Patent Publication Number: US-6218538-B1

Title: 2-aryl dihydropyrimidine compounds

Description:
FIELD OF INVENTION 
     This invention relates to certain novel 2-aryl dihydropyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. A further objective is to provide compounds which are potent ligands for N-type neuronal calcium channels. 
     BACKGROUND OF THE INVENTION 
     It is well known that there are several different types of voltage-gated calcium channels which can be distinguished on the basis of biophysical and pharmacological properties. These calcium channels are defined by differences in the amino acid sequence of the α 1  subunits (“Molecular Determinants of Ca 2+  Channel Function and Drug Action”  TiPS  1995, 16, 43-49), and by different sensitivities to various ligands (“Synthetic Organic Ligands Active at Voltage-Gated Calcium Channels”,  Ann. N.Y. Acad. Sci.,  1991, 635, 123-138). These publications teach that the L-type calcium channel differs from the N-type calcium channel in regard to the amino acid sequence of the α 1  subunits and the sensitivity to dihydropyridines (L-channels are sensitive, N-channels are not) and the sensitivity to ω-Conotoxins GVIA and MVIIA (N-channels are sensitive, L-channels are not). 
     L-Type calcium channel antagonists are clinically proven compounds for the treatment of cardiovascular disease, particularly hypertension. 
     The use of compounds which bind to N-type neuronal calcium channels has been discussed with respect to the treatment of a range of disorders involving abnormal calcium flux in cells, including ischaemia, Alzheimer&#39;s disease, neuroprotection and analgesia (“Neuronal Voltage-Sensitive Calcium Channels”  Drug News  &amp;  Perspectives,  1994, 7, 261-268). N-Type neuronal calcium channels have also been found to be involved in the release of various neurotransmitters and therefore, compounds that bind to N-type calcium channels may also be useful in various disease states characterised by abnormal neurotransmitter release, for example, anxiety, schizophrenia, Parkinson&#39;s disease and migraine. 
     U.S. Pat. No. 4,822,798 discloses dihydropyrimidines of general structure:                    
     as agents having circulation-influencing action. These compounds are distinguished from the scope of the present application by virtue of the definition of group R 5 , and by their different pharmacological activity. 
     DISCLOSURE OF THE INVENTION 
     According to the invention we provide a compound of formula (I)                    
     wherein: 
     R 1  represents a monocyclic aromatic ring optionally incorporating one to three heteroatoms which may be the same or different and are selected from N, O or S, which ring may be optionally substituted by halogen, alkyl C1 to 6, alkoxy C1 to 6 or trifluoromethyl; 
     R 2  represents alkyl C1 to 6 or unsaturated alkyl C2 to 6, either optionally including O or S, and which is substituted by a phenyl or a monocyclic heteroaryl ring, which aromatic ring is optionally substituted by one or more substituents independently selected from halogen, alkyl C1 to 6 or alkoxy C1 to 6; 
     R 3  represents a monocyclic or bicyclic aromatic ring optionally incorporating one heteroatom selected from N, O or S, optionally substituted by one or more substituents independently selected from halogen, alkyl C1 to 6, alkoxy C1 to 6, cyano, benzyloxy, trifluoromethyl, amino, hydroxy, nitro or carbomethoxy; 
     R 4  and R 5  independently represent hydrogen, alkyl C1 to 6, or benzyl; 
     or the group NR 4 R 5  together represents piperidinyl, morpholinyl, 3,4-dehydropiperidinyl, perhydroazepinyl, thiomorpholinyl, pyrrolidinyl, piperazinyl or piperazinyl further substituted at N-4 by alkyl C1 to 6; 
     X represents O, S or NR 6 ; 
     R 6  represents hydrogen or alkyl C1 to 6; 
     and n represents an integer 2 to 4; 
     and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof. 
     Examples of said “monocyclic or bicyclic aromatic ring optionally incorporating one heteroatom selected from N, O or S” include, but are not limited to, phenyl; 1- and 2-naphthyl; 2-, 3- and 4-pyridyl; 2- and 3-thienyl; 2- and 3-furyl; quinolyl; isoquinolyl; indolyl; benzothienyl and benzofuryl. 
     Examples of said “monocyclic aromatic ring optionally incorporating one to three heteroatoms selected from N, O or S” include, but are not limited to, phenyl; 2-, 3- and 4-pyridyl; pyrimidinyl; 2- and 3-thienyl; 2- and 3-furyl; oxazolyl; thiazolyl; isoxazolyl; imidazolyl; and thiadiazolyl. 
     Unless otherwise indicated, the term “alkyl C1 to 6” referred to herein denotes a straight or branched chain alkyl group having from 1 to 6 carbon atoms or a cyclic alkyl group having from 3 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopentyl and cyclohexyl. 
     Unless otherwise indicated, the term “unsaturated alkyl C2 to 6” referred to herein denotes a straight or branched chain alkyl group having from 2 to 6 carbon atoms and including one double bond or one triple bond or a cyclic alkyl group having from 3 to 6 carbon atoms and including one double bond. Examples of such groups include ethenyl, ethynyl, 1- and 2-propenyl, 1- and 2-propynyl, 2-methyl-2-propenyl, 2-butenyl, 2-butynyl,cyclopentenyl and cyclohexenyl. 
     Unless otherwise indicated, the term “alkoxy C1 to 6” referred to herein denotes a straight or branched chain alkoxy group having from 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy. 
     Unless otherwise indicated, the term “halogen” referred to herein denotes fluorine, chlorine, bromine and iodine. 
     1,4-Dihydropyrimidines such as compounds of formula (I) may exist to a greater or lesser extent in the tautomeric 3,4-dihydro form (Ia):                    
     Wherever compounds are shown or named as 1,4-dihydropyrimidines, it is to be understood that both the 1,4-dihydro and 3,4-dihydro tautomers and mixtures thereof are included within the scope of the invention. 
     Preferred compounds of the invention are compounds of formula (I) wherein: 
     R 1  represents 2-furyl, 2-thienyl, phenyl or pyridyl, optionally further substituted; 
     R 2  represents 3-phenylpropyl or 3-(1-phenoxy)propyl, optionally substituted on the phenyl ring by halogen; 
     R 3  represents a 4-substituted phenyl, optionally further substituted in the 2- or 3-position, or 2-quinolyl; 
     R 4  and R 5  independently represent alkyl C1 to 6; 
     or the group NR 4 R 5  together represents piperidinyl, pyrrolidinyl or piperazinyl further substituted at N-4 by alkyl C1 to 6; 
     X represents O; 
     and n=2. 
     Particularly preferred compounds of the invention include: 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-methylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-methoxycarbonylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(4-pyridyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-4-(2-quinolyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(4-methyl-1-piperazinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-2-phenyl-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (+)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (−)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (−)-(4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (+)-(4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (−)-4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (+)-4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-cyanophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (+)-4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (−)-4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (+)-2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl (−)-2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(4-chlorophenyl)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-difluorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(3-methoxy-4-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-(3-pentyloxy)phenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-methoxy-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-chloro-3-fluorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-cyanophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dimethylphenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-chloro-3-nitrophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-perhydroazepinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-pyrrolidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-(2-thienyl)ethyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidiny)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylprop-2-enyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(4-benzyloxyphenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(4-methylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(4-methoxyphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-(2-thienyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-(4-pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-(3-pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-(2-pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(3-hydroxy-4-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     3-phenylpropyl 2-(2-furyl)-4-(4-hydroxy-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate, 
     and tautomers thereof and pharmaceutically acceptable salts thereof. 
     The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids. 
     According to the invention, we further provide a process for the preparation of compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, which comprises: 
     (a) preparing a compound of formula (I) by reacting a corresponding compound of formula (II)                    
     wherein R 2 , R 4 , R 5 , X, and n are as defined above with a compound of formula (III) or an acid addition salt thereof                    
     wherein R 1  is as defined above and with a compound of formula (IV)                    
     wherein R 3  is as defined above; 
     (b) preparing a compound of formula (I) by reacting a corresponding compound of formula (V)                    
     wherein R 2 , R 3 , R 4 , R 5 , X, and n are as defined above with a compound of formula (III) or an acid addition salt thereof                    
     wherein R 1  is as defined above; or 
     (c) preparing a compound of formula (I) by reacting a corresponding compound of formula (VI)                    
     wherein R 1 , R 2  and R 3  are as defined above with a compound of formula (VII)                    
     wherein R 4 , R 5 , X and n are as defined above; 
     and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, to a pharmaceutically acceptable salt thereof, or vice versa. 
     In process (a), the reaction will take place on stirring a mixture of compounds of formula (II), (III) and (IV) in a suitable solvent at a temperature between 15° and 150° C., preferably between 25° and 75° C., with or without addition of an acid or a base. Suitable solvents include tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, ethanol or isopropanol, preferably N,N-dimethylformamide, ethanol or isopropanol. Sodium acetate, potassium carbonate and sodium hydrogen carbonate are preferred bases. The reaction time will depend inter alia on the solvent and the temperature used, and may be up to several days. 
     In process (b), the reaction will take place on stirring a mixture of compounds of formula (III) and (V) in a suitable solvent at a temperature between 15° and 150° C., preferably between 25° and 75° C., with or without addition of an acid or a base. Suitable solvents include tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, ethanol or isopropanol, preferably N,N-dimethylformamide, ethanol or isopropanol. The reaction time will depend inter alia on the solvent and the temperature used, and may be up to several days. 
     In process (c), the reaction will take place on stirring a mixture of compounds of formula (VI) and (VII) in a suitable inert solvent such as tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide, ethanol or isopropanol. 
     Salts of compounds of formula (I) may be formed by reacting the free base or a salt, enantiomer, tautomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble, or in a solvent in which the salt is soluble followed by subsequent removal of the solvent in vacuo or by freeze drying. Suitable solvents include, for example, water, dioxan, ethanol, isopropanol, tetrahydrofuran or diethyl ether, or mixtures thereof. The reaction may be a metathetical process or it may be carried out on an ion exchange resin. 
     Certain novel intermediates of formulae (II), (III), (IV), (V) and (VI) form another aspect of the invention. 
     Compounds of formula (II) may be formed by reaction of a compound of formula (VIII)                    
     wherein R 2  is as defined above with a compound of formula (VII) in a suitable solvent with or without the addition of a base. The choice of the solvent and the base will depend inter alia on the nature of the group X. Suitable solvents include ethers, tetrahydrofuran or N,N-dimethylformamide. Suitable bases include metal hydrides such as sodium hydride or potassium hydride, carbonates such as sodium carbonate or potassium carbonate, tertiary amines such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably sodium hydride or potassium carbonate. 
     Compounds of formula (VIII) may be prepared by heating a compound of formula (IX) 
      R 2 —OH  (IX) 
     wherein R 2  is as defined above with a compound of formula (X)                    
     in an inert solvent such as toluene, benzene or dichloromethane. The use of toluene as solvent in conjunction with the azeotropic removal of ethanol represents a preferred procedure. 
     Alternatively, the order of the above steps may be varied such that compounds of formula (II) are formed by reaction of a compound of formula (X) with a compound of formula (VII), and then reaction of the product therefrom with a compound of formula (IX). 
     Compounds of formula (V) may be formed by reaction of compounds of formula (II) with compounds of formula (IV) under standard conditions known to one skilled in the art. 
     Compounds of formula (VI) may be made by bromination of a compound of formula (XI)                    
     using methods well known to one skilled in the art. 
     Compounds of formula (XI) can be made by condensation of a mixture of compounds of formula (III), (IV) and (XII)                    
     wherein R 2  is as defined above under conditions similar to those used for the preparation of compounds of formula (I) according to process (a) above. 
     Compounds of formula (III), (IV), (VII), (IX), (X) and (XII) are either commercially available or may be prepared by methods known to one skilled in the art. 
     Intermediate compounds may be prepared as such or in protected form. In particular amine groups may be protected. Suitable protecting groups are described in the standard text “Protective Groups in Organic Synthesis”, 2nd Edition (1991) by Greene and Wuts. Amine-protecting groups which may be mentioned include alkyloxycarbonyl such as t-butyloxycarbonyl, phenylalkyloxycarbonyl such as benzyloxycarbonyl, trifluoroacetate or phthaloyl. Deprotection will normally take place on treatment with aqueous base or aqueous acid, or, in the case of phthaloyl, with hydrazine. 
     Other syntheses of compounds of formula (II), (V), (VI) and (XI) will be readily apparent to one skilled in the art. 
     The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques. 
     The compounds of formula (I) may exist in tautomeric, enantiomeric or diastereoisomeric forms, all of which are included within the scope of the invention. The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques such as fractional crystallisation or HPLC. Alternatively, the individual enantiomers may be made by reaction of the appropriate optically active starting materials under reaction conditions which will not cause racemisation. 
     Intermediate compounds may also exist in enantiomeric or tautomeric forms and may be used as purified enantiomers, diastereomers, racemates, tautomers or mixtures thereof. 
     Compounds of formula (I) are blockers of N-type neuronal calcium channels and as such are useful in the treatment or prophylaxis of disorders arising from a dysfunction of N-type neuronal calcium channels. While not being limited by theory, it is believed that blockers of N-type neuronal calcium channels will be useful in the treatment or prophylaxis of a range of CNS diseases. Thus, the utility of the compounds of the present invention is in the treatment or prophylaxis of cerebrovascular ischaemia, due to such conditions as stroke, head trauma, cardiac arrest, spinal cord injury, anoxia, hypoxia and cardiac surgery, particularly coronary artery bypass surgery;neurodegenerative disorders such as Alzheimer&#39;s disease, Parkinson&#39;s disease and AIDS-related dementia; pain, including nociceptive and neuropathic pain syndromes; cognitive or attention disorders; psychotic disorders, particularly schizophrenia; affective disorders such as anxiety and depression; and migraine. 
     Compounds of formula (I) are predicted to be particularly useful in the treatment or prophylaxis of cerebrovascular ischaemia, stroke, head trauma, pain, Alzheimer&#39;s disease and schizophrenia. 
     Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition. 
     Thus according to a further aspect of the invention we provide a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, for use as a medicament. 
     According to another feature of the invention we provide the use of a compound of formula (I) or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of the aforementioned diseases or conditions; and a method of treating or reducing the risk of, one of the aforementioned diseases or conditions which comprises administering to a person suffering from or susceptible to such a disease or condition, a therapeutically effective amount of a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof. 
     For the above mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are expected to be obtained when the compounds are administered to a human at a daily dosage of between 0.5 mg and 2000 mg (measured as the active ingredient) per day, particularly at a daily dosage of between 2 mg and 500 mg. 
     The compounds of formula (I), and optical isomers and racemates thereof and pharmaceutically acceptable salts thereof, may be used on their own, or in the form of appropriate medicinal formulations. Administration may be by, but is not limited to, enteral (including oral, sublingual or rectal), intranasal, topical or parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988. 
     According to the invention, there is provided a pharmaceutical formulation comprising preferably less than 99% by weight, more preferably less than 80% by weight, and even more preferably less than 50% by weight, of a compound of formula (I), or an optical isomer or racemate thereof or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable diluent or carrier. 
     We also provide a method of preparation of such a pharmaceutical formulation which comprises mixing the ingredients. 
     Examples of such diluents and carriers are: for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes. 
     Compositions in a form suitable for oral, i.e. oesophageal administration include: tablets, capsules and dragees; sustained release compositions include those in which the active ingredient is bound to an ion exchange resin which is optionally coated with a diffusion barrier to modify the release properties of the resin. 
     The pharmacological activity of the compounds of the present invention may be assessed using one or more of the following assays: 
     1) Assay for Affinity at N-type Calcium Channels—[ 125 I]-MVIIA Binding to Rat Synaptic Membranes 
     Preparation of Synaptic Membranes 
     Rat brains minus cerebella were homogenized in ice-cold 0.32M sucrose containing protease inhibitors (SPI: 1 μM leupeptin; 2 μM pepstatin; 1.0 mM EGTA; 1 mM EDTA). The homogenate was centrifuged at 1000 g for 15 minutes at 4° C. The resulting supernatant was centrifuged at 12,000 g for 15 minutes at 4° C. The pellets were washed by recentrifugation, resuspended in SPI buffer and layered over a discontinuous (0.6M/0.8M/1.2M) sucrose gradient in Beckman Ultraclear Ultracentrifuge tubes. After centrifugation at 140,000 g for 75 minutes at 4° C., the 0.8M layers including the 0.8/1.2M interfaces were collected, pooled and diluted to 0.32M sucrose with ice cold water containing protease inhibitors. This suspension was centrifuged at 15,000 g for 15 minutes at 4° C. The pellets were resuspended in ice cold water containing protease inhibitors and frozen at −140° C. Membranes were harvested from thawed suspensions by 3-fold dilution with ice cold water containing protease inhibitors, polytron homogenization, and centrifugation at 41,000 g for 20 minutes at 4° C. The pellets were resuspended in phosphate buffered saline containing protease inhibitors and stored in aliquots at −70° C. until used. 
     Assay 
     Compounds in 20 μl DMSO were added to 100 μL buffer (75 mM NaCl, 0.1 mM EDTA, 0.1 mM EGTA, 0.1% bovine serum albumin, 100 μg/ml chymostatin, 0.35 μg/ml aprotinin, 10 μg/ml leupeptin, 20 mM HEPES, pH 7.0) containing 18 pM [ 125 I]-MVIIA. The reaction was started by adding 380 μL buffer containing 2 μg synaptic membrane protein. After incubation at room temperature for 1 hour, bound radioactivity was recovered by filtration onto Packard GF/C Unifilter plates (presoaked in 0.3% polyethylenimine containing 100 μM neomycin sulfate). After washing, 25 μl MicroScint scintillation fluid was added to each filter well and radioactivity was measured in a Packard TopCount scintillation counter. Nonspecific binding was measured in the presence of 100 μM neomycin sulfate. 
     In the screen for affinity for N-type calcium channels, compound activity is expressed as IC 50  (the concentration of drug substance which gives 50% binding inhibition in the assay). IC 50  values for test compounds were initially estimated from the inhibiting activity of 1, 10 and 100 μM solutions of the compounds. Compounds that inhibited the binding by at least 50% at 10 μM were re-tested using more appropriate concentrations so that an IC 50  could be determined. 
     2) In Vitro Method for Assaying Antagonism of N-type Voltage Operated Calcium Channels 
     SHSY5Y cells, a human neuroblastoma line, were cultured in 96 well microplates and differentiated with retinoic acid. The cells were loaded with Fluo-3/AM, a calcium fluorescent indicator, and treated with appropriate concentrations of test compound in the presence of 1 μM nifedipine for 30 minutes. Calcium channels were activated by depolarizing the cells by the addition of KCl (75 mM final concentration). Peak fluorescence intensity resulting from increased intracellular levels of calcium was measured simultaneously in all wells using a Fluorescence Imaging Plate Reader. The decrease in peak fluorescence intensity relative to untreated control cells was used to determine calcium channel antagonism. IC 50  values were generated for test compounds as an index of antagonist potency. 
     3) Electrophysiological Assay of N-type Calcium Channel Currents 
     Superior cervical ganglion cells were isolated from 2 week old rat pups using a modification of the method described by K. J. Swartz,  Neuron,  1993, 11, 305-320. The cells were maintained in Leibovitz L-15 buffer on ice, plus oxygen for up to 8 hours (no bubbles). 
     Whole-cell patch clamp recordings were performed in bath buffer (115 mM NaCl; 10 mM D-glucose; 10 mM HEPES; 4.9 mM KCl; 2.5 mM MgCl 2 ; 10 mM TEACl; 0.5 μM TTX; 10 mM BaCl 2 ; pH 7.4) with pipette buffer (130 mM CsCl; 10 mM EGTA; 20 mM HEPES; 5 mM D-glucose; 3 mM ATP-Na 2 ; 5 mM MgCl 2 -ATP; 0.25 mM GTP-Li; pH 7.1 with CsOH). Channels were elicited to open by voltage pulses to 0 mV from a holding potential of −80 mV. Test compounds were dissolved in DMSO at 1000 times their final concentrations and then diluted in bath buffer. Currents were measured in a flow-through chamber before and after application of the test compound. Percent inhibition was calculated from the difference in these two measurements. 
     The compounds of Examples 1 to 44 below showed significant activity when tested in one or more of the above assays. This activity at N-type neuronal calcium channels indicates that such compounds are predicted to show particularly useful therapeutic activity. 
    
    
     The invention is illustrated by the following non-limiting examples: 
     PREPARATION 1 
     3-Phenylpropyl 4-chloroacetoacetate 
     A solution of ethyl 4-chloroacetoacetate (134 g, 815 mmol) and 3-phenyl-1-propanol (111 mL, 821 mmol) was heated in toluene, with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (214 g). Electrospray MS  m /z 219 [M−Cl+H] + . 
     PREPARATION 2 
     3-Phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate 
     2-(1-Piperidinyl)ethanol (15 mL, 113 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (7 g, 175 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 1 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (22 mL, 103 mmol) in THF (50 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The combined extracts were washed with brine, dried and evaporated to give the title compound (24 g) as an oil. Electrospray MS  m /z 348 [M+H] + . 
     Following the general method of Preparation 2, the following compounds were prepared: 
     3-Phenylpropyl 4-(2-(1-pyrrolidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 334 [M+H] + . 
     3-Phenylpropyl 4-(2-(1-perhydroazepinyl)ethoxy)acetoacetate. Electrospray MS  m /z 362 [M+H] + . 
     PREPARATION 3 
     3-Phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate 
     N,N-Diethylaminoethanol (7.49 mL, 56.6 mmol) in THF (25 mL) was added dropwise to a suspension of sodium hydride (3.5 g, 87.5 mmol) in THF (100 mL) at 0° C. The mixture was then stirred for 30 minutes at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (11.10 mL, 51.5 mmol) in THF (25 mL) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were washed two times with ethyl acetate and then made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform three times. The combined extracts were washed with brine, dried and evaporated to give the title compound (16.3 g) as an oil. Electrospray MS  m /z 336 [M+H] + . 
     Following the general procedure for Preparation 3, the following compound was synthesized: 
     3-Phenylpropyl 4-(2-(N,N-dimethylamino)ethoxy)acetoacetate. Electrospray MS  m /z 308 [M+H] + . 
     PREPARATION 4 
     2-Amidinofuran Monohydrochloride 
     To a cold solution of hydrogen chloride gas (3.3 g) in ethanol (5.28 mL) and ether (50 mL) was added dropwise 2-furonitrile (5 g). The mixture was stirred cold for four hours and then put into the freezer for 15 days. The crystals were then collected, washed with ether and dried. The iminoether (4.5 g) was then put back into cold ethanol (50 mL) and ammonia gas (6 g) was added. After stirring cold for 15 minutes the reaction mixture was stirred at room temperature overnight. The product was collected from ether to yield the title compound (3.49 g). Electrospray MS  m /z 111 [M+H] + . 
     PREPARATION 5 
     2-Amidinofuran Monohydrochloride 
     To a cold solution of 2-furonitrile (24.19 g) in dichloromethane (250 mL) was added ethanethiol (17.77 g). Hydrogen chloride gas was bubbled into the cold reaction mixture for 6 h before allowing it to warm to room temperature overnight. The white precipitate was collected and dried (37.04 g). The precipitate was then slurried in 6M ammonia in ethanol for 24 to 48 h. The title compound was collected by filtration (13.85 g). Electrospray MS  m /z 111 [M+H] + . 
     PREPARATION 6 
     2-(4-Methyl-1-piperazinyl)ethanol 
     2-Chloroethanol (36.0 g, 30 mL, 0.44 mol) was added to 1-methylpiperazine (27.0 g, 30 mL, 0.27 mol) and potassium carbonate (40 g, 0.29 mol) in acetonitrile (100 mL) with stirring. The reaction mixture was heated under reflux for 48 h, then filtered, and the solids were washed with acetonitrile. The combined filtrates were evaporated under reduced pressure and the resulting oil was distilled at 12 mm Hg to give the title compound (31 g, 0.21 mol) as a light tan oil. Electrospray MS  m /z 145 [M+H] + . 
     PREPARATION 7 
     3-Phenylpropyl 4-(2-(4-methyl-1-piperazinyl)ethoxy)acetoacetate 
     2-(4-Methyl-1-piperazinyl)ethanol (8.14 g, 56.5 mmol) in THF (50 mL) was added dropwise to a suspension of sodium hydride (3.5 g, 87.5 mmol) in THF (200 mL) at 0° C. The mixture was then stirred for 3 h at room temperature, cooled to 0° C., 3-phenylpropyl 4-chloroacetoacetate (11.10 mL, 51.5 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 1N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted twice more with 1N hydrochloric acid. The combined acid layers were washed two times with ethyl acetate and then made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform three times. The combined extracts were washed with brine, dried and evaporated to give the title compound (8.8 g) as an oil. Electrospray MS  m /z 363 [M+H] + . 
     PREPARATION 8 
     4-Chlorobenzamidine Monohydrochloride 
     To a solution of 4-chlorobenzonitrile (5.0 g) in methanol (40 ml) was added sodium methoxide (0.20 g) and the reaction was stirred at room temperature for 3 days. Ammonium chloride (1.94 g) was added and the reaction was stirred overnight. The reaction was filtered and the filtrate concentrated to an oil. After the addition of ether the off-white precipitate was collected and dried to give the title compound (3.62 g). Electrospray MS  m /z 155 [M+H] + . 
     PREPARATION 9 
     p-Toluamidine Monohydrochloride 
     To a solution of p-tolunitrile (10.0 g) in methanol (85 mlb) was added sodium methoxide (0.46 g) and the reaction was stirred at room temperature for 5 days. Ammonium chloride (4.6 g) was added and the reaction was stirred overnight. The reaction was filtered and the filtrate concentrated to an oil. After the addition of ether the off-white precipitate was collected and dried to give the title compound (4.52 g). Electrospray MS  m /z 135 [M+H] + . 
     PREPARATION 10 
     4-Methoxybenzamidine Monohydrochloride 
     To a solution of 4-methoxybenzonitrile (10.0 g) in methanol (75 ml) was added sodium methoxide (0.41 g) and the reaction was stirred at room temperature for 5 days. Ammonium chloride (4.6 g) was added and the reaction was stirred overnight. The reaction was filtered and the filtrate concentrated to an oil. After the addition of ether the off-white precipitate was collected and dried to yield the title compound (3.77 g). Electrospray MS  m /z 151 [M+H] + . 
     PREPARATION 11 
     3-(2-Thienyl)propionic Acid 
     To a solution of 3-(2-thienyl)acrylic acid (7 g) in ethanol was added 5% palladium on carbon and the mixture was hydrogenated at 50 psi in a Parr apparatus. The catalyst was filtered off and the solvent was removed by evaporation to yield the title compound (5.5 g) as an oil. Electrospray MS  m /z 155 [M−H] + . 
     PREPARATION 12 
     3-(2-Thienyl)propanol 
     To a solution of 3-(2-thienyl)propionic acid (5.0 g, 32.0 mmol) in tetrahydrofuran (20 ml) at 0° C. was added 1 M borane tetrahydrofuran complex (33.5 ml, 33.5 mmol) dropwise over 30 minutes. The reaction mixture was then stirred for 18 h whilst warming to room temperature. The temperature was then reduced to 0° C. and water (20 ml) was added to quench the reaction. The solution was then basified with potassium carbonate, the layers separated and the aqueous layer washed with diethyl ether. The combined organic layers were washed with brine, dried and concentrated to yield the title compound (4.71 g) as an oil. DCI MS  m /z 142 [M+H] + . 
     PREPARATION 13 
     Ethyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate 
     2-(1-Piperidinyl)ethanol (15 ml, 113 mmol) in THF (50 ml) was added dropwise to a suspension of sodium hydride (7 g, 175 mmol) in THF (200 ml) at 0° C. The mixture was then stirred for 2 h at room temperature, cooled to 0° C., ethyl 4-chloroacetoacetate (14 ml, 103 mmol) in THF (50 ml) was added dropwise and the reaction mixture was then stirred for 18 h whilst warming to room temperature. 
     3N Hydrochloric acid was added until the mixture was acidic and the aqueous layer was then separated. The organic layer was extracted three times more with 3N hydrochloric acid. The combined acid layers were made basic to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The combined extracts were dried and evaporated to give the title compound (15.76 g) as an oil. Electrospray MS  m /z 258 [M+H] + . 
     PREPARATION 14 
     3-(4-Pyridyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate 
     A solution of ethyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (6.46 g, 25.20 mmol) and 3-(4-pyridyl)propanol (1.9 ml, 14.49 mmol) was heated in toluene (500 ml), with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (8.35 g). Electrospray MS  m /z 349 [M+H] + . 
     Following the general procedure of Preparation 14, the following compounds were synthesized: 
     3-(3-Pyridyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 349 [M+H] + . 
     3-(2-Pyridyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 349 [M+H] + . 
     3-(2-Thienyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 354 [M+H] + . 
     2-(2-Thienyl)ethyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 340 [M+H] + . 
     3-Phenylprop-2-enyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate. Electrospray MS  m /z 346 [M+H] + . 
     EXAMPLE 1 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (2.7 g, 7.77 mmol), 3,4-dichlorobenzaldehyde (1.63 g, 9.32 mmol), 2-amidinothiophene hydrochloride (1.52 g, 9.32 mmol) and sodium hydrogen carbonate (0.79 g, 9.35 mmol) was stirred in N,N-dimethylformamide (20 mL) for 4 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (0.73 g) as an oil. Electrospray MS  m /z 612/614 [M+H] + . 
     Following the general procedure for Example 1 but using the appropriately substituted benzaldehyde, the compounds of Examples 2 to 6 were synthesized: 
     EXAMPLE 2 
     3-Phenylpropyl 4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 603 [M+H] + . 
     EXAMPLE 3 
     3-Phenylpropyl 4-(3-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 578 [M+H] + . 
     EXAMPLE 4 
     3-Phenylpropyl 4-(4-methylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 558 [M+H] + . 
     EXAMPLE 5 
     3-Phenylpropyl 4-(4-chlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 578 [M+H] + . 
     EXAMPLE 6 
     3-Phenylpropyl 4-(4-methoxycarbonylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 602 [M+H] + . 
     EXAMPLE 7 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (3.22 g, 9.27 mmol), 3,4-dichlorobenzaldehyde (1.62 g, 9.27 mmol), 2-amidinofuran hydrochloride (1.36 g, 9.27 mmol) and sodium hydrogen carbonate (0.78 g, 9.27 mmol) was stirred in N,N-dimethylformamide (15 mL) for 3 days at room temperature and then heated to 60° C. for 6 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (617.1 mg) as an oil. Electrospray MS  m /z 596/598 [M+H] + . 
     EXAMPLE 8 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(4-pyridyl)-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (1.50 g, 4.32 mmol), 3,4-dichlorobenzaldehyde (0.907 g, 5.18 mmol), 4-amidinopyridine hydrochloride (0.816 g, 5.18 mmol) and sodium acetate (0.425 g, 5.18 mmol) was stirred in N,N-dimethylformamide (10 mL) for 14 days at room temperature and then heated to 60° C. for 6 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography to give the title compound (81.7 mg) as an oil. 
     Electrospray MS  m /z 607/609 [M+H] + . 
     Following the general procedure of Example 8, the compound of Example 9 was synthesised: 
     EXAMPLE 9 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-pyridyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 607/609 [M+H] + . 
     EXAMPLE 10 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate (2.0 g, 5.96 mmol), 3,4-dichlorobenzaldehyde (1.15 g, 6.56 mmol), 2-amidinofuran hydrochloride (0.962 g, 6.56 mmol) and sodium hydrogen carbonate (0.551 g, 6.56 mmol) was stirred in N,N-dimethylformamide (10 mL) for 24 h at room temperature and then heated to 60° C. for 5 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (66.3 mg) as an oil. Electrospray MS  m /z 584/586 [M+H] + . 
     Following the general procedure of Example 10, the compounds of Examples 11 and 12 were synthesised: 
     EXAMPLE 11 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 572/574 [M+H] + . 
     EXAMPLE 12 
     3-Phenylpropyl 6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-4-(2-quinolyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 567 [M+H] + . 
     EXAMPLE 13 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(4-methyl-1-piperazinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(4-methyl-1-piperazinyl)ethoxy)acetoacetate (500 mg, 1.38 mmol), 3,4-dichlorobenzaldehyde (241.5 mg, 1.38 mmol), 2-amidinofuran hydrochloride (202.3 mg, 1.38 mmol) and catalytic amounts of piperidine (1 μL) and acetic acid (10 μL) was stirred in N,N-dimethylformamide (5 mL) for 2 days at room temperature. Sodium hydrogen carbonate was added and the reaction mixture was stirred for an additional 5 days at room temperature before heating to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography to give the title compound (48 mg) as an oil. Electrospray MS m /z 611/613 [M+H] + . 
     EXAMPLE 14 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-2-phenyl-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (1.50 g, 4.32 mmol), 3,4-dichlorobenzaldehyde (0.907 g, 5.18 mmol), benzamidine hydrochloride (0.811 g, 5.18 mmol) and sodium acetate (0.425 g, 5.18 mmol) was stirred in N,N-dimethylformamide (10 mL) for 14 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (60 mg) as an oil. Electrospray MS  m /z 606/608 [M+H] + . 
     EXAMPLE 15 
     Resolution of 3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     The racemate of the title compound (Example 1, 60 mg) was dissolved in 12% ethanol-isooctane and loaded onto a Chiralcel OD column (20×250 mm; detector wavelength: 300 nm) and eluted with 3% ethanol-isooctane (flow rate 20 mL/min.) with baseline separation. There was recovered approximately 10 mg of each enantiomer with an optical purity of at least 99.4%. 
     3-Phenylpropyl (+)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate. 
     Electrospray MS  m /z 612/614 [M+H] + . [α] D +51° (c=0.21, MeOH). 
     3-Phenylpropyl (−)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate. 
     Electrospray MS  m /z 612/614 [M+H] + . [α] D −59° (c=0.19, MeOH). 
     EXAMPLE 16 
     Resolution of 3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     The racemate of the title compound (Example 11, 40 mg) was dissolved in 17% ethanol-isooctane and loaded onto a Chiralcel OD column (20×250 mm; detector wavelength: 300 nm) and eluted with 2-5% ethanol-isooctane (flow rate 20 mL/min.) over 90 minutes with baseline separation. There was recovered approximately 12 mg of each enantiomer with an optical purity of at least 99.5%. 
     3-Phenylpropyl (−)-(4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 572/574 [M+H] + . 
     3-Phenylpropyl (+)-(4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-thienyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 572/574 [M+H] + . 
     EXAMPLE 17 
     Resolution of 3-phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate 
     Following the method of Example 16, the racemate of the title compound (Example 10) was resolved. Each enantiomer had an optical purity of at least 99.6%. 
     3-phenylpropyl (−)-4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2- furyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 584/586 [M+H] + . [α] D −20.4° (c=0.44, EtOH). 
     3-phenylpropyl (+)-4-(3,4-dichlorophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 584/586 [M+H] + . [α] D +19.0° (c=0.40, EtOH). 
     EXAMPLE 18 
     3-Phenylpropyl 4-(4-cyanophenyl)-6-[(2-(N,N-diethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate (2.0 g, 5.96 mmol), 4-cyanobenzaldehyde (0.86 g, 6.56 mmol), 2-amidinofuran hydrochloride (0.962 g, 6.56 mmol) and sodium hydrogen carbonate (0.551 g, 6.56 mmol) was stirred in N,N-dimethylformamide (10 mL) for 24 h at room temperature and then heated to 60° C. for 5 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (683.7 mg) as an oil. Electrospray MS  m /z 541 [M+H] + . 
     EXAMPLE 19 
     Resolution of 3-phenylpropyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     The racemate of the title compound (Example 7, 140 mg) was dissolved in 7% ethanol-hexane and loaded onto a Chiralcel OD column (20×250 mm; detector wavelength: 300 nm) and eluted with 1-7.5% ethanol-hexane (flow rate 20 mL/min.) over 1 h with baseline separation. There was recovered 47 and 48 mg of the two enantiomers with optical purity of at least 99.0%. 
     3-Phenylpropyl (+)-4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 596/598 [M+H] + . [α] D +20.9° (c=0.41, EtOH). 
     3-Phenylpropyl (−)-4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 596/598 [M+H] + . [α] D −21.8° (c=0.47, EtOH). 
     EXAMPLE 20 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-6-[(2-(N,N-dimethylamino)ethoxy)methyl]-2-(2-furyl)-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(N,N-dimethylamino)ethoxy)acetoacetate (2.85 g, 9.27 mmol), 3,4-dichlorobenzaldehyde (1.62 g, 9.27 mmol), 2-amidinofuran hydrochloride (1.36 g, 9.27 mmol) and sodium hydrogen carbonate (0.78 g, 9.27 mmol) was stirred in N,N-dimethylformamide (15 mL) for 3 days at room temperature and then heated to 60° C. for 7 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (578.3 mg) as an oil. Electrospray MS  m /z 556/558 [M+H] + . 
     EXAMPLE 21 
     3-Phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (10.0 g, 28.78 mmol), 4-methyl-3-nitrobenzaldehyde (4.75 g, 28.78 mmol), 2-amidinofuran hydrochloride (4.20 g, 28.78 mmol), morpholine (3.75 ml, 43.17 mmol), acetic acid (3.29 ml, 57.56 mmol), and sodium sulfate (8.17 g, 57.56 mmol) was stirred in ethanol (50 ml) for 1 hour at room temperature and then heated to 50° C. for 7 days. The ethanol was removed in vacuo and ethyl acetate was added to the residue. The mixture was filtered and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC (twice) to give the title compound (150 mg) as an oil. Electrospray MS  m /z 587 [M+H] + . 
     EXAMPLE 22 
     Resolution of 3-phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     The racemate of the title compound (Example 21, 2×75 mg) was dissolved in 18% ethanol-hexane and loaded onto a Chiralcel OD column (20×250 mm; detector wavelength: 280 nm) and eluted with 1-10% ethanol-hexane (flow rate 20 ml/min.) over 1.5 h with baseline separation. There was recovered 59.1 and 49.3 mg of the two enantiomers with optical purity of at least 98.1%. 
     3-Phenylpropyl (+)-2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate. 
     Electrospray MS  m /z 587 [M+H] + . [α] D +22.38° (c=0.3 1, EtOH). 
     3-Phenylpropyl (−)-2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate. 
     Electrospray MS  m /z 587 [M+H] + . [α] D −20.0° (c=0.32, EtOH). 
     EXAMPLE 23 
     3-Phenylpropyl 2-(4-chlorophenyl)-4-(3,4-dichlorophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (5.46 g, 15.70 mmol), 3,4-dichlorobenzaldehyde (2.75 g, 15.70 mmol), 4-chlorobenzamidine hydrochloride (3.0 g, 15.70 mmol) and potassium carbonate (2.17 g, 15.70 mmol) was stirred in N,N-dimethylformamide (15 ml) for 5 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (300 mg) as an oil. Electrospray MS  m /z 640/642 [M+H] + . 
     Following the general method of Example 23, but using 2-amidinofuran monohydrochloride together with the appropriately substituted benzaldehyde derivative and the appropriate acetoacetate derivative, the compounds of Examples 24 to 36 were synthesised. Reactions were monitored by MS and were terminated after an appropriate period of time (normally several days): 
     EXAMPLE 24 
     3-Phenylpropyl 4-(3,4-difluorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 564 [M+H] + . 
     EXAMPLE 25 
     3-Phenylpropyl 2-(2-furyl)-4-(3-methoxy-4-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 603 [M+H] + . 
     EXAMPLE 26 
     3-Phenylpropyl 2-(2-furyl)-4-(4-(3-pentyloxy)phenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 614 [M+H] + . 
     EXAMPLE 27 
     3-Phenylpropyl 2-(2-furyl)-4-(4-methoxy-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 603 [M+H] + . 
     EXAMPLE 28 
     3-Phenylpropyl 4-(4-chloro-3-fluorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 580 [M+H] + . 
     EXAMPLE 29 
     3-Phenylpropyl 4-(4-cyanophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 553 [M+H] + . 
     EXAMPLE 30 
     3-Phenylpropyl 4-(3,4-dimethylphenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 556 [M+H] + . 
     EXAMPLE 31 
     3-Phenylpropyl 4-(4-chloro-3-nitrophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 607 [M+H] + . 
     EXAMPLE 32 
     3-Phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-perhydroazepinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 601 [M+H] + . 
     EXAMPLE 33 
     3-Phenylpropyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-pyrrolidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 573 [M+H] + . 
     EXAMPLE 34 
     3-(2-Thienyl)ethyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1 4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 588/590 [M+H] + . 
     EXAMPLE 35 
     3-Phenylprop-2-enyl 4-(3,4-dichlorophenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 594/596 [M+H] + . 
     EXAMPLE 36 
     3-Phenylpropyl 4-(4-benzyloxyphenyl)-2-(2-furyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 634 [M+H] + . 
     EXAMPLE 37 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-2-(4-methylphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (7.9 g, 22.7 mmol), 3,4-dichlorobenzaldehyde (4.0 g, 22.7 mmol), p-toluamidine hydrochloride (3.87 g, 22.7 mmol) and glacial acetic acid (1.3 mL, 22.7 mmol) was stirred in N,N-dimethylformamide (40 ml) for 2 days at room temperature and then heated to 60° C. for 7 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (45 mg) as an oil. Electrospray MS  m /z 620/622 [M+H] + . 
     Following the general procedure of Example 37, the compound of Example 38 was synthesised: 
     EXAMPLE 38 
     3-Phenylpropyl 4-(3,4-dichlorophenyl)-2-(4-methoxyphenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 636/638 [M+H] + . 
     EXAMPLE 39 
     3-(2-Thienyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     A mixture of 3-(2-thienyl)propyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (4.0 g, 11.32 mmol), 4-methyl-3-nitrobenzaldehyde (1.87 g, 11.32 mmol), 2-amidinofuran hydrochloride (1.65 g, 11.32 mmol), morpholine (1.48 ml, 16.98 mmol), acetic acid (1.29 ml, 22.64 mmol), and sodium sulfate (3.21 g, 22.64 mmol) was stirred in ethanol (45 ml) for 1 hour at room temperature and then heated to 40° C. for 9 days. The ethanol was removed in vacuo and ethyl acetate was added to the residue. The filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (120 mg) as an oil. Electrospray MS  m /z 593 [M+H] + ,  m /z 297 [M+2H] ++ . 
     Following the general procedure of Example 39, the compounds of Example 40 to 44 were synthesised: 
     EXAMPLE 40 
     3-(4-Pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 588 [M+H] + . 
     EXAMPLE 41 
     3-(3-Pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 588 [M+H] + . 
     EXAMPLE 42 
     3-(2-Pyridyl)propyl 2-(2-furyl)-4-(4-methyl-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 588 [M+H] + . 
     EXAMPLE 43 
     3-Phenylpropyl 2-(2-furyl)-4-(3-hydroxy-4-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 589 [M+H] + . 
     EXAMPLE 44 
     3-Phenylpropyl 2-(2-furyl)-4-(4-hydroxy-3-nitrophenyl)-6-[(2-(1-piperidinyl)ethoxy)methyl]-1,4-dihydropyrimidine-5-carboxylate 
     Electrospray MS  m /z 589 [M+H] + .