°/o of theory, were obtained.

This compound can also be obtained by the catalytic reduction of 4-a-acetoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo ,3,l,o5i 7^decane (2117), prepared as. described in Example 2, for instance by treatment with hydrogen in the presence of palladium on active carbon in an analogous manner to that described in Example 3 of Israel Specification No. 35768.

Example 8 4-a-Ethylcarbamoyl-8-methoxy-3 , 10-dimethyl-2 , 9-dioxatricyclo-[4,3,l,03'7]decane (2026). 5.0 g. of 4-a-hydroxy-8-methoxy-3, 10-dimethyl-2,9-dioxatricyclo [h, 3, 1 , Or** and 5 ml. of ethyl isocyanate were dissolved " n benzene, a little acetic acid being added as a catalyst. After a few hours, the formation of the corresponding carbamate had been practically quantitatively completed. The -solution was first neutralised with sodium bicarbonate and then washed with water, whereafter the benzene phase was concentrated after having been dried.

A white crystalline product was immediately obtained.

The yield of 4-a-ethylcarbamoyl-8-methoxy-3 , 10-dimethyl- 3 7 2,9-dioxatricyclo[4,3,l,0 ' ]decane (2026) was practically quantitative .

Example 9 4- -Carbamoyl-8-methoxy-3-methyl-10-methylene-2 , 9- 3 7 dioxatricyclo[4,3,l,0 ' ]decane (2230) . 6 g. of -p-hydroxy-8-methoxy-3-methyl-10-methylene-2 , 9- dioxatricyclo ¾, 3 , l, 03»7]aeca e were mixed with 7 g. of ethyl urethane and 0.4 g. of aluminium isopropylate and the mixture* was kept at a temperature of 150 to 154°C. under a pressure of 200 mm. Hg for 5 hours. The end of the reaction could be recognised by the quantity of ethanol that had come over. Towards the end of the' reaction, the principal quantity of ' the excess ethyl urethane was distilled off at reduced pressure ( 50 mm. Hg), leaving a highly viscous yellowish residue. This was chromatographically purified on silica gel and the desired carbamate was crystallised - from a mixture of ethanol and carbon tetrachloride. The yield of 4-B-carbamoyl-8-methoxy-3-methyl-10-methylene- 2,9-dioxatricyclo[4,3,l,03,7]decane (2230) was 87.3% of theory. Example 10 4-a-N-Allylcarbamoyl-3-methyl-10-methylene-8-methoxy- 2 , 9-dioxatricyclo [½, 3 , 1 , 03,7]decane . 5 g. of '--a-hydroxy-3-methyl-10-methylene-8-methoxy-2 , 9- dioxatricyclo[ , 3,l, 03'7ldecane and 6. 5 g. of allyl isocyanate 44145/2 were dissolved in 70 ml. of dry benzene and refluxed for 2k hours. The reaction mixture was then first evaporated In vacuo , whereafter 50 ml. Of ethanol were added to the residue and re-evaporated in vacuo to remove excess allyl isocyanate. The residue \^as then taken up in 150 ml. of water and extracted four times with 100 ml. of diethyl ether. The. combined ether extracts were dried over magnesium sulphate, clarified with a little charcoal and, after filtration, re-evaporated in a vacuum. 7.5 g. of a crystalline product was the result. After re-crystallisation from diethyl ether/hexane (l : 9; vol/vol) . g. of white crystals were obtained (71.5°/o of theory) .

C15H21N05> Molecular weight = 295.35 Mp. = 98 - 101°C. (Kofler, uncorrected) L^D"5 + 5S° (methanol) Example 11 4-β-Ν-All lcarbamoyl-3-methy1-10-methylene-8-methoxy- 2, 9-dioxatricyclo ½, 3, 1 , O^ > 7] decane . 5 g. of - -hydroxy-3-methyl-10-methylene-8-methoxy-2, 9-dioxatricyclo ji,3,l, O-^'^decane were reacted in benzene with allyl isocyanate and worked up in an analogous manner to that described in Example- 10. . 7.5 g. of an oily product were obtained. This first had to be chromatographed on 100 g. of silica gel with (80 : 20;*vol/vol) before it was sufficiently pure to crystallise.

Yield:- 5.0 g. of white crystals (79.3 of theory).

C15H21N05» Molecular weight = 295.35 Mp. = 52 - 53°C. (Kofler, uncorrected) [a]3 = + 6° (methanol) Example 12 4-a-N-Allcarbamoyl-3 , 10-dimethyl-8-methoxy-2 , 9- dioxatricyclo [ , 3, 1 , 0^' ^] decane . 4.5 g. of 4-a-hydroxy-3, 10-dimethyl-8-methoxy-2,9- dioxatricyclo , 3 , 1 , 0^' 7] decane were heated at 50 to 60°C. for 24 hours together with 4 g. of allyl isocyanate in benzene and with the addition of. a few drops of glacial acetic acid, and then worked, up in an analogous manner to that described in Example 10.

After recrystallisation of the product (6.0 g.) from n-hexane/diethyl ether (l : 9; vol/vol), 4.2 g. of a white crystalline product were obtained (67 of theory).

C15H23 05» Molecular weight = 297.35 Mp. = 56 - 58°C. (Kofler, uncorrected) WD2 = 32° (methanol) Example 13 4-cx-N-Cyclohexylcarbamoy 1-3 , 10-dimethyl-8-methoxy-2 , 9-dioxatr cyclo [4, 3, 1 , 0^» decane. 5 g. of 4-a-hydroxy-3, 10-dimethyl-8-methoxy-2, 9-dioxatricyclo [k , 3, 1 , 0^' decane were refluxed for 6 hours together with 5 g. of cyclohexyl isocyanate in 70 ml. of benzene with the addition of 3 drops of glacial acetic acid, and worked up in the same way as described in Example 10. The product which was at first oily could be crystallised from n-hexane.

Yield:- 6.2 g. (i.e. 78°/o of theory).

White crystals, . Molecular weight = 339.45 Mp. = 109 - 110°C. -(Kofler, uncorrected) [a] 21 = _26° (methanol) 44145/2 Example 14 6.5 g. of 4-oc-hydroxy-3-methyl-10-methylene-8-methoxy- 2, 9-dioxatricyclo [ , 3, 1 , 0^» ^decane were reacted in "benzene with 15 g. of cyclohexyl isocyanate and worked up in a manner analogous to that described in Example v13. As the final product could not be crystallised, it was first purified chromatographically on thick layer plates of silica gel (17 plates 20 x 20; solvent:- n-hexane, ethyl acetate, n-propanol 70 : 24 : 6; vol/vol/vol). Yield: 5.5 g. of a colourless oil, i.e. 59 of theory.

Molecular weight = 337.40 [ajg1 = + 62° (methanol) Example 15 4- -Phenylcarbamoyl-3 , 10-dimethyl-8-methoxy- 2 ,9- ' dioxatricyclo ¾, 3, 1 , 0-^' ^decane . , ■- 3.4 g. of 4- -hydroxy-3, 10-dimethyl-8-methoxy-2,9- dioxatricyclo 4,3,1, 0^'^^decane and 5.13 g. of phenyl isocyanate were dissolved in 200 ml. of benzene with the addition of 10 drops of glacial acetic acid, and then heated at 60°C. for 15 minutes. The solution was then allowed to cool to room temperature and thus kept for 24 hours. After 'concentration in vacuo the , further processing was as in Example 10.

After re-crystallisation from benzene, 4.1 g. of a white crystalline product representing 79 theory, were obtained.

C,oHo_N0e: Molecular weight = 333.3 18 23 5 . · Mp. = 15 - 156°C. (Kofler,. uncorrected) 44145/2 4-3-Phenylcarbamoy1-3,10-dimethy1-8-methoxy-2 ,9-dioxatricyclo is a β-compound and therefore has no narcotic effect, but it does have an effect on the nervous system which in th case of white mice could be recognised as analgesic (ED5Q m 140 mg./kg. ; LDJJQ « 1500 mg./kg/ p.o. ) , muscle relaxing (comparable with phenobarbital) and spasmolytic (the ED5Q being one tenth of the for atropine) .

Claims (6)

44145/3 CLAIMS :

1. 4-Hydroxy-2,9-dioxatricyclo[4,3,l,0 ' Jdecane esters with an alkanoic or carbamic acid, of the general formula I wherein is an alkyl group containing 1 to k carbon atoms, R2 is an OCOR^ or OCONHR,. group when R. is a hydrogen atom, and R-j is an OCONHR,. group when R2 is a hydrogen atom, and wherein R^ is an alkyl group containing 1 to 4 C-atoms and Rj is a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an ethylenically unsaturated aliphatic hydrocarbon radical containing 2 to 6 carbon atoms , a cyclo-aliphatic hydrocarbon radical containing 3 to 6 C-atoms or a phenyl group, and the 10,11 double bond may be hydrogenated.

2. A compound of the formula defined in Claim 1 substantially as hereinbefore described in any on of the foregoing Examples.

3. ' 3. A method of producing an ester of a 4a-hydroxy-2.9-dioxatricyclo[^,3,l,o5>7 decane of the. eneral formula q 44145/3 where R^ is an alkyl group containing 1 to- 4 C-atoms, ~ R2 is an OCOR4 or OCONHR,. group and R^ is a' hydrogen atom, where R^ is an alkyl group containing 1 to 4 C-atbms and

4. R^ is a hydrogen atom, an alkyl group containing 1 to 6 carbon atoms, an ethylenically unsaturated aliphatic hydrocarbon radical containing 2 to 6 carbon atoms , a cycloaliphatic hydrocarbon radical containing 3 to 6 C-atoms or a phenyl group, and the 10,11 double bond may be hydrogenated, wherein a 3 7 2,9-dioxatri ' ] decanone of the general formula where R^ has the above specified meaning and the 10,11 double bond may be hydrogenated, is reduced and the resulting ½a-hydroxy compound either is reacted with a carboxylic acid chloride of the general formula R^COCl, a carboxylic acid anhydride of the general formula (R^C0)20, an isocyanate of the general formula R..NC0 or with an ester or chloride of a carbamic acid of the general formula R^NHCORg, where R^ has the above specified meaning and Rg is a chlorine atom or an alkoxy group; or is reacted with phosgene to form the chloroformic acid ester which is then reacted with the corresponding amine R.-NH0.

5. \ . A method as claimed in Claim 3, wherein the reduction is effected with a metal hydride. 44145/2 the general formula where is as defined in Claim 1, 1¾2 is a hydrogen atom and is an OCONHR-. group as defined in Claim 1 and the 10,11 double bond may be hydrogenated, wherein a 48-hydroxy- 2 ,9-dioxatricyclo[ ,3 ,1,0 3 ■ 7 ]decane of the general formula wherein has the above specified meaning, R" is a hydrogen atom and R" is OH and the 10,11 double bond may be hydrogenated, either is reacted with a carboxylic acid chloride, a carboxylic anhydride, an isocyanate of the general formula R^NCO or with an ester or chloride of a carbamic acid of the general formula R-jNHCORg , where R^ has the above specified meaning and Rg is a chlorine atom or an alkoxy group, or is reacted with phosgene to form the chloroformic acid ester which is then reacted with the corresponding amine R^-NI^.

6. A method of producing a compound of the formula defined in Claim 1 substantially as hereinbefore described in any one of Examples 2 to 15 of the foregoing Examples.