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WO2001007043A1 - Derives de l'azetidine carboxamine pour le traitement de troubles cerebrovasculaires - Google Patents

Derives de l'azetidine carboxamine pour le traitement de troubles cerebrovasculaires Download PDF

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Publication number
WO2001007043A1
WO2001007043A1 PCT/GB2000/002840 GB0002840W WO0107043A1 WO 2001007043 A1 WO2001007043 A1 WO 2001007043A1 GB 0002840 W GB0002840 W GB 0002840W WO 0107043 A1 WO0107043 A1 WO 0107043A1
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Prior art keywords
use according
azetidine
compound
carboxamide
hydroxypropyl
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PCT/GB2000/002840
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English (en)
Inventor
Mike Frederick Snape
Allan Fletcher
Kelly Jean Stanhope
Nathaniel Julius Monck
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Ligand UK Research Ltd
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Vernalis Research Ltd
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Priority to JP2001511927A priority Critical patent/JP2003505418A/ja
Priority to AU60079/00A priority patent/AU6007900A/en
Priority to EP00946207A priority patent/EP1196166A1/fr
Publication of WO2001007043A1 publication Critical patent/WO2001007043A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

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 ( ⁇ MDA) and ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) 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).
  • ⁇ MDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
  • glutamate-synthesis inhibitors glutamate-release antagonists
  • GABA ⁇ -aminobenz
  • 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/GABA A 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 Applications Nos. PCT/GB99/00224, PCT/GB99/00219 and 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 use of a compound of formula (I)
  • R 1 is aryl; and R 2 , R 3 , R 4 , R 5 and R 6 which may be the same or different are selected from H, alkyl and aryl; 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 (including allyl) or alkynyl (including propargyl)) hydrocarbyl radical.
  • the alkyl group is preferably Ci to C 12 , more preferably C ⁇ 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 C ⁇ 2 , more preferably C 5 to C 8 and an acyclic alkyl group is preferably d to C , more preferably 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.
  • alkyl and aryl groups may be substituted or unsubstituted. In one embodiment, only the alkyl and aryl groups defined above as R ⁇ to R may be substituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 or 2 substituents. Substituents may include:
  • 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. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl), ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl), oxo aldehydes (e.g. carboxaldehyde), ketones (e.g.
  • alkylcarbonyl alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl
  • acids e.g. carboxy, carboxyalkyl
  • acid derivatives such as esters
  • aminocarbonyl e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl, aminocarbonylalkyl, mono- or di- alkylaminocarbonylalkyl, arylaminocarbonyl
  • nitrogen containing groups such as amines (e.g. amino, mono- or di-alkylamino, aminoalkyl, mono- or di-alkylaminoalkyl), azides, nitriles (e.g. cyano, cyanoalkyl), nitro; sulphur containing groups such as thiols, thioethers, sulphoxides and sulphones
  • alkylthio alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more, preferably one, heteroatom, (e.g.
  • 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, naphthyl and indanyl, more preferably R 1 is a substituted phenyl, naphthyl or indanyl, more preferably R 1 is a phenyl, naphthyl or indanyl having 1 to 3 substituents and, more preferably, R 1 is a phenyl, naphthyl or indanyl having 1 or 2 substituents.
  • R 1 is a mono- or di-substituted phenyl or naphthyl, preferably a mono- or di-substituted phenyl, and most preferably a mono-substituted phenyl.
  • R 1 is a phenyl having 1 substituent
  • the phenyl group is preferably meta- or para- substituted.
  • the phenyl group is preferably a 3,4- disubstituted phenyl or a 3,5-disubstiruted phenyl, more preferably a 3,4-disubstituted phenyl.
  • R 1 is a naphthyl group it is preferred that R is a 2-naphthyl group. Where R 1 is an indanyl group, it is preferred that R is a 5-indanyl group.
  • R 1 is substituted
  • the preferred substituents are selected from chloro, fluoro, bromo, iodo, trifluoromethyl, tertiary-butyl, phenyl, CO 2 Me and CN, preferably from chloro, fluoro, trifluoromethyl and tertiary-butyl, and more preferably from chloro, trifluoromethyl and tertiary-butyl.
  • each substituent is independently selected from halo, preferably chloro and fluoro.
  • R 1 is di-substituted, it is preferred that R 1 is substituted by two chloro groups or by one chloro and one fluoro group, and more preferably by two chloro groups.
  • R 1 groups are selected from 3-chlorophenyl, 4-chlorophenyl, 4- fluorophenyl, 4-tert-butylphenyl, 4-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3,4- dichlorophenyl and 3,5-dichlorophenyl.
  • R 2 is selected from H, alkyl (including hydroxyalkyl such as CH 2 OH) and aryl.
  • R 2 is selected from H and alkyl.
  • R 2 is preferably methyl.
  • R 2 is aryl, R 2 is preferably phenyl.
  • R 2 is H or methyl. More preferably R 2 is methyl.
  • R 3 is selected from H, alkyl (including hydroxyalkyl such as CH 2 OH) and aryl.
  • R 3 is selected from H and alkyl. Where R 3 is alkyl, R 3 is preferably methyl. Where R 3 is aryl, R 3 is preferably phenyl.
  • R 3 is H or methyl.
  • R is selected from H and alkyl (including hydroxyalkyl).
  • R 4 is H or methyl. More preferably R 4 is H.
  • R 5 is selected from H and alkyl (including carboxy, alkoxycarbonyl and aminocarbonyl).
  • R 5 is preferably H or methyl. More preferably R 5 is H.
  • R 6 is selected from H and alkyl (including carboxy, alkoxycarbonyl and aminocarbonyl).
  • R 6 is preferably H or methyl. More preferably R 6 is H.
  • R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from H and alkyl.
  • R 2 is H and R 3 is methyl or R 2 is methyl and R 3 is H.
  • R 4 , R 5 and R 6 are H.
  • R 2 and R 4 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 5 membered ring, such as tetrahydrofuran.
  • R 2 and R 3 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 6 membered ring, such as cyclohexane.
  • R 2 and R 5 may optionally be linked by a saturated divalent radical chain of carbon atoms to form a 5, 6 or 7 membered ring, preferably a 6 membered ring, such as cyclohexane.
  • any of Ri to R 6 , and particularly Rj, is selected from aryl substituted by two alkyl groups, particularly two alkyl groups which are in adjacent ring positions on said aryl ring, then said alkyl groups may be cychsed to form a 5, 6 or 7 membered ring, preferably a 5 or 6 membered ring, more preferably a 5 membered ring.
  • the preferred compounds are (#)-3-(4-tert-butylphenoxy)-N-(2- hydroxypropyl)azetidine- 1 -carboxamide, Cr?)-3-(4-chlorophenoxy)-N-(2- hydroxypropyl)azetidine- 1 -carboxamide, GS)-3-(4-chlorophenoxy)-N-(2- hydroxypropyl)azetidine- 1 -carboxamide, ( ⁇ )-3-(3,4-dichlorophenoxy)-N-(2- hydroxypropyl)azetidine- 1 -carboxamide, ( J R)-3-(4-trifluoromethyl)phenoxy-N-(2- hydroxypropyl)azetidine- 1 -carboxamide and Cr?)-3-(3-trifluoromemyl)phenoxy-N-(2- hydroxypropyl)azetidine- 1 -carboxamide.
  • 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 (5)-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 (J?)-enantiomer of the compound of formula (I) in relation to the (5)-enantiomer of the compound of formula (I).
  • the term "substantially free of its (iS)-enantiomer”, as used herein, means that the composition contains at least 90 % by weight of the (ft)-enantiomer and 10 % by weight or less of the (iS)-enantiomer.
  • the term "substantially free of its (5)-enantiomer” means that the composition contains at least 99 % by weight of the (i?)-enantiomer and 1 % or less of the (6)-enantiomer. In another preferred embodiment, the term “substantially free of its (5)-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
  • 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 retinitis.
  • 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 cr sequentially.
  • the 3- (aryloxy)azetidine (m) may be formed by reaction of the azetidinol (II) either with an arylalkanol (R'OH) and diethylazo dicarboxylate and triphenyl phosphine or with a substituted aryl fluoride (R'F) and a strong base such as sodium hydride. Formation of the azetidine (IV) is achieved by reaction of (LTf) with a suitable nitrogen deprotection agent.
  • deprotection may be carried out by treatment with 1 -chloroethyl chloroformate followed by methanol.
  • the urea (I) is formed by reaction of azetidine (TV) with an N-alkylisocyanate or an N-alkylcarbamoyl chloride and a base such as triethylarnine or potassium carbonate.
  • the urea may be prepared directly from the azetidine (HI) without isolation of an intermediate such as the secondary amine (TV).
  • azetidine (L ⁇ ) may be treated with phosgene followed by alkylamine R 4 O.CR 2 R 3 .CR 5 R 6 .NH 2 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 or 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 co 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) 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.
  • Triphenylphosphine 13.11 g, 50.0 mmol was added to a stirred solution of 1- (diphenylmethyl)-3-azetidinol (11.97 g, 50.0 mmol) and 4-tert-butylphenol (7.50 g, 50.0 mmol) in acetonitrile (200 mL). Diethyl azodicarboxylate (7.9 mL, 8.7 g, 50.0 mmol) was added dropwise to the solution with water cooling. The suspension was heated under reflux for 4 h, the solution allowed to cool and concentrated in vacuo. The gum was suspended in ether (200 mL), and the suspension was refrigerated overnight.
  • This product was prepared from from 3-(4-chlorophenoxy)-l-(diphenylmethyl)azetidine and (5)-l-amino-2-propanol using the procedure described for compound (2) (57 % yield), m.p. 104-105 °C. Found: C, 54.7; H, 6.0; N, 9.7. C ⁇ 3 H, 7 N 2 O 3 requires C, 54.8; H, 6.0; N, 9.8%.
  • This product was prepared from 3-(4-chlorophenoxy)-l-(diphenylmethyl)azetidine and 1- amino-2-methyl-2-propanol using the procedure described for compound (2) (35 % yield), m.p. 121-122 °C. Found: C, 56.0; H, 6.6; N, 8.85. C 14 H ⁇ 9 N 2 O 3 requires C, 56.3; H, 6.4; N, 9.4%.
  • This product was prepared from 3-(4-fluorophenoxy)-l-(diphenylmethyl)azetidine (as described in US-4,956,359, the disclosure of which is incorporated herein by reference) and (./?)- l-amino-2-propanol using the procedure described for compound (2) (76 % yield), m.p. 112-114 °C. Found: C, 58.3; H, 6.4; N, 10.4. C ]3 H ⁇ 7 FN 2 O 3 requires C, 58.2; H, 6.4; N, 10.4%.
  • This product was prepared from 3-(4-chlorophenoxy)-l-(diphenylmethyl)azetidine and (d,l)- l-amino-2-propanol using the procedure described for compound (2) (81% yield), m.p. 104- 105°C. Found: C, 55.1; H, 6.1; N, 9.8. C ⁇ 3 H 17 N 2 O 3 requires C, 54.8; H, 6.0; N, 9.8%.
  • This product was prepared from 3-(4-trifluoromethyl)phenoxy)-l-(diphenylmethyl)azetidine and (i ⁇ -l-amino-2-propanol using the procedure described for compound (2) (60% yield), m.p. 112.5-113 °C. Found; C, 52.9; H, 5.4; N, 8.7. C ]4 H 17 F 3 N 2 O 3 requires C, 52.8; H, 5.4; N, 8.8%.
  • Footnote a IR: 3300, 2927, 1638, 1545, 1490, 1466, 1378, 1242, 1091, 825, 665 cm "1 .
  • Footnote b IR: 3519, 3271, 2926, 2855, 2233, 1624, 1606, 1506, 1458, 1397, 1260, 1171, 1126, 832, 550 cm "1 .
  • Footnote c IR: 3350, 2925, 2854, 1627, 1549, 1488, 1469, 1397, 1374, 1326, 1273, 1149, 1137, 1088, 803 cm "1 .
  • This model of middle cerebral artery occlusion used relies on an intraluminal filament technique in the rat (Zhao Q. et al, Ada 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.
  • 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 1 shows that compound 10 exhibits significant neuroprotection at a dose of 60 mg/kg i.p. in the mouse permanent MCAo model.
  • Figure 2 shows that compound 58 exhibits significant neuroprotection at a dose of 60 mg/kg i.p. in the mouse permanent MCAo model.

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Abstract

L'invention concerne l'utilisation d'un composé de la formule (I), dans laquelle R1 représente aryle, et R?2, R3, R4, R5 et R6¿, qui peuvent être identiques ou différents sont choisis dans H, alkyle, et aryle, ou un sel promédicament pharmaceutiquement acceptables de ceux-ci, lors de la fabrication d'un médicament de neuroprotection chez un patient ou pour le traitement d'ischémie cérébrale, de lésion du système nerveux central ou de troubles des yeux.
PCT/GB2000/002840 1999-07-23 2000-07-21 Derives de l'azetidine carboxamine pour le traitement de troubles cerebrovasculaires Ceased WO2001007043A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2001511927A JP2003505418A (ja) 1999-07-23 2000-07-21 Ｃｎｓ障害の処置のためのアゼチジンカルボキサミド誘導体
AU60079/00A AU6007900A (en) 1999-07-23 2000-07-21 Azetidine carboxamide derivatives for the treatment of cns disorders
EP00946207A EP1196166A1 (fr) 1999-07-23 2000-07-21 Derives de l'azetidine carboxamine pour le traitement de troubles cerebrovasculaires

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001007023A3 (fr) * 1999-07-23 2001-05-25 Vernalis Res Ltd Composes chimiques - ii
US11053234B2 (en) 2016-10-13 2021-07-06 Glaxosmithkline Intellectual Property Development Limited 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitors
WO2022049134A1 (fr) * 2020-09-03 2022-03-10 F. Hoffmann-La Roche Ag Composés hétérocycliques
US11608347B2 (en) 2018-01-08 2023-03-21 Hoffmann-La Roche Inc. Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0102740A1 (fr) * 1982-09-02 1984-03-14 A.H. Robins Company, Incorporated N-Formyl et N-hydroxyméthyl phénoxy-3 azétidinecarboxamides-1, leur préparation et leur usage
EP0194112A1 (fr) * 1985-02-28 1986-09-10 A.H. Robins Company, Incorporated Aryloxy-3 azétidinecarboxamides à activité relaxante et antispasmodique à l'égard de muscles et à activité anticonvulsive et antiépileptique
WO1999037614A1 (fr) * 1998-01-23 1999-07-29 Vernalis Research Limited Derives d'azetidinecarboxamide destines au traitement de troubles du systeme nerveux central

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0102740A1 (fr) * 1982-09-02 1984-03-14 A.H. Robins Company, Incorporated N-Formyl et N-hydroxyméthyl phénoxy-3 azétidinecarboxamides-1, leur préparation et leur usage
EP0194112A1 (fr) * 1985-02-28 1986-09-10 A.H. Robins Company, Incorporated Aryloxy-3 azétidinecarboxamides à activité relaxante et antispasmodique à l'égard de muscles et à activité anticonvulsive et antiépileptique
WO1999037614A1 (fr) * 1998-01-23 1999-07-29 Vernalis Research Limited Derives d'azetidinecarboxamide destines au traitement de troubles du systeme nerveux central

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001007023A3 (fr) * 1999-07-23 2001-05-25 Vernalis Res Ltd Composes chimiques - ii
US11053234B2 (en) 2016-10-13 2021-07-06 Glaxosmithkline Intellectual Property Development Limited 1,3 di-substituted cyclobutane or azetidine derivatives as hematopoietic prostaglandin D synthase inhibitors
US11608347B2 (en) 2018-01-08 2023-03-21 Hoffmann-La Roche Inc. Octahydropyrido[1,2-alpha]pyrazines as MAGL inhibitors
WO2022049134A1 (fr) * 2020-09-03 2022-03-10 F. Hoffmann-La Roche Ag Composés hétérocycliques
US11981661B2 (en) 2020-09-03 2024-05-14 Hoffmann-La Roche Inc. Heterocyclic compounds

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AU6007900A (en) 2001-02-13

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