DE2106705A1 - Ester derivatives of Tetrahydrocanna binolen - Google Patents

Description

DR. L. WESSELY

PATENT ADVOCATE

MONKS 19

MQNTENSTRASSE 9/1

ARTHUR D. LITTLE ING., Cambridge, Mass., USA

Ester derivatives of tetrahydrocannabinols. The present invention relates to new ester derivatives of <Δ ~,

Q Q

Δ- and Zv-tetrahydrocannabinols, their preparation and pharmaceutical compositions containing them.

According to one of its aspects, the invention relates to a class of chemical compounds which are classified as 1 - / "" tu ¹ - (di-lower alkyl amino) -acyloxy_7-3-alkyl (and cycloalkyl-lower alkyl) 6a, 7 , 8,10a- (and 6a, 7,10,10a- and 7,8,9,10-) tetrahydro-6,6,9-tri-lower-alkyl-6H-dibenzo / b ", d_7pyrane are called, and acid salts and quaternary salts thereof. Some of the acid salts are water-soluble. Compounds according to this aspect of the invention have inherent utility properties of having biological activity as determined by standard pharmacological test methods for therapeutic agents, and are useful as therapeutic agents Compounds of the invention are amino esters and some of their acid addition salts are water soluble. These esters offer the possibility of being hydrolyzed in vivo to form the corresponding phenolic compound. The rate of such hydrolysis can be adjusted by the nature of the ester chain.

It is therefore a primary object of the present invention to provide

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of new chemical compounds and a process for their production. Another object of the invention is to provide of compositions that have properties affecting the central nervous system and the possibility of hydrolysis in vivo offer. Other objects and objects of the invention will appear from the following description.

The invention accordingly relates to the various stages and the relationship of one or more such stages to each of the other stages and the compounds and compositions that define the properties, characteristics and relationship of Have components as illustrated by the compounds and compositions described below.

Examples of 1 - / "" UJ- (di-lower-alkylamino) -acyloxv / -5-alkyl- (and cycloalkyl-lower-alkyl-) 6a, 7,8,1Oa- (and 6a, 7,1O, 1Oa- and 7,8,9,10-) tetrahydro-6,6,9-tri-lower-alkyl-6H -d-ibenzo ^ b ", d7pyrane and preferred compounds among these are those of formula I.

CH (CH- ) K \

in which η is an integer from 0 to 6, R ₁ , R ₂ *% ^and R »are lower alkyl radicals, R ^ is an alkyl or cycloalkyl-lower alkyl radical and Rg is a hydrogen atom or a lower alkyl radical.

The compounds of the class of the formula I can have the Λ , £ s or A structure. Those of the A. ^a structure or the

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■ 1 - / Zj - (di-lower-alkylamino) -acylox27-3-alkyl- (and cycloalkyl-lower-alkyl-) 7,8,9,1O-tetrahydro-6,6,9-tri-lower-alkyl-6H -dibenzo ^ S, d7pyrane correspond to formula II

O'rr

II I ⁶ ,

O ₇ C-CH (CH ₂ ) _n N (

II

The compounds of the A structure or "! - / ÖJ-CDi-lower-alkylamino) -aoylox27-3-alkyl- (and cycloalkyl-lower-alkyl-) 6a, 7,10, -1Oa-tetrahydro-6,6 , 9-tri-lower-alkyl-6H-dibenzo ^ B, d7pyrans correspond to the formula III

R,

Il I ⁶
0-C-CH (CH ₉ ) N.

III

The compounds of the A structure or the 1- / ü / '- (di-lower-alkylaraino) -acyloxy7-3-alkyl- (and cycloalkyl-lower-alkyl-) 6a, 7,8,1oatetrahydro-6 , 6, S-tri-lower-alkyl-öH-dibenzo ^ b ", d7pyrane correspond of formula IV

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O R,

Il I ⁶

O-C-CH

_T / ^R 3

IV

• The preferred acid addition salts of the new. 1- ^ CJ- (di-lower alkylamino) -acylQxy / -3-alkyl- (and cycloalkyl-lower-alkyl-) 6a, 7, -8,1Qa- (and 6a, 7,10,1Oa- and 7,8 , 9,10-} tetrahydro-6 _t 6,9-tri-lower alkyl-6H-dibenzo / b ", d7pyrans are those of the formula V

■ R.

O Rg

ft I ⁶
CCH

ft I
-C-CH (CH-)

Acid

, These acid addition salts of the formula V can or, have Δ structure, as in the formulas of the free bases of the Formulas II, III and IV.

In the formulas II to V, η and R have a compound meanings given with formula I.

those above in connection with the term "lower alkyl" as used herein are saturated to understand monovalent aliphatic radicals, including straight-chain and branched radicals, with 1 to 6 carbon atoms, for which, without making a limitation, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, amyl, hexyl,

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and the like are examples.

As used herein the term "alkyl" means sat - * -; - Invalid aliphatic residues, including straight. .- _Ο,; Γ and branched radicals, with 1 to 20 carbon atoms, for which, without imposing a restriction, methyl, n-amyl, n-hexyl, 2-heptyl, n-heptyl, 3-methyl-2-octyl , n-octyl, 2-nonyl, 2-tetradecyl, n-hexadecyl, 2-sicosanyl, and the like are examples.

as used herein the term "cycloalkyl" means cyclishe To understand saturated aliphatic radicals with 3 to 8 carbon atoms, for which, without making a limitation, Cyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclohexyl, 4-methylcyclohexyl, cyclooctyl, and the like are examples. -

According to one of its process aspects, the invention applies Process in which a compound of the formula VI

OH

VI

in the

R2 and

the meanings given above

^, R2 and R ^
with an aliphatic U ^ -di-lower-alkylamino acid of the formula

⁶ , λ
HOOC-CH (CBUV

VII

and R. niedri

in which η is an integer from 0 to 6, ge are alkyl radicals and Rg is a hydrogen atom or a never represents drigen alkyl radical, is implemented. The response is in

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OBlGfNAt iNSPECTBD

a solvent for the cannabinol, which is essentially is inert under the reaction conditions, such as methylene chloride, methanol, ethanol, dimethylformamide or water / water, and carried out in the presence of a condensing agent. The reaction can be represented as follows:

OH

COOH

Rg-CH

I ³

^R 4

VII

Eondensa solvent

According to another of its method aspects, the invention relates a method in which an acid addition salt of the following Formula Vila of the compound of Formula VII with the compound of the formula VI is converted to directly an acid addition salt the compound of formula V to form. This reaction can be represented as follows:

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COOH I.
R ₆ -CH

R ₄ -NR ₃ acid

Vila

Condensation τκ »,,« ». ™ * ++ ^ + medium ^ solvent

O _R acid

IM ⁶ * /

0-C-CH (CH ₀ ) N {I ■ ζ. η \.

JThis reaction will be in the same way as that in the the free base is formed, carried out.

The compounds of the formula VI can be prepared according to the method described by T.Petrzilka, Vf. Haefliger and C. Sikemeier, Helvetica Ghimica Acta, jj2_, 1102 0969) »described process.

Condensing agents used in the preparation of the compounds of Formulas I to V include the carbodiimides (water-soluble and water-insoluble) and related compounds that enable the achievement of the necessary dehydrative Allow coupling of the hydroxyl group of tetrahydrocannabinol to the amino acid. Those suitable as condensing agents Carbodiimides are described in the literature, compare for example Journal of Organic Chemistry 2J_, 439 (1956) and

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£ 6, 2525 (1961)} Bulletin de la Societe Chimique de France (1956), p. 1360; and U.S. Patent 3,135,748 /. The functional group of these 'carbodiimides is the group -N = O = IT-, and a number of these, including theirs Acid addition products, is soluble in water. To others

. Applicable condensing agents include diethylcyanamide ^ CC ₂ Hc) ₂ NCN7, cyananiide (H ₂ NCH, which in its tautomeric form is a carbodiimide) and N-ethyl-5-phenylisoxazolium-3-sulfonate. These condensing agents can be used in aqueous solutions. Finally, examples of other condensing agents that act in non-aqueous media are Ιί, ΐϊ'-carbonyldiimidazole and ethoxyacetylene, which are dehydrative binding agents, and bis (2,4-dinitrophenyl) carbamate and 2-ethoxypyridine-1-oxide, which "bind through the formation of active ester".

As previously mentioned, the acid addition salts can be prepared directly without the need to form the free base first will. However, the free bases of the formula I can easily be converted into acid addition salts by reacting the base with a Acid are transferred. Likewise, the free bases can be regenerated from the acid addition salts in the usual way means by treating the salts with aqueous strong bases, such as alkali hydroxides, alkali carbonates and Alkali bicarbonates. The bases regenerated in this way can with the the same or a different acid are reacted to give the same salt or a different acid addition salt again. The new bases and all of their acid addition salts can thus easily be converted into one another.

Due to the presence of a basic tertiary amino group the compounds according to the invention also form quaternaries Ammonium salts.

The quaternary ammonium salts of the Yerbinduagen of the formulas I to IV are made by adding esters of strong acids to the compounds obtained in the form of the free bases, these esters having a molecular weight below about 300. To a preferred one

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Class of esters include the alkyl, alkenyl and phenyl lower alkyl esters of strong inorganic acids or organic sulfonic acids, including compounds such as Methyl chloride, methyl bromide, methyl iodide, ethyl bromide, Propyl chloride, allyl chloride, allyl bromide, methyl sulfate, Methylbenzenesulfonate, methyl-p-toluenesulfonate, benzyl chloride, Benzyl bromide and substituted benzyl halides, such as p-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride, pentachlorobenzyl chloride, p-nitrobenzyl chloride, p-methoxybenzyl chloride, and the same.

It has been found that G-around of the common structural * .Aufbaus of the bases and of their acid addition salts as well as the square) ternary ammonium salts, these compounds have pharmacodynamic activity of a type to be described in more detail below. This pharmacodynamic activity inherent in the compounds according to the invention can be exploited in a valuable manner for pharmaceutical purposes by using the free bases themselves or the acid addition salts or quaternary ammonium salts which are formed from pharmaceutically acceptable acids or esters of strong acids, i.e. acids or esters opposite their anions are harmless to the organism in effective doses of the salts, so that the beneficial properties inherent in the general structure of the free bases are not adversely affected by side effects attributable to the anions.

In the recovery of this pharmacodynamic activity of the According to the invention, the use of pharmaceutically acceptable salts is of course preferred.

The pharmaceutical compositions according to the invention contain thus at least one of the compounds according to the invention in the form of the bases and / or the pharmaceutically usable acid addition salts and / or the pharmaceutically usable quaternary ones Ammonium salts.

Although water insolubility, high toxicity or lack of

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- ίο -

crystalline character, some particular salts are unsuitable or less suitable for use in a given pharmaceutical application can make suitable, the water-insoluble or toxic salts can be converted into the corresponding pharmaceutically acceptable salts Bases are converted by decomposition of the acid addition salts with an aqueous base, as explained above, or that Acid addition salt can be converted into any desired pharmaceutically acceptable acid addition salt by double conversion Involvement of the anion, for example through ion exchange processes, be transferred.

As in the case of acid addition salts, insolubility in water, high toxicity or a lack of crystalline character of some quaternary ammonium salts at a given pharmaceutical Make application unsuitable or less suitable. The water-insoluble or toxic salts can, however, be converted into the corresponding pharmaceutically acceptable salts by double conversion with the participation of the anion, for example by ion exchange processes. Alternatively, reacts when the anion of the original quaternary salt forms a water-insoluble silver salt, the quaternary salt with silver oxide in aqueous medium to form the corresponding cuaternary ammonium hydroxide, the original anion as Precipitation is removed. The quaternary ammonium hydroxide solution can then be mixed with any desired weakness or concentration strong acid are neutralized to form a new quaternary ammonium salt in which the anion of that of the original salt is different. In this way, quaternary ammonium salts are formed in which the anion of comes from a weak acid.

Apart from their usefulness in pharmaceutical applications are the salts according to the invention for characterization or identification of free foods or useful for isolation or purification processes. Such for characterization or Suitable acid addition salts can be used for cleaning like all acid addition salts, to regenerate the pharmaceutical

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table-usable free bases by reacting the salts with an aqueous base can be used, or the acid addition salts or quaternary ammonium salts can alternatively be used in a pharmaceutically acceptable salt, for example by ion exchange processes, be transferred.

From the above it can be seen that all acid addition salts and quaternary ammonium salts of the new bases are valuable compounds regardless of considerations solubility, toxicity, physical form, and the like, and accordingly are within the scope of the present invention.

The new features of the compounds according to the invention are * especially in the concept of the bases and the cationic forms of the new compounds of the formulas I to V and not in a special acid or ester part or anion which is present in the salt forms of the compounds. The acid or ester group or anions which may be present in the salt forms are not as such new and not critical and can therefore be any Anions or acidic substances capable of forming salts with bases. In aqueous solutions they have Base form or water-soluble acid addition salt form of the compounds according to the invention, a customary protonated cation or Ammonium ion.

Suitable acid addition salts are therefore those which are derived from different acids, such as formic acid, Acetic acid, isobutyric acid, o6-mercaptopropionic acid, Malic acid, fumaric acid, succinic acid, succinic acid monoamide, Tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, Phthalic acid, anthranilic acid, naphthalenecarboxylic acid (1), Cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, Crotonic acid, acetylenedicarboxylic acid, sorbic acid, furancarboxylic acid (2), cholic acid, pyrene carboxylic acid, pyridine-2-carboxylic acid, Indoleacetic acid- ^)> quinic acid, sulphamic acid, methanesulfonic acid, Isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, Benzenesulfinic acid, butylarsonic acid, diethylphosphinic acid,

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p-aminophenylarsinic acid, phenylantimonic acid, phenylphosphinous Acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, Hydrochloric acid, hydrobromic acid, hydrogen iodide acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic acid, molybdic acid, .Phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, Picrolonic acid, barbaric acid, boron trifluoride and the like.

The acid addition salts can be added directly by dissolving the free Base in an aqueous solution containing the appropriate acid and isolating the salt by evaporation of the solution or be prepared by reacting the free base and an acid in an organic solvent, in the latter If the salt separates out directly or can be obtained by concentrating the solution.

The quaternary ammonium salts are made by mixing the free Base prepared with an ester of a strong acid in an inert solvent. It can be heated to facilitate the reaction but salt formation usually occurs easily at room temperature. The quaternary ammonium salt separates directly from or can be obtained by concentrating the solution.

The compounds of formulas I through V have been found to have activity on the central nervous system as evidenced by the large apparent changes made by administration at home in standard tests including observations of psychomotor activity, reactivity to stimuli and ability perform normal, unconditioned motor tasks induced vmrden ^ sFerglei- ■ before Irwin, Animal and Clinical Pharmacologic Techniques in Drug evaluation, Year Book Medical Publishers, Inc., Chicago, Illinois, pages 36 to 54 (1964J7 * ^Bin Seispiel for this activity is that the compounds are depressors of spontaneous motor activity in doses on the order of 10 to 20 mg / kg when administered parenterally or orally.

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An example of reactivity to stimuli was given EDcQ value of about 45 mg / kg in the eddy test with a hot plate intended for parenteral administration / for a complete Description of the test used see N, B. Eddy and D. leimbach, Journal of Pharmacology and Experimental Therapeutics, 160, 21? (1968) 7- These activities show utility of compounds as psychotherapeutic agents.

The compounds can be ready for use by dissolving a salt form of the compounds in water (or an equivalent amount of a non-toxic acid if the free base is used) or in a physiologically acceptable aqueous medium, such as a saline solution, prepared under sterile conditions and stored in ampoules for intramuscular injection. Alternatively, they can be in unit dosage form as tablets or capsules for oral administration either alone or together with suitable adjuvants, such as Calcium carbonate, starch, lactose, talc, magnesium stearate, Agar-agar and the like. The compounds can also be used for oral administration in aqueous alcoholic, glycolic or oily solutions or in oil-water emulsions are prepared in the same way, as usual medicinal preparations are made.

The molecular structure of the compounds according to the invention was on the basis of the examination of their infrared, ultraviolet and NMR spectra and their conversion products, and by "matching the calculated values and those found Elemental analysis values confirmed for typical examples.

The following examples serve to further illustrate the invention.

example 1

1 -ß.- (diethylamino) -butyryloxy / O-pentyl-oa, 7,8,1 Oa-t e trahydro-

6,6,9-trimethyl-6H-dibenzo / b ", d / pyran hydrochloride

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-H-

Sine solution of 2.1 g (about 6.7 mmol) of A -Tetrahydrocannabinol (1-Hydroxy-3-pentyl-6a, 7,8,1Oa-tetrahydro-6,6,9-trimethyl-6H-dibenzo ^ jdTpyran) , prepared according to Petrzilka, Haefliger and Sikemeier, Helvetica Chimica Aeta, 52, 1102 (1969), 1.45 g (7.05 mmol) of dicyclohexylcarbodiimide (condensation agent) and 1> 35 S (6.9 mmol) of 4-diethylaminobutyric acid hydrochloride ^ made according to the method of FF. Looks, V / .B. Wright, Jr., and MI ¹ . Zienty, Journal of the American Chemical Society, 63 , 2488-2490 (1941.17 ^{in 12} 5 ml of methylene chloride was stirred for about 15 hours at room temperature. The dicyclohexylurea formed as a by-product from the condensing agent was removed by filtration.

The solvent was removed from the reaction mixture and the residue (3.7 g) was treated with about 30 ml of water and filtered. The filtrate was frozen and the water removed by lyophilization. The glassy residue (2.3 g) was treated with 50 ml of ether, and the white solid substance obtained was collected and dried in vacuo. 1.5 g of product with an ^{temperature of 116 to 121 °} C. were obtained in this way. This solid was dissolved in about 15 ml of benzene, treated with decolorizing charcoal and filtered. The filtrate was heated (40 to 45 ^° C.) and treated with about 40 ml of ether. The product crystallized in fine white needles; 0.88 g ($ 27 yield); F = 127.5 to 129 ° C. A small amount was recrystallized again (benzene ether), F = 128.5 to 130 ^° C.

Analysis: C ₂₈ H ^ ₅ NO ₅ -ECl (molecular weight: 480.14): calculated: C 70.04, H 9.66, N 2.92 Cl 7.38 found: C 70.21, H 9.26 N 2.76 Cl 7.15 ^. / Öc7 ^ ⁶ = -143 ° (c = 0.61, CHCl ₃ ). The infrared and NMR spectra were recorded and were consistent with the following structure:

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CH.

HCl

Il t

0-C-CH (CH ₀ ), N- (O ₃ H,.), ·

Δ ί Δ D Δ

Example 2

1 - ^ - (diethylamino) -butyryloxv7-3-pentyl-6a, 7,8,1 Oa-tetrahydro-6,6, ^ trimethyl-eH-dibenzo / b ", d7pyran

The procedure of Example 1 was repeated with the exception that 4-diethylaminobutyric acid instead of 4-diethylaminobutyric acid hydrochloride was used. The purified free amino ester of the formula obtained

CH.

OH II I OC-CH (CH ₂ ) ₂ N (C ₂ H ₅ )

^C 5 ^H 11

, was identified by NMR. It was then converted to the corresponding hydrochloride of Example 1 by treatment with ethanolic hydrogen chloride and recrystallized (benzene-ether), I ¹ = 128.5 to 13O ⁰ C.

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Example 3

1- ^ 4 "- (diethylamino) -butyryloxy_7-3 ~ pentyl-6a, 7» 10.1Oa-tetrahydro · 6,6,9-trimethyl-6H-dibenzo / B, dJ7pyran-hydro chloride

The procedure of Example 1 was carried out using A-tetrahydrocannabinol (1-hydroxy-3-pentyl-6a, 7,9,1Oa-tetrahydro-6,6,9-trimethyl-6H-dibenzo / B, d7py * ^> an) instead of the in

Example 1 used A compound repeatedly. The work-up out of water was omitted. The yield of the pure end product, which is identified by infrared and MR spectrum as

CH.

H HCl QC-CH (CH ₀ ) ₀ N (C ₀ H _1. )

was identified, was 70 ^, P = 151 to 152.5 ⁰ C Recrystallization from a Cyclchexan-benzene mixture was possible.

Analysis: C ₂₈ H ^ ₅ NOj ₄ HCl (molecular weight 480.14) Calculated: C 70.04 H 9.66 IT 2.92 Cl 7.38 # Found: C 70.33 H 9.50 N 2.73 Cl $ 7.57 läj? ¹ = -183 ° (c = 0.66, CHCl ₃ ).

Example 4

1 - /? - (diethylamino) -butyryloxv / -3-pentyl-6a, 7,10,1 Oa-tetrahydro-6,6 "9- $ rimethyl-6H-dibenzo / B, d / pyran

The procedure of Example 3 is repeated with the exception

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that 4-diethylaminobutyric acid instead of 4-diethylamino-butyric acid hydrochloride is used. After purification, the product obtained is the free amino ester of the formula

N (C ₂ H ₅ )

This free amino ester can then be converted into the corresponding hydrochloride of Example 5 by treatment with ethanolic hydrogen chloride converted to give a product identical to that of Example 3.

It can be seen that the above and from the description apparent objectives have been effectively achieved and that certain changes have been made in the implementation of the above Methods and compositions can be made which are within the scope of the invention.

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Claims (1)

.Patent claims Compounds of the Pormel (a) in which η is an integer from 0 to 6, R ^, Rg, Hrz and R, mean lower-alkyl radicals, R ₁ - is an alkyl or cycloalkyl-lower-alkyl radical and Hg is a hydrogen atom or a lower-alkyl radical, Compounds of the Pormel (b) in which η represents an integer from 0 to 6, RJ, R2, R * and Ri represent lower-alkyl radicals, R _{5 represents} an alkyl or cycloalkyl-lower-alkylres-fc and Rg represents a hydrogen atom or a lower-alkyl radical. 1 - ^ - (diethylamino) - "butyrylox £ 7-3-pentyl-6a, 7,8,10a-tetrahydro-eje ^ -trimethyl-eH-dibenzo ^ Bj ^ pyran (Pormel b: η = 2, R ₁ and R ₂ - methyl, R ^ and R ₄ = ethyl, Rc * pentyl, 109836 / Ί704 = Hydrogen). 4 ·. Compounds of the formula (C) in which η is an integer from 0 to 6, R ₁ , R ₂ , R ^ and R. mean lower-alkyl radicals, R, - is an alkyl or cycloalkyl-lower-alkyl radical and R ₆ denotes a hydrogen atom or a lower-alkyl radical, 5.1 - ^? - (diethylamino) -butyrylox2; 7-3-pentyl-6a, 7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo / E, d7pyran (Formula c: η = 2, R ₁ and R ₂ = methyl, R ₅ and R ^ = ethyl, R ₅ = pentyl, R ₆ = hydrogen). 6. Compounds of the formula ! II
-C-CH (CH ₂ ) (d) in which η is an integer from 0 to 6, and R 1 denotes lower-alkyl radicals, R _{5 denotes} a R ₁ , R ₂ , Represents alkyl or cycloalkyl-lower-alkyl radical, and Rg denotes a hydrogen atom or a lower-alkyl radical. 109835/1704 7. Quaternary salts of the compounds of the formula ~ ■. "R, ■ R _e (e) in which η is an integer from 0 "to 6, RJ, R ₂ , R * and R. denote lower-alkyl radicals, R, - represents an alkyl or cycloalkyl-lower-alkyl radical and Rg denotes a hydrogen atom or a lower-alkyl radical, 8 * compounds of the formula _R 16 0-C-CH (CH ₀ ) Ν acid in which η is an integer from 0 to 6, R ₁ , R ₂ , R ^ and R ^ are lower-alkyl radicals, R ^ is an alkyl or cycloalkyl- _{lower-alkyl radical and R fi is} a hydrogen atom or a lower-alkyl radical means. Compounds of the formula 109835/1704 acid (β) in which η represents an integer from 0 to 6, R, mean lower-alkyl radicals, R ^ a Represents alkyl or cycloalkyl-lower alkyl radical and Rg denotes a hydrogen atom or a lower-alkyl radical. 10. Hydrogen chloride addition salt of 1- ^ 4- (diethylamino) -butyryloxy-7-3-pentyl-6a, 7,8,1 Oa-te trahydro-6,6,9-trimethy 1-6H-dibenzo ^ B, d7pyran (Formula g: η = 2, R- and R ₂ = methyl, R ₅ and R ^ = ethyl, R ₅ = pentyl, Rg = hydrogen, acid = HCl). 11. Compounds of the formula acid (H) Rr in which η represents an integer from 0 to 6 ,. RJ, R ₂ , Rz and H. denote lower-alkyl radicals, Rj- denotes an alkyl or cycloalkyl-lower-alkyl radical and Rg denotes a hydrogen atom or a lower-alkyl radical Hydrogen chloride addition salt of 1 - </? - (diethylamino) -butyryloxy / -3-pentyl-6a, 7,10,1Oa-tetrahydro-6,6,9-trimethyl- 6H-dibenzo / B, d7pyran (formula h: η »" 2, ORiGiNAt IhföPECTED 10 9 8 3 5/1 704 and R2 - Methyl, IU and R, = ethyl Acid = HCl), - 22 - = Pentyl, R / - = pulp, 13. Process for the preparation of compounds of the formula O-C-CH (CH ₉ ) N < in which η is an integer from 0 to 6, R ₁ , Rg, Rz and R. are lower-alkyl radicals, Rj- is an alkyl or cycloalkyl-lower-alkyl radical and Rg is a hydrogen atom or a lower-alkyl radical, thereby characterized in that a compound of the formula in which R ₁ , R2 and R, - the meanings given above be sit with an aliphatic (jü -Di-lower-alkylamino acid of the formula HOOC-CH (CH ₀ ) -N η in which n, R ^ i R ^, and Rg have the meanings given above, Is reacted in the presence of a condensing agent. 109835/1704 14. The method according to claim 13, characterized in that a carbodiimide is used as the condensing agent. 15. Process for the preparation of the acid addition salts of compounds the formula . R, in the R ₁ , R Rr η represents an integer from 0 to 6, 2, R * and R, mean lower-alkyl radicals, Rc one Alkyl-Rg an interprets formula or Cyoloalkyl-lower-alkyl radical and Hydrogen atom or a lower-alkyl radical be, characterized in that a compound of OH in which R ₁ , R ₂ and R5 have the meanings given above, with an acid addition salt of an α, '- di-lower alkylamino acid of the formula HOGC R ₆ -CK -mA acid in which n, R ,, R * and Rg have the meanings given above, reacted in the presence of a condensing agent 109835/1704 will. 16. The method according to claim 15, characterized in that a carbodiimide is used as the condensing agent. 17. Process for the preparation of the water-soluble hydrogen chloride addition salts of ester derivatives of tetrahydro cannabinols of the formula CH ₃ characterized in that the tetrahydrocannabinol with the hydrogen chloride addition salt of a dialkyl amino acid the formula I /
HOOC-CH (CH ₉ ) - NC HCl in which R, and R ^, mean lower-alkyl radicals and Rg is hydrogen atom or a lower-alkyl radical, reacted in the presence of a carbodiimide condensing agent will. Process according to Claim 17, characterized in that R ^ and R are ethyl radicals and the carbodiimide is dicyclohexylcarbodiimide is used. 19. The method according to claim 17, characterized in that the reaction is carried out in a substantially inert solvent for the tetrahydrocannabinol. 109835/1704 20. "Method according to. Claim 19» characterized in that methylene chloride is used as the solvent. 109835/1704