Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
  • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
  • C07H19/16—Purine radicals

Definitions

• the present invention relates to a method for treating ischaemia, epilepsy and pain, to compounds for use in such a method and to pharmaceutical compositions containing the said compounds.
• Adenosine can be considered to be a hormone which has been shown to have a number of significant effects on the mammalian central nervous system (CNS) [Annual Reports in Medicinal Chemistry, 1988, 23, 39-48; International Review of Neurobiology (Smythies, J.R. and Bradley, R.J., eds.) Academic Press Inc., 1985, 27, 63-139], especially under conditions of neuronal stress where the compound appears to act as an endogenous neuroprotectant (Progress in Neurobiology, 1988, 31 , 85-108, Trends in Pharmacological Sciences, 1988, 9, 193-194).
• the concentra- tion of adenosine has been demonstrated to rise greatly in certain brain regions following epileptic seizures or conditions of neuronal ischaemia/a- noxia (Brain Research 1990, 516, 248-256).
• adenosine receptor agonists or compounds which increase extracellular adenosine levels can exhibit what is termed neuromodulator activity.
• Such substances influence the release of neurotransmitters in regions of the central nervous system (Annual Review of Neuroscience, 1985, 8, 103-124; Trends in Neurosciences, 1984, 164-168), with particular inhibitory effects on the release of the excitatory amino acid glutamic acid (glutamate) (Nature, 1985, 316, 148-150, Journal of Neurochemistry, 1992, 58, 1683-1689).
• CNS ailments for which this adenosine receptor mediated neuromodulator activity could be of clear therapeutic benefit. Examples of these would include the treatment of convulsive disorders (European Journal of Pharmacology, 1991, 195, 261-265; Journal of Pharmacology and Experimental Therapeutics, 1982, 220, 70-76), prevention of neurodegenera- tion under conditions of brain anoxia/ischaemia (Neuroscience Letters, 1987, 83, 287-293; Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia 1990, (Kriegelstein, J. and Oberpichler, H.
• Adenosine receptors represent a subclass (P1) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. This subclass has been further classified into two distinct receptor types which have become known as A1 and A2. Extensive research has been carried out in a quest to identify selective ligands at these sites [see, for example, Comr ahensive Medicinal Chemistry, Volume 3, (Hansch, C, Sam es, P.G. and .-- lor, J.B., Eds., Pergamon Press PLC: 1990, pp 601-642)].
• adenosine receptor agonists most selective for the A1 receptor over the A2 receptor are the examples where the adenine nucleus is substituted with a cycloalkyf group on the amino function, for example J-cyclopentyla- denosine and Nl-cyclohaxyiadenosine (Journal of Medicinal Chemistry, 1985, 28, 383-1384) or 2-chldro-.N-cyclopentyladenosine (Naunyn-Schmiede- berg's Arch. Pharmacol. 1988, 337, 687-689).
• J-cyclopentyla- denosine and Nl-cyclohaxyiadenosine Journal of Medicinal Chemistry, 1985, 28, 383-1384
• 2-chldro-.N-cyclopentyladenosine Naunyn-Schmiede- berg's Arch. Pharmacol. 1988, 337, 687-689.
• GB 1 ,143,150 (equivalent to USP 3,551 ,409) and GB 1 ,123,245 disclose a number of adenosine derivatives, having interesting cardiac and circulatory actions.
• adenosine derivatives some of which are claimed in GB 1,143,150, has potential therapeutic utility for treating central nervous system ailments such as cerebral ischaemia, epilepsy and pain in humans. They have a clear CNS effect in relevant animal models at the same time as having a superior side-effect profile with respect to cardiovascular properties.
• the compounds have utility within myocardial ischaemia.
• the following compounds possess therapeutic utility within the above-mentioned CNS indications: - -Y -
• the present invention relates to adenosine analogues of formula
• X is hydrogen, amino, halogen, hydroxy, lower alkoxy or lower alkyl
• R 2 and R 5 is H or lower, straight or branched alkyl
• R 3 is H or lower alkyl, or
• R 2 and R 3 can together form a cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring,
• Z is oxygen, methylene, sulphur, sulphonyl or a valence bond
• R 4 is H, lower alkyl, aralkyl a mono or bicyclic aromatic system optionally substituted with halogen, hydroxy, haloalkyl, alkyl, alkoxy, aryloxy, acyloxy or alkylmercapto radicals, or a pharmaceutically acceptable salt thereof as these compounds have been found useful in treatment of a number of CNS-related ailments, such as cerebral ischaemia, epilepsy and pain.
• the compounds of formula (I) are found to be useful agents, for lowering plasma free fatty acid (FFA) levels, as cardiovascular agents and also have application to myocardial ischaemia.
• FFA plasma free fatty acid
• the invention also relates to methods of preparing the above mentioned compounds. These methods comprise:
• a compound of formula (I) may be prepared by reacting a substance of formula (II), wherein L represents a leaving group such as a halogen atom (e.g. a chlorine or bromine atom) or a trimethylsilyloxy group, P 1 , P 2 and P 3 are the same or different and represent hydrogen or a protecting group such as benzoyl-, p-toluoyl- lower alkanoyl- (e.g. acetyl-), a substituted silyl group (e.g.
• L represents a leaving group such as a halogen atom (e.g. a chlorine or bromine atom) or a trimethylsilyloxy group
• P 1 , P 2 and P 3 are the same or different and represent hydrogen or a protecting group such as benzoyl-, p-toluoyl- lower alkanoyl- (e.g. acetyl-), a substituted silyl group (e.g.
• suitable conditions for deprotection include the use of methanolic ammonia, an alkali metal carbonate in metha ⁇ nol, or an alkali metal alkoxide in the corresponding alcohol.
• suitable methods for deprotection include, for example, treatment with tetra- alkylammonium fluorides or aqueous hydrolysis in the presence of acid or base.
• suitable conditions for deprotection include, for example, hydrolysis with aqueous mineral acid.
• a compound of formula (I) wherein X represents -NH 2 , O-alkyl or hydroxy may be prepared by reacting a substance of general formula (V) General process (B)
• the present invention provides a method for treating cerebral ischaemia, epilepsy and pain in human or non-human animals, which method comprises administering an effective, non-toxic amount of a com ⁇ pound of formula I or a pharmaceutically acceptable salt thereof, to human or non-human animals suffering from cerebral ischaemia, epilepsy or pain.
• the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt trareof in the preparation of a medica- ment for use in the treatment of cerebral ischaemia, epilepsy or pain.
• the present invention further provides a pharmaceutical composition for use in the treatment of cerebral ischaemia, epilepsy or pain which comprises an effective amount of a compr. sd of formula I of a pharmaceutically accep- table salt thereof and a pharmaceutically acceptable carrier.
• a pharmaceutical composition for use in the treatment of cerebral ischaemia, epilepsy or pain which comprises an effective amount of a compr. sd of formula I of a pharmaceutically accep- table salt thereof and a pharmaceutically acceptable carrier.
• Such composi ⁇ tions may be prepared in the manner as described below.
• salts of compounds of formula (I) can be prepared which can be considered physiologically acceptable. These include addition salts derived from inorganic or organic acids, for example, acetates, fumarates, glutara- tes, glutaconates, lactates, maleates, methanesulphonates, phosphates, salicylates, succinates, sulphates, sulphamates. tartrates and paratoluene- sulphonates. In some cases, solvates of either the free nucleosides or the acid addition salts can be isolated and these solvates may, for example, be hydrates or alcoholates.
• the compounds of the invention together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically-accep- table acid addition salt thereof, may be placed into the form of pharmaceuti ⁇ cal compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets of filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including sub ⁇ cutaneous .administration and infusion).
• Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the adenosine receptor agonist commensurate with the intended daily dosage range to be employed.
• the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
• Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active com ⁇ pounds.
• Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhyroxyethoxylated castor oil, gelatine, lactose, amylose, magne ⁇ sium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrroli- done.
• the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
• injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
• Ampoules are convenient unit dosage forms.
• a syrup, elixir or the like can be used in cases where a sweetened vehicle can be employed.
• the compounds of this invention are dispensed in unit form comprising 0.05-100 mg in a pharmaceutically acceptable carrier per unit dosage.
• the dosage of the compounds according to this invention is 0.1-300 mg/day, preferably 10-100 mg/day, when administered to patients, e.g. humans, as a drug.
• a typical tablet which may be prepared by conventional tabletting tech ⁇ niques contains:
• the compounds of the invention are extremely useful in the treatment of related symptoms in mammals, when administered in an amount effective for agonist activity of compounds of the invention.
• the compounds of the invention may accor- dingly be administered to a subject, e.g., a living animal body, including a human, in need of an adenosine receptor agonist, and if desired in the form of a pharmaceutically-acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultanously, or together with a pharmaceutically-acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount of aden
• a pharmaceutically-acceptable acid addition salt thereof such as the hydrobromide, hydrochloride
• Suitable dosage ranges are 1 -200 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject in volved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
• HPLC was carried out on a Waters or Merck chromatograph with a multiwavelength detector and a reversed phase C 8 column (250 > 4 mm, 5 ⁇ m, 10 ⁇ A; eluent flow rate 1 mL/ min at 35°C). Retention times are given in minutes.
• the title compound was prepared by reacting 1-phenoxy-2-propylamine (16.62 g, 0.11 mol) with 9-(2,3,5-tri-0-acetyl- ⁇ -D-ribofuranosyl)-2,6-dichloro- 9H-purine (24.6 g, 55 mmol) in dioxan (250 ml) in the presence of triet- hylamine (7.23 g, 71.5 mmol) followed by deprotection of the product using a solution of sodium (0.15 g, 6.5 mmol) in methanol (250 ml). The reaction mixture was neutralized with citric acid, and treated with a mixture of ethyl acetate (300 ml) and water (200 ml).
• the ethyl acetate phase was separa ⁇ ted, dried (MgS0 4 ) and evaporated before being purified by flash chroma- tography on silica gel, eluting initially with dichloromethane, and later with a mixture of dichloromethane and ethanol (9:1).
• the corresponding maleate salt was prepared by dissolving the above 2-chloro-N-(1-phenoxy-2- ⁇ ropyl)adenosine (1.7 g, 3.9 mmol) in THF (10 ml), adding diethyl ether (60 ml) followed by maleic acid (0.45 g, 3.9 mmol). The residue on evaporation was treated with diethyl ether (50 ml) whereupon the maleate salt precipitated and was collected by filtration (1.15 g), m.p. 102-104°C.
• the title compound was prepared by reacting 2-phenoxyethylamine hydrochloride (0.80 g, 4.6 m mol) with 9-(2,3,5-tri-0-benzoyl- ⁇ -D-ribofuran- osyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol) in dioxan (25 ml) in the pre- sence of triethylamine (1.0 g, 9.6 mmol) followed by deprotection of the purified product using methanolic ammonia to provide the title nucleoside (0.75 g, 60%) (following flash chromatography) as an amorphous foam, 1 H NMR (DMSO-d ⁇ S 3.52 - 3.59 (1H, m, H-5'J, 3.64 - 3.71 (1H, m, H-5' b ), 3.82 (2H, q, -CH 2 -), 3.96 (1H, q, H-4'), 4.14 (1H,
• the title compound was prepared by reacting L-amphetamine (0.49 g, 3.6 mmol) with 9-(2,3,5-tri- ( J-benzoyl- ⁇ -D-ribofuranosyl)-2,6-dichloro-9H-purine (1.9 g, 3.0 mmol) in dioxan (25 ml) in the presence of diisopropylethylamine (0.58 g, 4.5 mmol) followed by deprotection of the purified product using methanolic ammonia. Evaporation of the reaction mixture provided a gum- my residue which crystallized on addition of dichloromethane (10 ml), to provide the title compound (0.26 g, 38%) as a solid, m.p.
• H 2 0 requires C, 53.2; H, 5.4; N, 16.3. Found: C, 53.3; H, 5.4; N, 16.3%.
• the ethyl ace- tate phase was then extracted with pH 2 dilute hydrochloric acid, and this acidic aqueous phase was washed with ethyl acetate (2 x 100 ml), and basified with sodium bicarbonate solution before extraction with ethyl aceta ⁇ te (100 ml).
• the ethyl acetate phase was was dried (MgS0 4 ) and eva ⁇ porated to give the title compound (0.43 g, 33%) a mixture of diastereoiso- mers as an amorphous foam, 1 H NMR (DMSO-d 6 ) «s 1.28 (3H, d, -CH 3 ),
• Trans-2-hydroxycyclopentylamine (0.35 g, 3.46 mmol) (prepared by reaction of cyclope ⁇ tene oxide with ammonia in a sealed vessel: see example 11) was reacted with 6-chloropurine riboside (i.e. 9- ⁇ -D-ribofuranosyl-9H-purine) (0.5 g, 1.7 mmol) in dioxan (30 ml) in the presence of triethylamine (0.93 g, 9 mmol). The reaction mixture was heated at 100°C for 70 h, cooled and evaporated. The resultant residue was purified by flash chromatography eluting with a mixture of ethyl acetate and methanol (19:1).
• This compound was prepared as a mixture of enantiomers by reaction of cyclopentene epoxide (8.0 g, 95.1 mmol) with a 25% aqueous ammonia solution (35 ml) in a sealed glass vessel at 110°C for 1.5 h.
• the reaction mixture was cooled and evaporated to half its original volume before 1 N sodium hydroxide solution (95 ml) and THF (100 ml) were introduced at 0°C.
• a solution of di-tert-butyl dicarbonate (21.8 g, 99.6 mmol) in THF (50 ml) was added dropwise and the reaction mixture stirred at room tempera ⁇ ture for 18 h.
• trans-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine was converted into cis-2-phenoxy-cyclopentyl-amine by the sequence of reac ⁇ tions described in Example 2 (i.e. phenyl ether formation by the Mitsunobu procedure resulting in inversion at the 2-position, followed by acidic hydroly ⁇ sis of the BOC- group using TFA).
• Trans-N-(tert-butvloxvcarbonv ⁇ -2-hvdroxvcvclopentvlamine (24.7 g, 123 mmol) (prepared as described in Example 11) was dissolved in THF (500 ml) and 4-nitrobenzoic acid (20.51 g, 123 mmol) was added, followed by triphenylphosphine (48.28 g, 184 mmol).
• a solution of diethylazodicarboxy- late (32.06 g, 184 mmol) in THF (250 ml) was introduced dropwise.
• reaction mixture was stirred for 18 h at room temperature, evaporated and purified by flash chromatography eluting with a mixture of cycohexane and ethyl acetate (4:1) to provide the intermediate 4-nitrobenzoyl ester as a solid (25.5 g), TLC R 0.52 [Si0 2 : cyclohexane/ ethyl acetate (1 :1)].
• This ester was suspended in a mixture of a mixture of methanol (180 ml) and 25% aque ⁇ ous ammonia solution (20 ml) and the mixture was stirred at room tempera- ture for 70 h before evaporation to a residue.
• the title compound was prepared by reacting 2-(phenylmethoxy)ethylamine hydrochloride (0.51 g, 2.7 mmol) with 9-(2,3,5-tri-0-benzoyl- ⁇ -D-ribofuran- osyl)-2,6-dichloro-9H-purine (1.43 g, 2.25 mmol), followed by debenzoyla- tion of the purified product using methanolic ammonia to provide the title 2- chloro-N-[2-(phenylmethoxy)ethyl]adenosine (0.38 g, 44%) (after column chromatography) as a solid, mp 115 -124°C, 1 H NMR (DMSO-d 6 ) ⁇ s 3.50 - 3.58 (1H, m, H-5' a ), 3.60 - 3.70 (4H, m, H-5' b , -CH 2 - and -CH-), 3.95 (1 H, q, H-4'), 4.
• 2-Methoxy-fvJ-[(R)-1-phenoxy-2-propyI]adenosine was prepared by reacting 2-chloro- J-((R)1-phenoxy-2-propyl) adenosine (Example 2) (0.30 g, 0.69 mmol) with a mixture of sodium hydroxide (0.32 g, 8.0 mmol) and methanol (15 ml) in a sealed vessel at 80 - 90°C for 4h. The cooled reaction mixture was neutralised with concentrated hydrochloric acid and evaporated to dryness. Water (30 ml) was added and the mixture was extracted with dich- loromethane (2 x 30 ml).
• the title compound was prepared by the procedure described in example 7 by reacting 2-methoxyethylamine hydrochloride (0.27 g, 3.6 mmol) with 6-c- hloropurine riboside (i.e. 9- ⁇ -D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in dioxan (30 ml) at room temperature for 72 h with triethylamine (1.04 ml, 7.5 mmol) present.
• 6-c- hloropurine riboside i.e. 9- ⁇ -D-ribofuranosyl-6-chloro-9H-purine
• the product (after purification by flash chromato ⁇ graphy) was debenzoylated with methanolic ammonia to provide the pro ⁇ duct (after column chromatography) as a foam which solidified on coeva- poration with dichloromethane.
• H 2 0 requires C, 51.6; H, 5.9; N, 13.7. Found: C, 52.0; H, 5.8; N, 13.3%.
• the title compound was prepared by reacting (2-methylphenyI)methylamine (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60°C for 6 h, cooled, filtered and evaporated.
• H 2 0 requires C, 57.0; H, 6.1 ; N, 16.6. Found: C, 57.0; H, 6.2; N, 16.8%.
• the compounds according to the invention possess desirable central nervous system properties. For example, they act as anticonvuisant agents, are effective in animal models of pain, and show cerebroprotective effects in laboratory test animals subjected to simulated cerebral ischaemia. In addi ⁇ tion, the compounds may have efficacy as neuroprotective agents in cases of cerebral oedema and traumatic head injury.
• seizures are induced by i.p. (intraperitoneal) dosing of methyl 6,7-dimethoxy-4-ethyl- ⁇ -carboline-3-carboxylate DMCM at 15 mg/kg.
• DMCM is an inverse agonist to the benzodiazepine receptor, presumably producing seizures by decreasing the potency of inhibition of the GABA receptor/benzodiazepine receptor/chloride ionophore complex.
• DMCM 15 mg/kg of DMCM dissolved in 0.02 N HCl (1 mg/ml) is administered i.p. in a volume of 300 ⁇ l to male NMRI mice weighing 20 ⁇ 2 g.
• DMCM is administered 30 min after an intraperitoneal injection of a test compound. Latency time for the presence of intense clonic and tonic convulsions and death is noted until 15 min after administration of DMCM. At least 5 doses of each test compound are tested with 8 mice per dose.
• An anticonvulsive ED 50 value is determined as the dose (mg/kg) protecting 50% of the animals against clonic convulsions; some representative values are shown in table II.
• Test compounds are generally dissolved in DMSO and diluted in 5% chre- mophore/saline before being dosed to nembutal anaesthetised 200 g fema- le Sprague Dawley rats which have not been starved or fasted.
• the rats are breathing spontaneously; blood pressure (BP) and heart rate (HR) is mea ⁇ sured 5 minutes after a bolus i.v. injection. Each measurement is repeated twice. Results for representative compounds are shown in table II.
• Transient global ischaemia was produced in Mongolian gerbils (60-70 g, males) anaesthetized with 2% halothane in 70% nitrous oxide and 30% oxy ⁇ gen.
• the common carotid arteries were occluded for 5 min. and the animals were allowed to recover for 4 days.
• the animals were reanaesthetized, de ⁇ capitated and the brains quickly removed and frozen in powdered dry ice.
• Coronal sections (20 ⁇ m) were taken through the brain at the level of the hippocampus and stained with cresyl violet and hematoxylineosin.
• the brain sections were rated for neuronal damage in the hippocampus CA1 region using a scale from 0 (undamaged) to 3 (total damage of CA1).
• the body temperature of all the animals was maintained at 37°C throughout the sur ⁇ gery and the animals were placed in warmed boxes during the recovery period.

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