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WO1996017612A1 - Utilisation de composes de phenylamidine et de phenylguanidine substitues dans le traitement de l'ischemie cerebrale et cardiaque, des convulsions et de la drepanocytose - Google Patents

Utilisation de composes de phenylamidine et de phenylguanidine substitues dans le traitement de l'ischemie cerebrale et cardiaque, des convulsions et de la drepanocytose Download PDF

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Publication number
WO1996017612A1
WO1996017612A1 PCT/EP1995/004673 EP9504673W WO9617612A1 WO 1996017612 A1 WO1996017612 A1 WO 1996017612A1 EP 9504673 W EP9504673 W EP 9504673W WO 9617612 A1 WO9617612 A1 WO 9617612A1
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Prior art keywords
carbon atoms
methyl
group
formula
phenyl
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PCT/EP1995/004673
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English (en)
Inventor
Robert Brian Jones
Richard David Green
Gillian Frodsham
Original Assignee
Knoll Aktiengesellschaft
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Publication date
Priority claimed from GBGB9424728.5A external-priority patent/GB9424728D0/en
Priority claimed from GBGB9425164.2A external-priority patent/GB9425164D0/en
Application filed by Knoll Aktiengesellschaft filed Critical Knoll Aktiengesellschaft
Priority to AU41763/96A priority Critical patent/AU4176396A/en
Publication of WO1996017612A1 publication Critical patent/WO1996017612A1/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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame

Definitions

  • This invention relates to a method for the treatment of cerebral and/or cardiac ischaemia , convulsion and sickle cell anaemia .
  • a method for the treatment and/or prevention of cerebral and/or cardiac ischaemia, convulsion and/or sickle cell anaemia in which a therapeutically effective amount of a compound of formula I
  • X is H, nitro, cyano, halo, phenyl (optionally substituted by halo and/or alkyl and/or alkoxy containing 1 to 3 carbon atoms or alkanoyl containing 2 to 4 carbon atoms, or a group of formula S(O) m R' wherein m is 0 or 1 or 2 and R' is an alkyl group containing 1 to 3 carbon atoms), an alkyl group containing 1 to 4 carbon atoms or a group of formula -(CH 2 ) n NR 1 R 2 in which n is 0 or 1 and R 1 and R 2 , which are the same or different, are (a) an aliphatic group containing 1 to 3 carbon atoms, said aliphatic group being optionally substituted by methoxy (b) a cycloalkyl group
  • R 8 represents H or an alkyl group containing 1 to 3 carbon atoms and B represents an alkylene group of 2 to 4 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms or the substituents on two adjacent carbon atoms of the alkylene group form a benzene ring or B represents an alkenylene group of 3 carbon atoms;
  • R 3 is a straight or branched alkyl group containing 1 to 7 carbon atoms or a guanidine group (optionally N-substituted in both the 1 and 3 positions with one or two alkyl groups containing 1 to 3 carbon atoms) or R 3 is a cycloalkyl group containing 3 to 7 carbon atoms or a group of formula III in which R 4 and R' 4 , which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; R 6 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy;
  • R 6 is (a) H, or phenyl (optionally substituted by halo and/or alkyl and/or alkoxy containing 1 to 4 carbon atoms) (b) a straight or branched aliphatic group of 1 to 6 carbon atoms optionally substituted by hydroxy or an acylated derivative thereof, by an alkoxy group containing 1 to 3 carbon atoms, by an alkylthio group containing 1 to 3 carbon atoms, by an optionally alkylated amino group, by a carbocyclic group containing 3 to 7 carbon atoms, by pyridyl or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon atoms and optionally substituted by hydroxy; or the group R 3 and the group R 5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV
  • R 6 is as hereinbefore defined
  • R 9 and R 10 which are the same or different, are H or an alkyl group of 1 to 4 carbon atoms optionally substituted by methoxy and D is an oxyethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups R 9 and R 10 or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms; or the group R 3 and the group R 5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V
  • R 6 is as hereinbefore described, R 11 is H or an alkyl group containing 1 or 2 carbon atoms, and E is an alkylene group of 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI
  • G is an alkylene or alkenylene group of 4 to 6 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl, sulphonyl, or nitrogen said nitrogen being optionally substituted by (a) a carbocyclic ring containing 3 to 7 carbon atoms (b) a methylsulphonyl group or (c) an alkyl group containing 1 to 3 carbon atoms and optionally substituted by hydroxy or an alkoxy group containing 1 to 3 carbon atoms; said alkylene group being optionally substituted by (a) one or more alkyl groups containing 1 to 3 carbon atoms and optionally substituted by hydroxy, (b) by one or more hydroxy groups or an ester thereof, (c) by one or more alkoxy groups, (d) by oxo or a derivative thereof (eg an oxime or oxime ether), (e) by dimethylcarbamoyl or (f) by one or more groups of formula S(O) p
  • R 7 represents H or a group of formula II above or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkylsulphinyl groups containing 1 to 3 carbon atoms, alkylsulphonyl groups containing 1 to 3 carbon atoms, alkoxycarbonyl groups containing a total of 2 or 3 carbon atoms, trifluoromethyl or cyano.
  • R 1 and R 2 which may be the same or different, are selected from (a) alkyl groups of 1 to 3 carbon atoms optionally substituted by methoxy (b) allyl groups or (c) cyclohexyl groups.
  • R 1 and R 2 are both alkyl, allyl or 2-methoxyethyl or R 1 is methyl and R 8 is 2-methoxyethyl or cyclohexyl.
  • the group NR 1 R 2 is dimethylamino, diethylamino, diallylamino, (2-methoxyethyl)methylamino, cyclohexylmethylamino or bis (2-methoxyethyl)amino.
  • the group NR 1 R 2 is 1-pyrrolidinyl, 2- methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl or 1-(1,2,5,6-tetrahydro)pyridyl.
  • the group ⁇ R 1 R 2 is morpholino or thiamorpholino.
  • the group R 3 preferably contains 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl,t-butyl or pentyl).
  • the group R 3 is a cycloalkyl group
  • the cycloalkyl group is preferably cyclohexyl.
  • R 4 and R 4 ' are K, methyl or ethyl and at least one of R 4 and R' 4 is other than H
  • R 3 is methylamino, dimethylamino or ethylamino
  • the group R 5 is H or an alkyl group containing 1 to 3 carbon atoms (eg methyl or ethyl) optionally substituted by methoxy (eg R 5 is methoxyethyl) or allyl.
  • R 6 is (a) H, (b) an alkyl group of 1 to 3 carbon atoms (eg ethyl) optionally substituted by methoxy, pyridyl or dimethylamino (eg R 6 is 2-methoxyethyl, 2-pyridylethyl or 2-dimethylaminoethyl) or (c) a phenyl group substituted by hydroxy.
  • R 6 is H or a straight or branched alkyl group containing 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl) optionally substituted by hydroxy (e.g. R 6 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, or 2,3- dihydroxypropyl), by an acylated derivative of hydroxy such as acetyloxy or benzoyloxy (e.g.
  • R 6 is 2- acetyloxyethyl or 2-benzoyloxyethyl) by methoxy (e.g. R 6 is 2-methoxyethyl), by methylthio (eg R 6 is 2-methylthioethyl), by dimethylamino (e.g. R 6 is 2-dimethylaminoethyl), by phenyl (e.g. R 6 is benzyl or 2-phenylethyl) or by cyano (e.g. R 6 is 2-cyanoethyl) or R 6 is a straight or branched alkylene group containing 3 to 6 carbon atoms (e.g. R 6 is allyl or 2-methyl-allyl).
  • R 6 is a cycloalkyl group
  • R 6 contains 5 or 6 carbon atoms (e.g. R 6 is cyclopentyl or cyclohexyl).
  • R 6 is cyclopentyl or cyclohexyl.
  • R 9 and R 10' which may be the same or different, are K or alkyl groups containing 1 to 3 carbon atoms (for example methyl, ethyl or isopropyl) optionally substituted by methoxy (eg R 9 and/or R 10 are methoxyethyl), D is selected from -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -CH 2 CMe 2 - or - O(CH 2 ) 2 - and the group R 6 is preferably H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl.
  • R 9 and R 10' which may be the same or different, are K or alkyl groups containing 1 to 3 carbon atoms (for example methyl, ethyl or isopropyl)
  • E is -CH 2 CH 2 -, -CMe 2 CH 2 -, -CHMeCHMe- , -(CH 2 ) 3 -, CHMeCH 2 - or -(CH 2 ) 4
  • R 11 is H, methyl or ethyl and R 6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methyIpropyl, 2-hydroxy- butyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl.
  • formula V represents:-
  • G represents a group selected from
  • the group NR5R 6 is 1-pyrrolidinyl, 2,6- dimethylmorpholmo, 3-hydroxy-1-pyrrolidinyl, piperidino, 1,2,5,6-tetrahydropyridyl, 4-methylpiperidino, 3-hydroxypiperidmo, 4-hydroxypiperidino, 4-hydroxy-4-methylpiperidino, 3-methoxypiperidino, 4 -methoxypiperidino, 3-hydroxymethylpiper1dino, 4-hydroxymethylpiperidino, 4-dimethylcarbamoyl- piperidino, 4-piperidinon-1-yl, 4-piperidinon-1-yl oxime, 4-piperidinon-1-yl oxime-O-methyl ether, morpholino, 2-methylmorpholino, 3,3-dimethylmorpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorph
  • R 7 represents H or one or more substituents (preferably one or two substituents) selected from fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, methoxycarbonyl, methylthio, methylsulphinyl, methylsulphonyl, trifluoromethyl or cyano.
  • N-(2-morpholiniphenyl)thiamorpholine-1-carboxamidine 1,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine
  • 1,1-dimethyl-2-(4-methoxy-2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-isobutyl-2-morpholinophenyl)- guanidine
  • X is phenyl or substituted phenyl
  • X is phenyl, 2-fluoropheny 1, 3-fluoropheny 1, 4-fluorophenyl, 4 -chloropheny 1, 4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, 3-methylthiophenyl, 3-methanesulphonyl- phenyl, 4-methanesulphonylphenyl or 4-acetylphenyl.
  • Specific compounds of formula I wherein X is phenyl or substituted phenyl are:-
  • R 5 is an aliphatic groupu containing 1 to 4 carbon atoms (eg methyl, ethyl or allyl)
  • R 6 is an aliphatic group of 1 to 4 carbon atoms optionally substituted by methoxy or methylthio (eg methyl, ethyl, allyl, methoxyethyl or methylthioethyl) or R 5 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI (e.g. morpholino or thiamorpholino) and R 7 is H, chloro, methyl, ethyl, methylthiomethyl or methylthio.
  • formula VI e.g. morpholino or thiamorpholino
  • Specific compounds falling within this further group of preferred compounds include:-
  • the compounds are used in the treatment of humans.
  • the preparation and use of many compounds of formula I, and salts thereof, in the treatment of diabetes is described in European Patent Publication No. 0385038 and in European Patent Publication No. 0536151 (WO92/00273) (all in the name of The Boots Company PLC).
  • the present invention further provides the use of a compound of formula I as defined above in the manufacture of a medicament for the treatment and/or prevention of cerebral and/or cardiac ischaemia.
  • the present invention further provides the use of a compound of formula I as defined above in the manufacture of a medicament for the treatment and/or prevention of sickle cell anaemia.
  • the present invention further provides the use of a compound of formula I as defined above in the manufacture of a medicament for use as an anticonvulsant.
  • the present invention further provides the use of a compound of formula I in the manufacture of a medicament for use as a neuroprotective agent.
  • compositions for the treatment and/or prevention of cerebral and/or cardiac ischaemia comprising a therapeutically effective amount of a compound of formula I as defined above in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the present invention further provides a pharmaceutical composition for the treatment and/or prevention of sickle cell anaemia comprising a therapeutically effective amount of a compound of formula I as defined above in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the present invention further provides a pharmaceutical composition for use as an anticonvulsant comprising a therapeutically effective amount of a compound of formula I as defined above in conjunction with a pharmaceutically acceptable diluent or carrier.
  • the compounds of the present invention are potassium ion channel "blockers”, more specifically charybdotoxin-sensitive-potassium-channel “blockers”, and ATP-dependent-potassium-channel "blockers”.
  • cardiac ischaemia also known as “ischaemic heart disease” as used herein denotes a clinical condition wherein there is an inadequate supply of blood to the heart (so that oxygen demand from the heart exceeds supply).
  • the term includes conditions such as angina pectoris, myocardial infarction, arrhythmias and many forms of heart failure.
  • Cerebral ischaemia denotes a clinical condition wherein there is an inadequate supply of blood to the central nervous system, especially the brain.
  • the term includes conditions such as stroke, brain trauma, head injuries and haemorrhage.
  • convulsion denotes a clinical condition giving rise to seizures and/or convulsions. It includes neurological disorders such as epilepsy.
  • Compounds of formula I may exist as salts with pharmaceutically acceptable acids.
  • Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [eg (+)-tartrates,
  • compounds of formula I may contain a chiral centre.
  • a compound of formula I may contain a single chiral centre it may exist in two enantiomeric forms.
  • the present invention includes the use of the individual enantiomers and mixtures of the enantiomers.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • a compound of formula I When a compound of formula I contains more than one chiral centre it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above.
  • the present invention included each diastereoisomer of compounds of formula I and mixtures thereof.
  • Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • the compound of formula I may be administered in any of the known pharmaceutical dosage forms.
  • the amount of the compound to be administered will depend on a number of factors including the age of the patient, the severity of the condition and the past medical history of the patient and always lies within the sound discretion of the administering physician but it is generally envisaged that the dosage of the compound to be administered will be in the range 150 to 1500 mg preferably 250 to 500 mg per day given in one or more doses.
  • Oral dosage forms are the preferred compositions for use in the present invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oil suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
  • Tablets may be prepared from a mixture of the active compound with fillers, for example calcium phosphate; disintegrating agents, for example maize starch; lubricating agents, for example magnesium stearate; binders, for example microcrystalline cellulose or polyvinylpyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example nydroxypropylmethylcellulose phthalate
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the contents of the capsule may be formulated using known methods so as to give sustained release of the active compound.
  • the tablets and capsules may conveniently each contain 1 to 500 mg of the active compound.
  • Other dosage forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxy-methylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
  • the active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example, water) before ingestion.
  • the granules may contain disintegrants, eg an effervescent couple formed from an acid and a carbonate or bicarbonate salt to facilitate dispersion in the liquid medium.
  • the therapeutically active compounds of formula I may be formulated into a composition which the patient retains in his mouth so that the active compound is administered through the mucosa of the mouth.
  • Dosage forms suitable for rectal administration are the known pharmaceutical forms for such administration, for example, suppositories with cocoa butter or polyethylene glycol bases.
  • Dosage forms suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
  • Dosage forms for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally.
  • a suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as a mineral oil, petrolatum and/or a wax, e.g. paraffin wax or beeswax, together with a potential transdermal accelerant such as dimethyl sulphoxide or propylene glycol.
  • the active compounds may be dispersed in a pharmaceutically acceptable cream, gel or ointment base.
  • the amount of active compound contained in a topical formulation should be such that a therapeutically effective amount of the compound is delivered during the period of time for which the topical formulation is intended to be on the skin.
  • the therapeutically active compound of formula I may be formulated into a composition which is dispersed as an aerosol into the patients oral or nasal cavity. Such aerosols may be administered from a pump pack or from a pressurised pack containing a volatile propellant.
  • the therapeutically active compounds of formula I used in the method of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be (a) liquid such as an oily suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or a lipophilic ester or (b) solid in the form of an implanted support, for example of a synthetic resin or waxy material, for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the amount of active compound present in an internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.
  • the compounds of the present invention may be beneficial to use in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • Hearts from male Olac Wistar strain rats (250-300g) were perfused via the aorta with Krebs Henseleit Bicarbonate buffer (using a procedure adapted from Neely & Rovetto, "Techniques for perfusing isolated rat hearts", Methods in Enzymology 1975, 38:43-60). Left ventricular pressure and heart rate were continuously monitored. Following a 15-20 minute stabilisation period, hearts were perfused for a further 10 minute period either with test compound or buffer. The heart was then made globally lschaemic by abolishing the flow of perfusate for 45 minutes. The heart was then reperfused for 30 minutes.
  • the haemodynamic function of the heart was monitored by measuring heart rate (HR) and left ventricular developed pressure (LVDP) (based on Grover et al in The Journal of Pharmacology and Experimental Therapeutics, 1989; 98-104) The following two parameters were used to assess the antnschaemic activity of compounds.
  • HR heart rate
  • LVDP left ventricular developed pressure
  • the % recovery of haemodynamic function was assessed by calculating the 'double product' (DP) (HR x LVDP) measured prior to the onset of ischaemia and at the end of the 30 minute reperfusion period. This was subject to statistical analysis using the Mann-Whitney test.
  • the number of hearts demonstrating any signs of recovery were determined and expressed as a fraction of tne total group size eg. 2/6, 3/4 Data was analysed using Fisher's exact test A compound was considered to be active in this test if it significantly improved both the % recovery of double product and the number of hearts recovering within the group (p ⁇ 0.05) compared to controls with vehicle only
  • Recovery No denotes the number of hearts recovering (shown over the total number of hearts in the group).
  • DP is defined above.
  • compositions of mixed solvents are given by volume.
  • Novel compounds were characterised by one or more of tne following: elemental analysis, nuclear magnetic resonance and infra-red spectroscopy.
  • Example 1 A solution of 2,6-difluoronitrobenzene (19.5g; preparable as described in J. Med. Chem. (1968) 11, 814) and morpholine (23.5 ml) in dry toluene (100 ml) was stirred and heated on a steam bath (95- 100°C) for 2 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane to give 4-(3-fluoro-2- nitrophenyl)morpholine (20.81 g).
  • N-methyl-N'-(2,6-dimorpholinophenyl)- thiourea 14.43 g
  • a solution of methyl iodide (1.6 ml, 26.2 mmols) and N-methyl-N'-(2,6-dimorpholinophenyl) thiourea (8 g; see 2 (c) above) in dry acetone (100 ml) was boiled under reflux for 2 hours. The resulting solution was evaporated to give a brown gum which was dissolved in ethanol (100 ml).
  • the acidic extracts were combined with the previous aqueous phase and basified to pH 10 with 5M sodium hydroxide solution.
  • the aqueous phase was extracted with dichloromethane (4 ⁇ 100 ml) and the organic extracts were dried over magnesium sulphate and then evaporated.
  • the resulting residue was heated under reflux in a mixture of ethanol (30 ml) and fumaric acid (2.21 g) for 1 hour.
  • the resulting solution was cooled to ambient temperature and was added dropwise over 1 hour to stirred, dry diethyl ether (1.2 1) to give a grey precipitate (very hygroscopic) which was dried in vacuo at 40°C over phosphorus pentoxide.
  • the solid was dissolved in dry ethanol (25 ml).
  • Fumaric acid (0.22 g) was added and the resulting solution was heated under reflux for 1 hour. The resulting solution was cooled to ambient temperature and was added dropwise over one hour to stirred, dry diethyl ether (1.2 1) to give a grey precipitate which was dried in vacuo at 40°C over phosphorus pentoxide. This solid was dissolved in water (100 ml), basified to pH 11 with 5M sodium hydroxide solution and extracted with dichloromethane (4 ⁇ 150 ml). The organic phases were dried over magnesium sulphate and evaporated to give a brown oil which was purified by flash column chromatography on silica gel eluting with industrial methylated spirits/triethylamine (9:1).
  • the ethanol was then distilled off and water (100 ml) and dichloromethane (100 ml) were added to the resulting residue.
  • the resulting mixture was stirred for 15 minutes at ambient temperature and then left for approximately 16 hours.
  • the mixture was then filtered through diatomaceous earth (available under the trade name "Celite") and the residue was washed with dichloromethane (4 ⁇ 100 ml).
  • the dichloromethane phase was separated off and the aqueous phase was washed with dichloromethane (1 ⁇ 100 ml). All dichloromethane phases were combined and extracted into 3M hydrochloric acid (3 ⁇ 100 ml) and the acidic aqueous phases were backwashed with dichloromethane (1 ⁇ 100 ml).
  • the acidic aqueous phase was then basified with 5M aqueous sodium hydroxide solution and the basic mixture was extracted with dichloromethane (3 ⁇ 100 ml). The extracts were dried over magnesium sulphate and then filtered and evaporated to give a light brown oil (17 g). 7.8 g of this oil was refluxed with ethanol (2.5 ml) and fumaric acid (2.8 g) for IV. hours. The resulting mixture was added to diethyl ether (200 ml) and the resultant gummy solid was washed with diethyl ether (4 ⁇ 100 ml) to give a solid which was filtered off and dried in vacuo at
  • Example 4 a) 3-Chloro-2-nitrotoluene (15 g) was heated with piperidine (74.3 g) at approximately 95°C for 96 hours and the resulting mixture was distilled under reduced pressure to dryness. The product was purified by flash chromatography on silica gel eluting with petroleum ether (bp 40-60°C)/ dichloromethane (5:1) to provide N-(3-methyl-2- nitrophenyl) piperidine (18.75 g; m.pt. 45°C). b) N-(3-Methyl-2-nitropnenyl)piperidine (18.66g; see 4
  • N-methyl-N'-(2-methyl-6-piperidinophenyl)thiourea 13.09 g; m.pt. 125-129°.
  • N-Methyl-N'-(2-methyl-6-piperidinophenyl)thiourea 13.06 g; see 4 (c) above
  • methyl iodide 3.4 ml
  • acetone 130 ml
  • the resulting mixture was distilled to dryness and crystallised from petroleum ether (bp 40-60°, 500 ml) to provide 2- methyl - 3 -me t hy l - 1 - ( 2 -me t hy l - 6 - piperidinophenyl)pseudothiourea hydroiodide (18.73 g; m.pt. 165-169°C).
  • the resulting mixture was filtered together through diatomaceous earth (available under the trade name "Celite”).
  • the aqueous phase was separated and the dichloromethane layer was washed with 3M hydrochloric acid (2 ⁇ 100 ml).
  • the acid phase was washed with dichloromethane (100 ml) and then basified with 5M aqueous sodium hydroxide solution.
  • the basic phase was extracted with dichloromethane (3 ⁇ 150 ml) and the combined basic extracts were dried over magnesium sulphate and then distilled to dryness to give an oil.
  • N-methyl-N'-(2-methyl-6-morpholinomethylphenyl)-thiourea (1 g; see 5 (c) above) in methanol (30 ml) and the solution was left for approximately 16 hours at ambient temperature. Further methyl iodide (0.1 ml) was added and the resulting mixture was left for a further 24 hours (approx). The solvent was removed by distillation to give the hydroiodide salt (1.5 g), which was dissolved in ethanol (20 ml). Butylamine (0.73 ml), potassium hydroxide (0.18 g) and lead (II) acetate trihydrate (0.64 g) were added and the resulting mixture was stirred and boiled under reflux for approximately 16 hours.
  • Example 6 a) A mixture of 2-amino-3-methylbiphenyl (7.2 g; preparable as described in WO 92/00273 in the name of The Boots Company PLC), methyl isothiocyanate (4.3 g) and dichloromethane (100 ml) was left at ambient temperature for approximately 6 hours and then boiled under reflux for 2 days. Further methyl isothiocyanate (2.2 g) in dichloromethane
  • Example 7 a A solution of o-toluidine (24.5 ml; available from the Aldrich Chemical Company, UK) and methyl isothiocyanate (24 ml) in dichloromethane (300 ml) was stirred at ambient temperature for 18 hours. The solvent was distilled off and the resulting residue was washed with petroleum ether (bp 60- 80°C; 2 ⁇ 200 ml) and filtered to give a purple solid.
  • N-methyl-N'-(2-tolyl) thiourea 35.38 g; m.pt 157-160°C.
  • b A mixture of N-methyl-N'-(2-tolyl)thiourea (35.38 g; see 7 (a) above), methyl iodide (30.7 g) and dry acetone (450 ml) was stirred at reflux for 4.4 hours. The acetone was distilled off and the resulting residue was washed with petroleum ether
  • the ethanol was distilled off and water (100 ml) and dichloromethane (100 ml) were added. The resulting mixture was stirred for 15 minutes at ambient temperature and filtered through diatomaceous earth (available under the trade name "Celite”). The filter pad was washed with more dichloromethane (3 ⁇ 100 ml). The dichloromethane phase was separated off and extracted with 3M hydrochloric acid (3 ⁇ 100 ml).
  • the filter pad was washed with dichloromethane (3 ⁇ 150 ml).
  • the dichloromethane phase was separated off, dried over magnesium sulphate, filtered and then evaporated to give a yellow oil.
  • the free base was liberated again by basification and dissolved in dichloromethane (200 ml).
  • the resulting mixture was extracted into 3M hydrochloric acid (2 ⁇ 150 ml) and the acidic aqueous phase was backwashed with dichloromethane (1 ⁇ 150 ml).
  • the acidic aqueous phase was then basified to pH 14 with 5M aqueous sodium hydroxide solution and extracted with dichloromethane (2 ⁇ 200 ml).
  • the fumarate salt was prepared by refluxing this oil with fumaric acid (3.1 g) and ethanol (70 ml) for 1 hour and then adding diethyl ether (300 ml) and cooling to 0°C. The resulting solid was filtered off, washed with diethyl ether (30 ml) and dried in vacuo at 60°C to give N-butyl -N, N' ' -dimethyl -N' - [ 6-methyl -2- morpholinophenyl] guanidine monofumarate (7.15 g; m.pt 169-172°C).
  • N-butyl-N'-(2-methyl-6-morpholinophenyl)thiourea N-butyl-N'-(2-methyl-6-morpholinophenyl)thiourea
  • the ethanol was distilled off, water (100 ml) and dichloromethane (100 ml) were added and the resulting mixture was filtered through diatomaceous earth (available under the trade name "Celite") washing the filter pad with more water (100 ml) and dichloromethane (100 ml).
  • the mixture was separated and the dichloromethane solution was extracted with 3M hydrochloric acid (2 ⁇ 100 ml) and the combined acid phase was washed with dichloromethane (150 ml).
  • the acid phase was basified with 5M aqueous sodium hydroxide solution and extracted with dichloromethane (3 ⁇ 150 ml).

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Abstract

L'invention concerne des méthodes de traitement et/ou de prévention de l'ischémie cérébrale et cardiaque, des convulsions et/ou de la drépanocytose, ces méthodes consistant à administrer à un mammifère nécessitant ledit traitement, une dose thérapeutiquement efficace d'un composé de formule (I), ou de son sel, avec un diluant ou un excipient acceptable. Dans la formule (I), X représente H, nitro, cyano, halo, phényle éventuellement substitué, alkyle ou -(CH2)n NR1R2, où R1 et R2 représentent un groupe aliphatique éventuellement substitué, cycloalkyle, ou forment un noyau avec leur atome d'azote; R3 représente alkyle, cycloalkyle, guanidine ou amine (ces deux derniers constituants étant éventuellement substitués en N); R5 représente H ou un groupe aliphatique éventuellement substitué; R6 représente H, ou phényle, cycloalkyle ou un groupe aliphatique (chacun étant éventuellement substitué); ou R3 et R5 forment un noyau; ou R3 et R5 forment un noyau comportant 2 atomes d'azote; ou R5 et R6 forment un noyau; et R7 représente H, un noyau contenant N, ou des substituants éventuels. Certains de ces composés sont nouveaux.
PCT/EP1995/004673 1994-12-08 1995-11-28 Utilisation de composes de phenylamidine et de phenylguanidine substitues dans le traitement de l'ischemie cerebrale et cardiaque, des convulsions et de la drepanocytose WO1996017612A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41763/96A AU4176396A (en) 1994-12-08 1995-11-28 Use of substituted phenylamidine and phenylguanidine compounds for the treatment of cerebral and cardiac ischaemia, convulsion and sickle cell anaemia

Applications Claiming Priority (4)

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GBGB9424728.5A GB9424728D0 (en) 1994-12-08 1994-12-08 Medical treatment
GB9424728.5 1994-12-08
GB9425164.2 1994-12-10
GBGB9425164.2A GB9425164D0 (en) 1994-12-10 1994-12-10 Medical treatment

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5952362A (en) * 1997-06-23 1999-09-14 Syntex (U.S.A) Inc. 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl alkylsulfonamides and ureas and their use
US6133267A (en) * 1996-12-18 2000-10-17 Knoll Aktiengesellschaft Use of 2-(2-morpholinophenyl) guanidine derivatives for the treatment of diabetes complications
US6514990B2 (en) 1996-02-15 2003-02-04 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310410A2 (fr) * 1987-10-02 1989-04-05 Kawate, Tsuneyoshi Contrôle du flux du potassium activé par le calcium de cellules endommagées du corps
EP0385038A1 (fr) * 1989-02-16 1990-09-05 The Boots Company PLC Dérivés ortho-substitués de phénylamidine et phénylguanidine, et agents antidiabétiques ou hypoglycémiques les contenant
WO1992000273A1 (fr) * 1990-05-17 1992-01-09 The Boots Company Plc Derives orthosubstitues d'amidine de diphenyle et de guanidine de diphenyle, et agents antidiabetiques ou hypoglycemiants les contenant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310410A2 (fr) * 1987-10-02 1989-04-05 Kawate, Tsuneyoshi Contrôle du flux du potassium activé par le calcium de cellules endommagées du corps
EP0385038A1 (fr) * 1989-02-16 1990-09-05 The Boots Company PLC Dérivés ortho-substitués de phénylamidine et phénylguanidine, et agents antidiabétiques ou hypoglycémiques les contenant
WO1992000273A1 (fr) * 1990-05-17 1992-01-09 The Boots Company Plc Derives orthosubstitues d'amidine de diphenyle et de guanidine de diphenyle, et agents antidiabetiques ou hypoglycemiants les contenant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JACKMAN, L.M. ET AL: "1H and 13C nuclear magnetic resonnance studies on the tautomerism, geometrical isomerism and conformation of some cyclic amidines, guanidines and related systems", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 97, no. 10, pages 2811 - 2818 *
JEN, T. ET AL: "Amidines and related compounds. 6. Studies on structure-activity relationships of antihypertensives and antisecretory agents related to clonidine", JOURNAL OF MEDICINAL CHEMISTRY, vol. 18, no. 1, pages 90 - 99 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514990B2 (en) 1996-02-15 2003-02-04 Scion Pharmaceuticals, Inc. Pharmaceutically active compounds and methods of use
US6770668B2 (en) 1996-02-15 2004-08-03 N. Laxma Reddy Pharmaceutically active compounds and methods of use
US6133267A (en) * 1996-12-18 2000-10-17 Knoll Aktiengesellschaft Use of 2-(2-morpholinophenyl) guanidine derivatives for the treatment of diabetes complications
US5952362A (en) * 1997-06-23 1999-09-14 Syntex (U.S.A) Inc. 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxyphenyl, and aminophenyl alkylsulfonamides and ureas and their use
US6057349A (en) * 1997-06-23 2000-05-02 F. Hoffman La Roche Ag 2-imidazoline, 2-oxazoline, 2-thiazoline, and 4-imidazole derivatives of methylphenyl, methoxphenyl, and aminophenyl alkylsulfonamides and ureas and their use

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