EP1196165A2 - Composes chimiques iii - Google Patents

Composes chimiques iii

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Publication number
EP1196165A2
EP1196165A2 EP00946187A EP00946187A EP1196165A2 EP 1196165 A2 EP1196165 A2 EP 1196165A2 EP 00946187 A EP00946187 A EP 00946187A EP 00946187 A EP00946187 A EP 00946187A EP 1196165 A2 EP1196165 A2 EP 1196165A2
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EP
European Patent Office
Prior art keywords
compound
use according
azetidine
trifluoromethyl
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00946187A
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German (de)
English (en)
Inventor
Mike Frederick Snape
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Vernalis Research Ltd
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Vernalis Research Ltd
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Publication date
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Publication of EP1196165A2 publication Critical patent/EP1196165A2/fr
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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

Definitions

  • the present invention relates primarily to neuroprotection and to the treatment of stroke and other cerebrovascular disorders.
  • Stroke and other acute brain injuries are major causes of mortality and morbidity in the adult population. Stroke is the third highest cause of death in major industrialised countries and the commonest cause of permanent disability. Each year, in the US and Europe, approximately 1 million people suffer an acute stroke. Between 25% and 35% of these patients die within the first three weeks, and of the survivors 25% to 50% will be totally dependant on family or institutional care for the rest of their lives. The incidence of stroke increases with age, roughly doubling with each passing decade, with 30% of persons aged over 65 years being affected.
  • Activase ® Genetech's thrombolytic recombinant tissue plasminogen activator
  • Activase is indicated for the management of acute ischaemic stroke in adults for improving neurological recovery and reducing the incidence of disability.
  • Treatment with Activase should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial haemorrhage by a cranial computerised tomography (CT) scan or other diagnostic imaging method sensitive for the presence of haemorrhage.
  • CT computerised tomography
  • Cytoprotective neuroprotective therapy includes drugs that act to prevent cell death during ischaemia and reperfusion.
  • agents include calpain inhibitors, voltage-sensitive calcium- and sodium-channel antagonists, receptor-mediated calcium-channel antagonists [including N-methyl-D-aspartate (NMDA) and ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMP A) antagonists], glutamate-synthesis inhibitors, glutamate-release antagonists, ⁇ -aminobenzoic acid (GABA) antagonists, 5-HT (serotonin) receptor agonists, gangliosides, antioxidants, growth factors, antiapoptotic agents, and antiadhesion molecules (Silver, B., Weber, J., Fisher, M., Clin. Neuropharmacol. 1996, 19, 101-128).
  • NMDA N-methyl-D-aspartate
  • AMP A ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
  • glutamate-synthesis inhibitors glutamate-release antagonists
  • GABA ⁇ -aminobenzoic
  • Excitotoxicity is a major determinant of neuronal death following the induction of cerebral ischaemia. Repetitive cell firing, persistent depolarisation and induction of supra-normal ionic flux across excitable membranes can initiate fatal cellular compromise via a variety of synergistic mechanisms during hypoxic excitotoxicity. Control of the state of excitability of neurons depends upon the net balance of excitatory and inhibitory influences acting on that neurone.
  • the primary excitatory influence impinging on neurones is mediated by the glutamatergic system, whilst primary inhibition is frequently determined by GABAergic innervation, since the main endogenous inhibitory amino acid in mammalian brain is GABA.
  • GABAergic innervation the main endogenous inhibitory amino acid in mammalian brain is GABA.
  • GABA uptake inhibitors such as CI-966, which was shown to be effective in a gerbil ischaemia model utilising global cerebral ischaemia of 5 min. duration (Phillis, J.W., Gen. Pharmacol. 1995, 26, 1061-1064).
  • the benzodiazepine receptor agonist diazepam has been shown to possess some neuroprotective properties (Karle, J., Witt, M. R., Nielsen, M., Brain Res. 1997, 765, 21- 29).
  • Felbamate an antiepileptic drug with inter alia GABA agonist properties, provided significant neuronal protection when administered both before and after ischaemia in all regions of the brain in the gerbil model of transient forebrain ischaemia. Protection was moderate when felbamate was used before ischaemia, but was highly significant when felbamate was given 30 min. after the insult. The structural protection with felbamate was very significant when used in the post-ischaemic period (Shuaib, A., Waqaar, T., Ijaz, M.S., Kanthan, R., Wishart, T., Howlett, W., Brain Res. 1996, 727, 65-70).
  • Piracetam is a derivative of GABA, and was the first commercially available nootropic drug. Although widely evaluated in the treatment of senile cognitive disorders and dyslexia, piracetam has also been assessed as a treatment for deficits associated with acute stroke. Data from a number of small, short term studies in patients treated within a few days of stroke suggest that piracetam is more effective than placebo for the treatment of functional deficits (Noble, S., Benfield, P., CNS Drugs 1998, 9, 497-511).
  • WO-A-99/25353 discloses the use of triazolo[4,3-b]pyridazine derivatives as benzodiazepine/GABAA modulators for the treatment of psychotic disorders and neurodegeneration.
  • WO-A-90/09174 discloses the use of the GABAergic agent Clomethiazole (chlormethiazole) in the prevention and/or treatment of neurodegeneration. Clomethiazole is thought to act through a GABAergic pathway, whereby it augments GABA's inhibitory effect on the CNS, giving the drug both hypnotic and neuroprotectant properties.
  • Azetidine-1-carboxamides and the use of these compounds in the treatment of anxiety and all forms of epilepsy is described in International Patent Application No. PCT/GB99/00223.
  • the object of the present invention is to provide such treatments.
  • azetidine-1-carboxamides show unexpected neuroprotectant efficacy when compared to reference GABAergic agents.
  • certain azetidine-1-carboxamides have been shown to potentiate the action of GABA in inhibiting neurones, and have also been shown to prevent the repetitive firing induced as a consequence of activation of glutamatergic mechanisms.
  • Such compounds are found to be neuroprotective following acute cerebral ischaemia in rats and mice, and reduced ischaemia-induced CNS damage in in vivo models of focal ischaemia in both species. According to the present invention, there is provided the use of a compound of formula (I)
  • R 1 is aryl; and R 2 is hydrogen or alkyl; or a pharmaceutically acceptable salt or prodrug thereof, in the manufacture of a medicament for neuroprotection in a subject or for the treatment of cerebral ischaemia, central nervous system injury or eye diseases.
  • alkyl means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
  • the alkyl group is preferably Ci to Cj 2 , more preferably d to C 8 (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl).
  • alkyl as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.
  • a cyclic alkyl group is preferably C 3 to 2 , more preferably C 5 to and an acyclic alkyl group is preferably Ci to do, more preferably Ci to C 6 , more preferably methyl, ethyl, propyl (n- propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl.
  • aryl means a mono or bicyclic aromatic group, such as phenyl or naphthyl.
  • the alkyl and aryl groups may be substituted or unsubstituted. In one embodiment, only the aryl group defined above as Rj and the alkyl group defined above as R 2 may be substituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 or 2 substituents.
  • Substituents may include: carbon containing groups such as alkyl aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen containing groups such as haloalkyl (e.g. trifluoromethyl); oxygen containing groups such as alcohols (e.g.
  • ethers e.g. alkoxy, alkoxyalkyl, aryloxyalkyl
  • aldehydes e.g. carboxaldehyde
  • ketones e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl
  • acids e.g. carboxy, carboxyalkyl
  • acid derivatives such as esters (e.g. alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl) and amides
  • aminocarbonyl e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, aminocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaminocarbonyl
  • nitrogen containing groups such as amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulphur containing groups such as thiols, thioethers, sulphoxides and sulphones
  • alkylthio alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and
  • Preferred substituents include alkyl, aryl, halo, or an halogen-containing group such as trifluoromethyl.
  • alkoxy means alkyl-O- and "alkoyl” means alkyl-CO-.
  • halogen means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.
  • the compounds of formula (I) may exist in a number of diastereomeric and/or enantiomeric forms. Unless otherwise stated, reference in the present specification to "a compound of formula (I)" is a reference to all stereoisomeric forms of the compound and includes a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.
  • a compound of formula (I) is the (R - enantiomer of the compound of formula (I), substantially free of its (S)-enantiomer.
  • R 1 is a substituted or unsubstituted aryl group selected from phenyl and naphthyl, more preferably R 1 is a substituted phenyl or naphthyl, more preferably R 1 is phenyl or naphthyl having 1 to 3 substituents and most preferably R 1 is phenyl or naphthyl having 1 or 2 substituents.
  • R 1 is a mono- or di-substituted phenyl group, preferably a mono-substituted phenyl group.
  • R 1 is napthyl, it is preferred that R 1 is 2-naphthyl.
  • the preferred substituent groups are selected from halo (preferably fluoro and chloro), trifluoromethyl and tertiary butyl, and more preferably from fluoro, chloro and trifluoromethyl.
  • R 1 is a phenyl having 1 substituent
  • the phenyl group is preferably para- or meta-substituted.
  • the phenyl group is preferably 2,3-disubstituted, 2,4-disubstituted, 3,4-disubstituted or 3,5-disubstituted, preferably 3,4- disubstituted.
  • R 1 is disubstituted, it is preferred that R 1 is substituted by two halo groups, the same or different, or by one halo group and one trifluoromethyl group. More preferably, R 1 is dichloro-, difluoro-, chloro-fluoro- or fluoro-trifluoromethyl-substituted.
  • the R 1 groups are preferably selected from 4-chlorophenyl, 4-fluorophenyl, 4- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 4- fluoro-3-(trifluoromethyl)phenyl and 3-chloro-5-fluorophenyl.
  • R is alkyl, preferably selected from C ⁇ -8 alkyl, more preferably from alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl and unsubstituted saturated cyclic and acyclic hydrocarbyl, and more preferably from propyl, 2-propenyl, 2-propynyl and 2-hydroxypropyl.
  • Particularly preferred compounds are as follows:-
  • the compound of formula (I) is 3-(4- (trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidine-l-carboxamide (la) or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound of formula (I) is the (r?)-enantiomer of 3 -(4-(trifluoromethyl)phenyl)-N-(2-hydroxypropyl)azetidine- 1 -carboxamide (lb), substantially free of its (S)-enantiomer, or a pharmaceutically acceptable salt or prodrug thereof.
  • a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • a method of treatment of cerebral ischaemia, central nervous system injury or eye diseases comprising administration to a subject in need of such treatment an effective dose of the compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.
  • treatment includes prophylactic treatment.
  • prodrug means any pharmaceutically acceptable prodrug of the compound of formula (I).
  • the compound of formula (I) may be prepared in a prodrug form wherein a free -OH group is derivatised (for example, via an ester, amide or phosphate bond) with a suitable group (the group may contain, for example, an alkyl, aryl, phosphate, sugar, amine, glycol, sulfonate or acid function) which is suitably labile so as it will be removed / cleaved (eg. by hydrolysis) to reveal the compound of formula (I) sometime after administration or when exposed to the desired biological environment.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, furnaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, furnaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic,
  • hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids particularly preferred are hydrochloric, hydrobromic, phosphoric, sulfuric and methanesulfonic acids, and most particularly preferred is the methanesulfonate salt.
  • Acceptable base salts include alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g. calcium, magnesium) and aluminium salts.
  • the term "substantially free of its (S)-enantiomer” means that the medicament or therapeutic composition comprising the compound of formula (I) used according to the present invention contains a greater proportion of the (R)-enantiomer of the compound of formula (I) in relation to the (S)-enantiomer of the compound of formula (I).
  • the term "substantially free of its (S)-enantiomer”, as used herein, means that the composition contains at least 90 % by weight of the (i?)-enantiomer and 10 % by weight or less of the (S)-enantiomer.
  • the term "substantially free of its (S)-enantiomer” means that the composition contains at least 99 % by weight of the K)-enantiomer and 1 % or less of the (S)-enantiomer. In another preferred embodiment, the term “substantially free of its (S)-enantiomer” means that the composition contains 100 % by weight of the (R)- enantiomer. The above percentages are based on the total amount of compound of formula (I) present in the medicament or therapeutic composition used according to the present invention.
  • Cerebral Ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke), subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, carbon monoxide poisoning, cardiac arrest and subdural haematoma; Central Nervous System Injury, including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus and spinal cord injury; and Eye Diseases, including drug-induced optic neuritis, cataract, diabetic neuropathy, ischaemic retinopathy, retinal haemorrhage, retinitis pigmentosa, acute glaucoma, chronic glaucoma, macular degeneration, retinal artery occlusion and
  • the compound of formula (I) may also be used to potentiate the effects of other treatments, for example to potentiate the neuroprotective effects of brain derived nerve growth factor.
  • the invention is particularly directed to the treatment of cerebral ischaemia and central nervous system injury.
  • the invention is also particularly directed to the treatment of post- asphyxial brain damage in new-born subjects.
  • the compound of formula (I) may be used in combination with one or more additional drugs useful in the treatment of the disorders mentioned above, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the 3-aryl-3-azetidinol (LU) may be formed by treatment of the ketone (II) with an organometallic reagent such as an aryllithium or an arylmagnesium halide.
  • Removal of the hydroxyl group to give the 3- arylazetidine (TV) may be effected by several methods including, for example, catalytic hydrogenolysis; treatment with lithium or sodium and ammonia; conversion to the xanthate by treatment with carbon disulphide, methyl iodide and base, followed by tin-mediated reduction; and conversion to the 3-aryl-3-chloroazetidine analogue using an alkylsulfonyl chloride and a base, followed by a reductive dechlorination using sodium, lithium or nickel. Formation of the azetidine (V) is achieved by reaction of (IV) with a suitable nitrogen deprotection agent.
  • deprotection may be carried out by either catalytic transfer hydrogenation (e.g. ammonium formate and palladium catalyst) or by treatment with 1-chloroethyl chloroformate followed by methanol.
  • the urea (I) is formed by reaction of azetidine (V) with an N-alkylisocyanate or an N-alkylcarbamoyl chloride and a base such as triethylamine or potassium carbonate.
  • the urea may be prepared directly from the azetidine (TV) without isolation of an intermediate such as the secondary amine (V).
  • azetidine (IV) may be treated with phosgene followed by amme R NH to give urea (I) directly.
  • the invention further provides a pharmaceutical composition comprising an effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining an effective amount of the compound of formula (I) with a pharmaceutically acceptable carrier or excipient.
  • the composition may contain components such as dextrans or cyclodextrins or ether derivatives thereof, which aid stability and dispersion, and decrease metabolism of the active ingredient.
  • compositions in which the pharmaceutically acceptable carrier comprises a cyclodextrin or an ether derivative thereof the active ingredient is intimately mixed with an aqueous solution of the cyclodextrin or ether derivative thereof, with optional addition of further pharmaceutically acceptable ingredients before, during or after said mixing.
  • the thus obtained solution is optionally lyophilized, and the lyophilized residue is optionally reconstituted with water.
  • the composition further comprises a buffer system, an isotonizing agent and water.
  • Compounds of formula (I) may be administered in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use including transmucosal and transdermal use, for example a cream, ointment, gel, aqueous or oil solution or suspension, salve, patch or plaster; for nasal use, for a example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oil solution cr suspension.
  • the above compositions may be prepared in a conventional manner using conventional excipients, using standard techniques well known to those skilled in the art of pharmacy.
  • the compound is administered
  • the compounds of formula (I) will generally be provided in the form of tablets or capsules or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • the compounds of formula (I) will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • dosage levels used may vary over quite a wide range depending upon the compound used, the severity of the symptoms exhibited by the patient and the patient's body weight.
  • the compound (2) was prepared according to the method of Anderson and Lok (J Org. Chem. 1972, 37, 3953, the disclosure of which is incorporated herein by reference), m.p. 111- 112 °C (lit. m.p. 113 °C).
  • This compound was prepared from 3-(4-chlorophenyl-l-(diphenylmethyl)azetidine (6) and propargylamine using the procedure outlined in Example 3, m.p. 160 °C (diethyl ether). Found C, 62.85; H, 5.38; N, 10.89 C 13 H 13 ClN 2 O requires C, 62.78; H, 5.27; N, 11.26%.
  • This compound was prepared from compound (3) and 3,4-dichlorophenylmagnesium bromide using the procedure described for compound (4).
  • This compound was prepared from compound (26) and propargylamine using the procedure described for compound (12). m.p. 105.5-107.5°C.
  • This compound was prepared from compound (3) and 4-(trifluoromethyl)phenylmagnesium bromide using the procedure described for compound (4).
  • This compound was prepared from compound (30) using the procedure described for compound (10).
  • This product was prepared from compound (32) and propargylamine using the procedure described for compound (12). m.p. 151-155°C.
  • This compound was prepared from compound (3) and 3-(trifluoromethyl)phenylmagnesium bromide using the procedure described for compound (4).
  • This compound was prepared from compound (32) using the procedure described for compound (10).
  • This compound was prepared from compound (38) and (R)-l-amino-2-propanol using the procedure described for compound (12). m.p. 81-82°C.
  • This compound was prepared from compound (38) and (S)-l-amino-2-propanol using the procedure described for compound (12). m.p. 80-82°C.
  • This product was prepared from compound (38) and propargylamine using the procedure described for compound (12). m.p. 121°C.
  • Footnote a IR: 3373, 3316, 2923, 2855, 1639, 1620, 1557, 1488, 1462, 1434, 1378, 1304, 1153, 815 cm “1 .
  • Footnote b IR: 3500, 3429, 3346, 3274, 2925, 2854, 1614, 1556, 1466, 1420, 1407, 1052, 824, 536 cm "1 .
  • Footnote c IR: 3414, 3320, 3253, 2925, 2855, 1606, 1544, 1492, 1460, 1376, 1316, 1092,
  • Footnote d IR: 3340, 3166, 2923, 2854, 1650, 1613, 1493, 1460, 1378, 1303, 1098, 820 cm "1 .
  • Footnote e IR: 3310, 2964, 2878, 1632, 1538, 1494, 1482, 1462, 1398, 1328, 1093, 1015,
  • Footnote f compound (102) was made by the oxidation of compound (33), by methods known to those skilled in the art.
  • Footnote g: compound (104) was made from compound (102) by methods known to those skilled in the art.
  • This model of middle cerebral artery occlusion used relies on an intraluminal filament technique in the rat (Zhao Q. et al, Acta Physiol. Scand. 1994, 152, 349-350).
  • Male Lister Hooded rats were used in these experiments and were divided into three groups (Group 1 : vehicle; Group 2: chlomethiazole (CMZ); Group 3: a compound of formula I). The sample size in each was 11 to 15. The animal was anaesthetised and the carotid artery exposed.
  • a heat rounded dermalon suture (3/0) of a specified diameter was introduced into the ligated carotid artery, past the bifurcations of the external and common carotid, the internal carotid and the pterygopalatine artery, into the intracranial circulation.
  • the filament then lodged in the narrow proximal anterior carotid occluding the middle cerebral artery. After 90 min. of middle cerebral artery occlusion, the filament was removed, allowing re-circulation. 22.5 h following reperfusion, the animal was perfused via the transaortic route, using 200 ml of a 4 percent solution of tetrazolium chloride warmed to 37° C.
  • the brain was removed and immersion fixed in 10 percent formalin/saline for at least 48 h. Following fixation, the brain was sliced into 0.5 mm sections on a vibroslice. Using this technique, viable tissue was stained dark red and infarcted tissue remains unstained. The area of infarction on each section was measured, and the total volume of infarction in the hemisphere, cortex and striatum computed, using the Kontron image analysis system.
  • Figure 1 shows the effect of (i) vehicle; (ii) 128 mg/kg of clomethiazole dosed intraperitoneally (i.p.); and (iii) 30 mg/kg i.p. of compound (lb), on infarct volumes (assessed using tetrazolium histochemistry) after transient middle cerebral artery occlusion.
  • Data are displayed as (mean + SEM) using absolute infarct volumes in mm 3 .
  • ** signifies p ⁇ 0.01
  • * signifies p ⁇ 0.05 in the t test.
  • Figure 1 illustrates that compound (lb) exhibits significant neuroprotection at a dose of 30 mg/kg i.p. in the rat transient MCAo model. Clomethiazole at a dose of 128 mg/kg i.p. was found not to be effective in this model (see Sydserff, S.G. et al.,. Br. J. Pharmacol. 1995, 114, 1631-1635).
  • MCA middle cerebral artery
  • halothane anaesthesia (1.5% halothane in nitrous oxide: oxygen (70:30)
  • a small craniectomy was made to expose the left MCA.
  • the distal portion of the MCA was occluded by electrocoagulation.
  • the incision site was sutured and anaesthetics withdrawn.
  • Figure 2 shows that that compound (lb) exhibits significant neuroprotection at a dose of 60 mg/kg i.p. in the mouse permanent MCAo model.

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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Toxicology (AREA)
  • Cardiology (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Utilisation d'un composé représenté par la formule (I) (I) dans laquelle R1 représente aryle et R2 représente hydrogène ou alkyle ; ou un de ses sels ou promédicaments acceptables sur le plan pharmaceutique afin de préparer un médicament de protection neurologique ou de traitement de l'ischémie cérébrale, du dysfonctionnement du système nerveux central ou de maladies oculaires.
EP00946187A 1999-07-23 2000-07-21 Composes chimiques iii Withdrawn EP1196165A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9917384 1999-07-23
GBGB9917384.1A GB9917384D0 (en) 1999-07-23 1999-07-23 Chemical compounds-III
PCT/GB2000/002817 WO2001007022A2 (fr) 1999-07-23 2000-07-21 Composes chimiques iii

Publications (1)

Publication Number Publication Date
EP1196165A2 true EP1196165A2 (fr) 2002-04-17

Family

ID=10857862

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00946187A Withdrawn EP1196165A2 (fr) 1999-07-23 2000-07-21 Composes chimiques iii

Country Status (5)

Country Link
EP (1) EP1196165A2 (fr)
JP (1) JP2003505413A (fr)
AU (1) AU6006000A (fr)
GB (1) GB9917384D0 (fr)
WO (1) WO2001007022A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5621087B2 (ja) * 2008-11-24 2014-11-05 インテグレイティブ・リサーチ・ラボラトリーズ・スウェーデン・アーベー 皮質のカテコールアミン作動性神経伝達のモジュレーターとして有用な新規な３−フェニル−アゼチジン誘導体
GB201415598D0 (en) 2014-09-03 2014-10-15 Univ Birmingham Elavated Itercranial Pressure Treatment

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB872447A (en) * 1958-12-23 1961-07-12 Lepetit Spa 1-carbamyl-3-substituted azetidines
ES2181387T3 (es) * 1998-01-23 2003-02-16 Vernalis Res Ltd Derivados de azetidinocarboxamida para el tratamiento de trastornos del sistema nervioso central.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0107022A2 *

Also Published As

Publication number Publication date
WO2001007022A3 (fr) 2001-06-14
WO2001007022A2 (fr) 2001-02-01
JP2003505413A (ja) 2003-02-12
AU6006000A (en) 2001-02-13
GB9917384D0 (en) 1999-09-22

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