GB2125793A - Morpholine derivatives - Google Patents

Abstract

3-[(2R*, 6S*)-2-Ethyl-4-methyl-6-n- propyl-2-morpholinyl]phenol and the pharmaceutically acceptable acid addition salts thereof have potent pure opiate antagonistic activity.

Description

SPECIFICATION Morpholine derivatives This invention relates to morpholine derivatives, to processes for their preparation and to pharmaceutical compositions containing them.

U.K. Patent Specification 2,061,272A describes morpholine derivatives of the general formula (I)

and their pharmaceutically acceptable acid addition salts. In this formula R1 represents lower alkyl, R2 represents hydrogen, lower alkyl, benzyl, (lower)alkoxymethyl or an acyl group, R3 represents hydrogen, lower alkyl or phenyl, R4, R5 and Rs are independently hydrogen or lower alkyl and R7 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl(lower)alkyl, 2-tetrahydrofurylmethyl or cycloalkylmethyl. The compounds are stated to possess pharmacological activity, in particular analgesic and/or opiate antagonistic activity.We have now found that a morpholine compound falling within the above general formula but not specifically exemplified nor mentioned in the specification, together with its pharmaceutically acceptable acid addition salts, possess extremely potent opiate antagonistic activity without any analgesic activity, as determined by standard pharmacological test procedures. Opiate antagonists are useful, for example, in treating heroin and other narcotic addiction. For such a use it is desirable that the antagonist itself does not possess analgesic activity. One of the common disadvantages of known pure antagonists, such as naloxone, is their comparative short duration of action.

According to the present invention there is provided 3-[(2R*, 6S*)-2-ethyl-4-methyl-6-n-propyl-2morpholinyl] phenol and the pharmaceutically acceptable acid addition salts thereof. The configuration of the substituents at the 2 and 6 positions of the morpholine ring are defined relative to each other and the compound of the inventon may be represented by the formulae

The compounds of the invention may be in the form of an isomer having the structure Ila or llb or a mixture of such isomers, particularly a racemic mixture.For convenience in the description and claims hereinbelow concerning the preparation of the compounds of the invention, the compounds of the invention and intermediates therefor having the 2R*, 6S* configuration are illustrated by structure Ila and structures for the intermediates showing corresponding configurations at the 2 and 6-position. It is to be understood that such illustrated structures represent all compounds having the 2R*, 6S* configuration (e.g. formulae Ila and llb and mixtures thereof for the compounds of the invention and corresponding formulae and mixtures for the intermediates) as well as mixtures of diastereoisomers of compounds of the 2R*, 6S* configuration with those of 2R*, 6R* configuration.

The compound of the invention and compounds of formula I exemplified in the above mentioned specification were tested for analgesic activity in a standard test, i.e. a phenylbenzoquinone-induced writhing test (based upon E. Siegmund et al, Proc. Soc. exp. Biol. Med., 1957,95,729-731) and for opiate antagonistic activity by a standard procedure based upon Aceto et al, Brit. J. Pharmac. 1969,36,225-239. The results are summarised in the following Table. In this Table the compounds, which are racemates, are defined with reference to formula (III) although the actual configurations of the groups at 2 and 6 -positions are merely relative to each other (compare structures Ila and llb above).The column for "activity" under "analgesia" indicates the number of mice (out of the total mice tested) in which the phenylbenzoquinoneinduced writhing is inhibited by administration of the drug at 25 mg/kg subcutaneously. Similarly, the column for "activity" under "opiate antagonist" indicates the number of mice (out of 10) in which morphine-induced Straub tail is antagonised by administration of the specified subcutaneous dose of drug.

Compounds showing good analgesic or opiate antagonistic activity in the primary screens were tested at various dosages and the ED50 (in m.p.k.) determined and the ED50,s are given in the Table.

TABLE

Compound Analgesia Opiate Antagonist R7 R1 R3 R4 Activity ED50 Activity ED50 (at specified mg/kg) A CH3 C2H5 C3H7 H 0/10 10/10(25) 0.1 B CH3 C2H5 H CH3 10/10 50 6110 (30) -30 C CH3 CH2H5 CH3 H 10/10 0.67 10/10 (30) 1.9 D CH3 C2H5 H H 1/10 5/10 (30) E CH3 CH3 H CH3 2/10 7/10 (30) 23.7 F CH3 CH3 CH3 H 5/10 -25 10/10 (30) 1.8 G H C2H5 H CH3 6/10 25 4/10 (25) H CH3 CH3 CH3 CH3 1/10 8/10 (30) 9.4 CH3 C2H5 CH3 CH3 11/20 21.5 10/10 (25) 4.3 J CH3 C2H5 C6H5 H 1/10 10/10(25) 6.2 K CH3 C2H5 H C5H5 0/10 2/10 (25) L CH3 CH3 H H 2/10 2/10 (30) M -CH2E C2H5 H CH3 0/10 10/10 (25) 7.8 Compound A is the compound of the invention and compounds B to M are compounds specifically exemplified in UK Specification 2,061,272A. The Table clearly shows that compound A possesses potent morphine antagonist activity wirhout signs of analgesic activity. Even when tested at a dosage of 100 mg/kg in another standard analgesic testing procedure (rat tail flick test, based upon D'Amour and Smith, J.

Pharmacol., 1941, 72, 74) the compound was inactive. In a further test, the compound lacked any analgesic agonist activity over a 10-9 to 1 o-6 molar concentration range when examined in the electrically stimulated isolated guinea pig ileum (based upon the procedure of Kosterlitz et al, Brit. J. Pharmacol. Chemotherap., 1968,33, 266-276). It also antagonised the effects of morphine with a pA2 of 8.3 (naloxone has a pA2, in this preparation, of 8.4).

Confirmation of the potent opiate antagonistic activity of the compound of the invention is shown by its effect on the binding of radiolabelled naloxone in rat brain homogenates in the presence and absence of sodium ions. The results revealed a relative displacement potency (morphine = 1.0) of 152 and a sodium response ratio of 0.078. This low sodium response ratio is in agreement with the opiate antagonistic activity of the compound.

The opiate antagonistic activity of the compound of the invention appears to be of longer duration than that of the standard antagonist, naloxone when tested in a hot water tail flick test in rats. Morphine (8 mg/kg s.c.) was injected to groups of 10 rats with either compound A (0.1 mg/kg s.c.) or naloxone (0.015 mg/kg s.c.) and the percentage of nociceptive rats determined at 30,60 and 90 minutes after administration of the test drug. It was found that with compound A the percentage was 70% at all three time points while with naloxone the percentage at 30 minutes was 60%, at 60 minutes it was 30% and at 90 minutes it was 20%.

The compounds of the invention may be prepared by the processes described in U.K. Patent Specification 2,061,272A. For example a compound of formula (IV)

where OR8 is an etherified hydroxy group such as lower alkoxy, lower alkoxymethoxy or benzyloxy may be de-etherified to give a compound in which OR8 is hydroxy. The ether group may be removed in known manner. For example the lower alkyl or benzyl ether may be treated with hydrogen bromide or boron tribromide, a lower alkyl ether may be treated with diisobutylaluminium hydride, a benzyl ether may be subjected to hydrogenolysis or a (lower)alkoxymethyl ether may be treated with dilute acid. [The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. The radical preferably contains 1 to 4 carbon atoms].

The compounds of the invention may also be prepared by N-methylating a compound of formula

In one method of N-methylation the compound of formula (V) is reacted with a methylhalide in the presence of an acid acceptor such as an alkali metal carbonate, preferably in solution in an organic solvent.

Alternatively the compound of formula (V) may be methylated by treatment with formaldehyde and hydrogen in presence of a hydrogenation catalyst, i.e. reductive alkylation.

The compounds of the invention may also be prepared by reduction of a compound of general formula

where OR9 is hydroxy or etherified hydroxy (such as lower alkoxy, lower alkoxymethoxy or benzyloxy) and X is oxo and Xa is

or X1 is oxo and Xis

and, where OR9 is etherified hydroxy, de-etherifying the product. Preferably X is oxo and X1 is

The reduction can be effected with, for example, a hydride transfer agent (e.g. lithium aluminium hydride).

The compounds of formulae (IV), (V) and (VI) may be prepared by the general methods disclosed in the above mentioned U.K. Specification 2,061,272A.

If in any of the processes described above the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional procedures for preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic and p-toluenesulphonic acids.

If the products of any of the processes or starting materials used in the processes are mixtures of diastereoisomers such mixtures may be separated by chromatography (e.g. high pressure liquid chromatography) or fractional crystallisation. The ratio of the diastereoisomers in the mixture may be affected by the choice of reagent used in the processes to produce the starting materials or final compounds.

Optical isomers may be prepared by resolving a racemic mixture by standard methods described in the literature. The racemate may be prepared by any of the processes outlined above. It is to be understood that the resolution may be carried out on the racemic mixture of the final desired product or it may be carried out on a racemic precursor of the desired compound provided further chemical reaction does not cause racemisation.

The invention provides a pharmaceutical composition comprising 3-[(2R*,6S*)-2-ethyl-4-methyl-6-n- propyl-2-morpholinyl]phenol or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99%, preferably 10-80% of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, lactose, pectin, dextrin starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvdent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable.In other instances other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredients; the unit dosage forms can be packaged compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 5 mg. or less to 500 mg. or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.

The following Examples illustrate the invention: EXAMPLE 1 (2R*,6R*) and (2R*,6S*)-2-ethyl-2-(3-methoxyphenyl )-4-methyl-6-n-propylmorpholine (i) (x-ethyl-3-methoxy-(x-(methylamino)methylbenzene methanol hydrochloride (10.59) was suspended in dichloromethane (400ml) containing triethylamine (14mi) and 2-chloropentanoic acid chloride (7.79) added dropwise with stirring and cooling in ice water. After stirring at ambient temperature for 2 hours the reaction mixture was washed with dilute hydrochloric acid and water. After drying (MgSO4) the solvent was removed under reduced pressure to leave 14g of an oil.

(ii) This crude material was dissolved in 2-propanol and added dropwise to 1 OM sodium hydroxide solution (20ml) in 2-propanol (100ml). After stirring at ambient for 2 hours the alcohol was removed under reduced pressure and the residue diluted with water and neutralised with cooling with concentrated hydrochloric acid. The product was extracted with dichloromethane, dried (MgSO4) and evaporated to an oil (12.09).

(iii) The oil was dissolved in ether (some) and added to a suspension of aluminium lithium hydride (5g) in ether (100ml). After heating under reflux for 2 hours the reaction mixture was cooled and decomposed by the addition of water (5ml), 1 OM sodium hydroxide (5ml) and water (5ml). The precipitate was filtered and washed with ether. After drying the solvent was removed under reduced pressure and the resulting colourless oil chromatographed on silica eluting with ethyl acetate-hexane (9:1 and 2% Et3N). The second fraction eluted from the column was (2R*,6S*) 2-ethyl-2-(3-methoxyphenyl)-4-methyl-6-n-propylmorpholine which gave a tosylate salt as colourless crystals, 4.769 from ether m.p. 180-10C.

(Analysis: Found C, 64.1; H, 7.9; N, 2.9%.

C17H27NO2TsOH requires C, 64.1; H, 7.85; N, 3.1%).

EXAMPLE 2 3-((2R*,6S*)-2-ethyl-4-methyl-6-propyl-2-morphol inyl)phenol The tosylate salt from the above example (4.79) was suspended in toluene (30ml) and treated with diisobutyl aluminium hydride (30ml of a 1.5M solution in toluene). After heating under reflux for 20 hours the reaction was cooled and decomposed by the addition of a saturated solution of Rochelle salt. The inorganic material was filtered and washed with hot toluene. The combined organic material was washed with saturated sodium chloride solution, dried (MgSO4) and evaporated to give a colourless oil which afforded 2.159 of colourless hydrochloride salt m.p. 244-6"C.

(Analysis: Found C, 63.3; H, 8.7; N, 4.3.

C16H25NO2HCl l/4H20 requires C, 63.2; H, 8.6; N, 4.6%).

Claims (8)

1. 3-[(2R*,6S*)-2-Ethyl-4-methyl-6-n-propyl-2-morpholinyl]phenol or a pharmaceutically acceptable acid addition salt thereof.

2. A process for preparing a compound claimed in Claim 1 in which a compound of formula (IV)

where OR8 is an etherified hydroxy group is de-etherified to give a compound in which OR8 is hydroxy and, if desired, a resulting base is converted into a pharmaceutically acceptable acid addition salt.

3. A process for preparing a compound claimed in Claim 1 in which a compound of formula (V)

is N-methylated and, if desired, a resulting base is converted into a pharmaceutically acceptable acid addition salt.

4. A process for preparing a compound claimed in Claim 1 in which a compound of general formula

where OR9 is hydroxy or etherified hydroxy and X is oxo and X1 is

orX1 isoxoandXis

is reduced and, where OR" is etherified hydroxy, the product is de-etherified, and if desired, a resulting base is converted into a pharmaceutically acceptable acid addition salt.

5. A process for preparing a 3-(2-ethyl-4-methyl-6-n-propyl-2-morpholinyl)phenol substantially as hereinbefore described with reference to Example 2.

6. A 3-(2-ethyl-4-methyl-6-n-propyl-2-morpholinyl)phenol whenever prepared by the process claimed in any one of Claims 2 to 5.

7. A pharmaceutical composition comprising a compound claimed in Claim 1 or 6 in association with a pharmaceutically acceptable carrier.

8. A compound claimed in Claim 1 or 6 for use as an opiate antagonist.