DE2306118A1 - 4-HYDROXY-2,9-DIOXATRICYCLO ANGULAR CLAMP ON 4,3,1,0 HIGH 3.7 ANGULAR CLAMP FOR DECANE AND ITS ESTER - Google Patents

Description

Kali-Chemie Pharma GmbH Hanover, February 2, 1973

Z3-PA.MH/BO

Patent application 4-Hydroxy-2,9-dioxatricyclo j_4,3,1 »Cr * 'J de cane

and their esters

The invention relates to 4-hydroxy-2,9-dioxatricyclo i.4,3> 1 »0 ' I decane of the general formula I.

in which R _{1 is} an alkyl radical with 1 to 4 carbon atoms, R _{2 is} OH, OCOR ^, OCONHR _{5 when R 1 is} hydrogen and R, OCONHR ₅ is when R 2 is hydrogen, where R ^ for an alkyl group with 1 to 4 carbon atoms and R _{5 represents} hydrogen or an alkyl group with 1 to 4 carbon atoms and the 10,11 double bond can be hydrogenated.

DOS 1 96I 433 describes certain 4-hydroxy-2,9-dioxatricyclo [4,3,1,0 ^ ' ⁷ decanes and their esters in which the OH or ester group is in the β position. These compounds have novel CNS depressant and vasodilator effects.

It has now been found that previously unknown C-4-epimeric alcohols

409833/1006

get these compounds and their esters both intravenously and intraperitoneally as well as after peroral application cation quickly and reliably with doses that are only a fraction of the LDcQ, either strongly sedative or already have a strong narcotic effect. The narcotic effect differs from that of known parapulmonary narcotics in the effective dose range through:

JI

1. the faster onset of action after oral administration,

2. the lack of anticonvulsant effects,

3. the lack of barbiturate potentiating effects after administration of narcotic doses of those not hydrogenated in the 10,11 position Links,

4. the rapid elimination and biotransformation,

5. in particular due to the lack of a depressive effect on the vasomotor and respiratory centers when used of doses capable of inducing anesthesia for up to an hour and without additional medication to obtain.

Anesthetic states induced with lower doses are the same State of physiological sleep, since the test animals can be awakened. .

The good oral absorbability and the rapid onset of action are conditions that are particularly important today Hypnotic or sedative. To the best of our knowledge, however, there is currently no hypnotic or sedative that additionally nor would have the advantage of not potentiating barbiturates. Despite the large number of parapulmonary ones on the market In narcotics, hypnotics and sedatives, the group of barbiturates has the largest market share and there is a real need of barbiturate-free hypnotics, narcotics and sedatives.

- ■ -3- 409833/1006

While in the alcohols described in DOS P 1 961 433 and esters the hydroxy group or acyloxy group is in the 4-position in the 0 position, in the new alcohols the 4-hydroxy or acyloxy group is Ester group in α position. This C-4 epimerization not only causes an expected change in all physical characteristics, but also a drastic change in the impact profile.

The epimerization succeeds, for example, by oxidation of the C-4-ß-alcohols to the 2,9-dioxatricyclo [4-3,1,0 J decanones of the formula II described in DOS 2 027 890

where small denotes an alkyl radical with 1 to 4 carbon atoms and the 10,11-position can be hydrogenated, followed by a reduction, preferably by means of metal hydrides, the C-4-alcohols being obtained with overall yields of 60 to 80 % of theory . The esterification can then take place in a manner known per se with carboxylic acid anhydrides, carboxylic acid chlorides and with alkyl isocyanates and also by transesterification.

To prepare the β-carbamic acid ester, a substituted 2,9-dioxatricyclo [4,3,1 »O ^ " J decane of the following formula III

Ro- Χ
Ι- H "0 * 1006 75 " 98 3 40 3 /

-4-

in which R is an alkyl group with 1 to 4 carbon atoms and the 10,11 double bond can be hydrogenated with alkyl isocyanates or carbamic acid esters implemented.

Some physical data are analogous to those in the examples the C-4 epimers prepared in the examples are compared in Table 1.

Table 1

t-U

Test
Wr. R. Mp ° C
(Kofier) (Methanol) C-4 substituents 981
2090 CH ₃
3 oil
63 + 42 °
+ 30 ° β-OH, α-H
α-ΟΗ, ß - H 2009
2117 CH ₃
3 58. + 69 °
+ 33 ° ^ β-OC0CH ₃ , α-H
ct-OCOCH ,,, ß - H
3 2043
2118 CH,
CH ₃ oil
51-53 + 70 °
+ 39 ° B-OCOCH ₂ CH ₃ , a - H "
■ (X-OCOCH ₀ CH *, ß - H 2067
2076 CH ₃
CH ₃ 77-79
123-124 + 54 °
+ 30 ° B-OCOIiHCH ₂ CH ₃ , α-H
0-OCONHCH ₂ CH ₇ , β-H 2166 CH,
3 oil + 33 ° Cx-OCONHCH (CH ₃ ) ₂ , β-H 2199 CH ₃ oil + 49 ° B-OCOCH ₂ CH (CH ₃ ) _2? α - H 2179 CH ₂ CH ^ oil + 17 ° Cr-OCONHCH ₂ CH- ,, β - H 2230 CH ₃ 142 + 42 ° B-OCONH ₂ , α-H

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Table i (continued)

I. R. Mp ° C
(Kofier) Γ T ²⁰
L ^cc j D
(Methanol) C-4 substituents Test ^!
No. CH ₃ oil
oil • - 36 °
- 61 ° B - OH, α - H
α - OH, β - H 1246
1561 CH ₃
CH ₃ oil
oil 0 °
- 35 ° B-OCOCH ₃ , α-H
(X-OCOCH ₃ , β-H 2045
2080 CH ₃
CH, 49-52
oil 0 °
- 32 ° B-OCOCH ₂ CH ₃ , α-H
Cx-OCOCH ₂ CH ₃ , β-H 2044
2081 ci4 91-93
103-105 - 2 °
- 31 ° B-OCONHCH ₂ CH ₇ , α-H
Cc-OCOHHCH ₂ CH ,, β-H 1767
2026 CH ₃ 128-132
oil 0 °
- 27 ° B-OCONHCH (CH ₃ ) ₂ , α-H
Cx-OCONHCH (CH ₇ ) ₂ , β-H '2057
2065 CH ₃ 130 - 5 ° B-OCOIiH ₂ , α-H 2198 CH ₂ -CH ₃ 73-75 - 17 ° 0-0COIiHCH ₂ CH ₃ , - β - H 2157

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The differences in action of some pairs of epimers and some homologous α-compounds are summarized in Table 2:

Tabel 2 ^LD 50 ^{i # p}
mouse
mg / kg Ataxia
mouse
mg / kg anesthesia
ED ₅₀ lp
mouse
mg / kg Hexobarbital
Anesthesia Ver
elongation
mouse
mg / kg 600
300 200
25th <300 100 Test
number LD ₅₀ po
mouse
mg / kg 390
527 50
50 <100 215 981
2090 610
774 802
527 <100 <i6o
100 2067
2076 872
1025 1200
1600 800
200 800 68
68 2179
2157 944
1470 1000
> 1000 200
50 - 316 1246
1561 > 1500
> 1500 436
1379 147
50 : 316 2045
2080 1470
> 147O 1000
118 147
12th 46.4 3-1.6 2044
2081 1470
-71470 890
297 400
68.1 . 100 31.6 2057
2065 > 1470
156 1767
2026 > 1500
518

A09833 / 1006

As criteria that can be easily observed and assessed, the Ataxia, the hexobarbital anesthesia extension and the anesthesia itself were chosen.

If one compares, for example, the pair of epimers with the test numbers 2067 and 2076, one can clearly see that with practically the same toxicity and with the same dose causing an ataxia, only the α-compound 2076 itself has an narcotic effect, but does not prolong the hexobarbital narcosis, while the / 3 compound does not have a narcotic effect, but prolongs the hexobarbital narcosis. In the case of the analogous pair of epimers hydrogenated in the C-10 position with the test designations 2057 and 2065, the differences are even greater. Here, however, neither anesthesia nor a hexobarbital anesthesia prolongation occurs with the -compound, but a very strong narcotic effect with the α-compound and, below the narcotic dose, a hexobarbital anesthesia prolongation effect. While 147 mg / kg are still required for triggering ataxia with the β -compound, only 12 mg / kg are required with the α-compound. This increase in effectiveness by a power of ten is, however, consistent with an increased toxicity. Nevertheless, the relation (effective dose to lethal dose) remains constant. If one also compares the effective doses of the C-4- β alcohols listed in Table 2 with their esters, there is also a significant increase in the central damping effects with a simultaneous reduction in toxicity through the esterification, for example with acetic, propionic, ethyl carbamine - and isopropylcarbamic acid. A potentiation up to the narcotic effect cannot be achieved by the esterification, although the lipophilicity compared to the alcohols is significantly increased.

409833/1006

2306718

• -8th-

The narcotic effectiveness of the 2,9-dioxatricyclo according to the invention [4.3 »1.0 (J decane is rather stereospecific the C-4-ct configuration bound, as from the comparison of the C-4 epimer pairs listed in Table 2 clearly emerge. '-

- Example 1 '. ". . _v .

Synthesis of 4 a- ^ droxy-S-methoxy ^ -niethyl-IO-methylene ^, 9-dioxatricyclo [4,3,1, Ö ^ ' ⁷ ] decane (2090).

9.56 g of 8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0'-decan-4-one prepared according to DOS 2 027 890 were dissolved in 150 ml of dry ether and the solution was slowly added dropwise under nitrogen into a slurry of 2.2 g of lithium anate (LiAlH.) in 150 ml of dry ether. Now, an hour, it was refluxed, then cooled to 20 ⁰ C and the reaction on Eiswasser.gegossen. After addition of ammonium sulphate was extracted several times with ether ,, The combined ether extracts were dried over sodium sulfate, clarified with animal charcoal _s filtered and concentrated in vacuo. Yield: 9.3 g of crystals, that is 96.4 % of theory,

Example 2

4-α-acetoxy-8-methoxy-3-methyl-1O-methylene-2,9-dioxatricyclo (4,3,1, O ³ ' ⁷ ? Decane (2117).

3.2 g of 4-oc-hydroxy-8-methoxy-3- prepared according to Example 1

40 9833/1006

methyl-10-methylene-2,9-dioxatricyclo [4 »3,1, O ^ ' ⁷ J decane (2090) were dissolved in a mixture of 2 ml of pyridine and 8 ml of acetic anhydride and left to stand for 24 hours at room temperature. Excess pyridine and acetic anhydride were then distilled off in vacuo, the residue was taken up in ice water and extracted with ether. After the ether extract had been dried over sodium sulfate and concentrated in vacuo, 4-α-acetoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0'J decane slowly crystallized out. Filtration and washing with cold n-hexane / ether resulted in 3.36 g of pure product, that is 87.6 % of theory.

Example 3

4-oc-propionoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^{3 '7} J decane (2118).

3.2 g of 4-a-hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo (4,3,1,0-decane (2090) were added to 15 ml of propionic anhydride as in Example 2 and 2 ml of pyridine reacted and worked up.Crystallization from ether / η-hexane resulted in 4.0 g of 4-α-propionoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1 , 0 ^ ' ⁷ J decane, that is 98.7 % of theory.

Example 4

8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1, O ^{5 7} J decane-4-a-ethyl carbamate (2076)

5 g of 4-a-hydroxy-8-methoxy-3-methyi-1O-methylene-2,9-dioxatricyclo J4,3,1,0 ^ 'J decane (2090) were dissolved in 50 ml of dry benzene and the approach followed Addition of 2.5 ml of ethyl isocyanate and 3 drops of glacial acetic acid for 11/2 hours at -6O ⁰ C.

A09833 / 1006

2306-18

After standing overnight at room temperature, the benzene was im. Evaporated in vacuo, the residue crystallizing. Crude yield of 8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1, CT "} decane-4-a-ethyl carbamate: 6.7 g, that is 99.5 % of the Theory. For analysis, it was recrystallized from ether / n-hexane.

Tests on cats and dogs were also carried out with this compound. With an iv LD ₁ -Q of 226 mg / kg, the duration of anesthesia was 10 minutes after administration of 5 mg / kg iv, 25 minutes after administration of 10 mg / kg iv and 60 minutes after administration of 15 mg / kg iv Minutes.

In the dog, an anesthetic of 17.5 mg / kg i.v. be generated.

Example 5

Preparation of 3 »10-dimethyl-8-methoxy-2,9-dioxatricyclo | _4,3,1,0 J decan- ^ ß-isopropylcarbamate (2057)

4 _f 5 g of 4-ß-hydroxy-8-methoxy 3,10-dimethyl-2,9-dioxatricyclo [■ 4,3,1,0 ^ ' ⁷ J decane (1246), prepared according to the method described in DOS 1 961 433, were added to a solution of 10 ml of isopropyl isocyanate in 50 ml of benzene and the clear solution was allowed to stand at room temperature after the addition of 5 drops of acetic acid. The residue was then evaporated several times in vacuo with the addition of benzene to remove excess isopropyl isocyanate Poured onto ice water and extracted with benzene. After washing the oil phase with water, drying over sodium sulfate and concentrating in vacuo, a yellowish oil was obtained which crystallized after trituration with ether / n-hexane. Yield of pure 3,1O-dimethyl- 8-methoxy-2,9-dioxatricyclo j_4,3,1jO ³ 'J decane-4-ß-isopropylcarbamate (2057): 4.7 g, that is, 75 % of theory.

- -11-40 9833/1006

Example 6

Preparation of 4-α-hydroxy-8-ynethoxy-3,10-dimethyl-2 _t 9-dioxatrjcyclo [4,3,1,0 ⁵ ' ⁷ jdecane (1561)

4 g of 3.1O% methyl-8-methoxy-2,9-dioxatricyclo [4,3,1,0 '(jdecan-4-one, prepared according to DOS 2 027 890, were treated analogously to Example 1 with LiAlIL · injcrockenem ether reduced to give 4-oc-hydroxy-3,1.0-dimethyl-8-methoxy-2,9-dioxatricyclo Ji, 3,1,0 ^{5 7} Jdecari was obtained in virtually quantitative yield (1561) '. (4.0 G)

Example 7

Preparation of 4-a-acetoxy-8-methoxy-3,10-dimethyl-2, "9-dioxatricyclo J4,3,1,0 ³ ' ⁷ jdecane (2080)

4.0 g of 4-oc-hydroxy-8-methoxy-3,1O-dimethyl-2,9-dioxatricyclo [4,3,1,0'-decane were dissolved in 12 ml of acetic anhydride and 4 ml of pyridine, and the clear solution was dissolved for 4 hours left to stand at room temperature. After the excess acetic anhydride and pyridine had been distilled off, the residue was poured onto ice water and extracted with ether. After washing the ether phase with 1 η NaOH and water, it was dried over sodium sulfate and concentrated in vacuo to constant weight. There were obtained 4.5 g of colorless oily 4-a-acetoxy-8-methoxy-3,10-dimethyl-2,9-dioxatricyclo [4,3,1,0 ^{3 '7} Jdecan (2080). that's 94 % of theory.

This compound can be prepared also starting from that according to Example 2 4-cc-acetoxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricycloJ4,3,1,0 ^{3 '7} Jdecan (2117) by catalytically ^ Reduction can be prepared in the usual way.

-12-

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2306178

Example 8

Preparation of 8-methoxy-3,10 ~ dimethyl-2,9-dioxatricyclo [4,3,1, O ³ ' ^7- decane-4-a-ethyl carbamate (2026)

5, Og 4-α-hydroxy-8-methoxy -3,10-dimethyl-2,9-dioxatricyclo 4,3,1,0 ^ 'decane and 5 ml of ethyl isocyanate were dissolved in benzene and mixed with a little acetic acid as a catalyst. After a few hours the addition of ethyl isocyanate to the Alcohol to the corresponding carbamate run practically quantitatively. It was first neutralized (with sodium bicarbonate), then washed against water and the benzal phase after Concentrated drying. White crystals immediately resulted. The yield of 8-methoxy-3,1O-dimethyl-2,9-dioxatricyclo [4,3,1,0 '{decane-4-α-ethyl carbamate (2026) was practical quantitatively.

Example 9

Preparation of 8-methoxy-3-methyl-1-O-methylene-2,9-dioxatricyclo [4,3,1,0 ^{5 '7} Jdecan-4-beta-carbamate (2230)

6 g of 4-β »hydroxy-8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [4,3,1,0 'i-decane, were mixed with 7 g of ethyl urethane and 0.4 g of aluminum isopropoxide and the Batch heated for 5 hours at 150 to 154 ° C and 200 Torr. The end of the reaction can be determined from the amount of ethanol distilled over. Towards the end of the reaction, most of the excess ethyl urethane was distilled off under reduced pressure (50 torr), a highly viscous yellowish residue remaining. This was purified by chromatography on silica gel and the desired carbamate was crystallized from ethanol / carbon tetrachloride. The yield of 8-methoxy-3-methyl-10-methylene-2,9-dioxatricyclo [h, ⁵ 3,1,0 ^'7 jdecan-4-beta-carbamate (2230) was 87.3% of theory.

409833/1006 ~ ¹³ ~

Claims (2)

-13 claims 1. 4-Hydroxy-2,9-dioxatricyclo [4,3,1, O ^ "Jdecane and their Esters with aliphatic carboxylic and carbamic acids of the general formula I. ■ fr 3
in which R ^ is an alkyl radical with 1 to 4 carbon atoms, Rp OHjOCOR ^, OCOKHRc when R ^ is hydrogen and R, OCONHR ₅ when Rp is hydrogen, where R ^ for an alkyl group with 1 to 4 C- Atoms and R, - stands for hydrogen or an alkyl group with 1 to 4 carbon atoms and the 10,11 double bond can be hydrogenated. 2. A method for producing the a mentioned in claim 1 Compounds, characterized in that 2,9-dioxa tricyclo [4,3,1,0'-decanones of the general formula II in which R _{1 is} an alkyl radical with 1 to 4 carbon atoms 409833/1006 tet and the 10,11 double bond can be hydrogenated, preferably reduced with metal hydrides and optionally in a manner known per se with carboxylic acid chlorides, car- " acidic anhydrides., carbamic acid esters and alkyl isocyanates implements. A method for producing those mentioned in claim 1
ß-carbamic acid ester, characterized in that one
Compounds of the general formula in which R ,. denotes an alkyl radical with 1 to 4 carbon atoms and the 10,11 double bond can be hydrogenated with alkyl isocyanates or carbamic acid esters are reacted in a manner known per se. 409833/1006