1,4-DIAZACYCLOHEPTANE COMPOUNDS, PROCESS FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS

Abstract: 1,4-Diazacyclo-heptanes of formula (I) wherein R is selected from hydrogen, C1-10alkyl, C2-8alkenyl, C3-8cycloalkyl, C3-8cycloalkyl C1-6alkyl, phenylC1-6alkyl and phenyl, R<1> at each occurrence is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C1-6alkoxy, halo, hydroxy, C1-6alkanoyl, haloC1-6alkyl, cyano and nitro, m is 4, R<2> at each occurrence is independently selected from hydrogen and C1-6alkyl, and n is 4, together with processes for their manufacture and compositions containing them. Compounds of formula (I) are pharmacologically useful.

Description: 1,4-DIAZACYCLOHEPTANE COMPOUNDS, PROCESS FOR THEIR PREPARAΗON, AND THEIR USE AS MEDICAMENTS Field of The Invention The present invention relates to chemical compounds, in particular 1 ,4-diazacyclo- 5 heptanes, to processes for their preparation and to chemical intermediates useful in such processes. The present invention further relates to 1 ,4-diazacycloheptanes, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment of animals including man, in particular in the treatment of neurological disorders. Background 10 Neurological disorders, to which the present invention relates, include stroke, head trauma, transient cerebral ischaemic attack, and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis and AIDS -related dementia. Emopamil has classically been thought of as a neuroprotective agent whose efficacy is 15 most likely derived from actions at either voltage-sensitive calcium channels (VSCC) or 5- HT 2 receptors. An apparent paradox to this logic is that verapamil, although chemically and pharmacologically very similar to emopamil, is not neuroprotective. While the lack of neuroprotective efficacy by verapamil was initially explained by lack of CNS penetration, recent studies suggest other factors may be involved (Keith et al., Br. J. Pharmacol. 113: 379- 20 384, 1994). [ 3 H]-Emopamil binding defines a unique high affinity site that is not related to VSCC, is found in the brain, but is most prevalent in the liver (Moebius et al., Mol. Pharmacol. 43: 139-148, 1993). Moebius et al. have termed this the "anti-ischaemic" binding site on the basis of high affinity displacement by several chemically disparate neuroprotective agents. In liver, 25 the [ 3 H] -emopamil binding site is localised to the endoplasmic reticulum. Neuroprotective compounds are known, for example emopamil and ifenprodil, that exhibit high affinity for the [ 3 H] -emopamil binding site. However these are not selective inhibitors and exhibit activity either at neuronal VSCC, the polyamine site of the NMDA receptor (N-Methyl-D-aspartate) and/or the sigma-1 binding site. It is thought that compounds 30 that interact with either the VSCC or the NMDA receptor, are responsible for the side effects usually seen with emopamil, such as hypotension, or those seen with ifenprodil, such as behavioural manifestations. Summary of The Invention We have now found a class of compounds that show selective binding at the [ 3 H]- emopamil binding site. The present invention provides compounds of formula I: I wherein: R is selected from hydrogen, C, , 0 alkyl, C 2 8 alkenyl, C, 8 cycloalkyl, C 38 cycloalkylC, 6 alkyl, phenylQ alkyl and phenyl; R' at each occurrence is independently selected from hydrogen, C, alkyl, C 2 6 alkenyl, C, 6 alkoxy, halo, hydroxy, C, 6 alkanoyl, haloC, alkyl, cyano and nitro; m is 4; R 2 at each occurrence is independently selected from hydrogen and C, 6 alkyl; n is 4; or a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate thereof. In particular compounds of the present invention, any phenyl ring in R may be optionally substituted, for example by up to five substituents, particularly by up to three substituents which may be the same or different. Typical substituents include: hydroxy; C, 6 alkoxy, for example methoxy; phenylC, 6 alkoxy, for example benzyloxy; mercapto; C, 6 alkylthio, for example methylthio; amino; C, 6 alkylamino, for example methylamino; di-(C, 6 alkyl)amino, for example dimethylamino; carboxy; carbamoyl; C, 6 alkylcarbamoyl, for example methylcarbamoyl; di-C, 6 alkylcarbamoyl, for example dimethylcarbamoyl; C, 6 alkylsulphonyl, for example methylsulphonyl; arylsulphonyl, for example phenylsulphonyl; C, 6 alkylaminosulphonyl, for example methylaminosulphonyl; di-(C, 6 alkyl)aminosulphonyl, for example dimethylaminosulphonyl; nitro; cyano; cyano-C, alkyl, for example cyanomethyl; hydroxyC, 6 alkyl, for example hydroxymethyl; amino-C, 6 alkyl, for example aminoethyl; C, 6 alkanoylamino, for example acetamido; C|. 6 alkoxycarbonylamino, for example methoxycarbonylamino; C, 6 alkanoyl, for example acetyl; C, alkanoyloxy, for example acetoxy; C,. 6 alkyl, for example methyl, ethyl, isopropyl or tert-butyl; halo, for example fluoro, chloro or bromo; trifluoromethyl and trifluoromethoxy. In particular compounds of the present invention, R is hydrogen, C, , 0 alkyl, C 2 . 8 alkenyl, C 3 gcycloalkyl, C λ . 8 cycloalkylC, 6 alkyl, or phenylC, 6 alkyl. As used herein, C, 10 alkyl is for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or pentyl (n-pentyl or 3- methylbutyl) or 2-ethylheptyl; C 2 8 alkenyl is for example, buten-2-yl or 3-methylbuten-2-yl; C 3 8 cycloalkyl is for example, cyclopropyl, cyclobutyl or cyclopentyl; C 3 8 cycloalkylC, alkyl is for example, cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl; and phenylC, 6 alkyl is for example, benzyl, 2-phenethyl or 3-phenylpropyl. In more particular compounds of the present invention, R is hydrogen, C, 4 alkyl or C 2 alkenyl. Most particularly R is hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, buten-2-yl or 3-methylbuten-2-yl. In particular compounds of the present invention, R 1 is halo, hydroxy, cyano, nitro, C, 6 alkyl, C 2 . 6 alkenyl, C, fi alkoxy, C, 6 alkanoyl, or haloC, 6 alkyl. As used herein, C,. 6 alkyl is for example, methyl, ethyl or propyl; C, alkoxy is for example, methoxy, ethoxy or propoxy; halo is for example, bromo, chloro or fluoro; C, alkanoyl is for example, formyl or acetyl; C 2 alkenyl is for example, vinyl; and haloC, 6 alkyl is for example, trifluoromethyl. In more particular compounds of the present invention, R 1 is C, 6 alkoxy, for example methoxy or ethoxy, or R 1 is halo, for example bromo, chloro or fluoro. In a particular compound of the invention, m is one and R 1 is methoxy. In more particular compounds of the present invention, R 2 is C, 6 alkyl for example methyl or ethyl. In particular compounds of the invention m is zero. In other particular compounds of the invention n is zero. A particular class of compounds of the invention have the formula II: π wherein R is hydrogen or C,. 4 alkyl, m is 1 and R 1 is hydrogen or C,. 6 alkoxy. Particular compounds of the present invention include those of the Examples hereinafter. Compounds of formula I possess a chiral centre at the 4-position of the 3,4-dihydro- 2H-benzopyran-4-yl ring system. Certain compounds of formula I may also have other chiral centres, for example when n is one or two and in any of the substituents R, R 1 and R 2 . certain of the optional substituents may also have chiral centres. It is to be understood that the invention encompasses all such optical isomers and diasteroisomers of compounds of formula I that bind at the [ 3 H]-emopamil binding site. The invention further relates to all tautomeric forms of the compounds of formula I. It is also to be understood that certain compounds of the formula I can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated and unsolvated forms. In compounds of the present invention that possess a chiral centre at the 4-position of the 3,4-dihydro-2H-benzopyran-4-yl ring system, it is preferred that this centre has S- stereochemistry under the Cahn-Prelog-Ingold sequence rules. It is further preferred that any R or S-enantiomer be substantially free of the corresponding S or R-enantiomer. Such substantially-pure enantiomers are suitably 90%, more suitably 95%, and for example 96%, 97%, 98% or 99% free of the other enantiomer. Suitable pharmaceutically-acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine. In v/vo-hydrolysable esters, amides and carbamates hydrolyse in the human body to produce the parent compound. Such esters, and carbamates can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in v/vo-hydrolysable groups include N-carbomethoxy and N-acetyl. In order to use a compound of the formula I, I' or I" or a pharmaceutically-acceptable salt or in v vo-hydrolysable ester, amide or carbamate thereof for the therapeutic or prophylactic treatment of mammals including humans, the compound is formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula I, I' or I" or a pharmaceutically- acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate and a pharmaceutically- acceptable carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use including intravenous, intramuscular or infusion, sterile aqueous or oily solutions or suspensions or sterile emulsions. A preferred route of administration is intravenously in sterile isotonic solution. In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be simultaneously or sequentially co-administered with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove. The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.05 to 75 mg/kg body weight (and preferably of 0.1 to 30 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art. Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. Therefore in a further aspect, the present invention provides a compound of the formula I or II, or a pharmaceutically-acceptable salt, an in v/vo-hydrolysable ester, amide or carbamate thereof, for use in a method of therapeutic treatment of the human or animal body. In yet a further aspect the present invention provides a method of treating a disease condition wherein inhibition of the [ 3 H]-emopamil binding site is beneficial, which method comprises administering to a warm-blooded animal an effective amount of a compound of the formula I or II, or a pharmaceutically-acceptable salt, an in v/vo-hydrolysable ester, amide or carbamate thereof. The present invention also provides the use of a compound of the formula I or II, or a pharmaceutically-acceptable salt, an in v/vo-hydrolysable ester, amide or carbamate thereof in the preparation of a medicament for use in a disease condition. In another aspect the present invention provides a process for preparing a compound of the formula I or II, a pharmaceutically-acceptable salt, an in v/vo-hydrolysable ester, amide or carbamate thereof which process comprises: a) reacting a compound of the formula III with a compound of the formula IV: wherein R, R 1 , R 2 , m and n are as hereinbefore defined and L is a leaving group; or b) deprotecting a compound of the formula V: V wherein R 1 , R 2 , m and n are as hereinbefore defined and Q is a protecting group for R; wherein any functional group is protected, if necessary, and: i) removing any protecting groups; ii) optionally converting a compound of the formula I into another compound of the formula I; iii) optionally forming a pharmaceutically-acceptable salt or an in v/vo-hydrolysable ester, amide or carbamate. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific classes of protecting groups for carboxy include C,., 2 alkyl, C, alkoxyC,. 6 alkyl, C, 6 alkanoyloxyC, 6 alkyl, C, 6 alkoxycarbonyloxyC, alkyl, arylC, 6 alkyl, tri-C, 6 alkylsilyl and C 2 6 alkenyl. Specific classes of protecting groups for hydroxy include C, , 2 alkyl, C 2 6 alkenyl, C, 6 alkanoyl, C, 6 alkoxycarbonyl, C 2 6 alkenyloxycarbonyl, arylC, 6 alkoxycarbonyl, tri-C, 6 alkylsilyl and arylC, alkyl. Specific classes of protecting groups for amino include formyl, arylC, 6 alkyl, C, 6 alkoxycarbonyl, C 26 alkenyloxycarbonyl, arylC, 6 alkoxycarbonyl, tri-C, 6 alkylsilyl, alkylidene and benzylidene groups. Methods appropriate for removal of carboxy, hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and photolytically for groups such as o- nitrobenzy loxycarbony 1. Compounds of the formula I wherein R is hydrogen may be converted to compounds of the formula I wherein R is other than hydrogen. For example such conversion may comprise conventional methods of alkylation with an appropriate alkylating agent or reductive amination. For example an isopropyl group may be prepared by reacting a compound of the formula I wherein R is hydrogen with acetone in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride. A 2-methylpropyl group may be prepared by reacting a compound of the formula I wherein R is hydrogen with isobutyric acid in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride. Thus, in another aspect the present invention provides a process for preparing a compound of the formula I wherein R is not hydrogen, especially where R is C, , 0 alkyl, from a compound of the formula I wherein R is hydrogen by reaction with an alkylating agent, or by reductive amination. Pharmaceutically-acceptable salts of the compound of the formula I may be prepared in any conventional manner for example from the free base and acid. In v/vo-hydrolysable esters, amides and carbamates may be prepared in any conventional manner. The reaction between the compounds of the formulae III and IV is performed in conventional manner. Typically this reaction takes place in organic solvent for example an anhydrous aprotic solvent such as dimethylformamide, dimethylacetamide or tetrahydrofuran. The reaction is generally performed in the presence of a catalyst, such as an iodide salt, for example potassium iodide, and is generally performed at ambient or elevated temperature, for example 0-100 °C, more preferably 40-80 °C. In the compounds of the formula III, L is a conventional leaving group such as halo for example chloro, iodo or bromo; or a tosylate for example p-toluenesulphonyloxy or methanesulphonyloxy. In the compounds of the formula III, the leaving group L may also represent oxo (=O), forming an 4-oxobenzopyran ring system. Such compounds may be reacted with a compound of the formula IV under conventional conditions for reductive amination. Suitable conditions include the presence of a reducing agent such as hydrogen and a hydrogenation catalyst (for example palladium on carbon), or zinc and hydrochloric acid, or sodium cyanoborohydride, or sodium triacetoxyborohydride, or sodium borohydride, iron pentacarbonyl and alcoholic potassium hydroxide, or borane and pyridine or formic acid. The reaction is preferably carried out in the presence of a suitable solvent such as an alcohol, for example methanol or ethanol, and at a temperature in the range of 0-50 °C, preferably at or near room temperature. Compounds of the formula III are either known or may be prepared in conventional manner as known to the organic chemist skilled in the art. One convenient manner is to convert the corresponding 4-hydroxy-3,4-dihydro-2H-benzopyran to the compound of the formula III; for example by treating with thionyl chloride in the presence of pyridine to prepare a compound of the formula III wherein L is chloro. Compounds of the formula V wherein Q is a protecting group convertible to R, may be deprotected in any standard manner. Any suitable N-protecting group may be used and deprotected in conventional manner. Favourably, Q is C,- 6 alkoxycarbonyl and such compounds may be converted to compounds of the formula I wherein R is methyl for example by treating with a reducing agent such as lithium aluminium hydride. Certain compounds of the formula V are also in v/vo-hydrolysable amides or carbamates of the compounds of the formula I. As mentioned hereinabove, the compounds of the present invention possess a chiral centre at the 4-position of the 3,4-dihydro-2H-benzopyran ring system and the present invention encompasses the racemate and individual enantiomers. Enantiomers of the compound of the formula I may be prepared in conventional manner by resolution of a racemic compound. By another process, enantiomers of the compounds of the formula I may be prepared in analogous manner to the racemates commencing with chiral starting-materials. By yet another process, a chemical intermediate, for example of the formula HI, or the corresponding hydroxy compound, or of the formula V, may be resolved and subsequently reacted to form a compound of formula I without destroying chirality. The following Biological Test Methods, Results and Examples serve to illustrate the present invention. Biological Test Methods 3 H-Emopamil binding to guinea pig liver membranes: Binding at the [ 3 H]-emopamil binding site was determined by a modification of the method described by Zech, C, Staudinger R., Mϋhlbacher, J. and Glossmann, H. Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)- 3 H- emopamil. Eur. J. Pharm. 208: 119-130, 1991. Guinea-pig liver membrane preparation: Male guinea pigs were sacrificed by CO asphyxiation with dry ice. The livers were quickly excised and weighed and rinsed in membrane preparation buffer containing 10 mM Hepes, 1 mM Tris base-EDTA, 250 mM sucrose, pH 7.4. The livers were then minced, homogenised in 10 times volume with a motor driven Teflon-glass homogeniser with three strokes on ice. The homogenate was centrifuged at 1000 x g in a SS34 rotor for 5 minutes at 4 °C. The supernatant was filtered through 4 layers of gauze and then centrifuged at 8000 x g for 10 minutes at 4 °C. This resulting supernatant was centrifuged at 40,000 x g for 15 minutes at 4 °C. The resulting pellet was resuspended in assay buffer and centrifuged again at 40,000 x g for 15 minutes at 4 °C. This pellet was resuspended in assay buffer (2.5 fold with respect to original wet weight) and homogenised with one stroke with the Teflon-glass homogeniser. Aliquots of 1 mL were stored at -70 °C. Assay Reaction Mixture: Assay buffer: 10 mM Tris-HCl, 0.1 mM phenylmethylsulfonyl fluoride (PMSF), 0.2% bovine serum albumin (BSA), pH 7.4 at 4 °C. Radioligand: 0.96 nM (-)- 3 H-emopamil (Amersham). Guinea pig liver membranes: 40mg/mL original wet weight. Compounds: 1-300 nM. Total volume: 500 μL. This mixture was incubated for 60 minutes at 37 °C. The incubation was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenimine (PEI) and washed three times with 5 mL of wash buffer containing 10 mM Tris-HCl, 10 mM MgCl 2 , 0.2% BSA, pH 7.4 at 25 °C. Specific binding was defined with 10 μM emopamil. In general compounds of the present invention bound to the [ 3 H]-emopamil binding site with an IC 5() below 300nM in this test. 3 H-D-888 binding to rat brain cortical membranes 3 H-D-888 binding was determined by a modification of Reynolds, I.J., Snowman, A.M. and Synder, S.H. (-)-[ 3 H] Desmethoxyverapamil labels multiple calcium channel modular receptors in brain and skeletal muscle membranes: differentiation by temperature and dihydropyridines. J. Pharmacol. Exp. Ther. 237: no.3, 731-738, 1986. Rat brain cortical membrane preparation Male Sprague-Dawley Rats were sacrificed by decapitation and the brains were quickly excised. The cerebellum and brain stem were removed and discarded; and the rest of the brain was rinsed in 320 mM sucrose. The brain was then homogenised in a 10- fold volume of 320 mM sucrose with a motor driven Teflon-glass homogeniser using 10 strokes on ice. The homogenate was spun at 1000 x g for 10 minutes at 4 °C in a SS-34 rotor. The supernatant was then spun at 29,000 x g for 20 minutes. The resulting pellet was resuspended in membrane buffer (5 mM Hepes, 0.2% BSA, pH 7.4) to a final concentration of 60 mg original wet weight/mL. Assay Reaction Mixture: Assay buffer: 50 mM Hepes, 0.2% BSA, pH 7.4 Radioligand: lηM 3 H-D888 (Amersham) Rat cortical membranes: 6 mg/mL original wet weight Compounds: 0.3-100 μM Total volume: 1000 μL This mixture was incubated for 60 minutes at 25 °C. The assay was terminated by filtering with a Brandel Cell Harvester over Whatman GF/C filters that had been soaked for at least 120 minutes in 0.3% polyethylenamine (PEI) and washed three times with 5 mL of wash buffer containing 20 mM Hepes, 20 mM MgCl , pH 7.4. Specific binding was measured with 10 μM methoxy verapamil (D-600). This assay was used to determine in vitro selectivity of compounds vs. L-type voltage sensitive calcium channels, i.e. high affinity for the Η-D888 binding site would show a lack of selectivity. Gerbil Global Model of Cerebral Ischaemia Male Mongolian gerbils (Charles River) weighing 60-70 grams are used in these experiments. They are housed in individual cages with food (Purina Rodent Chow) and water available ad libitum. The animal room is maintained at 23 ± 2 °C, and is on an automatic 12 hour light cycle. The gerbils are brought to the surgical suite and dosed intraperitoneally with the test agent or vehicle, forty five minutes prior to surgery. Drugs are administered at a volume of 5 mL/kg (intraperitoneal). Vehicle is generally saline, with sodium phosphate added to adjust the pH, if needed. Forty-five minutes after dosing the gerbils are anaesthetised with halothane (3.3%) which is delivered along with oxygen (1.5 1/M) through a face mask. After the gerbils are anaesthetised, halothane is continued at a maintenance level of 1.5-2 % along with oxygen. The ventral surface of the neck is shaved and cleaned with alcohol. Surgical procedures are carried out on a thermostat-controlled heating pad set to 37 °C. An incision is made in the neck, the carotid arteries are dissected away from the surrounding tissue, and isolated with a 5 cm length of Silastic tubing. When both arteries have been isolated they are clamped with microaneurysm clips (Roboz Instruments). The arteries are visually inspected to determine that the blood flow has been stopped. After 5 minutes the clips are gently removed from the arteries and blood flow begins again. A sham control group is treated identically but is not subjected to carotid artery occlusion. The incisions are closed with suture and the gerbils removed from the anaesthesia masks and placed on another heating pad to recover from the anaesthesia. When they have regained the righting reflex and are beginning to walk around, 5 they are again dosed with the test compound and returned to their home cages. This occurs approximately five minutes after the end of surgery. Twenty-four hours post ischaemia gerbils are tested for spontaneous locomotor activity, using a Photobeam Activity System from San Diego Instruments. They are individually placed in Plexiglas chambers measuring 27.5 cm x 27.5 cm x 15 cm deep. The 10 chambers are surrounded by photocells, and every time a beam is broken one count is recorded. Each gerbil is tested for two hours, and cumulative counts are recorded at 30, 60, 90, and 120 minutes. Mean counts are recorded for each group and drug groups are compared to control with an ANOVA and Bonferroni post test. After each gerbil is tested it is returned to its home cage. At this time gerbils are also observed for any changes from normal 15 behaviour. For the next two days no specific testing is performed, but the gerbils are observed two to three times per day for any unusual behaviours or obvious neurological symptoms (i.e. ataxia, convulsions, stereotypic behaviour). Four days post ischaemia the gerbils are sacrificed by decapitation and their brains removed and preserved in 10% buffered formalin. Brains 0 were removed, fixed and stained with hematoxylin and eosin. Under a light microscope, hippocampal fields were observed and graded for damage to the CA1 subfield: 0 to 4 scale, with 0 representing no damage and 4 representing extensive damage. Transient focal ischaemia in rats The method was performed substantially as described by Lin, T-N., He, Y.Y., Wu, G., 25 Khan, M. And Hsu, C. Y. Effect of brain edema on infarct volume in a focal model cerebral ischaemia model in rats. Stroke 24: 117-121, 1993. This model is generally considered to be relevant to the clinical situation. Male Long-Evans rats 250-350 g were used. Surgery to establish a focal ischaemia was conducted under anaesthesia induced with 100 mg/kg ketamine and 5 mg/kg i.m. xylazine. Rectal temperature was monitored and maintained at 30 37.0+0.5 °C. The right middle cerebral artery (MCA) was exposed using microsurgical techniques. The MCA trunk was ligated immediately above the rhinal fissure with 10-0 suture. Complete interruption of blood flow was confirmed under an operating microscope. Both common carotid arteries were then occluded using non traumatic aneurysm clips. After a predetermined duration of ischaemia (45 min), blood flow was restored in all three arteries. Twenty-four hours post occlusion, rats were killed under ketamine anesthesia by intracardiac perfusion with 200 mL of 0.9% NaCl. The brain was removed and processed with 2% triphenyltetrazolium chloride to identify and quantitate the infarcted brain region. Compounds were administered by intravenous infusion for 4 hours. The examples which follow are intended to illustrate but not limit the invention. In the Examples, unless otherwise stated:- (i) concentrations were carried out by rotary evaporation in vacuo; (ii) operations were carried out at ambient temperature, that is in the range 18-26 °C and under a nitrogen atmosphere; (iii) column chromatography (by the flash procedure) was performed on Merck Kieselgel silica (Art. 9385); (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the formula I were generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were determined in DMSO-d 6 unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz; chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; bs, broad singlet; d, doublet; AB or dd, doublet of doublets; t, triplet, dt, double of triplets, m, multiplet; bm, broad multiplet; fast-atom bombardment (FAB) mass spectral data were obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected, in this application, (M+H) + is quoted; (vi) intermediates were not generally fully characterised and purity was in general assessed mass spectral (MS) or NMR analysis; and (vii) in which the following abbreviations (also used hereinabove) may be used: DMF is N,N-dimethylformamide; DMSO is dimethylsulphoxide; CDC1 3 is deuterated chloroform; m/s is mass spectroscopy; THF is tetrahydrofuran; DCM is dichloromethane, and NMP is N-methylpyrrolidone. Examples: Example 1: 1 -Methyl-4-(3 ,4-dihydro-2H-benzopyran-4-yl)homopiperazine Preparation of 4-chloro-3,4-dihydro-2H-benzopyran was as follows. A 100 mL 3- necked flask equipped with a condenser protected with anhydrous calcium sulphate (8 mesh), an addition funnel and magnetic stirring bar was charged with 4-hydroxy-3,4-dihydro-2H- benzopyran (2.1 g, 13.78 mmol) in dry diethyl ether (40 mL). Pyridine (0.3 mL) was added. A solution of thionyl chloride (5.5 mL, 74.4 mmol) in ether (15 mL) was then added dropwise in 10 minutes and stirring continued overnight. The reaction mixture was then poured into ice/water (50 g) and diluted with ether (100 mL). The organic phase was separated, washed with brine and dried with sodium sulphate. Filtration and removal of solvent in vacuo using a rotary evaporator and water bath at 35°C gave a yellow oil (2.98 g), homogeneous by tic (silica gel, 9: 1 hexane: ethyl acetate), Rf 0.56; Η nmr δ 2.23-2.31 (m, IH), 2.41-2.51 (m, IH), 4.28-4.34 (m, IH), 4.41-4.49 (m, IH), 5.21-5.23 (IH), 6.80-6.83 (d, IH), 6.87-6.92 (t, IH), 7.16-7.21 (t, IH), 7.25-7.29 (d, IH). This material was used without further purification. A 50 mL 3-necked flask equipped with a condenser and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of N-methylhomopiperazine (2.8 mL, 22 mmol) in DMAC (10 mL). Potassium iodide (0.4 g) was added followed by the addition of the solution of 4-chloro-3,4-dihydro-2H-benzopyran (1.76 g, 10.47 mmol) in DMAC (10 mL) by pipette within one minute. This solution was then heated at 65 °C for 20 hours, cooled, poured into water (100 mL), and extracted several times with ethyl acetate which was washed with brine and dried with sodium sulphate. Filtration and evaporation of solvent gave a brown oil ( 1.90 g) which was distilled using a kugelrohr to give the title compound as an oil (1.01 g), bp (air bath temperature) 105-115 °C at 25 mtorr; homogeneous by tic (silica gel, 89:10: 1 CH 2 Cl 2 :CH 3 OH:NH 4 OH), R f 0.57; Η nmr δ 3.98-4.12 (m, 2H), 4.33-4.38 (m, IH), 6.74-6.77 (d, IH), 6.86-6.91 (t, IH), 7.07-7.12 (t, IH), 7.59-7.61 (d, IH). A solution of the above base in ethanolic HC1 was treated with ether to the cloud point and left at ambient temperature. The resulting white solid was collected by filtration and dried in a drying pistol at 45 °C and 150 mtorr to yield the dihydrochloride of the title compound; mp 206-208 °C. Anal; Calcd. for Cι 5 H 22 N 2 O-2HC1 0.25H 2 O: C, 55.64; H, 7.63; N, 8.65. Found: C, 55.48; H, 7.56; N, 8.44. Example 2: N-(3.4-Dihvdro-2H-benzopyran-4-yl)homopiperazine A 100 mL 3-necked flask equipped with a condenser and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of homopiperazine (6.74 g, 66.9 mmol) in DMAC (30 mL). Potassium iodide (500 mg) was added followed by the addition by pipette of a solution of l-chloro-3,4-dihydro-2H-benzopyran (2.25 g, 13.38 mmol) in DMAC (20 mL). This solution was then heated in an oil bath at 65 °C over the weekend. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried with sodium sulphate. Filtration and evaporation of solvent gave a brown oil (2.5 g). Kugelrohr distillation gave the title compound as a yellow oil (2.14 g), bp (air bath temperature) 100-110 °C at 30 mtorr; tic analysis on silica gel (CH 2 Cl 2 :CH 3 OH:NH 4 OH, 89: 10: 1) showed a single component, R f 0.40; Η nmr δ 1.65-1.78 (m, 2H), 1.99-2.06 (m, 2H), 2.61-2.98 (m, 8H), 4.01- 4.12 (m, 2H), 4.31-4.38 (m, IH), 6.75-6.78 (d, IH), 6.86-6.91(t, IH), 7.08-7.13 (t, IH), 7.60- 7.62 (d, IH). Anal. Calcd. for Cι 4 H 20 N 2 O 0.15H 2 O: C, 71.54; H, 8.70; N, 11.91. Found: C, 71.44; H, 8.63; N, 1 1.69. Example 3: S (+) N-(3 -4-Dihvdro-2H-benzopyran-4-yl)homopiperazine S(+) N-(3,4-Dihydro-2H-benzopyran-4-yl)homopiperazine was obtained as the first material to elute on subjecting racemic material, prepared as in Example 2, to preparative Chiral Pak AD HPLC resolution using a 90: 10: 1 hexane:ethanol:diethylamine solvent system. The enantiomeric purity was determined on an analytical scale using hexane:ethanol: diethylamine (90: 5:.05, v/v) and detection at 230 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (0.768 g), [α] 22 +59° (c = 0.71, methanol); >98% ee. Example 4: S(+) l-Methyl-4-(3,4-dihvdro-2H-benzopyran-4yl)homopiperazine Preparation of S(+) N-carbethoxy-N'-(3,4-dihydro-2H-benzopyran-4- yl)homopiperazine was as follows. A dry 250 mL 3-necked flask equipped with a condenser, addition funnel and magnetic stirring bar under a nitrogen atmosphere was charged with S(+) 5 N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (3.15 g, 13.58 mmol) and methylene chloride (30 mL). Triethylamine (2.5 mL, 17.9 mmol), was added and the flask was cooled in a Dry Ice/acetone bath. Ethyl chloroformate, 1.6 mL (16.7 mmol) in methylene chloride (10 mL) was added dropwise and the mixture was allowed to warm to ambient temperature slowly. After stirring overnight, the content of the flask was partitioned between water and 10 methylene chloride, the organic phase was washed with brine and the solution was dried with magnesium sulphate. Filtration and removal of solvent gave an amber oil (3.8 g), essentially homogeneous by tic (silica gel, ethyl acetate), R f 0.66. This material was used without further purification. A dry 100 mL 3-necked flask equipped with a condenser, addition funnel and 15 magnetic stirring bar was charged with lithium aluminum hydride (1.05 g, 27.67 mmol) and dry THF (30 mL) under a nitrogen atmosphere. S(+) N-Carbethoxy-N'-(3,4-dihydro-2H- benzopyran-4-yl)homopiperazine (3.8 g, 12.5 mmol) in THF (20 mL) was added dropwise and the solution was heated to reflux for 2.5 hours and cooled to ambient temperature. Saturated sodium sulphate (25 mL) was added dropwise at a rate amenable to maintaining control of the 20 reaction and the content of the flask was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was partitioned between water and ether which was dried with magnesium sulphate. Filtration and removal of solvent in vacuo gave an oil (2.86 g) which was kugelrohr distilled to give the title compound (2.53 g), bp (air bath temperature) 120-130 °C at 50 mtorr., essentially homogeneous by tic (silica gel, CH 3 OH:CH 2 Cl 2 :NH 4 OH 22 25 10:89:1), R f 0.42; [α] D +57.2° (c = 1.03, methanol). To a stirred solution of the above base (2.52 g) in ethanol (10 mL) was added by pipette a dispersion of maleic acid (2.98 g) in ether (60 mL). Upon completion of the addition, a white precipitate formed. This solid was collected by filtration and was dried overnight in a drying pistol (50 °C at 125 mtorr) to yield the dimaleate salt of the title 30 compound (4.72 g), mp 90.5-91 °C; Η-nmr (300 MHz, CD 3 OD) δ4.01-4.18 (m, 2H), 4.29- 4.35 (m, IH), 6.28 (s, 4H, CH=CH maleic acid), 6.72-6.75 (d, 1Η), 6.86-6.92 (t, 1Η), 7.07- 7.12 (t, IH), 7.57-7.60 (d, IH): Anal: Calcd. for C, 5 H 22 N 2 O-2C 4 H 4 O 4 : C, 57.72; H, 6.32; N, 5.85. Found: C, 57.68; H, 6.61; N, 5.74. Example 5: R(-) N-(3 ,4-Dihvdro-2H-benzopyran-4-yl)homopiperazine R(-) N-(3,4-Dihydro-2H-benzopyran-4-yl)homopiperazine was obtained as the second material to elute on subjecting racemic material, prepared as in Example 2, to preparative Chiral Pak AD HPLC resolution using a 90:10:1 hexane:ethanol:diethylamine solvent system. The enantiomeric purity was determined on an analytical scale using hexane:ethanol: diethylamine (90:5:.05, v/v) and detection at 230 nm. The solution containing this enantiomer was concentrated using a rotary evaporator to give the title compound (0.74 g), [ ] 22 -57° (c = 0.625, methanol); >98% ee. Example 6: R(-) 1 -Methyl-4-(3,4-dihydro-2H-benzopyran-4yl)homopiperazine Preparation of R(-) N-Carbethoxy-N'-(3,4-dihydro-2H-benzopyran-4- yl)homopiperazine was as follows. A dry 250 mL 3-necked flask equipped with a condenser, addition funnel and magnetic stirring bar under a nitrogen atmosphere was charged with R(-) N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (3.15 g, 13.58 mmol) and methylene chloride (30 mL). Triethylamine (2.5 mL, 17.9 mmol) was added and the flask was cooled in a Dry Ice/acetone bath. Ethyl chloroformate (1.6 mL, 16.7 mmol) in methylene chloride (15 mL) was added dropwise over 10 minutes and the mixture was allowed to warm to room temperature and was stirred overnight. The content of the flask was partitioned between water and methylene chloride, the organic phase was washed with saturated sodium bicarbonate, brine and the solution was dried with magnesium sulphate. Filtration and removal of solvent gave an amber oil (3.3 g), essentially homogeneous by tic (silica gel, ethyl acetate), R f 0.70. This material was used without further purification. A dry 100 mL 3-necked flask equipped with a condenser, addition funnel and magnetic stirring bar was charged with lithium aluminum hydride (1.05 g, 27.67 mmol) and dry THF (20 mL) under a nitrogen atmosphere. R(-) N-Carbethoxy-N'-(3,4-dihydro-2H- benzopyran-4-yl)homopiperazine (3.3 g, 10.86 mmol), in THF (20 mL) was added dropwise and the solution was heated to reflux for 2 hours and cooled to ambient temperature. Tic analysis (silica gel, CH 3 OH:CH 2 Cl 2 :NH 4 OH 10:89: 1) of an aliquot partitioned between water and ethyl acetate showed a major component with Rf 0.47 and the absence of the starting carbamate. Saturated sodium sulphate (25 mL) was then added dropwise at a rate amenable to maintaining control of the reaction and the content of the flask was filtered through diatomaceous earth and the solvent was removed in vacuo. The residue was partitioned between water and ether which was dried with magnesium sulphate. Filtration and removal of solvent in vacuo gave an oil (2.7g) which was kugelrohr distilled to give the title compound (2.29 g) bp (air bath temperature) 115-125 °C at 100 mtorr.; 1H nmr δ 2.37 (s, 3H), 4.08-4.11 (m, 2H), 4.32-4.39 (m, IH), 6.75-6.78 (d, IH), 6.86-6.92 (t, IH), 7.08-7.13 (t, IH), 7.60-7.62 (d, IH); [«] 22 - 50 - 8 ° ( c = °- 61 ' methanol). To a stirred solution of the above base (2.28 g, 9.26 mmol) in ethanol (10 mL), was added a dispersion of maleic acid (2.98 g) in ether (60 mL) by pipette followed by ether (10 mL). Upon completion of the addition, a white precipitate formed. This solid was collected by filtration and was dried overnight in a drying pistol (50 °C at 125 mtorr) to yield the dimaleate salt of the title compound (4.28 g), mp 96.5-97 °C; Η-nmr (300 MHz, CD 3 OD) δ 1.95-2.08 (m,4H), 2.86-2.94 (m, 7H), 3.30-3.31 (m, 2H), 3.45-3.35 (m, 2H), 4.06-4.09 (m, 2H), 4.29-4.34 (m, 1H),6.28 (s, 4H, CH=CH , maleic acid), 6.72-6.75 (d, IH), 6.87-6.92 (t, IH), 7.07-7.11 (t, IH), 7.56-7.59 (d, IH): Anal: Calcd. for Cι 5 H 22 N 2 O-2C 4 H 4 O 4 : C, 57.72; H, 6.32; N, 5.85. Found: C, 57.26; H, 6.49; N, 5.61. Example 7: S(+) N-Isopropyl-N'-(3,4-dihvdro-2H-benzopyran-4-yl)homopiperazine A 50 mL 3-necked flask under nitrogen atmosphere was charged sequentially with S(+) N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (0.25 g; 1.08 mmol) in THF (7 mL), methanol (3.5 mL) and acetone (1.1 mL, 15 mmol). To this stirred solution, sodium cyanoborohydride (0.10 g, 1.62 mmol) was added as a solid followed by acetic acid (0.08 mL; 1.4 mmol). After stirring at ambient temperature for one hour, tic analysis (silica gel, 9: 1 CHC1 3 :CH 3 0H) of an aliquot revealed the absence of starting amine (Rf 0.05) and presence of a single component with Rf 0.27. The content of the flask was then concentrated in vacuo. The residue was treated with aqueous sodium bicarbonate and extracted several times with ethyl acetate which was then dried with sodium sulphate. Filtration and removal of solvent in vacuo gave an oil (0.32 g) which was kugelrohr distilled to yield the title compound (0.26 g), bp (air bath temperature) 142-146 °C at 140 mtorr; tic (ibid), R f 0.27; Η nmr δl.02-1.05 (6H), 4.01-4.10 (m, 2H), 4.32-4.38 (m, IH), 6.74-6.77 (d, IH), 6.83-6.91 (t, IH), 7.04-7.13 22 (t,lH), 7.57-7.62 (d, IH). Mp +45° ( c = °- 58 > methanol). Anal: Calcd. for C 17 H 26 N 2 O; C, 74.41; H, 9.55; N, 10.21. Found: C, 74.31; H, 9.58; N, 10.07. Example 8: R(-) N-Isopropyl-N ' -(3 ,4-dihydro-2H-benzopyran-4-yl)homopiperazine A 50 mL 3-necked flask under nitrogen atmosphere was charged sequentially with R(-) N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (0.25 g; 1.08 mmol) in THF (7 mL), methanol (3.5 mL) and acetone (1.1 mL, 15 mmol). To this stirred solution, sodium cyanoborohydride (0.10 gm, 1.6 mmol) was added as a solid followed by acetic acid (0.08 mL, 1.4 mmol). After stirring at ambient temperature for one hour, tic analysis (silica gel, 9: 1 CHCl 3 :CH 3 OH) of an aliquot revealed the absence of starting amine (Rf 0.05) and presence of a single component with Rf 0.21. The content of the flask was then concentrated in vacuo. The residue was treated with aqueous sodium bicarbonate and extracted several times with ethyl acetate which was then dried with sodium sulphate. Filtration and removal of solvent in vacuo gave an oil (0.32 g) which was kugelrohr distilled to yield the title compound (0.27 g), bp (air bath temperature) 141-147 °C at 150 mtorr. ;Η nmr δ 1.01-1.07 (6H), 3.99-4.10 (m, 2H), 4.32-4.38 (m, IH), 6.75-6.77 (d, IH), 6.91-6.95 (t, IH), 7.07-7.18 (t, IH), 7.62-7.65 (d, 22 IH). M -45° (c = 1.09, methanol). Anal- Ca lcd. for C 17 H 26 N 2 O; C, 74.41; H, 9.55; N, 10.21. Found: C, 74.20; H, 9.36; N, 10.10. Example 9: N-Isoamyl-N ' -(3 ,4-dihvdro-2H-benzopyran-4-yl)homopiperazine A 100 mL 3-necked flask under nitrogen atmosphere was charged sequentially with N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (1.43 g; 6.16 mmol) in THF (40 mL), methanol (20 mL) and isovaleraldehyde (9.2 mL, 86 mmol). To this stirred solution, sodium cyanoborohydride (0.58 gm, 9.2 mmol) was added as a solid followed by acetic acid (0.46 mL, 8.01 mmol). A fine suspension formed after one hour. After stirring at ambient temperature for 22 hours, tic analysis (silica gel, ethyl acetate) of an aliquot treated with sodium bicarbonate and ethyl acetate revealed the absence of starting amine (R f , origin ) and presence of a single component with Rf 0.11. The content of the flask was then concentrated in vacuo. The residue was treated with aqueous sodium bicarbonate and extracted several times with ethyl acetate which was then dried (MgSO 4 ). Filtration and removal of solvent in vacuo gave a yellow oil (3.31 g) which was kugelrohr distilled to yield the title compound (1.82 g), bp (air bath temperature) 129-135 °C at 60-70, mtorr.; homogeneous by tic (ibid);Η nmr (300 MHz, CDC1 3 ) δ 0.88-0.90 (d, 6H, C(CH 3 ) 2 ), 3.98-4.15 (m, 2Η, ArCHN, ArOCH), 4.33-4.37 (m, 1Η, ArOCH). Anal: Calcd. for Cι 9 Η 30 N 2 O; C, 75.45; H, 10.00; N, 9.26. Found: C, 75.23; H, 10.02; N, 9.15 A portion (0.63 g) in 12 mL of ethanol was treated with 24 mL of a saturated solution of maleic acid in ether, followed by dilution with an additional 5 mL of ether. After 20 hours at ambient temperature, the resulting white solid was collected by filtration, washed with ether and dried in vacuo to give 1.03 g, mp 144.7-145.4 °C. Anal: Calcd. for Cι 9 H 30 N 2 O-2C 4 H 4 O 4 : C, 60.66; H, 7.16; N, 5.24. Found: C, 60.61; H, 7.17; N, 5.32. Example 10: N-n-Propyl-N ' -(3 ,4-dihvdro-2H-benzopyran-4-yl)homopiperazine A 100 mL 3-necked flask under nitrogen atmosphere was charged sequentially with N-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine (1.43 g; 6.16 mmol) in THF (40 mL), methanol (20 mL) and propionaldehyde (6.2 mL, 86 mmol). To this stirred solution, sodium cyanoborohydride (0.58 gm, 9.2 mmol) was added as a solid followed by acetic acid (0.46 mL, 8.01 mmol). A fine suspension formed after three hours. After stirring at ambient temperature for 22 hours, tic analysis (silica gel, ethyl acetate) of an aliquot treated with sodium bicarbonate and ethyl acetate revealed the absence of starting amine (R f , origin ) and presence of a major component with R f 0.08. The content of the flask was then concentrated in vacuo. The residue was treated with aqueous sodium bicarbonate and extracted several times with ethyl acetate which was then dried (MgSO 4 ). Filtration and removal of solvent in vacuo gave a yellow oil (3.79 g) which was kugelrohr distilled to yield the title compound (1.02 g), bp (air bath temperature) 124-132 °C at 60-70, mtorr.; 1H nmr (300 MHz, CDC13) δ 0.88-0.90 (t, 3H, CH 3 ), 3.99-4.15 (m, 2Η), 4.32-4.38 (m, IH). A portion (0.66 g) in 13 mL of ethanol was treated with 26 mL of a saturated solution of maleic acid in ether, followed by dilution with an additional 5 mL of ether. After 20 hours at ambient temperature, the resulting white solid was collected by filtration, washed with ether and dried in vacuo to give 0.88 g, mp 105.5-106.2 °C. Anal: Calcd. for Cι 9 H 30 N 2 O-2C 4 H 4 O 4 : 5 C, 59.28; H, 6.77; N, 5.53. Found: C, 58.96; H, 6.77; N, 5.52. Example 11: N-(3-Methyl-2-butenyl)-N'-(3,4-dihvdro-2H-benzopyran-4-yl)homopiperazine A 25 mL 3-necked flask under nitrogen atmosphere was charged with N-(3,4-dihydro- 10 2H-benzopyran-4-yl)homopiperazine (1.53 g; 6.59 mmol) in DMF (13 mL) and potassium carbonate (2.19g, 15.8 mmol) and the stirred mixture was treated with 0.78 mL (6.78 mmol) of prenyl bromide. After heating at 58 °C for four hours, the mixture was stirred overnight at ambient temperature and concentrated in vacuo to remove most ot the DMF. The residue was treated with water and extracted several times with ethyl acetate which was then dried 15 (MgSO 4 ). Filtration and concentration in vacuo left 1.63 g of a tan oil which was kugelrohr distilled to give the title compound (1.21 g), bp (air bath temperature) 128-137 °C at 70-80 mtorr; tic analysis (silica gel, ethyl acetate) indicated a single component with R f 0.13; Η nmr (300 MHz, CDC13) δ 1.68 (s, 3H), 1.74 (s, 3H), 3.98-4.12 (m, 2H), 4.32-4.37 (m, IH), 5.24- 5.28 (t, IH, =CH). 20 A portion (0.72 g) in 14 mL of ethanol was treated with 28 mL of a saturated solution of maleic acid in ether, followed by dilution with an additional 6 mL of ether. After 20 hours at ambient temperature, an off-white solid had formed and additional crystallization was promoted by scratching. This solid was collected by filtration, washed with ether and dried in vacuo to give 1.15 g, mp 135.5-136.3 °C. Anal: Calcd. for Cι 9 H 28 N 2 O-2C 4 H 4 O 4 0.5H 2 O: C, 25 59.88; H, 6.89; N, 5.17. Found: C, 59.90; H, 6.88; N, 5.28. Example 12: N-(Benzyl)-N'-(3,4-dihydro-2H-benzopyran-4-yl)homopiperazine A 25 mL 3-necked flask under nitrogen atmosphere was charged with N-(3,4-dihydro- 30 2H-benzopyran-4-yl)homopiperazine (1.09 g; 4.69 mmol) in DMF (9 mL) and potassium carbonate (1.56 g, 11.3 mmol) and the stirred mixture was treated with 0.59 mL (4.94 mmol) of benzyl bromide. After heating at 58 °C for two hours, tic analysis on silica gel (CHCl 3 :CH 3 OH 9:1) indicated the absence of starting amine. The content of the flask was added to water, forming a small amount of white solid which was removed by filtration. The filtrate was extracted several times with ethyl acetate which was then dried (MgSO ). Filtration and concentration in vacuo left 0.32 g of a tan oil which was kugelrohr distilled to give the title compound (0.24 g), bp (air bath temperature) 116-123 °C at 70-80 mtorr; tic analysis (silica gel, ethyl acetate) indicated a single component with R 0.53; 1H nmr (300 MHz, CDC13) δ 3.66 (s, 2H, ArCH 2 N), 4.01-4.13 (m, 2Η), 4.33-4.38 (m, IH), 6.74 (d, IH), 6.86-6.91 (t, IH), 7.07-7.12 (t, IH), 7.22-7.36 (m, 5H), 7.54-7.36 (d, IH). Example 13: Following conventional procedures well known in the pharmaceutical art the following representative pharmaceutical dosage forms containing a compound of formula I can be prepared: (a) Tablet Ingredient mg/tablet Compound of Formula I 50.0 Mannitol, USP 223.75 Croscarmellose sodium 60 Maize starch 15.0 Hydroxypropylmethylcellulose (HPMC), USP 2.25 Magnesium stearate 3.0 (b) Capsule Ingredient mg/capsule Compound of Formula I 10.0 Mannitol, USP 488.5 Croscarmellose sodium 15.0 Magnesium stearate 1.5 (c) Injectable solution For intravenous administration, a 5 mg/mL of a compound of Formula I is dissolved in an isotonic sterile solution .

Claims: Claims: We claim: 1. Any compound of to formula I: I wherein: R is selected from hydrogen, C 0 alkyl, C 2 8 alkenyl, C 3 8 cycloalkyl, C 3 8 cycloalkylC,. 6 alkyl, phenylC ,. 6 alkyl and phenyl; R 1 at each occurrence is independently selected from hydrogen, C, 6 alkyl, C 2 alkenyl, C, 6 alkoxy, halo, hydroxy, C, 6 alkanoyl, haloC, 6 alkyl, cyano and nitro; m is 4; R 2 at each occurrence is independently selected from hydrogen and C, 6 alkyl; n is 4; or a pharmaceutically-acceptable salt or in v/vo-hydrolysable ester, amide or carbamate thereof. 2. A compound according to Claim 1 , wherein R is selected from phenylC, 6 alkyl and phenyl, where any phenyl ring in R is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected at each occurrence from hydroxy; C, 6 alkoxy, phenylC, 6 alkoxy, mercapto, C, 6 alkylthio, amino, C, 6 alkylamino, di-(C, 6 alkyl)amino, carboxy, carbamoyl, C, 6 alkylcarbamoyl, di-C, 6 alkylcarbamoyl, C, 6 alkylsulphonyl, arylsulphonyl, C, 6 alkylaminosulphonyl, di-(C, 6 alkyl)aminosulphonyl, nitro, cyano, cyano-C, 6 alkyl, hydroxyC, 6 alkyl, amino-C, 6 alkyl, C, 6 alkanoylamino, C, 6 alkoxycarbonylamino, C, 6 alkanoyl, C, 6 alkanoyloxy, C, alkyl, halo, trifluoromethyl and trifluoromethoxy. 3. A compound according to Claim 2, wherein R is selected from phenylC ,- 6 alkyl and phenyl, where any phenyl ring in R is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents independently selected at each occurrence from hydroxy, methoxy, benzyloxy, mercapto, methylthio, amino, methylamino, dimethylamino, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methylsulphonyl, phenylsulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, nitro, cyano, cyanomethyl, hydroxy methyl, aminoethyl, acetamido, methoxycarbonylamino, acetyl, acetoxy, methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, bromo trifluoromethyl and trifluoromethoxy. 4. A compound according to Claim 1 , wherein: R is selected from hydrogen, C,.,„alkyl, C 2 . 8 alkenyl, C 3 - 8 cycloalkyl, C 3 . 8 cycloalkylC,- 6 alkyl, and phenylC, . 6 alkyl. 5. A compound according to Claim 4, wherein: R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3- methylbutyl, 2-ethylheptyl, buten-2-yl, 3-methylbuten-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 2-phenethyl and 3-phenylpropyl. 6. A compound according to Claim 5, wherein: R is selected from hydrogen, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, buten-2-yl and 3-methylbuten-2-yl. 7. A compound according to Claim 1, wherein: R 1 is selected from halo, hydroxy, cyano, nitro, C,. 6 alkyl, C 2 - 6 alkenyl, -^alkoxy, C,. 6 alkanoyl, and haloC,- 6 alkyl. 8. A compound according to Claim 7, wherein: R' is selected from hydroxy, cyano, nitro, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, bromo, chloro or fluoro, formyl, acetyl, vinyl and trifluoromethyl. A compound according to Claim 1, having the formula II: π 5 wherein R is hydrogen or C,. 4 alkyl, m is 1 and R is hydrogen or C,. 6 alkoxy. 10. A pharmaceutical composition comprising as an active ingredient an effective amount of a compound according to any of Claims 1 to 9, together with a pharmaceutically-acceptable 10 carrier. 11. Use of a pharmaceutical composition according to Claim 10, for the therapy or treatment of stroke, head trauma, transient cerebral ischaemic attack, Alzheimer's disease, Parkinson's disease, diabetic neuropathy, amyotrophic lateral sclerosis, multiple sclerosis or 15 AIDS-related dementia. 12. A method for treating or preventing neurological diseases by inhibition of the [ [ 33 HH]]--eemmooppaammiill bbiinnddiinngg ssiittee,, ccoommpprriissiinngg aaddmmiiinistering to a mammal an effective amount of a compound according to any of Claims 1 to 11. 20 13. Use of a compound according to any of Claims 1 to 9, for preparation of a therapeutic agent or prophylactic agent for diseases treatable by inhibition of the [ H] -emopamil binding site. 25 14. A method for treating or preventing diseases treatable by inhibition of the [ 3 H]-emopamil binding site, comprising administering to a mammal an effective amount of a compound according to any of Claims 1 to 9. 15. A process for preparing a compound according to Claim 1, or a pharmaceutically- acceptable salt, in v/vo-hydrolysable ester, amide or carbamate thereof, which process comprises either: a) reacting a compound of the formula III with a compound of the formula IV: wherein R, R . 1 , τ R-> 2 ~ , m and n are as defined in Claim 1, and L is a leaving group; or b) deprotecting a compound of the formula V: V wherein R . 1 , R r > 2 , m and n are as defined in Claim 1, and Q is a protected form of the group R; wherein any functional group is protected, followed by: i) removing any protecting groups; ii) optionally converting a compound of the formula I into another compound of the formula I; iii) optionally forming a pharmaceutically-acceptable salt or an in v vo-hydrolysable ester, amide or carbamate.

Inventors: CHAUDHARI BIPINCHANDRA BHUDHAR, KEITH RICHARD ALAN, MCLAREN CHARLES DAVID, SIMON-BIERENDAUM RICHARD ELLIO, WARAWA EDWARD JOHN, CHAUDHARI, BIPINCHANDRA, BHUDHARLAL, KEITH, RICHARD, ALAN, MCLAREN, CHARLES, DAVID, SIMON-BIERENDAUM, RICHARD, ELLIOT, WARAWA, EDWARD, JOHN
Applicants: ASTRAZENECA UK LTD, CHAUDHARI BIPINCHANDRA BHUDHAR, KEITH RICHARD ALAN, MCLAREN CHARLES DAVID, SIMON BIERENDAUM RICHARD ELLIO, WARAWA EDWARD JOHN, ASTRAZENECA UK LIMITED, CHAUDHARI, BIPINCHANDRA, BHUDHARLAL, KEITH, RICHARD, ALAN, MCLAREN, CHARLES, DAVID, SIMON-BIERENDAUM, RICHARD, ELLIOT, WARAWA, EDWARD, JOHN
Application year: 1999
Main classification: C07D311
IPC codes: A61K31, A61P9, A61P17, A61P25, A61P31, A61P43, C07D405