The present invention relates to morphine-3-esters, drugs containing morphine-3-esters, the use of the morphine-3-esters for preparing a morphine analgesic, for the preparation of a sustained release form of morphine and a process for preparing the morphine-3-esters .

Morphine is a frequently used analgesic which in particular is used for alleviating chronic pain. For a successful pain therapy it is required that the morphine plasma level is con¬ stant. Morphine, because of its very low half-life, is admini¬ stered in the form of tablets capable of a controlled release of the active ingredient or by means devices, such as pumps, for a controlled release of the active ingredient. However, these application forms are subject to hard restrictions in practice.

Another drawback of the long-term morphine administration is the occurrence of side-effects such as obstipations which may become so serious that the pain therapy using morphine will have to be discontinued or even abandoned.

It is the object of the invention to provide morphine derivatives which represent retard forms of morphine and, upon enteral application, do not exhibit any interactions with the intestinal receptors involved.

Said object, surprisingly, is attained by morphine-3- esters, the enzymatic hydrolysis of which has a half-life of from 0.5 to 12 hours under physiologic conditions and the non-enzymatic hydrolysis of which has a half-life in excess of 24 hours in an aqueous medium at pH values of 6-8, especially at pH 7, except for 3-pivaloyl morphine.

The morphine- -esters according to the invention, due to their structure, have only weak affinity or do not have any affinity at all to the morphine receptor. The active compound is released and enabled to display its activity only after hydrolysis of the ester by specific or non-specific esterases present under physiological conditions. On the other hand, the compounds according to the invention are relatively insensitive to a non-enzymatic hydrolysis at physiological pH values, as is evident from their half-lives in excess of 24 hours in an aqueous medium at pH values of 6-8, especially at pH 7.

WO 93/03051 describes 3-morphine esters synthesized as intermediates for the preparation of morphine-6-glucuronides . WO 93/03051 fails to disclose any relevant data with respect to the activity of the 3-morphine ester derivatives described therein, especially 3-pivaloyl morphine, 3-propionyl and 3-iso- butyryl morphine. Data on the rate of hydrolysis under physio¬ logical or other conditions have not been reported either.

The morphine esters according to the invention are prefer¬ ably characterized in that the rate of hydrolysis and/or dispo¬ sition of the morphine ester for an esterolytic activity is adjusted by steric or electronic effects of the acid moiety of the morphine ester.

Morphine esters according to the invention, more specific¬ ally, are those having the following formula (I)

wherein R either is a moiety having the following formula (II)

wherein

R ³ and/or R ⁴ = H, if

R ³ and/or R ⁴ is not H, then the respective other residue independently or simultaneously has the following meaning:

R ³ and/or R ⁴ = straight-chain or branched alkyl group (CH ₂ ) _n CH ₃ with n being an integer between 0 and 10;

R ³ and/or R ⁴ is a substituted straight-chain or branched alkyl group X- (CH ₂ ) _n CH ₃ with n being an integer between 0 and 10, wherein X = O, S, N ist; (CK ₂ ) _n -X-R ⁵ , wherein X is as defined above and R ⁵ is an alkyl, isoalkyl, alkenyl, alkynyl, cyclo- alk(-en- or -yn-)yl, aryl, aralkyl, heteroaryl, heteroalkyl or cycloheteroalk ( -en- or -yn-)yl moiety;

X- (CH ₂ ) _n -Y-R ⁵ , wherein Y = X, or Y independently of X has the meaning of X as defined above, R ⁵ is as defined above;

R ³ and/or R ⁴ = halogen, alkenyl, alkynyl, cycloalk ( -en- or

-yn-)yl, cycloheteroalk ( -en- or -yn-)yl as well as aryl- and heteroaryl moities with or without -I- or -M-substituents .

These compounds have the appropriate hydrolysis rates .

Particularly preferred are morphine esters, wherein the subscituents R ³ and R ⁴ are in the o- or p-positions relative to each other.

In another preferred embodiment of the invention the morphine esters are characterized in that the moiety R in formula (I) is represented by the following formula (III)

wherein R ¹ has the meaning as defined for R ³ and R with the proviso that R ¹ is either equal to R ³ and/or R ⁴ or different therefrom;

R ² stands for +M- , +1- or -I- substituents .

Especially preferred are morphine esters wherein R ² is a substituted or free amino group to form β-aminocinnamic acid esters .

Further contemplated are morphine esters according to the invention having the formula (I) wherein R is a cycloalk ( -en- or -yn-)yl of the following formula (IV)

(IV)

R ⁴ R ¹ wherein R ¹ , R ³ and/or R ⁴ are as defined above, with the proviso that individual carbon atoms of the moiety R have been replaced by heceroatoms such as 0, N and/or S.

Morphine esters, in a further embodiment, are characterized in that R is represented by the formula (V)

wherein the substituents R ¹ , R ³ and/or R ⁴ have the meanings as defined above.

As preferred morphine-3-esters there are to be mentioned 3- (2-methylbenzoyl) morphine, 3- (2-chlorobenzoyl) morphine, 3- (2 , 6-dichlorobenzoyl) morphine, 3- (α-methylcinnamoyl) morphine, 3- (2, 6-dimethylbenzoyl) morphine, 3- (2, 6-dipropylbenzoyl) morphi¬ ne, 3- (2 , 6-diphenylbenzoyl) morphine, 3- (2-phenylbenzoyl) morphi¬ ne, 3- (2 , 6-dimethoxybenzoyl) morphine, 3- (2, 6-diethoxybenzoyl) - morphine, 3- (2-cyclohexylbenzoyl) morphine, 3- (α-methyl-β-di- methylamino-cinnamoyl)morphine, 3- (α-ethyl-β-dimethylaminocin- namoyl) morphine,3- (β-dimethylamino-α-propyl-cinnamoyl) morphine, 3- (β-diethylamino-α-methylcinnamoyl) morphine, 3- (β-dibenzyl- amino-α-methylcinnamoyl)morphine, 3- (α-methyl-β-phenylamino- cinnamoyl) morphine, 3- (α-ethyl-4-methoxy-cinnamoyl) morphine, 3- (4-ethoxy-α-methyl-β-dimethylaminocinnamoyl) morphine, 3- (1-ethylcyclohexyl-l-carbonyl) morphine, 3- (1-propylcyclo- hexyl-1-carbonyl) morphine, 3- (1-phenylcyclohexyl-l-carbonyl) - morphine, 3-(1-naphthylcyclohexyl-l-carbonyl) morphine, 3- di¬ methyl-4-propylpiperidin-4-yl-carbonyl) morphine, 3- (N-methyl- 4-phenylpiperidin-4-yl-carbonyl)morphine, 3 - (2-methyl-2-phenyl- propionyl) morphine, 3- (2 , 2-diphenylpropionyl) morphine, 3- (2- ethyl-2-phenylbutyryl) morphine .

The morphine esters according to the invention can be used as medicaments. The medicament according to the invention con¬ tains an effective amount of at least one of the morphine-3- esters according to the invention, including 3-pivaloyl morphi¬ ne. More particularly, the morphine-3-esters according to the invention may be present in the form of their pharmaceutically compatible salts, optionally in combination with further auxili¬ ary materials and carriers.

The morphine-3-esters according to the invention, more particularly, can be used for the preparation of a morphine analgesic which avoids the side-effects caused by the morphine analgesics of prior art. As a serious side-effect, there is mentioned, by way of example, obstipation. Furthermore, the morphine-3-esters according to the invention can be utilized as a sustained release form of morphine. This sustained release

form of morphine may be enterally and/or parenterally admini¬ stered.

The amount to be administered in a dosage unit of morphine- 3-ester corresponds to from about 0.5 mg to about 10 mg per 1 kg of body weight .

The morphine derivatives according to the invention can be prepared by a method according to J. Org. Chem. 19, 1409 (1954) . In accordance therewith, a solution of morphine hydrochloride in water in the presence of sodium hydrogencarbonate is admixed with the appropriate carboxylic acid component, preferably an excess amount thereof, of the ester to be formed in the form of an activated derivative thereof such as an acid halide, acid anhydride e tc . . The mixture is stirred until the reaction is complete. The reaction may be monitored, for example, by means of thin layer chromatography. The morphine-3-ester formed may be extracted, especially with water-immiscible organic solvents, such as, for example, methylene chloride. The organic solvent used for the extraction of the morphine-3-ester is evaporated, and the residue is purified, for example by column chromato¬ graphy using suitable carriers such as silica gel. This method is not suitable for the preparation of 3- (2 , 6-dimethoxybenzoyl) - morphine. The latter compound may rather be prepared by a con¬ ventional method using pyridine as a base and removal of the mono-ester by column chromatography.

The invention is furtner illustrated by way of the following Examples .

Example 1

Preparation of morphιne-3-esters :

A vigorously stirred solution of 2 mmol of morpnme hydro- chloride in 50 ml of water is admixed in tne presence of 5 g of sodium hydrogencarbonate with 10 mmol of the acid chloride in

3 equal portions. The mixture is stirred until the reaction is complete. The reaction is checked by thin layer chromatography on silica gel in an eluent system of methylene chloride/methan- ol/concentrated ammonia = 90/10/0.5, until no further reaction is detectable. Then the reaction batch is extracted with methylene chloride, the extract is dried over anhydrous Na ₂ S0 ₄ and the extractant is evaporated. The obtained residue is purified by column chromatography on silica gel using an appro¬ priate eluent.

Table

Compound Yield Melting point

1 3-(2-Methylbenzoyl)morphine 40 % 1 40 °C

(hydrochloride 1 27 °C)

3-(2-Chlorobenzoyl)morphine 35 % 1 58 °C

3-(2,6-Dichlorobenzoγl)morphine 52 % 1 86 ° C

(hydrochloride 277-278 ° C with decomposition)

! 4 3-Pivaloylmorphine 33 % 1 02 ° C

^! 5 3-(σ-Methylcinnamoyl)morphine 38 % 1 1 2 ° C (as hydrochloride)

6 3-(2,2-Diphenylpropιonyl)morphine 26 % 148 ° C (hydrochloride 250 ° C)

^' 7 3-(2-Phenylbenzoyl)morphιne 33 % 208 ° C

I (hydrochloride 1 80 °C)

Example 2

Preparation of 3- (2 , 6-dimethoxybenzoyl) morphine

A stirred solution of 285 mg of morphine base (1 mmol) in 2 ml of pyridir.e base is admixed while cooled with 500 mg of 2 , 6-dimethoxybenzoyl chloride (2.5 mmol) and is heated on a

water bath in the absence of moisture for 30 minutes. Then the resulting product is poured into ice-water. The mixture is extracted three times with 20 ml each of methylene chloride, and the organic phase is thoroughly washed with water, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo , and the residue is purified by column chromatography

(silica gel, CH ₂ C1 ₂ /CH ₃ 0H/NH ₃ cone. 90/10/0.5) . Yield 31 %; m.p. 192-193 °C, decomp. ) .