WO1998054196A1

WO1998054196A1 - Glycoconjugates of opiated substances

Info

Publication number: WO1998054196A1
Application number: PCT/GB1998/001578
Authority: WO
Inventors: Gregorio Valencia; Raquel Emilia Rodriguez
Original assignee: Rolabo Sl
Priority date: 1997-05-29
Filing date: 1998-05-29
Publication date: 1998-12-03
Also published as: EP0984974A1; GB9711118D0

Abstract

α-glycosides of opiates have been found to possess interesting and valuable pharmacological properties, particularly analgesic properties. The invention provides a compound being a sugar derivative of a biologically active opiate comprising at least one sugar residue coupled with at least one opiate residue through an α-glycosidic bond and salts, analogues and complexes thereof.

Description

GLYCOCONJUGATES OF OPIATED SUBSTANCES

The present invention relates to sugar derivatives of biologically active opiates and their use as analgesics, particularly to -sugar derivatives .

Morphine and its synthetic analogues eg. hydromorphone, diamorphine and oxymorphone are the most widely used pharmaceutical materials for the control of chronic pain. Codeine, dihydrocodeine and nalbuphine are also commonly employed for their milder analgesic properties. Morphine and its analogues will be referred to collectively herein as opiates, which term is intended to include all non-peptide substances which bind specifically to opioid receptors and which may be referred to elsewhere as opioids or opioid analgesics.

Traditionally it was thought that conjugation of a pharmacologically active compound had an adverse effect on the pharmacological activity which that compound exhibited. However, it is now known that a certain glyconjugate metabolite of morphine, namely morphine-6- glucoronide, is several times more active as an analgesic than the parent or than the 3-glucoronide compound (G.J. Mulder, Trends in Pharmacol. Sci . , Vol. 13, 8/92, pps 302-304 and Osborne et al . , The Lancet, April 9, 1988, 828) . The potential for this enhanced analgesic activity to be exploited has been recognised in inter alia WO-A-93/15737 (Danbiosyst UK Limited) .

In spite of this advance, to date there has been little or no reported work on chemical glycosidation of opiates with simple sugars other than glucoronides .

It has now been found that α-glycosidation of opiates leads to compounds having interesting and valuable pharmacological properties, particularly analgesic properties.

Thus viewed from one aspect the present invention provides a compound being a sugar derivative of a biologically active opiate comprising at least one sugar residue coupled with at least one opiate residue through an α-glycosidic bond and salts, analogues and complexes thereof .

Whilst the sugar residue and opiate residue may be coupled indirectly through a linker group (eg. an NHCO or HCS group) , preferably the residues are coupled directly and the α-glycosidic bond is an O-glycosidic bond.

The sugar residue is preferably a five or six membered ring, eg. a furanose or pyranose.

While pyranoses are preferred, furanoses are also suitable. The preferred furanoses are the aldopentoses such as ribose, arabinose, xylose, lyxose and 2-deoxy- ribose. Also preferred are varous ketohexoses such as fructose, psicose, sorbose and tagatose, and ketopentoses such as ribulose and xylulose.

In one embodiment, the compound according to the invention is of formula I :

(wherein: n is 0 or 1;

R₂ is H when n is 1 and H or CH₂OR₅ when n is 0 ;

R denotes the residue of a biologically active opiate of formula R-OH, wherein the OH group is either an alcoholic or phenolic OH group;

X denotes an O-glycosidic bond or a linker group;

Ri denotes hydrogen, a CH₂OR₅, CH₂OCOR₅ or COZ group;

Z denotes an 0R₅, NR₃R₄, 0(CO)R₅, C_J.__J.B-alky1 or C_J.__J.8- alkenyl group; R₃ and R₄ independently denote hydrogen, a C^e- alkyl,

or aryl group;

R₅ denotes hydrogen, a

aryl, sulphate, phosphate or silyl group; and

R₆ independently denotes hydrogen, a

C_x_ _1B-alkenyl, aryl, COR₅, phosphate, sulphate or silyl group) , while one or more 0R₆ groups may optionally be replaced by hydrogen atoms (eg. as in 2-deoxy-D-ribose) ; and the salts, analogues and complexes thereof.

Where a group is specified as C₁_₁₈-alkyl or Cj_._₁₈- alkenyl it is optionally hydroxylated, aminated, carboxylated, amidated, esterified, sulphated or phosphated and it is more preferably

or Cj.g- alkenyl. Where aryl is specified it is more preferably phenyl .

Preferred compounds of the invention are those in which R₆ denotes hydrogen, especially preferably those in which R₆ denotes hydrogen and R_x denotes CH₂0R₅.

The α-sugar residue may be an α-D-furanose (eg. fructofuranose, ribofuranose or 2-deoxy-ribofuranose) or more preferably an α-D-pyranose eg. a glucose, galactose or mannose residue, preferably a galactose residue.

Preferred compounds are those of formula II

(wherein: R_{l t} R₃, R, R₅, R₆ X and Z are as hereinbefore defined) and the salts and analogues thereof, especially those of formula II in which R₆ denotes hydrogen, particularly those in which R₆ denotes hydrogen and R_x denotes CH₂OR₅. Especially preferred compounds according to the invention are 6-morphinyl α-D-mannopyranoside acetate and 6-morphinyl α-D-galactopyranoside acetate and salts, analogues and complexes thereof .

By biologically active opiate is meant compounds having pharmacological and therapeutic activities in relation to analgesia, cough, dysponea, constipation, anesthesia, sedation or diarrhea or which stimulate or inhibit such activity. This includes full agonists, partial agonists, mixed agonist-antagonists and antagonists. These biologically active opiates include opiate substances isolated from nature or synthesized and their salts and analogues. The following may be mentioned as examples of opiates: morphine, codeine, hydromorphone, diamorphone, oxymorphone, naloxone, nalbuphine, buprenorphine , pholcodine, meperidine, loperamide, sufentanil, methadone, pethidine, oxycodone, levorphanol, fentanyl, alfentanil, butorphanol, propoxyphene, metazocine, dezocine phenazocine and pentazocine.

Preferred sugars or carbohydrates may be, for example, any known mono- or oligosaccharide, especially a mono-, di- or trisaccharide or analogues thereof (eg. an amino and/or carboxylic acid and/or reduced and/or esterified and/or sulfated and/or phosphated analogue thereof) .

In formulae I and II, only one sugar moiety per opiate is denoted. However, the invention also covers α-sugar derivatives of opiates having more than one free hydroxyl group on the opiate residue and therefore these structures may contain 2 or more sugar residues per opiate residue. Preferably opiates contain 1 to 3 monosaccharide units which may also be joined to the active molecule as a disaccharide or trisaccharide. Similarly a single sugar residue linked to more than one opiate residue is within the scope of the invention.

In formula I and II, the sinuous line ( —_- ) indicates that the stereochemistry at a particular carbon of the sugar residue is undefined and that the formulae is intended to cover both epimers .

The following residues may be mentioned as specific α-sugar residues: glucosyl , galactosyl, mannosyl, allosyl, altrosyl, talosyl, gulosyl, idosyl, xylosyl, glucosaminyl , N-acetyl-glucosaminyl , octylglucopyranosyl , cyclohexylglucopyranosyl , benzylglucopyranosyl , glucosyl sulfate, glucosyl phosphate, glucosaminyl sulfate, N-acetyl -glucosaminyl sulfate, lactosyl, gentiobiosyl, chitobiosyl, N-acetyl-lactosaminyl, cellobiosyl, maltosyl, melibiosyl and L-sorbosyl; α-sugar derivatives of the uronic acid series such as glucuronic acid, galacturonic acid, glucuronamide , glucosaminuronic acid, octylgalacturonamide , cyclohexylgalacturonate , decylglucuronate and benzylglucuronamide; and complex α- sugar acids such as muramic acid, neuraminic acid, acetyl muramic, acetyl neuraminic and sialic acid.

Preferred compounds of the invention are α-sugar derivatives of opiates structurally related to morphine eg. opiates of morphinan structure and their analogues. Particularly preferred are the α-sugar derivatives of compounds of formula III:

Formula III

(wherein: _x is a hydroxyl, methoxy, ethoxy, acetoxy or -0CH₂CH₂N ) group;

M₂ is hydrogen, a hydroxyl, oxy, acetoxy, methoxy or methene group;

M₃ is a methyl, methylene cyclopropyl, methylene cyclobutyl or allyl group;

M₄ is hydrogen or a hydroxyl group; the bond between carbon atoms in positions 6-7 and 7-8 can be either single or double; and the ether function between position 4 and 5 can be either present or not present on the molecule) . Compounds of formula III can exist either in the form of levo or dextrorotatory isomers as well as salts, analogues and complexes thereof.

Preferred compounds of formula III are those in which M_: and M₂ are hydroxyl, M₃ is methyl, M₄ is hydrogen and a double bond exists between positions 7-8 and an ether function between positions 4-5 (ie. morphine) and in which Mi is hydroxyl, M₂ is oxy, M₃ is allyl, M₄ is hydroxyl and a single bond exists between positions 7-8 and an ether function between positions 4-5 (ie. naloxone) .

Accordingly, definitions for codeine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, levorphanol, dextromethorphan, nalorphine, naltrexone, levallorphan, thebacone, ethyl morphine, dihydrocodeine, nalmefene, nalbuphine, butorphanol and pholcodine may be deduced from formula III. Other analogues such as metopon and buprenorphine that may not be deduced from formula III directly are also preferred morphinan compounds .

More preferred sugar derivatives of morphinan structure are those which have an α-sugar residue on either positions C-3 and C-6 of the morphinan backbone. Particularly preferred compounds are the 3- and 6- derivatives of morphine, codeine and naloxone.

Further preferred compounds of the invention are α- sugar derivatives of opiates of the meperidine (pethidine) series ie. of the phenylpiperidine type and their complexes and analogues, including piperidine type structures in which radicals have been modified to introduce suitable functions such as hydroxyl groups that may allow further coupling reactions with sugar residues .

Particularly preferred are the α-sugar derivatives of compounds of formula IV:

Formula IV

(wherein:

Ej_. is a methyl, phenylethyl, p-phenylethylamine, -(CH₂)₃-NH-C₆H₅, -(CH₂)₂-C(C₆H₅)₂-CN, ^

- (CH₂)₂-C(C₆H₅)₂-CO-N(CH₃)₂, -(CH₂)₂-N N-CH₂-CH₃ or

\ ' i "^'»

-(CH₂)₂-^ group;

E₂ is hydrogen, a phenyl , m-hydroxyphenyl, p-chlorophenyl, methylenemetoxide or piperidinyl group; and

E₃ is a hydroxyl, ethylcarbonyl , carboxamide, ethyloxycarbonyl, ethylcarboxyl or -N (C₆H₅) -CO-CH₂-CH₃ group) .

More preferred compounds of formula IV are those in which Ej_. is methyl, E₂ is phenyl, and E₃ is ethoxycarbonyl (ie. meperidine) and in which Ej_. is

- (CH₂) ₂-C(C₆H₅) ₂-CN, E₂ is phenyl and E₃ is ethoxycarbonyl (ie. diphenoxylate) .

Accordingly, definitions for loperamide, fentanyl, sufentanil, alfentanil, cetobemidon, piritramide, anileridine, piminodine may be deduced directly from formula IV. Other analogues such as alphaprodine, ^' fenpipramide, ethoheptazine, tilidin and nefopam which may not be deduced from formula IV are also preferred.

Especially preferred α-glycosilated opiates of the meperidine type are those which are glycosilated on one hydroxyl group already present or introduced for binding purposes on radicals E₂ and E₃ of formula IV, most especially those of meperidine, loperamide and cetobemidon.

Further preferred compounds of the invention are the α-sugar derivatives of opiates of the methadone type and their complexes and analogues ie . opiates which are structurally closely related to methadone. Analogues of methadone include structures in which radicals have been modified with functions such as hydroxyl groups to allow coupling with α-sugar residues.

Particularly preferred are the α-sugar derivatives of compounds of formula V:

Formula V

(wherein :

Dj_. is a phenyl or benzyl group;

D₂ is a -CH₂-CH(CH₃) -, -CH (CH₃) -CH₂- or -(CH₂)₂- group; and

D₃ is an ethylcarbonyl, ethylcarboxyl or -CH(OCOCH₃) -CH₂-CH₃ group).

More preferred compounds of formula V are those in which Dj_. is phenyl, D₂ is -CH₂-CH (CH₃) - and D₃ is ethylcarbonyl (ie. methadone) or in which Dj_. is benzyl, D₂ is -CH(CH₃) -CH₂- and D₃ is ethylcarboxyl (ie. propoxyphene) .

Definitions for normethadone and methadyl acetate may be deduced directly from formula V. Other analogues such as dextromoramide which may not be deduced from formula V are also preferred.

Particularly preferred α-sugar derivatives of opiates of the methadone type are those which are glycosilated on a hydroxyl group which has been introduced for coupling purposes on radicals D_x and D₃ of formula V, especially those of methadone.

Further preferred compounds of the invention are the α-sugar derivatives of opiates of the benzomorphane group and their complexes and analogues ie. compounds with structures which correspond to the benzomorphane motif.

Preferred are the α-sugar derivatives of compounds of formula VI :

Formula VI

(wherein:

T is a methyl, phenylethyl, methylcyclopropyl or -CH₂-CH=C(CH₃)₂ group) .

More preferred are those compounds of formula VI in which T is a methyl, phenylethyl, methylcyclopropyl or -CH₂-CH=C(CH₃) ₂ group (ie. methazocine, phenazocine, ciclazocine or pentazocine respectively) .

Other analogues such as dezocine and meptazinol which may -not be deduced directly from formula VI are also preferred opiates of the benzomorphane group of compounds .

The α-sugar derivatives of opiates of the benzomorphane group are preferably those which are glycosilated on the phenol function of formula VI, especially those of methazocine, pentazocine and cyclazocine.

In order to prepare the compounds according to the invention, α-sugar residues may be coupled to appropiate residues of a biologically active opiate. In preferred compounds of the invention, the sugar residue is attached to an hydroxyl group of the opiate residue by - lo an α-O-glycosidic bond. This group of compounds of the invention may be prepared by any of the known methods of α-O-glycosidic bond formation, eg., the Koenigs-Knorr reaction, Helferich, Hannessian or Schmidt procedures. Coupling through a linker group (X) may equally be achieved conventionally.

Thus viewed from a further aspect the present invention provides a process for preparing the compounds according to the invention, said process comprising the following steps: a) reacting an optionally protected opiate (acyl acceptor) having a free hydroxyl group with an optionally protected, activated reducing α-sugar derivative (acyl donor) in the presence of a promoter; and b) subsequently removing any protecting groups. The process of the invention may require the use of one or more suitable protecting groups for reactive functions in both the α-sugar and the opiate reagent to prevent them hindering the reaction. These may be added and removed by known techniques.

When a modification on the sugar molecule is to be introduced, a separate reaction step is required _^either before or after step (a) and may involve other reaction procedures such as phosphate or sulphate bonding, or ester or amide bond formation which may be carried out by conventional procedures using reagents such as acid halides, carbodiimides, phosphonium or uronium salts, active esters and symmetrical anhydrides.

Step (a) may be carried out by conventional glycosidic bond formation. The promoter may be conveniently an Ag⁺ or Hg⁺⁺ compound (eg. silver triflate or AgC0₃) or a Lewis acid such as BF₃OEt₂ or LiOH. A tertiary organic amine may be added. The reaction is preferably carried out in a solvent such as dichloromethane, acetonitrile, methanol or methylene chloride, at temperatures in the range -100°C to reflux temperature, preferably in the range -40°C to room temperature .

Starting materials for these reactions are not described here but in some cases may be known or may be prepared by conventional means, eg., using known methods described in the literature for analogous compounds. The compounds according to the invention may be converted into salts thereof, more particularly for pharmaceutical use into physiologically acceptable salts thereof with inorganic or organic acids (eg. sulphuric acid, hydrochloric acid, acetic acid, tartaric acid. The invention seeks to provide compounds which facilitate blood-brain barrier passage. The compounds have improved analgesic potency and a longer lasting analgesic effect.

Thus viewed from a still further aspect the present invention provides the use of a compound according to the invention as an analgesic.

Viewed from a yet further aspect the present invention provides a composition for use as an analgesic comprising a compound according to the invention or a salt or complex thereof together with one or more pharmaceutically acceptable carriers or diluents..

Viewed from a still further aspect the present invention provides the use of a compound according to the invention or a salt or complex thereof for the manufacture of an analgesic medicament .

Viewed from an even further aspect the present invention provides a method of treatment of the human or non-human, preferably mammalian, body to combat pain, said method comprising administering to said body a compound according to the invention or a physiologically acceptable salt or complex thereof.

The compounds according to the invention or their pharmaceutical compositions may be used to combat cancer pain, central pain, labour pain, mycardial infarction pain, pancreatic pain, colic pain, postoperative pain and pain associated with intensive care. More generally, they may be used to combat conditions relating to cough, dysponea, constipation or diarrhea and in anesthesia or sedation.

In the compositions according to the invention, the active compound may be formulated with other analgesics including non-opioids (eg. paracetemol or aspirin) or with weak or strong opioid analgesics, with adjuvants to increase analgesia or reduce side effects (eg. antiemetics) and optionally with conventional carriers or excipients. Formulation aids such as flavouring agents, antioxidants, os olality adjusting agents, solubilizing agents, emulsifiers, buffers, viscosity enhancing agents, preservatives and stabilisers may also be present .

Where the composition is in liquid form eg. formulated as syrup, solution, dispersion, suspension or linctus in an appropriate solvent such as water or aqueous vehicle such as sodium chloride solution, Ringers solution, dextrose solution, lactated Ringers solution, it may be combined with ethanol, glycerol, sorbitol, polyethylene-glycol or propyleneglycol and optionally filled into capsules.

Conveniently the compositions according to the invention are formulated in solid form eg. as granules, tablets, coated tablets, capsules, powders or pellets, preferably for sustained release, optionally together with diluents or excipients such as lactose, starch and derivatives thereof, microcrystalline cellulose or derivatives thereof, cornstarch, glucose, magnesium polyvinylpyrrolidone, citric acid, tartaric acid, fatty substances and adjuvants such as binders and lubricants.

For treating or preventing pain, the dosage of active compound and its administration route will vary according to the level and type of pain. Typically it may be administered rectally, subcutaneously, intraspinally, intramuscularly, intranasally or intraveneously, but more desirably orally. Parenteral doses may be administered as bolus injections or continuous or intermittent infusions adjusted to analgesic requirements. Dosages may vary from 50 μg to more than 2500 mg every 4 hours, although more typically 100 mg or less, preferably 0.05 to 20 mg, every 4 hours if administered orally and generally less if administered parenterally. Preferably the active ingredient is administered in a sustained release form.

The Examples which follow are intended to illustrate the invention in a non-limiting manner.

Example 1

6-Morphinyl-α-D-mannopyranoside acetate

A solution of 0.13 g of 6- (3-0-acetyl) -morphinyl-α-D- mannopyraήoside tetraacetate in 8 ml of 0.1 M sodium methoxide in methanol were stirred at room temperature. After 60 minutes the reaction mixture was neutralized with acetic acid and the solvent removed under vacuum. The crude residue was purified on a silica gel column eluted with a solvent mixture of ethyl acetate/water/ methanol (3:2:1). After this procedure, lyophilization of the pure fraction from an aqueous acetic acid solution afforded 106 mg of the title compound as a white solid.

ESI-MS: 448.5 [M+H] ⁺ and 470.4 [M+Na] ⁺ and *H and ¹³C NMR spectral data in accordance with the structure of the title compound.

The intermediate product was prepared as follows. a) 6- (3-O-acetvl) -morphinyl-α-D-mannopyranoside tetraacetate

Under an argon atmosphere, a solution of 0.93 g of 3-O- acetyl-morphine and 1 g of 1,2, 3,4,6-penta-O-acetyl-α-D- mannopyranose in 10 ml of dry methylene chloride, 1.6 ml of borontrifluoride ethyl etherate complex were added dropwise. The mixture was stirred at 0°C for 30 minutes and then kept overnight at room temperature. The reaction mixture was diluted with 100 ml of methylene chloride and washed with saturated solution of NaCl . After drying, the organic layer was evaporated to dryness. The residue was finally purified on a silica gel column eluted with a chloroform/methanol mixture (8:2) yielding 0.13 g of the title compound.

ESI-MS: 658.7 [M+H] ⁺ and 680.4 [M+Na] ⁺ and ^XH and ¹³C NMR spectral data in good agreement with the structural features of the title compound.

Example 2

6-Morphinyl-α-D-αalactopyranoside acetate

A solution of 0.67 g of 6- (3-O-acetyl) -morphinyl-tetra- O-benzyl-α-D-galactopyranoside in 10 ml methanol is treated for 3 hours with hydrogen in the presence of 10% Pd on active carbon. The reaction mixture is filtered. After evaporation, the filtrate is treated for 60 minutes with 0.1 M of NaOH, neutralized with acetic acid and the solvent removed under vacuum. The crude residue is finally purified on a silica gel column eluted with a solvent mixture of ethyl acetate/water/methanol (3:2:1). After this procedure, lyophilization of the pure fraction from an aqueous/acetic acid solution affords 250 mg of the title compound as a white solid. ESI-MS: 448.7 [M+H] ⁺ and 470.3 [M+Na]⁺ and *H and ¹³C NMR spectral data in accordance to the structure of title compound.

The intermediate products can be prepared as follows.

a) 6- .3-O-acetγl) -morphinvl-tetra-O-benzyl-α-D- σalactopyranoside

First, 3 -O-acetyl-morphine (0.43 g) is dried by azeotropic distillation with benzene. Under argon atmosphere, a solution is prepared with the morphine derivative and 10 ml of dry dichloromethane . Tetra-O- benzyl-α-D-galactopyranosyl trichloroacetimidate (0.9 g) , borontrifluoride diethyl etherate complex (0.18 g) and 4 A molecular sieves are added. After stirring at room temperature overnight, the reaction mixture is diluted with methylene chloride, washed with aqueous bicarbonate, dried over sodium sulfate and the solvent evaporated. The residue is purified on a silica gel column eluted with a chloroform/methanol mixture (20:1 to 8:2) yielding 0.67 g of the title compound.

ESI-MS: 851.2 [M+H] ⁺ and 873.4 [M+Na] ⁺ and ^XH and ¹³C NMR spectral data in good agreement to the proposed structure of the title compound.

b) Tetra-0-benzγl-α-D-σalactopγranoByl trichloroacetimidate

To a solution of 2,3,4,6 tetra-O-benzyl-D- galactopyranose (1 g) in dichloromethane (8 ml) , trichloroacetonitrile (0.83 ml) and NaH (5 mg) are added. After stirring the solution for 1 hour, the reaction is filtered and the filtrate is evaporated to dryness. The residue is applied to a silica gel column which is eluted with hexane-ethyl acetate (4:1). A mixture of anomers is obtained which is later separated by a second column of hexane-ethyl acetate (7:1) yielding 0.9 g of the α-anomer with spectral data in accordance with the expected structure.

Example 3

6-Morphinyl-α-D-σlucopyranoside acetate

The corresponding glucopyranosyl analogue is prepared by a similar procedure as described for the galactosyl analogue following a procedure such as the one of Example 2 using a trichloroacetimidate intermediate of glucose .

Example 4

6-Morphinyl .α-D-glucopyranosyl) uronic acid acetate

The glucu onic acid analogue is synthesized by the method described for the galactoside analogue of Example 2.

Example 5

6-Morphinyl (α-D-σalactopγranosγl) uronic acid acetate

By a similar procedure given for Example 2 the galacturonic acid analogue is also prepared.

Example 6

6-Morphinγl (α-D-αlucoPvranosyl) uronamide acetate

Example 2 is also followed for the analogous preparation of the corresponding glucuronamide analogue of morphine. Example 7

6-Morphinyl (α-D-αalactopyranosyl) uronamide acetate

The title compound is also prepared essentially as described for the compound of Example 2.

Example 8

6-Codeinyl-α-D-mannopyranoside acetate

Following an analogous procedure as described for 6- morphinyl-α-D-mannopyranoside acetate (Example 1) the corresponding codeine analogue is synthesized.

Example 9

6-Codeinyl-α-D-galactopyranoside acetate

The synthetic pathway leading to title compound of Example 2 is followed for the preparation of this codeine analogue.

Example 10

Methadyl-α-D-mannopγranoside acetate

The title compound is prepared from methadol following an analogous procedure to the one described for 6- morphinyl-α-D-mannopyranoside acetate (Example 1) .

Example 11

Methadyl-α-D-galactopvranoside acetate

Taking as a reference the synthetic route for the 6- morphinyl-α-D-galactopyranoside acetate (Example 2) this derivative is prepared analogously using the appropriate trichloroacetimidate sugar.

Example 12

Methadyl-α-D-glucopγranoside acetate

The corresponding glucopyranosyl analogue is prepared by a similar procedure as described in Example 2 using a glucose intermediate.

Example 13

Methadyl (α-D-glucopyranosyl) uronic acid acetate

The glucuronic acid analogue of methadol is synthesized by an analogous method to that used to prepare the compound of Example 2.

Example 14

Methadyl (α-D-galactopyranosyl) uronic acid acetate

An analogous procedure to the previous example (Example 13) is followed for the preparation of the galacturonic acid analogue of methadol .

Example 15

Methadyl (α-D-glucopvranosyl) uronamide acetate

Starting from the suitable trichloroacetimidate of glucuronamide, the title compound is prepared analogously to the compound of Example 2. Example 16

Methadyl .α-D-galactopyranosyDuronamide acetate

An analogous route as for previous example (Example 15) leads to the corresponding galacturonamide analogue of methadol . '

Example 17

6-Pentazocyl-α-D-mannopyranoside acetate

This analogue is prepared from pentazocine by a similar reaction pathway as for the corresponding morphine analogue of Example 1.

Example 18

6-Pentazocyl-α-D-galactopyranoside acetate

The pentazocine analogue of the morphine compound of Example 2 "is also prepared analogously to Example 2 from the corresponding galactose trichloroacetimidate.

ANALGESIC ACTIVITY

To male Sprague-Dawley rats weighing 200g were administered intraperitoneally 100-500 μl volumes of selected opiate compounds in saline solution. Analgesia was assessed by the tail flick test and expressed as a percentage 15 and 30 minutes post-injection. The biological action of the compounds was reversed by a 5 mg/kg doses of intraperitoneal naloxone. The results are expressed in Table 1 for the compound of Example 1, a comparison compound (morphine sulphate) , a control (saline) and untreated animals. TABLE 1

Compound Dosis.i.p.) Animals Analgesia(%) Duration (mg/Kg) 15 min 30 min (hrs)

Morphine 5 10 45 72 2.5

Sulfate 1 10 -- --

Morphine-6-0-α 5 10 83 100 5

-D-mannose 1 10 56 100 5

0.5 15 54 100 5

0.2 10 57 100 5

0.1 15 50 100 5

0.05 20 56 84 5

0.02 15 19 51 3.5

0.01 15 -- 22 2

Control 40 5 5

(saline)

Non-treated 30 3 4

Claims

1. A compound being a sugar derivative of a biologically active opiate comprising at least one sugar residue coupled with at least one opiate residue through an α-glycosidic bond and salts, analogues and complexes thereof .

2. A compound as claimed in claim 1 wherein said sugar residue comprises a mono, di or trisaccharide sugar.

3. A compound as claimed in claim 1 of formula I :

(wherein: n is 0 or 1;

R₂ is H when n is 1 and H or CH₂OR₅ when n is 0;

X denotes an O-glycosidic bond or a linker group;

R_x denotes hydrogen, a CH₂OR₅, CH₂OCOR₅ or COZ group;

Z denotes an 0R₅, NR₃R₄ , 0(CO)R₅, Cj_._₁₈-alkyl or Cj_._₁₈- alkenyl group;

R₃ and R₄ independently denote hydrogen, a C_x__1B-alkyl,

or aryl group;

R₅ denotes hydrogen, a

^• aryl, sulphate, phosphate or silyl group; and

R₆ independently denotes hydrogen, a Cj.ig-alkyl, Cj_._₁₈- alkenyl, aryl, C0R₅, phosphate, sulphate or silyl group) , while one or more OR₆ groups may optionally be replaced by hydrogen atoms; and øalts, analogues and complexes thereof .

4. A compound as claimed in claim 3 wherein each R₆ is hydrogen .

5. A compound as claimed in claim 3 or 4 wherein R_x is CH₂OR₅.

6. A compound as claimed in anyone of claims 3 to 5 wherein X represents an O-glycosidic bond.

7. A compound as claimed in anyone of claims 3 to 6 wherein n=l .

8. A compound as claimed in anyone of claims 1 to 7 wherein the sugar residue is an α-D-pyranose.

9. A compound as claimed in claim 8 wherein the sugar residue is a glucose, galactose or mannose residue.

10. A compound as claimed in anyone of claims 1 to 9 wherein said compound is. a sugar derivative of a compound of formula III:

Formula III

(wherein:

Mj is a hydroxyl, methoxy, ethoxy, acetoxy or -OCH₂CH₂N O group;

M₂ is hydrogen, a hydroxyl, oxy, acetoxy, methoxy or methene group; M₃ is a methyl, methylene cyclopropyl, methylene cyclobutyl or allyl group;

M₄ is hydrogen or a hydroxyl group; the bond between carbon atoms in positions 6-7 and 7-8 can be either single or double; and the ether function between position 4 and 5 can be either present or not present on the molecule) or analogues, salts or complexes thereof; or said compound is a sugar derivative of metopon or buprenorphine .

11. A compound as claimed in claim 10 wherein said compound of formula (III) is morphine, codeine, heroin, hydromorphone, hydrocodgne, oxymorphone, oxycodone, levorphanol, dextromethqrphan, nalorphine, naltrexone, levallorphan, thebacone, ethyl morphine, dihydrocodeine, nalmefene, nalbuphine, butorphanol, pholcodine or naloxone .

12. A compound as claimed in claim 11 wherein said said compound of formula (III) is morphine, codeine or naloxone .

13. A compound as claimed in anyone of claims 10 to 12 wherein the sugar residue is bound to the opiate residue via the 3 or 6 position on the morphinian backbone.

14. A compound as claimed in anyone of claims 1 to 9 wherein said compound is a sugar derivative of a compound of formula IV:

Formula IV

(wherein:

E_j is a methyl, phenylethyl, p-phenylethylamine, - (CH₂)₃-NH-C₆H₅, -(CH₂)₂-C(C₆H₅)₂-CN, - (CH₂) -CH₂-CH₃ or

- (CH₂)

E₂ is hydrogen, a phenyl, m-hydroxyphenyl, p-chlorophenyl, methylenemetoxide or piperidinyl group; and

E₃ is a hydroxyl, ethylcarbonyl, carboxamide, ethyloxycarbonyl, ethylcarboxyl or -N(C₆H₅) -CO-CH₂-CH₃ group) or analogues, salts or complexes thereof; or said compound is a sugar derivative of alphaprodine, fenpipramide, ethoheptazine, tilidin or nefopam.

15. A compound as claimed in claim 14 wherein said compound of formula (IV) is meperidine, diphenoxylate, loperamide, fentanyl, sufentanil, alfentanil, cetobemidon, piritramide, anileridine or piminodine.

16. A compound as claimed in claim 15 wherein said compound of formula (IV) is meperidine or diphenoxylate.

17. A compound as claimed in anyone of claims 1 to 9 wherein said compound ia a sugar derivative of a compound of formula V:

Formula V

(wherein:

Dj is a phenyl or benzyl group;

D₂ is a -CH₂-CH(CH₃)-, -CH (CH₃) -CH₂- or -(CH₂)₂- group; and

D₃ is an ethylcarbonyl, ethylcarboxyl or -CH(OCOCH₃) -CH₂-CH₃ group) or analogues, salts or complexes thereof; or said compound is a sugar derivative of dextromoramide .

18. A compound as claimed in claim 17 wherein said compound of formula (V) is methadone, propoxyphene, normethadone or methadyl acetate.

19. A compound as claimed in anyone of claims 1 to 9 wherein said compound is a sugar derivative of methazocine, phenazocine, ciclazocine, pentazocine, dezocine and meptazinol.

20. The use of a compound as claimed in anyone of claims 1 to 19 as an analgesic.

21. A composition for use as an analgesic comprising a compound as claimed in anyone of claims 1 to 19 together with one or more pharmaceutically acceptable carriers or diluents.

22. The use of a compound as claimed in anyone of claims 1 to 19 or a salt or complex thereof for the manufacture of an analgesic medicament.

23. A method of treatment of the human or non-human, preferably mammalian, body to combat pain, said method comprising administering to said body a compound as claimed in anyone of claims 1 to 19 or a physiologically acceptable salt or complex thereof.

24. A process for preparing the compounds according to the invention, said process comprising the following steps : a) reacting an optionally protected opiate (acyl acceptor) having a free hydroxyl group with an optionally protected, activated reducing α-sugar derivative (acyl donor) in the presence of a promoter; and b) subsequently removing any protecting groups.