DE2362396A1 - 2,9-Dioxa-tricyclo/4,3,1,0/decan-4-ol carbamates - prepd. e.g. by reacting the 4-ol cpd. with an isocyanate - Google Patents

Abstract

Carbamate of formula (I): (where a is a single or double bond; R1 is 1-4C alkyl; and one of R2 and R3 is H and the other is OCONHR5, R5 being an unsatd. aliphatic, cycloaliphatic or aromatic 1-6C residue), e.g., 4alpha-(N-alkylcarbamoyl)-3-methyl-10-methylene-8-methoxy-2,9-dio- xatricyclo 4.3.1.03,7 decane, are new cpds. They can be prepd. by the process of parent patent DT 2306118. Thus, the corresp. cpds. in which one of R2 and R3 is H and the other is OH may be reacted with R5NCO, an N-R5-carbamic acid ester or chloride, or with COCI2 followed by R5NH2. (I) has CNS depressant activity, being more active or less toxic than the corresp. cpds. in which R5 is a satd. alkyl.

Description

2362336

Hanover, December 12, 1972 Z3-PA.MH/Ka

■ Patent application for carbamates of the 4-hydroxy-8-alkoxy-2 _t 9-dioxatricycle »

Addendum to patent (patent application P 23 06 118.9)

In the patent application P 23 06 118.9 are 4-hydroxy-8-alkoxy-2,9-dioxatricyclof4,3,1,0 ^ "Jdecane and their esters described with the following general formula:

in which R ^ is an alkyl radical with 1 to 4 carbon atoms, R = OH, OCO-R,, OCONH-R ₅ when R- is hydrogen, and R, OCONH-R ₅ is when Rp is hydrogen, where R 1 stands for an alkyl group with 1 to 4 carbon atoms and R ₅ for hydrogen or an alkyl group with 1 to 4 carbon atoms and the 10,11 double bond can be hydrogenated.

The present invention relates to carbamates of 4-hydroxy-8-alkoxy-2,9-dioxatricyclor4.3.1 _t 0 decanes of the general formula I.

5 09825/106 0

= OCONHR ₅ means in which R _{1 is} an alkyl radical with 1 to 4 carbon atoms, OCONHR ^, when R- is hydrogen, and
tet when R2 is hydrogen, where R ^ is an unsaturated aliphatic, cycloaliphatic or aromatic radical having 1 to 6 carbon atoms, and in which the 10,11 double bond can be hydrogenated.

It was found, surprisingly, that through exchange the alkyl group compared to aliphatic unsaturated, cycloaliphatic or aromatic radicals a considerable improvement the quality of effect is achieved. This applies to both the α and the ß compounds.

For example, the allylcarbamic acid esters of the 10,11 -non hydrogenated, as well as the 10,11 -hydrogenated compound the aforementioned formula I very much more intensive CNS-dampening or they are less toxic than the corresponding n-propylcarbamic acid esters, as can be seen in Table 1 below.

509 8 25/1060

ORiGfNAL INSPECTED

- 3 - table

0-CO-NH-R

OCONHR

-CH ₂ -CH ₂ -CH ₃

CH ₂ -CH = CH

CH ₂ -CH ₂ -CH ₃

CH ₀ -CH = CH ₀

LD ₁ -Q po mouse

D ₁₅₀ ip mouse
Ptosis mouse

decreased mouse motility

Lateral position (anesthesia) mouse

Haffner reflex
missing mouse

619 mg / kg

516 mg / kg 100 mg / kg

100 mg / kg 100 mg / kg 200 mg / kg

970 mg / kg

444 mg / kg 50 mg / kg

50 mg / kg

50 mg / kg

100 mg / kg

327 mg / kg

244 mg / kg
100 mg / kg

50 mg / kg
100 mg / kg
100 mg / kg

339 mg / kg

279 mg / kg 100 mg / kg

25 mg / kg 100 mg / kg 100 mg / kg

The 4β-phenylcarbaminoyl-3,10-dimethyl-8-methoxy-2,9-dioxatricycloC4,3,1,0 'Udecari described in Example 6 shows as. ß-compound no narcotic effect, but an effect on the nervous system, which in the white mouse as analgesic (ED ₅₀ = 140 mg / kg; LD 1500 mg / kg po), muscle relaxant (comparable to phenobarbital!) and spasmolytic (ED = 0.1 papaverine and 0.2 ED ₁₀₀ atropine) could be detected.

50982 5/10

The carbamates according to the invention are prepared as in the parent application P 23 06 118 described. The esterification of the OH group in the 4-position can be carried out in a known manner with a Isocyanate of the general formula R NCO take place, where FU the

has the meaning given above. It is also possible to react the OH compound with an appropriately substituted carbamic acid ester or chloride. The carbamates according to the invention are prepared via phosgene by reacting the 4-hydroxy-8-alkoxy-2,9-dioxatricyclo £ 4, 3,1,0 'I decane with phosgene to give the chloroformic acid ester, from which by reaction with the corresponding amine R ₁ -NH ₀ the desired carbamate is obtained.

509825 / 1.060

example 1

4a-N "-Allylcarbaminoyl-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3,1,0 'Idecan

5 g of 4α-hydroxy-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3,1, Cr * '] decane and 6.5 g of allyl isocyanate dissolved in 70 ml of dry benzene were 24 Heated at reflux for hours. The reaction mixture was then first evaporated in vacuo, the residue was treated with 50 ml of ethanol to remove excess allyl isocyanate and again concentrated in vacuo. It was then taken up with 150 ml · water and extracted 4 with 100 ml ether. 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 resulted. After recrystallization from ether / hexane (1: 9; V / V), 4.5 g of white crystals were obtained (71.5 % of theory). .

₁₅₂₁₅ , M = 295.35

Mp. 98-101 ⁰ C (Kofier, uncorrected) [α] ψ + 38 ° (methanol)

509825/1060

Example 2

4β-N-Allylcart) aminoyl-3-diethyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3,1,0 ^ "decane

5 g of 4β-hydroxy-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3,1,0 "decane were first reacted and processed with allyl isocyanate in benzene as in Example 1. The following were obtained: 7.5 g of an oily crude product. This could only be obtained so pure after chromatography on 100 g of silica gel with CCl ^ / CHCl ^ (80:20; V: V) that it crystallized. Yield: 5.0 g of white crystals (79.3 % of theory). C ₁₅ H ₂₁ NO ₅ , M = 295.35
Mp. 52-53 ⁰ C (Kofier, uncorrected) [cc] Jp + 46 ° (methanol)

Example "5

4oc-N-Allylcarbaminoyl-3,10-dimethyl-8-methoxy-2,9-dioxatricyclo [4,3,1, O ³ ' ⁷ i-decane

4.53 4-hydroxy-3,10-dimethyl-8-methoxy-2,9-dioxatrieyclo- [4,3,1jO 'Jdecan were mixed with 4 g of allyl isocyanate in benzene with addition of a few drops of glacial acetic acid for 24 hours at 50 60 ⁰ C. heated and then worked up analogously to Example 1.

After recrystallization of the crude product (6.0 g) from n-hexane / diethyl ether (1: 9; V: V) 4.2 g of white crystals were obtained (67 % of theory).

C ₁₅ H ₂₃ NO ₅ , M = 297.35

Mp 56 - 58 ° C (Kofier, uncorrected)

L ^a JD ² " ³² ° ( ^Methano1 )

509825/1060

Example. 4th

4cx -N-Cyclohexylcarbaminoyl-3,1O-dimethyl-8-methoxy-2,9-dioxatricyclo [4,3,1> 0 ^ "decane

5 g of 4-hydroxy-3,10-dimethyl-8-methoxy-2,9-dioxatricyclo [4,3,1, 0 '' Jdecan were mixed with 5 g of cyclohexyl! Diisocyanate in 70 ml of benzene under addition was of 3 drops of glacial acetic acid Boiled under reflux for 6 hours. Work-up was carried out as in Example 1. The initially oily crude product could be crystallized from η-hexane. Yield: 6.2 g (that is 78 % of theory).

White crystals, C ₁₈ H ₂₉ NO ₅ , M = 339.43 ·.

Mp. 109-110 ⁰ C (Kofier, uncorrected) [a] Q ¹ - 26 ° (methanol) -

Example 5

4α-Cyclohexylcarbaminoyl-3-methyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3,1,0 ^5j7 ] decane ·

6.5 g of a-hydroxy-J-methyl-IO-methylen-e-methoxy-E ^ -dioxatricyclo [4,3,1,0 "decane were reacted in benzene with 15 g of cyclohexyl isocyanate as in Example 4 and worked up ■ tet. However, since the end product could not be crystallized, it was purified by chromatography on silica gel on thick-layer plates (17 plates 20 χ 20; mobile phase: η-hexane, ethyl acetate, n-propanol 70: 24: 6; V: V: V )
Yield: 5.5 g of a colorless oil, that is 59 % of theory.

C ₁₈ H ₂₇ NO ₅ , M = 337.40

[ctj ^ ¹ + 62 ° (methanol).

609825/10 60

Example 6

4SS-N-Phenylcarbaminoyl-3,10-dimethyl-8-methoxy-2,9-dioxatricyclo [4,3,1,0 ^{3 '7]} .decan

3.4 g of 4ß-hydroxy-3,10-dimethyl-8-methoxy-2,9-dioxatricyclo [4,3,1 »0 'i-decane and 5» 13 g of phenyl isocyanate were dissolved in 200 ml of benzene with 10 drops of glacial acetic acid was added, dissolved and ^{heated to 16 0} C for 15 minutes. It was then cooled to room temperature and left to stand for 24 hours. The mixture was then concentrated in a vacuum and worked up analogously to Example 1.

After recrystallization from benzene, 4.1 g of white crystals were obtained, that is 79 % of theory.

C ₁₈ H ₂₃ NO ₅ , M = 333.3

Mp 154-156 ° C (Kofier, uncorrected). Yes] ^ ⁰ + 17 ° (methanol)

509825/106 0

Claims (1)

Claim 1 ..) of 2,9-dioxatricyclo [4,3,1, 0] decanes of the general formula I in which R. is an alkyl radical with 1 to 4 carbon atoms, EL = OCONHR ₅ when R _{3 is} hydrogen, and R ₃ = OCONHR ₅ when Rp is hydrogen, where R _{5 is} an unsaturated aliphatic, cycloaliphatic or aromatic Radical with 1 to 6 carbon atoms, and in which the 10,11 double bond can be hydrogenated. 509825/1060