CA1071644A - Carbamates and their use as pharmaceuticals - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

This invention is concerned with a process for the production of a new carbamate of the formula I:

I, in which the dotted line denotes a double bond which may be hydrogenated, X is an alkylene bridge of 1 or 2 carbon atoms, R1 is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen, R3 is hydrogen and R4 is hydrogen, a linear of branched alkyl of 1 to 4 carbon atoms or a phenyl. This process comprises the steps of reacting a diene of the formula V:

V, with a dienophile of the formula VI:

Description

The present applicatlon is a division of Canadian application seria] nurnber 208,733 filed Septem~er 9, 1974.
1'he invention relates to new carbamates derived from substi-tu~ed ~ -hydroxylactones, to their production and to their use as pharmaceuticals.
'l'~le new com~ounds may be represented by the general formula (I):

Rl 1l ~-~ \C/- R3 (I) R o-Cj-7-R4 In this formula the dotted line represents a double bond which may be hydrogenated:
X is an alkylene bridge of l or 2 carbon atoms;
Rl is hydrogen or an alkyl of l to 4 carbon a-toms;
R2 and R3 are each hydrogen;
R is hydrogen or a linear or branched alkyl of l to 4 carbon atoms or a phenyl.
~xamples of alkylene bridges for X are, for example, methylene and e-thylene-1,2.
~xamples of radicals for Rl are (in addition to ; hydrogen): methyl, ethyl, propyl, isopropyl, bu-tyl, isobutyl, sec.-butyl and tert.butyl.
R4 may have the meanings given above for R .
The alkyls for R4 may bear substituents such as, for example, chlorine; alkoxy of one to four carbon atoms such as methoxy, ethoxy, propoxy, butoxy or isopropoxy, dialkylamino .~ .

.
having one to ~our carbon atoms in the alkyl which may bear substituents; or phenyl.
In the preferred compounds R~ is hydrogen or linear or branched, alkyl or 1 to 4 carbon atoms which may bear chloro, alkoxy, amino or phenyl as substituents. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, vinyl, allyl, ~ -chloroethyl, methoxymethyl, metho-xyethyl, ~ -ethoxyethyl, propoxymethyl, ~ -methylthioethyl, 3 -dimethylamino, @-diethylamino, ~ -piperidinoethyl, benzyl or ~ -phenylethyl.
The following compounds are examples of compounds according to the invention:
~-oxa-5-~N-methoxymethylcarbamoyloxy)-tricyclo / 5,2,2,02'6~-undecan-3-one, 4-oxa-5-(N-methylcarbamoyloxy) tricyclo r5,2,2,O2'6 ~-undecan-3-one, 4-oxa-5-(N-ethylcarbamoy-loxy)-tricyclo/ 5,2,2,0 ' ~-undec-8-en-3-one, 4-oxa-5-(carbamoy loxy)-tricyclo r 5,2,2,0 ' _/undec-8-én-3-one, 4-oxa-5-(carbamoy-loxy)-tricyclo ~5,2,1,0 ' ~decan-3-one, 4-oxa-5-(N-n-propylcar-bamoyloxy)-tricyclo r 5,2,1,0 '6_7decan-3-one, 4-oxa-5-(N-~ -chlo-roethylcarbamoyloxy)-tricyclo ~5,2,1,02'6_/decan-3-one, ~-oxa-5 - ( N- ~ - (N ', N ' ~dimethylaminoethyl)-carbamoyloxy)--tricyclo - - 2,6 ~ d 8 3 one 4~oxa-5-ethyl-5-(N-me-thylcarbamoyloxy)-tricyclo/ 5,2,1,02'~
dec--8-en--3--on~, . '.... '. :,: ' : . .. .
' . . ', ' , '' ".',. ' ' . ,' ' .,, , , . . .:
"' ' " ' ' '., . '. :' . : . ., '' ,' '' ' .:, - , . .. . . . . .
.: ' -', ' . ' ' ", '. ''' ' ' '.' . .' ' ' ' '': ' :

- 2 6-4-oxa-5-methyl-5-(~-ethylcarbamoyloxy)-tricyclo/5,2,1,0 ' dec-8-en-3-one, 4-oxa-5-(N-methoxymethylcarbamoyloxy)-tetracyclo/5,3,2,02'608'1 ~ _ dodec-ll-en-3-one, 4-oxa-5-(~-methylcarbamoyloxy)-tetracyclo/5,4,2, o 2 ~ 608' tideca-9-12-dien-3-one~

,, . .,: . -. .
- , . . - :
:.: :: ~
.: - ........... .: . ,:
.
-: . -' ''. .:, ~ : ,., :.':' ' -. . ' ~ ' . ' . :

- . : ~ . ... . . : ,. . . . . .
. . - , :' ., :: ' . . - :
. .: .

~, , , . . :
. . .

A me-thod of preparing the compounds of formula (I) according to the invention is disclosed and claimed in the origi-nal application 208,733 filed on September 9, 1974. This method comprises the steps of reacting a substituted ~-hydroxylactone of the general formula (II):

Rl 2 C, /O_R3 (II) R OH

with an isocyanate of the general formula (III):
R -N-C=O (III) or the hydrochloric acid addition compound of the same, that is a carbamoyl chloride of the general formula (IV) ' ~ R4-N-C-Cl ' " (IV) H O
which is capable of liberating the isocyanate under the reaction conditions in the presence of a base at a temperature of at least the room temperature and hydrogenating the obtained unsaturated carbamate when desired.

R to R and X in the formulae (II), (III) and (IV) have the meanings given above.
When an unsaturated compound of formula (II) is used as starting material the double bond may be hydrogenated by a conventional method, if desired.
In accordance with the present invention, another method of preparing the compounds of formula (I) according to the invention consists in reacting a 1,3~diene of the formula (V):

Rl \ C-EI
~ \
~I-C X

H--C ~ / (V) C-H

with a dienophile of the general formula (VI):
o C\
HC o Il /3 ~C - C-R (VI) O-C-N-R
Il l O H
in which Rl to R~ and X have the meanings given above according to the ~iels-Alder reaction at a temperature of from 15 to 220 C

and hydrogenating the double bond of the obtained unsaturated carbamate, when desired.
The Diels-Alder reaction of compounds of formula (IV) with compounds of the formula (VI) may be carried out in a conventional manner conveniently in an inert organic solvent or diluent at a temperature of from 15 to 220C. It may also be carried out without a solvent. Examples of suitable solven-ts or diluents are benzene, toluene, chlorobenzene, chloroform, carbon tetrachloride, dioxane, an ether, ethyl acetate or acetone. Carrying out the process while using a pressure of up to 50 atmospheres may be advantageous.
Ilydrogenation of the double bond in the ring system of formula (I) may be carried out without difficulty by a conventional method.
A convenient method consists in dissolving or suspending the appropriate unsaturated carbamate in a solvent which is inert under hydrogenation conditions and hydrogenating it in the presence of a catalyst. Lower alcohols, for example methanol, ethanol, a dialkyl ether or cyclic ether such as diethyl ether, tetrahydrofuran or dioxane or a cyclic hydro-carbon such as cyclohexane may be used as solvents. Platinummetal catalysts, if desiréd on carriers, such as Pd/CaCO3, Pd/carbon, Pt/carbon, platinum dioxide, or cobalt or nickel, if desired on carriers such as SiO2, may be used. The hydroge-nation may be carried out at room -temperature or a-t elevated temperature and at atmospheric pressure or in an autoclave at superatmospheric pressure depending on the activity of the catalyst. After the necessary amount of hydrogen has been absorbed the catalyst is removed and the hydrogenation product is purified in the usual way by recrystallization. Hydrogenation is carried out at a temperature of from 10 to 100C. Hydrogen pressures of up to 200 atmospheres may be used.
The starting compounds of Pormula (V) and (VI) are for the most part known compounds and may be prepared by methods known from the literature.
Compounds of the formula (~I) - N - substituted carbamoyl-2,5-dihydrofuran-5-ones - may be prepared by a conven-tional method from 2-hydroxy-2,5-dihydrofuran-5-ones and the appropriate isocyanates for example as described in Liebigs Ann. Chem. 697 (1966), 42 to 61.
It is not necessary and in the case of reaction products which are difficult to crystallize not even advisable to isolate the ~-substituted carbamoyloxy-2,5-dihydrofuran-5-one thus synthesized and then react it with the desired diene, but the reaction mixture obtained may be directly used in the following Diels-Alder reaction. In principle the reaction may also be carried out by reacting the appropriate 2-hydroxy-2,5-dihydrofuran-5-one with the diene component and the isocyanate, if desired in the presence of a catalyst, in a one-vessel reaction to form the end product of formula (I).
The compounds according to the invention h~ve valuable pharmacological properties. They inhibit or stimulate certain functions of the central nervous system. A pronounced antinociceptive effect, for example in the hot plate -test, the tail flick test, the writhing test or the Randall-Selitto test may be exhibited in the pharmacological investigation oE

test animals and the effective dosage is usually far below the range of toxic dosage.
The valuable pharmacological properties of the compounds according to the invention may be shown for example for 4-oxa-5-(N-methylcarbamoyloxy)-tricyclo/ 5,2,1,02'67dec-8-en-3-one, reference being made to the accompanying drawings wherein Figs. 1 to 4 shows the results of hot plate, tail flick, writhing and Randall-Selitto tests effected on mice respectively, and Fig. 5 shows graphica~ly dosage-effect relationship for the writhing test of different analgesics.
As can be seen, the tested product exhibits a pronounced anti-nociceptive effect on the test animal, on the mouse in the hot , , :
. , ~
,, ~ . -.
,-': . ', ' ' ' , ' ' ;, , , -, ~, - ':
.
. , ~ - , . :

o~ z~ ~ol o99 plate test, tall fllck test and writhing test and on the rat in the Randall-Selitto test.
1. Hot plate test (Figure 1):
The hot plate ls kept at 57C and reaction is appralsed by the lift-ing off and simultaneous shaking of the hind legs. The period from being placed on the plate until the occ~rence o~ the said reaction is measured as the latency period. Observation is limited to thirty seconds.
Figure l shows the latency prolongation in percent after di~
ferent doses (21~5; 31.6; 46.4; 6801; 82.5 and 100.0 mg/kg of body weight) in dependence on time (in minutes) after application. The percentage latency p~longation is plotted on the ordinates and the time after applica~ion (in minutes) on the abcissae~
2. Tail ~lick test (Figure 2):
The source of heat used is an incandescent lamp (6 v, 5 w) in a con-cave reflector. The animals are placed singly in a measuring cage which is at a fixed distance from the heat source and the tail which has been passed out through a slot is irradiated. The period before there is a clear retractlon Or the tail ls measured1 Figure 2 shows the prolongation of latency in percent after different doses ~21.5; 31.6; 46.4; 56.2; 68.1; 82.5 and 100 mg/kg ; of body weight) in dependence on time after application (in minutes).
I~ Figure 2 the percentage latency prolongation is plotted as or-din~tes and the time in minutes after applicatlon is plotted as abscissae.

3. Writhing test (Figure 3)o Pain is initlated by p-benzoquinone ln a 0.02~ aqueous solutlon in a volume of 10 ml/kg of body weight i~p~o The measurable parameter is the latency (the period up to the rirst reactlon) and the sum Or the stretching reactions wlthin f'ifteen minutes Or admlnistration.
Figure 3 shows the sum o~ the reactions within fifteen minutes after different doses (;00.0, 82.5; 68.1; 46.4; 31.6; 26.; and 21.5 mg/kg of hodY weight) ln dependence on tlme (in minutes) after app-lication. The sum of the reactions ls plotted as ordinates in O.Z 30,099 Figure 3 and the t~me (in minutes) after app~icati~n is plotted as abscissae.

4. Randall-Selitto test (~igure 4):
The test equipment is the analgesia meter of Ugo Basile (Milan). To increase sensitivity to pain the rat receives 00 05 ml Or a 1~
aqueous carrageenin solution as a plantar s.c. injection in the left hind paw. The blank measurement is carried out 150 minutes arter this injection. After the blank checkithe test substance is applied and measurement is taken 30, 60 and 120 minutes thereafter.
Figure 4 shows the percentage increase in the paw load endured after different doses (31.6; 46.4; 58.2; 68.1 and 100.0 mg/kg of bo-dy weight) in dependence on time (in minutes) after application. The percentage increase in paw load is plotted as ordinates in Figure 4 and the time after application is plotted as abscissae.
The substance tested has an efrect in the analgesia test which is about ten tlmes as weak as morphine but without impairing respi-ration and circulation so that in spite of the weaker effect there is a greater therapeutic breadth. The therapeutic breadth is also greater as compared with dextropropoxyphene with a similar action.
In a pharmacological analysis of the effect on facilitated and unfacilitated reflex discharges of ~-motoneurons carried out expe-rimentally the effect mechanism of 4-oxa-5-(N-methylcarbamoyloxy)-tricyclor5~2,1,02'6~dec 8-en-3-one is about the same as that of mor-phine and dif'~ers clearly ~rom DOLANTIN (Pethidine) and weaker analgesics such as phenacetin, aminophenazone and the like.
In tests on the ef'~ect on circulation and respiration in rabbits it is f'ound that there is no appreciable efrect on blood pressure and pulse rrequency and no change in respiratlon volume ~or the said substance up to a dose o~ 215 mg/kg of body weight, whereas arter morphine has been administered in doses ofi'from 3.16 to 21.5 m~g/kg of' body weight the blood pressure and pulse f'requency d~cllme sharp-ly depend~ng on the dose and the resplratlon volume ln thls dose range f'alls to the point of failure of respiration and death of the animal.
_9_ .
~ . ''-o~z~ ~oJo99 Similar pharmacological effects may be shown in the case of other compounds according to the invention o~ which the following may be particularly mentioned: 4-oxa-5-(carbamoyloxy)-tricyclo-~,2,1~02'5~dec-8-en~3-one, 4-oxa-5-(N-me~hylcarbamoyloxy)-trlcyclo-~,2,2,02'~ undec-8-3n-3-one and 4-oxa-9-methyl-5-(N methylcarbamoyl-oxy)-tricyclo [5,2,1,02'6~dec-8-en-~-one~
While having similar pharmacological effectiveness ~hese com-pounds have in some cases less side effects so that the ratio of erfects to side e~fects is more favorable.
~xamples Or further erfective compounds are as follows:
4-oxa-5-(N-methylcarbamoyloxy~ricycloL5,2,1,02'6]decan-~-one, 4-oxa-1-methyl-5-(N-methylcarbamoyloxy)-tricyclo ~5,2,1, o2 ~ 6~dec-8-en-3-one, 4-oxa-5-(N-ethylcarbamoyloxy)-tricyclo L5J 2,1~02'6]dec-8-en-~-one, 4-oxa-5-(N-propylcarbamoyloxy)-tricyclo[5,2,1, o2~ 6]dec-8-en-~-one, 4-oxa 9-methyl-5 (N-~thylcarbamoyloxy)-tricyclo[5,2,1,02'6~dec-8-en-3-one, and 4-oxa-1-methyl-5-(N-methoxymethylcarbamoyloxy)-tricyclo-[5 3 2~1,02'6~-- dec-8-en-3-one.
Figure 5 shows graphically dosage-effect relationship for the writhlng test of different analgesics (morphineJ curve A; tilidine, curve B; dextropropoxyphene, curve C; codeine, curve F~ pentazocine, curve G; phenacetine, curve H) and of 4-oxa-5-(N-methylcarbamoyloxy)-tricyclo[5,2,1,0 '6]dec-8-en-~-one, curve D and 4-oxa-5-(carbamoyl-oxy)-trioyolo[5,2,1,02'6~dec-8-en-3-oneD curve E.
; The ef~ect given as a percentage inhlbition o~ the writhing reactlons is plotted as ordinates and the dosds (mg/kg) are plotted logarithmically as abscis~a~. The point o~ intersectlon of the dotted vertical lines with the horizontal full line gives the ED50, i.e.
~0 that dose under which the number of writhing reactions is decreased by 50%-I'he graph shows that the two substances according to khe inven-tion (curves D and E) have practically the same effect and should be classified among the medium strength analgesics tilidine,dextroprop~

~ ~7'~

oxyphene and codeine.
Therapeutic a~ents which contain at least one compound of formula (I~ as active ingredien-t may be prepared with conven-tional carriers or diluents and the conventionally used pharma-ceutical auxiliaries in accordance with the type of application in a conventional way with a dosage suitable for use. These therapeutic agents may be used as analgesics for pain of medium and strong intensity. Individual doses of from 20 to 200 mg and preferably from 50 to 100 mg are suitable for the treatment of pain.
The preferred pharmaceutical preparations are in a form suitable ~or oral or parenteral administration. Such forms include in particular tablets, coated tablets, dragées, capsules, suppositoires and preparations which contain the active ingredient, particularly a pharmacologically compatible salt, in an aqueous suspension, sterilized water, isotonic salt solution or other solution.
As a rule the preparations consist of the active ingredient to be used according to the invention with a carrier, or diluted with a carrier, or filled into or encapsulated by a carrier in the form of a capsule, bag, medicinal capsule or other container as a carrier substance which may serve as a medium, flavoring or diluent for the therapeutically active ingredient. This carrier may be a solid, semisolid or liquid substance.
Examples of carriers which may be used are: lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquid paraffin, coconut butter, cocoa butter, alginates, tragacanth, gelatins, invert sugar syrup, methyl cellulose, polyoxyethylenesorbitan monolaurate, methyl-hydroxybenzoate and propylhydroxybenæoate. When preparing tablets a lubricant may be added to prevent the powdered .,~ - 11- ,, components from sticki~g in the tablet mold or tablet press.
examples of suitable lubricants are talc, aluminum stearate, magnesium stearate and calcium stearate.
The following Examples will illustrate the production of the new compounds without the scope of the invention being limited to the specific Examples. The compounds are confirmed in their structure by _ __ _ _ __ _ :, . , : . , ~ - '.

.. . . .
- : . . , . : ~ . : ,: .: , .. .. :, .. ...

o~z~ ~o~o99 analysis and spectral data.

4-oxa-5-(N-methylcarbamoyloxy)-tr~cyclo[5j2,1,02'5]dec-g-en-3-one, A solution of 33.2 g o~ 4-oxa-5-hydroxytricyclo-~,2,1,02' ~-dec-8-en-3-one in 50 ml o~ tetrahydro~uran is heated with 11.4 g of methylisocyanate ~or five hours at 70C and then cooled to 0C . The crystals which have separated are suction filtered and recrystalliz-ed ~rom methanol. The yield is 22.6 g o~ the melting point 160 to 16~C.
Elementary analysis (CllHl~N04):
calculated: C 58~8 H 5.8 N 6.3 0 28.7 ~ound: C 58.9 H 5.9 N 6.2 0 28.3-EXAMPLE~ 2 T0 12 Carbamates are prepared analogously to Example 1 from 4-oxa-~-hydroxytricyclo L5,2,1,02'6]dec-8-en-3-one and the appropriate iso-cyanate and are recrystallized ~rom ethyl acetate or from a mixture of ethyl acetate and hexane, 4 oxa-5-(oarbamoyl)-tri¢yclo[592,19 o2 dec-8-en-3-ones in whlch the radical R4 on the nitrogen has di~ferent meanlngs are contained ln the following Table.
E 1 R4 Meltin oint (C) xamp e _ _ ~ p 2 C2H5 1 o8 - 1 1 o 3 i-C~H7 118 - 120 4 n-C4H9 101-102 CH2-CH=CH2 97 98 7 (CH2)2 c2 5 89 - 91 /~
8 CH2 ~ 1 o8 1 os 9 ~ 175 - 1~6 ~ 176 - 177 Cl 7~
O.Z. 30,099 Example R4 Meltin~ polnt (C) 11 ~ 175 - 176 12 ~ 189 - 1~0 Cl ~XAMPLES 13 T0 24 The following carbamates are prepared analogously to Example 1;
melting points in C are given in parenthesis:
TC = tricyclo[5,2,1,0 ' ]; TC' = tetracyclo[5,3,2,02'6,0 ' ].
13. 4-oxa-5-methyl-(N-methylcarbamoyloxy)-TC-dec-8-en-3-one (99-lO1) 14. 4-oxa-5-methyl-5-(N-methoxymethylcarbamoyloxy)-TC-dec-8-en-3-one (96-lO0) 15. 4-oxa-5-(N-methylcarbamoyloxy)-TC-undec-8~en-3~one (145-147) 16. 4-oxa-5-(N-methoxymethylcarbamoyloxy)-TC-undec-8-en-3-one (121-122) 17, 4-oxa-5-(N-methylcarbamoyloxy)-TC'-dodec-1-en-~-one (172-175) 18, 4-oxa-10-isopropylidene-5-(N-methylcarbamoyloxy)-TC-dec-8-en-3-one (96-97) 19. 4-oxa-7-methyl-5-(N-methylcarbamoyloxy)-TC-dec-8-en-3-one (169-170) 20. 4-oxa-9-methyl-5-(N-methylcarbamoyloxy)-TC-dec-8-en-3-one (1~8-140) 21. 4-oxa-9-methyl-5-(N^~hyloarbamoyloxy)-TC-dec-8-en-3-one (111-114) 22. 4-oxa-9-methyl-5-~N-methoxymethylcarbamoyloxy)-TC-dec-8-en-3-one ~99-103) 23. 4-oxa-1-mothyl-5-(N-methylcarbamoyloxy)-TC-dec-8-en-3-one (120-122) 24. 4-oxa-1-methyl-5-(N-methoxymethylcarbamoyloxy)-TC-dec-8-- en-~-one (125-127).

4-oxa-5-(N-methylcarbamoyloxy)-tricyclo[5,2J1,02'6]dec,8-en-3-one: -13-.
.,; - , . . . , . , . . :
,- . : , . ... . .
- " '- ' ~ .' ' . . . ~ .. ' ' ' ' ' , " ' ' , ' '." ' , ' o ~ z ~ ~o.~ o99 A solution Or 3~o2 g of' 4~oxa~5-hydroxytricyclo[592,1,02'6]-dec-8-en-3-one in 50 ml o~ tetrahydrofuran has 12.5 g of' methyl isocyanate and 170 mg of tin(II) octanoate added to it at room tem-perature. The sllghtly exothermic reaction is over w~thin ninety mi-nuteS. The pasty reaction product ls diluted With ~0 ml o~ ether -and cooled to 2C. The crystalline product is suction riltered. The yield is ~8.5 g and the melting point is 16~ to 165C, The following carbamates are synthesized analogously to Ex-ample 25. Melting points in C 2re given in parenthesis. TC~=
tricyclo ~,2,1, o2~ 6]dec-8-en-~-one.
26. ~oxa-5-(N-n-propylcarbamoyloxy)-TCD (81-83) 27, 4-oxa-5-(N-sec.-butylcarbamoyloxy)-TCD (105-108) 28. 4-oxa~5-(N-cyclopentylcarbamoyloxy)-TCD (132~
29. 4-oxa-5-(N-cycloh~xylcarbamoyloxy)-TCD (164-167) 30. 4-oxà-5-(N-(l'-methylthioprop-2'-yl)-carbamoyloxy)-TCD (108-110) 31. 4-oxa-5~(N-pent~ yn-~' yl)-carbamoyloxy)-TCD (142-145) 32. 4-oxa-5~(N-(3'-¢hloromethylprop-3'-yl)-carbamoyloxy)-TCD (99-101 33. 4-oxa-5-(N-~-methylthioethylcarbamoyloxy)-TCD (122-124) ~4. 4-oxa-5-(N-~-ethylthioethylcarbamoyloxy)-TCD (lQ~-107) ~5. 4-oxa-5-(N-B-chloroethylcarbamoyloxy)-TCD (106-108).

4-oxa-5-(N-methylcarbamoyloxy)-tricyclo[532,1, o2~ 6~ -decan-3-one:
33,5 g of 4-oxa-5-(N-methylcarbamoyloxy)-tricyclor5,2 ~ 1 ~ o2 J 6~_ dec-8-en-3-one is hydrogenated in 170 ml of tetrahydroruran ln con-tact with an Ni/Si02 catalyst (25% nickel) at 60C and a hdrogen pressure of 170 atmospheres gauge. The catalyst is separatedO The solvent ls removed in vacuo. The resldue is recrystallized from a mixture Or ethyl acet~te and hexane wikh an addition of activated carbon. The yield 18 18.1 ~ and the meltln~ point is 144 to 146C, Elementary analysis: (CllH15N04) calculated: C 58.7 H 6.7 N 6.2 0 28,4 found: C 59.2 H 6.9 N 6.~ 0 28.1.

, . ,~
- . -. . . : , : , . . : . .

12 9 of 4-oxa-5(N-benzylcarbamoyloxy)-tricyclo-/5,2,1,02'_7dec-8-en-3-one is hydrogenated as described in Example 36 and 11.8 g of 4-oxa-5-(N-benzylcarbamoyloxy)~tricyclo/
/5,2,1,02'6 /decan-3-one is obtained which has a melting point of 123 to 126C.

14.5 g of 4-oxa-5-(N-phenylcarbamoyloxy)-tricyclo ~5,2,1,02'6_/dec-8-en-3-one is hydrogenated in 80 ml of tetra-hydrofuran at 60C and 170 atmospheres gauge hydrogen pressure as described in Example 36. 12.2 g of 4-oxa-5-(N-phenylcarba-moyloxy)-tricyclo/5,2,1,02'6 ~ -decan-3-one is obtained having a melting point of 167 to 168C.
_XAMPLE 39 83 g of 4-oxa-5-hydroxytricyclo~5,2,1,02'6J dec-8-en-3-one is added within fif~een minutes to 145 g of methyl isocyanate at a temperature of 30 to 38C. The added ~-hydroxy-lactone added thus passes into solution with an exothermic reaction. When the reaction is over, crystals separate out and these are suction Eiltered and recrystallized from acetone.
The yield is 52.2 g of 4-oxa-5-(N-methylcarbamoyloxy)-tricyclo /5,2,1,02'6_fdec-8-en-3-one having a melting point of 159 to 161C.

- A mixture of 16.7 g of cyclopentadiene and 5 ml of ethyl acetate is added to a solution of 40.6 g of 2-(N-phenyl-carbamoyloxy)-2,5-dihydrofuran-5-one in 150 ml of ethy] acetate at-a temperature of 40C and the whole is left for two and a half hours at this temperature. The solvent is distilled off.
A crystalline residue remains which after it has been recrystal-lized from ethyl acetate melts at 172 to 175C. 36 g of 4-oxa-5-(N-phenylcarbamoyloxy)-tricyclof5,2,1,02'6J dec-8-en-~ - 15 -.

~7~

3-one is obtained..

A solution of 5.2 g of 2-~N-methylcarbamoyloxy)-2,5-dihydrofuran-5-one in 14 ml of tetrahydrofuran has a mixture of 4.4 g of cyclopentadiene and 4 ml of tetrahydrofuran added ~ to it at room temperature and then the whole is left at room : temkerature for sixteen ~

.. .. ..... .. .. ..... ..

, .,.. , , :, . : , . : : ~ ., ` . ' . . ' ` , , : ::
- , .. .. . . . .
- ~ . ' : ' , . ~': ' : , ,'` :

. : .: . . . :
.~ :. . . : . :

- . . ~ ~ . . , .: : :

O.Z ~O,O99 hours and cooled to 0C. The cryst~1ls whlch have been deposited are suction filtered. The yield is 6.1 g of the melting point 163 to 164C. This is 4-oxa-4-(5-methylcarbamoyloxy)-tricycloL5~2,1,02' q -dec-8-en-~-one.

24 g o~ cyclohexadiene-l,~ and 100 mg of hydroquinone are add-ed to a solution of 21 g of 2-(N-methylcarbamoyloxy)-2,5-dihydrofuran-

5-one in 40 ml o~ tetrahydrofuran and the whole is heated for six hours at 120C in an autoclave having a capacity Or 500 ml. The re-actlon product is treated with activated carbon, the solution is concentrated and the residue is crystallized from ethyl acetate.
8.7 g of 4-oxa-(N-methylcarbamoyloxy)-trlcyclo[5,2~ 2,0 ' q -undec-8-en-~-one of the melting point 146 to 148C is obtained.
EXAMPLE 4~
2.64 g of cyclopentadiene ~s added to a solution of 1.4~ g of 2-carbamoyloxy-2,5-dihydrofuran-5-one (prepared by the reactlon Or malealdehyde pseudoacid with chlorosulfonyl isocyanate followed by hydrolysls) in 40 ml of ethyl acetate at 40C and thé whole is heat-- ed ~or three hours at 60C and then cooled to 0C0 The crystals whlch have been deposited are suction flltered. The yield is 103 g of 4-oxa-5-(carbamoyloxy)-trlcyclo~5,2,1,02'63dec-8-en-3-one havlng : 20 a melting point Or 179 to 182C.
EXAMPLE ~4 24 g Or cyclohexadiene and 100 mg of hydroquinone are added to a solution o~:l.43 g o~ 2-carbamoyloxy-2,5-dihydroruran-5-one in 80 - ml of tetrahydrofuran and the whole is heated ~or six hours at 130C
(ln an autocla~e havlng a capaclty Or 500 ml). The reactlon product . . ..
is ~lltered and the solutlon is corlcentra~ed. 6.~ g oI 4-oxa-~-(carbamoyloxy)-trlcycloL5,2,2,02'6~undec-8-en-~-one having a meltln~
point o~ 1~6C crystallizes out.
The compounds set out ln Examples 1 to ~5 are obtained in a corresponding manner by a Dlels~Alder reaction With comparable yields.

"

".6~ o. z~ 30~ ogg ~XAMPLE FOR TABLETS
1. 4-oxa-5-(.N~methylcarbamoyloxy) -t.ricyclo-[5,2~1,0 ' ]dec-8-en-3-one 30 mg 2. polyvinylpyrrolidone (mean molecular weight 25,000) 20 mg 3. polyethylene glycol (mean molecular weight 4~) 14 mg 4. hydroxypropylmethylcellulose 40 mg 5. talc 4 mg

6. magnesium stearate 2 110 mg The actlve ingredient is moistened with polyvinylpyrrolidone in 10~ aqueous solution, forced through a sieve having an internal mesh width Or 1~0 mm and dried at 50C. The granules are mlxed with poly-ethylene glycol (mean molecu~r weight ~,000), hydroxypropylmethyl-cellulose, talc and magneslum stearate and pressed into tablets Or 110 mgO
EXAMPLE FOR DRAGEES

1. 4-oxa-5-(carbamoyloxy)-tricyclo[5,2,19 o2~ 6~ dec-~-en-3-one 60 mg 2. lactose 80 mg 3. maize starch ~0 mg 4. polyvlnylpyrrolidone 4 mg 5. magnesium stearate 1 mg 175 mg A mixture of the active ingredient with lactose and maize starch is granulated wlth an 8% aqueous solutlon of the polyvlnyl-pyrrolldone throuKh a sleve 1.5 mm, drled at 50C and a~ain rubbed through a sieve at 1.0 mm. The granules obtalned are mixed with magnesium stearate and pressed to dragee core,s. The dragee cores ob tained are provlded in the conventional way with a ¢oatlng co~slst-lng essentially o~ sugar and talc.
. EXAMPLE FOR GELATIN CAPSULES
A gelatin capsule contains:

'~' ~ . .

O.Z. 30,09g 1, 4-oxa-5-(N-methylcarbamoyloxy)-tricyclo-[5,2,2,02J6]undec-8-en-3~one ~ 80.0 mg 2. maize starch 210.0 mg 3. silicone dioxide (AEROSIL ~) 6.o mg 4. magnesium stearate 4.0 m~
~00.0 mg The substances are mixed intensely and filled into gelatin cap-sules.

EXA~PLE FO~ SUPPOSITORI~S

One cone contains:

1, 4-oxa-5-(N-methylcarbamoyloxy)~tricyclo-[5,2,1, o2~ 6~ dec-8-en-~-one 100.0 mg ~-2. Suppository substance, ~or example Adeps neutralis (STADIMOL ~ ) 1650,0 mg 1750.0 mg ' - The finely powdered active ingredient is stirred by means of an lmmersion homogenizer into the melted supposltory substance which has been cooled to 40C. The product is poured at ~8C into slightly precooled molds.

. .

Claims (7)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the production of a compound of the formula I:

I, in which the dotted line denotes a double bond which may be hydrogenated, X is an alkylene bridge of 1 or 2 carbon atoms, R1 is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen, R3 is hydrogen and R4 is hydrogen, a linear of branched alkyl of 1 to 4 carbon atoms or a phenyl, which process comprises the steps of reacting a diene of the formula V:

V, in which R1, R2 and X have the above meanings with a dienophile of the formula VI:
VI, in which R3 and R4 have the above meanings, according to the Diels Alder reaction, at a temperature of from 15° to 220°C, and hydrogenating the double bond of the obtained unsaturated carbamate, when desired.

2. A process as claimed in claim 1, wherein the reaction is carried out in an inert organic solvent or diluent.

3. A process as claimed in claim 1, wherein the unsaturated carbamate is hydrogenated with hydrogen in an inert solvent in the presence of a platinum metal, cobalt or nickel catalyst at a temperature of from 10° to 100°C.

4. A process as claimed in claim 3, wherein the hydrogenation is carried out at a hydrogen pressure of up to 200 atmospheres.

5. A process as claimed in claim 1 or 2, wherein 2-(N-methylcarbamoyloxy)-2,5-dihydrofuran-5-one is reacted with cyclopentadiene.

6. A process as claimed in claim 1 or 2, wherein 2-carbamoyloxy-2,5-dihydrofuran-5-one is reacted with cyclo-pentadiene.

7. A process as claimed in claim 1 or 2, wherein 2-(N-methylcarbamoyloxy)-2,5-dihydrofuran-5-one is reacted with cyclohexadiene-1,3.