WO2002102392A1 - Use of adenosine a1 receptor agonists for the treatment of nociceptive pain - Google Patents

Use of adenosine a1 receptor agonists for the treatment of nociceptive pain Download PDF

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Publication number
WO2002102392A1
WO2002102392A1 PCT/GB2002/002817 GB0202817W WO02102392A1 WO 2002102392 A1 WO2002102392 A1 WO 2002102392A1 GB 0202817 W GB0202817 W GB 0202817W WO 02102392 A1 WO02102392 A1 WO 02102392A1
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alkyl
alk
group
optionally substituted
formula
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PCT/GB2002/002817
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French (fr)
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Charanjit Bountra
Nicholas Maughan Clayton
Susanne Denise Collins
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Glaxo Group Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

Definitions

  • the present invention is concerned with medicaments, and more particularly medicaments for use in the treatment of nociceptive pain.
  • W099/67262 discloses certain adenosine derivatives of formula (I):
  • X represents O or CH 2 ;
  • R 2 represents C ⁇ -3 alkoxy, halogen or hydrogen
  • R 3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, Cj_6 alkoxy, alkylO(CH ) n - where n is 0-6, C 3-7 cycloalkyl, C]_ 6 hydroxyalkyl, halogen or a C ⁇ -6 straight or branched alkyl, C ⁇ . 6 alkenyl or C ⁇ -6 alkynyl group optionally substituted by one or more halogens;
  • Y and Z represent O, N, CH, N(C ⁇ -6 alkyl);
  • W represents CH, O, N, S, N(C M alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or
  • W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R 3 cannot be H;
  • R 4 and R 5 independently represent H or a C ⁇ .6 straight chain or branched alkyl group
  • R 1 represents hydrogen or a group selected from:
  • cycloalkyl including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, - (C ⁇ -3 ) alkoxy, wherein (alk) represents C ⁇ -3 alkylene and n represents 0 or 1;
  • B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -C0 2 -(C ⁇ -3 alkyl);
  • R c and R d may each independently represent hydrogen, or C ⁇ -3 alkyl or when part of a group NR c R d , R c and R d together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more
  • R e represents C ⁇ -3 alkyl; and their salts and solvates as Al agonists.
  • the utility of the compounds of formula (I) and their salts and solvates as anti-lipolytic agents, in therapy of cardiovascular disorders, as cardioprotective agents, in treating ischaemic damage to organs and disorders arising as a result of widespread atheromatus disease, in therapy of hypertension and heart failure, as CNS agents and in treating sleep apnoea is disclosed in W099/67262.
  • the compounds of formula (I) and their pharmaceutically acceptable acid addition salts are also disclosed as preemptive analgesics for the treatment of acute pain, chronic pain, neuropathic pain and pain associated with cancer and fibromyalgia. Treatment or prevention of pain associated with functional bowel disorders, non-cardiac chest pain and non-ulcer dyspepsia is also disclosed.
  • Nociceptive pain is provoked pain that is only elicited when intense (noxious) stimuli threaten to damage normal tissue. As a component of the behavioural and reflex avoidance strategy this pain may be seen as protective and so its complete elimination is not always desired. Clinical examples of such pain include headaches, labour pain, menstrual pain and early post-operative pain.
  • the present invention therefore provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof for use in the treatment of nociceptive pain, and methods of treating nociceptive pain employing compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.
  • the treatment of nociceptive pain mentioned hereinbefore includes the treatment of headaches, labour pain, menstrual pain and early post-operative pain.
  • the compound of formula (I) is a compound of formula (lb):
  • X represents O or CH 2 ;
  • R 2 represents C ⁇ -3 alkyl, C ⁇ -3 alkoxy, halogen or hydrogen
  • R 3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, alkoxy, C ⁇ -6 alkylO(CH 2 ) n where n is 0-6, C -7 cycloalkyl, C ⁇ .e hydroxyalkyl, halogen or a C ⁇ -6 straight or branched alkyl, C ⁇ _ 6 alkenyl or C ⁇ .6 alkynyl group optionally substituted by one or more halogens;
  • Y and Z represent O, N, CH, or N(C w alkyl); W represents CH, O, N, S, or N(C ]-6 alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R 3 cannot be H;
  • R 4 and R 5 independently represent H or a . 6 straight chain or branched alkyl group
  • R 1 represents hydrogen or a group selected from:
  • B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -C0 2 -(C ⁇ -3 alkyl);
  • R c and R d may each independently represent hydrogen, or C ⁇ -3 alkyl or when part of a group NR c R d , R c and R d together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C ⁇ -3 alkyl groups;
  • R e represents C 1-3 alkyl
  • W, Y and Z containing heterocyclic groups include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles and thiadiazoles.
  • Preferred W, Y and Z containing heterocyclic groups are isoxazoles, and 1,2,4- and 1,3,4- oxadiazoles.
  • R 2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.
  • R 1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of -C0 2 -(C ⁇ . 4 )alkyl.
  • the aliphatic heterocyclic group is unsubstituted or when the substituent is - C0 2 (C ⁇ . 4 )alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.
  • the heterocyclic ring is 6 membered and more preferably contains only one O, N or S heteroatom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N.
  • R 1 may represent a phenyl group which is substituted by one or two substituents selected from OH, alkyl, particularly C ⁇ -4 alkyl and halogen.
  • the phenyl is disubstituted in the 2- and 4- positions.
  • both substituents are halogen more particularly, fluorine and chlorine.
  • a particularly preferred combination is 2-fluoro and 4-chloro.
  • R 4 and R 5 represent hydrogen.
  • the compounds useful in the invention are adenosine derivatives of formula (I) as disclosed in W099/67262.
  • a particularly preferred compound of formula (I) is (2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]- oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol,
  • the compounds of the present invention may also be utilized in the form of pharmaceutically acceptable salts or solvates thereof.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts.
  • suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like.
  • acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • suitable basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.
  • solvates For example, a complex with water is known as a "hydrate”.
  • Solvates of the compound of formula (I) are within the scope of the invention. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • compositions are conveniently administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • compositions of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention further provides for a pharmaceutical formulation comprising compound of formula (I) together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, macrocrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, m
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the tablets may be coated according to methods well-known in the art.
  • the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example.
  • formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid.
  • Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • a sterile liquid carrier for example, water-for-injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • treatment extends to prophylaxis (e.g. before stimuli known to predispose to nociceptive pain), as well as the treatment of established diseases or symptoms.
  • amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day, more preferably 2-20 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
  • the compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents.
  • the invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of nociceptive pain.
  • compositions comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
  • each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • (2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]-oxadiazol-2-yl)-5-[6-(4-chIoro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol was compared with ibuprofen.
  • the threshold at which the paw was withdrawn following a progressive increase in weight to the left or right hindpaw was determined. To give a final readout in grams, the threshold at which the paw was withdrawn was multiplied by a factor of 10.

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Abstract

Use of adenosine derivatives of formula (I) in the treatment of nociceptive pain.

Description

ENOSINE Al RECEPTOR AGONISTS FOR THE TREATMENT OF NOCICEPTIVE PAIN
The present invention is concerned with medicaments, and more particularly medicaments for use in the treatment of nociceptive pain.
W099/67262 (Glaxo Group Limited) discloses certain adenosine derivatives of formula (I):
R'
Figure imgf000002_0001
wherein X represents O or CH2;
R2 represents
Figure imgf000002_0002
Cι-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, Cj_6 alkoxy,
Figure imgf000002_0003
alkylO(CH )n- where n is 0-6, C3-7 cycloalkyl, C]_6 hydroxyalkyl, halogen or a Cι-6 straight or branched alkyl, Cι.6 alkenyl or Cι-6 alkynyl group optionally substituted by one or more halogens;
Y and Z represent O, N, CH, N(Cι-6 alkyl);
W represents CH, O, N, S, N(CM alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or
W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H;
R4 and R5 independently represent H or a Cι.6 straight chain or branched alkyl group;
R1 represents hydrogen or a group selected from:
(1) -(alk)n - (C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, - (Cι-3) alkoxy, wherein (alk) represents Cι-3 alkylene and n represents 0 or 1; (2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(C1-3)alkyl, -C02-(C1- )alkyl, -CO(CI-3alkyl), -S(=0)n-(C1-3alkyl), -CO RaRb (wherein Ra and Rb independently represent H or Chalky!) or =0; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (=0)n, where n is 1 or 2;
(3) straight or branched C\.\2 alkyl, optionally including one or more O, S(=0)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and R independently represent hydrogen, C3- cycloalkyl or a Cμβ straight chain or branched alkyl optionally substituted by C3-7 cycloalkyl;
(4) a fused bicyclic aromatic ring:
Figure imgf000003_0001
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -C02 -(Cι-3alkyl);
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, -SO3H, -(alk)nOH, -(alk)n -cyano, -(0)n
Figure imgf000003_0002
(optionally substituted by one or more halogens), - (alk)n -nitro, -(0)m -(alk)n-C02Rc, - (alkn)- CONRcRd -(alk)n -COR°, -(alk)n -SORe, -(alk)n -S02Re, -(alk)n- S02 RcRd, -(alk)nOR°, -(alk)n -(CO)m- NHS02Re, -(alk)n- NHCOR0, -(alk)n- NR°Rd wherein m and n are 0 or 1 and alk represents a Cι-6alkylene group or
C .6 alkenyl group;
(6) a phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by Cι-3alkyl or NR°Rd; Rc and Rd may each independently represent hydrogen, or Cι-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more
Cι-3 alkyl groups; Re represents Cι-3alkyl; and their salts and solvates as Al agonists.
The utility of the compounds of formula (I) and their salts and solvates as anti-lipolytic agents, in therapy of cardiovascular disorders, as cardioprotective agents, in treating ischaemic damage to organs and disorders arising as a result of widespread atheromatus disease, in therapy of hypertension and heart failure, as CNS agents and in treating sleep apnoea is disclosed in W099/67262. The compounds of formula (I) and their pharmaceutically acceptable acid addition salts are also disclosed as preemptive analgesics for the treatment of acute pain, chronic pain, neuropathic pain and pain associated with cancer and fibromyalgia. Treatment or prevention of pain associated with functional bowel disorders, non-cardiac chest pain and non-ulcer dyspepsia is also disclosed.
Surprisingly, it has been found that compounds of formula (I) and their pharmaceutically acceptable salts and solvates as disclosed in W099/67262 may be useful in the treatment of nociceptive pain.
Nociceptive pain is provoked pain that is only elicited when intense (noxious) stimuli threaten to damage normal tissue. As a component of the behavioural and reflex avoidance strategy this pain may be seen as protective and so its complete elimination is not always desired. Clinical examples of such pain include headaches, labour pain, menstrual pain and early post-operative pain.
The present invention therefore provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof for use in the treatment of nociceptive pain, and methods of treating nociceptive pain employing compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof.
There is also provided as a further aspect of the invention the use of compounds of formula
(I) or pharmaceutically acceptable salts or solvates thereof in the manufacture of a medicament for use in the treatment of nociceptive pain. In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, suffering from or susceptible to nociceptive pain, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
It will be appreciated that any reference to treatment herein is intended to include prophylaxis as well as the alleviation of established symptoms.
The treatment of nociceptive pain mentioned hereinbefore includes the treatment of headaches, labour pain, menstrual pain and early post-operative pain.
Preferably the compound of formula (I) is a compound of formula (lb):
R1
Figure imgf000005_0001
wherein X represents O or CH2;
R2 represents Cι-3alkyl, Cι-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group,
Figure imgf000005_0002
alkoxy, Cι-6 alkylO(CH2)n where n is 0-6, C -7 cycloalkyl, Cι.e hydroxyalkyl, halogen or a Cι-6 straight or branched alkyl, Cι_6 alkenyl or Cι.6 alkynyl group optionally substituted by one or more halogens;
Y and Z represent O, N, CH, or N(C w alkyl); W represents CH, O, N, S, or N(C]-6 alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H;
R4 and R5 independently represent H or a .6 straight chain or branched alkyl group;
R1 represents hydrogen or a group selected from:
(1) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group
Figure imgf000006_0001
-C02-(C1- )alkyl, -CO(C1-3alkyl), -S(=0)n-(C1-3alkyl), -CONRaRb (wherein Ra and Rb independently represent H or Cι-3alkyl) and =0; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (=0)n, where n is 1 or 2;
(2) a fused bicyclic aromatic ring
Figure imgf000006_0002
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -C02 -(Cι-3alkyl);
(3) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, -S03H, -(alk)nOH, -(alk)n-cyano, -(0)n -(C1.6)alkyl (optionally substituted by one or more halogens), - (alk)n -nitro, -(0)m -(alk)n-C02Rc, -
(alkπ)- CONRcRd -(alk)n -CORc, -(alk)n -SORe, -(alk)n -S02Re, -(alk)n- S02NRcRd, -(alk)nOR°, -(alk)n -(CO)m- NHS02Re, -(alk)n- NHCOR0, and - (alk)n- NRcRd wherein m and n are 0 or 1 and (alk) represents a Ci-βalkylene group or C2-6 alkenyl group; and (4) a phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C^alkyl or NRcRd;
Rc and Rd may each independently represent hydrogen, or Cι-3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more Cι-3 alkyl groups;
Re represents C1-3alkyl;
and salts and solvates thereof.
Examples of W, Y and Z containing heterocyclic groups include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles and thiadiazoles.
Preferred W, Y and Z containing heterocyclic groups are isoxazoles, and 1,2,4- and 1,3,4- oxadiazoles.
R2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.
Alternatively R1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of -C02 -(Cι.4)alkyl.
Conveniently, the aliphatic heterocyclic group is unsubstituted or when the substituent is - C02(Cι.4)alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom. Preferably the heterocyclic ring is 6 membered and more preferably contains only one O, N or S heteroatom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N.
Alternatively R1 may represent a phenyl group which is substituted by one or two substituents selected from OH, alkyl, particularly Cι-4 alkyl and halogen. Preferably the phenyl is disubstituted in the 2- and 4- positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro. Preferably R4 and R5 represent hydrogen.
The compounds useful in the invention are adenosine derivatives of formula (I) as disclosed in W099/67262.
A particularly preferred compound of formula (I) is (2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]- oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol,
Example 14 of W099/67262, the structure of which is indicated below:
Figure imgf000008_0001
or pharmaceutically acceptable salts or solvates thereof.
Compounds of formula (I) are prepared according to processes disclosed in W099/67262.
W099/67262 is incorporated by reference herein as though fully set forth.
It will be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of pharmaceutically acceptable salts or solvates thereof. The pharmaceutically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of formula (I) are within the scope of the invention. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The compounds of the invention are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Accordingly, the present invention further provides for a pharmaceutical formulation comprising compound of formula (I) together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, macrocrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non- aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis (e.g. before stimuli known to predispose to nociceptive pain), as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day, more preferably 2-20 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
No toxicological effects are indicated/expected when a compound of the invention is administered in the above-mentioned dosage range.
The compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of nociceptive pain.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
When a compound of formula (I) is used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
The present invention will now be further illustrated by the accompanying examples which should not be construed as limiting the scope of the invention in any way. EXAMPLES
The following abbreviations are used in the examples: s.c. - subcutaneous administration p.o. - oral route.
Example 1
In order to gauge the efficacy of compounds of formula (I) in the treatment of nociceptive pain, (2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]-oxadiazol-2-yl)-5-[6-(4-chIoro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol was compared with ibuprofen.
(2S,3 S,4R,5R)-2-(5-tert-butyl-[ 1 ,3 ,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol (l-10mg/Kg p.o.), or ibuprofen (10-150mg/Kg p.o.) were each given one hour before determining the mechanical paw withdrawal threshold.
Mechanical paw withdrawal threshold
In order to gauge the development of mechanical hypersensitivity the Randall paw withdrawal test was employed using an algesymeter (L.O. Randall et al, Arch. Int.
Pharmacodyn., 1957, 61, 409-419). The threshold at which the paw was withdrawn following a progressive increase in weight to the left or right hindpaw was determined. To give a final readout in grams, the threshold at which the paw was withdrawn was multiplied by a factor of 10.
In each of the studies male Random Hooded rats (180-250g) were used.
Results
(2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)- purin-9-yl]-tetrahydrofuran-3,4-diol (lOmg/kg p.o.) produced a small increase in the mechanical paw withdrawal threshold (26%). Ibuprofen (15-150mg/kg p.o.) had no significant effect on the mechanical paw withdrawal threshold.
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any novel feature or combination of features described herein. This may take the form of product, composition, process or use claims and may include, by way of example and without limitation, one or more of the following claims.

Claims

The use of a compound of formula (I):
R'
Figure imgf000015_0001
wherein X represents O or CH2;
R2 represents Cι-3alkyl, Cι-3alkoxy, halogen or hydrogen;
R3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, .6 alkoxy, C].6 alkylO(CH2)n where n is 0-6, C3-7 cycloalkyl, Cι-6 hydroxyalkyl, halogen or a C1-6 straight or branched alkyl, Cι.6 alkenyl or C1-6 alkynyl group optionally substituted by one or more halogens;
Y and Z represent O, N, CH, N(C1-6 alkyl);
W represents CH, O, N, S, N(CW alkyl); and wherein at least one of W and Z represents a heteroatom (and when Y, Z and/or
W is N, the presence or absence of an additional H would be apparent to a person skilled in the art); with the proviso that when W represents CH, Z represents N and Y represents O, R3 cannot be H;
R4 and R5 independently represent H or a C e straight chain or branched alkyl group;
R1 represents hydrogen or a group selected from:
(1) -(alk)n - (C3- ) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, - (Cι-3) alkoxy, wherein (alk) represents Cμ3 alkylene and n represents 0 or 1;
(2) an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(Cι-3)alkyls -C02-(C1-4)alkyl, -CO(Cι-3alkyl), -S(=0)n-(C1-3alkyl), -CONRaRb (wherein Ra and Rb independently represent H or C]-3alkyl) or =0; where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by (=0)n, where n is 1 or 2;
(3) straight or branched .^ alkyl, optionally including one or more O, S(=0)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3-7 cycloalkyl or a Cι-6 straight chain or branched alkyl optionally substituted by C3.7 cycloalkyl;
(4) a fused bicyclic aromatic ring:
Figure imgf000016_0001
wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula (I) via a ring atom of ring A and ring B is optionally substituted by -C02 -(Cι-3alkyl);
(5) a phenyl group optionally substituted by one or more substituents selected from:
-halogen, -S03H, -(alk)nOH, -(alk)n -cyano, -(0)„ -(Cι-6)alkyl (optionally substituted by one or more halogens), - (alk)n -nitro, -(0)m -(alk)n-C02R°, - (alkn)- CONR°Rd -(alk)n -CORc, -(alk)n -SORe, -(alk)n -S02Re, -(alk)n-
SO2NR0Rd, -(alk)nOR°, -(alk)n -(CO)m- NHS02Re, -(alk)n- HCOR0, -(alk)n- NRcRd wherein m and n are 0 or 1 and alk represents a C1-6alkylene group or C2-6 alkenyl group;
(6) a phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by Cι-3alkyl or NR°Rd;
Rc and Rd may each independently represent hydrogen, or Cμ3 alkyl or when part of a group NRcRd, Rc and Rd together with the nitrogen atom may form a 5 or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more Cι-3 alkyl groups; Re represents Cι-3alkyl;
or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of nociceptive pain.
2. The use according to claim 1 in which the compound of formula (I) is (2S,3S,4R,5R)- 2-(5-tert-butyl-[l,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9- yl]-tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt or solvate thereof.
3. Use according to any preceding claim wherein the medicament is formulated in unit doses.
4. A method of treatment of nociceptive pain in a mammal which comprises administration of a therapeutically effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceuticaly acceptable salt or solvate thereof to said mammal.
5. A method according to claim 4 in which the compound of formula (I) is (2S,3S,4R,5R)-2-(5-tert-butyl-[l,3,4]-oxadiazol-2-yl)-5-[6-(4-chloro-2- fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol or a pharmaceutically acceptable salt or solvate thereof.
6. Use of a compound of formula (I) as defined in claim 1 for the treatment of nociceptive pain.
PCT/GB2002/002817 2001-06-20 2002-06-19 Use of adenosine a1 receptor agonists for the treatment of nociceptive pain WO2002102392A1 (en)

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